NIH Guide, Volume 26, Number 35, October 17, 1997

PA NUMBER:  PA-98-003

National Institute on Alcohol Abuse and Alcoholism


The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is
seeking research grant applications on the clinical use of
medications to treat alcohol abuse and alcoholism.  Relevant topics
include investigation of drugs to treat various aspects of
alcoholism, particularly acute and protracted alcohol withdrawal,
post-treatment relapse, alcohol craving, psychiatric comorbidity,
alcohol-induced cognitive dysfunction, intoxication, and alcohol-
induced organ damage.  This program announcement also solicits
research on behavioral issues surrounding use of medications in
alcoholism treatment, such as compliance to the medicational
regimen.  In this program announcement, the research is to be
conducted in humans.  For animal studies, see the program
announcements "Neurobiology of Ethanol-Related Behaviors"
(PA-94-77) and "Alcohol, Hormones, and Medical Complications"
(PA-97-062).  This program announcement replaces the announcement
"Research on Promising Pharmacotherapies for Alcoholism" issued
February 1990.


The Public Health Service (PHS) is committed to achieving the
health promotion and disease prevention objectives of "Healthy
People 2000," a PHS-led national activity for setting priority
areas.  This program announcement, Clinical Use of Medications to
Treat Alcoholism, is related to the priority areas of alcohol abuse
reduction and alcoholism treatment.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing
Office, Washington, DC 20402-9325 (Telephone  202-512-1800).


Applications may be submitted by domestic and foreign, for-profit
and non-profit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of State and
local governments, and eligible agencies of the Federal Government. 
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators. 
Foreign institutions are not eligible for First Independent
Research Support and Transition (FIRST) Awards (R29).


Research support may be obtained through applications for a regular
research project grant (R01) or First Independent Research Support
and Transition (FIRST) Award (R29).  Applicants may also submit
Investigator-Initiated Interactive Research Project Grants (IRPG)
under this program announcement.  Interactive Research Project
Grants require the coordinated submission of related regular
research project grant applications and, to a limited extent, FIRST
Award applications from investigators who wish to collaborate on
research, but do not require extensive shared physical resources. 
Program Project Grants applications (P01) will not be accepted
under this program announcement. Investigators who wish to submit
a new application that requests $500,000 or more for direct costs
in any year must obtain written approval from the NIAAA prior to
submitting an application.


It is estimated that up to $2 million will be available for FY 1998
to fund approximately five to eight grants under this program
announcement.  Since pharmacotherapy for alcoholism treatment is
designated as a Special Emphasis Area of high program relevance for
the NIAAA similar funding is expected for future years. 
Nevertheless, this level of support is dependent on the receipt of
a sufficient number of applications of high scientific merit and
availability of funds.


Over the past 5 years, research on pharmacotherapy for alcoholism
treatment has burgeoned (Litten et al., 1996).  As a result,
pharmacologic agents have been successfully employed in the broad
gamut of situations encountered in clinical practice.  The most
tangible evidence of the fruits of this research has been the
approval of naltrexone, the first drug approved by the Food and
Drug Administration (FDA) for alcoholism treatment in almost 50

Pharmacological agents for facilitating the alcoholism treatment
process can be categorized as follows:

o  Agents Used to Treat Acute Alcohol Withdrawal

Acute alcohol withdrawal is characterized by a highly variable
range of symptoms.  These include relatively mild symptoms such as
sweating, tachycardia, hypertension, tremors, and anxiety to more
serious consequences including seizures and delirium tremens
(Naranjo and Sellers, 1986).  Its etiology has been hypothesized to
involve perturbation of one or more neuronal and hormonal systems,
including noradrenergic hyperactivity, gamma-aminobutyric acid
(GABA)-benzodiazepine receptor alteration, elevated hypothalamic-
pituitary-adrenal axis, and changes in the N-methyl-D-aspartate
(NMDA) glutamate receptors.

For more than two decades, benzodiazepines have been the most
widely used medication for pharmacological management of alcohol
withdrawal.  They have consistently been demonstrated to assuage
many symptoms of withdrawal.  The most recent studies have focused
on benzodiazepine dosing strategies.  For example, a "loading dose"
technique in which benzodiazepines are given every 1 or 2 hours
until withdrawal symptoms subside, appears effective in preventing
over- and under-dosing of medication (Wartenberg et al., 1990;
Sullivan et al., 1991; Saitz et al., 1994).  Yet in spite of their
benefits, benzodiazepines have adverse effects including memory
impairment, drowsiness, lethargy, and cognitive problems.

Other medications are also being explored in the management of
withdrawal symptoms, including carbamazepine, GABAergic agents,
NMDA antagonists, dopaminergic agents, calcium channel antagonists,
and nitrous oxide (Litten et al., 1996).

Another research topic under active investigation is alcohol
withdrawal "kindling" or sensitization.  Kindling suggests that the
severity of withdrawal symptoms increases as a function of the
number of previous alcohol withdrawals, a hypothesis that has been
supported by several animal and human studies (Anton and Becker,

Several research questions remain in treating acute alcohol
withdrawal.  For example, are there medications more effective and
safer than benzodiazepines in treating withdrawal?  What is the
optimal dosing regimen?  Is the kindling effect real?  How
important is kindling in terms of physical risk as well as future
vulnerability to drinking?  How can kindling be effectively curbed? 
What procedures should be employed to determine advisability of
outpatient detoxification?

o  Agents that Directly Reduce the Desire to Drink

Over the past 5 years significant progress has been made with
medications that diminish the desire to drink (sometimes referred
to as "anticraving" medications).  This progress has been
highlighted by the recent FDA-approval of the opioid antagonist
naltrexone.  In the two landmark studies of Volpicelli et al.(1992)
and O'Malley et al.(1992), alcohol dependent patients were treated
with naltrexone for 3 months and experienced higher sobriety rates,
fewer days drinking, and lower craving for alcohol than did
placebo-treated subjects.  In particular, naltrexone-treated
subjects who sampled alcohol were less likely to continue to drink
than were those who had received placebo.

In O'Malley's study, an interaction was found between naltrexone
and two types of psychosocial intervention.  Naltrexone-treated
subjects who received a supportive therapy emphasizing abstinence
enjoyed a higher rates of sobriety.  If drinking was initiated,
those treated with naltrexone and coping-skill training, however,
were more successful in avoiding a return to heavy drinking.

In addition to opioid antagonists, other types of agents appear
promising, the most notable being acamprosate (calcium
acetylhomotaurinate). Acamprosate has been studied extensively in
Europe and appears to be quite helpful and to have no major adverse
effects (Paille et al., 1995; Sass et al., 1996; Whitworth et al.,
1996).  The most common side-effect is diarrhea.  Acamprosate has
no drug abuse potential and its effects are not additive with
alcohol.  Although the mechanism underlying acamprosate's effect is
still being investigated, it appears that acamprosate interacts
with the GABA system and excitatory amino acids such as glutamate.

Although the NIAAA is currently funding several clinical
pharmacotherapy studies, a range of questions remain, dealing with
agents that reduce the drinking urge.  What is the optimal dose of
naltrexone and other medications to reduce drinking?  Would other
opioid antagonists work well, particularly, those that bind
specifically to the subtype opioid receptors, such as mu and delta
receptors?  How does acamprosate reduce or prevent drinking?  What
is the most effective psychosocial intervention to be used in
combination with a medication?  What are the optimal parameters of
frequency, intensity, and duration of the medication-psychosocial
therapy? Are pharmacologic agents effective in the context of
minimal psychosocial interventions?   Are medications effective for
non-dependent subjects in primary care settings? Can specific
pharmacologic-psychosocial treatments be matched to subtypes of
alcoholics?  How can patient compliance be augmented?

o  Agents to Treat the Protracted Withdrawal Syndrome

The protracted withdrawal syndrome, also known as protracted
abstinence, late withdrawal, or "dry drunk," is in the very early
stages of research. Pharmacological treatment has been hampered by
lack of agreement on the distinctive symptoms and the duration of
the syndrome.  Some of the purported symptoms include anxiety,
irritability, hostility, depression, insomnia, fatigue, and

Recent research has suggested that the kindling effect may
contribute to symptoms of protracted withdrawal, thereby leading to
alcohol craving and relapse (Adinoff et al., 1995).  Research is
needed to determine the efficacy of medications in preventing
kindling and reducing the symptoms associated with it.  It is
likely that some of these medications may overlap with
pharmacologic agents described above in reducing the desire to

o  Aversive Agents

Pharmacologic agents that prevent drinking by causing aversive
consequences have been used for approximately 50 years to treat
alcoholism.  The most widely employed agent has been disulfiram
(Antabuse) which inhibits aldehyde dehydrogenase, a liver enzyme
that catabolizes acetaldehyde, the first metabolic product of
alcohol.  Elevated blood acetaldehyde results in a number of
uncomfortable physical symptoms, such as palpitations, difficulty
in breathing, headaches, and nausea.  Fear of the "disulfiram-
ethanol reaction" is believed to dissuade recovering alcoholics on
disulfiram from drinking or at least drinking heavily.

In spite of its long-term availability in the treatment community,
only a few well-designed studies have been conduced with
disulfiram. The most rigorous trial was conducted by Fuller et
al.(1986).  Findings of this project revealed no change in
abstinence, time to first drink, or employment status associated
with disulfiram.  Nevertheless, it did reduce frequency of drinking
in alcoholics.

A major problem with disulfiram is low-patient compliance.  One
approach to increase compliance is to supervise its administration. 
This is usually carried out by assigning a designated person to
observe the patient taking the medication.  Chick et al.(1992)
conducted a supervised disulfiram trial and found that patients
treated with disulfiram reduced alcohol intake and decreased blood
levels of gamma-glutamyltranspeptidase (GGT), a liver enzyme
serving as a marker of alcohol consumption.

Aversive agents are not as actively researched in comparison to the
"anticraving" agents.  They may, nevertheless, be beneficial in
treating subpopulations of alcoholics, particularly when used in
conjunction with a compliance-enhancing program.  Further research
is needed to confirm this possibility.  Also, psychosocial programs
that may further enhance outcome of disulfiram treatment need to be
identified.  In addition, dosing regimen and duration of treatment
need to be explored, e.g., constant versus "as needed" dosage and
short- versus long-term administration.  Finally, efficacy of
combining an aversive agent with an anticraving medication needs to
be explored.

o  Agents to Treat Psychiatric Problems Concomitant with Alcoholism

Co-occurrence of alcohol dependency and psychiatric disorders is
common in patients seeking treatment for either condition.  Still,
little research has been conducted on optimal treatment of this
population.  Recently, a few well-designed pharmacologic-
psychosocial trials have been conducted.  For instance, Mason et
al.(1996) found that desipramine, a tricyclic antidepressant, was
helpful in alleviating symptoms of depression and reducing relapse
to drinking in alcoholic patients suffering major depression.

In another recent study, McGrath et al.(1996) treated patients
suffering from alcoholism and depression with imipramine, another
tricyclic antidepressant.  Although imipramine reduced severity of
depression, no differences were observed in the frequency or amount
of drinking between the imipramine and placebo groups. 
Nevertheless, when the subjects were divided according to response
versus nonresponse in depressive symptoms, a significant effect was
determined.  Imipramine-treated responders had fewer drinks per
drinking day and fewer heavy drinking days than placebo-treated
responders and imipramine- and placebo-treated nonresponders.

Other studies have also shown promise in treating alcoholic
psychiatric comorbidity.  In a recent study, the serotonin reuptake
inhibitor fluoxetine improved depression and reduced drinking in
depressed alcoholics (Cornelius et al., 1997).  The anxiolytic
agent buspirone also appears efficacious in relieving symptoms of
anxiety and increasing treatment retention in alcoholics suffering
anxiety disorders (Litten et al., 1996).  Its effects on drinking,
however, were unclear.

This research field remains in early stages and many fundamental
questions persist.  For example, how does treatment of alcoholism
or psychiatric disorder affect outcome of the other?  Do alcoholics
with psychiatric comorbidity respond differently to medications
than alcoholics without a comorbid condition? What is the optimal
sequencing of treatment for alcohol and psychiatric problems?  Can
specific pharmacologic-psychosocial treatments be matched to
different aspects of alcoholism and comorbid psychopathogy?

o  Agents to Treat Concurrent Alcohol and Drug Abuse Problems

Over the past several years the number of alcoholics with
collateral illicit drug addiction has increased alarmingly.  In
addition, 90 percent of alcoholics have a nicotine dependence. 
Very little research, however, has been conducted on the treatment
of this comorbid population.  A range of salient issues remain. 
For instance, does treatment of alcoholism or drug dependency
influence the outcome of the other addiction?  Should separate
treatments be conducted for each disorder?  Is the distinction
between primary versus secondary alcoholism relevant to determining
choice of treatments?

o  Agents to Improve Cognitive Dysfunction

Medications to improve cognitive function in alcoholics,
particularly in alcoholic dementia and Korsakoff's psychosis, would
lead to enrichment in quality of life of alcoholics as well as
reduction in costs of long-term institutionalization.  Recent
studies have shown that serotonin reuptake inhibitors can improve
memory to a clinically meaningful degree in some patients with
alcohol-induced amnesia.  Unfortunately, very little research has
been conducted on developing pharmacologic cognitive enhancers, a
topic of major concern in alcoholism treatment.

o  Agents Used to Induce Sobriety in Intoxicated Individuals

The search for a single effective amethystic agent (alcohol
antagonist) has to-date been unsuccessful, perhaps due to alcohol's
diverse effects on body systems.  Continued research in this area
is important since a significant number of people die each year
from alcohol overdose.  Development of medications to quickly and
safely induce sobriety is particularly needed to assist treatment
in emergency room settings.

o  Agents Used to Treat Alcohol-Induced Organ/Tissue Damage

Organ/tissue damage is the major medical consequence of chronic
alcohol abuse. Medications are needed to prevent, alleviate, or
counteract alcohol-induced tissue injury.  Diseases include
alcohol-induced hepatitis, portal hypertension, cardiomyopathy, and


It is the policy of the NIH that women and members of minority
groups and their subpopulations must be included in all NIH
supported biomedical and behavioral research projects involving
human subjects, unless a clear and compelling rationale and
justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of
1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects
should read the "NIH Guidelines For Inclusion of Women and
Minorities as Subjects in Clinical Research," which have been
published in the Federal Register of March 20, 1994 (FR 59
14508-14513) and in the NIH Guide for Grants and Contracts, Volume
23, Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.


Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits
are available at most institutional offices of sponsored research
and may be obtained from the Division of Extramural Outreach and
Information Resources, National Institutes of Health, 6701
Rockledge Drive, MSC 7710, Bethesda, MD 20892-7910, telephone:
301-710-0267, email:  The title and number of
the program announcement must be typed in section 2 on the face
page of the application.

Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the
original application. FIRST award (R29) applications submitted
without the required number of reference letters will be considered
incomplete and will be returned without review.

The completed original application and five legible copies must be
sent or delivered to:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)


Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in
accordance with the standard NIH peer review procedures.  As part
of the initial merit review, all applications will receive a
written critique and undergo a process in which only those
applications deemed to have the highest scientific merit, generally
the top half of the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council.


Criteria for the scientific and technical merit review of regular
research grant (R01) applications are as follows:

Significance:  Does this study address an important problem?  If
the aims of the application are achieved, how will scientific
knowledge be advanced? What will be the effect of these studies on
the concepts or methods that drive this field?

Approach:  Are the conceptual framework, design, methods, and
analyses adequately developed, well-intergrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?

Innovation:  Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative?  Does the project
challenge existing paradigms or develop new methodologies or

Investigator:  Is the investigator appropriately trained and well-
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?

Environment:  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements? 
Is there evidence of institutional support?

Budget:  Is the requested budget and estimation of time to
completion of the project appropriate for the proposed research?

In addition, plans for the recruitment and retention of subjects
will be evaluated as will the adequacy of plans to include both
genders and minorities and their subgroups as appropriate for the
scientific goal of the research.

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment. The review criteria for FIRST Awards (R29)
are contained in the FIRST program guidelines (revised August


Applications recommended for approval will be considered for
funding on the basis of the overall scientific and technical merit
of the proposal as determined by peer review, programmatic needs
and balance, and the availability of funds.


Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Raye Z. Litten, Ph.D.
Division of Clinical and Prevention Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0796
FAX:  (301) 443-8774

Direct inquiries regarding fiscal matters to:

Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4704
FAX:  (301) 443-3891


This program is described in the Catalog of Federal Domestic
Assistance, No. 93.273.  Awards are made under the authorization of
the Public Health Service Act, Sections 301 and 464H, and
administered under the PHS policies and Federal Regulations at
Title 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency Review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-
use of all tobacco products.  In addition, Public Law 103-227, the
Pro-Children Act of 1994, prohibits smoking in certain facilities
(or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children. This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.


Adinoff, B., O'Neill, K., and Ballenger, J.C. (1995) Alcohol
withdrawal and limbic kindling: A hypothesis of relapse.  The
American Journal on Addictions 4:5-17.

Anton, R.F. and Becker, H.C. (1995) Pharmacotherapy and
pathophysiology of alcohol withdrawal.  In H.R. Kranzler (editor),
The Pharmacology of Alcohol Abuse, New York: Springer-Verlag, pp.

Chick, J., Gough, K., Falkowski, W., Kershaw, P., Hore, B., Mehta,
B., Ritson, B., Ropner, R., and Torley, D. Disulfiram treatment of
alcoholism. British Journal of Psychiatry 161:84-89.

Cornelius, J.R., Salloum, I.M., Ehler, J.C., Jarrett, P.J.,
Cornelius, M.D., Perel, J.M., Thase, M.E., and Black, A. (1997)
Fluoxetine in depressed alcoholics: A double-blind, placebo-
controlled trial.  Archives  of General Psychiatry 54:700-705.

Fuller, R.K., Branchey, L., Brightwell, D.R., Derman, R.M., Emrick,
C.D., Iber, F.L., James, K.E., Lacoursiere, R.B., Lee, K.K.,
Lowenstam, I., Maany, I., Neiderhiser, D., Nocks, J.J., and Shaw,
S. (1986) Disulfiram treatment of alcoholism: A Veterans
Administration cooperative study. Journal of the American Medical
Association 256:1449-1455.

Litten, R.Z., Allen, J., and Fertig J. (1996) Pharmacotherapies for
alcohol problems: A review of research with focus on developments
since 1991. Alcoholism: Clinical and Experimental Research.

Mason, B.J., Kocsis, J.H., Ritvo, E.C., and Cutler R.B. (1996) A
double-blind placebo-controlled trial of desipramine in primary
alcoholics stratified on the presence or absence of major
depression.  Journal of the American Medical Association 275:1-7.

McGrath, P.J., Nunes, E.V., Stewart, J.W., Goldman, D., Agosti V.,
Ocepek-Welikson, K., and Quitkin, F.M. (1996) Imipramine treatment
of alcoholics with primary depression: A placebo-controlled
clinical trial.  Archives of General Psychiatry 53:232-240.

Naranjo, C.A. and Sellers, E.M. (1986)  Clinical assessment and
pharmacotherapy of the alcohol withdrawal syndrome.  In M. Galanter
(editor),  Recent Developments in Alcoholism, Volume 4, New York:
Plenum Press, pp. 265-281.

O'Malley, S.S., Jaffe, A.J., Chang, G., Schottenfeld, R.S., Meyer,
R.E., and Rounsaville, B. (1992) Naltrexone and coping skills
therapy for alcohol dependence: A controlled study.  Archives of
General Psychiatry 49:881-887.

Paille, F.M., Guelfi, J.D., Perkins, A.C., Royer, R.J., Steru, L.,
and Parot, P. (1995) Double-blind randomized multicentre trial of
acamprosate in maintaining abstinence from alcohol.  Alcohol &
Alcoholism 30:239-247.

Saitz, R., Mayo-Smith, M.F., Roberts, M.S., Redmond, H.A., Bernard,
D.R., and Calkins, D.R. (1994) Individualized treatment for alcohol
withdrawal: A randomized double-blind controlled trial.  Journal of
the American Medical Association 272:519-523.

Sass, H., Soyka M., Mann, K., and Zieglgansberger, W. (1996)
Relapse prevention by acamprosate: Results from a placebo-
controlled study on alcohol dependence. Archives of General
Psychiatry 53:673-680.

Sullivan, J.T., Swift, R.M., and Lewis, D.C. (1991) Benzodiazepine
requirements during alcohol withdrawal syndrome: Clinical
implications of using a standardized withdrawal scale.  Journal of
Clinical Psychopharmacology 11:291-295.

Volpicelli, J.R., Alterman, A.I., Hayashida, M., and O'Brien, C.P.
(1992) Naltrexone in the treatment of alcohol dependence.  Archives
of General Psychiatry 49:876-880.

Wartenberg, A.A., Nirenberg, T.D., Liepman, M.R., Silvia, L.Y.,
Begin, A.M., and Monti, P.M. (1990)  Detoxification of alcoholics:
Improving care by symptom-triggered sedation.  Alcoholism: Clinical
and Experimental Research 14:71-75.

Whitworth, A.B., Fischer, F., Lesch, O.M., Nimmerrichter, A.,
Oberbauer, H., Platz, T., Potgieter, A., Walter, H., and
Fleischhacker, W.W. (1996) Comparison of acamprosate and placebo in
long-term treatment of alcohol dependence. Lancet 347:1438-1442.

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