Opiate Receptors and Antagonists: From Bench to Clinic PDF
Preview Opiate Receptors and Antagonists: From Bench to Clinic
Opiate Receptors and Antagonists From Bench to Clinic Edited by Reginald Dean, Edward J. Bilsky, S. Stevens Negus N N OH O O HO OH HO O Opiate Receptors and Antagonists For other titles published in this series, go to www.springer.com/series/7626 Reginald L. Dean III · Edward J. Bilsky S. Stevens Negus Editors Opiate Receptors and Antagonists From Bench to Clinic Editors Reginald L. Dean, III, M.S. Edward J. Bilsky, Ph.D. Life Sciences/Toxicology Department of Pharmacology Alkermes, Inc. University of New England Cambridge, MA 02139 College of Osteopathic Medicine USA Biddleford ME 04005 USA S. Stevens Negus, Ph.D. Department of Pharmacology and Toxicology Virginia Commonwealth University Richmond, VA 23298 USA ISBN: 978-1-58829-881-2 e-ISBN: 978-1-59745-197-0 DOI: 10.1007/978-1-59745-197-0 Library of Congress Control Number: 2008941670 © Humana Press, a part of Springer Science+Business Media, LLC 2009 All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, c/o Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, n either the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper springer.com Preface The evolution in our understanding of opioid receptors and their subtypes is inti- mately linked to the development of new pharmacological treatments for diseases/ disorders as diverse as addiction, self-injurious behavior, pain, cancer, inflam- mation, eating disorders, traumatic injury, pruritis, and movement disorders. These potential treatments involve both novel chemical entities and classic opioid antagonists with improved drug delivery systems. The contributions contained in Opioid Receptors and Antagonists: From Bench to Clinic represent the efforts from some of the leading international scientists and clinicians making use of the lat- est information emerging from the study of the opioid receptor system. Given the number of researchers currently active in this and related fields of study, it would be inappropriate to suggest that the entire range of activities is fully reflected in this single volume. Instead, a variety of experimental and clinical approaches involving the fields of neuroscience, molecular biology, biochemistry, anatomy, pharmacology, psychology, and psychiatry have been chosen to illustrate rapidly developing experimental and therapeutic areas. Opioid Receptors and Antagonists: From Bench to Clinic opens with a for- ward describing, from first-hand knowledge of the author, the history behind the clinical development of the classic opioid antagonist naltrexone. The book is subsequently organized into seven sections. The first section contains four chapters characterizing the opioid receptor. The second section contains six chapters describing the chemistry and pharmacology of opioid antagonists of different subtypes of receptors. The next four sections concentrate on the thera- peutic areas for opioid antagonists. These sections provide support for the use of opioid antagonists for substance abuse (seven chapters), alcohol and ingestive behaviors (four chapters), behavioral disorders (four chapters), and medical indi- cations, supported by nonclinical and clinical evidence (nine chapters). Finally, the seventh section provides five chapters which concentrate on the development of exciting and innovative drug-delivery approaches that are being used with opioid antagonists. It is hoped that this volume will serve as a useful reference while also stimulat- ing continued research on the opioid receptor system and its interactions with hor- monal and other transmitter systems. The ultimate goal of these efforts is to assist v vi Preface in the development of treatments for “brain reward” disorders and for other medical indications that may be responsive to opioid receptor antagonists. Reginald L. Dean III S. Stevens Negus Edward J. Bilsky Foreword Opiate Receptors and Antagonists It would have been very difficult to predict the scope of this volume in the early 1970s when the race to learn about the functions of the newly discovered endog- enous opioid system began. The first clinical studies of naltrexone were published by Bill Martin and Don Jasinski based on studies done in heroin addicts living in the USPHS Prison Hospital in Lexington, Kentucky (Martin et al 1973). Founded in the 1930s, this research unit was the forerunner of the NIH intramural program which for NIDA is now located in Baltimore. The Lexington unit at that time was one of the few places in the world doing scientific studies of addiction. After reading the results of naltrexone studies in Lexington, several groups began trials of the medication as a new treatment for heroin addiction. My original IND for naltrexone dates to 1973 when this medication created great excitement as the antag- onist with better properties than cycloazine and fewer side effects. This was a very exciting time for both basic and clinical research on the opioid system. Naltrexone was being hailed as the perfect medication. It was non-addicting with few side effects but it blocked virtually all of the effects of heroin and other opioids. Of course, we now know that naltrexone as a treatment for opioid addiction appeals to few patients. Thus, compliance of the oral form is very low. After several clinical trials in which naltrexone was tested against placebo, it was found that clas- sic, double-blind studies did not work with this drug (Hollister 1978). If the patient tested the blockade, they immediately knew which drug they were on and they often would simply stop the medication in order to get high. If they failed to test with a trial dose of heroin-, it made no difference whether they were on placebo or naltrex- one. In fact, those on placebo would have a tendency to do better because there were fewer but not zero side effects from placebo. When naltrexone was finally approved by the FDA in 1984 as a treatment for heroin addiction, approval was based on its pharmacology and not on clinical trials. Still, the Dupont Company celebrated it as a major treatment advance. All of the scientists who had been studying naltrexone, however, had warned the company that naltrexone (Trexan®) was not appealing to patients and therefore it would likely sell very poorly. In fact that prediction came true and a disappointed Dupont Merck rapidly lost interest in the product. vii viii Foreword Basic scientists, however, continued to study the opioid system and a major method for determining its function was to block it utilizing specific antagonists such as naloxone or naltrexone. One of the earliest workers in this field was Larry Reid who showed that both opiate agonists and opiate antagonists influenced alco- hol drinking (Reid and Hunter 1984). Clear evidence of a role for opiate antagonists in blocking self administration of alcohol was first published by Hal Altshuler of Houston, Texas who presented a paper at the CPDD Meeting in 1979 showing a dose-related naltrexone effect on suppression of intravenous alcohol self-admin- istration in 8 of 22 Rhesus monkeys (Altshuler et al 1980). This work led me to propose naltrexone as potentially useful in the treatment of alcoholism. I sent a protocol to the FDA and eventually received an IND in 1983 to study naltrexone in alcoholics. I tested it in an open trial with alcoholics, some of whom seemed to do very well. I was encouraged enough to begin a double-blind trial in our Veterans Administration day treatment center for alcoholism. The subjects were 70 male alcoholics with an average of 20 years of alcoholic drinking and numerous relapses after detoxification. The treatment program involved intensive psychotherapy including 12-step/Alcoholics Anonymous groups plus family therapy and 5 days per week (25 hours) in the day hospital program. Recruitment of subjects was very difficult because of outright hostility by coun- selors who were often recovering alcoholics themselves and were opposed to the use of medication. The first postdoctoral fellow who was assigned to this study was able to recruit only a handful of subjects over a year but the next post-doctoral fel- low, Joe Volpicelli, was convinced that naltrexone was potentially useful because he had also conducted animal studies with the drug (Volpicelli et al 1986). His enthu- siasm and determination convinced the counselors to give the study a chance and we recruited a total of 70 male alcoholics. Half were randomized to 50 mg per day of naltrexone, a dose selected because this was what we used for the treatment of heroin addiction. The other half received an identically appearing placebo. Efforts to obtain funding for this study were completely unsuccessful but because we had a VA Research Center and a Postdoctoral Research Training Program, we were able to devote some resources to this effort. The initial results were positive and we began to report them at various meet- ings but having the paper published was difficult (Volpicelli et al 1990; 1992). Fortunately, Stephanie O’Malley at Yale attempted to replicate our work and found almost identical results in a population that included both males and females and less intensive psychotherapy (O'Malley et al 1992). This sequence of testing a laboratory finding in a clinical population points to the validity of animal models in the study of addiction. The history of new medica- tions for the treatment other psychiatric disorders is usually the reverse: an effect is noticed by an astute clinician prescribing the drug for a different reason and laboratory studies come later. The diversity among the chapters in this volume is a testimony to the widespread influences of the endogenous opioid system. The role in alcoholism seems to be important at least for a subset of alcoholics which could be the first biologically defined endophenotype for this disorder. Since we initially began trying naltrexone Foreword ix as a treatment in patients more than three decades ago, great progress has been made. The future, in my opinion, lies in pharmacogenetics. All clinical trials hence- forth should include a request for DNA from the participants. Well-characterized patients including information on treatment response can be extremely useful in the future if DNA is preserved. Using such retrospective analysis, we found that a functional allele of the gene for the µ receptor predicts good response to naltrexone (Oslin et al 2003). Another group led by Ray Anton recently reported the same finding in their sample (Anton R 2006). A very recent analysis of the sub-sample of the VA multisite failed to show a correlation between polymorphism and treatment outcome (Gelernter et al 2007).Family history plays a major role in alcoholism and it is likely that other genetic variations will be discovered that have consistent treatment relevance. A prospective study of the A118G allele certainly should be accomplished. Future studies will also have the advantage of using the extended release naltrexone preparation so that the medication compliance variable can be more effectively managed (Pettinati et al 2000). We have come a long way since 1973 and I predict that a specific drug such as naltrexone will become even more important as we become more specific in our genetic diagnoses. We still do not know the relative contribution of antagonism at μ, κ and d receptors on the therapeutics effects of naltrexone. Recent research on the nociception-orphanon receptor will likely yield even more therapeutic potential as medications targeting those receptors are discovered. The up to date reviews in this volume will give the reader a chance to catch up on the recent advances in knowledge of the endogenous opioid system and provide clues to the future as research continues. Charles P. O'Brien, M.D., Ph.D. University of Pennsylvania Health System Penn Behavioral Health Charles O’Brien Center of Addiction Treatment Philadelphia, PA References Altshuler HL, Phillips PA, Feinhandler DA (1980): Alteration of ethanol self-administration by naltrexone. Life Sciences 26:679-688. Anton R OMS, Couper D, Swift R, Pettinati H, Goldman D, Oraczi G (2006): Does a com- mon variant of the mu opiate receptor gene predict response to naltrexone in the treatment of alcoholism? Results from the COMBINE study. Neuropsychopharmacology 31 Suppl 1:S24. Gelernter J, Gueorguieva R, Kranzler HR, Zhang H, Cramer J, Rosenheck R, Krystal JH (2007): Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study. Alcohol Clin Exp Res 31:555-563. Hollister L (1978): Clinical evaluation of naltrexone treatment of opiate-dependent individuals. Arch Gen Psychiatry 35:335-340. x Foreword Martin W, Jasinski D, Mansky P (1973): Naltrexone, an antagonist for the treatment of heroin dependence. Arch Gen Psych 28:784-791. O'Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B (1992): Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiat 49:881-887. Oslin DW, Berrettini W, Kranzler HR, Pettinati H, Gelernter J, Volpicelli JR, O'Brien CP (2003): A functional polymorphism of the mu-opioid receptor gene is associated with nal- trexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546-1552. Pettinati HM, Volpicelli JR, Pierce JD, Jr., O'Brien CP (2000): Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients. J Addict Dis 19:71-83. Reid LD, Hunter GA (1984): Morphine and naloxone modulate intake of ethanol. Alcohol 1(1):33-37. Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP (1992): Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49:876-880. Volpicelli JR, Davis MA, Olgin JE (1986): Naltrexone blocks the post-shock increase of ethanol consumption. Life Sciences 38:841-847. Volpicelli JR, O'Brien CP, Alterman AI, Hayashida M (1990): Naltrexone and the treatment of alcohol dependence: initial observations. In: Reid LB editor. Opioids, Bulimia, Alcohol Abuse and Alcoholism. New York: Springer-Verlag, pp 195-214.
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