nmda receptor antagonists for the treatment ... -...

NEUROPATHIC PAIN SECTION

Review ArticleNMDA Receptor Antagonists for the Treatmentof Neuropathic Painpme_981 1726..1742

Susan Collins, MSc,*†‡ Marnix J. Sigtermans, MD,†§

Albert Dahan, Prof, MD,†§ Wouter W. A. Zuurmond,Prof, MD,*† and Roberto S. G. M. Perez, PhD*†‡

*Department of Anesthesiology, VU University MedicalCenter, Amsterdam;

†Knowledge Consortium Trauma Related NeuronalDysfunction, Leiden;

‡EMGO+ Institute for Health and Care Research,Amsterdam, VU University Medical Center,Amsterdam;

§Department of Anesthesiology, Leiden UniversityMedical Center, Leiden, the Netherlands

Reprint requests to: Susan Collins, MSc, VU UniversityMedical Center, Department of Anesthesiology, DeBoelelaan 1117, 1081 HV Amsterdam, theNetherlands. Tel: 003-120-444-0293; Fax:003-120-444-4385; E-mail: [email protected].

This study is part of TREND (Trauma RElatedNeuronal Dysfunction), a knowledge consortium thatintegrates research on Complex Regional PainSyndrome type 1 (CRPS 1). This project is supportedby a Dutch Government grant (BSIK03016).

Abstract

Objective. The N-methyl-D-Aspartate (NMDA)receptor has been proposed as a primary target forthe treatment of neuropathic pain. The aim of thepresent study was to perform a meta-analysis evalu-ating the effects of (individual) NMDA receptorantagonists on neuropathic pain, and the response(sensitivity) of individual neuropathic pain disordersto NMDA receptor antagonist therapy.

Design. PubMed (including MEDLINE), EMBASEand CENTRAL were searched up to October 26, 2009for randomized placebo controlled trials (RCTs) onneuropathic pain. The methodological quality of theincluded trials was independently assessed by twoauthors using the Delphi list. Fixed or random

effects model were used to calculate the summaryeffect size using Hedges’ g.

Setting. NA.

Patients. The patients used for the study were neu-ropathic pain patients.

Interventions. The interventions used were NMDAreceptor antagonists.

Outcome measurements. The outcome of measure-ments was the reduction of spontaneous pain.

Results. Twenty-eight studies were included,meeting the inclusion criteria. Summary effect sizeswere calculated for subgroups of studies evaluatingketamine IV in complex regional pain syndrome(CRPS), oral memantine in postherptic neuralgia and,respectively, ketamine IV, and oral memantine in pos-tamputation pain. Treatment with ketamine signifi-cantly reduced pain in postamputation pain (pooledsummary effect size: -1.18 [confidence interval (CI)95% -1.98, -0.37], P = 0.004). No significant effect onpain reduction could be established for ketamine IVin CRPS (-0.65 [CI 95% -1.47, 0.16], P = 0.11) oralmemantine in postherptic neuralgia (0.03 [CI 95%-0.51, 0.56], P = 0.92) and for oral memantine in pos-tamputation pain (0.38 [CI 95% -0.21, 0.98], P = 0.21).

Conclusions. Based on this systematic review, noconclusions can yet be made about the efficacy ofNMDA receptor antagonists on neuropathic pain.Additional RCTs in homogenous groups of painpatients are needed to explore the therapeuticpotential of NMDA receptor antagonists in neuro-pathic pain.

Key Words. Meta-Analysis; NMDA ReceptorAntagonists; Neuropathic Pain

Introduction

Neuropathic pain is pain arising as a direct consequenceof a lesion or disease affecting the somatosensory sys-tem [1]. Neuropathic pain is manifested in disorders ofvarious etiologies such as post-herpetic neuralgia, dia-betic neuropathy, and complex regional pain syndrome

Pain Medicine 2010; 11: 1726–1742Wiley Periodicals, Inc.

1726

[2]. Symptoms associated with neuropathic pain are allo-dynia, hyperalgesia, and spontaneous pain. A number ofmechanisms have been described that may contribute tothe generation of neuropathic pain. Examples includenociceptor sensitization, ectopic excitability of sensoryneurons, alterations in ion channel expression on theperipheral level and spinal and/or cortical reorganizationand changes in inhibitory pathways and central sensitiza-tion on the central level [3–5].

Several therapies have been developed for the treatmentof neuropathic pain; however, these methods are notequally effective for all neuropathic pain patients [6]. TheN-methyl-D-Aspartate (NMDA) receptor has been pro-posed as a primary target for the treatment of neuropathicpain. Evidence suggests that the NMDA receptor withinthe dorsal horn plays an important role in both inflamma-tion and nerve injury-induced central sensitization [7]. Pro-longed pain stimuli of high intensity induce a cascade ofevents which activate the NMDA receptor. Activation ofthe NMDA receptor is associated with abnormalities in thesensory (peripheral and central) system, resulting in neu-ronal excitation and abnormal pain manifestations (spon-taneous pain, allodynia, hyperalgesia) [8–10]. Blocking ofthese receptors by antagonists may possibly impede orreverse the pain pathology, leading to a reduction of pain[11].

The effects of NMDA receptor antagonists on neuro-pathic pain patients of various etiologies have beeninvestigated in clinical trials in which positive as well asnegative outcomes on pain relief were found. Consider-ing the present ambiguity with respect to the generalefficacy of NMDA receptor antagonists, a research syn-thesis of literature is warranted. To date, no meta-analysis has been performed with respect to the efficacyof NMDA receptor antagonists for treatment of featuresof neuropathic pain.

Therefore, the aim of the present study was to perform ameta-analysis evaluating the effects of NMDA receptorantagonists on neuropathic pain.

Furthermore, subgroup analyses will be performed inassessing the effects of individual NMDA receptor antago-nists on neuropathic pain and their response on individualneuropathic pain disorders, testing the hypothesis thatNMDA receptor antagonists are effective in the treatmentof neuropathic pain.

Methods

Inclusion Criteria

Studies were sought that examined the effect of NMDAreceptor antagonists on spontaneous pain in acute andchronic neuropathic pain [1] patients of all ages. Studieshad to be blinded, randomized, placebo controlled, andthe outcome pain had to be recorded on a numericalrating scale.

Search Strategy

PubMed (including MEDLINE) (from 1966 to October 26,2009), EMBASE (Elsevier Embase.com) (from 1980 toOctober 26, 2009) and Cochrane Central Register ofControlled Trials (CENTRAL) databases were searchedfor studies written in the English, German or Dutchlanguage. In PubMed, MeSH terms (“Receptors, N-Methyl-D-Aspartate/antagonists and inhibitors,” “N-Methylaspartate/antagonists and inhibitors,” “Pain,” “Anal-gesia,” “Analgesia, Patient-Controlled,” “Analgesics,”“Hyperalgesia,” “Sensation,” “Proprioception”) were usedas well as free text terms (“nmda, N-Methyl-D-Aspartate,”“inhibit*,” “block*,” “antagoni*,” “pain,” “pains,” “analgesi*,”“hyperalgesi*,” “allodynia,” “hyperaesthesia,” “hyperes-thesi*,” “ache,” “aches,” “neuralgi*,” “neuropath*,” “sensi-tization,” “sensitization,” “arthralgi*,” “proprioception,”“sensation,” sciatica,” “metatarsalgia”). In addition, a ran-domized placebo controlled trials (RCTs) search filter rec-ommended by the Cochrane Collaboration was used [12].

EMBASE was searched with the EMtree terms: “n Methyld aspartic acid receptor blocking agent,” “Pain,” “Analge-sia,” and “Analgesic agent.”

CENTRAL was searched with the search terms: NMDAand “N Methyl D Aspartate” linked to inhibition*, inhibited,inhibit, block* and antagoni*, as well as the search termspain, pains, analgesi*, hyperalgesi*, allodynia, hyperaes-thesi*, hyperesthesi*, ache, aches, neuralgi*, neuropath*,sensitization, sensitization, arthralgi*, proprioception, sen-sation, sciatica, and metatarsalgia.

Quality Assessments

In order to determine the quality of the studies, identifiedstudies were independently scored by the authors SC andMS using the Delphi list [13]. The Delphi list consists ofnine items, with addition of two criteria (“Were theoutcome measurements described clearly” and “Wereadverse events described?”) to ascertain the method-ological and clinical accuracy of the trials. All criteria werescored with yes (= 1), no (= 0), or don’t know (0), withequal weights given to all criteria. The number of positivescores contributed to the quality scores, ranging from 0 to11. Disagreements were solved by consensus and if nec-essary by a third party (RP), studies with scores of 6 orhigher were considered as good quality studies [14].

Quantitative Analysis

The studies were analyzed using the effect size Hedges’ g(standardized mean difference) [15,16], which is calcu-lated by the difference between the experiment andcontrol treatment at the end of the treatment period,divided by the pooled standard deviation (SD) (see Appen-dix). A heterogeneity test statistics I2 [17,18] was deter-mined to assess whether a fixed or random effects modelwas appropriate to calculate the summary effect sizeusing Hedges’ g. A fixed effect model was used when the

1727

NMDA Receptor Antagonists for Neuropathic Pain

pooled effects of studies could be considered homog-enous (I2 statistics below 25%) [18].

The difference in pain relief between experimental andplacebo conditions as measured on a numerical ratingscale was taken as the primary outcome measure. In casedata for quantitative analysis were not present in thearticle, written permission for additional data wasrequested from the authors of these articles. If no addi-tional information was obtained from the author, the effectsize was estimated from significance levels, assumingconservative values (e.g., P = 0.5 if not significant;P = 0.05 if significant). For each study, a weighting factor(Wi) was estimated, assigning larger weights to effect sizesfrom studies with larger samples and, thus, smaller vari-ances. For studies evaluating different interventions ordifferent doses within the same study, the interventionswere regarded as independent treatments and thereforeeffect sizes were calculated separately for each interven-tion compared with placebo.

The summary effect size was then established by averag-ing the individual effect sizes. For each individual effectsize and for the summary effect size, a 95% confidenceinterval was obtained. The summary effect size was onlycalculated for comparable studies, evaluating the effectsof similar interventions in patients with the same painconditions. Furthermore, the summary effect size will onlybe reported for studies with a quality assessment score ofmore than 50% [13]. Cohen [19] has provided referencepoints to serve as guide in the interpretation of effect sizes:0.20 for “small” effects, 0.50 for “moderate” effects and0.80 for “large” effects. For all outcome variables, thesignificance level was set at 0.05.

Results

Quality of Studies

Twenty-eight studies were included meeting the inclusioncriteria (Figure 1) [20–46]. One included study was writtenby MS [45], accordingly, the methodological quality of thisstudy was independently assessed by SC and RP. Thelevel of agreement between the authors, with respect tothe quality assessment, as measured with the kappa wasgood (mean kappa for the 11 items: 0.93 SD 0.09). Thestudies were of good quality (median quality score 8 [inter-quartile range 7–9]) (Table 1), except for the studies ofFuruhashi-Yonaha [46] and Schiffito [41] in which a qualityscore of 2 and 3, respectively, were found.

Description of Studies

Twenty-three studies were of a crossover design and infive studies, a parallel design was used (Table 1). In twostudies, active placebo (lorazepam) were used [27,32].The interventions were evaluated in 572 neuropathic painpatients of various etiologies (complex regional pain syn-drome n = 126; postherptic neuralgia n = 103; amputationpain n = 75; diabetic neuropathy n = 55; peripheral neur-opathy other than diabetic n = 19; HIV pain n = 45; sci-atica n = 30; pain caused by operation n = 23; caused bytraumas other than operation n = 32; peripheral nerveinjury n = 24; verified nerve injury n = 10; posttraumaticneuralgia n = 11; trigeminal neuropathy n = 10; anesthesiadolorosa n = 4; idiopathic trigeminal neuralgia n = 2; vis-ceral pain n = 2; spinal cord injury n = 1). Pain was mea-sured with numerical rating scale (0–10 or 0–100) scoresexcept for the study of Sang et al. which used the Gracely

Figure 1 Flow chart of studyselection.

1728

Collins et al.

Tab

le1

Incl

uded

stud

ies

Aut

hors

QS

NP

atie

nts

Inte

rven

tions

App

lD

esig

nP

rimar

you

tcom

eR

esul

tsIn

divi

dual

effe

ctsi

ze(in

vers

eva

rianc

e)

Max

etal

.19

957

7P

osttr

aum

atic

pain

and

allo

dyni

aK

etam

ine:

2h,

0.75

mg/

kg/h

IVC

ross

over

VA

Spa

inaf

ter

2ho

urs

Ket

amin

esi

gnifi

cant

lyre

duce

dba

ckgr

ound

pain

,p

=0.

01

-0.8

8[-

1.98

,0.

22]

Fel

sby

etal

.19

95a

810

Chr

onic

neur

opat

hic

pain

(afte

ram

puta

tion

(n=

3),

afte

rop

erat

ion

(n=

5),

afte

rra

diat

ion

(n=

2))

Ket

amin

e:10

min

,0.

2m

g/kg

and

50m

in,

0.3

mg/

kg/h

IVC

ross

over

VA

Spa

in15

min

afte

rin

fusi

on

Ket

amin

esi

gnifi

cant

lyre

duce

dpa

inin

tens

ity,

p=

0.00

6

-0.4

2[-

1.41

,0.

45]

Fel

sby

etal

.19

95b

810

Chr

onic

neur

opat

hic

pain

(afte

ram

puta

tion

(n=

3),

afte

rop

erat

ion

(n=

5),

afte

rra

diat

ion

(n=

2))

MgC

l2:

10m

in,

0.16

mm

ol/k

gan

d50

min

0.16

mm

ol/k

g/h

IVC

ross

over

VA

Spa

in15

min

afte

rin

fusi

on

MgC

l2si

gnifi

cant

lyre

duce

dpa

inin

tens

ity,

p=

0.08

4

-0.2

9[-

1.22

,0.

64]

Nic

kola

jsen

etal

.19

96

811

Pos

tam

puta

tion

stum

pan

dph

anto

mlim

bpa

inK

etam

ine:

bolu

s0.

1m

g/kg

/5m

inan

d7

mgr/

kg/m

info

r40

min

IVC

ross

over

VA

Spa

inaf

ter

infu

sion

Ket

amin

esi

gnifi

cant

lyre

duce

dst

ump

and

phan

tom

pain

,p

<0.

05*

-0.8

9[-

1.78

,0.

01]

Eis

enbe

rget

al.

1998

1020

Pos

ther

ptic

neur

algi

aM

eman

tine:

wk

1:10

mg/

d,w

k2/

5:20

mg/

d

Ora

lP

aral

lel

VA

S(0

–10)

pain

afte

r5

wee

ks

No

stat

istic

ally

sign

ifica

ntdi

ffere

nce

inre

duct

ion

ofpa

in

0.23

[-0.

65,

1.11

]

Pud

etal

.19

987

13S

urgi

caln

euro

path

icpa

inin

canc

erpa

tient

sA

man

tadi

ne:

200

mg

in3

hour

sIV

Cro

ssov

erV

AS

pain

afte

r3

hin

fusi

ons

Am

anta

dine

sign

ifica

ntly

redu

ced

pain

,p

=0.

0001

-1.4

6[-

2.32

,-0

.60]

Med

rik-

Gol

dber

get

al.

1999

930

Sci

atic

aA

man

tadi

ne:

2.5

mg/

kgin

2ho

urs

IVC

ross

over

VA

Spa

inaf

ter

180

min

No

stat

istic

ally

sign

ifica

ntdi

ffere

nce

inre

duct

ion

ofsp

onta

neou

spa

in

0.04

[-0.

47,

0.55

]

Gal

eret

al.

2000

a9

22P

erip

hera

lneu

ropa

thic

pain

(pos

ther

ptic

neur

algi

a(n

=13

),di

abet

icpo

lyne

urop

athy

(n=

1),

perip

hera

lne

urop

athy

othe

rth

andi

abet

ic(n

=8)

)

Rilu

zole

:10

0m

g/d

for

2w

eeks

Ora

lC

ross

over

VA

Spa

inaf

ter

2w

eeks

No

stat

istic

ally

sign

ifica

ntdi

ffere

nce

inal

levi

atin

gpe

riphe

raln

euro

path

icpa

in,

p>

0.10

0.26

[-0.

34,

0.86

]

1729


Tab

le1

Con

tinue

d

Aut

hors

QS

NP

atie

nts

Inte

rven

tions

App

lD

esig

nP

rimar

you

tcom

eR

esul

tsIn

divi

dual

effe

ctsi

ze(in

vers

eva

rianc

e)

Gal

eret

al.

2000

b9

21P

erip

hera

lneu

ropa

thic

pain

(pos

ther

ptic

neur

algi

a(n

=9)

,di

abet

icpo

lyne

urop

athy

(n=

1),

perip

hera

lne

urop

athy

othe

rth

andi

abet

ic(n

=11

))

Rilu

zole

:20

0m

g/d

for

2w

eeks

Ora

lC

ross

over

VA

Spa

inaf

ter

2w

eeks

No

stat

istic

ally

sign

ifica

ntdi

ffere

nce

inin

alle

viat

ing

perip

hera

lne

urop

athi

cpa

in,

p>

0.10

-0.0

7[-

0.68

,0.

54]

Gilr

onet

al.

2000

816

Fac

ialn

eura

lgia

s(p

ossi

ble

trig

emin

alne

urop

athy

(n=

10),

anae

sthe

sia

dolo

rosa

(n=

4),

idio

path

ictr

igem

inal

neur

algi

a(n

=2)

)

Dex

trom

etho

rpha

n:12

0m

g/d,

titra

ted

tom

ax92

0m

g/d

for

6w

eeks

Ora

lC

ross

over

VA

Sov

eral

lda

ilypa

inaf

ter

6w

eeks

No

stat

istic

ally

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in,

p=

0.81

0.05

[-0.

64,

0.74

]

Nic

kola

jsen

etal

.20

007

15N

euro

path

icpa

inaf

ter

ampu

tatio

n(n

=12

)or

oper

atio

n(n

=3)

Mem

antin

e:w

k1:

5m

g/d,

wk

2:10

mg/

d,w

k3:

15m

g/d,

wk4

/5:

20m

g/d

Ora

lC

ross

over

VA

S(0

–10)

pain

durin

gw

k4/5

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngsp

onta

neou

spa

in

-0.4

1[-

1.14

,0.

32]

Leun

get

al.

2001

712

Neu

ropa

thic

pain

(pos

ther

ptic

neur

algi

a(n

=4)

,C

RP

S(n

=7)

,sp

inal

cord

inju

ry(n

=1)

)

Ket

amin

e:ta

rget

plas

ma

leve

lsof

50,

100

and

150

ng/m

l

IVC

ross

over

VA

Spa

inat

3pl

asm

ale

vels

No

sign

ifica

ntre

duct

ion

insp

onta

neou

spa

in*

0.28

[-0.

52,

1.08

]

Abr

aham

etal

.20

02a

83

Pha

ntom

pain

inca

ncer

ampu

tees

Dex

trom

etho

rpha

n:1

wk

120

mg/

dO

ral

Cro

ssov

erV

AS

pain

afte

r1

wee

kD

extr

omet

horp

han

sign

ifica

ntly

redu

ced

post

ampu

tatio

nph

anto

mlim

bpa

in,

p<

0.05

*

-2.2

7[-

4.42

,-0

.12]

Abr

aham

etal

.20

02b

83

Pha

ntom

pain

inca

ncer

ampu

tees

Dex

trom

etho

rpha

n:1

wk

180

mg/

dO

ral

Cro

ssov

erV

AS

pain

afte

r1

wee

kD

extr

omet

horp

han

sign

ifica

ntly

redu

ced

post

ampu

tatio

nph

anto

mlim

bpa

in,

p<

0.05

*

-2.2

7[-

4.42

,-0

.12]

1730

Collins et al.

Bril

leta

l.20

029

7P

osth

erpt

icne

ural

gia

MgS

O4:

30m

g/kg

MgS

O4

in30

min

IVC

ross

over

VA

Spa

inaf

ter

30m

inut

esM

gSO

4si

gnifi

cant

lyre

duce

dpo

sthe

rptic

neur

algi

apa

in,

p=

0.01

6*

-1.5

0[-

2.68

,-0

.36]

Fur

uhas

hi-

Yona

haet

al.

2002

28

(CR

PS

(n=

4),

visc

eral

pain

(n=

2),

post

herp

ticne

ural

gia

(n=

1),

phan

tom

limb

pain

(n=

1))

Ket

amin

e:0.

5m

g/kg

ever

ysi

xho

urs

for

aw

eek

Ora

lC

ross

over

VA

Spa

inaf

ter

1w

eek

Ora

lket

amin

esi

gnifi

cant

lyre

duce

dse

verit

yof

the

pain

,p

<0.

05

-1.5

7[-

2.68

,-0

.44]

San

get

al.

2002

a8

19D

iabe

ticne

urop

athy

Dex

trom

etho

rpha

n:7

wk

titra

tion

until

max

tole

rate

ddo

ses

and

2w

km

aint

enan

ce,

med

ian

dose

s40

0m

g/d

Ora

lC

ross

over

Gra

cely

Box

Sca

ledu

ring

last

wee

kof

trea

tmen

tpe

riod

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in-0

.41

[-1.

05,

0.23

]

San

get

al.

2002

b8

17P

osth

erpt

icne

ural

gia

Dex

trom

etho

rpha

n:7

wk

titra

tion

until

max

tole

rate

ddo

ses

and

2w

km

aint

enan

ce,

med

ian

dose

s40

0m

g/d

Ora

lC

ross

over

Gra

cely

Box

Sca

ledu

ring

last

wee

kof

trea

tmen

tpe

riod

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in-0

.03

[-0.

70,

0.64

]

San

get

al.

2002

c8

19D

iabe

ticne

urop

athy

Mem

antin

e:7

wk

titra

tion

until

max

tole

rate

ddo

ses

and

2w

km

aint

enan

ce,

med

ian

dose

s55

mg/

d

Ora

lC

ross

over

Gra

cely

Box

Sca

ledu

ring

last

trea

tmen

tw

eek

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in-0

.04

[-0.

68,

0.60

]

San

get

al.

2002

d8

17P

osth

erpt

icne

ural

gia

Mem

antin

e:7

wk

titra

tion

until

max

tole

rate

ddo

ses

and

2w

km

aint

enan

ce,

med

ian

dose

s55

mg/

d

Ora

lC

ross

over

Gra

cely

Box

Sca

ledu

ring

last

wee

kof

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tmen

tpe

riod

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in0.

08[-

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59]

Wal

lace

etal

.20

027

62N

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path

icpa

in(p

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ural

gia

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ry(n

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nce

inre

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ngsp

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[-0.

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Abr

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etal

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pute

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days

All

patie

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repo

rted

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sein

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nsity

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eatm

ent

Not

estim

able

**

1731


Tab

le1

Con

tinue

d

Aut

hors

QS

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atie

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rven

tions

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03b

610

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pain

inca

ncer

(n=

8)an

dno

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2)am

pute

es

Dex

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rpha

n:10

days

180

mg/

dO

ral

Cro

ssov

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AS

pain

afte

r10

days

All

patie

nts

repo

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0%de

crea

sein

pain

inte

nsity

afte

rtr

eatm

ent

Not

estim

able

**

Am

inet

al.

2003

817

Dia

betic

perip

hera

lne

urop

athy

Am

anta

dine

:1

¥20

0m

gin

500

ml0

.9%

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lIV

Cro

ssov

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AS

pain

afte

r1

wee

kA

man

tadi

nesi

gnifi

cant

lyre

duce

dpa

inin

tens

ityp

=0.

003

-0.9

8[-

1.71

,-0

.25]

Joru

met

al.

2003

712

Pos

ttr

aum

atic

neur

algi

a(n

=11

)an

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a(n

=1)

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amin

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and

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in

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ross

over

VA

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inaf

ter

infu

sion

keta

min

esi

gnifi

cant

lyre

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dsp

onta

neou

spa

inp

=0.

015*

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8[-

1.94

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Mai

eret

al.

2003

1116

Chr

onic

phan

tom

limb

pain

afte

ram

puta

tion

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mor

leg

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mg/

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mg

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30m

g/d

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ross

over

VA

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inaf

ter

3w

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No

sign

ifica

ntdi

ffere

nce

inre

duci

ngph

anto

mlim

bpa

in*

0.24

[-0.

46,

0.94

]

Car

lsso

net

al.

2004

713

Neu

ropa

thic

pain

oftr

aum

atic

orig

inD

extr

omet

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han:

1¥27

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AS

pain

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rpha

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gnifi

cant

lyre

duce

dpa

in,

p<

0.05

-0.8

1[-

1.61

,-0

.01]

Wie

chet

al.

2004

88

Chr

onic

phan

tom

limb

pain

Mem

antin

e:w

k1:

10m

g/d,

wk

2:20

mg/

d,w

k3/

4:30

mg/

d

Ora

lC

ross

over

VA

Spa

inaf

ter

4w

eeks

trea

tmen

t

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngin

tens

ityof

chro

nic

limb

pain

,p

=0.

16*

0.74

[-0.

27,

1.05

]

Got

trup

etal

.20

068

19V

erifi

edne

rve

inju

rypa

inK

etam

ine:

bolu

s0.

1m

g/kg

in10

min

and

0.00

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g/kg

min

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min

IVC

ross

over

VA

Spa

indu

ring

infu

sion

Ket

amin

esi

gnifi

cant

lyre

duce

dsp

onta

neou

spa

in,

p<

0.01

-0.3

5[-

0.99

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Sch

ifitto

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ated

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ory

neur

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tine:

wk

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dw

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g/d,

wk

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mg/

d

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lP

aral

lel

VA

Spa

inaf

ter

16w

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No

sign

ifica

ntdi

ffere

nce

inre

duci

ngH

IVas

soci

ated

sens

ory

neur

opat

hy,

p=

0.87

*

0.05

[-0.

54,

0.64

]

For

stet

al.

2007

a10

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path

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in(p

osth

erpt

icpa

in(n

=3)

,po

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aum

atic

inju

ry(n

=6)

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RP

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)

Nov

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ngle

dose

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5mg

r

Ora

lC

ross

over

VA

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inaf

ter

12ho

urs

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in0.

16[-

0.64

,0.

96]

1732

Collins et al.

For

stet

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b10

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path

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osth

erpt

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in(n

=2)

,di

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athy

(n=

3),

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mat

icin

jury

(n=

6),

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PS

(n=

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Nov

elgl

utam

ate

anta

goni

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NS

5161

HC

l:si

ngle

dose

of25

0mg

r

Ora

lC

ross

over

VA

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inaf

ter

12ho

urs

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in0.

30[-

0.51

,1.

11]

For

stet

al.

2007

c10

14N

euro

path

icpa

in(d

iabe

ticne

urop

athy

(n=

8),

post

trau

mat

icin

jury

(n=

4),

CR

PS

(n=

2))

Nov

elgl

utam

ate

anta

goni

stC

NS

5161

HC

l:si

ngle

dose

of50

0mg

r

Ora

lC

ross

over

VA

Spa

inaf

ter

12ho

urs

No

sign

ifica

ntdi

ffere

nce

inre

duci

ngpa

in,

p=

0.11

-0.4

0[-

1.15

,0.

35]

Eic

henb

erge

ret

al.

2008

810

Chr

onic

phan

tom

limb

pain

afte

rtr

aum

a(n

=6)

and

surg

ery

(n=

4)

Ket

amin

e:0.

4m

g/kg

in1

hour

IVC

ross

over

VA

Spa

in60

min

afte

rin

fusi

on

Ket

amin

esi

gnifi

cant

lyre

duce

dph

anto

mlim

bpa

in,

p<

0.00

1*

-1.7

5[-

2.06

,-0

.72]

Sch

war

tzm

anet

al.

2009

919

CR

PS

Ket

amin

e:m

ax0.

35m

g/kg

/hin

4ho

urs

for

10da

ys

IVP

aral

lel

VA

Sov

eral

lpa

inaf

ter

2w

eeks

Ket

amin

esi

gnifi

cant

lyre

duce

dov

eral

lpai

n,p

<0.

05

-0.5

5[-

1.00

,0.

09]

Sig

term

ans

etal

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098

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RP

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etam

ine

(S+)

:22

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mg/

h(m

ean

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ter

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amin

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lyre

duce

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neou

spa

in,

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0.00

1

-5.5

9[-

6.76

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.47]

Fin

chet

al.

2009

720

CR

PS

Ket

amin

e10

%cr

eam

Topi

cal

Cro

ssov

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AS

pain

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r30

min

No

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ifica

ntdi

ffere

nce

inre

duci

ngpa

in0.

00[-

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20]

QS

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ality

scor

e.A

ppl:

appl

icat

ion.

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ous.

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PS

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mpl

exre

gion

alpa

insy

ndro

me.

*:ef

fect

size

estim

ated

from

sign

ifica

nce

leve

ls,

ifp

valu

esw

ere

not

repo

rted

p=

0.5

ifno

tsi

gnifi

cant

and

p=

0.05

ifsi

gnifi

cant

wer

eas

sum

ed.

**:

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ctsi

zew

asno

tes

timab

lebe

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eno

info

rmat

ion

was

repo

rted

abou

tth

edi

rect

ion

(sig

nific

ant

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n-si

gnifi

cant

)of

sign

ifica

nce

leve

ls.

1733


Pain Box (0–20] scale for rating pain intensity, which wastransformed into a scale from 1 to 100. Positive resultsafter treatment with NMDA receptor antagonists werereported in 13 studies [22,24,30,31,34–36,38,40,43–46].

The effects of the NMDA receptor antagonist ketaminewas investigated in 11 studies [20–22,29,36,40,43–47], inwhich the effects of the S(+) enantiomer of ketamine wasevaluated by the study of Sigtermans et al. [45], while theother 10 studies investigated racemic (R/S) ketamine. Sixstudies evaluated memantine [23,28,32,37,39,41], fivestudied the effects of dextromethorphan [27,30,32,34,38],and three studies investigated amantadine [24,25,35].Furthermore, the effects of MgSO4 [31], MgCl2 [20], rilu-zole [26], GV196771 (a glycine antagonist) [33] and CNS5161 HCl (a novel NMDA receptor antagonist) [42] wereinvestigated. Adverse events after treatment with the dif-ferent interventions are presented in Table 2.

Quantitative Analysis

In 13 studies [22–27,32,35,40,42,44–46], data (mean andSD) was available for directly calculating hedges’ g statis-tical analysis. Authors of the remaining studies were con-tacted for additional data, of whom four [20,28,38,47]provided additional data. For the remaining studies[21,29–31,33,36,37,39,41], effect sizes were calculatedusing P-values and t statistics (see appendix). For thestudy by Abraham et al. [34], no information was providedabout the placebo group, therefore the individual effectsize could not be estimated for this study. Three studiesused different doses of NMDA receptor antagonists[26,30,42] and one evaluated more than one NMDAreceptor antagonist [32]. Effect sizes for the individualstudies and (different doses of) interventions are pre-sented in Table 1.

In order to calculate the summarize effect size in compa-rable studies with respect to used interventions, route ofadministration and evaluated pain patients, studiesassessing an intervention in one type of neuropathic painpatient and providing adequate data for analysis (a total of12 studies) were categorized according to pain disorder,resulting in four pain patients groups: CRPS, postherpticneuralgia, diabetic neuropathy and postamputation pain(Figure 2). Within these pain patient groups, the summaryeffect size was calculated for minimum two studies evalu-ating the same intervention.

Summary effect sizes were calculated for subgroups ofstudies evaluating intravenous ketamine in CRPS patients,oral memantine in postherptic neuralgia patients and,respectively, intravenous ketamine and oral memantine inpostamputation pain. The results of the two trials evaluat-ing dextromethorphan in postamputation pain were notsummarized, because the two trials (using different dosesof dextromethorphan) were performed and reported withinthe same study, and pooling of results would therefore bequestionable. Treatment with ketamine IV significantlyreduced postamputation pain (pooled summary effectsize: -1.18 [confidence interval (CI) 95% -1.98, -0.37],P = 0.004) (Figure 3). No significant effect on pain reduc-tion could be established for ketamine IV in CRPS (pooledsummary effect size -0.65 [CI 95% -1.47, 0.16], P = 0.11)oral memantine in postherptic neuralgia treatment (pooledsummary effect size 0.03 [CI 95% -0.51, 0.56], P = 0.92)and for oral memantine in postamputation pain (pooledsummary effect size 0.38 [CI 95% -0.21, 0.98], P = 0.21)(see Figures 4–6).

Discussion

Since the late 1980s, NMDA receptor antagonists havebeen known to decrease neuronal hyperexitability and

Table 2 Adverse events of interventions

Intervention Adverse events

Ketamine Sedation, dreams, hallucinations, dissociative reaction, nausea, headache, dizziness, fatigue,changes in mood, altered sight, feeling of unreality, dry mouth, light-headedness, paresthesia,changed taste, dysarthria, euphoria, tinnitus, drunkenness, itching, muteness, andhyperventilation.

Memantine Nausea, fatigue, dizziness, agitation, headache, sedation, dry mouth, gastrointestinal distress,anorexia, constipation, vertigo, restlessness, excitation, insomnia, blurred vision and tinnitus.

Amantadine Nausea.Dextromethorphan Cognitive impairment, dizziness, ataxia, light-headedness, drowsiness, vision disturbances,

euphoria, hot flushes, nausea, speaking difficulties, unpleasantness, numbness, concentrationproblems, shivers, vomiting, itching, dry mouth, tinnitus, rash, sedation, gastrointestinal distressand anorexia.

GV 196771 Dizziness.CNS 5161 HCl Headache, blurred vision, flatulence, dyspepsia, abdominal comfort and nausea.MgSO4 Mild feeling of warmth at the site of infusion.MgCl2 Heat sensations, injection pain and sedation.Riluzole Not mentioned.

1734

Collins et al.

reduce pain, and the efficacy of several NMDA receptorantagonists has been investigated in preclinical and clini-cal pain studies [48]. Despite the large number of studies,there is still no consensus on the efficacy of NMDA recep-tor antagonist on neuropathic pain therefore the presentsystematic review was performed.

We found several randomized placebo controlled studiesinvestigating the effects of a variety of interventions on adiversity of neuropathic pain patients. In order to pool orsummarize results to achieve an overall estimation of theeffectiveness of a therapeutic intervention, studies haveto be similar in the used intervention, route of adminis-tration and the investigated patients. Only half of the

found studies evaluated the intervention in one typeof neuropathic pain patient [21,23–25,28,30–32,35–37,39,41,43–45,47], of which only a few evaluated thesame NMDA receptor antagonists using same routes ofadministration in patients with similar neuropathic painetiologies. Consequently, we could only summarize theresults of two studies investigating ketamine IV in CRPS[44,45], two studies evaluating oral memantine in pos-therptic neuralgia [23,32] and, respectively, two studiesinvestigating ketamine IV [21,43] and two studies evalu-ating oral memantine in postamputation pain [37,39].Ketamine IV was shown to have a large effect [19] inreducing postamputation pain. Based on the smallnumber of pooled results and the lack of information

Figure 2 Included studiesdivided in four pain patientsgroups. *Summarize effect sizewas calculated for minimal twostudies evaluating the sameintervention and route of admin-istration in the same pain patientgroup. †Results of the trialswere not summarized, becausetrials were performed andreported within the same study.IV = intravenous; O = oral; T =topical.

1735


about the effects of other NMDA receptor antagonistsbesides ketamine and memantine on other pain condi-tions, we consider it speculative to draw definite conclu-sions about the efficacy of NMDA receptor antagonists

on neuropathic pain. Further, RCTs including well-definedneuropathic pain disease groups are needed to elucidatethe effects of NMDA receptor antagonists on neuro-pathic pain.

Figure 3 Intravenous ketamineversus placebo in postamputa-tion pain. I2 = 0%. Pooled sum-marized effect size, fixed effectmodel: -1.18 (confidence inter-val 95% -1.98, -0.37), P =0.004.

Figure 4 Intravenous and topi-cal ketamine versus placebo inCRPS. I2 = 55%. Pooled sum-marized effect size, randomeffect model: -0.65 (confidenceinterval 95% -1.47, 0.16),P = 0.11.

1736

Collins et al.

Besides increasing the ability to compare and/or poolindividual studies, examining just one type of pain patientalso increases the homogeneity of the investigated sampleand therefore reduces bias within a study. Neuropathic

pain consists of a very heterogeneous group of patientsregarding the type and degree of their complaints [49].This heterogeneity could also be expressed in the com-position of the NMDA receptor. The NMDA receptor is

Figure 5 Oral memantineversus placebo in postherpticneuralgia. I2 = 0%. Pooled sum-marized effect size, fixed effectmodel: 0.03 (confidence interval95% -0.51, 0.56), P = 0.92.

Figure 6 Oral memantineversus placebo in postamputa-tion pain. I2 = 0%. Pooled sum-marized effect size, fixed effectmodel: 0.38 (confidence interval95% -0.21, 0.98), P = 0.21.

1737


constructed of different subunits (NR1, NR2A-D andNR3A-C), which can be combined in different ways (NR1in combination with 2A–D or 3A–C) [48,50]. The differentsubtype combinations are known to have distinct bio-physical and pharmacological characteristics [51], whichmay influence binding of NMDA receptor antagonists. Inaddition, NMDA receptor antagonists are known to differin their NMDA subtype selectivity and affinity for specificcombinations of NMDA receptor subtypes. At present,little is known about the NMDA subtype pattern in dif-ferent neuropathic pain disorders. The expression of dif-ferent subunit combinations may result in differentselectivity and binding sensitivities for NMDA receptorantagonists, which may lead to differences in pain relief.Research in which the effects of NMDA receptor antago-nists are evaluated in homogenous groups of neuro-pathic pain patients is therefore required to assesspossible disease related differences in treatment effectsof NMDA receptor antagonists.

In this meta-analysis, we evaluated pain in neuropathicpain patients. Neuropathic pain has recently been rede-fined by the International Association for the Study ofPain as pain arising as a direct consequence of a lesionor disease affecting the somatosensory system [1]. Con-ditions without a clearly demonstrated lesion or diseaseaffecting the somatosensory nervous system, such asfibromyalgia, are not considered neuropathic pain. In thepast, there has been some discussion about CRPSbeing a neuropathic pain syndrome. We have includedstudies on CRPS patients, as recent findings of periph-eral pathological changes [52] and damage in the inner-vations of the skin in CRPS [53,54] support the conceptof CRPS being a peripheral neuropathic condition. Infibromyalgia patients, no physical or biological findingshave yet been made that relate directly to a lesion ordisease of the somatosensory system. However, abnor-mally enhanced temporal summation of second pain,expansion of receptive fields, hyperalgesia after electricalstimulation, and late evoked potentials have beendescribed in these patients [55–57]. These central hyper-sensitivities are indicative of the existence of central sen-sitization, suggestive of the presence of a neuropathiccomponent in fibromyalgia. NMDA receptor antagonistswere shown to reduce pain in fibromyalgia [58]. Furtherresearch is warranted to determine the effects of NMDAreceptor antagonists in fibromyalgia and other disorderswith features of neuropathic pain.

Ketamine is probably the most investigated NMDA recep-tor antagonists for the treatment of neuropathic pain [48],which explains the large number of trials using ketamine inour review. Ketamine is known to equally bind the NMDAsubtypes 2A to 2D and may therefore have a more favor-able effect in such a heterogenic disease as neuropathicpain, compared with NMDA receptor antagonists withmore discriminative NMDA subtype selectivity. In addition,ketamine is a high affinity NMDA receptor antagonist,resulting in long-term blocking of the receptor and stronginhibiting of the neuronal hyperexcitability occurring in neu-ropathic pain. A disadvantage of this undiscriminating and

strong binding property, however, is the higher proportionsof side effects due to binding of the antagonists to neuronalstructures not involved in pain.

The use of the S(+) eantiomer of ketamine in clinical trials[45], may be favorable regarding side effects. S(+) ket-amine is twice as potent in analgesic effect comparedwith racemic ketamine [59]; therefore, lower doses ofS(+) ketamine may reduce side effects, while providingpain reduction resembling racemic ketamine. In thepresent review, a statistically significant effect in reducingneuropathic pain for ketamine was only found for post-amputation pain. Evaluation of the individual effect sizes,however, revealed five large effect trials [19], in whichketamine was used in four trials (in patients with post-amputation pain [21,43], posttraumatic, postherptic neu-ralgia [36], and CRPS [45], respectively). Therefore, weargue that ketamine (and especially S(+) ketamine) maybe a promising intervention for pain relief in neuropathicpain. In this respect, a reservation has to be made withregard to the inclusion of an article by a member of ourgroup [45], therewith introducing possible interpretationbias. However, quality assessments for this article werenot performed by those directly involved in the study inquestion. Furthermore, omitting this article from theanalysis would not have lead to significantly differentconclusions.

Our methodology only considers spontaneous pain asoutcome measurement after treatment with NMDAreceptor antagonists. Many studies found in this reviewalso investigated the effects of NMDA receptor antago-nists on evoked pain (allodynia, hyperalgesia, winduppain) [22–27,30,35,40,42–44,47]. These studies usedvarious stimulus modalities of different strengths toevoke pain. In order to diminish the heterogeneity andmake comparison of different interventions possible, weonly used spontaneous pain as outcome measurement.Consequently, we have no information about the effectsof NMDA receptor antagonists on other aspects of sen-sitization. Possibly, some antagonists may affect spon-taneous pain, allodynia or hyperalgesia in a differentmanner. Further (meta-analytic) research may elucidatethe effects on NMDA receptor antagonists on otheraspect of sensitization.

Another methodological consideration in this study is thefact that only comparisons between NMDA receptorantagonists and placebo were taken into account. Com-parisons with active (real) interventions could possibly leadto lower effect sizes than those found in the present meta-analysis. On the other hand, one should bear in mind thateffect sizes in general will be negatively influenced by theheterogeneity of the included studies, thereby limiting theirmagnitude.

Conclusions

Based on the results found in this systematic review, noconclusions can yet be made about the efficacy of NMDA

1738

Collins et al.

receptor antagonists on neuropathic pain. However, evi-dence in favor of the effectiveness of NMDA receptorantagonists for the treatment of neuropathic pain, of whichketamine seems to be the most potent, is accumulating.Additional randomized placebo controlled studies inhomogenous groups of pain patients are needed to explorethe therapeutic potential of NMDA receptor antagonists inneuropathic pain.

Acknowledgments

We would like to express our gratitude to Ingrid Riphagen,MSc (Medical Library, VU University, Amsterdam, theNetherlands) for her expertise and support in searchingthe literature and to Prof Dr Riekie de Vet (EMGO+ Institutefor Health and Care Research, Amsterdam, VU UniversityMedical Center Amsterdam, the Netherlands) for heradvice with regard to the methodological assessment.This study is part of TREND (Trauma RElated NeuronalDysfunction), a knowledge consortium that integratesresearch on Complex Regional Pain Syndrome type 1(CRPS-1). This project is supported by a Dutch Govern-ment grant (BSIK03016).

Appendix [15,16,18,60–63]

Calculating Hedges’ g from the Mean, StandardDeviation and Number of Subjects

g M M SD pooledi e c= −( )

SD pooledSD n 1 +

SD n 1 n n 2e

2e

c2

c e c

=( ) −( )⎡⎣ ⎤⎦(

) −( )⎡⎣ ⎤⎦ +( ) − )Where, gi = hedges’ g for individual study i, M = mean,e = experimental group, c = control group, SD = standarddeviation, n = sample size in a particular group.

Calculating Hedges’ g from the t-Test

g tt

i e c e c e

c i

n n n n , and when n andn are equal g 2 N= +( ) ( )

=

Where, t = value of the t-test, N = total sample size.

Calculating Hedges’ gi from Significance Levels

When only P-values are reported, t-values can beobtained using a calculator or looked up in a table ofthe t distribution using P-levels and the degrees offreedom. From the t-test, hedges’ gi can be calculated(see above).

Calculating 95% Confidence Intervals (CI) forHedges’ gi

CI 1.96 two-tailed and a critical value at 0.05 Vi= ± ( ) ×

V N n n g 2Ni e c i2= ( ) + ( )

Where Vi = within-study variance of individual effect size i.

Calculating Summarized Effect Size Hedges’gAccording to Fixed Effect Model

g g W Ws i i/ i= ∑ ∑Wi 1 Vi=

Where, gs = summarized hedges’ g, Wi = estimatedweight for individual study i.

Calculating Homogeneity Statistics I2

I proportion of total variability explainedby heterogenei

2 =tty

I Q k 1 Q 100%, for Q k 12 = − −( )( ) × > −( )I 0, for Q k 12 = ≤ −( )

Q Wg Wg Wi i2

i i2

i= − ( )∑ ∑ ∑Q Q statistics=

A random effect model must be used when the pooledeffects of studies could be considered heterogeneous(I2 statistics � 25%).

Calculating Summarized Effect Size Hedges’gAccording to Random Effects Model

g g W Ws i i/ i= ∑ ∑Wi 1 V *i=

V * V,i2

i= +σθ

σθ2 Q k 1 c,= − −( )( )c W W Wi i

2i= − ( ) )( )∑ ∑ ∑

Where Vi* = total variance, sq2 = between study variance,

Q = Q statistics, k = number of studies in the meta-analysis.

Calculating 95% CI for gs

CI 1.96 two-tailed and a critical value at 0.05 Vs= ± ( ) ×

V 1 Ws i= ∑Where, Vs = variance of summarized effect size.

Calculating P-Values for gs

Z g Vs s=

Where, Z = Z-value.

P vales can be obtained using Z table.

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