1. The COMBINE Study: Results and Implications Social Work Research and Multidisciplinary Studies: Findings from Major Landmark Studies SSWR Annual Conference San Francisco, CA January 13, 2007 Allen Zweben, DSW Associate Dean and Professor Columbia University School of Social Work

2. Primary Outcome Manuscript Writing Group Raymond F. Anton, MD (Study Chair)Richard Longabaugh, EdD Stephanie S. O’Malley, PhD (Former Study Chair) Barbara J. Mason, PhD Domenic A. Ciraulo, MDMargaret E. Mattson, PhD (NIAAA) Ron A. Cisler, PhDWilliam R. Miller, PhD David Couper, PhDHelen M. Pettinati, PhD Dennis M. Donovan, PhDCarrie L. Randall, PhD David R. Gastfriend, MDRobert Swift, MD James D. Hosking, PhDRoger D. Weiss, MD Bankole A. Johnson, MD, PhDLauren D. Williams, MD Joseph S. LoCastro, PhDAllen Zweben, DSW

3. Primary Outcome Manuscript Writing Group Raymond F. Anton, MD –Center for Alcohol Programs, Medical University of South Carolina, Charleston, SC Stephanie S. O’Malley, PhD –Substance Abuse Treatment Unit, Yale University School of Medicine, New Haven, CT Domenic A. Ciraulo, MD –Boston University School of Medicine, Boston, Massachusetts James D. Hosking, PhD –Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC Dennis M. Donovan, PhD –Addictions Treatment Center, University of Washington, Seattle, WA Principal Investigators

4. Primary Outcome Manuscript Writing Group (continued) David R. Gastfriend, MD –Formerly: Massachusetts General Hospital, Boston, MA; currently: Alkermes, Inc. Bankole A. Johnson, MD, PhD –Formerly: University of Texas Health Science Center at San Antonio, TX; currently: University of Virginia Health Systems, Charlottesville, VA Richard Longabaugh, EdD –Roger Williams Medical Center, Brown University, Providence, RI Barbara J. Mason, PhD –Formerly: University of Miami School of Medicine, Miami, FL; currently: The Scripps Research Institute, La Jolla, CA Margaret E. Mattson, PhD –National Institute of Alcohol Abuse and Alcoholism, Bethesda, MD

5. Primary Outcome Manuscript Writing Group (continued) William R. Miller, PhD –Center on Alcoholism, Substance Abuse and Addiction, University of New Mexico, Albuquerque, NM Helen M. Pettinati, PhD –Treatment and Research Center, University of Pennsylvania, Philadelphia, PA Robert Swift, MD –Roger Williams Medical Center, Brown University, Providence, RI Roger D. Weiss, MD –Harvard University/McLean Hospital, Belmont, MA Lauren D. Williams, MD –University of Miami School of Medicine, Miami, FL Allen Zweben, DSW –Formerly: University of Wisconsin - Milwaukee, Milwaukee, WI; currently: Columbia University School of Social Work, New York, NY

6. Primary Outcome Manuscript Writing Group (continued) Ron A. Cisler, PhD –University of Wisconsin - Milwaukee, Milwaukee, WI David Couper, PhD –Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC Joseph S. LoCastro, PhD –VA Boston Healthcare System/Boston University School of Medicine, Boston, MA Carrie L. Randall, PhD –Center for Alcohol Programs, Medical University of South Carolina, Charleston, SC Co-Investigators

7. COMBINE Centers

8. Rationale for COMBINE Recent advances have occurred in the development of pharmacological and behavioral treatments for alcohol dependence The hypothesis that pharmacological and behavioral treatments may enhance each other and yield optimal improvement rates requires investigation COMBINE evaluated the efficacy of naltrexone, acamprosate, and specialized behavioral counseling individually and in combination.

9. Promising BehavioralTreatments: Moderate Intensity Models Project MATCH designed three treatments to be nonoverlapping in terms of content. COMBINE will incorporate the putative strengths of each of these treatments. –Motivational enhancement –Cognitive behavioral skills training –Facilitation in mutual-help groups Patients receiving CBI could have a maximum of 20 sessions (50 min.) over 16 weeks of manual driven therapy by masters level, trained and certified counselors.

10. Medical Management (MM) Ecological validity Enhancement of medication compliance and support for sobriety Prior support for effectiveness Cost effective alternative to CBI Lower intensity to produce differential effects Available manuals All subjects (except one group – CBI only) received 9 sessions (15-20 min.) of MM by a health care professional (physician, nurse, physician assistant)

11. Rationale For Choice Of Drugs Strong evidence of efficacy for both naltrexone and acamprosate Clinical observations suggest that the drugs may work differently. –Acamprosate may be effective early in treatment (treatment of prolonged withdrawal or cue-induced craving) –Naltrexone may block positive reinforcing effects of ethanol and reduce craving.

12. COMBINE: Standardization of Psychosocial Interventions Permits a carefully controlled evaluation of the efficacy of the medications and of the behavioral interventions Published research on acamprosate has not specified the intensity or content of the psychosocial component of treatment Published studies of naltrexone have used more intensive behavioral treatments, and the effectiveness of naltrexone with less intensive treatment is unknown.

13. Primary Objective The primary objective of COMBINE is to assess the efficacy of combinations of behavioral and pharmacological interventions in the treatment of alcohol dependence.  Are naltrexone and acamprosate effective in a large, well controlled, multi-center trial?  Is a specialist delivered behavioral intervention more effective than an intervention provided by health care professionals?

14. Study Design Randomized clinical trial 11 clinical centers 1,383 participants with DSM-IV alcohol dependence

15. Study Design COMBINE used an additive design to test whether combinations of behavioral and pharmacological interventions are more effective than medical management and placebo in the treatment of alcohol problems.

16. Treatment Group Combinations (1383 Randomized participants)

17. Primary Outcome Measures Percent Days Abstinent during treatment period Time to relapse (number relapsed) to heavy drinking –Males: 5 drinks / day; Females: 4 drinks / day Secondary Outcome Measures Global Clinical Outcome -No more than 2 heavy drinking days, 11 (women) or 14 drinks (men) per week, and no alcohol problems in a given follow-up interval

18. Dosing Target Doses –Naltrexone 100 mg daily, given as two 50 mg tablets orally in AM –Acamprosate 3 grams (3000 mg) given as two 500 mg tablets orally in AM, mid-day, and PM

19. Schedule of Assessments Pre-Intake Screening Baseline (Drinking, Physical, Social, Lab) Within Treatment – weekly drinking, craving, adverse medication events Within Treatment -- Month 2 Post-Treatment Follow-Up –Weeks 16, 26, 52, and 68 after randomization

20. Statistical Methods Mixed effect linear models for PDA –Intention to treat population: all randomized patients with any post-randomization drinking data Proportional hazards models for time to relapse to heavy drinking –Intention to treat population: all randomized patients (loss to follow-up treated as relapse)

21. Study Sample

22. Participant (n=1383) Characteristics at Baseline

23. Drinking and Severity Measures at Baseline

24. Retention and Adherence

25. Adherence and Validity Measures 94% of 16 week, and 82% of 1 year follow-up drinking data were obtained Dose reductions: 8% placebo, 12% acamprosate, 12% naltrexone, 21% naltrexone plus acamprosate Mean medication adherence: naltrexone 85.4%, acamprosate 84.2% Median visits: CBI = 10, MM = 9 Therapist (CBI and MM) protocol adherence on random tapes by independent raters was 6 on a 7 point scale

26. PDA during Treatment (16 weeks)

27. PDA during Treatment (continued)

28. PDA Effect Size at Week 16

29. Relapse to Heavy Drinking During Treatment (16 weeks)

30. Relapse to Heavy Drinking by Week 16 (continued)

31. Composite Clinical Outcome* during Last 8 Weeks of Treatment *No more than 2 days heavy drinking and no more than 11 (women) or 14 (men) drinks per week and no alc. problems *Naltrexone by CBI interaction, p=0.02

32. Summary There was marked improvement in all groups Acamprosate showed no greater efficacy than placebo. This is surprising since previous studies suggested otherwise There was no increase in efficacy by combining acamprosate with naltrexone Adding naltrexone to CBI did not prove to be more effective as indicated in previous studies In the context of medical management both naltrexone and CBI were more efficacious than placebo Effects observed during treatment were still present but waned during the one year follow-up

33. Implications Take Home Message: Alcohol dependent patients may benefit from being treated by a health care professional who adopts medical management and utilizes either naltrexone and/or refers to a specialized alcohol counselor using CBI-like techniques. This broadens options for treatment for those not previously being treated.Alcohol dependent patients may benefit from being treated by a health care professional who adopts medical management and utilizes either naltrexone and/or refers to a specialized alcohol counselor using CBI-like techniques. This broadens options for treatment for those not previously being treated.

34. Data presented in this report were collected as part of the multisite COMBINE trial sponsored by the National Institute on Alcohol Abuse and Alcoholism, in collaboration with the COMBINE Study Research Group. Acamprosate, naltrexone and their matching placebos were kindly donated by Lipha Pharmaceuticals. Data and Safety Monitoring was conducted by: R Hingson ScDC Meinert PhD R Kadden PhD R Saitz MD MPH M McCaul PhDGerard Connors PhD A full listing of the staff of the COMBINE Study can be found at http://www.cscc.unc.edu/combine/.