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The COMBINE Study: A Randomized Controlled Trial

Raymond F. Anton, MD; Stephanie S. O’Malley, PhD; Domenic A. Ciraulo, MD; Ron A. Cisler, PhD; David Couper, PhD; Dennis M. Donovan, PhD; David R. Gastfriend, MD; James D. Hosking, PhD; Bankole A. Johnson, MD, PhD; Joseph S. LoCastro, PhD; Richard Longabaugh, EdD; Barbara J. Mason, PhD; Margaret E. Mattson, PhD; William R. Miller, PhD; Helen M. Pettinati, PhD; Carrie L. Randall, PhD; Robert Swift, MD; Roger D. Weiss, MD; Lauren D. Williams, MD; Allen Zweben, DSW; for the COMBINE Study Research Group

JAMA. 2006;295:2003-2017.

Context  Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.

Objectives  To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.

Design, Setting, and Participants  Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.

Interventions  Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.

Main Outcome Measures  Percent days abstinent from alcohol and time to first heavy drinking day.

Results  All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone x behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.

Conclusions  Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.

Trial Registration  clinicaltrials.gov Identifier: NCT00006206

Author Affiliations: Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston (Drs Anton and Randall); Substance Abuse Treatment Unit, Yale University School of Medicine, New Haven, Conn (Dr O’Malley); Boston University School of Medicine, Boston, Mass (Dr Ciraulo); University of Wisconsin–Milwaukee (Drs Cisler and Zweben); Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill (Drs Couper and Hosking); Addictions Treatment Center, University of Washington, Seattle (Dr Donovan); Massachusetts General Hospital, Boston (Dr Gastfriend); University of Texas Health Science Center at San Antonio (Dr Johnson); Veterans Affairs Boston Healthcare System/Boston University School of Medicine, Boston, Mass (Dr LoCastro); Roger Williams Medical Center, Brown University, Providence, RI (Drs Longabaugh and Swift); University of Miami School of Medicine, Miami, Fla (Drs Mason and Williams); National Institute of Alcohol Abuse and Alcoholism, Bethesda, Md (Dr Mattson); Center on Alcoholism, Substance Abuse and Addiction, University of New Mexico, Albuquerque (Dr Miller); Treatment and Research Center, University of Pennsylvania, Philadelphia (Dr Pettinati); and Harvard University/McLean Hospital, Belmont, Mass (Dr Weiss). Dr Gastfriend is now affiliated with Alkermes Inc, Cambridge, Mass; Dr Johnson is now with University of Virginia Health Systems, Charlottsville; Dr Mason is now with The Scripps Research Institute, La Jolla, Calif; and Dr Zweben is now with Columbia University School of Social Work, New York, NY.

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Pharmacotherapy and Behavioral Intervention for Alcohol Dependence
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