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Recent Developments in the Pharmacotherapy of Alcoholism Henry R. Kranzler, M.D. Alcohol Research Center Univ. of CT Sch PowerPoint Presentation
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Recent Developments in the Pharmacotherapy of Alcoholism Henry R. Kranzler, M.D. Alcohol Research Center Univ. of CT School of Medicine. Potential Conflicts of Interest. Consulting and Research Support: Ortho-McNeil Pharmaceuticals (current study) Bristol-Myers Squibb Co. (recent study)

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slide1
Recent Developments in the Pharmacotherapy of AlcoholismHenry R. Kranzler, M.D.Alcohol Research CenterUniv. of CT School of Medicine
potential conflicts of interest
Potential 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)
objectives
Objectives

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 disorders
Prevalence of Alcohol Use Disorders

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

Any Alcohol Use Disorder

17.6 million (8.5%)

Alcohol Abuse

9.7 million (4.7%)

Alcohol Dependence

7.9 million (3.8%)

NIAAA= National Institute on Alcohol Abuse and Alcoholism

Grant BF, et al. Arch Gen Psychiatry. 2004;61:807-816.

unmet treatment needs
Unmet 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 treatment of alcohol dependence
Medications Approved in the US for Treatment of Alcohol Dependence
  • Disulfiram (Antabuse): 1949
  • Naltrexone (ReVia): 1994
  • Acamprosate (Campral): 2004
  • Long-Acting Naltrexone (Vivitrol): 2006
medications approved in the us for treatment of other disorders
Medications Approved in the US for Treatment of Other Disorders
  • Selective Serotonin Reuptake Inhibitors (SSRIs)
  • Ondansetron (Zofran)
  • Topiramate (Topamax)

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

slide9

.

#

4/4

The Brain Symphony Orchestra

ALCOHOL THE CONDUCTOR

DRUMS TRUMPETS CLARINETS HARP VIOLIN FLUTE

[Anxiolysis ]

[Sedation ]

[

[

[

]

]

[ Muscle relax.]

Preference]

Euphoria

CNS stim.

INDIVIDUAL FACTORS

influencing the reward symphony

Genetics Age Hormones Environment

( J.A. Engel, 1994 )

medications for alcohol rehabilitation
Medications 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

slide12

Disulfiram and Abstinence Rates (VA Cooperative Study)

50

Disulfiram 250 mg (N=202 men)

Disulfiram 1 mg (N=204 men)

40

Placebo (N = 199 men)

30

Percent Remaining Abstinent

20

10

0

Compliant (20%)

Noncompliant (80%)

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

drinking days among those who drank

100

80

Disulfiram 250 mg

60

Disulfiram 1 mg

40

Placebo

20

0

Treatment Group

Drinking Days Among Those Who Drank

*p < .05

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

summary
Summary
  • 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 rehabilitation1
Medications for Alcohol Rehabilitation
  • Disulfiram
  • Naltrexone
  • Acamprosate
  • Serotonin reuptake inhibitors
  • Ondansetron
  • Topiramate
pharmacology of naltrexone
Pharmacology 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 alcohol dependence
Naltrexone (Revia) in the Treatment of Alcohol Dependence

1.0

0.9

0.8

0.7

0.6

Cumulative Proportion with No Relapse

0.5

0.4

0.3

Naltrexone (N=35)

Placebo (N=35)

0.2

0.1

0.0

0

1

2

3

4

5

6

7

8

9

10

11

12

Number of Weeks Receiving Medication

Volpicelli et al., Arch Gen Psychiatry, 1992

oral naltrexone studies in alcohol dependence
Oral Naltrexone Studies in Alcohol Dependence

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

Metabolized to CO2 and H20

Vivitrex (Alkermes, Inc.)

+

Dry Powder Microspheres

Diluent

Microsphere Suspension

Hypodermic Needle

IM

Once Monthly Dosing

mean steady state naltrexone concentration following vivitrex 380 mg compared to daily oral dosing

380 mg IM Mean ± SD

50 mg Oral Mean ± SD

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

40

35

30

25

Naltrexone (ng/mL)

20

15

10

5

0

0

5

10

15

20

25

30

Time (Days)

results heavy drinking days

75th Percentile

25th Percentile

Pretreatment

Vivitrex 380 mg

Results: Heavy Drinking Days

30

25

Placebo

19.3

20

Vivitrex 190 mg

Median Heavy Drinking Days per Month

15

10

6.0

4.5

5

3.1

0

n = 624

Garbutt et al., 2005

effect of long acting naltrexone on maintenance of abstinence

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

Vivitrex (n = 28)

Effect of Long-Acting Naltrexone on Maintenance of Abstinence

Subjects with 4-day lead-in abstinence

100

90

80

70

60

Percent without Relapse

50

40

p < 0.025

30

20

10

0

Weeks

Placebo (n = 28)

targeted naltrexone for problem drinkers
Targeted 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 effects on heavy drinking
Daily vs. Targeted Naltrexone: Effects on Heavy Drinking

Med:p = .092, 19.0% reduction;

Med X Sched X Time: p = .001

Kranzler et al., J Clin Psychopharmacol, 2003

summary1
Summary
  • 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 rehabilitation2
Medications for Alcohol Rehabilitation
  • Disulfiram
  • Naltrexone
  • Acamprosate
  • Serotonin reuptake inhibitors
  • Ondansetron
  • Topiramate
pharmacology of acamprosate campral
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 study

43%

21%

37%

17%

Sass et al. Study

Treatment Period*

Follow-Up Period†

100

Acamprosate (N=136)

80

Placebo (N=136)

60

% of Patients Abstinent

40

20

0

0

24

48

72

96

Weeks

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

us acamprosate study itt analysis
US Acamprosate Study: ITT Analysis

ES = 0.129

ES = 0.036

Mason et al. 2006

ES = Effect Size

us acamprosate study itt adjusted analysis
US Acamprosate Study: ITT (Adjusted) Analysis*

Linear Dose Effect: p=0.01

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

Mason et al. 2006

summary2
Summary
  • 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 alcohol dependent patients
NTX, ACA, and NTX/ACA for Relapse Prevention in Alcohol-Dependent Patients

Naltrexone plus acamprosate

1.0

Naltrexone

0.9

Acamprosate

0.8

Placebo

0.7

Proportion ofSurvivors(Nonrelapsing)

0.6

0.5

0.4

0.3

0.2

0.1

0

10

20

30

40

50

60

70

80

Time, d

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

relapse to heavy drinking during treatment
Relapse to Heavy Drinking During Treatment

The COMBINE STUDY, JAMA, 2006

composite clinical outcome during last 8 weeks of treatment
Composite Clinical Outcome* During Last 8 Weeks of Treatment

Naltrexone by CBI

interaction, p=0.02

*No more than 2 days

heavy drinking over 8

weeks, no more than

11 (women) or 14 (men)

Drinks/week, and

no alcohol problems

medications for alcohol rehabilitation3
Medications for Alcohol Rehabilitation
  • Disulfiram
  • Naltrexone
  • Acamprosate
  • Serotonin reuptake inhibitors
  • Ondansetron
  • Topiramate
slide38

Fluoxetine and Relapse Rates

(N=101)

1.0

0.9

Weeks in Treatment

0.8

0.7

0.6

Proportion Abstinent

0.5

0.4

0.3

Fluoxetine

0.2

Placebo

0.1

0.0

0

1

2

3

4

5

6

7

8

9

10

11

12

Kranzler et al., Am J Psychiatry, 1995

completely abstinent during treatment
% Completely Abstinent During Treatment

70

p<0.0001*

Sertraline

60

Placebo

50

40

Percent (%)

30

20

10

0

Type B

Type A

Pettinati et al., Alcohol Clin Exp Res, 2000

summary3
Summary
  • 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 rehabilitation4
Medications for Alcohol Rehabilitation
  • Disulfiram
  • Naltrexone
  • Acamprosate
  • Serotonin reuptake inhibitors
  • Ondansetron
  • Topiramate
ondansetron
Ondansetron

Johnson et al., JAMA, 2000

summary4
Summary
  • Ondansetron reduces drinking behavior only among early-onset alcoholics.
  • Independent replication of this finding is needed.
medications for alcohol rehabilitation5
Medications for Alcohol Rehabilitation
  • Disulfiram
  • Serotonin reuptake inhibitors
  • Ondansetron
  • Naltrexone
  • Acamprosate
  • Topiramate
topiramate topamax mean change from pretreatment
Topiramate (Topamax): Mean Change from Pretreatment

P = 0.0004

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

Johnson et al., Lancet 2003

topiramate treatment of alcohol dependence
Topiramate Treatment of Alcohol Dependence

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

P<.003

P<.0004

Days Abstinent

Heavy Drinking Days

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

conclusions
Conclusions
  • 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.