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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.
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