The Combine Study

Combining Medication and Behavioral Intervention in Treating Alcohol Dependence

The COMBINE Study was a multisite clinical trial sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), to test whether combinations of medication and behavioral intervention would be more effective than monotherapies in the treatment of alcohol dependence.  The University of New Mexico Center on Alcoholism, Substance Abuse and Addictions (CASAA) served as one clinical performance site, and also as the central treatment training and monitoring center for the trial.

                Two behavioral interventions were developed specifically for this trial.  One was a Medication Management protocol (MM; Pettinati et al., 2004, 2005), to be used as a platform for delivering the two medications being tested in the trial: acamprosate and naltrexone.  All participants who received medication or placebo were also offered the 11-session MM intervention, which was designed to monitor medication effects and promote adherence.

                The COMBINE team also sought to develop a state-of-the-art psychotherapy for alcohol dependence, drawing in particular on what had been learned in Project MATCH.  The new Combined Behavioral Intervention (CBI, Miller, 2004; Longabaugh et al., 2005) was intended to combine the best components  of the MATCH cognitive-behavioral and motivational-enhancement therapies, and also to encourage involvement in 12-step or other mutual support networks.  By random assignment, CBI was offered (or not) to participants with or without medication.  The nine treatment groups in the trial were:

                Acamprosate + Placebo (with MM), no CBI

                Naltrexone + Placebo (with MM), no CBI

                Acamprosate + Naltrexone (with MM), no CBI

                Double Placebo (with MM), no CBI

                Acamprosate + Placebo (with MM) + CBI

                Naltrexone + Placebo (with MM) + CBI

                Acamprosate + Naltrexone (with MM) + CBI

                Double Placebo (with MM) + CBI

                CBI alone, without pills or MM  (Weiss et al., 2005)

                The trial findings (Anton et al., 2006; Donovan et al., 2008) supported the efficacy of CBI and of Naltrexone, but showed no benefit from Acamprosate.  Surprisingly, the combination of CBI and Naltrexone was no more effective than either one alone.  Another unexpected finding was that the group given CBI but no pills or MM showed significantly poorer outcomes (compared, for example, to those given CBI plus placebo).  One possible explanation is that given the high profile of medication in this trial, there may have been adverse expectancy effects among participants who were denied medication   A corollary of this finding was a very strong placebo effect – that participants taking pills in addition to CBI showed significantly better outcomes, even when both pills were placebos.  Given the study design, it was not possible to separate the placebo effect from the effect of the MM intervention that always accompanied it.

Publications from the COMBINE Study

COMBINE Study Research Group (2003). Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: Rationale and methods.  Alcoholism: Clinical and Experimental Research, 27, 1107-1122.

COMBINE Study Research Group (2003).  Testing combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE Study): A pilot feasibility study.  Alcoholism: Clinical and Experimental Research, 27, 1123-1131.

Miller, W. R. (Ed.) (2004).  Combined Behavioral Intervention: A clinical research guide for therapists treating individuals with alcohol abuse and dependence.  COMBINE Monograph Series, (Vol.1) National Institute on Alcohol Abuse and Alcoholism, Public Health Service, U.S. Dept of Health and Human Services.

Pettinati, H. M., Weiss, R., Miller, W. R., Donovan, D., & Rounsaville, B. J. (2004). Medical Management (MM) treatment manual: A guide for medically-trained clinicians providing pharmacotherapy as part of the treatment for alcohol dependence.

Longabaugh, R., Zweben, A., LoCastro, J. S., & Miller, W. R. (2005).  Origins, issues and options in the development of the Combined Behavioral Intervention.  Journal of Studies on Alcohol, Supplement No. 15, 179-187.

Miller, W. R., LoCastro, J. S., Longabaugh, R., O’Malley, S., & Zweben, A. (2005).  When worlds collide: Blending the divergent traditions of pharmacotherapy and psychotherapy outcome research.  Journal of Studies on Alcohol, Supplement No. 15, 17-23

Pettinati, H. M., Weiss, R. D., Dundon, W., Miller, W. R., Donovan, D., Ernst, D. B., & Rounsaville, B. J. (2005).  A structured approach to medical management (MM): A psychosocial intervention to support pharmacotherapy in the treatment of alcohol dependence.  Journal of Studies on Alcohol, Supplement No. 15, 170-178.

Weiss, R. D., LoCastro, J. S., Swift, R., Zweben, A., Miller, W. R., Longabaugh, R., & Hosking, J. D. (2005).  The use of a “psychotherapy with no pills” treatment condition as part of a combined pharmacotherapy-psychotherapy research study of alcohol dependence.  Journal of Studies on Alcohol, Supplement No. 15, 43-49.

Anton, R. F., Miller, W. R., O’Malley, S. S., Zweben, A., & Hosking, J. D. (2006).  Pharmacotherapy and behavioral intervention for alcohol dependence: In reply.  Journal of the American Medical Association, 296, 1728-1729.

Anton, R. F., O’Malley, S. S., Ciraulo, D. A., Cisler, R. A., Couper, D., Donovan, D. M., Gastfriend, D. R., Hosking, J. D., Johnson, B. A., LoCastro, J. S., Longabaugh, R., Mason, B. J., Mattson, M. E., Miller, W. R., Pettinati, H. M., Randall, C. L., Swift, R., Weiss, R. D., Williams, L. D., & Zweben, A. for the COMBINE Study Research Group (2006).  Combined pharmacotherapies and behavioral interventions for alcohol dependence.  The COMBINE study: A randomized controlled trial.  Journal of the American Medical Association, 295, 2003-2017.

Donovan, D. M., Anton, R. F., Miller, W. R., Longabaugh, R., Hosking, J. D., & Youngblood, M. for the COMBINE Study Research Group (2008).  Combined pharmacotherapies and behavioral interventions for alcohol dependence (the COMBINE study): Examination of post-treatment drinking outcomes.  Journal of Studies on Alcohol and Drugs, 69, 5-13.