National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Acute Cocaine Intoxication: Current Methods of Treatment 123 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Acute Cocaine Intoxication: Current Methods of Treatment Editor: Heinz Sorer, Ph.D. NIDA Research Monograph 123 1992 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT This Monograph is based on the papers and discussions from a technical review on “Acute Cocaine Intoxication: Current Methods of Treatment” held on July 9-10, 1991, in Bethesda, MD. The technical review was sponsored by the National Institute on Drug Abuse (NIDA). COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published materials as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder’s permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without 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 or any other part of the U.S. Department of Health and Human Services. The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essential in the context of the studies reported herein. NIDA Research Monographs are indexed in the Index Medicus. They are selectively included in the coverage of American Statistics Index, Biosciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psvchopharmacology Abstracts. NIH Publication No. 93-3498 Printed 1993 ii Contents Page The Medications Development Program: A New Initiative of the National Institute on Drug Abuse 1 Heinz Sorer Cocaine-Related Medical Crises: Evidence From the Drug Abuse Warning Network 20 James D. Colliver, Andrea N. Kopstein, and Arthur L. Hughes Preclinical Assessment of Cocaine Toxicity: Mechanisms and Pharmacotherapy 44 Jeffrey M. Witkin and Jonathan L. Katz The Cardiovascular Effects of Cocaine—Update 1992 70 Lewis R. Goldfrank and Robert S. Hoffman Cocaine-Related Emergency Department Presentations 110 Kathleen S. Schrank Cerebrovascular Complications From Cocaine: Possible Long-Term Sequelae 129 Bruce L. Miller, Frances Chiang, Lora McGill, Todd Sadow, Mark A. Goldberg, and lsmael Mena Cocaine Levels and Elimination in Inpatients and Outpatients: Implications for Emergency Treatment of Cocaine Complications 147 Michael C. Rowbotham iii Potential Adverse Interactions of Drugs With Cocaine 156 Paul R. Pentel and Timothy N. Thompson The Pathology of Cocaine: Perspectives From the Autopsy Table 172 Charles V. Wetli Summary Comments 183 Marian W. Fischman, Reese T. Jones, and James W. Cornish List of NIDA Research Monographs 185 iv The Medications Development Program: A New Initiative of the National Institute on Drug Abuse Heinz Sorer INTRODUCTION The National Institute on Drug Abuse (NIDA) plays a leading role in the Federal research effort to increase knowledge about the causes and treatment of drug abuse and addiction and to identify means of preventing and controlling drug abuse and ultimately to eliminate the demand for illicit drugs in this country. Congress passed the Anti-Drug Abuse Act of 1988 as a legislative response to the drug abuse epidemic. Cocaine and crack use were important considerations in the development and passage of this legislation, which authorized up to $2.7 billion for all Federal activities in the War on Drugs. NIDA received almost $300 million for use in data collection, treatment evaluation, demonstration projects, and for the first time, the development of new and improved medications to fight drug abuse. Of this $2.7 billion, $10 million was allocated for medications development. In subsequent years, the budget for medications development has increased as programs were initiated and studies funded. The 1988 act also entailed the setting up of a new division within NIDA, the Medications Development Division (MDD), which was outlined in 1989 although it did not become official until 1990. Its goals include: Conducting necessary studies to identify, develop, and obtain Food and Drug Administration (FDA) marketing approval for new medications for the treatment of drug addiction and other brain and behavioral disorders Developing and administering a national program of basic and clinical pharmaceutical research designed to develop innovative biological and pharmacological treatment approaches for addictive disorders 1 Establishing a close working relationship with pharmaceutical and chemical companies in the United States and abroad and with medications development programs in other agencies in the United States and abroad Figure 1 shows the current organization of NIDA. MDD is one of six research divisions within the Institute. Figure 2 shows the organization of MDD. Its setup is much like that of a minipharmaceutical company, with the same branches or departments that are found at a large pharmaceutical manufacturer. The Division consists of the following branches: Chemistry/Pharmaceutics, Pharmacology/Toxicology, Clinical Trials, Regulatory Affairs, and Biometrics. Since 1989 MDD has grown to 33 employees and a budget of $30 million. The Division is expected to reach its projected size of 35 to 40 staff members within one year, with a growing budget to meet its expanding needs and capabilities. By hiring staff and contracting for scientific services, NIDA has the capacity to develop medications from the point of discovery to preclinical studies to clinical testing. By means of the Government contracting process, MDD is developing the intrinsic capacity to perform all necessary chemistry, pharmacokinetic, pharmacology, and toxicology studies necessary to support clinical trials to treat substance abuse. The Division has established a close working relationship with FDA and the Pharmaceutical Manufacturers Association. When used appropriately, medications work in the treatment of addiction. There is a need to increase treatment capacity and effectiveness, and medications are tools in this effort. NIDA is providing leadership by committing itself on a long-term financial, programmatic, and scientific basis to the development of such medications. These medications will not be magic bullets; rather, they will be part of a comprehensive treatment program addressing the psychological, social, and behavioral aspects of addiction. It is hoped that the medications will be able to normalize an individual whose brain has been biochemically deranged by drugs. The aim is to bring as many patients as possible to a drug-free state; the pharmacologic agents will act as bridges to such a state. MDD is not focused solely on drug abuse treatment. It also coordinates medications development with NIDA’s sister research institutes, the National Institute on Alcohol Abuse and Alcoholism and the National Institute of Mental Health. In this case, MDD will assist in developing studies of medications to 2 FIGURE 1. Current organization of NIDA FIGURE 2. Current organization of MDD treat alcoholism and less studied forms of mental illness, such as refractory depression, a form of depression unresponsive to any marketed medications. In fiscal year (FY) 1991, the budget for the Medications Development Program was about $40 million, or about 9.5 percent of NIDA’s budget. MDD has been using a multipronged approach to medications development to help speed up the process. By hiring staff and contracting for scientific services, NIDA has the capacity to develop medications from the point of preclinical studies to clinical testing. By means of the Government contracting process, MDD has developed the intrinsic chemistry, pharmacokinetic, pharmacology, and toxicology studies necessary to support clinical trials for medications to treat substance abuse. The Division has brought together the Federal Government, pharmaceutical companies, and academia in new and innovative cooperative ventures. Specifically, the Division has expanded NIDA’s pharmacologic research capabilities, forged drug development agreements with pharmaceutical firms, and established a network of clinical research sites at universities and Department of Veterans Affairs (DVA) medical centers nationwide. The following are brief descriptions of some of the ongoing MDD programs. This survey provides an overview and is not all inclusive. COCAINE TREATMENT DISCOVERY PROGRAM The goal of the program is to identify new pharmacologic entities that may be of use in the treatment of cocaine abuse, which has proven to be refractory to most standard methods of treatment. Critical reviews of the current scientific literature are being carried out to identify potential treatment medications. Efforts also are being directed toward understanding the types of physiological mechanisms that mediate the effects of cocaine to identify additional drug classes that might serve as useful medications. These functions are