1. Background and Rationale for COMBINE A Multisite Clinical Trial Sponsored by National Institute on Alcohol Abuse and Alcoholism NIH, DHHS Margaret E. Mattson, Ph.D Margaret E. Mattson, Ph.D National Institute on Alcohol Abuse and Alcoholism

2. Background for COMBINE (a) Variety of effective behavioral counseling treatments were available by the end of the 1990’s. Growing excitement in the field about potential for pharmacologic treatment, with two new medications available (naltrexone and acamprosate.) Pressures from managed care on treatment system increased interest in less intense, out- patient types of therapy.

3. Background for COMBINE (b) Refinement of clinical trials methodology & experience with multisite trials technology, (e.g. Project MATCH) extended capabilities. UNKNOWN: What combinations of medication & behavioral treatments are the most effective and appropriate for changing system needs?

4. Hypothesis of COMBINE Combinations of pharmacological and behavioral treatments may enhance each other and improve outcomes.

5. Rationale For Choice Of Drugs (a) Strong evidence of efficacy for both naltrexone and acamprosate Clinical observations suggest that the drugs may work differently –Acamprosate may be effective in the early treatment period by alleviating protracted withdrawal symptoms. –Naltrexone may block positive reinforcing effects of ethanol and reduce craving.

6. Rationale for Choice of Drugs(b) Proposed mechanisms of action of the drugs are different. –Acamprosate thought to act through the glutamate system to alter neuronal excitability. Naltrexone acts by opioid receptor blockade. Combination therapy may provide additive or synergistic therapeutic effects. –But the effects on compliance & toxicity of the combination were unknown

7. Rationale for Behavioral Therapies Decision to test contrasting therapies of moderate intensity versus lower intensity. Aim was to test two behavioral treatments to determine if more specialized behavioral treatment yields better outcomes over and beyond a primary care model of counseling.

8. Moderate Intensity Model: Combined Behavioral Therapy (CBI) Built on previously validated treatments –Motivational Enhancement Therapy (MET) –Cognitive Behavioral Therapy (CBT) –Facilitation in mutual-help groups (TSF) –Couples Therapy –Community Reinforcement Therapy Delivered by a behavioral health specialist

9. Less Intensive Model: Medication Management (MM) Starting point was previously validated models of brief intervention used to support medication treatment in primary care settings. Components included: – strategies to promote medication compliance – provide information about alcoholism and the medications –support for abstinence – referral to peer support groups. Delivered by health care provider

10. Treatment Manuals Are Available to the Community Both manuals can be ordered through the NIAAA website http://www.niaaa.nih.gov or or http://pubs.niaaa.nih.gov

11. Primary Study Questions Are naltrexone and acamprosate safe and effective in a large, well-controlled, multicenter trial both singly and in combination? Is behavioral counseling of moderate intensity delivered by a specialist more effective than a less intense, primary care model of counseling? Are combinations of these treatments more effective than the separate treatments?

12. Secondary Questions Secondary Questions How well are treatment gains maintained over one year of follow-up? What is the effect of taking pills and receiving monitoring and counseling from a health care provider on patients also receiving a moderately intense behavioral treatment?