1. Recent Developments in the Pharmacotherapy of Alcoholism Henry R. Kranzler, M.D. Alcohol Research Center Univ. 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 Alcohol Dependence 7.9 million (3.8%) Alcohol Abuse 9.7 million (4.7%) NIAAA= National Institute on Alcohol Abuse and Alcoholism Grant BF, et al. Arch Gen Psychiatry. 2004;61:807-816. Any Alcohol Use Disorder 17.6 million (8.5%) NIAAA – National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)

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. 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.

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) Noncompliant (80%) Compliant (20%) 0 10 20 30 40 50 Percent Remaining Abstinent Fuller RK et al. JAMA. 1986; 256:1449-1455 Disulfiram 250 mg (N=202 men) Disulfiram 1 mg (N=204 men) Placebo (N = 199 men)

13. Drinking 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

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 Number of Weeks Receiving Medication 1023456789101112 0.0 0.1 0.2 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.3 Cumulative Proportion with No Relapse Naltrexone (N=35) Placebo (N=35) 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. Vivitrex (Alkermes, Inc.)  Common biodegradable medical polymer that is used for sutures, extended release pharmaceuticals  Metabolized to CO 2 and H 2 0 Dry Powder Microspheres Diluent Microsphere Suspension Hypodermic Needle IM Once Monthly Dosing +

20. Time (Days) 051015202530 Naltrexone (ng/mL) 0 5 10 15 20 25 30 35 40 Mean Steady State Naltrexone Concentration Following Vivitrex ® 380 mg Compared to Daily Oral Dosing 380 mg IM Mean ± SD 50 mg Oral Mean ± SD

21. Results: Heavy Drinking Days Pretreatment Placebo Vivitrex 190 mg Vivitrex 380 mg 75 th Percentile 25 th Percentile Median Heavy Drinking Days per Month 0 5 10 15 20 25 30 n = 624 19.3 3.1 6.0 4.5 Garbutt et al., 2005

22. Effect of Long-Acting Naltrexone on Maintenance of Abstinence 0 10 20 30 40 50 60 70 80 90 100 Percent without Relapse p < 0.025 Placebo (n = 28) Vivitrex (n = 28) Subjects with 4-day lead-in abstinence 12354678109111213151416171820192122232524262728302931 Weeks

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 Kranzler et al., J Clin Psychopharmacol, 2003 Med: p =.092, 19.0% reduction; Med X Sched X Time: p =.001

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. Sass et al. Study Sass et al. Study % of Patients Abstinent 100 Weeks 80 60 40 20 0 024487296 Treatment Period*Follow-Up Period † Sass et al., Arch Gen Psychiatry, 1996 *p=0.001; † p=0.003 Sass et al., Arch Gen Psychiatry, 1996 43% 21% 17% 37% Placebo (N=136) Acamprosate (N=136)

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

31. US Acamprosate Study: ITT (Adjusted) Analysis* Mason et al. 2006 Linear Dose Effect: p=0.01 * Adjusted for severity, readiness to change, psychological antecedents, ASI score, treatment exposure

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 Kiefer F et al. Arch Gen Psychiatry. 2003;60:92-99. 01020304050607080 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Proportion of Survivors (Nonrelapsing) Time, d Placebo Acamprosate Naltrexone Naltrexone plus acamprosate

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. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0123456789101112 Fluoxetine Placebo Fluoxetine and Relapse Rates Weeks in Treatment Proportion Abstinent Kranzler et al., Am J Psychiatry, 1995 (N=101)

39. % Completely Abstinent During Treatment 0 10 20 30 40 50 60 70 Type BType A Sertraline Placebo Pettinati et al., Alcohol Clin Exp Res, 2000 Percent (%) p<0.0001*

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 Pretreatment: 68.3% (topiramate) vs. 60.8% (placebo) Johnson et al., Lancet 2003 P = 0.0004

46. Topiramate Treatment of Alcohol Dependence Percent Change From Baseline in Self-Reported Drinking at Week 12 Heavy Drinking Days Days Abstinent P<.0004 P<.003 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.