Recent Developments in the Pharmacotherapy of Alcoholism Henry R. Kranzler, M.D. Alcohol Research Center Univ. of CT Sch

1. Recent Developments in the Pharmacotherapy of AlcoholismHenry R. Kranzler, M.D.Alcohol Research CenterUniv. of CT School of Medicine

2. 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)

3. 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

4. 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.

5. 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

6. 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

7. Medications Approved in the US for Treatment of Alcohol Dependence • Disulfiram (Antabuse): 1949 • Naltrexone (ReVia): 1994 • Acamprosate (Campral): 2004 • Long-Acting Naltrexone (Vivitrol): 2006

8. 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

9. . # 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 )

10. Medications for Alcohol Rehabilitation • Disulfiram • Naltrexone • Acamprosate • Serotonin Reuptake Inhibitors • Ondansetron • Topiramate

11. 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

12. 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

13. 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

14. 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

15. Medications for Alcohol Rehabilitation • Disulfiram • Naltrexone • Acamprosate • Serotonin reuptake inhibitors • Ondansetron • Topiramate

16. 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

17. 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

18. 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

19. 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

20. 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)

21. 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

22. 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)

23. 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

24. 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

25. 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.

26. Medications for Alcohol Rehabilitation • Disulfiram • Naltrexone • Acamprosate • Serotonin reuptake inhibitors • Ondansetron • Topiramate

27. 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)

28. 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

29. 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

30. US Acamprosate Study: ITT Analysis ES = 0.129 ES = 0.036 Mason et al. 2006 ES = Effect Size

31. 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

32. 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.

33. 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.

34. Relapse to Heavy Drinking During Treatment The COMBINE STUDY, JAMA, 2006

35. Relapse to Heavy Drinking: Naltrexone x CBI Interaction The COMBINE STUDY, JAMA, 2006

36. 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

37. Medications for Alcohol Rehabilitation • Disulfiram • Naltrexone • Acamprosate • Serotonin reuptake inhibitors • Ondansetron • Topiramate

38. 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

39. % 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

40. 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.

41. Medications for Alcohol Rehabilitation • Disulfiram • Naltrexone • Acamprosate • Serotonin reuptake inhibitors • Ondansetron • Topiramate

42. Ondansetron Johnson et al., JAMA, 2000

43. Summary • Ondansetron reduces drinking behavior only among early-onset alcoholics. • Independent replication of this finding is needed.

44. Medications for Alcohol Rehabilitation • Disulfiram • Serotonin reuptake inhibitors • Ondansetron • Naltrexone • Acamprosate • Topiramate

45. Topiramate (Topamax): Mean Change from Pretreatment P = 0.0004 Pretreatment: 68.3% (topiramate) vs. 60.8% (placebo) Johnson et al., Lancet 2003

46. 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.

47. 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.