Benzodiazepines: A Review of Research Results, 1980 Editors: Stephen I. Szara, M.D., D.Sc. Jacqueline P. Ludford, M.S. National Institute on Drug Abuse NIDA Research Monograph 33 A RAUS Review Report DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse Division of Research 5600 Fishers Lane Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 The NIDA Research Monograph series is prepared by the Division of Research of the National institute on Drug Abuse. Its primary objective is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, integrative research reviews and significant original research. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisory Board Avram Goldstein, M.D. Addiction Research Foundation Palo Alto, California Jerome Jaffe, M.D. College of Physicians and Surgeons Columbia University, New York Reese T. Jones, M.D. Langley Porter Neuropsychiatric Institute University of California San Francisco, California Jack Mendelson, M.D. Alcohol and Drug Abuse Research Center Harvard Medical School McLean Hospital Belmont, Massachusetts Helen Nowlis, Ph.D. Office of Drug Education, DHHS Washington, D.C. Lee Robins, Ph.D. Washington University School of Medicine St. Louis, Missouri NIDA Research Monograph series William Pollin, M.D. DIRECTOR, NIDA Marvin Snyder, Ph.D. DIRECTOR, DIVISION OF RESEARCH, NIDA Robert C. Petersen, Ph.D. EDITOR-IN-CHIEF Eleanor W. Waldrop MANAGING EDITOR Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Benzodiazepines: A Review of Research Results, 1980 ACKNOWLEDGMENT This monograph is based upon papers and discussion from the RAUS Review Conference on Benzodiazepines, held September 12, 1980, in Rockville, Maryland. Arrangements for the conference, sponsored by the Division of Research, National Institute on Drug Abuse, were made by CDP Associates, Inc., Rockville, Maryland 20852, under NIDA contract No. 271-79-3636. COPYRIGHT STATUS The chapter entitled "Benzodiazepines: Clinical Use Patterns," by Karl Rickels, M.D., is adapted from copyrighted material and therefore may be under copyright. It is used with the permission of Raven Press, New York. Before reproducing, readers are advised to determine its copyright status or to secure permission of the copyright holder. The table and figures in that chapter are copy- righted as noted in the text and are reproduced herein with per- mission. Further reproduction is prohibited without specific per- mission of the copyright holders. All other material in this volume is in the public domain and may be used or reproduced with- out permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse; Alcohol, Drug Abuse, and Mental Health Administration; Public Health Service; or the Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commer- cial product or commodity. Trade or proprietary names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. Library of Congress catalog card number 81-600106 DHHS publication number (ADM)81-1052 Printed 1981 NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of BioSciences Informa- tion Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. iv Preface The Research Analysis and Utilization System (RAUS) is designed to serve four functions: Collection and systematic classification of findings of all intramural and extramural research supported by the National Institute on Drug Abuse (NIDA); Evaluation by scientific peers of the latest research find- ings; Regular dissemination of findings to researchers in the field and to administrators, planners, instructors, and other interested persons: Provision of a feedback mechanism to NIDA staff and plan- ners so that administration and monitoring of the NIDA research program reflect the very latest knowledge gleaned from research in the field. Since there is a limit to the number of research findings that can be intensively reviewed annually, four subject areas are chosen each year and subjected to a thorough review. The reviewers, distin- guished scientists in the selected field, are provided with copies of all pertinent literature and reports from NIDA-funded research. They are invited to add to this any information derived from their own research and that of colleagues not funded by NIDA. Each reviewer writes a state-of-the-art paper in his or her particular subject area. These papers make up a RAUS Review Report in the NIDA Research Monograph series. Additionally, an evaluative meeting is held for presentation of the papers and exchange of ideas among the scientists and with NIDA staff. This meeting has sometimes been referred to as the "therefore" meeting: Here is our position: therefore, where are we going next, and where should further research lead? Should we alter our path? Step up NIDA support because new needs have arisen or new develop- ments hold special promise? Discussions at the meeting and the specific recommendations of the experts in the field provide a basis upon which NIDA evolves its plans for future research. V In Fiscal Year 1980 the abuse liability of the benzodiazepines was chosen as an area for RAUS review. The subject was ripe for review because much conflicting information was circulating among scientists and clinicians about the abuse liability of the highly popular "tranquilizers"; because of pronounced public interest, as reflected by the Congress and the press; and because of a per- ceived need by NIDA for objective evaluation of research on the benzodiazepines. The reviewers were invited to discuss: The basic biochemistry and neuroanatomy underlying the question of the abuse potential of benzodiaze- pines, including the existence and sites of receptors involved; Studies on self-administration in animals and humans; Carryover effectiveness, rebound insomnia, and per- formance effects; Clinical use patterns and their relationship to misuse and abuse; Dependence on benzodiazepines. The results of these reviews are presented in this monograph. The review meeting was chaired by Dr. William Martin, of the University of Kentucky, former Director of the Addiction Research Center, in Lexington, Kentucky. Dr. Edward Truitt, of Northeast Ohio College of Medicine, summarized the reviews and discussions. Dr. Stephen Szara, Chief, Biomedical Branch, NIDA Division of Research, served as moderator and directed the scientific discussion. Jacqueline P. Ludford, M.S. Coordinator Research Analysis and Utilization System vi Contents Preface Jacqueline P. Ludford . v Introduction Stephen I. Szara . 1 Benzodiazepines: Biochemistry to Function John F. Tallman . 4 The Benzodiazepine Receptor: Anatomical Aspects Michael J. Kuhar . 12 Benzodiazepine Self-Administration in Animals and Humans: A Comprehensive Literature Review Roland R. Griffiths and Nancy A. Ator . 22 Benzodiazepine Dependence Studies in Rodents William R. Martin and L. F. McNicholas . 37 Benzodiazepines: Clinical Use Patterns Karl Rickels . 43 Benzodiazepine Hypnotics: Carryover Effectiveness, Rebound Insomnia, and Performance Effects Anthony Kales . 61 Dependence on Benzodiazepines Leo E. Hollister . , . 70 Benzodiazepines: Executive Summary and Discussion Edward B. Truitt, Jr. 83 Benzodiazepines: Biochemistry to Function . 84 The Benzodiazepine Receptor: Anatomical Aspects . 85 Benzodiazepine Self-Administration . 86 Benzodiazepine Dependence Studies in Rodents . 87 Benzodiazepines: Clinical Use Patterns . 88 Benzodiazepine Hypnotics: Carryover Effectiveness, Rebound Insannia, and Performance Effects . 89 Dependence on Benzodiazepines . 90 General Discussion . 91 RAUS Summary of New Directions for Research Jacqueline P. Ludford and Stephen I. Szara. 93 Participants, RAUS Review Conference on Benzodiazepines . 96 List of NIDA Research Monographs . 97 vii Introduction Stephen I. Szara, M.D., D.Sc. The benzodiazepines represent a class of drugs that are widely prescribed and used as so-called "minor tranquilizers." At the latest count, in 1979 alone, 62.3 million prescriptions for minor tranquilizers were filled (National Prescription Audit 1979). Because of the sheer volume of traffic in these drugs, if there is a potential for misuse and abuse, it is inevitable that a potential also exists for creation of a public health problem. When widespread clinical use of benzodiazepines began some 20 years ago, they were considered to have a relatively large margin of safety and they were prescribed quite liberally. Very soon, how- ever, some adverse reactions started to appear, and by the mid-70's concerns about the potential problems of abuse of the newly devel- oped congeners of benzodiazepines prompted the National Institute on Drug Abuse (NIDA) to convene a technical review to discuss the need for new methodologies to assess the abuse potential of these drugs. That meeting took place in 1976 at the Addiction Research Center in Lexington, Kentucky, under the chairmanship of Dr. William