This spring, the federal government launched a major randomized study of behavioral and drug treatments for alcohol dependence, uniting--for the first time--research in two fields of treatment that have evolved largely in isolation.
The "Combining Medications and Behavioral Interventions" study, or COMBINE, is the first large-scale examination of both pharmacologic and behavioral treatments for alcoholism alone and in combination. The study is funded and coordinated by the National Institute on Alcohol Abuse and Alcoholism (NIAAA).
Over the next two years, researchers at 11 treatment research centers around the United States will recruit 1,375 people who meet criteria for alcohol dependence. Participants in the study will be randomly assigned to one of several treatment conditions, allowing researchers to assess the benefits of the pharmaceutical and psychosocial treatments alone and in combination with others.
"Current treatments for alcohol dependence are not successful with as many people as we'd like them to be," says Yale University Medical School psychologist Stephanie S. O'Malley, PhD, one of the study's lead investigators and president-elect of the Research Society on Alcoholism. "Through the COMBINE trial," she says, "we're moving forward in trying to improve our success rates. We know that no two people are alike, and it's important for us to have a range of treatments available in order to best respond to individual patients."
"This should provide hope for alcoholics who have failed other treatments before," adds Medical University of South Carolina psychiatrist Raymond Anton, MD, chair of the COMBINE steering committee.
In addition, he notes, because the study is so large and pieces of it are dispersed across the United States, COMBINE is expected to raise public awareness that alcoholism, as a disease, can be treated by integrating psychosocial and medical approaches.
Advances in treatment
In recent years, scientists have made great strides in understanding the biological basis of alcohol dependence. As a result, two new pharmacologic treatments--naltrexone and acamprosate--have emerged, holding promise for helping alcoholics remain abstinent.
Naltrexone, approved by the U.S. Food and Drug Administration (FDA) in 1994, blocks opioid receptors in the brain, thus weakening alcohol's rewarding effects and helping prevent alcoholics from returning to heavy drinking after a small relapse.
Acamprosate, which has been in regular use in Europe for 14 years under the brand name Campral and is under review by the FDA, works differently. Although its action is not wholly understood, scientists believe the drug normalizes abnormalities in two other neurotransmitter systems in the brain, called the glutamate and GABA systems. The drug appears to ease the discomfort of long-term abstinence from alcohol, reducing the risk of relapse.
At the same time, behavioral scientists have identified several promising psychosocial interventions. In particular, in 1996 NIAAA's Project MATCH found three approaches to be effective in helping people remain abstinent from alcohol:
Motivational enhancement programs that raise people's awareness of the impact that alcohol has on their lives and that encourage them to commit to changing their behavior.
Cognitive behavioral therapy that provides people with skills to recognize and cope with urges to drink--for example, by training them to recognize what triggers drinking, to manage negative moods and to orient their social lives to something other than drinking.
12-step facilitation programs, which encourage and help people to become involved with a traditional 12-step program, such as Alcoholics Anonymous.
In the double-blind COMBINE study, participants will be randomly assigned to receive either a placebo, naltrexone, acamprosate or both during four months of treatment.
In addition, each participant will receive one of two behavioral treatments. In the lower-intensity "medical management" treatment condition, designed to boost medication compliance, health professionals in primary-care settings will administer brief weekly interventions that emphasize the importance of sobriety and provide general information about drug side effects and other concerns.
The moderate-intensity "combined behavioral intervention" will offer lengthier and more intensive treatment sessions that include the three psychosocial interventions shown effective in Project MATCH: motivational enhancement, cognitive behavioral therapy and 12-step facilitation.
Following the four-month treatment period, all participants will return for follow-up visits for one year.
"We hope this will be a definitive study," says neurobiologist Margaret Mattson, PhD, NIAAA staff collaborator for the COMBINE study. "It brings together two fields of research that have been progressing somewhat independently for a long time."
In addition to the main COMBINE study, an ancillary study will investigate genetic variations that might influence how successful particular pharmacologic or behavioral treatments are likely to be for a given person.
"What's excited people most about the genome revolution is the realization that therapy can be individualized," says NIAAA's David Goldman, MD, who heads the genetic study.
In the case of alcoholism, he explains, several potential genetic "gatekeepers," or genetic variants, may alter the effects of a particular drug or psychosocial treatment.
One, for example, is a common gene variant, or polymorphism, known as the mu receptor genotype, which alters how some chemicals bind to opioid receptors in the brain. Because naltrexone is one such chemical, Goldman and his colleagues are interested in whether people who carry one form of the gene respond differently to naltrexone therapy.
This differential response might cause better or worse response to treatment or could be manifested as a difference in side effects experienced with naltrexone. Either effect could be important in a treatment study.
It's equally possible, Goldman notes, that genetic polymorphisms might also influence people's responses to non-pharmaceutical interventions--and would be equally valuable to know about in designing individualized treatment plans. For example, for people who possess a genetic variant that heightens the intensity of alcohol craving, behavioral treatments might especially focus on ways to cope with craving.
Goldman concludes, "The COMBINE study represents an extraordinary opportunity to look at genetic interactions not only with two of the newest and most promising drugs available for alcoholism, but it also provides an opportunity to look at the role of genetic factors in the context of a very thorough and methodologically sound study of medical and behavioral intervention in alcoholism."