Winner of Resident Paper Award 2014

Benzodiazepines for PTSDA Systematic Review and Meta-Analysis

Objective Although benzodiazepines (BZDs)are commonly used in the treatment of post-traumatic stress disorder (PTSD) no system-atic review or meta-analysis has specificallyexamined this treatment The goal of this studywas to analyze and summarize evidence con-cerning the efficacy of BZDs in treating PTSDMethods The review protocol was undertakenaccording to the principles recommended bythe Preferred Reporting Items for SystematicReviews and Meta-Analyses (PRISMA) state-ment and is registered with the PROSPEROinternational prospective register of systematicreviews (httpwwwcrdyorkacukPROSPEROregistration number CRD42014009318) Twoauthors independently conducted a search ofall relevant articles using multiple electronicdatabases and independently abstracted infor-mation from studies measuring PTSD out-comes in patients using BZDs Eighteen clinicaltrials and observational studies were identi-fied with a total of 5236 participants Outcomeswere assessed using qualitative and quantita-tive syntheses including meta-analysisResults BZDs are ineffective for PTSD treat-ment and prevention and risks associatedwith their use tend to outweigh potentialshort-term benefits In addition to adverseeffects in general populations BZDs are asso-ciated with specific problems in patients withPTSD worse overall severity significantlyincreased risk of developing PTSD with useafter recent trauma worse psychotherapyoutcomes aggression depression and sub-stance use Potential biopsychosocial explan-ations for these results are proposed based onstudies that have investigated BZDs PTSDand relevant animal modelsConclusions The results of this systematicreview suggest that BZDs should be consideredrelatively contraindicated for patients withPTSD or recent trauma Evidence-based treat-ments for PTSD should be favored over BZDs(Journal of Psychiatric Practice 201521281ndash303)

Key Words benzodiazepine sedative traumastress disorder posttraumatic stress disorderpsychopharmacology

The use of benzodiazepines (BZDs) in the treatmentof posttraumatic stress disorder (PTSD) is bothcommon and controversial Although BZDs areprescribed to 30 to 74 of patients with PTSD1ndash2

there is little literaturemdashand no reviews before thisarticlemdashfocusing exclusively on the use of BZDs toprevent or treat PTSD Considering all the servicemembers returning from Afghanistan and Iraq withcombat-related PTSD there is no better time toevaluate this topic than now

Some argue that BZDs are effective symptomatictreatments for the anxiety insomnia and irrita-bility associated with PTSD and they defend theprescription of BZDs for PTSD as necessary fortreatment-resistant patients with severe symp-toms Others contend that BZDs may diminishsubjective anxiety in the short term at the cost ofworsening other features of PTSD such as pro-moting avoidance in the long term They explainthe correlation between BZDs and increasedsymptom severity as the result of BZDs actuallyprolonging and worsening PTSD

JEFFREY GUINA MDSARAH R ROSSETTER MD

BETHANY J DeRHODES MDRAMZI W NAHHAS PhDRANDON S WELTON MD

GUINA Wright State University Department of Psychiatryand Wright-Patterson Air Force Base Medical Center Day-ton OH ROSSETTER Wright State University Departmentof Psychiatry DERHODES Wright State University Depart-ment of Psychiatry and Miami Valley Hospital Dayton OHNAHHAS Wright State University Department of Commun-ity Health WELTON Wright State University Department ofPsychiatry and Veterans Affairs Medical Center Dayton OH

Copyright copy 2015 Wolters Kluwer Health Inc All rightsreserved

Registration PROSPERO international prospective registerof systematic reviews (CRD42014009318 httpwwwcrdyorkacukPROSPERO)

The authors declare no conflicts of interest

Please send correspondence to Jeffrey Guina MD Wright-Patterson Medical Center Mental Health 4881 Sugar MapleDr Wright-Patterson Air Force Base Dayton OH 45433(jeffreyguinawrightedu)

DOI 101097PRA0000000000000091

Journal of Psychiatric Practice Vol 21 No 4 July 2015 281

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Most PTSD practice guidelines pay little attentionto BZDs or caution against their use citing weakevidence risks that outweigh benefits and contra-indication for conditions that are commonly comorbidwith PTSD such as traumatic brain injury (TBI) andsubstance use disorder (SUD) Some guidelines gofurther declaring BZDs contraindicated for combat-related PTSD (Veterans Affairs and Department ofDefense)3 traumatic grief (British National For-mulary)4 and all PTSD (International Society forTraumatic Stress Studies)5

Despite the abundance of articles about PTSDand the frequent prescription of BZDs littleresearch has evaluated the use of BZDs for PTSDIn our literature review we attempted to captureevery available study about BZDs in PTSD toexamine 3 questions

(1) What are the effects of BZDs on the develop-ment of PTSD in trauma patients

(2) What are the effects of BZDs on PTSD-associ-ated outcomes in patients with PTSD

(3) What are the effects of BZDs on PTSD-associ-ated outcomes in trauma patients with andwithout PTSD

METHODS

Study Selection

Studies were included for review using the followingeligibility criteria

(1) Study design clinical trials or observationalstudies

(2) Participants any patient with a history oftrauma assessed for PTSD

(3) Intervention any dose duration or type of BZD(4) Outcomes measured PTSD-associated symptoms

Studies were excluded if they were reviews oranecdotal or if BZDs were not distinguished fromother medications

The authors conducted electronic searches usingPubMed PsycINFO MEDLINE Cochrane Libraryand Google Scholar (all the studies eventuallyselected are available in PubMed) Search parame-ters included all English-language articles pub-lished until June 30 2014 Search terms includedPTSD stress disorder benzodiazepine and the

generic names of the different BZDs For examplethe following search was used in PubMed

((PTSD) OR (stress disorder)) AND ((benzodia-zepine) OR (alprazolam) OR (chlordiazepoxide)OR (clonazepam) OR (clorazepate) OR (diaze-pam) OR (flurazepam) OR (lorazepam) OR(midazolam) OR (oxazepam) OR (temazepam)OR (triazolam))

References in retrieved articles were further scan-ned for additional relevant articles Duplicate articleswere not counted in the total sample of identifiedrecords Abstracts were screened for relevance Full-text articles were retrieved to determine eligibilityTwo authors independently determined eligibility forwhich interobserver agreement was calculated usingpercent agreement and kappa statistics Disagree-ments regarding eligibility were resolved by consensusamong the authors For each eligible study 2 authorsindependently abstracted information concerningstudy characteristics

Data Synthesis

The findings of the selected articles were catego-rized according to levels of scientific evidence basedon clinical practice guidelines from the US Depart-ment of Health and Human Services6

A Multiple double-blind placebo-controlled trialsand a confirmatory meta-analysis (in addition tolevel B of evidence)

B At least 1 double-blind placebo-controlled trial(in addition to level C of evidence)

C Anecdotal reports case series and open trialsin addition to expert endorsement or consensus

D Few case reports without any expert panelendorsement

To evaluate evidence for an association betweenBZDs and PTSD the following 3 null hypotheseswere tested

H1 BZDs are not associated with the develop-ment of PTSD in trauma patientsH2 BZDs are not associated with PTSD-associ-ated symptoms in patients with PTSDH3 BZDs are not associated with PTSD-associ-ated symptoms in trauma patients with andwithout PTSD

282 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

In each case the hypothesis was tested using ameta-analysis carried out in the MetaEasy Exceladd-in (httpwwwstatanalysiscoukmeta-analysishtml) Studies included in the meta-analysis werethose that compared outcomes between a group ofpatients given BZDs and a control group An esti-mate and 95 confidence interval (CI) for thestandardized effect size (ES) was computed for eachoutcome in a study To compute a single effect esti-mate for each study MetaEasy uses the within-study median ES and confidence limits Finally ameta-analysis was used to test each hypothesis afterpooling information over all of the relevant studiesNote that the meta-analysis for H3 is not simplypooling the other 2 meta-analyses but includes allPTSD-related outcomes in addition to ldquoPTSD diag-nosisrdquo which was the only outcome measured in H1

Using a random-effects model (to account for theheterogeneity between studies) we estimated the ESand 95 CI associated with each hypothesis Alltests were 2 sided and at the 005 level ofsignificance

RESULTS

Study Characteristics

The authors reviewed 8422 citations 249 abstractsand 109 full-text articles The selection process isillustrated in Figure 1 using the PRISMA flowdiagram7 with reasons for exclusion The percentagreement (kappa statistic) for eligibilitywas as follows full-text review 899 (κ=063)randomized-controlled trials (RCTs) 991

FIGURE 1 Flow diagram of literature search results from identification to inclusion of studies

Records identified through database searching

(n = 9093) Google Scholar (n = 8392) PubMed (n = 515) PsycINFO (n = 162) MEDLINE (n = 22) Cochrane Library (n = 14)

Records after duplicates removed(n = 8422)

Records screened (n = 249)

Records excluded (n = 140)

Not related to benzodiazepines in PTSD

Full-text articles assessed for eligibility

(n = 109)

Full-text articles excluded (n = 91)

Reviewspractice guidelines (n = 58) No PTSD treatment outcomes (n = 18) Case reportsseries (n = 6) Benzodiazepines not distinguished from

other medications (n = 5) Participants not PTSD or trauma

patients (n = 4)Studies included in qualitative

synthesis (n = 18)

Studies included in meta-analysis

(n = 12)

Additional records identified through other sources

(n = 6) Unique references from

retrieved records

Iden

tifi

cati

on

S

cree

nin

g

Elig

ibili

ty

Incl

ud

ed

PTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 283

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

In each case the hypothesis was tested using ameta-analysis carried out in the MetaEasy Exceladd-in (httpwwwstatanalysiscoukmeta-analysishtml) Studies included in the meta-analysis werethose that compared outcomes between a group ofpatients given BZDs and a control group An esti-mate and 95 confidence interval (CI) for thestandardized effect size (ES) was computed for eachoutcome in a study To compute a single effect esti-mate for each study MetaEasy uses the within-study median ES and confidence limits Finally ameta-analysis was used to test each hypothesis afterpooling information over all of the relevant studiesNote that the meta-analysis for H3 is not simplypooling the other 2 meta-analyses but includes allPTSD-related outcomes in addition to ldquoPTSD diag-nosisrdquo which was the only outcome measured in H1

Using a random-effects model (to account for theheterogeneity between studies) we estimated the ESand 95 CI associated with each hypothesis Alltests were 2 sided and at the 005 level ofsignificance

RESULTS

Study Characteristics

The authors reviewed 8422 citations 249 abstractsand 109 full-text articles The selection process isillustrated in Figure 1 using the PRISMA flowdiagram7 with reasons for exclusion The percentagreement (kappa statistic) for eligibilitywas as follows full-text review 899 (κ=063)randomized-controlled trials (RCTs) 991

FIGURE 1 Flow diagram of literature search results from identification to inclusion of studies

Records identified through database searching

(n = 9093) Google Scholar (n = 8392) PubMed (n = 515) PsycINFO (n = 162) MEDLINE (n = 22) Cochrane Library (n = 14)

Records after duplicates removed(n = 8422)

Records screened (n = 249)

Records excluded (n = 140)

Not related to benzodiazepines in PTSD

Full-text articles assessed for eligibility

(n = 109)

Full-text articles excluded (n = 91)

Reviewspractice guidelines (n = 58) No PTSD treatment outcomes (n = 18) Case reportsseries (n = 6) Benzodiazepines not distinguished from

other medications (n = 5) Participants not PTSD or trauma

patients (n = 4)Studies included in qualitative

synthesis (n = 18)

Studies included in meta-analysis

(n = 12)

Additional records identified through other sources

(n = 6) Unique references from

retrieved records

Iden

tifi

cati

on

S

cree

nin

g

Elig

ibili

ty

Incl

ud

ed

PTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 283

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

andObse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Rothb

aum

etal

8Ran

domized

-controlled

trial

103pa

tien

tswith

PTSD

invirtua

lrealityex

posu

retherap

y(sufficien

tda

taformeta-

analysis

was

availableon

lyfor

69pa

tien

ts)

Alprazolam

(025

mgpe

rsession

for5sessions

)

12mo

CAPS

Tho

setakingBZDssign

ificantlymorelike

lyto

have

PTSD

at3mopo

sttrea

tmen

tthan

those

takingplaceb

o(83

compa

redwith48

)No

sign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

PTSD

symptom

sat

anyother

time

PCL

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

thech

ange

inPTSD

symptom

sOrbicularis

oculiEMG

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

startleresp

onse

Salivary

cortisol

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

cortisol

leve

ls

Mellm

anet

al9

Ran

domized

-controlled

trial

22recent

physical

trau

mapa

tien

tswithinsomnia

Tem

azep

am(30

mgfor5nigh

tsthen

15mgfor

2nigh

ts)

6wkor

before

starting

nons

tudy

med

ication

CAPS

Tho

setakingBZDsmorelike

lyto

deve

lop

PTSD

than

thosetakingplaceb

o(55

compa

redwith27

)bu

tdifferen

cewas

not

sign

ificant

Sleep

diary

Tho

setakingBZDshad

sign

ificantlyincrea

sed

slee

pdu

ration

onthefirstnightcompa

red

withthosetakingplaceb

oNosign

ificant

differen

cebe

twee

nBZDsan

dplaceb

oon

any

slee

pmea

sure

atan

yother

time

Braun

etal

10Ran

domized

-controlled

trial

10pa

tien

tswith

PTSD

Alprazolam

(15-6

mgdfor

5wk

then

2wk

tape

r)

12wk

PTSD

Scale

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

PTSD

symptom

s

IES

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

PTSD

symptom

sHAM-A

Tho

setakingBZDshad

sign

ificantlyde

crea

sed

anxietycompa

redwiththosetakingplaceb

oHAM-D

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

depr

ession

VAS

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oin

overallwell-be

ing

Cates

etal

11Ran

domized

-controlled

trial

6pa

tien

tswith

PTSD

Clona

zepa

m(1

mgfor7

nigh

tsthen

2mgfor7nigh

ts

then

1wktape

r)

5wk

CAPS-

adap

ted

slee

pdiary

Nosign

ificantdifferen

cebe

twee

nBZDsan

dplaceb

oon

anyslee

pmea

sure

orin

nigh

tmares

Gelpinet

al12

Non

rand

omized

-controlled

trial

26recent

physical

trau

mapa

tien

tsAlprazolam

(25

mgd)

orclon

azep

am(27plusmn08mgd)

for1-6mo

6mo

CAPS

Tho

setakingBZDssign

ificantlymorelike

lyto

deve

lopPTSD

than

thosenot

takingBZDs

(69

vs15

)

284 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

IES

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

PTSD

symptom

sMIS

SNosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

PTSD

symptom

sSCID

Tho

setakingBZDssign

ificantlymorelike

lyto

deve

lopmajor

depr

essive

disord

erthan

those

not

takingBZDs(54

vs0

)Nosign

ificant

differen

cebe

twee

nBZDsan

dnoBZDsin

deve

lopm

entof

phob

ias

alcohol

abusep

anic

disord

eror

dysthym

iaSTAI

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

anxiety

BDI

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

depr

ession

Hea

rtrate

Tho

setakingBZDshad

decrea

sedhea

rtrate

inthefirstwee

kcompa

redwiththosenot

takingBZDs

butthis

differen

cewas

not

sign

ificantNosign

ificantdifferen

cebe

twee

nBZDsan

dnoBZDsin

hea

rtrate

atan

yother

time

Sha

levet

al13

Non

rand

omized

compa

rison

trial

18pa

tien

ts(9

with

PTSD9with

panicdisord

er)

Alprazolam

(205plusmn

069

mgd)

2wk

HAM-A

Nosign

ificantdifferen

cebe

twee

nPTSD

and

panic

disord

erin

prestimulation

anxiety

Orbicularis

oculiEMG

skin

cond

uctanc

ehe

artrate

Nosign

ificantdifferen

cebe

twee

npa

tien

tswithPTSD

andpa

nic

disord

erin

physiologicalmea

suresbe

fore

BZDs

Acoustic

startleresp

onsesin

PTSD

werenot

statisticallydifferen

tbe

fore

andafterBZDs

butthey

weresign

ificantlyde

crea

sedin

patien

tswithpa

nic

disord

erafterBZDs

Zatzicket

al14

Prosp

ective

coho

rt29

31ph

ysical

trau

mapa

tien

tsAny

agen

tdo

se

anddu

ration

12mo

PCL

Tho

sereceivingBZDsbe

fore

injury

sign

ificantlymorelike

lyto

hav

ePTSD

symptom

sthan

thosenot

takingBZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 285

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Shinet

al15

Prosp

ective

coho

rt37

6pa

tien

tswith

PTSD

Any

agen

tdo

se

anddu

ration

5-12

mo

CTS

Tho

sewithahistory

ofag

gression

taking

BZDshad

sign

ificantlyincrea

sedag

gression

compa

redwiththosenot

takingBZDsan

dthosewithou

tahistory

ofag

gression

Kostenet

al16

Prosp

ective

coho

rt37

0pa

tien

tswith

PTSD

inmen

tal

health

trea

tmen

t

Any

agen

tdo

se

anddu

ration

12mo

MIS

STho

setakingBZDshad

sign

ificantlyincrea

sed

PTSD

symptom

sat

baselinecompa

redwith

thosenot

takingBZDs

BSI

Tho

setaking

BZD

sha

dsign

ificantly

increa

sed

anxietyat

baselin

ecompa

redwiththoseno

ttaking

BZD

sNosign

ificant

diffe

rencebe

tween

BZD

san

dno

BZD

sin

chan

gein

anxiety

NVVRS-

derive

dinstru

men

t

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

violen

ceat

baseline

Thosewith

comorbidSUD

takingBZDshad

less

impr

ovem

entin

violen

cecompa

redwith

thosewithcomorbidSUD

not

takingBZDs

butthis

differen

cewas

not

sign

ificant

ASI

Tho

setakingBZDshad

sign

ificantlyincrea

sed

alcohol

use

atba

selinecompa

redwiththose

not

takingBZDs

Nosign

ificantdifferen

cebe

twee

nBZDsan

dnoBZDsin

chan

gein

subs

tance

use

orsocial

functioning

Those

withcomorbidSUD

takingBZDshad

less

impr

ovem

entin

subs

tance

use

compa

red

withthosewithcomorbidSUD

not

taking

BZDs

butthis

differen

cewas

not

sign

ificant

Rosen

etal

17Prosp

ective

coho

rt28

3pa

tien

tswith

PTSD

(140

inpr

olon

ged

expo

sure14

3in

presen

t-centered

psycho

therap

ysu

fficien

tda

tafor

meta-an

alysis

was

only

availablefor

143pa

tien

ts)

Any

agen

tdo

se

anddu

ration

6mo

CAPS

Nosign

ificance

differen

cebe

twee

nBZDswith

prolon

gedex

posu

rean

dnoBZDswitheither

therap

yin

PTSD

symptom

sThosetaking

BZDsin

presen

t-centeredps

ychotherap

yhad

sign

ificantlyworse

posttrea

tmen

tmaintenan

ceof

impr

ovem

ents

inPTSD

symptom

scompa

redwithother

grou

psPCL

Inpr

esen

t-centeredtherap

ythosetaking

BZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

sdu

ringps

ychotherap

ycompa

redwiththosenot

takingBZDs

Significance

ofresu

ltsforpr

olon

gedex

posu

rewerenot

determ

inab

ledu

eto

presen

ceof

aninteractionterm

andtheway

theresu

lts

werepr

esen

ted

286 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Jone

set

al18

Prosp

ective

coho

rt23

8recent

trau

mapa

tien

ts(ICU)

Any

agen

tdo

sean

ddu

ration

3mo

PTSS-14

Higher

BZD

dosesin

theIC

Uas

sociated

with

sign

ificantlyincrea

sedPTSD

symptom

s

Sam

uelson

etal

19Prosp

ective

coho

rt22

6recent

trau

ma

patien

ts(ICU)

Midaz

olam

(any

dose

ordu

ration

)

2mo

IES-R

Tho

sereceivingBZDssign

ificantlymorelike

lyto

deve

lopPTSD

than

thosenot

takingBZDs

(68

vs30

)

Bienv

enu

etal

20Prosp

ective

coho

rt18

6recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

3-24

mo

IES-R

Higher

BZD

dosesin

theIC

Unot

associated

withsign

ificantch

ange

sin

therisk

ofde

velopingPTSD

Baran

yiet

al21

Prosp

ective

coho

rt12

6trau

ma

patien

ts(solid-organ

tran

splants)

Any

agen

tdo

se

anddu

ration

Mea

nof

249

mo

PTSS-10

Chronic

BZD

useeither

before

orafter

surgery

associated

withsign

ificantly

increa

sedrisk

ofPTSD

symptom

s

Girardet

al22

Prosp

ective

coho

rt43

recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

6mo

PTSS-10

Greater

BZD

administrationin

theIC

Uas

sociated

withsign

ificantlyincrea

sedrisk

ofde

velopingPTSD

Van

Minne

net

al23

Prosp

ective

coho

rt43

patien

tswith

PTSD

inpr

olon

ged

expo

sure

Daily

useof

any

agen

tor

dose

3mo

PSS-SR

Tho

setakingBZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

san

dmore

drop

outs

compa

redwiththosenot

taking

BZDs

McG

hee

etal

24Retrosp

ective

coho

rt21

1trau

ma

patien

ts(bur

nsrequ

iringsu

rgery)

Midaz

olam

(any

dose

intrao

perative

)

Any

upto

4y

PCL

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

risk

ofde

velopingPTSD

Sha

levan

dRog

el-

Fuc

hs25

Cross-section

al18

patien

tswith

PTSD

Clona

zepa

m(27plusmn11mgd)

Not ap

plicab

leOrbicularis

oculiEMG

skin

cond

uctanc

ehe

artrate

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

mag

nitude

orhab

ituationrate

ofacou

stic

startleresp

onses

ASIindicates

Addiction

SeverityIn

dexB

DIBeckDep

ressionIn

ventoryB

SIBrief

Sym

ptom

Inventory

BZDb

enzodiazepineCAPSC

linician-administeredPTSD

Sca

leCTSCon

flicts

Tac

tics

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRatingSca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionIC

U

intensive

care

unitI

ESIm

pact

ofEvent

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDN

VVRSNational

Vietnam

Veteran

sRea

djustmen

tStudy

PCLP

TSD

ChecklistPSS-SRP

TSD

Sym

ptom

Sca

leSelf-repo

rtP

TSSP

osttra

umatic

StressSyn

dromeSca

leP

TSDp

osttra

umatic

stress

disorderS

CID

StructuredClinical

Interview

fortheDSMSTAI

State-Tra

itAnxietyIn

ventoryS

UDsu

bstance

use

disorderVASvisu

alan

alog

scale

Journal of Psychiatric Practice Vol 21 No 4 July 2015 287

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

umaTyp

e(

)

Rothb

aum

etal

8IIraq

andor

Afgha

nistan

veterans

DSM-IVcriteria

forPTSD

dueto

militarytrau

mave

rified

throug

hdischa

rgepa

pers

discon

tinu

edtaking

long

-actingBZD

sfor1moan

dsh

ort-

acting

BZD

sfor2wkbe

fore

screen

ing

stab

ledo

sesof

othe

rps

ycho

trop

icmed

ications

forat

leas

t2wkbe

fore

thestud

ywritten

inform

edconsent

EMed

ically

unstab

leps

ycho

sis

bipo

lardisord

erc

urrent

suicidal

risk

cu

rren

talcoho

lor

drug

depe

nden

ce

preg

nanc

ygluc

ocorticoids

BZD

sch

ronicallyus

edop

ioids

354

Black

50

White

42

Hispa

nic5

Other3

Com

bat10

0

Mellm

anet

al9

IAdm

ittedto

leve

lItrau

macenterr

ecallof

trau

ma

atleas

tmod

erateim

pairmen

tof

slee

pinitiation

ormainten

ance

mee

tfullcriteria

forat

leas

t2PTSD

symptom

clus

ters

inDSM-IVwilling

andab

leto

prov

idewritten

inform

edcons

ent

EIn

toxication

attimeof

trau

ma

braininjurypr

eexisting

psychiatricdisord

ers

3636

Hispa

nic8

2White

9Black

9

MVC68

Assau

lt2

3Acciden

t9

Braun

etal

10I

DSM-III

criteria

forPTSDwilling

andab

leto

prov

ide

written

inform

edconsentfreeof

psycho

trop

icmed

ications

atleas

t2wkbe

fore

stud

yEPhy

sicallyun

healthy

sign

ificant

head

injury

38Com

bat40

MVC30

Acciden

t20

Terrorism

10

Cates

etal

11I

DSM-IV

criteria

forPTSDat

leas

tthrice

wee

klypr

oblems

withslee

pan

dnigh

tmaresw

illing

andab

leto

prov

ide

written

inform

edconsent

Elt

18yold

unstab

lemed

ical

cond

itions

sen

sitivity

toBZD

scu

rren

tBZD

use

subs

tanc

eab

useor

depe

nden

cein

past

4wk

inab

ilityto

attend

regu

larfollow

-upvisitswom

enwho

wereeither

preg

nant

orof

child-be

aringpo

tentialan

dno

tus

ingcontraceptivesde

men

tia

cogn

itivedisord

er

520

Com

bat10

0

Gelpinet

al12

IEmerge

ncyroom

admission

swithatrau

ma

ETak

ingps

ycho

trop

icmed

ications

before

thetrau

ma

coma

head

injuryloss

ofcons

ciou

sness

2946

MVCs

77

Terrorism

19

Acciden

t4

Sha

levet

al13

IDSM-III-R

criteria

forPTSD

orpa

nicdisord

ermed

ication

free

EPsych

osism

ajor

depr

ession

cur

rent

orpa

stsu

bstanc

eor

alcoho

lus

epa

tien

tswithPTSD

withsp

ontane

ouspa

nic

attack

spa

tien

tswithpa

nicdisord

erwithahistoryof

trau

ma

3439

288 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

Zatzicket

al14

I18

-84yold

Eng

lish

-spe

akingor

Spa

nish

-spe

akingpa

tien

ts

arrive

daliveat

hosp

italm

oderateto

seve

reinjuries

Eg

reater

than

oreq

ual

toge65

yoldwithafirstlisted

diag

nosisof

hipfracturem

ajor

burn

strea

tmen

tde

lays

gt24

hincarcerated

attimeof

injury

4135

White

67

Black

16

Hispa

nic13

Other3

Injury10

0

Shinet

al15

I18

-69yold

militaryve

terans

servingin

Vietnam

eraor

laterat

leas

ton

eou

tpatient

VAvisitwithaPTSD

diag

nosis

EN

oPTSD

diag

nosisin

thepr

ior2y

4250

White

65

Black

17

Hispa

nic10

Other3

Kostenet

al16

IDSM-III

criteria

forPTSDmilitaryve

terans

450

White

75

Rosen

etal

17I

femaleve

teranor

active

duty

soldier

DSM-IV

criteria

for

PTSDCAPSscoregt45

EC

oncu

rren

tPTSD

psycho

therap

yothe

rthan

briefvisits

withan

existing

therap

istor

participationin

self-help

grou

psc

hang

ein

psycho

active

med

ications

during

the2mo

before

stud

yrecruitm

entsu

bstanc

ede

pend

ence

notin

remission

forat

leas

t3mo

curren

tps

ycho

ticsymptom

sor

man

iab

ipolar

disord

erpr

ominen

tcu

rren

tsu

icidal

orho

micidal

idea

tion

cogn

itiveim

pairmen

tcu

rren

tinvo

lvem

entin

violen

trelation

shipself-m

utilationwithin

thepa

st6mo

100

White

55

Black

33

Hispa

nic

6Other7

Sex

ual93

Acciden

t82

Disas

ter

72

Com

bat25

Jone

set

al18

Igt18

yold

mecha

nicallyve

ntilated

IC

Uleng

thof

stay

atleas

t48

hEP

rior

PTSDa

dmittedaftersu

icideattemptp

reex

isting

orconc

omitan

tps

ycho

ticillness

reside

sgt30

kmfrom

hosp

ital

unresolved

confus

ionen

rolled

inan

othe

rresearch

stud

y

6138

Life-threaten

ingmed

ical

condition

10

0

Sam

uelson

etal

19I

gt18

yold

mecha

nicallyve

ntilated

ge

neralIC

Uleng

thof

stay

atleas

t24

hEH

eadinjuryps

ycho

ticillness

men

talretard

ation

intoxication

adm

ittedaftersu

icideattempth

earing

spe

ech

disa

bilityno

n-Swed

ishsp

eaking

tran

sferredto

anothe

rho

spitalm

echa

nicallyve

ntilated

atdischa

rge

mecha

nically

ventilated

gt24

hpr

eadm

ission

6348

Life-threaten

ingmed

ical

condition

10

0

Bienv

enuet

al20

IMecha

nicallyve

ntilated

withacutelung

injury

EN

eurologicalsp

ecialtyIC

Upr

eexistingillnesswithalife

expe

ctan

cylt6mo

pree

xistingcogn

itiveim

pairmen

tor

commun

icationlang

uage

barriersn

ofixe

dad

dress

tran

sfer

toastud

ysite

ICU

withpr

eexistingacutelung

injury

gt24

h

45

Life-threaten

ingmed

ical

condition

10

0

Journal of Psychiatric Practice Vol 21 No 4 July 2015 289

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

IES

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

PTSD

symptom

sMIS

SNosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

PTSD

symptom

sSCID

Tho

setakingBZDssign

ificantlymorelike

lyto

deve

lopmajor

depr

essive

disord

erthan

those

not

takingBZDs(54

vs0

)Nosign

ificant

differen

cebe

twee

nBZDsan

dnoBZDsin

deve

lopm

entof

phob

ias

alcohol

abusep

anic

disord

eror

dysthym

iaSTAI

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

anxiety

BDI

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

depr

ession

Hea

rtrate

Tho

setakingBZDshad

decrea

sedhea

rtrate

inthefirstwee

kcompa

redwiththosenot

takingBZDs

butthis

differen

cewas

not

sign

ificantNosign

ificantdifferen

cebe

twee

nBZDsan

dnoBZDsin

hea

rtrate

atan

yother

time

Sha

levet

al13

Non

rand

omized

compa

rison

trial

18pa

tien

ts(9

with

PTSD9with

panicdisord

er)

Alprazolam

(205plusmn

069

mgd)

2wk

HAM-A

Nosign

ificantdifferen

cebe

twee

nPTSD

and

panic

disord

erin

prestimulation

anxiety

Orbicularis

oculiEMG

skin

cond

uctanc

ehe

artrate

Nosign

ificantdifferen

cebe

twee

npa

tien

tswithPTSD

andpa

nic

disord

erin

physiologicalmea

suresbe

fore

BZDs

Acoustic

startleresp

onsesin

PTSD

werenot

statisticallydifferen

tbe

fore

andafterBZDs

butthey

weresign

ificantlyde

crea

sedin

patien

tswithpa

nic

disord

erafterBZDs

Zatzicket

al14

Prosp

ective

coho

rt29

31ph

ysical

trau

mapa

tien

tsAny

agen

tdo

se

anddu

ration

12mo

PCL

Tho

sereceivingBZDsbe

fore

injury

sign

ificantlymorelike

lyto

hav

ePTSD

symptom

sthan

thosenot

takingBZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 285

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Shinet

al15

Prosp

ective

coho

rt37

6pa

tien

tswith

PTSD

Any

agen

tdo

se

anddu

ration

5-12

mo

CTS

Tho

sewithahistory

ofag

gression

taking

BZDshad

sign

ificantlyincrea

sedag

gression

compa

redwiththosenot

takingBZDsan

dthosewithou

tahistory

ofag

gression

Kostenet

al16

Prosp

ective

coho

rt37

0pa

tien

tswith

PTSD

inmen

tal

health

trea

tmen

t

Any

agen

tdo

se

anddu

ration

12mo

MIS

STho

setakingBZDshad

sign

ificantlyincrea

sed

PTSD

symptom

sat

baselinecompa

redwith

thosenot

takingBZDs

BSI

Tho

setaking

BZD

sha

dsign

ificantly

increa

sed

anxietyat

baselin

ecompa

redwiththoseno

ttaking

BZD

sNosign

ificant

diffe

rencebe

tween

BZD

san

dno

BZD

sin

chan

gein

anxiety

NVVRS-

derive

dinstru

men

t

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

violen

ceat

baseline

Thosewith

comorbidSUD

takingBZDshad

less

impr

ovem

entin

violen

cecompa

redwith

thosewithcomorbidSUD

not

takingBZDs

butthis

differen

cewas

not

sign

ificant

ASI

Tho

setakingBZDshad

sign

ificantlyincrea

sed

alcohol

use

atba

selinecompa

redwiththose

not

takingBZDs

Nosign

ificantdifferen

cebe

twee

nBZDsan

dnoBZDsin

chan

gein

subs

tance

use

orsocial

functioning

Those

withcomorbidSUD

takingBZDshad

less

impr

ovem

entin

subs

tance

use

compa

red

withthosewithcomorbidSUD

not

taking

BZDs

butthis

differen

cewas

not

sign

ificant

Rosen

etal

17Prosp

ective

coho

rt28

3pa

tien

tswith

PTSD

(140

inpr

olon

ged

expo

sure14

3in

presen

t-centered

psycho

therap

ysu

fficien

tda

tafor

meta-an

alysis

was

only

availablefor

143pa

tien

ts)

Any

agen

tdo

se

anddu

ration

6mo

CAPS

Nosign

ificance

differen

cebe

twee

nBZDswith

prolon

gedex

posu

rean

dnoBZDswitheither

therap

yin

PTSD

symptom

sThosetaking

BZDsin

presen

t-centeredps

ychotherap

yhad

sign

ificantlyworse

posttrea

tmen

tmaintenan

ceof

impr

ovem

ents

inPTSD

symptom

scompa

redwithother

grou

psPCL

Inpr

esen

t-centeredtherap

ythosetaking

BZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

sdu

ringps

ychotherap

ycompa

redwiththosenot

takingBZDs

Significance

ofresu

ltsforpr

olon

gedex

posu

rewerenot

determ

inab

ledu

eto

presen

ceof

aninteractionterm

andtheway

theresu

lts

werepr

esen

ted

286 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Jone

set

al18

Prosp

ective

coho

rt23

8recent

trau

mapa

tien

ts(ICU)

Any

agen

tdo

sean

ddu

ration

3mo

PTSS-14

Higher

BZD

dosesin

theIC

Uas

sociated

with

sign

ificantlyincrea

sedPTSD

symptom

s

Sam

uelson

etal

19Prosp

ective

coho

rt22

6recent

trau

ma

patien

ts(ICU)

Midaz

olam

(any

dose

ordu

ration

)

2mo

IES-R

Tho

sereceivingBZDssign

ificantlymorelike

lyto

deve

lopPTSD

than

thosenot

takingBZDs

(68

vs30

)

Bienv

enu

etal

20Prosp

ective

coho

rt18

6recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

3-24

mo

IES-R

Higher

BZD

dosesin

theIC

Unot

associated

withsign

ificantch

ange

sin

therisk

ofde

velopingPTSD

Baran

yiet

al21

Prosp

ective

coho

rt12

6trau

ma

patien

ts(solid-organ

tran

splants)

Any

agen

tdo

se

anddu

ration

Mea

nof

249

mo

PTSS-10

Chronic

BZD

useeither

before

orafter

surgery

associated

withsign

ificantly

increa

sedrisk

ofPTSD

symptom

s

Girardet

al22

Prosp

ective

coho

rt43

recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

6mo

PTSS-10

Greater

BZD

administrationin

theIC

Uas

sociated

withsign

ificantlyincrea

sedrisk

ofde

velopingPTSD

Van

Minne

net

al23

Prosp

ective

coho

rt43

patien

tswith

PTSD

inpr

olon

ged

expo

sure

Daily

useof

any

agen

tor

dose

3mo

PSS-SR

Tho

setakingBZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

san

dmore

drop

outs

compa

redwiththosenot

taking

BZDs

McG

hee

etal

24Retrosp

ective

coho

rt21

1trau

ma

patien

ts(bur

nsrequ

iringsu

rgery)

Midaz

olam

(any

dose

intrao

perative

)

Any

upto

4y

PCL

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

risk

ofde

velopingPTSD

Sha

levan

dRog

el-

Fuc

hs25

Cross-section

al18

patien

tswith

PTSD

Clona

zepa

m(27plusmn11mgd)

Not ap

plicab

leOrbicularis

oculiEMG

skin

cond

uctanc

ehe

artrate

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

mag

nitude

orhab

ituationrate

ofacou

stic

startleresp

onses

ASIindicates

Addiction

SeverityIn

dexB

DIBeckDep

ressionIn

ventoryB

SIBrief

Sym

ptom

Inventory

BZDb

enzodiazepineCAPSC

linician-administeredPTSD

Sca

leCTSCon

flicts

Tac

tics

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRatingSca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionIC

U

intensive

care

unitI

ESIm

pact

ofEvent

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDN

VVRSNational

Vietnam

Veteran

sRea

djustmen

tStudy

PCLP

TSD

ChecklistPSS-SRP

TSD

Sym

ptom

Sca

leSelf-repo

rtP

TSSP

osttra

umatic

StressSyn

dromeSca

leP

TSDp

osttra

umatic

stress

disorderS

CID

StructuredClinical

Interview

fortheDSMSTAI

State-Tra

itAnxietyIn

ventoryS

UDsu

bstance

use

disorderVASvisu

alan

alog

scale

Journal of Psychiatric Practice Vol 21 No 4 July 2015 287

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

umaTyp

e(

)

Rothb

aum

etal

8IIraq

andor

Afgha

nistan

veterans

DSM-IVcriteria

forPTSD

dueto

militarytrau

mave

rified

throug

hdischa

rgepa

pers

discon

tinu

edtaking

long

-actingBZD

sfor1moan

dsh

ort-

acting

BZD

sfor2wkbe

fore

screen

ing

stab

ledo

sesof

othe

rps

ycho

trop

icmed

ications

forat

leas

t2wkbe

fore

thestud

ywritten

inform

edconsent

EMed

ically

unstab

leps

ycho

sis

bipo

lardisord

erc

urrent

suicidal

risk

cu

rren

talcoho

lor

drug

depe

nden

ce

preg

nanc

ygluc

ocorticoids

BZD

sch

ronicallyus

edop

ioids

354

Black

50

White

42

Hispa

nic5

Other3

Com

bat10

0

Mellm

anet

al9

IAdm

ittedto

leve

lItrau

macenterr

ecallof

trau

ma

atleas

tmod

erateim

pairmen

tof

slee

pinitiation

ormainten

ance

mee

tfullcriteria

forat

leas

t2PTSD

symptom

clus

ters

inDSM-IVwilling

andab

leto

prov

idewritten

inform

edcons

ent

EIn

toxication

attimeof

trau

ma

braininjurypr

eexisting

psychiatricdisord

ers

3636

Hispa

nic8

2White

9Black

9

MVC68

Assau

lt2

3Acciden

t9

Braun

etal

10I

DSM-III

criteria

forPTSDwilling

andab

leto

prov

ide

written

inform

edconsentfreeof

psycho

trop

icmed

ications

atleas

t2wkbe

fore

stud

yEPhy

sicallyun

healthy

sign

ificant

head

injury

38Com

bat40

MVC30

Acciden

t20

Terrorism

10

Cates

etal

11I

DSM-IV

criteria

forPTSDat

leas

tthrice

wee

klypr

oblems

withslee

pan

dnigh

tmaresw

illing

andab

leto

prov

ide

written

inform

edconsent

Elt

18yold

unstab

lemed

ical

cond

itions

sen

sitivity

toBZD

scu

rren

tBZD

use

subs

tanc

eab

useor

depe

nden

cein

past

4wk

inab

ilityto

attend

regu

larfollow

-upvisitswom

enwho

wereeither

preg

nant

orof

child-be

aringpo

tentialan

dno

tus

ingcontraceptivesde

men

tia

cogn

itivedisord

er

520

Com

bat10

0

Gelpinet

al12

IEmerge

ncyroom

admission

swithatrau

ma

ETak

ingps

ycho

trop

icmed

ications

before

thetrau

ma

coma

head

injuryloss

ofcons

ciou

sness

2946

MVCs

77

Terrorism

19

Acciden

t4

Sha

levet

al13

IDSM-III-R

criteria

forPTSD

orpa

nicdisord

ermed

ication

free

EPsych

osism

ajor

depr

ession

cur

rent

orpa

stsu

bstanc

eor

alcoho

lus

epa

tien

tswithPTSD

withsp

ontane

ouspa

nic

attack

spa

tien

tswithpa

nicdisord

erwithahistoryof

trau

ma

3439

288 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

Zatzicket

al14

I18

-84yold

Eng

lish

-spe

akingor

Spa

nish

-spe

akingpa

tien

ts

arrive

daliveat

hosp

italm

oderateto

seve

reinjuries

Eg

reater

than

oreq

ual

toge65

yoldwithafirstlisted

diag

nosisof

hipfracturem

ajor

burn

strea

tmen

tde

lays

gt24

hincarcerated

attimeof

injury

4135

White

67

Black

16

Hispa

nic13

Other3

Injury10

0

Shinet

al15

I18

-69yold

militaryve

terans

servingin

Vietnam

eraor

laterat

leas

ton

eou

tpatient

VAvisitwithaPTSD

diag

nosis

EN

oPTSD

diag

nosisin

thepr

ior2y

4250

White

65

Black

17

Hispa

nic10

Other3

Kostenet

al16

IDSM-III

criteria

forPTSDmilitaryve

terans

450

White

75

Rosen

etal

17I

femaleve

teranor

active

duty

soldier

DSM-IV

criteria

for

PTSDCAPSscoregt45

EC

oncu

rren

tPTSD

psycho

therap

yothe

rthan

briefvisits

withan

existing

therap

istor

participationin

self-help

grou

psc

hang

ein

psycho

active

med

ications

during

the2mo

before

stud

yrecruitm

entsu

bstanc

ede

pend

ence

notin

remission

forat

leas

t3mo

curren

tps

ycho

ticsymptom

sor

man

iab

ipolar

disord

erpr

ominen

tcu

rren

tsu

icidal

orho

micidal

idea

tion

cogn

itiveim

pairmen

tcu

rren

tinvo

lvem

entin

violen

trelation

shipself-m

utilationwithin

thepa

st6mo

100

White

55

Black

33

Hispa

nic

6Other7

Sex

ual93

Acciden

t82

Disas

ter

72

Com

bat25

Jone

set

al18

Igt18

yold

mecha

nicallyve

ntilated

IC

Uleng

thof

stay

atleas

t48

hEP

rior

PTSDa

dmittedaftersu

icideattemptp

reex

isting

orconc

omitan

tps

ycho

ticillness

reside

sgt30

kmfrom

hosp

ital

unresolved

confus

ionen

rolled

inan

othe

rresearch

stud

y

6138

Life-threaten

ingmed

ical

condition

10

0

Sam

uelson

etal

19I

gt18

yold

mecha

nicallyve

ntilated

ge

neralIC

Uleng

thof

stay

atleas

t24

hEH

eadinjuryps

ycho

ticillness

men

talretard

ation

intoxication

adm

ittedaftersu

icideattempth

earing

spe

ech

disa

bilityno

n-Swed

ishsp

eaking

tran

sferredto

anothe

rho

spitalm

echa

nicallyve

ntilated

atdischa

rge

mecha

nically

ventilated

gt24

hpr

eadm

ission

6348

Life-threaten

ingmed

ical

condition

10

0

Bienv

enuet

al20

IMecha

nicallyve

ntilated

withacutelung

injury

EN

eurologicalsp

ecialtyIC

Upr

eexistingillnesswithalife

expe

ctan

cylt6mo

pree

xistingcogn

itiveim

pairmen

tor

commun

icationlang

uage

barriersn

ofixe

dad

dress

tran

sfer

toastud

ysite

ICU

withpr

eexistingacutelung

injury

gt24

h

45

Life-threaten

ingmed

ical

condition

10

0

Journal of Psychiatric Practice Vol 21 No 4 July 2015 289

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Shinet

al15

Prosp

ective

coho

rt37

6pa

tien

tswith

PTSD

Any

agen

tdo

se

anddu

ration

5-12

mo

CTS

Tho

sewithahistory

ofag

gression

taking

BZDshad

sign

ificantlyincrea

sedag

gression

compa

redwiththosenot

takingBZDsan

dthosewithou

tahistory

ofag

gression

Kostenet

al16

Prosp

ective

coho

rt37

0pa

tien

tswith

PTSD

inmen

tal

health

trea

tmen

t

Any

agen

tdo

se

anddu

ration

12mo

MIS

STho

setakingBZDshad

sign

ificantlyincrea

sed

PTSD

symptom

sat

baselinecompa

redwith

thosenot

takingBZDs

BSI

Tho

setaking

BZD

sha

dsign

ificantly

increa

sed

anxietyat

baselin

ecompa

redwiththoseno

ttaking

BZD

sNosign

ificant

diffe

rencebe

tween

BZD

san

dno

BZD

sin

chan

gein

anxiety

NVVRS-

derive

dinstru

men

t

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

violen

ceat

baseline

Thosewith

comorbidSUD

takingBZDshad

less

impr

ovem

entin

violen

cecompa

redwith

thosewithcomorbidSUD

not

takingBZDs

butthis

differen

cewas

not

sign

ificant

ASI

Tho

setakingBZDshad

sign

ificantlyincrea

sed

alcohol

use

atba

selinecompa

redwiththose

not

takingBZDs

Nosign

ificantdifferen

cebe

twee

nBZDsan

dnoBZDsin

chan

gein

subs

tance

use

orsocial

functioning

Those

withcomorbidSUD

takingBZDshad

less

impr

ovem

entin

subs

tance

use

compa

red

withthosewithcomorbidSUD

not

taking

BZDs

butthis

differen

cewas

not

sign

ificant

Rosen

etal

17Prosp

ective

coho

rt28

3pa

tien

tswith

PTSD

(140

inpr

olon

ged

expo

sure14

3in

presen

t-centered

psycho

therap

ysu

fficien

tda

tafor

meta-an

alysis

was

only

availablefor

143pa

tien

ts)

Any

agen

tdo

se

anddu

ration

6mo

CAPS

Nosign

ificance

differen

cebe

twee

nBZDswith

prolon

gedex

posu

rean

dnoBZDswitheither

therap

yin

PTSD

symptom

sThosetaking

BZDsin

presen

t-centeredps

ychotherap

yhad

sign

ificantlyworse

posttrea

tmen

tmaintenan

ceof

impr

ovem

ents

inPTSD

symptom

scompa

redwithother

grou

psPCL

Inpr

esen

t-centeredtherap

ythosetaking

BZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

sdu

ringps

ychotherap

ycompa

redwiththosenot

takingBZDs

Significance

ofresu

ltsforpr

olon

gedex

posu

rewerenot

determ

inab

ledu

eto

presen

ceof

aninteractionterm

andtheway

theresu

lts

werepr

esen

ted

286 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Jone

set

al18

Prosp

ective

coho

rt23

8recent

trau

mapa

tien

ts(ICU)

Any

agen

tdo

sean

ddu

ration

3mo

PTSS-14

Higher

BZD

dosesin

theIC

Uas

sociated

with

sign

ificantlyincrea

sedPTSD

symptom

s

Sam

uelson

etal

19Prosp

ective

coho

rt22

6recent

trau

ma

patien

ts(ICU)

Midaz

olam

(any

dose

ordu

ration

)

2mo

IES-R

Tho

sereceivingBZDssign

ificantlymorelike

lyto

deve

lopPTSD

than

thosenot

takingBZDs

(68

vs30

)

Bienv

enu

etal

20Prosp

ective

coho

rt18

6recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

3-24

mo

IES-R

Higher

BZD

dosesin

theIC

Unot

associated

withsign

ificantch

ange

sin

therisk

ofde

velopingPTSD

Baran

yiet

al21

Prosp

ective

coho

rt12

6trau

ma

patien

ts(solid-organ

tran

splants)

Any

agen

tdo

se

anddu

ration

Mea

nof

249

mo

PTSS-10

Chronic

BZD

useeither

before

orafter

surgery

associated

withsign

ificantly

increa

sedrisk

ofPTSD

symptom

s

Girardet

al22

Prosp

ective

coho

rt43

recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

6mo

PTSS-10

Greater

BZD

administrationin

theIC

Uas

sociated

withsign

ificantlyincrea

sedrisk

ofde

velopingPTSD

Van

Minne

net

al23

Prosp

ective

coho

rt43

patien

tswith

PTSD

inpr

olon

ged

expo

sure

Daily

useof

any

agen

tor

dose

3mo

PSS-SR

Tho

setakingBZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

san

dmore

drop

outs

compa

redwiththosenot

taking

BZDs

McG

hee

etal

24Retrosp

ective

coho

rt21

1trau

ma

patien

ts(bur

nsrequ

iringsu

rgery)

Midaz

olam

(any

dose

intrao

perative

)

Any

upto

4y

PCL

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

risk

ofde

velopingPTSD

Sha

levan

dRog

el-

Fuc

hs25

Cross-section

al18

patien

tswith

PTSD

Clona

zepa

m(27plusmn11mgd)

Not ap

plicab

leOrbicularis

oculiEMG

skin

cond

uctanc

ehe

artrate

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

mag

nitude

orhab

ituationrate

ofacou

stic

startleresp

onses

ASIindicates

Addiction

SeverityIn

dexB

DIBeckDep

ressionIn

ventoryB

SIBrief

Sym

ptom

Inventory

BZDb

enzodiazepineCAPSC

linician-administeredPTSD

Sca

leCTSCon

flicts

Tac

tics

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRatingSca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionIC

U

intensive

care

unitI

ESIm

pact

ofEvent

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDN

VVRSNational

Vietnam

Veteran

sRea

djustmen

tStudy

PCLP

TSD

ChecklistPSS-SRP

TSD

Sym

ptom

Sca

leSelf-repo

rtP

TSSP

osttra

umatic

StressSyn

dromeSca

leP

TSDp

osttra

umatic

stress

disorderS

CID

StructuredClinical

Interview

fortheDSMSTAI

State-Tra

itAnxietyIn

ventoryS

UDsu

bstance

use

disorderVASvisu

alan

alog

scale

Journal of Psychiatric Practice Vol 21 No 4 July 2015 287

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

umaTyp

e(

)

Rothb

aum

etal

8IIraq

andor

Afgha

nistan

veterans

DSM-IVcriteria

forPTSD

dueto

militarytrau

mave

rified

throug

hdischa

rgepa

pers

discon

tinu

edtaking

long

-actingBZD

sfor1moan

dsh

ort-

acting

BZD

sfor2wkbe

fore

screen

ing

stab

ledo

sesof

othe

rps

ycho

trop

icmed

ications

forat

leas

t2wkbe

fore

thestud

ywritten

inform

edconsent

EMed

ically

unstab

leps

ycho

sis

bipo

lardisord

erc

urrent

suicidal

risk

cu

rren

talcoho

lor

drug

depe

nden

ce

preg

nanc

ygluc

ocorticoids

BZD

sch

ronicallyus

edop

ioids

354

Black

50

White

42

Hispa

nic5

Other3

Com

bat10

0

Mellm

anet

al9

IAdm

ittedto

leve

lItrau

macenterr

ecallof

trau

ma

atleas

tmod

erateim

pairmen

tof

slee

pinitiation

ormainten

ance

mee

tfullcriteria

forat

leas

t2PTSD

symptom

clus

ters

inDSM-IVwilling

andab

leto

prov

idewritten

inform

edcons

ent

EIn

toxication

attimeof

trau

ma

braininjurypr

eexisting

psychiatricdisord

ers

3636

Hispa

nic8

2White

9Black

9

MVC68

Assau

lt2

3Acciden

t9

Braun

etal

10I

DSM-III

criteria

forPTSDwilling

andab

leto

prov

ide

written

inform

edconsentfreeof

psycho

trop

icmed

ications

atleas

t2wkbe

fore

stud

yEPhy

sicallyun

healthy

sign

ificant

head

injury

38Com

bat40

MVC30

Acciden

t20

Terrorism

10

Cates

etal

11I

DSM-IV

criteria

forPTSDat

leas

tthrice

wee

klypr

oblems

withslee

pan

dnigh

tmaresw

illing

andab

leto

prov

ide

written

inform

edconsent

Elt

18yold

unstab

lemed

ical

cond

itions

sen

sitivity

toBZD

scu

rren

tBZD

use

subs

tanc

eab

useor

depe

nden

cein

past

4wk

inab

ilityto

attend

regu

larfollow

-upvisitswom

enwho

wereeither

preg

nant

orof

child-be

aringpo

tentialan

dno

tus

ingcontraceptivesde

men

tia

cogn

itivedisord

er

520

Com

bat10

0

Gelpinet

al12

IEmerge

ncyroom

admission

swithatrau

ma

ETak

ingps

ycho

trop

icmed

ications

before

thetrau

ma

coma

head

injuryloss

ofcons

ciou

sness

2946

MVCs

77

Terrorism

19

Acciden

t4

Sha

levet

al13

IDSM-III-R

criteria

forPTSD

orpa

nicdisord

ermed

ication

free

EPsych

osism

ajor

depr

ession

cur

rent

orpa

stsu

bstanc

eor

alcoho

lus

epa

tien

tswithPTSD

withsp

ontane

ouspa

nic

attack

spa

tien

tswithpa

nicdisord

erwithahistoryof

trau

ma

3439

288 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

Zatzicket

al14

I18

-84yold

Eng

lish

-spe

akingor

Spa

nish

-spe

akingpa

tien

ts

arrive

daliveat

hosp

italm

oderateto

seve

reinjuries

Eg

reater

than

oreq

ual

toge65

yoldwithafirstlisted

diag

nosisof

hipfracturem

ajor

burn

strea

tmen

tde

lays

gt24

hincarcerated

attimeof

injury

4135

White

67

Black

16

Hispa

nic13

Other3

Injury10

0

Shinet

al15

I18

-69yold

militaryve

terans

servingin

Vietnam

eraor

laterat

leas

ton

eou

tpatient

VAvisitwithaPTSD

diag

nosis

EN

oPTSD

diag

nosisin

thepr

ior2y

4250

White

65

Black

17

Hispa

nic10

Other3

Kostenet

al16

IDSM-III

criteria

forPTSDmilitaryve

terans

450

White

75

Rosen

etal

17I

femaleve

teranor

active

duty

soldier

DSM-IV

criteria

for

PTSDCAPSscoregt45

EC

oncu

rren

tPTSD

psycho

therap

yothe

rthan

briefvisits

withan

existing

therap

istor

participationin

self-help

grou

psc

hang

ein

psycho

active

med

ications

during

the2mo

before

stud

yrecruitm

entsu

bstanc

ede

pend

ence

notin

remission

forat

leas

t3mo

curren

tps

ycho

ticsymptom

sor

man

iab

ipolar

disord

erpr

ominen

tcu

rren

tsu

icidal

orho

micidal

idea

tion

cogn

itiveim

pairmen

tcu

rren

tinvo

lvem

entin

violen

trelation

shipself-m

utilationwithin

thepa

st6mo

100

White

55

Black

33

Hispa

nic

6Other7

Sex

ual93

Acciden

t82

Disas

ter

72

Com

bat25

Jone

set

al18

Igt18

yold

mecha

nicallyve

ntilated

IC

Uleng

thof

stay

atleas

t48

hEP

rior

PTSDa

dmittedaftersu

icideattemptp

reex

isting

orconc

omitan

tps

ycho

ticillness

reside

sgt30

kmfrom

hosp

ital

unresolved

confus

ionen

rolled

inan

othe

rresearch

stud

y

6138

Life-threaten

ingmed

ical

condition

10

0

Sam

uelson

etal

19I

gt18

yold

mecha

nicallyve

ntilated

ge

neralIC

Uleng

thof

stay

atleas

t24

hEH

eadinjuryps

ycho

ticillness

men

talretard

ation

intoxication

adm

ittedaftersu

icideattempth

earing

spe

ech

disa

bilityno

n-Swed

ishsp

eaking

tran

sferredto

anothe

rho

spitalm

echa

nicallyve

ntilated

atdischa

rge

mecha

nically

ventilated

gt24

hpr

eadm

ission

6348

Life-threaten

ingmed

ical

condition

10

0

Bienv

enuet

al20

IMecha

nicallyve

ntilated

withacutelung

injury

EN

eurologicalsp

ecialtyIC

Upr

eexistingillnesswithalife

expe

ctan

cylt6mo

pree

xistingcogn

itiveim

pairmen

tor

commun

icationlang

uage

barriersn

ofixe

dad

dress

tran

sfer

toastud

ysite

ICU

withpr

eexistingacutelung

injury

gt24

h

45

Life-threaten

ingmed

ical

condition

10

0

Journal of Psychiatric Practice Vol 21 No 4 July 2015 289

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

1Summar

yof

Clinical

and

Obse

rvat

ional

Stu

diesof

Ben

zodiaze

pin

esin

Pos

ttra

umat

icStres

sDisor

der

(PTSD)(con

tinued

)

Refer

ence

sStu

dy

Design

Particip

ants

(N)

Ben

zodia

zepin

eFollow-up

Assessm

ent

Outcom

es

Jone

set

al18

Prosp

ective

coho

rt23

8recent

trau

mapa

tien

ts(ICU)

Any

agen

tdo

sean

ddu

ration

3mo

PTSS-14

Higher

BZD

dosesin

theIC

Uas

sociated

with

sign

ificantlyincrea

sedPTSD

symptom

s

Sam

uelson

etal

19Prosp

ective

coho

rt22

6recent

trau

ma

patien

ts(ICU)

Midaz

olam

(any

dose

ordu

ration

)

2mo

IES-R

Tho

sereceivingBZDssign

ificantlymorelike

lyto

deve

lopPTSD

than

thosenot

takingBZDs

(68

vs30

)

Bienv

enu

etal

20Prosp

ective

coho

rt18

6recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

3-24

mo

IES-R

Higher

BZD

dosesin

theIC

Unot

associated

withsign

ificantch

ange

sin

therisk

ofde

velopingPTSD

Baran

yiet

al21

Prosp

ective

coho

rt12

6trau

ma

patien

ts(solid-organ

tran

splants)

Any

agen

tdo

se

anddu

ration

Mea

nof

249

mo

PTSS-10

Chronic

BZD

useeither

before

orafter

surgery

associated

withsign

ificantly

increa

sedrisk

ofPTSD

symptom

s

Girardet

al22

Prosp

ective

coho

rt43

recent

trau

ma

patien

ts(ICU)

Any

agen

tdo

se

anddu

ration

6mo

PTSS-10

Greater

BZD

administrationin

theIC

Uas

sociated

withsign

ificantlyincrea

sedrisk

ofde

velopingPTSD

Van

Minne

net

al23

Prosp

ective

coho

rt43

patien

tswith

PTSD

inpr

olon

ged

expo

sure

Daily

useof

any

agen

tor

dose

3mo

PSS-SR

Tho

setakingBZDshad

sign

ificantlyless

impr

ovem

entin

PTSD

symptom

san

dmore

drop

outs

compa

redwiththosenot

taking

BZDs

McG

hee

etal

24Retrosp

ective

coho

rt21

1trau

ma

patien

ts(bur

nsrequ

iringsu

rgery)

Midaz

olam

(any

dose

intrao

perative

)

Any

upto

4y

PCL

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

risk

ofde

velopingPTSD

Sha

levan

dRog

el-

Fuc

hs25

Cross-section

al18

patien

tswith

PTSD

Clona

zepa

m(27plusmn11mgd)

Not ap

plicab

leOrbicularis

oculiEMG

skin

cond

uctanc

ehe

artrate

Nosign

ificantdifferen

cebe

twee

nBZDsan

dno

BZDsin

mag

nitude

orhab

ituationrate

ofacou

stic

startleresp

onses

ASIindicates

Addiction

SeverityIn

dexB

DIBeckDep

ressionIn

ventoryB

SIBrief

Sym

ptom

Inventory

BZDb

enzodiazepineCAPSC

linician-administeredPTSD

Sca

leCTSCon

flicts

Tac

tics

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRatingSca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionIC

U

intensive

care

unitI

ESIm

pact

ofEvent

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDN

VVRSNational

Vietnam

Veteran

sRea

djustmen

tStudy

PCLP

TSD

ChecklistPSS-SRP

TSD

Sym

ptom

Sca

leSelf-repo

rtP

TSSP

osttra

umatic

StressSyn

dromeSca

leP

TSDp

osttra

umatic

stress

disorderS

CID

StructuredClinical

Interview

fortheDSMSTAI

State-Tra

itAnxietyIn

ventoryS

UDsu

bstance

use

disorderVASvisu

alan

alog

scale

Journal of Psychiatric Practice Vol 21 No 4 July 2015 287

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

umaTyp

e(

)

Rothb

aum

etal

8IIraq

andor

Afgha

nistan

veterans

DSM-IVcriteria

forPTSD

dueto

militarytrau

mave

rified

throug

hdischa

rgepa

pers

discon

tinu

edtaking

long

-actingBZD

sfor1moan

dsh

ort-

acting

BZD

sfor2wkbe

fore

screen

ing

stab

ledo

sesof

othe

rps

ycho

trop

icmed

ications

forat

leas

t2wkbe

fore

thestud

ywritten

inform

edconsent

EMed

ically

unstab

leps

ycho

sis

bipo

lardisord

erc

urrent

suicidal

risk

cu

rren

talcoho

lor

drug

depe

nden

ce

preg

nanc

ygluc

ocorticoids

BZD

sch

ronicallyus

edop

ioids

354

Black

50

White

42

Hispa

nic5

Other3

Com

bat10

0

Mellm

anet

al9

IAdm

ittedto

leve

lItrau

macenterr

ecallof

trau

ma

atleas

tmod

erateim

pairmen

tof

slee

pinitiation

ormainten

ance

mee

tfullcriteria

forat

leas

t2PTSD

symptom

clus

ters

inDSM-IVwilling

andab

leto

prov

idewritten

inform

edcons

ent

EIn

toxication

attimeof

trau

ma

braininjurypr

eexisting

psychiatricdisord

ers

3636

Hispa

nic8

2White

9Black

9

MVC68

Assau

lt2

3Acciden

t9

Braun

etal

10I

DSM-III

criteria

forPTSDwilling

andab

leto

prov

ide

written

inform

edconsentfreeof

psycho

trop

icmed

ications

atleas

t2wkbe

fore

stud

yEPhy

sicallyun

healthy

sign

ificant

head

injury

38Com

bat40

MVC30

Acciden

t20

Terrorism

10

Cates

etal

11I

DSM-IV

criteria

forPTSDat

leas

tthrice

wee

klypr

oblems

withslee

pan

dnigh

tmaresw

illing

andab

leto

prov

ide

written

inform

edconsent

Elt

18yold

unstab

lemed

ical

cond

itions

sen

sitivity

toBZD

scu

rren

tBZD

use

subs

tanc

eab

useor

depe

nden

cein

past

4wk

inab

ilityto

attend

regu

larfollow

-upvisitswom

enwho

wereeither

preg

nant

orof

child-be

aringpo

tentialan

dno

tus

ingcontraceptivesde

men

tia

cogn

itivedisord

er

520

Com

bat10

0

Gelpinet

al12

IEmerge

ncyroom

admission

swithatrau

ma

ETak

ingps

ycho

trop

icmed

ications

before

thetrau

ma

coma

head

injuryloss

ofcons

ciou

sness

2946

MVCs

77

Terrorism

19

Acciden

t4

Sha

levet

al13

IDSM-III-R

criteria

forPTSD

orpa

nicdisord

ermed

ication

free

EPsych

osism

ajor

depr

ession

cur

rent

orpa

stsu

bstanc

eor

alcoho

lus

epa

tien

tswithPTSD

withsp

ontane

ouspa

nic

attack

spa

tien

tswithpa

nicdisord

erwithahistoryof

trau

ma

3439

288 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

Zatzicket

al14

I18

-84yold

Eng

lish

-spe

akingor

Spa

nish

-spe

akingpa

tien

ts

arrive

daliveat

hosp

italm

oderateto

seve

reinjuries

Eg

reater

than

oreq

ual

toge65

yoldwithafirstlisted

diag

nosisof

hipfracturem

ajor

burn

strea

tmen

tde

lays

gt24

hincarcerated

attimeof

injury

4135

White

67

Black

16

Hispa

nic13

Other3

Injury10

0

Shinet

al15

I18

-69yold

militaryve

terans

servingin

Vietnam

eraor

laterat

leas

ton

eou

tpatient

VAvisitwithaPTSD

diag

nosis

EN

oPTSD

diag

nosisin

thepr

ior2y

4250

White

65

Black

17

Hispa

nic10

Other3

Kostenet

al16

IDSM-III

criteria

forPTSDmilitaryve

terans

450

White

75

Rosen

etal

17I

femaleve

teranor

active

duty

soldier

DSM-IV

criteria

for

PTSDCAPSscoregt45

EC

oncu

rren

tPTSD

psycho

therap

yothe

rthan

briefvisits

withan

existing

therap

istor

participationin

self-help

grou

psc

hang

ein

psycho

active

med

ications

during

the2mo

before

stud

yrecruitm

entsu

bstanc

ede

pend

ence

notin

remission

forat

leas

t3mo

curren

tps

ycho

ticsymptom

sor

man

iab

ipolar

disord

erpr

ominen

tcu

rren

tsu

icidal

orho

micidal

idea

tion

cogn

itiveim

pairmen

tcu

rren

tinvo

lvem

entin

violen

trelation

shipself-m

utilationwithin

thepa

st6mo

100

White

55

Black

33

Hispa

nic

6Other7

Sex

ual93

Acciden

t82

Disas

ter

72

Com

bat25

Jone

set

al18

Igt18

yold

mecha

nicallyve

ntilated

IC

Uleng

thof

stay

atleas

t48

hEP

rior

PTSDa

dmittedaftersu

icideattemptp

reex

isting

orconc

omitan

tps

ycho

ticillness

reside

sgt30

kmfrom

hosp

ital

unresolved

confus

ionen

rolled

inan

othe

rresearch

stud

y

6138

Life-threaten

ingmed

ical

condition

10

0

Sam

uelson

etal

19I

gt18

yold

mecha

nicallyve

ntilated

ge

neralIC

Uleng

thof

stay

atleas

t24

hEH

eadinjuryps

ycho

ticillness

men

talretard

ation

intoxication

adm

ittedaftersu

icideattempth

earing

spe

ech

disa

bilityno

n-Swed

ishsp

eaking

tran

sferredto

anothe

rho

spitalm

echa

nicallyve

ntilated

atdischa

rge

mecha

nically

ventilated

gt24

hpr

eadm

ission

6348

Life-threaten

ingmed

ical

condition

10

0

Bienv

enuet

al20

IMecha

nicallyve

ntilated

withacutelung

injury

EN

eurologicalsp

ecialtyIC

Upr

eexistingillnesswithalife

expe

ctan

cylt6mo

pree

xistingcogn

itiveim

pairmen

tor

commun

icationlang

uage

barriersn

ofixe

dad

dress

tran

sfer

toastud

ysite

ICU

withpr

eexistingacutelung

injury

gt24

h

45

Life-threaten

ingmed

ical

condition

10

0

Journal of Psychiatric Practice Vol 21 No 4 July 2015 289

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

umaTyp

e(

)

Rothb

aum

etal

8IIraq

andor

Afgha

nistan

veterans

DSM-IVcriteria

forPTSD

dueto

militarytrau

mave

rified

throug

hdischa

rgepa

pers

discon

tinu

edtaking

long

-actingBZD

sfor1moan

dsh

ort-

acting

BZD

sfor2wkbe

fore

screen

ing

stab

ledo

sesof

othe

rps

ycho

trop

icmed

ications

forat

leas

t2wkbe

fore

thestud

ywritten

inform

edconsent

EMed

ically

unstab

leps

ycho

sis

bipo

lardisord

erc

urrent

suicidal

risk

cu

rren

talcoho

lor

drug

depe

nden

ce

preg

nanc

ygluc

ocorticoids

BZD

sch

ronicallyus

edop

ioids

354

Black

50

White

42

Hispa

nic5

Other3

Com

bat10

0

Mellm

anet

al9

IAdm

ittedto

leve

lItrau

macenterr

ecallof

trau

ma

atleas

tmod

erateim

pairmen

tof

slee

pinitiation

ormainten

ance

mee

tfullcriteria

forat

leas

t2PTSD

symptom

clus

ters

inDSM-IVwilling

andab

leto

prov

idewritten

inform

edcons

ent

EIn

toxication

attimeof

trau

ma

braininjurypr

eexisting

psychiatricdisord

ers

3636

Hispa

nic8

2White

9Black

9

MVC68

Assau

lt2

3Acciden

t9

Braun

etal

10I

DSM-III

criteria

forPTSDwilling

andab

leto

prov

ide

written

inform

edconsentfreeof

psycho

trop

icmed

ications

atleas

t2wkbe

fore

stud

yEPhy

sicallyun

healthy

sign

ificant

head

injury

38Com

bat40

MVC30

Acciden

t20

Terrorism

10

Cates

etal

11I

DSM-IV

criteria

forPTSDat

leas

tthrice

wee

klypr

oblems

withslee

pan

dnigh

tmaresw

illing

andab

leto

prov

ide

written

inform

edconsent

Elt

18yold

unstab

lemed

ical

cond

itions

sen

sitivity

toBZD

scu

rren

tBZD

use

subs

tanc

eab

useor

depe

nden

cein

past

4wk

inab

ilityto

attend

regu

larfollow

-upvisitswom

enwho

wereeither

preg

nant

orof

child-be

aringpo

tentialan

dno

tus

ingcontraceptivesde

men

tia

cogn

itivedisord

er

520

Com

bat10

0

Gelpinet

al12

IEmerge

ncyroom

admission

swithatrau

ma

ETak

ingps

ycho

trop

icmed

ications

before

thetrau

ma

coma

head

injuryloss

ofcons

ciou

sness

2946

MVCs

77

Terrorism

19

Acciden

t4

Sha

levet

al13

IDSM-III-R

criteria

forPTSD

orpa

nicdisord

ermed

ication

free

EPsych

osism

ajor

depr

ession

cur

rent

orpa

stsu

bstanc

eor

alcoho

lus

epa

tien

tswithPTSD

withsp

ontane

ouspa

nic

attack

spa

tien

tswithpa

nicdisord

erwithahistoryof

trau

ma

3439

288 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

Zatzicket

al14

I18

-84yold

Eng

lish

-spe

akingor

Spa

nish

-spe

akingpa

tien

ts

arrive

daliveat

hosp

italm

oderateto

seve

reinjuries

Eg

reater

than

oreq

ual

toge65

yoldwithafirstlisted

diag

nosisof

hipfracturem

ajor

burn

strea

tmen

tde

lays

gt24

hincarcerated

attimeof

injury

4135

White

67

Black

16

Hispa

nic13

Other3

Injury10

0

Shinet

al15

I18

-69yold

militaryve

terans

servingin

Vietnam

eraor

laterat

leas

ton

eou

tpatient

VAvisitwithaPTSD

diag

nosis

EN

oPTSD

diag

nosisin

thepr

ior2y

4250

White

65

Black

17

Hispa

nic10

Other3

Kostenet

al16

IDSM-III

criteria

forPTSDmilitaryve

terans

450

White

75

Rosen

etal

17I

femaleve

teranor

active

duty

soldier

DSM-IV

criteria

for

PTSDCAPSscoregt45

EC

oncu

rren

tPTSD

psycho

therap

yothe

rthan

briefvisits

withan

existing

therap

istor

participationin

self-help

grou

psc

hang

ein

psycho

active

med

ications

during

the2mo

before

stud

yrecruitm

entsu

bstanc

ede

pend

ence

notin

remission

forat

leas

t3mo

curren

tps

ycho

ticsymptom

sor

man

iab

ipolar

disord

erpr

ominen

tcu

rren

tsu

icidal

orho

micidal

idea

tion

cogn

itiveim

pairmen

tcu

rren

tinvo

lvem

entin

violen

trelation

shipself-m

utilationwithin

thepa

st6mo

100

White

55

Black

33

Hispa

nic

6Other7

Sex

ual93

Acciden

t82

Disas

ter

72

Com

bat25

Jone

set

al18

Igt18

yold

mecha

nicallyve

ntilated

IC

Uleng

thof

stay

atleas

t48

hEP

rior

PTSDa

dmittedaftersu

icideattemptp

reex

isting

orconc

omitan

tps

ycho

ticillness

reside

sgt30

kmfrom

hosp

ital

unresolved

confus

ionen

rolled

inan

othe

rresearch

stud

y

6138

Life-threaten

ingmed

ical

condition

10

0

Sam

uelson

etal

19I

gt18

yold

mecha

nicallyve

ntilated

ge

neralIC

Uleng

thof

stay

atleas

t24

hEH

eadinjuryps

ycho

ticillness

men

talretard

ation

intoxication

adm

ittedaftersu

icideattempth

earing

spe

ech

disa

bilityno

n-Swed

ishsp

eaking

tran

sferredto

anothe

rho

spitalm

echa

nicallyve

ntilated

atdischa

rge

mecha

nically

ventilated

gt24

hpr

eadm

ission

6348

Life-threaten

ingmed

ical

condition

10

0

Bienv

enuet

al20

IMecha

nicallyve

ntilated

withacutelung

injury

EN

eurologicalsp

ecialtyIC

Upr

eexistingillnesswithalife

expe

ctan

cylt6mo

pree

xistingcogn

itiveim

pairmen

tor

commun

icationlang

uage

barriersn

ofixe

dad

dress

tran

sfer

toastud

ysite

ICU

withpr

eexistingacutelung

injury

gt24

h

45

Life-threaten

ingmed

ical

condition

10

0

Journal of Psychiatric Practice Vol 21 No 4 July 2015 289

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

Zatzicket

al14

I18

-84yold

Eng

lish

-spe

akingor

Spa

nish

-spe

akingpa

tien

ts

arrive

daliveat

hosp

italm

oderateto

seve

reinjuries

Eg

reater

than

oreq

ual

toge65

yoldwithafirstlisted

diag

nosisof

hipfracturem

ajor

burn

strea

tmen

tde

lays

gt24

hincarcerated

attimeof

injury

4135

White

67

Black

16

Hispa

nic13

Other3

Injury10

0

Shinet

al15

I18

-69yold

militaryve

terans

servingin

Vietnam

eraor

laterat

leas

ton

eou

tpatient

VAvisitwithaPTSD

diag

nosis

EN

oPTSD

diag

nosisin

thepr

ior2y

4250

White

65

Black

17

Hispa

nic10

Other3

Kostenet

al16

IDSM-III

criteria

forPTSDmilitaryve

terans

450

White

75

Rosen

etal

17I

femaleve

teranor

active

duty

soldier

DSM-IV

criteria

for

PTSDCAPSscoregt45

EC

oncu

rren

tPTSD

psycho

therap

yothe

rthan

briefvisits

withan

existing

therap

istor

participationin

self-help

grou

psc

hang

ein

psycho

active

med

ications

during

the2mo

before

stud

yrecruitm

entsu

bstanc

ede

pend

ence

notin

remission

forat

leas

t3mo

curren

tps

ycho

ticsymptom

sor

man

iab

ipolar

disord

erpr

ominen

tcu

rren

tsu

icidal

orho

micidal

idea

tion

cogn

itiveim

pairmen

tcu

rren

tinvo

lvem

entin

violen

trelation

shipself-m

utilationwithin

thepa

st6mo

100

White

55

Black

33

Hispa

nic

6Other7

Sex

ual93

Acciden

t82

Disas

ter

72

Com

bat25

Jone

set

al18

Igt18

yold

mecha

nicallyve

ntilated

IC

Uleng

thof

stay

atleas

t48

hEP

rior

PTSDa

dmittedaftersu

icideattemptp

reex

isting

orconc

omitan

tps

ycho

ticillness

reside

sgt30

kmfrom

hosp

ital

unresolved

confus

ionen

rolled

inan

othe

rresearch

stud

y

6138

Life-threaten

ingmed

ical

condition

10

0

Sam

uelson

etal

19I

gt18

yold

mecha

nicallyve

ntilated

ge

neralIC

Uleng

thof

stay

atleas

t24

hEH

eadinjuryps

ycho

ticillness

men

talretard

ation

intoxication

adm

ittedaftersu

icideattempth

earing

spe

ech

disa

bilityno

n-Swed

ishsp

eaking

tran

sferredto

anothe

rho

spitalm

echa

nicallyve

ntilated

atdischa

rge

mecha

nically

ventilated

gt24

hpr

eadm

ission

6348

Life-threaten

ingmed

ical

condition

10

0

Bienv

enuet

al20

IMecha

nicallyve

ntilated

withacutelung

injury

EN

eurologicalsp

ecialtyIC

Upr

eexistingillnesswithalife

expe

ctan

cylt6mo

pree

xistingcogn

itiveim

pairmen

tor

commun

icationlang

uage

barriersn

ofixe

dad

dress

tran

sfer

toastud

ysite

ICU

withpr

eexistingacutelung

injury

gt24

h

45

Life-threaten

ingmed

ical

condition

10

0

Journal of Psychiatric Practice Vol 21 No 4 July 2015 289

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

2Summar

yof

Par

ticipan

tChar

acteristicsin

Rev

iewed

Stu

diesof

Ben

zodiaze

pin

esin

PTSD

(con

tinued

)

Refer

ence

sIn

clusion

(I)and

Exc

lusion

(E)Criteria

Mea

nAge

(y)

Fem

ale

()

Race

()

Tra

uma

Typ

e(

)

gt5dof

mecha

nicalve

ntilationbe

fore

acutelung

injurya

physicianorde

rforno

escalation

ofIC

Ucare

atthetimeof

stud

yeligibility

Baran

yiet

al21

IPatientsreceivingsolid-orga

ntran

splantsan

dIC

Utrea

tmen

t52

31

White

100

Life-threaten

ingmed

ical

condition

10

0

Girardet

al22

IIn

med

ical

orcorona

ryIC

Umecha

nicallyve

ntilated

EN

eurologicaldiseas

eim

pairingcogn

itivefunc

tion

men

tal

retard

ation

nonndash

Eng

lish

spea

king

sens

oryde

ficits

impa

iringcommun

ication

5253

Black

16

Life-threaten

ingmed

ical

condition

10

0

Van

Minne

net

al23

IDSM-III-R

criteria

forPTSD

for3moor

more

3774

Sex

ual22

Violence21

Battering

19

Acciden

t14

MVC13

Other11

McG

heeet

al24

IThe

rmal

injuries

during

militaryde

ploy

men

tssu

rgery

within30

dof

injury

betw

een20

04an

d20

08P

CL

betw

een

2004

and20

08

Com

bat10

0

Sha

levan

dRog

el-

Fuc

hs25

IDSM-III-R

criteria

forPTSDreceivingclon

azep

amor

med

icationfree

EP

anic

disord

ers

ubstan

cede

pend

ence

3511

BZD

indica

tesbenz

odiazepine

CAPSC

linician-administeredPTSD

Sca

leD

SMD

iagn

ostican

dStatistical

Man

ual

ofMen

talDisorders

ICUintensive

care

unit

MVCmotor

vehicle

collisionP

CLPTSD

ChecklistPTSDpo

sttrau

matic

stress

disorderVAVeteran

sAffairs

290 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

(κ=089) nonrandomized clinical trials 100(κ=100) observational studies 977 (κ=063) Thepercent agreement for data abstraction was 761

After excluding ineligible articles 18 studies wereselected for review and are summarized in Table 1

Sample sizes varied from 6 to 2931 with a total of5236 completers Because not every study reportedthe same characteristics the following numberswere calculated using available data for partic-ipants as summarized in Table 2 Participants

TABLE 3 Summary of Outcomes of Reviewed Studies of Benzodiazepines in PTSD

Randomized-controlled

Trials

Double-blind Other

NonrandomizedClinical Trials

ObservationalStudies

Level ofEvidence

Efficacy 1 1 0 0 DAnxiety short term 1 0 0 0 DSleep short term 0 1 0 0 DPTSD core symptoms 0 0 0 0 Ddagger

Long term 0 0 0 0 Ddagger

Inefficacy 2 2 2 12 ADaggerOverall severity 2 1 1 10 ADaggerStartle reflex 1 0 1 1 BPsychotherapy outcomes 1 0 0 2 BDepression 1 0 1 0 BOverall well-being 1 0 0 0 BSleep 0 2 0 0 CNightmares 0 1 0 0 CAnxiety 0 0 1 1 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CSocial functioning 0 0 0 1 C

Worsened outcomes 1 1 1 10 BOverall severity 1 1 1 9 BPsychotherapy outcomes 1 0 0 2 BDepression 0 0 1 0 CAggression 0 0 0 2 CSubstance use 0 0 0 1 CAnxiety 0 0 0 1 C

Note that studies with multiple measures or mixed results are counted more than once and bolded rows summarize the studies inthe areas listed belowThe findings of the selected articles were categorized according to levels of scientific evidence based on clinical practice guidelinesfrom the US Department of Health and Human Services6

A Multiple double-blind placebo-controlled trials and a confirmatory meta-analysis (in addition to level B of evidence)B At least 1 double-blind placebo-controlled trial (in addition to level C of evidence)C Anecdotal reports case series and open trials in addition to expert endorsement or consensusD Few case reports without any expert panel endorsement

No expert consensus supports this findingdaggerNothing but case reports supports this findingDaggerSupported by meta-analysisPTSD indicates posttraumatic stress disorder

Journal of Psychiatric Practice Vol 21 No 4 July 2015 291

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

Rothb

aum

etal

82

3CAPSpo

sttrea

tmen

t35

34minus002

14minus049

34045

052

3CAPS3mo

2923

minus052

97minus107

70001

762

3CAPS6mo

2523

minus057

87minus114

50minus001

242

3CAPS12

mo

2220

minus022

17minus082

73038

382

3PCLpo

sttrea

tmen

t35

34minus013

70minus060

89033

502

3PCL3mo

2923

minus050

31minus105

03004

422

3PCL6mo

2523

minus067

87minus124

50minus011

242

3PCL12

mo

2220

minus031

91minus092

47028

642

3PTSD

posttrea

tmen

t35

34minus001

72minus048

92045

472

3PTSD

3mo

2923

minus077

67minus132

40minus022

952

3PTSD

6mo

2523

minus070

07minus126

70minus013

442

3PTSD

12mo

2220

minus017

63minus078

19042

922

3CAPSpo

sttrea

tmen

tch

ange

3534

minus018

51minus065

71028

69

23

PCLpo

sttrea

tmen

tch

ange

3534

minus020

41minus067

61026

792

3CAPS12

moch

ange

2220

minus002

77minus063

32057

792

3PCL12

moch

ange

2220

minus003

20minus063

76057

352

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus021

29minus076

97034

39

Mellm

anet

al9

13

PTSD

diag

nosis

1111

minus057

74minus141

31025

841

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus057

74minus141

31025

84

3CAPS

1111

minus028

76minus112

34054

813

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus043

25minus126

82040

33

Braun

etal

102

3PTSD

Scale

Intrus

ion

1010

054

33minus033

32141

992

3PTSD

Scale

Avo

idan

ce10

10016

32minus071

33103

982

3HAM-D

1010

002

81minus084

84090

472

3HAM-A

1010

068

08minus019

58155

732

3IE

SIn

trus

ion

1010

052

41minus035

25140

062

3IE

SAvo

idan

ce10

10011

03minus076

63098

682

3VAS

1010

052

17minus035

48139

822

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

052

17minus035

48139

82

Cates

etal

112

3Sleep

onsetpr

oblems

66

113

03minus000

13226

192

3Mid-sleep

awak

ening

66

021

96minus091

20135

122

3Early-m

orning

awak

ening

66

074

58minus038

58187

742

3Difficu

ltyfallingas

leep

66

050

21minus062

95163

37

292 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

Sleep

quan

tity

66

030

16minus083

00143

322

3Sleep

quality

66

041

10minus072

06154

262

3Distressing

drea

ms

freq

uenc

y6

6minus018

51minus131

67094

65

23

Distressing

drea

ms

intens

ity

66

minus013

81minus126

97099

36

23

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

035

63minus077

53148

79

Gelpinet

al12

13

PTSD

diag

nosis

1313

minus129

99minus206

86minus053

111

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus129

99minus206

86minus053

11

3Major

depr

ession

diag

nosis

1313

minus152

75minus229

63minus075

873

Sim

pleph

obia

diag

nosis

1313

043

64minus033

23120

523

Socialph

obia

diag

nosis

1313

024

25minus052

62101

133

Alcoh

olab

usediag

nosis

1313

minus040

82minus117

70036

053

Pan

icdisord

erdiag

nosis

1313

minus040

82minus117

70036

053

Dysthym

ia13

13040

82minus036

05117

703

STAI-State

1313

minus015

11minus091

99061

763

STAI-Trait

1313

minus017

43minus094

31059

453

IESIn

trus

ion

1313

minus029

33minus106

20047

553

IESAvo

idan

ce13

13027

80minus049

08104

683

BDI

1313

minus036

91minus113

79039

963

MIS

S13

13minus046

28minus123

15030

603

HR

1313

037

29minus039

59114

173

Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus023

38minus100

26053

50

Sha

levet

al13

23

HAM-A

99

144

30051

91236

702

3Resting

EMG

99

minus009

74minus102

13082

662

3Bas

eEMG

99

047

04minus045

35139

442

3EMG

1sttone

resp

onse

99

043

04minus049

35135

442

3EMG

15th

tone

resp

onse

99

minus024

95minus117

34067

452

3Mea

nEMG

resp

onse

99

029

52minus062

88121

912

3EMG

resp

onse-TTC

99

minus003

71minus096

11088

682

3Resting

SC

99

037

22minus055

18129

612

3Bas

eSC

99

minus095

85minus188

25minus003

462

3SC

1sttone

resp

onse

99

minus097

37minus189

76minus004

97

Journal of Psychiatric Practice Vol 21 No 4 July 2015 293

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

TABLE

4Summar

yof

Effec

tSizes

(ES)an

dCon

fiden

ceIn

terv

als(C

I)byStu

dyan

dOutcom

eMea

sure

(con

tinued

)

Sample

Size(n

)

Refer

ence

sHyp

otheses

(H1H

2H

3)

Outcom

eMea

sure

BZD

Con

trol

ES

95

CI

23

SC

15th

tone

resp

onse

99

007

89minus084

51100

282

3Mea

nSC

resp

onse

99

minus013

90minus106

30078

492

3SC

resp

onse-TTC

99

minus022

20minus114

59070

202

3Resting

HR

99

011

13minus081

27103

522

3Bas

eHR

99

minus047

93minus140

32044

472

3Mea

nHR

resp

onse

99

minus036

32minus128

71056

082

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus006

73minus099

12085

67

Zatzicket

al14

13

PCL

9928

32minus037

11minus057

15minus017

07Rosen

etal

172

3CAPSps

ycho

therap

y29

114

001

93minus038

83042

702

3CAPSfollow

-up

2911

4minus019

44minus060

20021

332

3PCLps

ycho

therap

y29

114

minus047

28minus088

05minus006

522

3PCLfollow

-up

2911

4minus010

96minus051

73029

802

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus015

20minus055

96025

56

Sam

uelson

etal

191

3IE

S-R

7515

1minus040

58minus068

27minus012

89Baran

yiet

al21

13

PTSS-10

2210

4minus045

70minus091

70000

29McG

heeet

al24

13

PCL

142

69minus009

66minus038

43019

10Sha

levan

dRog

el-

Fuc

hs25

23

STAI

99

minus015

92minus108

32076

472

3MIS

S9

9minus067

77minus160

16024

632

3IE

S9

9minus068

84minus161

24023

552

3HR

baseline

99

minus025

58minus117

98066

812

3HR

1sttone

resp

onse

99

minus074

62minus167

01017

782

3HR

15th

tone

resp

onse

99

minus004

04minus096

44088

352

3SC

1sttone

resp

onse

99

minus004

43minus096

83087

962

3SC

15th

tone

resp

onse

99

minus034

31minus126

70058

092

3SC

resp

onse-TTC

99

minus038

09minus130

48054

312

3EMG

1sttone

resp

onse

99

minus070

93minus163

33021

462

3EMG

15th

tone

resp

onse

99

minus026

36minus118

76066

032

3EMG

resp

onse-TTC

99

minus060

23minus152

63032

172

3Poo

ledstud

y(m

edianES

andCIby

hypo

thesis)

minus036

20minus128

59056

20

BDIindicates

BeckDep

ressionIn

ventoryBZDbenzodiazepine

CAPSC

linician-administeredPTSD

Sca

leEMGelectrom

yograp

hy

HAM-A

Ham

iltonRating

Sca

leforAnxiety

HAM-D

Ham

iltonRatingSca

leforDep

ressionH

Rh

eart

rateIESImpa

ctof

Event

Sca

leM

ISSM

ississippi

RatingSca

leforPTSDP

CLP

TSD

ChecklistPTSDp

osttra

umatic

stress

disorderP

TSSP

osttra

umatic

StressSyn

dromeSca

leS

Cskinconductan

ceS

TAIState-Tra

itAnx

iety

Inventory

TTCtrials

tohab

ituationcriterionVASvisu

alan

alog

scale

294 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

survived 1 or more of the following physical injuries(n=2979) life-threatening medical conditions(n=841) combat-related trauma (n=431) sexualtrauma (n=277) disaster exposure (n=203) andother traumas (n=47) The majority of the partic-ipants (approximately 67) survived a physicalinjury The mean age was approximately 44 yearsand approximately 38 were women

Qualitative Synthesis

Table 3 compares study designs outcomes andlevels of evidence

The studies supporting BZD efficacy for PTSDdemonstrate short-term improvement in sleep9 andanxiety10

The studies demonstrating BZD inefficacy forPTSD demonstrate no significant improvementcompared with controls for overall severity of PTSDsymptoms8ndash10121416ndash24 startle reflex81325 psycho-therapy outcomes81723 depression1012 overallwell-being10 sleep911 nightmares11 anxiety1216

aggression15ndash16 substance use16 and social functio-ning16

The studies showing BZDs being associated withworsened PTSD outcomes demonstrate worsenedoverall severity of PTSD symptoms8ndash9121416ndash23 psy-chotherapy outcomes81723 depression12 aggression15ndash16

substance use16 and anxiety16

Meta-analysis

Twelve studies (4 RCTs 2 nonrandomized 6observational) obtained data sufficient for estimat-ing ESs for PTSD-associated symptoms Individualoutcome measures and their associated ESs and95 CIs are shown in Table 4 Figure 2 summarizesthe ESs and CIs in forest plots by study forhypotheses H1 H2 and H3 Results are presented sothat a positive ES corresponds to BZDs improvingPTSD-associated outcomes and a negative ES cor-responds to BZDs worsening PTSD-associated out-comes The row labeled ldquoPOOLEDrdquo contains theestimated ES and 95 CI for the meta-analysisThe row labeled ldquoRCTs onlyrdquo illustrates the resultswhen restricted to only the 4 RCTs (denoted byldquoRCTrdquo to the right of the corresponding CI)

The estimated ES of BZDs on the development ofPTSD in trauma patients was minus03974 with a 95

CI of (minus06057 minus01891) Thus we reject H1 andconclude that BZDs increase the likelihood ofdeveloping PTSD when taken by trauma patients

The estimated ES of BZDs on PTSD-associatedsymptoms in PTSD patients was minus00839 with a95 CI of (minus03544 01866) Thus we have insuffi-cient evidence to reject H2 That is we have insuf-ficient evidence to conclude that BZDs alleviatePTSD-associated symptoms when taken by patientswho already have PTSD

The estimated ES of BZDs on PTSD-associatedsymptoms in trauma patients with and withoutPTSD (here ldquosymptomsrdquo includes all PTSD-relatedoutcomes including PTSD diagnosis for traumapatients who were not previously diagnosed withPTSD) was minus02798 with a 95 CI of (minus03981minus01616) Thus we reject H3 and conclude thatBZDs have an overall adverse impact in the pre-vention and treatment of PTSD When the analysiswas restricted only to the 4 RCTs the estimated ESof BZDs on PTSD-associated symptoms in traumapatients with and without PTSD was minus00422 witha 95 CI of (minus04505 03661) Thus the RCTs alonedo not provide sufficient evidence to reject H3 Onthe basis of the RCTs alone we conclude that thereis no evidence that BZDs alleviate PTSD-associatedsymptoms in PTSD patients or prevent the devel-opment of PTSD in trauma patients

DISCUSSION

Inefficacy (Level of Evidence A)

Before our study the ceiling for the level of evidencefor inefficacy was at B due to the lack of a con-firmatory meta-analysis However this meta-anal-ysis and at least 1 measure in every study that wasreviewed including all 4 RCTs of BZDs inPTSD8ndash11 suggest a lack of efficacy of BZDs forPTSD All PTSD-specific measures that wereused such as the Clinician-administered PTSDScale (CAPS) and the PTSD Checklist demon-strated that BZDs are at best not significantlydifferent from placebo or no BZD for PTSD BZDinefficacy is also endorsed by every availablePTSD practice guideline These findings are likelyexplained in part by the tolerance and cognitiveeffects associated with BZDs and also indicate thatBZDs appear to inadequately target PTSD patho-physiology

Journal of Psychiatric Practice Vol 21 No 4 July 2015 295

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

A major disadvantage of BZDs is that tolerancedevelops to hypnotic and myorelexant effects withindays to weeks and to anticonvulsant and anxiolyticeffects within weeks to months26ndash28 ThereforeBZDs are unlikely to be effective long-term hyp-notics or anxiolytics which is confirmed by severalgeneral studies of BZDs for sleep and anxiety2728

Tolerance to BZDs is a distinct problem in PTSDbecause most patients have symptoms that persistfor longer than 3 months29

BZDs may be ineffective for PTSD because ofamnestic effects that unintentionally target learninghow to cope with PTSD symptoms rather than trau-matic memories Although therapeutic effectsdecrease with tolerance cognitive effects (ie BZD-induced neurocognitive disorder) usually persist forattention memory and learning28 Cognitiveimpairments are more common with long-term useand high doses but they can also occur with short-term use and low doses2829 Unfortunately PTSD isa risk factor for BZD-induced neurocognitive dis-order as are conditions that are often comorbid withPTSD such as SUD neurocognitive disorders(including TBI) and psychotic bipolar and depres-sive disorders29

BZDs may be ineffective for PTSD because thepathophysiology of PTSD differs from that of theanxiety disorders for which BZDs have some effi-cacy Studies of flumazenil which have demon-strated that GABA-receptor antagonism inducespanic in patients with panic disorder but not inhealthy controls or patients with PTSD3031 suggestthat the pathophysiology underlying anxiety inPTSD is different from that in panic disorderdespite experiential similarities Researchers in 2 ofthe studies that were reviewed1325 concluded thatwhile locus ceruleus dysregulation is implicated inboth panic disorder and PTSD the amygdala andhippocampus are also implicated in PTSD anxietyShalev et al13 speculated that these structures maybe less responsive to BZDs than the locus ceruleusIn addition rather than targeting specific impli-cated structures BZDs indiscriminately depressglobal brain function (including structures such asthe prefrontal cortex that are already hypoactive inPTSD and which when functioning adequatelyallow for various cognitive processes and modu-lation of the amygdala) Therefore anxiety in PTSDmay be different than anxiety in other disordersand may require different treatments

Worsened Outcomes (Level of Evidence B)

Thirteen of the studies that were reviewed(including 2 RCTs) several practice guidelines andsome case reports suggest that BZDs have the riskof worsening the severity and prognosis of PTSDAll but 21024 of the 13 studies that used PTSD-specific measures (eg CAPS PTSD Checklist)demonstrated that BZDs are associated with worseoverall severity of symptoms when compared withplacebo or no BZD Potential biopsychosocialexplanations for BZDs worsening PTSD outcomesinclude discontinuation symptoms disruption ofnormal stress responses avoidance of cognitive andemotional processing of trauma and worsening ofunderlying PTSD pathophysiology (eg effects onthe hypothalamic-pituitary-adrenal [HPA] axis andon gamma-aminobutyric acid [GABA] glutamateand serotonin systems)

Discontinuation symptoms provide a model for howBZDs may worsen PTSD Chronic BZD use leadsto GABA-receptor desensitization and glutamatereceptor sensitization2632 When BZDs are suddenlydiscontinued in tolerant patients the patients expe-rience decreased inhibition from GABA and hyper-active excitation from glutamate causing withdrawalsymptoms that can mimic and worsen PTSD symp-toms (eg anxiety insomnia agitation autonomichyperactivity perceptual disturbances) Althoughless severe than withdrawal rebound symptomswhich are the inverse of the therapeutic effects ofBZDs and include worsened anxiety insomnia andirritability can occur shortly after discontinuationincluding between doses (especially with BZDs thathave a short half-life) Discontinuation symptoms arecommonly misinterpreted as a worsening of under-lying conditions while the iatrogenic contribution ofBZDs is overlooked272833 Although anxiety insom-nia and irritability may be temporarily exacerbatedduring withdrawal general studies of BZDs havedemonstrated that these symptoms are usually lesssevere after discontinuation than while takingBZDs2728 Both PTSD and BZD use have beenassociated with decreased GABA-receptor sensitivityand hyperactive glutamatergic activity34 BecauseBZDs can synergistically worsen underlying PTSDpathophysiology BZDs may actually exacerbatePTSD symptoms rather than improve them

One of the most consistent findings in this reviewwhich was supported by an RCT9 a nonrandomized-

296 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

controlled trial12 6 observational studies and a sys-tematic review of PTSD risk factors in patients on anintensive care unit35 is that BZD use after traumaincreases the risk of developing PTSD Only 2 studiesof trauma patients receiving BZDs2024 did not findan increased risk for PTSD although both suggestedinefficacy for PTSD prevention Those studies pro-viding sufficient data91219 suggest that the risk ofdeveloping PTSD is 2 to 5 times higher in groupsreceiving BZDs than in control groups BZDs likelydisrupt normal HPA axis stress responses andmemory-related processes Interfering with normalevolutionarily advantageous physiological responsesseems to increase vulnerability to subsequent stressand worsen outcomes in PTSD36 Three animalstudies43337 have demonstrated that BZDs increaseposttraumatic behaviors upon subsequent exposureto stress suggesting that the fear-sensitizing effectsof BZDs may act synergistically with trauma-relatedfear creating a generalized fear response to sub-sequent stressors (eg trauma-related cues) Despitetheoretical predictions that BZDs might preventthe development of PTSD after trauma (eg byinhibiting memory consolidation and preventingstress-induced changes in the noradrenergic sys-tem)12 no studies support BZDs for PTSD pre-vention and this review suggests that the short-termantistress effects of BZDs may actually increase thelong-term risk of PTSD In hindsight Gelpin et al12

acknowledged

The inhibitory effect of benzodiazepines onmemory acquisition is mostly anterogradeHence benzodiazepines do not alter memoryfor prior episodes and therefore should nothave affected traumatic memories whenadministered several days after the traumaMoreover recovery from trauma should not beequated with forgetting but rather adaptationreappraisal and learning Administered duringthe recovery phase benzodiazepines may infact interfere with such relearning hellip it may beargued that early treatment with benzodiaze-pines negatively affected survivors who mighthave otherwise recovered (p 393)

Three studies examined the effects of BZDs inpatients receiving psychotherapy Van Minnenet al23 found that daily BZD use was associatedwith worse outcomes and Rosen et al17 and

Rothbaum et al8 had mixed results (ie inefficacy orworsening depending on whether measures wererated by observers or patients) Rather than aug-menting psychotherapy BZDs seem to do nothingor to inhibit recovery Evidence-based trauma-focused psychotherapies (eg prolonged exposurecognitive processing therapy) require that patientsexperience and then master anxiety BZDs canimpair that experience by numbing emotionsdecreasing learning efficiency and inhibitingmemory processing of material learned in ther-apy1738 BZD-induced ldquoemotional anesthesiardquo26

directly interferes with the therapeutic effects ofexposure to anxiety-provoking stimuli (in psycho-therapy or the natural environment) by inhibitingfear activation a ldquonecessary condition for effectiveexposure therapyrdquo23 Several animal and humanstudies have demonstrated that BZDs interferewith fear extinction which is critical to exposuretherapy23940 For fear extinction to occur patientsmust emotionally and cognitively process theexperience of anxiety but BZDs allow patients toavoid these processes Some patients with PTSDuse distraction techniques to avoid internalreminders of trauma some rarely leave places ofcomfort to avoid external reminders and othersengage in reckless behaviors to ldquoescaperdquo29 BZDsmay provide another form of avoidance an attemptto self-medicate hyperarousal numb feelings sup-press memories and escape thoughts Overcomingavoidance behaviors is essential for successfultreatment but it is often the patientrsquos largestobstacle for recovery As Herman41 explains

The helpless person escapes from her situationnot by action in the real world but rather byaltering her state of consciousness hellip Trauma-tized people who cannot spontaneously disso-ciate may attempt to produce similar numbingeffects by using alcohol or narcotics hellipAlthough dissociative alterations in conscious-ness or even intoxication may be adaptive atthe moment of total helplessness they becomemaladaptive once the danger is past Becausethese altered states keep the traumatic experi-ence walled off from ordinary consciousnessthey prevent the integration necessary forhealing hellip They narrow and deplete thequality of life and ultimately perpetuate theeffects of the traumatic event (p 44)

Journal of Psychiatric Practice Vol 21 No 4 July 2015 297

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Because an avoidant coping style is a poor prog-nostic factor for trauma-related disorders29 andBZDs are inherently avoidant (eg they inhibitcognitive processing and induce emotional numb-ing) BZDs may prolong and worsen PTSD

Two studies that were reviewed measuredaggression both of which found that BZDs wereassociated with aggression in some patients withPTSD1516 In general BZDs have been known tocause ldquoparadoxical reactionsrdquo (eg behavioral dis-inhibition impulsivity irritability aggression) inwhich patients may engage in uncharacteristicbehaviors such as assaults theft or sexual indis-cretions without any history of similar behaviorsbefore use or after discontinuation26324243 This istroublesome for patients with PTSD who oftenalready display irritability aggression and recklessbehavior Proposed mechanisms for paradoxicalreactions include rebound irritability inhibition ofserotonin regulation inhibition of emotional reac-tivity to aversive events that deters behavioralactivation and inhibition of cognitive processing inwhich causal associations are formed betweenbehaviors and their consequences3242 Risk factorsfor paradoxical reactions include several conditionscommon in PTSD SUD (especially alcohol use dis-order) neurocognitive disorders (especially TBI)anxiety disorders (comorbid to and includingPTSD) previous impulsivity and previous aggres-sion2151640 Unfortunately factors such as SUDTBI and comorbid anxiety disorders are also cor-related with increased prescription of BZDs forPTSD1239

Two of the studies that were reviewed measureddepression Braun et al10 found that BZDs wereineffective for depression in PTSD and Gelpinet al12 found that BZD use after trauma increasedthe risk of developing major depressive disorder Ingeneral BZDs have been known to cause or worsendysphoria and suicidality (ie BZD-induced depres-sive disorder) even in individuals without a historyof depression5394344 Unfortunately although thetherapeutic effects of BZDs decrease with tolerancedepression and impulsivity with high suicidal riskcommonly persist27 The mechanisms responsiblefor BZD-induced depression are a matter of spec-ulation but they may be similar to those causingparadoxical reactions (eg inhibition of serotoninregulation impulsivity) Regardless of the explan-ation the prospect of BZDs worsening depression is

of concern for patients with PTSD who commonlyhave negative moods and cognitions anhedoniasuicidality and comorbid depressive disorders

One study16 that was reviewed measured sub-stance use and the findings suggested that BZDsare associated with substance use in some patientswith PTSD Although BZDs are some of the morecommonly misused substances following traumadata about BZDs and SUD specific to patients withPTSD are limited In general 58 to 100 of thoseprescribed chronic BZDs become physicallydependent (especially with high doses and short-acting BZDs)2845 Risk factors for developing BZDuse disorder include preexisting or active SUDfamily history early onset of use medical avail-ability chronic medical conditions chronic painchronic anxiety chronic insomnia chronic dyspho-ria previous impulsivity and personalitydisorders227ndash2945 Unfortunately SUD and chronicanxiety are also correlated with increased pre-scriptions for BZDs for PTSD1239 Because BZD usedisorder develops in at least 50 of patients with ahistory of SUD who are prescribed BZDs manyauthors and organizations have declared BZDscontraindicated in all patients with histories ofSUD except during withdrawal2640 Although aprevious SUD may be the predominant risk factorwhen BZDs are continuously available drugreinforcement can lead to misuse by patients with-out any history of substance misuse46 ldquoTheirgreatest asset is also their greatest liability drugsthat work immediately tend to be addictiverdquo26 SUDoccurs in 21 to 43 of patients with PTSD47 andin as many as 50 of veterans with PTSD3 Thishigh comorbidity suggests that PTSD and SUD arefunctionally related a concept supported by severalstudies that indicate a pathway related to cortico-tropin-releasing hormone and norepinephrinewhereby PTSD precedes SUD47 The high risk ofSUD in patients with PTSD is one reason why somany authors and organizations recommendagainst treating PTSD with BZDs

Efficacy (Level of Evidence D)

A few anecdotal reports and parts of 2 RCTs supportshort-term symptomatic treatment but there is noavailable expert consensus endorsing BZDs for PTSDtreatment so the ceiling for the level of evidence is D

298 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

Although both the studies supporting efficacy areRCTs910 they had mixed findings (ie they also dem-onstrated inefficacy or worsening of PTSD) and at bestthey only supported short-term use for some PTSD-associated symptoms For example Mellman et al9

found that temazepam initially improved sleep but thatit was not significantly different from placebo after thefirst night and worsened overall PTSD severity in thelong term Braun et al10 found short-term improve-ment in anxiety (described as a ldquoslight reductionrdquoldquomodestrdquo and ldquodisappointingrdquo) but no significantdifference from placebo in any other measure (overallseverity of PTSD symptoms depression overall well-being) Other studies that were reviewed demon-strated inefficacy for sleep11 and anxiety1216 Only 1other nonanecdotal study supported efficacy Leeet al48 found that lorazepam improved intrusivesymptoms but the RCT was excluded from thisreview because the participants experienced an arti-ficial ldquotraumardquo by video and were assessed only 1 daylater (less than the 1month threshold for PTSD) Thestudy by Lee and colleagues also found no significantimprovement in anxiety depression or arousal Theauthors suggested that lorazepam is ldquoatypicalrdquo anddiffers from other BZDs such as diazepam that cantrigger intrusion Even if BZDs improve PTSD-asso-ciated symptoms on a short-term basis the benefitsare unlikely to last due to tolerance

There is no evidence besides anecdotal reports thatsupports the use of BZDs for the treatment of PTSDcore symptoms (ie intrusion avoidance hyper-arousal) or for long-term symptomatic treatment ofPTSD Many researchers have criticized the frequentcitation of case reports to justify the use of BZDs totreat patients with PTSD ldquodespite risks and lack ofstudiesrdquo11 These case reports are mostly retro-spective and based on subjective reports Patientsrsquoreports of their experiences while taking BZDs areinherently unreliable as 1 case series49 concedes

It is possible that patientsrsquo memories ofsubjective sensations while intoxicated do notcorrespond to their actual affective state Forinstance many people report euphoria after thefact with alcohol intoxication even though atthe time of intoxication they were tearful andagitated (p 374)

In the case of sleep BZDs are often credited (likealcohol) for improving sleep quality but they actually

promote sleep induction while inhibiting the deepestmost restorative stages of sleep2845 At times sub-jective reports of improvement with BZDs may reflectdistortions due to cognitive impairments or they maybe due to patients mistaking the temporary relief ofdiscontinuation symptoms for improvement of base-line symptoms or mistaking sedation for genuineimprovement of their condition

The findings of Mellman et al50 highlight theimportance of caution when extrapolating the resultsof anecdotal evidence to clinical practice In this pro-spective case series of 4 recent trauma patients withinsomnia the researchers found that short-termtemazepam was associated with improved PTSDsymptoms however this was a pilot study for Mell-man et al9 the RCT that found that short-termtemazepam increases the risk of developing PTSD Inaddition ldquobecause benzodiazepines reduce anxietywithout addressing the underlying PTSD cliniciansmay incorrectly believe the patient has improved thusdelaying definitive PTSD carerdquo40 BZDs ldquoneed to becarefully considered taking into account their poten-tial harm to the spontaneous recovery process and thetrajectory of PTSD and not only judging themaccording to their immediate (comforting) effectsrdquo36

Limitations

There was little consistency in participants diagnosticmethod trauma type recency severity interventionfollow-up or outcome measures among the studiesselected for review For example the studies con-ducted in intensive care units examined only life-threatening medical conditions18ndash2022 whereasMcGhee et al24 examined only combat-related PTSDNine articles studied the use of any BZD whereasothers studied specific agents Follow-up ranged from2 weeks to 4 years Seven studies used multipleassessment instruments and no instrument was usedin more than 4 studies These inconsistenciesresulted in heterogeneity among the studies How-ever random-effects models were used in the meta-analyses to account for this heterogeneity resultingin wider CIs for ESs than would have resulted if afixed-effects approach had been used

Our meta-analytic approach also had some limi-tations In particular publication bias if presentwould result in an underreporting of nonsignificantstudies However in the present context there is

Journal of Psychiatric Practice Vol 21 No 4 July 2015 299

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

less reason for studies with nonsignificant resultsnot to have been published as they would havesupported the view that BZDs are not harmful Anadditional potential limitation is that the meta-analytic method chosen implicitly assumes thatthere is no systematic bias across these studiesfavoring positive associations

Although there is evidence that BZDs can worsenPTSD-associated symptoms the authors cannotexclude the likelihood that those patients who weretreated with BZDs in the observational studies thatwere reviewed were more severely affected and hadworse prognoses For example the results of the

intensive care unit studies were likely confounded byindication (eg patients who are more delirious agi-tated or anxious in the ICU may be more likely toreceive higher BZD doses) Therefore BZD use may bean indicator rather than a cause of poorer prognosisHowever such confounding factors were eliminated ina study by Treggiari et al51 a RCT that found thatlower sedation in critically ill patients is associatedwith fewer PTSD symptoms (this study was excludedfrom this review because it did not distinguish BZDsfrom other sedatives) Likewise similar confoundingfactors were eliminated in the reviewed RCTs thatdemonstrated worsening of PTSD89

FIGURE 2 AndashC Summary of effect sizes (boxes) and confidence intervals (horizontal lines) ofreviewed studies of benzodiazepines (BZDs) in posttraumatic stress disorder (PTSD)

A H1 BZDs are not associated with the development of PTSD in trauma patients B H2 BZDs are not associated with PTSD-associated symptoms in patients with PTSD C H3 BZDs are not associated with PTSD-associated symptoms in trauma patientswith and without PTSD

300 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

The greatest limitation of this review was thelimited number of RCTs available Of the 4 placebo-controlled trials only 2 were double-blind810

whereas 111 was single-blind and another was open-label9 Nevertheless the authors believed it wasworthwhile to compile the data from all of theavailable studies given the widespread use of BZDsfor PTSD and disagreements and misconceptionsamong clinicians about this practice When themeta-analysis was limited only to the RCTs theresults were inconclusive due to the small samplesizes of those RCTs and the great amount of het-erogeneity among the studies with 2 showing non-significant negative effects and 2 showing non-significant positive effects Although one mightargue that only RCTs should be considered forinclusion in a rigorous review in light of the limitednumber of studies of BZDs in PTSD we elected touse more expansive inclusion criteria to create acomprehensive review of the available literatureand to stimulate clinical thought and furtherresearch Further studies are recommended espe-cially randomized placebo-controlled trials withextended follow-up

CONCLUSIONS

Although BZDs have been in use since 1960 andtrauma survivors have always existed hardknowledge is scanty Nevertheless based on ourmeta-analysis and qualitative synthesis we canconclude that BZDs are more likely to be ineffectivethan effective for the treatment or prevention ofPTSD and that risks tend to outweigh potentialshort-term benefits Consistent evidence supports alack of efficacy especially for PTSD core symptomspsychotherapy augmentation and depressionThere is also suggestive evidence that BZDs mayworsen outcomes with BZDs being correlated withworse overall severity of PTSD symptomsincreased risk of trauma patients developing PTSDand worse psychotherapy outcomes However moredouble-blind placebo-controlled trials are neededbefore it can be concluded that BZDs consistentlyworsen PTSD There is little evidence for anythingexcept the most transient efficacy which is limitedto a few symptoms and this is outweighed by betterevidence for inefficacy and potential risks For thesereasons and others BZDs should be consideredrelatively contraindicated in trauma patients

Most studies specific to BZDs in PTSD are small andfew are RCTs However taken together and in com-bination with general BZD studies they raise enoughquestions about potential harms that providers shoulduse considerable caution when continuing BZD pre-scriptions and would be safer to avoid starting themaltogether in PTSD patients Some of these potentialproblems are general concerns about the medicationclass (eg cognitive effects dependence misuse) andothers are specific to the diagnosis (eg adverse effectssynergistically worsening PTSD symptoms inhibitingpsychotherapy promoting avoidance) Although BZDsmight be effective if they were to selectively inhibit thestress and anxiety centers of the brain that are oftenhyperactive in PTSD (eg amygdala HPA axis) theyindiscriminately target the entire brain includingthose areas that are already hypoactive in PTSDincluding the cognitive and memory centers (eg pre-frontal cortex hippocampus) and serotonergic circuits(implicated in PTSD anxiety depression suicidalityimpulsivity aggression) Although it may be temptingto treat PTSD-associated symptoms with BZDs theyare best avoided due to evidence of long-term risksoutweighing evidence of any short-term benefits andthe difficulty of discontinuing BZDs once startedWhen patients with PTSD are already taking BZDsproviders should evaluate whether the treatment isactually improving the patientsrsquo functioning or if thereare anymdashoften subtlemdashiatrogenic effects on the courseof their condition After weighing risks and benefitssome providers will choose to continue BZDs somewill unilaterally discontinue or change medicationsand some will work through the stages of change tohelp patients transition toward evidence-based treat-ments Regardless recovery from PTSD should denoteimproved functioning (eg healthy relationshipsemployment) not simply sedation

Although there is little evidence of benefits asso-ciated with BZDs in PTSD substantial evidencesupports the benefits associated with other treat-ments A myriad of evidence-based treatments forPTSD exist (eg psychotherapy serotonergic anti-depressants adrenergic inhibitors)33840 all ofwhich should be exhausted before BZDs are con-sidered For years sedatives were the only thing wehad in our armamentarium for PTSD Now wehave many more tools and our patientsmdashwhethersurvivors of assault combat or any other traumamdashdeserve those treatments that have been proven tobe safer and more effective than BZDs

Journal of Psychiatric Practice Vol 21 No 4 July 2015 301

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

REFERENCES

1 Harpaz-Rotem I Rosenheck RA Mohamed S et alPharmacologic treatment of posttraumatic stress disor-der among privately insured Americans Psychiatr Serv2008581184ndash1190

2 Lund BC Bernardy NC Vaughan-Sarrazin M et alPatient and facility characteristics associated withbenzodiazepine prescribing for veterans with PTSDPsychiatr Serv 201364149ndash155

3 Veterans Affairs and Department of Defense VADoDclinical practice guideline for management of post-trau-matic stress 2010 Available at httpwwwhealthqualityvagovguidelinesMHptsdcpg_PTSD-FULL-201011612pdf Accessed April 8 2013

4 Matar MA Zohar J Kaplan Z et al Alprazolam treat-ment immediately after stress exposure interferes withthe normal HPA-stress response and increases vulner-ability to subsequent stress in an animal model of PTSDEur Neuropsychopharmacol 200919283ndash295

5 Foa EB Keane TM Friedman MJ et al EffectiveTreatments for PTSD Practice Guidelines From theInternational Society for Traumatic Stress Studies 2nded New York NY Guilford 2009566

6 US Department of Health and Human Services ClinicalPractice Guideline No 5 Depression in Primary Care Vol2 Treatment of Major Depression Rockville MDAHCPR Publications 199371ndash123

7 Moher D Liberati A Tetzlaff J et al Preferred reportingitems for systematic reviews and meta-analyses thePRISMA statement PLoS Med 20096e1000097

8 Rothbaum OR Price M Jovanovic T et al A randomizeddouble-blind evaluation of D-cycloserine or alprazolamcombined with virtual reality exposure therapy forposttraumatic stress disorder in Iraq and Afghanistanwar veterans Am J Psychiatry 2014171640ndash648

9 Mellman TA Bustamante V David D et al Hypnoticmedication in the aftermath of trauma J Clin Psychiatry2002631183ndash1184

10 Braun P Greenberg D Dasberg H et al Core symptomsof posttraumatic stress disorder unimproved by alprazo-lam treatment J Clin Psychiatry 199051236ndash238

11 Cates ME Bishop MH Davis LL et al Clonazepam fortreatment of sleep disturbances associated with combat-related posttraumatic stress disorder Ann Pharmac-other 2004381395ndash1399

12 Gelpin E Bonne O Peri T et al Treatment of recenttrauma survivors with benzodiazepines a prospectivestudy J Clin Psychiatry 199657390ndash394

13 Shalev AY Bloch M Peri T et al Alprazolam reducesresponse to loud tones in panic disorder but not inposttraumatic stress disorder Biol Psychiatry 19984464ndash68

14 Zatzick DF Rivara FP Nathens AB et al A nationwide USstudy of post-traumatic stress after hospitalization forphysical injury Psychol Med 2007371469ndash1480

15 Shin HJ Rosen CS Greenbaum MA et al Longitudinalcorrelates of aggressive behavior in help-seeking USveterans with PTSD J Trauma Stress 201225649ndash656

16 Kosten TR Fontana A Sernyak MJ et al Benzodiaze-pine use in posttraumatic stress disorder among veteranswith substance abuse J Nerv Ment Dis 2000188454ndash459

17 Rosen CS Greenbaum MA Schnurr PP et al Dobenzodiazepines reduce the effectiveness of exposure

therapy for posttraumatic stress disorder J Clin Psy-chiatry 2013741241ndash1248

18 Jones C Backman C Capuzzo M et al Precipitants ofpost-traumatic stress disorder following intensive care ahypothesis generating study of diversity in care Inten-sive Care Med 200733978ndash985

19 Samuelson KAM Lundberg D Fridlund B Stressfulmemories and psychological distress in adult mechan-ically ventilated intensive care patientsmdasha 2 monthfollow-up study Acta Anaesthesiol Scand 200751671ndash678

20 Bienvenu OJ Gellar J Althouse BM et al Post-traumatic stress disorders symptoms after acute lunginjury a 2-year prospective longitudinal study PsycholMed 2013432657ndash2671

21 Baranyi A Krauseneck T Rothenhausler HB Posttrau-matic stress symptoms after solid-organ transplantationpreoperative risk factors and the impact on health-related quality of life and life satisfaction Health QualLife Outcomes 201311111

22 Girard TD Shintani AK Jackson JC et al Risk factorsfor post-traumatic stress disorder symptoms followingcritical illness requiring mechanical ventilation a pro-spective cohort study Crit Care 200711R28

23 Van Minnen A Arntz A Keijsers GPJ Prolongedexposure in patients with chronic PTSD predictors oftreatment outcome and dropout Behav Res Ther200240439ndash457

24 McGhee LL Maani CV Garza TH et al The relationshipof intravenous midazolam and posttraumatic stressdisorder development in burned soldiers J Trauma200966(suppl)S186ndashS190

25 Shalev AY Rogel-Fuchs Y Auditory startle reflex in post-traumatic stress disorder patients treated with clonaze-pam Isr J Psychiatry Relat Sci 1992291ndash6

26 Longo LP Johnson B Addiction part I Benzodiazepinesmdashside effects abuse risk and alternatives Am FamPhysician 2000612121ndash2128

27 Michelini S Cassano GB Frare F et al Long-term use ofbenzodiazepines tolerance dependence and clinical prob-lems in anxiety and mood disorders Pharmacopsychiatry199629127ndash134

28 Ashton H The diagnosis and management of benzodiaze-pine dependence Curr Opin Psychiatry 200518249ndash255

29 American Psychiatric Association Diagnostic and Statis-tical Manual of Mental Disorders Fifth ed Arlington VAAmerican Psychiatric Association 2013265ndash290 550ndash560

30 Coupland NJ Lillywhite A Bell CE et al A pilotcontrolled study of the effects of flumazenil in posttrau-matic stress disorder Biol Psychiatry 199741988ndash990

31 Randall PK Bremner JD Krystal JH et al Effects of thebenzodiazepine antagonist flumazenil in PTSD BiolPsychiatry 199538319ndash324

32 Tasman A Kay J Lieberman JA Psychiatry 3rd ed Vol 1Chichester UK John Wiley amp Sons 20081186ndash12002603ndash2615

33 Li S Murakami Y Wing M et al The effects of chronicvalproate and diazepam in a mouse model of posttrau-matic stress disorder Pharmacol Biochem Behav200685324ndash331

34 Geuze E van Berckel BNM Lammertsma AA et alReduced GABAA benzodiazepine receptor binding inveterans with post-traumatic stress disorder Mol Psy-chiatry 20081374ndash83

35 Davydow DS Gifford JM Desai SV et al Posttraumaticstress disorder in general intensive care unit survivors

302 July 2015 Journal of Psychiatric Practice Vol 21 No 4

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved

a systematic review Gen Hosp Psychiatry 200830421ndash434

36 Zohar J Juven-Wetzler A Sonnino R et al New insightsinto secondary prevention in post-traumatic stressdisorder Dialogues Clin Neurosci 201113301ndash309

37 Hebert MA Potegal M Moore T et al Diazepamenhances conditioned defeat in hamsters PharmacolBiochem Behav 199655405ndash413

38 Berger W Mendlowicz MV Marques-Portella C et alPharmacologic alternatives to antidepressants in post-traumatic stress disorder a systematic review ProgNeuropsychopharmacol Biol Psychiatry 200933169ndash180

39 Hawkins EJ Malte CA Imel ZE et al Prevalence andtrends of benzodiazepine use among Veterans Affairspatients with posttraumatic stress disorder 2003ndash2010Drug Alcohol Depend 2012124154ndash161

40 Jeffreys M Capehart B Friedman MJ Pharmacotherapyfor posttraumatic stress disorder review with clinicalapplications J Rehabil Res Dev 201249703ndash715

41 Herman J Trauma and Recovery The Aftermath ofViolencemdashFrom Domestic Abuse to Political Terror NewYork NY Basic Books 199244ndash45

42 Bond AJ Drug-induced behavioural disinhibition inci-dence mechanisms and therapeutic implications CNSDrugs 1998941ndash57

43 PDR Network Physiciansrsquo Desk Reference 2014 Avail-able at httpwwwpdrnet Accessed March 5 2014)

44 Baldwin DS Anderson IM Nutt DJ et al Evidence-based guidelines for the pharmacological treatment ofanxiety disorders recommendations from the BritishAssociation for Psychopharmacology J Psychopharmacol200519567ndash596

45 Pary R Lewis S Prescribing benzodiazepines in clinicalpractice Resid Staff Physician 2008548ndash17

46 Griffiths RR Weerts EM Benzodiazepine self-adminis-tration in humans and laboratory animalsmdashimplicationsfor problems of long-term use and abuse Psychopharma-cology 19971341ndash37

47 Jacobsen LK Southwick SM Kosten TR Substance usedisorders in patients with posttraumatic stress disordera review of the literature Am J Psychiatry 20011581184ndash1190

48 Lee HS Lee HP Lee SK et al Anti-intrusion effect oflorazepam an experimental study Psychiatry Investig201310273ndash280

49 Bremner JD Southwick SM Darnell A et al ChronicPTSD in Vietnam combat veterans course of illness andsubstance abuse Am J Psychiatry 1996153369ndash375

50 Mellman TA Byers PM Augenstein JS Pilot evaluationof hypnotic medication during acute traumatic stressresponse J Trauma Stress 199811563ndash569

51 Treggiari MM Romand JA Yanez ND et al Randomizedtrial of light versus deep sedation on mental health aftercritical illness Crit Care Med 2009372427ndash2534

Journal of Psychiatric Practice Vol 21 No 4 July 2015 303

BENZODIAZEPINES FOR PTSD

Copyright copy 2015 Wolters Kluwer Health Inc All rights reserved