Tuesday, March 4, 1997

DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health

Statement by Enoch Gordis, M.D., Director
National Institute on Alcohol Abuse and Alcoholism
March 4, 1997

Formal statement before the House Committe on Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies, Tuesday, March 4, 1997.

I am pleased to be here with you today to discuss the many scientific advances and research opportunities at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

The NIAAA is the foremost Federal agency supporting biomedical and behavioral research directed towards improving the prevention and treatment of alcohol abuse and alcoholism and reducing associated health, economic, and social consequences. NIAAA funds 90 percent of all alcohol research in the United States and provides leadership in the country's effort to combat these problems by developing new knowledge that will decrease the incidence and prevalence of alcohol abuse and alcoholism, and its associated morbidity and mortality.

Alcoholism research has the potential to impact on the lives of approximately 14 million alcoholics, alcohol abusers and their families--an estimated 98 million Americans. Although a dollar figure cannot adequately reflect the social and human devastation caused by these illnesses, it is estimated that the economic and health care costs to society from alcoholism and alcohol abuse approach $100 billion annually. (Rice, Dorothy P. The Economic Cost of Alcohol Abuse and Alcohol Dependence: 1990. Alcohol Health and Research World 17(1):10-11, 1993.) Research findings that improve the prevention or treatment of alcohol abuse and alcoholism have tremendous potential for affecting the quality of life of nearly every American and can influence thinking in other areas of medicine.

Among the areas where alcoholism research has made significant strides is the demonstration that a significant amount of the vulnerability to alcoholism is inherited. Previous twin and adoption studies laid the foundation for current genetics work, much by individual NIAAA intramural scientists but most extensively in the Collaborative Study on the Genetics of Alcoholism (COGA) supported by NIAAA. COGA is a multi-site collaborative, tightly controlled study of large families who have alcoholism multiply represented among their members. COGA involves six extramural research study centers in which investigators are searching the entire human genome for genetic markers linked with alcoholism.

COGA scientists developed accurate, valid, reliable, and specific comprehensive interviewing tools, the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) and its companion version for children (C-SSAGA-C) and adolescents (C-SSAGA-A). These new interviewing tools represent a major advance in currently available interviewing techniques, and are in use internationally. Resources subsequently developed by COGA include diagnostic and pedigree data on 3000 individuals belonging to about 300 families with alcoholism, along with corresponding biochemical, genetic, and neurophysiological data. Also developed is a collection of DNA samples and immortalized cell lines derived from these individuals and maintained in a Cell Repository. COGA resources will thus provide a wealth of data available to the scientific community for further investigation.

We are very pleased to report that initial COGA findings have identified promising chromosomal locations relating to alcoholism, and colloquially referred to as "hot spots." Distinct from this research is the finding of chromosomal locations for a specific brain wave pattern, P3, found in persons at high risk for alcoholism. Each chromosomal location contains many genes and the next task is to identify the precise genes. The payoff for this research is the development of new medications, targeted prevention programs, and a precise understanding of both the genetic and environmental influences on the development of alcoholism.

Another area where alcohol research has advanced is in the use of animal models for studying complex behavior, such as, alcohol consumption. Molecular biology techniques are being used to identify quantitative trait loci (QTL) which give investigators the ability to define the contribution of single genes, any of which together create the quantitative trait. We are pleased to report that an NIAAA-sponsored investigator has located two sex-specific genes influencing alcohol consumption in mice. One QTL (Alcp1) is active only in males; the other (Alcp2) is active only in females, and only when inherited through the maternal lineage. Because of similarities between the mouse and human genes, this work promises to accelerate locating human genes that contribute to alcoholism.

Earlier work led to the conclusion that the neurotransmitter, serotonin, is involved in alcohol consumption. Recently, a study identified one precise serotonin receptor subtype, 5-HT1B , that is involved in regulating the consumption of alcohol in mice. This was accomplished by genetically removing the serotonin receptor, 5-HT1B , and observing increases in alcohol consumption. Stimulation of the 5-HT1A serotonin receptor subtype, however, reduces consumption. Other investigators showed that clinically realistic doses of alcohol affect several neurotransmitters including, NMDA subtype of glutamate receptor, the GABAA receptor, and other serotonin receptors. The effect of alcohol on these receptors varies among brain locations in single animals and between strains raised to demonstrate major differences in alcohol related behaviors.

Advances are also being made in understanding the mechanism of alcohol-induced tissue damage (toxicology). These findings include: the fact that alcohol can influence the expression of cytokine-regulated genes in the liver; that clinical management of alcohol-induced liver injury might be improved by reducing the number of gram-negative bacteria producing endotoxin in the intestine; and that the pathogenesis of fibrosis in alcoholic liver damage may involve the direct deposition of collagen induced by acetaldehyde, the first product of alcohol metabolism.

Advances are also beginning to unravel the mechanisms of alcohol's effects on human fetal development leading to the manifestations of fetal alcohol syndrome (FAS). Two findings suggest reasonable mechanisms for alcohol's effects on the fetus. One finding is that alcohol induces excessive cell death through the formation of free radicals in pre-migratory neural crest cells resulting in subsequent malformation. The addition of a free-radical scavenger can ameliorate alcohol-induced cell death. The second finding is that at clinically relevant levels, alcohol completely inhibits the activity of the L1 cell adhesion molecule which helps guide newly forming neural cells to their proper location.

Research on effective medications is built upon findings such as those previously mentioned. Naltrexone, nalmefene, and acamprosate are among the most promising medications. The use of naltrexone which was recently approved by the FDA for the treatment of alcoholism is based on clinical and basic science observations. NIAAA-sponsored clinical trials are now determining which groups of patients are most responsive to this medication and the benefits and side effects of long-term use. Nalmefene, another opioid antagonist, also appears promising and has several potential advantages over naltrexone including a longer half-life, enhanced bioavailability, less liver toxicity, and more complete blockage of opioid receptors. Acamprosate, now under an FDA investigational new drug protocol, has been tested in clinical studies throughout Europe with promising results. It appears to act on NMDA and GABA receptors. NIAAA is providing consultation on methodology and trial design to pharmaceutical companies planning clinical trials on acamprosate.

In addition to medications development, other aspects of treatment research are also advancing rapidly. We are ready to begin advanced clinical trials built upon data obtained from both medication studies and from the recently completed multi-site treatment trial, called Project MATCH. This study compared the effects of different treatment types when matched to specific patient characteristics and was the largest, most complex randomized clinical trial ever undertaken in alcoholism treatment. A number of alternative treatments for alcohol problems are available. They range from brief, motivational interventions to "broad spectrum" treatments, such as social skills training, and the 12-step "Minnesota model". Frequently two or more treatment types are combined in one therapeutic approach.

Based upon the literature and previous small studies, the hypothesis was advanced that matching patient characteristics to specific treatment modalities would be the most efficacious. Patients were randomly assigned to well-specified treatment strategies. Subsequently the relationship between treatment outcome, patient characteristics, and treatment type were assessed. A total of 1728 patients were recruited from nine states, with ample representation of women (25 percent) and minorities (20 percent). Three specific, well-defined, and well-controlled treatment approaches were tested. The findings from MATCH, however, did not confirm this expectation.

Instead, the three treatments achieved comparable outcomes and the data indicate that each treatment type resulted in substantial reductions in drinking. Furthermore, this reduction in drinking was generally sustained for 12 months. With the exception of patients with serious psychiatric problems, it appears that matching patient characteristics to a specific treatment type did not improve outcome. This study demonstrates that well-designed treatments, in combination with good training of therapists, contribute to excellent retention rates in treatment. Furthermore, these findings run counter to the belief that treatment gains are inconsequential and short-lived.

The next major step is to build upon the findings from Project MATCH and the randomized trials for medication, such as those previously reported for naltrexone. The major goal is to combine MATCH with new insights gained from medications research. Follow-up clinical trials will include new pharmacotherapies, such as naltrexone, nalmefene, and acamprosate, combined with standardized behavioral strategies. In sum, we expect findings from genetics research, neuroscience, and medications development to inform the development of increasingly improved treatment strategies.

Prevention research is also a priority at NIAAA, the goal of which is to obtain scientifically objective and measurable effects attributable to specific interventions. To ensure the acquisition of meaningful results, these studies employ rigorously defined scientific methodologies including random selection and control communities. One excellent example is a recent study nearing completion which may provide a model alcohol use prevention program that can be implemented in communities around the country. The Northland study used a multi-component, multi-year, community trial to delay, prevent, and reduce the prevalence of alcohol use and alcohol-related problems among a group of adolescents from 22 school districts in northeastern Minnesota. The project targets the Class of 1998 and has been ongoing for five years, beginning with students in the sixth grade and following them through grade 10. Interim results look quite hopeful. At the end of three years of program (grade 8) the rates of alcohol use were significantly lower among students in the program school districts compared to the reference districts. When compared to reference districts, 19 percent fewer students who received the program used alcohol in the past month, and past week use was 29 percent lower. Of great significance is the fact that overall fewer students initiated alcohol use. For instance, past month alcohol use by 8th graders who did not drink in grade 6 was 28 percent lower in program communities than in reference communities.

In addition, NIAAA is taking a leading role in educating the public and physicians about alcoholism. Our Alcohol, Health and Research World is an award winning journal and information about nearly all of NIAAA's activities are available on our web site, including grant and funding information. This past year we published and disseminated 75,000 copies of The Physicians' Guide to Helping Patients with Alcohol Problems. At the request of the Office of National Drug Control Policy (ONDCP), an additional 165,000 copies were printed for distribution by ONDCP. DuPont Pharma is also significantly aiding in this effort at their own expense by printing and distributing through their field representatives an additional 60,000 copies to primary care physicians nationwide.

In conclusion, alcohol research is progressing rapidly and the scientific advances and opportunities in our field are very encouraging. Mr. Chairman, the FY 1998 President's budget request for the National Institute on Alcohol Abuse and Alcoholism is $208,112,000. Thank you. I will be happy to answer any questions the committee may have.