National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Medications Development for the Treatment of Pregnant Addicts and Their Infants 149 U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health Medications Development for the Treatment of Pregnant Addicts and Their Infants Editors: C. Nora Chiang, Ph.D. Loretta P. Finnegan, M.D. NIDA Research Monograph 149 1995 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 from a technical review on “Medications Development for the Treatment of Pregnant Addicts and Their Infants” held on August 26-27, 1993. The review meeting was sponsored by the National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has obtained permission from the copyright holders to reproduce certain previously published material 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. National Institute on Drug Abuse NIH Publication No. 95-3891 Printed 1995 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 Psychopharmacology Abstracts. ii Contents Introduction: Medications Development for the Treatment of Pregnant Addicts and Their Infants C. Nora Chiang and Loretta P. Finnegan . . . . . . . . . . . . . . . . . . . . . 1 Overview: Medications Development for the Treatment of Drug Abuse Frank Vocci, C. Nora Chiang, Lee Cummings, and Richard Hawks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Overview of the Effects of Abuse and Drugs on Pregnancy and Offspring Barry Zuckerman, Deborah Frank, and Elizabeth Brown . . . . . . . .16 Clinical Management of Drug Dependency in Pregnancy James R. Woods, Jr. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .39 Methadone Use During Pregnancy Margaret A.E. Jarvis and Sidney H. Schnoll . . . . . . . . . . . . . . . . . .58 Treatment Options for Drug-Exposed Infants Stephen R. Kandall . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . .78 Opioid Receptor Approaches for the Development of Medications for Pregnant Women Hazel H. Szeto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Pharmacokinetic and Pharmacodynamic Considerations for the Design and Screening of Potential Medications C. Lindsay DeVane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .116 The Application of the Principles of Toxicology and Teratology in Evaluating the Risks of New Drugs for the Treatment of Drug Addiction in Women of Reproductive Age Robert L. Brent ........................................ 130 iii Drug Delivery Systems: Possible Applications in the Treatment of Drug Addiction Stella T. Chao ......................................... 185 Clinical Trials of Pharmacologic Treatments in Pregnant Women- Methodologic Considerations Richard S. Schottenfeld . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Legal and Ethical Issues Diane Aiken .......................................... 224 Testing Medications for the Treatment of Addiction in Pregnancy: One Reviewer’s Opinion Curtis Wright. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 iv Introduction: Medications Development for the Treatment of Pregnant Addicts and Their Infants C. Nora Chiang and Loretta P. Finnegan A technical review entitled Medications Development for the Treatment of Pregnant Addicts and Infants was held on August 26 and 27, 1993, at the Pooks Hill Marriott in Bethesda, MD. The purpose of this meeting was to review the current strategy for the treatment of pregnant drug- dependent women and their infants, to assess the needs for new pharmacotherapies, and to discuss issues related to the development of new pharmacotherapies, with special emphasis on approaches and methodologies for the design and development of medications with minimal risks to the fetus. It is the consensus that new and improved medications for the treatment of pregnant drug-dependent women are critically needed. Although methadone has been used for treating opioid addicts since the 1960s the effective use of methadone in pregnancy and the developmental effects on children exposed in utero are still unclear. Therefore, research is needed to define the optimal treatment strategy for using methadone in pregnancy, including a pharmacokinetic and pharmacodynamic study to determine the proper dosage regimen, a study to investigate when and how medically supervised withdrawal can be safely performed, and a followup study to investigate the developmental effects of methadone on the children exposed in utero. Infants suffering from neonatal withdrawal syndrome due to in utero drug exposure can be managed adequately with current medications. However, research on improved formulations, such as transdermal drug delivery systems that are convenient to use, will be encouraged. Pharmacotherapy for treating pregnant women can be very complicated. As pregnancy advances, pharmacokinetics and pharmacodynamics of a medication can change and necessitate careful monitoring of the effects and adjustment of the dosage regimen. Because there is also concern about the effects of the medication on the developing fetus, neonates must be assessed at the time of delivery. In some cases, followup of 1 children’s development is also required. Additional complications with the treatment of pregnant addicts require a comprehensive intervention program. Pharmacotherapy serves only as a safe replacement for abused drugs to help maintain pregnant addicts in a health care system. The behavioral intervention and social services provided by addiction-treatment professionals are essential in the successful treatment of addicts. Obstetricians and general health care providers often do not know how to deal with addicts. A top priority for treating this population is to familiarize health care providers with the needs of pregnant drug- dependent women and establish communications between obstetricians and addiction treatment professionals. Medications development is very complex and requires a multidisci- plinary approach. Basic research is necessary for the discovery of potential treatment medications. Pharmacological and toxicological evaluations must be performed in animals before the medications can be advanced to clinical studies. Basic pharmacokinetic and pharmaco- dynamic information should be obtained in preclinical evaluations and in early clinical trials to guide further clinical development. Prior to the use of a medication by pregnant women, its effects on fetuses throughout the gestational, neonatal, and postnatal periods must be assessed by developmental toxicity studies in animals. The Food and Drug Administration (FDA) has no established guidelines on how to carry out clinical trials in pregnant women. Communication among FDA, National Institute on Drug Abuse (NIDA), and scientific communities is necessary to clarify issues prior to beginning clinical trials. An integrated effort involving researchers with expertise in obstetrics, addiction treatment, and neonatology is required for the design and execution of the clinical protocol. It is of paramount importance to decide the objectives of the study and then to design the proper outcome measures. When outcome measures include following children’s development, pediatricians and epidemiologists must also be included to create a registry and follow the children over time. It is also important to establish a common database for collecting information nationwide across institutes so that data can be collected, analyzed, and disseminated. There are additional social, economic, and practical issues related to medications development for this population. One issue is who should be responsible for medications development for treating pregnant addicts. 2 There are ethical concerns as well as fear of litigation about clinical studies in pregnant patients. Therefore, institutional review board (IRB) approval sometimes is difficult. The reluctance of pharmaceutical companies to develop medications for this population probably is due to the concern over financial feasibility and fear of litigation. Orphan drug status could provide some incentive to the industry. Federal Government agencies should encourage research in this area by providing sufficient funds to scientific communities, by facilitating IRB approval, and by actively collaborating with industry and interacting with FDA to advance medications development. Research is urgently needed to develop treatments for pregnant drug- dependent women and their infants. A multidisciplinary approach is essential for medications development, and a comprehensive treatment program is necessary for the success of the treatment of pregnant addicts. AUTHORS C. Nora Chiang, Ph.D. Project Officer Medications Development Division Loretta P. Finnegan, M.D. Senior Advisor on Women’s Issues Office of the Director National Institute on Drug Abuse 5600 Fishers Lane Rockville, MD 20857 3 Overview: Medications Development for the Treatment of Drug Abuse Frank Vocci, C. Nora Chiung, Lee Cummings, and Richard Hawks INTRODUCTION In 1988, it was estimated that drug addiction cost Americans at least $58.3 billion each year in health, social, lost productivity, and law enforcement costs. When costs associated with the care of infants born addicted or exposed to illicit drugs, the exacerbation of the AIDS epidemic, and other consequences are considered, the economic costs of drug abuse and addiction may have exceeded $100 billion in 1991 (Rice et al. 1991). Because of the tremendous cost associated with drug addiction, the development of effective treatments for drug addiction is therefore a top priority of the National Institute on Drug Abuse (NIDA). Pregnant women who are addicted to drugs and their infants who suffer adverse effects due to in utero drug exposure are among the people to be treated. Current treatment programs are a complex mix of medical, psychosocial, and rehabilitation services. An important part of such treatment is the availability of pharmacotherapeutic adjuncts to help stabilize addicts and allow them to succeed in their overall addiction treatment program. At the present time, no medications are available for treating cocaine addiction, and only three medications are available for treating opioid dependence: methadone, naltrexone, and 1-alpha-acetylmethadol (LAAM, which was approved by the Food and Drug Administration [FDA] in July 1993). This scarcity of medications for drug abuse treatment is partly due to factors such as the limited commercial market and the difficulties associated with conducting clinical trials in drug- abusing populations. These factors have historically created a reluctance in the pharmaceutical industry to develop medications for treatment of drug abuse. Medications development is an extraordinarily complex activity involving a broad range of basic and applied research including chemical 4