CLINICAL USE OF MEDICATIONS TO TREAT ALCOHOLISM NIH Guide, Volume 26, Number 35, October 17, 1997 PA NUMBER: PA-98-003 National Institute on Alcohol Abuse and Alcoholism PURPOSE 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. HEALTHY PEOPLE 2000 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). ELIGIBILITY REQUIREMENTS 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). MECHANISM OF SUPPORT 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. FUNDS AVAILABLE 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. RESEARCH OBJECTIVES 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 years. 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, 1995). 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 craving. 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 drink. 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 pancreatitis. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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. APPLICATION PROCEDURES 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: asknih@od.nih.gov. 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) NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) REVIEW CONSIDERATIONS 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. REVIEW CRITERIA 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 technologies? 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 1996). AWARD CRITERIA 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 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 Email: rlitten@willco.niaaa.nih.gov 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 Email: lhilley@willco.niaaa.nih.gov AUTHORITY AND REGULATIONS 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. REFERENCES 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. 315-367. 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. 20:859-876. 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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