Treatment of Substance Use

Disorders in Primary and Integrated

Care

Elena Volfson, MD, MPH

Outline of the lecture

• DSM V vs DSM IV substance use disorders

• Current epidemiology of substance use in the

US from NSDUH 2013

• Neurobiology of substance use

• Current review of treatment strategies by

substances : alcohol, tobacco, opiates,

cannabis

DSM-IV and DSM-V Substance Use

Disorders

• Added craving criterion

• Eliminated dependence and abuse distinction

• Eliminated legal problems as criterion

• Mild (2-3), moderate (4-5) and severe (>6) out

of 11

Past month alcohol consumption in

>12 in 2012

Past month alcohol use by race 2012

Past month tobacco use >12 2012

Tobacco use by women >12 2012

Past month cigarette use over age 12

2012

Past month illicit drug use by age 2012

Daily or almost daily cannabis use >12

2012

Initiation of use by substances 2012

(excluding tobacco)

Goal of Addiction Treatment

• Recovery as "a voluntarily maintained lifestyle

characterized by sobriety, personal health, and

citizenship“ (J Subst Abuse Treat. 2007;33(3):221)

• Restoration of medical and social well-being

• Acquiring or regaining cortical/executive

control over one’s behavior and life

Proprietary Recipe: Most Effective Treatments

for Any Mental Illness by Dr. Volfson

• Brain transplant

• Re-parenting

• Injection of common sense and perspective

Psychotherapy is the best treatment unless the

patient is actively psychotic, demented or

mentally retarded. Functional frontal lobes are

required for therapy.

14

Model of Addiction

CravingReward /

Euphoria

ControlEmotion

Memory

Orbital Prefrontal Cortex

Ventral Tegmentum

Hippocampus

Nucleus Accumbens

Temporal - Parietal

Used with permission from David Oslin, 2012

15

Model of Addiction

CravingReward /

Euphoria

ControlEmotion

Memory

12 Step / CBT

Naltrexone

Acamprosate

Naltrexone

Acamprosate

Antidepressants

Mood Stabilizers

Therapy

Used with permission from David Oslin, 2012

Addiction is a Compulsive Relapsing

Disorder

Two essential features:

• impaired ability to regulate the drive to

obtain and use substances

• reduced drive to obtain natural rewards

Change in the reward circuitry : substances

usurp normal learning circuitry to create the

pathology of addiction

Kalivas and O’Brien, 2008

Vulnerabilities in Development of

Addiction

• Genetic

• Developmental

• Social

• Drug-induced brain plasticity

Core Addiction Syndrome

• Common neuroplastic changes in response to chronic administration of different substances of abuse

• Addiction is “overlearned “ with repeated associations between substances and life events mediated by dopamine release

• Addictive behaviors and chronic relapse vulnerability are maintained by glutamatergicneurotransmission

Kalivas and O’Brien, 2008

Core Addiction Syndrome

• Hypofrontality- subcortical glutamatergic

connections assume primacy and reduce

cortical control over drug-seeking (automatic

behavior)

• Drug-associated stimuli activate PFC

excessively, whereas natural reinforcers (sex,

food, danger etc.) elicit poor response -

maladaptive process

Staged Neuroplasticity of Addiction

• Abstinence

• Social Use

• Chronic Use

• Regulated relapse – conscious choice

• Compulsive relapse- inability to make a

conscious choice(Kalivas and O’Brien 2008)

Neurobiological Changes with Chronic

Substance Use

• Motivation/reward system DA/endorphine

• Glutamate/GABA dysregulation

• HPA axis dysregulation

• Hypofrontality

• Sex hormones dysregulation

• Cravings

• Relapse

Pharmacologic Strategies to Treat

Addiction

• Dopaminergic (D1-D5)

• Glutamatergic (NMDA, AMPA, KA, metabotropic)

• GABA ergic (GABA A and B)

• Cholinergic (Ach M and N)

• Noradrenergic (Alpha and beta)

• Serotonergic (14 subtypes)

• Endogenous opioids (mu, delta, kappa, OFQ-N)

• Endogenous cannabinoids (CB1 and CB2)

• Many others (NPY, DARPP-32, galanin, orexin, CRF, substance P, melanocortins, leptin, BDNF etc.)

Most Effective Treatment for

Substance Abuse Disorders

• Combination of medications and therapy

• Treatment of co-morbid mood and anxiety

disorders

• Free up the frontal lobes by quieting

subcortical areas for the therapy

• Therapy: relapse prevention, motivational

interviewing, 12-step facilitation, CBT, family

therapy etc.

Addiction Therapy may be related to activation

of Frontal Cortex

(Boettiger, et.al. 2009)(Crews and Boettiger et.al. 2009)

Importance of Simultaneous

Treatment for All Substances Involved

• One craving breeds another

• One addiction drives another (priming effect)

• Very important to address tobacco

dependence

• Stress increases cravings and relapse

Low-risk drinking limits

• If no cardio-vascular disease

• Men: Not more than 2 standard drinks per day

and not more than 4 drinks on an occasion

and not more than 14 drinks per week

• Women and elderly: 1-1.5 drinks per day

Medications for alcohol dependenceMedications for alcohol dependence

Disulfiram

• First medication approved for alcoholism

• Blocks acetaldehyde dehydrogenase

• Works best if dose observed

Medications for Alcohol Use Disorders

• Disulfiram

• Acamprosate

• Naltrexone oral/injectable/implantable

• Topiramate

Disulfiram Reduces Drinking Days

0%

5%

10%

15%

20%

25%

% D

ay

s D

rin

kin

g

Counseling

Disulfiram 1mg

Disulfiram 250 mg

Fuller et al. JAMA. 1986 Sep 19;256(11):1449-55.

*

*p<.05

Acamprosate

• Glutamate antagonist

• Reduced protracted withdrawal

• Reduces cravings

Acamprosate Promotes Abstinence

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Percent patients without relapse

Acamprosate

Placebo

Sass et al. Arch Gen Psychiatry. 1996;53(8):673-80

Meta-Analysis of Acamprosate: Abstinence

Improved

StudyTreatment

n/NControl

n/NPeto OR

(95% CI Fixed) Weight %Peto OR

(95% CI Fixed)

Besson 1998

Chick 2000

Geerlings 1997

Gual 2001

Ladewig 1993

Paille 1995

Pelc 1997

Poldrugo 1997

Sass 1996

Tempesta 2000

Whitworth 1996

Total (95%CI)

14/55

35/289

14/128

49/141

12/29

45/361

52/126

53/122

54/136

62/164

27/224

417/1775

3/55

32/292

7/134

38/147

7/32

16/177

9/62

37/124

23/136

48/166

11/224

231/1549

3.1

12.6

4.1

12.9

2.8

10.1

7.7

12.1

11.7

15.5

7.4

100.00

4.56 [1.63, 12.76]

1.12 [0.67, 1.86]

2.16 [0.89, 5.27]

1.52 [0.92, 2.52]

2.45 [0.83, 7.18]

1.41 [0.80, 2.48]

3.37 [1.76, 6.44]

1.79 [1.07, 3.01]

3.06 [1.81, 5.18]

1.49 [0.94, 2.35]

2.50 [1.29, 4.87]

1.88 [1.57, 2.25]

Test for heterogeneity: chi-square = 17.00; df = 10; P = 0.074

Test for overall effect: z = 6.87; P < 0.0001

CI = confidence interval; OR = odds ratioBouza et al. Addiction. 2004;99:811.

Outcome: Abstinence Rate

.2.1 1 5 10

Volpicelli et al. , Arch Gen Psychiatry 1992;49(11):876-80

No. of Weeks Receiving Medication

10 2 3 4 5 6 7 8 9 10 11 12

0.0

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.3Naltrexone HCl (N=35)

Placebo (N=35)

Cumulative Rate of Alcohol Relapse

Medications for alcohol dependence

Naltrexone

• Blocks opiate receptors – prevents

endorphines from binding to GABA-

interneurons

• Blocks subsequent dopamine release

• Effective is a subset of alcoholics

Meta-Analysis: Oral Naltrexone Reduces

Relapse

StudyTreatment

n/NControl

n/NPeto OR

(95% CI Fixed) Weight %Peto OR

(95% CI Fixed)

Anton 1999

Chick 2000

Guardia 2002

Heinala 2001

Hersch 1998

Kranzler 2000

Krystal 2001

Latt 2002

Monti 2001

Morris 2001

Oslin 1997

O’’’’Malley 1992

Volpicelli 1995

Volpicelli 1997

Total (95%CI)

26/68

59/90

8/101

49/63

15/31

29/61

142/378

19/56

16/64

19/55

3/21

16/52

10/54

17/48

428/1142

38/63

54/85

19/101

51/58

15/33

31/63

83/187

27/51

19/64

26/56

8/23

31/52

17/45

26/49

445/930

7.5

9.2

5.4

4.0

3.7

7.1

27.4

6.0

5.8

6.1

1.9

5.9

4.5

5.5

100.0

0.42 [0.21, 0.82]

1.09 [0.59, 2.03]

0.39 [0.17, 0.88]

0.50 [0.19, 1.27]

1.12 [0.42, 2.98]

0.94 [0.46, 1.89]

0.75 [0.53, 1.08]

0.46 [0.22, 0.99]

0.79 [0.36, 1.72]

0.61 [0.29, 1.30]

0.34 [0.09, 1.33]

0.32 [0.15, 0.68]

0.38 [0.16, 0.93]

0.49 [0.22, 1.09]

0.62 [0.52, 0.75]

Bouza et al. Addiction. 2004;99:811.

Test for heterogeneity: chi-square = 17.00; df =10; P = 0.074

Test for overall effect: z = 6.87; P < 0.0001

.2.1 1 5 10

Favors Naltrexone Favors Control

CI = confidence interval; OR = odds ratio

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

% p

ati

ents

rel

ap

sed

Non-Adherent Adherent

Placebo

Naltrexone

Arch Gen Psychiatry 1997 Aug;54(8):737-42

Naltrexone is effective in compliant

patients

*

*p = .002

• Naltrexone embedded in microspheres

• Elimination: polymer eventually

metabolized and eliminated as CO2 and

H2O

Hydration Diffusion Erosion

Dean. Front Biosci. 2005;10:643.

Extended Release Injectable Naltrexone

• Multicenter study, 624 patients

• 3 groups: placebo, 190 mg, and 380 mg

• All patients received BRENDA

• About 8% of patients were abstinent for

1 week prior to treatment

• 6 months of treatment

Garbutt et al. JAMA 2005;293:1617

Extended-release Injectable Naltrexone: Pivotal Trial

Reductions in Heavy Drinking with Naltrexone

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

All Patients

Patients Without Lead-in Abstinence

Patients With Lead-in Abstinence

P = 0.02 vs PBO

P = 0.05 vs PBO

P = 0.005 vs PBO

PBO = placebo

Perc

en

t R

ed

ucti

on

Rela

tive

to

Pla

ceb

o

Garbutt et al. JAMA. 2005;293:1617

0

2

4

6

8

10

12

14

16

% D

ay

s H

eav

y D

rin

kin

g

Low Moderate High

Density of Familial Alcohol Problems

Naltrexone

Placebo

Family History Predicts Naltrexone Response

Monterosso et al. Am J Addict. 2001;10:258-68.

48%

26%

61%

56%

0%

10%

20%

30%

40%

50%

60%

70%

% R

ela

pse

d

Naltrexone-treated subjects Placebo-treated subjects

AA allele

AG or GG allele

Mu Receptor Polymorphism Predicts Naltrexone Response

Oslin et al. Neuropsychopharmacology 2003;28(8):1546-52..

*

* p=.04

Pharmacology of Topiramate

• Antagonist at AMPA and kainate receptors

• Allosteric agonist at the GABA-A receptor

• Blocks voltage-dependent Na and l-type voltage-gated Ca channels

• Inhibits carbonic anhydrase

• Enhances K+ conductance

Medications for alcohol dependence

Johnson et al. Lancet. 2003;361(9370):1677-85

Topiramate Promotes AbstinenceFrom Alcohol

Meta-analysis by Blodgett et al. (2014)

Placebo-Controlled Trial of Topiramate to

Reduce Heavy Drinking

• 12-week study of 138 heavy drinkers whose

goal was to reduce drinking to safe levels

• Topiramate 100 mg twice daily (N=67) or

matching placebo (N=71) with dosage

increased gradually over 6 weeks

• Brief behavioral counseling at each visit

• Moderator analysis of rs2832407 in GRIK1

Kranzler et al., Am J Psychiatry, 2014

Screenin

g

(n=200)

Baseline

(n=138)

12-Week

Treatment

Topiramate

(n=67; 82.1%

completed tx)

12-Week

Treatment

Placebo

(n=71; 87.3%

completed tx)

3-month

Follow-up

Topiramate

(n=60;

90%)

3-month

Follow-up

Placebo

(n=63;

88.7%)

6-month

Follow-up

Topiramate

(n=59;

88.1%)

3-month

Follow-up

Placebo

(n=59;

83.1%)

Study Design

Kranzler et al., Alcohol Clin Exp Res, in press

Within-Treatment Heavy Drinking Days/Week

Within-Treatment Abstinent Days/Week

Genotype Groups

• We genotyped participants for

rs2832407 in GRIK1 as a moderator

of topiramate’s adverse effects and effects on drinking behavior.

• The genotypes in European

Americans (n=122) were in Hardy-Weinberg Equilibrium:

• CC (n=51)

• AC (n=53)

• AA (n=18)Kranzler et al., Am J Psychiatry, 2014

Heavy Drinking Days by Medication and Genotype

Groups

Abstinent Days by Medication and Genotype

Groups

Figure : Main effect of medication group (A), and moderating effect of rs2832407 (B and C)

The population of veterans

52

Prevention only Heavy

DrinkingAddiction

• Brief Advice/Intervention– Shown to decrease drinking and adverse health

outcomes for non dependent individuals

– Two components:• Advice

• Link drinking to health

• PCMHI staff– Provide training

– Provide Brief interventions

– Assess for comorbidities

Brief Interventions – Heavy Drinking

Integrating treatment for addiction

The BHL Model

• Stepped Care Approach

• Strong ties to mental health supervision

• Initial decisions and prescribing in primary care

• Assessment based

• Tracking important – need informatics support

• Emphasis on patient self-management support

• Behavioral Health Provider – facilitates communication and education of team

• Offer telephone contacts – Much appreciated by patients

• Provider: BHS – nurse, psychologist, SW

• BHS meets with patient for 18 sessions over 6 months either in person or by telephone

• Collaborates with PCP to:– Increase motivation to abstain

– Be supportive and optimistic

– Encourage naltrexone

– Encourage AA attendance

– Provide education (health risks and detrimental outcomes)

Alcohol Care Management -

Dependence

Drinking Outcomes

0

10

20

30

40

50

60

70

Su

bje

cts

en

ga

ge

d i

n t

rea

tme

nt

(%)

Alcohol Care

Management

Specialty Addiction care

Relapse to heavy drinking

57

0

10

20

30

40

50

60

Pe

rce

nt

da

ys

of

he

av

y d

rin

kin

g

Alcohol Care

Management

Specialty Addiction care

Tobacco Use Disorder Treatment

• No contraindications for NRT (ICU, CVD, pregnancy)

• Patients may smoke while using the patch

• Gradual replacement of cigarettes may work better than fixed quit date

• Combination NRT beats varenicline (Surgeon General Report on Tobacco, 2008)

• Need to give enough of NRT (2-4 mg per cigarette)

• Many patients need long term NRT (up to 6 months or longer)

• Women metabolize nicotine faster – need higher doses

Nicotine Replacement Treatment

Nicotine Levels Obtained by Various Forms of

Replacement

Pre-Cessation NRT

• Meta-analysis (2008): Effectiveness of and abstinence rates for

smokers not willing to quit (but willing to change their smoking

patterns or reduce their smoking) after receiving NRT compared

to placebo (n = 5 studies)

• Placebo 3.6 % (OR1)

• Nicotine replacement (gum, inhaler,or patch)

• 8.4% (5.9–12.0) (OR 2.2)

• www.surgeongeneral.gov/tobacco/gdlnrefs.htm

• www.cochrane.org

Treatment of Tobacco Dependence with

Antidepressants

�Bupropion (36 trials, N = 11,140, risk ratio [RR] 1.69; 95% confidence interval [CI] 1.53 to 1.85) and nortriptyline (six trials, N = 975, RR 2.03; 95% CI 1.48 to 2.78) both significantly increased long term cessation

� From the available data bupropion and nortriptyline appear to be equally effective and of similar efficacy to nicotine replacement therapy. The mode of action of bupropion and nortriptyline is independent of their antidepressant effect.

�SSRIs not effective, MAOIs (moclobemide, selegiline) and venlafaxine (SNRI) not effective

Treatment of Tobacco Dependence with

Varenicline (Partial Nicotinic Agonist)

• RR for continuous abstinence at six months for

varenicline vs placebo was 2.33 (95% confidence

interval [CI] 1.95 to 2.80).

• The pooled RR for varenicline versus bupropion at one

year was 1.52 (95% CI 1.22 to 1.88).

• The RR for varenicline versus NRT at one year was 1.31

(95% CI 1.01 to 1.71)

Varenicline vs.Bupropion

• Comparable in efficacy (a bit higher with varenicline)

• Agonist (?) and partial agonist on nicotinic receptor

• 2008 FDA suicidal warning on both: 90% of suicides on varenicline, 7% on bupropion and 3% on NRT (Moore,Tet al,2011)

• Varenicline may exacerbate CVD (FDA, 2011) but 2012 meta-analysis does not confirm it (Prochaska,J et al, 2012)

• Varenicline is contraindicated in pilots and traffic controllers (FAA)

• Both can be safely used in combination (Ebbert,J et al, 2008)

Cannabis: Clinical Issues

• 60 cannabinoids and cannabinoid-antagonists, one of them is THC

• Associated with early onset of psychosis (Large,M et all, 2011), may be causal

• Causes neuropsych decline (Meier,M et al,2012); amotivational syndrome (1970-1980s); lower educational attainment; lower income (Gruber,A et al,2003); lower life satisfaction (Fergusson,D et al, 2008)

• Respiratory effects comparable to tobacco (Moore, B et al, 2005), more carcinogens

• Use declines with age

Cannabis: Treatment

• No FDA approved meds

• Oral THC 10 mg 5 times daily and Divalproex 1500 mg daily (Haney, M et al, 2004)

• Dronabinol (Levin,F et al,2008)

• Gabapentin 1200 mg daily (Mason,B et al, 2012)

• Mirtazapine 15-45 mg nightly (Benyamina,A 2008)

• NAC (N-Acetylcysteine) : 1200 mg twice daily for 8 weeks and contingency management – beats placebo in negative urines OR 2.4 (Gray, K et al, 2012)

Cannabis: Clinical Pearls

• Rimonabant (CB 1 blocker) off the market

• Medical marijuana

• Decriminalization vs. legalization debate

Opiate relapse prevention medications

Relapse prevention

–Methadone

–Buprenorphine

–Naltrexone

What is goal of pharmacological treatment?

The Ideal Medication

– Stops withdrawal

– Reduces craving

– Blocks the high from abused drugs

Methadone Maintenance

• Stops withdrawal

• Reduces craving

• Blocks the high from heroin

• Saves lives

Opiate relapse prevention medications

0

100A

DM

ISS

ION

Pre- | 1st Year | 2nd Year | 3rd Year | 4th YearAdmission

*

*

Adapted from Ball & Ross - The Effectiveness of Methadone Maintenance

Treatment, 1991

Methadone Maintenance Treatment is Effective

Problems with Methadone

•Methadone is a full opiate agonist

•Strict federal state and local controls

•Limited to methadone clinics

•Too little availability

Buprenorphine

• Partial mu opiate agonist, kappa antagonist

• Parenteral analgesic (Buprenex®)

• Available for opiate dependence since 2002

Opiate relapse prevention medications

Buprenorphine Is As Effective as Methadone

Johnson et al. N Engl J Med. 2000;343(18):1290-7.

0

5

10

15

20

25

30

% P

ati

ents

12 or more consecutive clean urines

Buprenorphine

High dosemethadone

Low dosemethadone

The Advantage of Buprenorphine

•Not improved efficacy but increased availability

•Buprenorphine is available for office use

Opiate relapse prevention medications

• Naltrexone

– Blocks opiate receptors

– Compliance impacts effectiveness

– It does not stop withdrawal

– Its anti-craving effect is weak

– Very effective in certain populations

Opiate relapse prevention medications

• 250 patients

• 6 month trial

• Double blind placebo controlled

• 380 mg extended release naltrexone monthly

Krupitsky et al. Lancet 2011; 377: 1506-13

Extended release naltrexone in Russia

Response ProfileCumulative % of Participants at Each Rate of Weekly

Confirmed Abstinence: XR-NTX 380 mg vs. Placebo

� Total abstinence (100% opioid-free weeks) during Weeks 5-24 was reported in 45 (35.7%)

of subjects in the XR-NTX group versus 28 (22.6%) subjects in placebo group (P=0.0224).

Cocaine: Treatment

• No FDA approved meds

• Disulfiram (250 mg daily) was effective in four trials (Carroll,Ket al, 2004) , not effective in one (Olivetto,A et al, 2011)

• Modafinil (200-400 mg daily) decreased cocaine intake in one controlled clinical trial (Dackis,C et al,2005) but not in a second larger trial (Anderson,A et al, 2009)

• Anticonvulsants are effective:

– topiramate (200 mg daily) (Kampman,K 2004), tiagabine(12 mg or 24 mg daily) (Gonzales, 2007), and vigabatrin (3 g/day) (Brodie, 2009)

– Gabapentin (1800 to 3200 mg/day) not effective (Brodie,2009)

Cocaine: Treatment

• Citalopram 10 mg daily (Moeller,F et al,2007)

• Ondansetron 4 mg twice daily (Johnson,B et al,2006)

• Agonist substitution with amphetamines (Mooney et al,2009; Shearer,J2008)

• Bupropion 300 g daily with contingency management (Poling,J 2006)

• Naltrexone 100 mg daily (Schmitz,J et al,2009; Pettinati,H et al, 2008; Schmitz,J et al, 2003, Hersh D, 1998)

• Buprenorphine/Naloxone 16-32 mg daily (Montoya,I et al,2004)

• Beta-blockers (Propranolol) reduces cravings (Leri, 2002),reinforcing

effects (Sofuoglu, 2000), withdrawal (Kampman,2001)

• Cocaine vaccine

• Acupuncture, herbal remedies – not effective