Journal of Studies on

Alcohol

MATTSON, M.E. AND LITTEN, R.Z. Combining Treatments for Alcoholism: Why and How? 

Treatment of alcohol disorders through the use of combinations of pharmacological and behavioral modalities may more effectively address the multicomponent nature of the disorder than single-modality approaches. Interdisciplinary models of the biological, psychological and social components of alcohol disorders are emerging rapidly from basic research, and treatment researchers have begun to test various strategies to combine medications and behavioral treatments. In addition to behavioral and pharmacological combinations, effective treatment pairs can be composed of two medications whose mechanisms of action are believed to be compatible and potentially additive, or even synergistic. Combining Medications and Behavioral Interventions (COMBINE) is a large multisite clinical trial sponsored by the National Institute on Alcohol Abuse and Alcoholism. Its goal is to determine if improvements in treatment outcome for alcohol dependence can be achieved by combining pharmacotherapy and behavioral interventions. Under evaluation is the efficacy of two promising medications (naltrexone and acamprosate), both singly and together, when used in conjunction with two behavioral treatments of differing intensities. This supplement describes in detail the methods and rationale for the approach taken in COMBINE. This first article in the supplement has three objectives: (1) to review strategies for conducting combination treatment studies as illustrated with selected examples from the literature, (2) to summarize the main design features of COMBINE as background for the articles in this supplement and (3) to comment on future directions for combination treatment research as the field moves beyond COMBINE. (J. Stud. Alcohol, Supplement No. 15: 8-16, 2005)

MILLER, W.R., LOCASTRO, J.S., LONGABAUGH, R., O’MALLEY, S. AND ZWEBEN, A. When Worlds Collide: Blending the Divergent Traditions of Pharmacotherapy and Psychotherapy Outcome Research 

Objective: The multisite COMBINE Study brought together a team of alcoholism investigators who varied in whether their expertise was primarily in pharmacotherapy research or in studying psychotherapy. The process of designing a single trial that tested combinations of psychotherapy and pharmacotherapy highlighted the differences in these two research traditions and necessitated a number of compromises that are the focus of this article. Method: The COMBINE trial was designed to investigate the efficacy, separately and in combination, of two medications (i.e., naltrexone, acamprosate) with Medical Management and a state-of-the-art psychotherapy, known as the Combined Behavioral Intervention. Results: Pharmacotherapy researchers favored studying outcome during the treatment period when medications were administered, viewing behavioral intervention as a means for minimizing variance during treatment and providing ethical care in placebo-controlled studies. In contrast, psychotherapy researchers focused on assessment of outcomes after treatment, regarding the behavioral intervention as a source of long-lasting change, necessitating careful training and monitoring of its implementation. The two traditions also differed on variables of interest in studying treatment process and secondary outcomes and methods of data collection and analysis. Some of the solutions reached by the COMBINE Study Research Group included studying both the short-term and long-term effects of treatment and selective inclusion of measures designed to evaluate processes specific to medications and to behavioral interventions. Conclusions: The successful compromises reached by the COMBINE Study Research Group may be helpful to other transdisciplinary research teams undertaking a combined evaluation of promising medications and behavioral interventions for alcoholism. (J. Stud. Alcohol, Supplement No. 15: 17-23, 2005)

COUPER, D.J., HOSKING, J.D., CISLER, R.A., GASTFRIEND, D.R. AND KIVLAHAN, D.R. Factorial Designs in Clinical Trials: Options for Combination Treatment Studies 

Objective: This study reviews the use of factorial designs in clinical trials investigating combinations of therapies. Method: Factorial designs may be used when (1) the factors are regarded as being independent or (2) the factors are thought to be complementary and a specific aim is to investigate these interactions. We describe what is meant by a factorial design and the issues that need to be addressed when using such a design. We discuss these issues in general and describe how they have been addressed in various prevention trials and in the COMBINE Study, which is a treatment trial of combinations of therapies for alcohol dependence. Results: Trials of type (1) can provide substantial cost savings in conducting multiple unrelated prevention studies in the same group of participants. Such a factorial trial poses few design challenges beyond those of a standard parallel group trial. Trials of type (2) require consideration of aspects that are intrinsic to the factorial design. Conclusions: A factorial design is a useful way to examine the effects of combinations of therapies, but it poses challenges that need to be addressed in determining the appropriate sample size and in conducting interim and final statistical analyses. (J. Stud. Alcohol, Supplement No. 15: 24-32, 2005)

HOSKING, J.D., CISLER, R.A., COUPER, D.J., GASTFRIEND, D.R., KIVLAHAN, D.R. AND ANTON, R.F. Design and Analysis of Trials of Combination Therapies

Objective: Combination therapies can have significant advantages over monotherapies. Combinations of therapies can provide additive (or even synergistic) effects on efficacy. They may permit use of lower doses of each component to achieve a given level of efficacy, improving tolerability and reducing adverse effects. A multicomponent treatment may facilitate tailoring of therapy to the needs of individual patients (e.g., treatment augmentation in nonresponders). These characteristics seem highly attractive in developing treatment strategies for alcohol abuse and dependence, because existing monotherapies have shown modest efficacy, at best. Method: However, trials of combination therapies present challenges in design, execution and interpretation, including: (1) choice of the treatment combinations to be compared; (2) definition of primary and secondary hypotheses; (3) differences between interventions in the duration of treatment, the time lag from the start of treatment to an observable effect on outcomes and interval for assessment of efficacy; (4) study power/sample size; (5) logistics of treatment delivery, masking and outcome assessment; and (6) attribution of adverse events. Results: Most of these issues arose in the COMBINE project, a sequence of trials intended to explore the use of combinations of behavioral and pharmacological approaches in the treatment of alcohol dependence. The resolution and impact of the challenges above for the COMBINE trial will be described. Conclusions: Trials of combination therapies address many important clinical questions; however, their level of complexity requires considerable forethought, pilot investigations and organization. (J. Stud. Alcohol, Supplement No. 15: 34-42, 2005)

WEISS, R.D., LOCASTRO, J.S., SWIFT, R., ZWEBEN, A., MILLER, W.R., LONGABAUGH, R. AND HOSKING, J.D. The Use of a “Psychotherapy with No Pills”
Treatment Condition as Part of a Combined Pharmacotherapy- Psychotherapy Research Study of Alcohol Dependence

Objective: The purpose of this article is to review issues related to the use of placebo medication in a study examining combined pharmacotherapy and psychotherapy for alcohol dependence. Method: Little is known about the strength of the placebo effect in alcohol-dependent patients. One way to study this is to compare placebo to no pharmacological treatment. The multisite National Institute on Alcohol Abuse and Alcoholism COMBINE Study is examining optimal combinations of two medications (acamprosate and naltrexone) and two behavioral treatments (a moderate-intensity treatment called Combined Behavioral Intervention [CBI] and a low-intensity treatment called Medical Management [MM]) for alcohol-dependent patients. The study initially included a 2  2  2 eight-cell design. This article relates our experience adding a ninth treatment condition (Cell 9), consisting of CBI alone, with no pills or MM. By comparing patients receiving CBI alone to patients receiving two placebos, MM and CBI, we can examine the strength of the placebo effect for these two medications in alcohol-dependent patients. Moreover, we can study CBI in the context in which it is frequently delivered clinically, that is, in the absence of pharmacotherapy and certainly in the absence of placebo medication. Results: This article explains the background and rationale behind the decision to include Cell 9 in COMBINE. Recruitment challenges faced as a result of adding this condition are reviewed, as is the experience implementing this condition in a pilot feasibility study. Conclusions: The use of a “psychotherapy with no pills” treatment condition as part of a combined pharmacotherapy-psychotherapy study of alcohol dependence is feasible and can help enrich the results of this research. (J. Stud. Alcohol, Supplement No. 15: 43-49, 2005)