Background and RationaleBackground and Rationalefor COMBINEfor COMBINE

A Multisite Clinical Trial A Multisite Clinical Trial Sponsored by Sponsored by

National Institute on Alcohol Abuse National Institute on Alcohol Abuse and Alcoholismand Alcoholism

NIH, DHHSNIH, DHHS

Margaret E. Mattson, Ph.DMargaret E. Mattson, Ph.D

National Institute on Alcohol Abuse National Institute on Alcohol Abuse and Alcoholism and Alcoholism

Background for COMBINE (a)Background for COMBINE (a)

Variety of effective behavioral counseling Variety of effective behavioral counseling treatments were available by the end of the treatments were available by the end of the 1990’s. 1990’s.

Growing excitement in the field about potential Growing excitement in the field about potential for pharmacologic treatment, with two new for pharmacologic treatment, with two new medications available (naltrexone and medications available (naltrexone and acamprosate.)acamprosate.)

Pressures from managed care on treatment Pressures from managed care on treatment system increased interest in less intense, out-system increased interest in less intense, out-patient types of therapy. patient types of therapy.

Background for COMBINE (b)Background for COMBINE (b)

Refinement of clinical trials methodology & Refinement of clinical trials methodology & experience with multisite trials technology, experience with multisite trials technology, (e.g. Project MATCH) extended capabilities.(e.g. Project MATCH) extended capabilities.

UNKNOWN: What combinations of UNKNOWN: What combinations of medication & behavioral treatments are medication & behavioral treatments are the most effective and appropriate for the most effective and appropriate for changing system needs?changing system needs?

Hypothesis of COMBINEHypothesis of COMBINE

Combinations of pharmacological Combinations of pharmacological and behavioral treatments and behavioral treatments

may enhance each other and may enhance each other and improve outcomes.improve outcomes.

Rationale For Choice Of DrugsRationale For Choice Of Drugs (a) (a)

Strong evidence of efficacy for both Strong evidence of efficacy for both naltrexone and acamprosatenaltrexone and acamprosateClinical observations suggest that the Clinical observations suggest that the drugs may work differentlydrugs may work differently– Acamprosate may be effective in the early Acamprosate may be effective in the early

treatment period by alleviating protracted treatment period by alleviating protracted withdrawal symptoms. withdrawal symptoms.

– Naltrexone may block positive reinforcing Naltrexone may block positive reinforcing effects of ethanol and reduce craving. effects of ethanol and reduce craving.

Rationale for Choice of Drugs(b)Rationale for Choice of Drugs(b)Proposed mechanisms of action of the Proposed mechanisms of action of the drugs are different. drugs are different. – AcamprosateAcamprosate thought to act through the thought to act through the

glutamate system to alter neuronal glutamate system to alter neuronal excitability. excitability. NaltrexoneNaltrexone acts by opioid acts by opioid receptor blockade.receptor blockade.

Combination therapy may provide additive Combination therapy may provide additive or synergistic therapeutic effects.or synergistic therapeutic effects.– But the effects on compliance & toxicity of the But the effects on compliance & toxicity of the

combination were unknown combination were unknown

Rationale for Behavioral TherapiesRationale for Behavioral Therapies

Decision to test contrasting therapies of Decision to test contrasting therapies of moderate intensity versus lower intensity. moderate intensity versus lower intensity.

Aim was to test two behavioral treatments Aim was to test two behavioral treatments to determine if more specialized to determine if more specialized behavioral treatment yields better behavioral treatment yields better outcomes over and beyond a primary care outcomes over and beyond a primary care model of counseling.model of counseling.

Moderate Intensity Model:Moderate Intensity Model:Combined Behavioral Therapy (CBI) Combined Behavioral Therapy (CBI)

Built on previously validated treatmentsBuilt on previously validated treatments– Motivational Enhancement Therapy Motivational Enhancement Therapy

(MET)(MET)– Cognitive Behavioral Therapy (CBT)Cognitive Behavioral Therapy (CBT)– Facilitation in mutual-help groups (TSF)Facilitation in mutual-help groups (TSF)– Couples TherapyCouples Therapy– Community Reinforcement TherapyCommunity Reinforcement Therapy

Delivered by a behavioral health Delivered by a behavioral health specialistspecialist

Less Intensive Model: Medication Less Intensive Model: Medication Management (MM)Management (MM)

Starting point was previously validated models of Starting point was previously validated models of brief intervention used to support medication brief intervention used to support medication treatment in primary care settings. treatment in primary care settings.

Components included:Components included:– strategies to promote medication compliancestrategies to promote medication compliance– provide information about alcoholism and the provide information about alcoholism and the

medications medications – support for abstinencesupport for abstinence– referral to peer support groups.referral to peer support groups.

Delivered by health care providerDelivered by health care provider

Treatment Manuals Are Available Treatment Manuals Are Available to the Communityto the Community

Both manuals can be Both manuals can be ordered through the ordered through the NIAAA website NIAAA website

http://www.niaaa.nih.govhttp://www.niaaa.nih.gov oror

http://pubs.niaaa.nih.govhttp://pubs.niaaa.nih.gov

Primary Study QuestionsPrimary Study QuestionsAre naltrexone and acamprosate safe and Are naltrexone and acamprosate safe and effective in a large, well-controlled, multicenter effective in a large, well-controlled, multicenter trial both singly and in combination?trial both singly and in combination?

Is behavioral counseling of moderate intensity Is behavioral counseling of moderate intensity delivered by a specialist more effective than a delivered by a specialist more effective than a less intense, primary care model of counseling?less intense, primary care model of counseling?

Are combinations of these treatments more Are combinations of these treatments more effective than the separate treatments?effective than the separate treatments?

Secondary QuestionsSecondary Questions

How well are treatment gains maintained over How well are treatment gains maintained over one year of follow-up?one year of follow-up?

What is the effect of taking pills and receiving What is the effect of taking pills and receiving monitoring and counseling from a health care monitoring and counseling from a health care provider on patients also receiving a moderately provider on patients also receiving a moderately intense behavioral treatment? intense behavioral treatment?