Recent Developments in the Pharmacotherapy of Alcoholism

Henry R. Kranzler, M.D.

Alcohol Research CenterUniv. of CT School of Medicine

Potential Conflicts of InterestPotential Conflicts of Interest

Consulting and Research Support:

Ortho-McNeil Pharmaceuticals (current study)

Bristol-Myers Squibb Co. (recent study)

Forest Pharmaceuticals (consulting, support for lectures)

Alkermes, Inc. (consulting, support for lectures)

DrugAbuse Sciences (consulting)

ObjectivesObjectives

Learn about:

• The medications currently approved in the US to treat alcohol dependence

Candidate medications that are currently in development for that indication

The neurotransmitter systems that underlie alcohol’s effects, which are relevant to future developments in this therapeutic area

Prevalence of Alcohol Use DisordersPrevalence of Alcohol Use Disorders

Alcohol DependenceAlcohol Dependence 7.9 million (3.8%)7.9 million (3.8%)

Alcohol AbuseAlcohol Abuse 9.7 million (4.7%)9.7 million (4.7%)

NIAAA= National Institute on Alcohol Abuse and AlcoholismGrant BF, et al. Arch Gen Psychiatry. 2004;61:807-816.

Any Alcohol Use DisorderAny Alcohol Use Disorder17.6 million (8.5%)17.6 million (8.5%)

NIAAA – National Epidemiologic Survey onNIAAA – National Epidemiologic Survey onAlcohol and Related Conditions (NESARC)Alcohol and Related Conditions (NESARC)

Unmet Treatment NeedsUnmet Treatment Needs

NESARC data indicate that only about a quarter of adults with alcohol abuse or dependence ever receive treatment: Self-help groups Psychotherapy Pharmacological treatments

What is the Goal of Alcohol Treatment?What is the Goal of Alcohol Treatment?

• Primary goal of alcohol treatment has traditionally been the initiation and maintenance of abstinence

• Reduced drinking may be a suitable alternative for some patients; unclear as to how such patients can be identified a priori

Medications Approved in the US for Medications Approved in the US for Treatment of Alcohol DependenceTreatment of Alcohol Dependence

Disulfiram (Antabuse): 1949

Naltrexone (ReVia): 1994

Acamprosate (Campral): 2004

Long-Acting Naltrexone (Vivitrol): 2006

Medications Approved in the US for Medications Approved in the US for Treatment of Other DisordersTreatment of Other Disorders

Selective Serotonin Reuptake Inhibitors (SSRIs)

Ondansetron (Zofran)

Topiramate (Topamax)

These medication are not FDA-approved for treatment of alcohol dependence

DRUMS TRUMPETS CLARINETS HARP VIOLIN FLUTE

INDIVIDUAL FACTORS influencing the reward symphony Genetics Age Hormones Environment

ALCOHOL THE CONDUCTOR

( J.A. Engel, 1994 )

[ Muscle relax.] CNS stim. Euphoria [ ] [ ] Preference][ [Anxiolysis ] [Sedation ]

The Brain Symphony Orchestra#

4/4 .

Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation

Disulfiram

Naltrexone

Acamprosate

Serotonin Reuptake Inhibitors

Ondansetron

Topiramate

Disulfiram (Antabuse)Disulfiram (Antabuse)

• An alcohol-sensitizing medication that produces an unpleasant reaction when alcohol is ingested; it is used to deter alcoholics from drinking

• Interferes with the breakdown of acetaldehyde, a toxic metabolite of alcohol

Ethanol Acetaldehyde Acetate

l

Disulfiram and Abstinence Rates (VA Cooperative Study)Disulfiram and Abstinence Rates (VA Cooperative Study)

Noncompliant (80%) Compliant (20%)0

10

20

30

40

50

Per

cen

t R

emai

nin

g A

bst

inen

t

Fuller RK et al. JAMA. 1986; 256:1449-1455

Disulfiram 250 mg (N=202 men)Disulfiram 250 mg (N=202 men)

Disulfiram 1 mg (N=204 men)Disulfiram 1 mg (N=204 men)

Placebo (N = 199 men)Placebo (N = 199 men)

Drinking Days Among Those Who DrankDrinking Days Among Those Who Drank

Fuller RK et al. JAMA. 1986; 256:1449-1455

0

20

40

60

80

100

Treatment Group

Disulfiram 250 mg

Disulfiram 1 mg

Placebo

*p < .05

SummarySummary

• Although not efficacious for maintenance of abstinence, disulfiram may reduce harm by reducing drinking days among those who relapse.

• Given the potential for serious adverse events (i.e., the disulfiram-ethanol reaction), disulfiram is probably not suitable for use as a primary harm reduction strategy

Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation

Disulfiram

Naltrexone

Acamprosate

Serotonin reuptake inhibitors

Ondansetron

Topiramate

Pharmacology of NaltrexonePharmacology of Naltrexone

• Orally bioavailable antagonist of mu, delta, and kappa opioid receptors

• Appears to reduce dopamine release associated with alcohol expectancies and consumption

• FDA-approved oral dosage: 50 mg/day

Naltrexone (Revia) in the Treatment of Naltrexone (Revia) in the Treatment of Alcohol DependenceAlcohol Dependence

Number of Weeks Receiving Medication

10 2 3 4 5 6 7 8 9 10 11 120.00.1

0.2

0.40.50.60.70.80.9

1.0

0.3

Cu

mu

lati

ve P

rop

ort

ion

w

ith

No

Rel

apse

Naltrexone (N=35)

Placebo (N=35)

Volpicelli et al., Arch Gen Psychiatry, 1992

Oral Naltrexone Studies in Alcohol Oral Naltrexone Studies in Alcohol DependenceDependence

Meta-analysis of 14 published studies involving more than 2000 patients revealed:

Clear effect of naltrexone on risk of relapse to heavy drinking [OR: 0.62 (0.52, 0.75), P<0.001]

Borderline effect of naltrexone on abstinence rate [OR: 1.26 (0.97,1.64), P=0.08].

Bouza et al., Addiction, 2004

Vivitrex (Alkermes, Inc.)Vivitrex (Alkermes, Inc.)

Common biodegradable medical polymer that is used for sutures, extended release pharmaceuticals

Metabolized to CO2 and H20

Dry Powder Microspheres Diluent

Microsphere Suspension

Hypodermic Needle

IM

Once Monthly Dosing

+

Time (Days)0 5 10 15 20 25 30

Na

ltre

xon

e (

ng

/mL

)

0

5

10

15

20

25

30

35

40

Mean Steady State Naltrexone Concentration Following Mean Steady State Naltrexone Concentration Following VivitrexVivitrex®® 380 mg Compared to Daily Oral Dosing 380 mg Compared to Daily Oral Dosing

380 mg IM Mean ± SD

50 mg Oral Mean ± SD

Results: Heavy Drinking DaysResults: Heavy Drinking Days

PretreatmentPlaceboVivitrex 190 mgVivitrex 380 mg

75th Percentile25th Percentile

Median Heavy Drinking Days per Month

0

5

10

15

20

25

30

n = 624

19.3

3.1

6.04.5

Garbutt et al., 2005

Effect of Long-Acting Naltrexone on Effect of Long-Acting Naltrexone on Maintenance of AbstinenceMaintenance of Abstinence

0102030405060708090

100

Per

cen

t w

ith

ou

t R

elap

se

p < 0.025

Placebo (n = 28) Vivitrex (n = 28)

Subjects with 4-day lead-in abstinence

1 2 3 54 6 7 8 109 11 12 13 1514 16 17 18 2019 21 22 23 2524 26 27 28 3029 31

Weeks

Targeted Naltrexone for Problem DrinkersTargeted Naltrexone for Problem Drinkers

• 8-week study of oral naltrexone • 150 subjects, whose goal was to reduce or

stop drinking• Targeted medication: one tablet/day for the

first week, reduced by one tablet/week; subjects urged to use medication 2 hr in anticipation of a situation self-identified as high risk for drinking

Kranzler et al., J Clin Psychopharmacol, 2003

Daily vs. Targeted Naltrexone: Daily vs. Targeted Naltrexone: Effects on Heavy DrinkingEffects on Heavy Drinking

0.1

0.15

0.2

0.25

1 2 3 4 5 6 7 8

Study Week

He

av

y D

rin

kin

g D

ay

s

Daily Placebo

TargetedPlacebo

DailyNaltrexone

TargetedNaltrexone

Kranzler et al., J Clin Psychopharmacol, 2003

Med: p = .092, 19.0% reduction; Med X Sched X Time: p = .001

SummarySummary

There is not consistent evidence of the efficacy of naltrexone for maintenance of abstinence; effects may depend on study design (i.e., initial abstinence requirement).

Naltrexone reduces the risk of heavy drinking and may be the medication of choice for harm reduction.

Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation

Disulfiram

Naltrexone

Acamprosate

Serotonin reuptake inhibitors

Ondansetron

Topiramate

Pharmacology of Acamprosate (Campral)

Acamprosate has complex effects on glutamate-NMDA activity and is a GABA agonist; the normal balance between these systems is altered by chronic drinking.

In animals trained to drink alcohol, acamprosate reduces deprivation-induced drinking.

FDA-approved dosage is 1998 mg/day (divided in 3 doses)

Acamprosate (Campral) Acamprosate (Campral)

In 11 European clinical trials (> 3,300 patients), acamprosate :

• Significantly improved the abstinence rate [OR = 1.88 (1.57, 2.25), P < 0.001]

• Significantly improved treatment retention [OR = 1.29 (1.13,1.47), P < 0.001].

Bouza et al., Addiction, 2004

Sass et al. StudySass et al. Study%

of

Pat

ien

ts A

bst

inen

t 100

Weeks

80

60

40

20

00 24 48 72 96

Treatment Period* Follow-Up Period†

*p=0.001; †p=0.003 Sass et al., Sass et al., Arch Gen PsychiatryArch Gen Psychiatry, 1996, 1996

43%

21%

17%

37%

Placebo (N=136)

Acamprosate (N=136)

US Acamprosate Study: ITT AnalysisUS Acamprosate Study: ITT Analysis

020406080

100

Percent Days Abstinent

Placebo

ACA 2g

ACA 3g

Mason et al. 2006

ES = 0.036 ES = 0.129

ES = Effect Size

US Acamprosate Study: ITT US Acamprosate Study: ITT (Adjusted) Analysis*(Adjusted) Analysis*

25

45

65

Percent Days Abstinent

Placebo

ACA 2g

ACA 3g

Mason et al. 2006

Linear Dose Effect: p=0.01

*Adjusted for severity, readiness to change, psychological antecedents, ASI score, treatment exposure

SummarySummary

There is a small effect size for acamprosate in the maintenance of abstinence.

The lack of efficacy in the US study may be due to greater sample heterogeneity, confounding the small advantage shown in European studies.

NTX, ACA, and NTX/ACA for Relapse Prevention in NTX, ACA, and NTX/ACA for Relapse Prevention in Alcohol-Dependent PatientsAlcohol-Dependent Patients

Kiefer F et al. Arch Gen Psychiatry. 2003;60:92-99.

0 10 20 30 40 50 60 70 80

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Proportion ofSurvivors

(Nonrelapsing)

Time, d

PlaceboAcamprosateNaltrexone

Naltrexone plus acamprosate

Relapse to Heavy Drinking During TreatmentRelapse to Heavy Drinking During Treatment

Acamprosate Main Effect

Placebo (n=618)

Acamprosate (n=608)

P

Percent 70.1 69.6 0.23

Naltrexone Main Effect

Placebo (n=612)

Naltrexone (n=614)

P

Percent 71.4 68.2 0.02

CBI Main Effect

No CBI (n=607)

CBI (n=619)

P

Percent 69.7 70.0 0.16

The COMBINE STUDY, JAMA, 2006

Relapse to Heavy Drinking: Naltrexone x CBI Interaction

The COMBINE STUDY, JAMA, 2006

Composite Clinical Outcome* During Last 8 Weeks of Treatment

Naltrexone by CBI interaction, p=0.02

*No more than 2 daysheavy drinking over 8weeks, no more than 11 (women) or 14 (men) Drinks/week, and no alcohol problems

Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation

Disulfiram

Naltrexone

Acamprosate

Serotonin reuptake inhibitors

Ondansetron

Topiramate

0.0

0.10.2

0.30.4

0.50.6

0.70.8

0.91.0

0 1 2 3 4 5 6 7 8 9 10 11 12

Fluoxetine

Placebo

Fluoxetine and Relapse RatesFluoxetine and Relapse Rates

Weeks in Treatment

Pro

po

rtio

n A

bst

inen

t

Kranzler et al., Am J Psychiatry, 1995Kranzler et al., Am J Psychiatry, 1995

(N=101)

% Completely Abstinent During Treatment% Completely Abstinent During Treatment

0

10

20

30

40

50

60

70

Type B Type A

Sertraline

Placebo

Pettinati et al., Alcohol Clin Exp Res, 2000Pettinati et al., Alcohol Clin Exp Res, 2000

Per

cen

t (%

)p<0.0001*p<0.0001*

SummarySummary

Similar findings with fluoxetine and fluvoxamine indicate that SSRIs do not reduce drinking behavior in an unselected sample of alcoholics.

In subgroups of alcoholics, some SSRIs may increase the likelihood of abstinence. Prospective validation of these findings is needed.

Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation

Disulfiram

Naltrexone

Acamprosate

Serotonin reuptake inhibitors

Ondansetron

Topiramate

OndansetronOndansetron

Drinks / Day among EOA at StudyEnd

0 1 4 160

1

2

3

4

: p < : p 0.01

Ondansetron doses in g/ kg b.i.d

Mean

drin

ks /

day

Johnson et al., JAMA, 2000

SummarySummary

Ondansetron reduces drinking behavior only among early-onset alcoholics.

Independent replication of this finding is needed.

Medications for Alcohol RehabilitationMedications for Alcohol Rehabilitation

Disulfiram

Serotonin reuptake inhibitors

Ondansetron

Naltrexone

Acamprosate

Topiramate

Topiramate (Topamax): Mean Change from PretreatmentTopiramate (Topamax): Mean Change from Pretreatment

-80

-70

-60

-50

-40

-30

-20

-10

0

0 1 2 3 4 5 6 7 8 9 10 11 12

Key:

Placebo

Topiramate

Study Weeks

Per

cen

t H

eavy

Dri

nki

ng

Day

s

-60.34 9.89

-32.73 11.03

Pretreatment: 68.3% (topiramate) vs. 60.8% (placebo)

Johnson et al., Lancet 2003

P = 0.0004

-80

-60

-40

-20

0

20

40

60Placebo (N=48)

Topiramate (N=55)

Topiramate Treatment of Alcohol DependenceTopiramate Treatment of Alcohol Dependence

Percent Change From Baseline in Self-Reported Percent Change From Baseline in Self-Reported Drinking at Week 12Drinking at Week 12

Heavy Drinking Days Days Abstinent

P<.0004

P<.003

Johnson et al. Lancet. 2003;361:1677-1685.

ConclusionsConclusions

Psychosocial treatments for alcohol dependence, while efficacious, are not adequate for many patients.

A growing number of medications are useful in preventing relapse or promoting abstinence.

Additional research is needed to resolve conflicting findings and to guide clinical care.