Opiate Receptors and Antagonists

For other titles published in this series, go towww.springer.com/series/7626

Reginald L. Dean III · Edward J. BilskyS. Stevens NegusEditors

Opiate Receptors and Antagonists

From Bench to Clinic

EditorsReginald L. Dean, III, M.S. Edward J. Bilsky, Ph.D. Life Sciences/Toxicology Department of PharmacologyAlkermes, Inc. University of New EnglandCambridge, MA 02139 College of Osteopathic MedicineUSA Biddleford ME 04005 USA

S. Stevens Negus, Ph.D.Department of Pharmacologyand ToxicologyVirginia Commonwealth UniversityRichmond, VA 23298USA

ISBN: 978-1-58829-881-2 e-ISBN: 978-1-59745-197-0DOI: 10.1007/978-1-59745-197-0

Library of Congress Control Number: 2008941670

© Humana Press, a part of Springer Science+Business Media, LLC 2009All 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, neither 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.

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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

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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 IIIS. Stevens NegusEdward 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.

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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 HealthCharles 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.

Contents

Part I Opioid Receptors

1 Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance ................................................. 3Lindsay H. Burns, Todd W. Vanderah, and Hoau-Yan Wang

2 Upregulation of Opioid Receptors ............................................................ 19Ellen M. Unterwald and Richard D. Howells

3 Imaging Human Brain Opioid Receptors: Applications to Substance Use Disorders ................................................ 45Mark K. Greenwald and Caren L. Steinmiller

4 Opioid Receptor Antagonist-Mediated Signalingin the Immune System ............................................................................... 67Jonathan Moorman, Zhi Qiang Yao, Edward J. Bilsky,and Deling Yin

Part II Opioid Antagonists: Chemistry and Pharmacology

5 The Chemistry and Pharmacology of m-Opioid Antagonists ................ 83Jean M. Bidlack and Jennifer L. Mathews

6 Medicinal Chemistry of Kappa Opioid Receptor Antagonists .............. 99Cécile Béguin and Bruce M. Cohen

7 The Chemistry and Pharmacology of Delta Opioid Antagonists .......... 119Beatriz Fioravanti and Todd W. Vanderah

8 Novel Opioid Antagonists with Mixed/Dual Selectivity .......................... 137Richard B. Rothman, Subramaniam Ananthan, and Edward J. Bilsky

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9 Experimental Utility and Clinical Potentialof Irreversible Opioid Antagonists ......................................................... 153Ellen A. Walker and Sandra D. Comer

10 Methylnaltrexone: A Peripherally Acting Opioid Antagonist .................................................................................... 175Chun-Su Yuan and Robert J. Israel

Part III Substance Abuse

11 Opioid Antagonist Effects in Animal Models Related to Opioid Abuse: Drug Discrimination and Drug Self-Administration ................................................................ 201S. Stevens Negus

12 Naltrexone for Initiation and Maintenance of Opiate Abstinence ................................................................................ 227Kevin A. Sevarino and Thomas R. Kosten

13 Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids ...................................................... 247Lindsay H. Burns, Francesco Leri, and Mary C. Olmstead

14 Can a Combination Formulation Containing a Neutral Opiate Antagonist Decrease the Abuse of m-Agonist Opiates .............................................................. 263John Mendelson, Mark Pletcher, and Gantt Galloway

15 Effects of Opioid Antagonists on the Abuse-Related Effects of Psychomotor Stimulants and Nicotine ............................................... 273Brenda J. Gehrke and Toni S. Shippenberg

16 Potential Use of Opioid Antagonists in the Treatment of Marijuana Abuse and Dependence .................................................... 299Bernard Le Foll, Zuzana Justinova, G. Tanda, Marcello Solinas, Peter Selby, and Steven R. Goldberg

17 Naltrexone in Smoking Cessation: A Review of the Literature and Future Directions ................................................. 315Andrea King, Rachel Torello, Suchitra Krishnan-Sarin, and Stephanie O’Malley

Contents xiii

Part IV Alcohol and Ingestive Behaviors

18 Opioid Antagonists and Ethanol’s Ability to Reinforce Intake of Alcoholic Beverages: Preclinical Studies ............................... 335Larry D. Reid

19 Clinical Use of Opioid Antagonists in the Treatment of Alcohol Dependence ............................................................................ 371Raymond F. Anton

20 Preclinical Effects of Opioid Antagonists on Feeding and Appetite .......................................................................... 387Richard J. Bodnar

21 CNS Opiate Systems and Eating Disorders ........................................... 407Elliot D. Luby and David Koval

Part V Behavioral Disorders

22 Potential Utility of Kappa Ligands in the Treatment of Mood Disorders .................................................................................... 425William A. Carlezon, Jr. and Bruce M. Cohen

23 Opioid Antagonists in the Treatment of Pathological Gambling and Kleptomania .................................................................... 445Jon E. Grant

24 Efficacy of Opioid Antagonists in Attentuating Self-Injurious Behavior ........................................................................... 457Curt A. Sandman

25 Pharmacotherapeutic Effects of Opioid Antagonistsin Alcohol-Abusing Patients with Schizophrenia .................................. 473Ismene Petrakis

Part VI Medical Indications

26 Current Issues in the Use of Opioid Antagonists (Naltrexone for Opiate Abuse: A Re-Educational Tool as Well as an Effective Drug) .................................................................. 487Colin Brewer and Emmanuel Streel

27 Emergency Room Use of Opioid Antagonists in Drug Intoxication and Overdose ...................................................................... 511Simon F.J. Clarke, Rob Török, Paul I. Dargan, and Alison L. Jones

xiv Contents

28 Kappa-Opioid Antagonists as Pruritogenic Agents .............................. 541Alan Cowan and Saadet Inan

29 Clinical Effect of Opioid Antagonists on Clinical Pruritus .................. 551Nora V. Bergasa

30 Effects of Opioid Antagonists on l-DOPA-Induced Dyskinesia in Parkinson’s Disease .......................................................... 569Susan H. Fox, Tom H. Johnston, and Jonathan M. Brotchie

31 Endocrine Effects of Opioid Antagonists ............................................... 581Jack H. Mendelson and Nancy K. Mello

32 Opioid Antagonists in Traumatic Shock: Animal and Human Studies .................................................................... 605Liangming Liu

33 The Efficacy of Opioid Antagonists Against Heatstroke-Induced Ischemia and Injury in Rats ................................ 625Mao-Tsun Lin, Ching-Ping Chang, and Sheng-Hsien Chen

34 A Review of the Opioid System in Cancer Patients and Preliminary Results of Opioid Antagonists in the Treatment of Human Neoplasms ................................................. 641Paolo Lissoni

35 Nonclinical Pharmacology of VIVITROL®: A Monthly Injectable Naltrexone for the Treatment of Alcohol Dependence ............................................................................ 655Reginald L. Dean, III

36 The Development of Sustained-Release Naltrexone and Clinical Use in Treating Opiate Dependence ................................. 675Gary K. Hulse, Sandra D. Comer, and Maria A. Sullivan

37 The Development of ProNeura Technology for the Treatment of Addictions .............................................................. 689Lauren C. Costantini

38 Development of Opioid Transdermal Delivery Systems ....................... 709Kalpana S. Paudel, Stan L. Banks, Paul K. Kiptoo, Dana C. Hammell, R. Reddy Pinninti, Caroline Strasinger, and Audra L. Stinchcomb

Contents xv

39 Intranasal Naloxone for Treatment of Opioid Overdose ...................... 729Anne-Maree Kelly, Debra Kerr, and Paul Dietze

Index .................................................................................................................. 741

Contributors

Subramaniam AnanthanOrganic Chemistry Department, Southern Research Institute, Birmingham, AL 35255

Raymond F. AntonCenter for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC 29425

Stan L. BanksAllTranz, Inc., Lexington, KY 40536

Cécile BéguinMolecular Pharmacology Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478

Nora V. BergasaDepartment of Medicine, Metropolitan Hospital Center,New York, NY 10029

Edward J. BilskyDepartment of Pharmacology, University of New England College of Osteopathic Medicine, Biddeford, ME 04005

Richard J. BodnarDepartment of Psychology, Queens College, City University of New York, Flushing, NY 11367

Colin BrewerThe Stapleford Centre, London SW1W 9NP, United Kingdom

Jonathan M. BrotchieToronto Western Research Institute, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

Lindsay H. BurnsPreclinical Development, Pain Therapeutics, Inc., San Mateo, CA 94404

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xviii Contributors

William A. Carlezon, Jr.Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478

Ching-Ping ChangDepartment of Biotechnology, Southern Taiwan University of Technology, Tainan, Taiwan 710, Republic of China

Sheng-Hsien ChenObstetrics and Gynecology, Chi-Mei Medical Center, Yung-Kang City, Tainan, Taiwan 710, Republic of China

Simon F.J. ClarkeEmergency Department, Frimley Park NHS Foundation Trust, Camberley, Surrey, United Kingdom GU16 7UJ

Bruce M. CohenMolecular Pharmacology Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478

Sandra D. ComerDivision on Substance Abuse, Department of Psychiatry, Columbia University, New York, NY 10032

Lauren C. CostantiniTitan Pharmaceuticals, Inc., South San Francisco, CA 94080

Alan CowanDepartment of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140

Paul I. DarganGuy’s and St. Thomas’ Poisons Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, United Kingdom

Reginald L. Dean, IIILife Sciences/Toxicology, Alkermes, Inc., Cambridge, MA 02139

Paul DietzeTurning Point Alcohol and Drug Centre, Monash Institute of Health Services Research, Clayton, Victoria 3168, Australia

Beatriz FioravantiDepartment of Pharmacology and Anesthesiology, College of Medicine at the University of Arizona, Tucson, AZ 85724

Bernard Le Foll, MD PhD CCFPHead, Translational Addiction Research Laboratory, CAMH. Associate Professor, University of Toronto. Centre for Addiction and Mental Health, Toronto, Canada M5S 2S1

Contributors xix

Susan H. FoxDivision of Neurology, University of Toronto, Toronto, ON M5V 2S8, Canada

Gantt GallowayAddiction Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, St. Luke’s Hospital, San Francisco, CA 94110

Brenda J. GehrkeIntegrative Neuroscience Section, NIH/NIDA Intramural Research Program, Baltimore, MD 21224

Steven R. GoldbergPreclinical Pharmacology Section, Behavioral Neuroscience Research Branch, NIDA, NIH, Department of Health and Human Services, Baltimore, MD 21224

Jon E. GrantDepartment of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55454

Mark K. GreenwaldSubstance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48207

Dana C. HammellDepartment of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536

Richard D. HowellsDepartment of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103

Gary K. HulseUnit for Research and Education in Drugs and Alcohol, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Western Australia 6009, Australia

Saadet InanDepartment of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA 19140

Robert J. IsraelProgenics Pharmaceuticals, Inc., Tarrytown, NY 10591

Tom H. JohnstonToronto Western Research Institute, Toronto Western Hospital, Toronto, ON M5T 2S8, Canada

Alison L JonesAustralian and Clinical Toxicology Unit, Mater Misericordiae Hospital, New Castle, New South Wales, Australia

xx Contributors

Zuzana JustinovaPreclinical Pharmacology Section, Behavioral Neuroscience Research Branch, NIDA, NIH, Department of Health and Human Services, Baltimore, MD 21224

Anne-Maree KellyJoseph Epstein Centre for Emergency Medicine Research, Department of Emergency Medicine, Western Hospital and The University of Melbourne, Victoria 3021, Australia

Debra KerrJoseph Epstein Centre for Emergency Medicine Research, The University of Melbourne, Victoria 3021, Australia

Andrea KingDepartment of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL 60637

Paul K. KiptooDepartment of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536

Thomas R. KostenDepartment of Psychiatry, Michael E. DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX 77030

David KovalDepartment of Psychiatry, Wayne State University, Detroit, MI 48202

Suchitra Krishnan-SarinDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT 06519

Francesco LeriDepartment of Psychology, University of Guelph, Guelph, ON N1G2W1, Canada

Mao-Tsun LinDepartment of Medical Research, Chi-Mei Medical Center, Yung-Kang City, Tainan, Taiwan 710, Republic of China.

Paolo LissoniDivisione di Radioterapia Oncologica, Ospedale San Gerardo, 20052 Monza, Italy

Liangming LiuState Key Laboratory of Trauma, Burns and Combined Injury, The Second Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, People’s Republic of China

Elliot D. LubyWayne State University Schools of Medicine and Law, Detroit, MI 48202

Contributors xxi

Nancy K. MelloAlcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, MA 02478

Jack H. MendelsonAlcohol and Drug Abuse Research Center, McLean Hospital-Harvard Medical School, Belmont, MA 02478

John MendelsonAddiction Pharmacology Research Laboratory, California Pacific Medical Center Research Institute, St. Luke’s Hospital, San Francisco, CA 94110

Jonathan P. MoormanDepartment of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 36714

S. Stevens NegusDepartment of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298

Mary C. OlmsteadDepartment of Psychology, Queen’s University, Kingston, ON K7L 3N6, Canada

Stephanie O’MalleyDepartment of Psychiatry, Yale University School of Medicine, New Haven, CT 06519

Kalpana S. PaudelDepartment of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536

R. Reddy PinnintiDepartment of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536

Mark PletcherDepartment of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94143

Larry D. ReidLaboratory for Psychopharmacology, Rensselaer Polytechnic Institute, Troy, NY 12180

Richard B. RothmanClinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS, Baltimore, MD 21224

Curt SandmanDepartment of Psychiatry and Human Behavior; Women and Childrens' Health and Well-Being Project, University of California-Irvine, Orange, California 92868

xxii Contributors

Peter SelbyAddiction Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON M5S 2S1, Canada

Kevin A. SevarinoVA Connecticut Healthcare System, Department of Psychiatry, Newington, CT 06111

Toni S. ShippenbergIntegrative Neuroscience Section, NIH/NIDA Intramural Research Program, Baltimore, MD 21224

Marcello SolinasInstitut de Biologie et Physiologie Cellulaires, Centre National de la Recherche Scientifique-6187, University of Poitiers, 86022 Poitiers, France

Caren L. SteinmillerSubstance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48207

Audra L. StinchcombDepartment of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536

Caroline StrasingerDepartment of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, KY 40536

Emmanuel StreelUniversite Libre de Bruxelles, ISEPK, B-1020 Bruxelles, Belgium

Maria A. SullivanDivision on Substance Abuse, Department of Psychiatry, Columbia University, New York, NY 10032

Gianluigi TandaPsychobiology Section, Medications Discovery Research Branch, Intramural Research Program, NIDA, NIH, Department of Health and Human Services, Baltimore, MD 21224

Rachel TorelloThe Chicago School of Professional Psychology, Chicago, IL 60610

Rob TörökEmergency Department, Dorset County Hospital, NHS Foundation Trust, London, United Kingdom

Ellen M. UnterwaldDepartment of Pharmacology and Center for Substance Abuse Research, Temple School of Medicine, Philadelphia, PA 19140 and The Rockefeller University, Biology of Addictive Diseases Laboratory, New York, NY 10021

Contributors xxiii

Todd W. VanderahDepartment of Pharmacology, College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724

Ellen A. WalkerDepartment of Pharmaceutical Sciences and Center for Substance Abuse Research, Temple University School of Pharmacy, Philadelphia, PA 19140

Hoau-Yan WangDepartment of Physiology and Pharmacology, City University of New York Medical School, New York, NY 10031

Zhi Qiang YaoDepartment of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 36714

Deling YinDepartments of Internal Medicine and Pharmacology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 36714

Chun-Su YuanCommittee on Clinical Pharmacology, Department of Anesthesia and Critical Care, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637

R. Dean et al. (eds.), Opiate Receptors and Antagonists, 3© Humana Press, a part of Springer Science + Business Media, LLC 2009

Chapter 1Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance

Lindsay H. Burns, Todd W. Vanderah, and Hoau-Yan Wang

Abstract Ultra-low-dose opioid antagonists have been shown to enhance opioid analgesia and attenuate the tolerance to analgesic effects normally seen with chronic opioid administration. This chapter reviews the early work with ultra-low-dose opioid antagonists starting with electrophysiological recordings of dorsal root ganglion neurons and continuing to antinociception in rodents. These phar-macological findings have not adhered to typical dose response curves and have instead been reported to occur at wide ranges of extremely low doses of several opioid antagonists as well as with the rare opioid agonist. Optimal dose ranges have also been reported to vary with sex and strain of rat. Translation into small clinical studies has been met with varied results, related to variations in dose, route of administration, and antagonist selected. Nevertheless, the clinical studies that have demonstrated enhanced analgesia or opioid sparing effects have utilized opioid antagonist doses in lower dose ranges than the studies that failed to demonstrate efficacy. Furthermore, a large double-blind, placebo- and active-controlled clinical trial demonstrated enhanced opioid analgesia with the extremely low dose of 2 μg naltrexone/patient/day. Preclinical data also extend the effects of ultra-low-dose opioid antagonists to neuropathic pain, which is comparatively resistant to opioid treatment and, interestingly, to cannabinoid analgesia. The mechanism of action has been shown to be the prevention of a chronic opioid-induced mu opioid receptor–G protein coupling switch that is associated with analgesic tolerance and depend-ence. Finally, recent data shows that this G protein coupling switch is controlled by filamin A and that a high-affinity interaction of naloxone or naltrexone with this scaffolding protein mediates their prevention of the altered coupling.

Keywords: Naloxone; Naltrexone; Neuropathic pain; G protein coupling; Filamin A

L.H. Burns (�), T.W. Vanderah, and H.-Y. Wang Pain Therapeutics, Inc., Preclinical Development, 2211 Bridgepointe Parkway, Suite 500, San Mateo, CA 94404e-mail: lburns@paintrials.com

4 L.H. Burns et al.

1.1 Introduction

Opioid analgesics are widely used to manage moderate or severe pain, yet their use is hampered by unwanted side effects, tolerance to their analgesic effects, and physical dependence. The fact that patients often balance analgesia with side effects illustrates the narrow therapeutic window of opioids. Side effects range from nausea, constipation, somnolence, and pruritis to the more serious respiratory depression. Chronic pain patients need analgesia over prolonged or indefinite time periods, yet these patients very often experience a loss of analgesic potency with continued use. Finally, physicians and patients alike are wary of initiating opioid therapy due to the fears or stigma around opioid dependence and even the potential for addiction. As a consequence, the field of pain management is in great need of improved analgesic therapies that provide adequate analgesia for moderate-to-severe pain with fewer adverse effects and minimal potential for tolerance, dependence, and addiction.

One such therapy involves the combination of opioid agonists with “ultra-low-dose” opioid antagonists. In contrast to the typical blockade of opioid receptor func-tions by higher concentrations of opioid antagonists, ultra-low-dose opioid antagonist cotreatment enhances and prolongs opioid analgesia and also prevents or reverses opioid analgesic tolerance. These phenomena have been demonstrated by preclinical data and have now randomized double-blind, controlled clinical trial data. This chap-ter will review the effects of ultra-low-dose opioid antagonists on analgesia, tolerance, and the hyperalgesia and allodynia in a model of neuropathic pain, while the attenu-ation of physical dependence and the addictive properties of opioids will be reviewed in Chapater 13. This chapter will also provide a historical overview of studies probing the mechanism of action for these effects from the initial electrophysiology findings to more recent molecular pharmacology data and identification of the high-affinity binding site. These studies indicate that chronic opioid administration causes altera-tions in the G protein system associated with mu opioid receptors (MORs) and that ultra-low-dose naloxone (and perhaps other opioid antagonists) suppresses these aberrant signaling changes via a picomolar interaction with filamin A.

1.2 Preclinical Evidence of Enhanced Opioid Analgesia and Reduced Tolerance

The history of ultra-low-dose opioid antagonists starts with electrophysiology studies on dorsal root ganglion (DRG) cell cultures. Crain and Shen first observed that while opioid agonists normally inhibit, or shorten, the action potential duration of DRG cells, lower doses of opioid agonists induce an opposite, excitatory effect – a prolongation of the action potential (39, 9). These researchers noted that prolonged exposure to an opioid agonist would also produce this prolongation of action potentials, and they theorized that these excitatory effects of opioids contributed to opioid tolerance (10). This same publication proposed a regula-

1 Low-Dose Naltrexone Improves Opioid Analgesia 5

tion by GM1 ganglioside, since exogenous administration of GM1 ganglioside mimicked the prolonged opioid exposure. The hypothesis that excitatory effects of opioids are mediated by opioid receptors coupling to the excitatory G protein Gs rather than the usual inhibitory G proteins, Gi or Go, was suggested by a blockade of the action potential prolongation by administration of cholera toxin-A, an agent that blocks Gs from being activated by receptor stimulation (40).

Using their in vitro model of action potential prolongation by low concentrations of morphine, Crain and Shen (11) showed that ultra-low-dose naloxone blocked the action potential prolongation when added at low picomolar concentrations. In the same 1995 publication, Crain and Shen showed that ultra-low-dose naltrexone (10 ng/kg, s.c.) also enhanced and prolonged morphine’s antinociceptive potency in mice. This seminal report also included data demonstrating that cotreatment with ultra-low-dose naltrexone dramatically attenuated morphine withdrawal after an acute high dose of morphine or after a 4-day, twice daily, progressively increasing morphine dosing schedule. Finally, an assessment of tolerance was made in the mice receiving the escalating 4-day morphine treatment, by comparing subsequent antinociception to that of naïve mice. Tolerance was partially prevented by ultra-low-dose naltrexone.

A subsequent study by a different lab extended the work of Crain and Shen, demonstrating enhanced morphine antinociception by ultra-low-dose naltrex-one administered either systemically or intrathecally to rats (36). This study also demonstrated that coadministration of ultra-low-dose naltrexone (0.05 ng) prevents analgesic tolerance over 7 days of daily intrathecal administration of morphine (15 μg). An even lower intrathecal dose of naltrexone (0.005 ng) as well as i.p. administration of both drugs was less effective. Using rats instead of mice, these data demonstrated enhanced morphine analgesia, a complete prevention of tolerance over a 7-day treatment period, a lower end of an effective ultra-low-dose range by intrathecal administration, and a spinal site of action. Data also showed that established morphine tolerance could be reversed, at least partially.

Crain and Shen also followed up their earlier work by demonstrating that both analgesic tolerance and precipitated withdrawal-associated hyperalgesia in mice could be prevented by ultra-low-dose naltrexone combined with either morphine (45) or oxycodone (44). In a further extension of their in vitro data, Crain and Shen demonstrated that acute hyperalgesia elicited by a low dose of an opioid agonist, referred to clinically as “paradoxical hyperalgesia” (27,29), could be reversed by ultra-low-dose naltrexone coadministration, yielding a strong analgesic effect (15).

While the early in vitro work primarily utilized naloxone, ultra-low doses of the kappa opioid antagonist nor-binaltorphamine (nor-BNI) and the mu opioid antago-nist beta-funaltrexamine (β-FNA) (Crain and Shen, personal communication), as well as the nonselective opioid antagonist diprenorphine (41), have also enhanced the inhibitory effects of opioid agonists in vitro. While most published in vivo work was initially limited to naltrexone, ultra-low-dose naloxone was also recently used in vivo to prevent analgesic tolerance (53; Fig. 1.1). In addition, ultra-low doses of naloxone and nalmefene have demonstrated beneficial effects in clinical studies dis-cussed below. Perhaps more surprisingly, ultra-low doses of the opioid agonists

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etorphine and dihydroetorphine (41) and of [des-Tyr] fragments of the endogenous opioids dynorphin A-(1–13) and β-endorphin (1–27) (42) also enhance the inhibi-tory effects of opioid agonists in vitro. Further, ultra-low-dose etorphine enhances morphine’s potency in vivo (43). Together, these findings hinted that these phenom-ena are not unique to naloxone or naltrexone and are also not dependent on opioid antagonist activity.

1.3 Dose Effects and Dependency on Strain and Sex

Ultra-low-dose opioid antagonist effects do not follow a typical dose-response pattern, but typically span several log units without conforming to bell-shaped curves. A wide range of doses has been used successfully. Although some initial studies tested antagonist:agonist ratios rather that discrete antagonist doses, the much narrower effective dose range for agonists than for ultra-low-dose antago-nists in enhancing agonist effects suggests that the antagonist dose is independ-ent of agonist dose. This method was likely initiated for ease of calculating antagonist dose. An examination of the antinociceptive effects of various ratios of naltrexone:oxycodone (1:109, 1:107, and 1:105) combined with a range of oxyco-done doses (0.03–3 mg/kg) in male Swiss Webster mice illustrates the wide range of effective doses of naltrexone (Fig. 1.2). Whereas all naltrexone:oxycodone dose ratios examined enhanced the areas under the curve (AUCs) of tailflick latencies

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Fig. 1.1 Co-treatment with ultra-low-dose NLX (10 ng/kg) prevented the antinociceptive tolerance caused by chronic morphine (10 mg/kg, s.c., twice daily for 7 days). Rats treated with mor-phine + NLX showed stable tail-flick latencies over the week of treatment, while tail-flick latencies of rats receiving morphine alone declined to a level not significantly different from NLX alone. *p < 0.05 and **p < 0.01 for morphine + NLX versus morphine. BLINE predrug baseline, NLX naloxone. Reprinted from Wang et al. (53), with permission from Elsevier

1 Low-Dose Naltrexone Improves Opioid Analgesia 7

of the oxycodone doses, the strongest antinociceptive effects were obtained with the 3 and 300 pg/kg naltrexone doses, which appear to enhance the antinociceptive effects of 3 mg/kg oxycodone to a greater extent than a 30 ng/kg dose.

While wide antagonist dose ranges have been used effectively, the optimal doses of antagonist vary with both the opioid agonist it is combined with as well as the sex of the animal. The prevention of tolerance and withdrawal-associated hyperalgesia by ultra-low-dose naltrexone was demonstrated at 0.3, 3, 300, and 3,000 ng/kg naltrexone when combined with 3 mg/kg morphine (45) and at 1 pg/kg or 1 ng/kg naltrexone when combined with oxycodone (44). The higher naltrexone doses used in these studies were used in males, suggesting males are less sensi-tive to ultra-low-dose antagonist effects. Interestingly, although these studies used the same morphine dose for males and females, a tenfold lower dose of oxycodone was administered to males, confirming the previously described increased sensitiv-ity to opioid analgesic effects in male rodents (28). Hence, while male rodents may be more sensitive to opioid analgesia, female rodents appear to be more sensitive to ultra-low-dose naltrexone, suggesting some degree of dissociation between the two. In addition, low doses of oxycodone elicited a greater degree of hyperalgesia in male than in female rats (23), while the reverse was reported with morphine-induced hyperalgesia (22). These findings likely contribute to the variations in

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Fig. 1.2 Dose-response of ultra-low-dose naltrexone:oxycodone ratios in enhancing oxycodone antinociception in the 52°C hot water immersion tail-flick tests in male Swiss Webster mice. Three different naltrexone:oxycodone ratios (1:109, 1:107, and 1:105) were superimposed onto a dose-response of oxycodone (0.03, 0.1, 0.3, 1, and 3 mg/kg, s.c.). These naltrexone:oxycodone ratios enhanced the effects of all doses of oxycodone, although the 1:109 and 1:107 ratios more potently enhanced the antinociceptive effect of the 3 mg/kg oxycodone dose than did the 1:105 dose ratio. Data are means ± SEM., n = 3. Reprinted from (2) in Recent Developments in Pain Research, with permission from Research Signpost

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optimal ultra-low-dose opioid antagonist dose ranges noted both with sex of the animal and the opioid used in combination.

In addition to sex differences, the effects of ultra-low-dose naltrexone on morphine antinociception and tolerance can also vary with rat strain (46). While the enhancement of morphine antinociception and attenuation of morphine toler-ance was observed in both Sprague–Dawley and Long–Evans rats, naltrexone at the dose range tested (0.1–100 ng/kg) did not enhance morphine antinociception over a range of doses (2.5–7.5 mg/kg) in Fisher 344 or Lewis rats, nor did 10 or 100 ng/kg naltrexone significantly attenuate tolerance in these two strains. Given that pg/kg doses of naltrexone most effectively enhanced oxycodone antinociception in females in the previously mentioned Shen study (44), the question remains whether this even lower range might enhance antinociception in these two rat strains. Nevertheless, clear strain differences exist expanding on the initial report that ultra-low-dose nal-trexone enhances morphine antinociception in Swiss Webster mice but antagonizes it in 129/SvEv mice (14). The authors attribute this opposite effect of ultra-low-dose naltrexone in 129/SvEv mice, along with the enhanced potency of morphine and general lack of tolerance in this strain, to its deficiency in GM1 ganglioside.

The Terner study (46) also noted strain-specific sex differences. In Sprague–Dawley rats, males and females differed in the dose that most effectively enhanced antinociception, with the best effect in males observed at 10 ng/kg and the highest efficacy in females occurring at the lowest dose tested at 0.1 ng/kg. This greater sensitivity to ultra-low-dose naltrexone in female Sprague–Dawley rats, despite the females being less sensitive to the opioid itself, concurs with the findings by Shen and colleagues in Swiss Webster mice (44, 45). An additional strain-dependent sex difference was revealed in the Terner study; 10 ng/kg naltrexone significantly reversed established morphine tolerance only in female Long–Evans rats. In a sepa-rate study examining age and sex effects, morphine antinociception was enhanced by low-dose naltrexone in mature female but not in mature male rats (18–22 weeks) and was negligible in younger rats (21). However, the naltrexone dose range used in that study was again comparatively high (0.002–2 μg/kg), and the effect in mature females was “inversely related to dose.”

1.4 Ultra-Low-Dose Naltrexone Effects on Neuropathic Pain and Cannabinoid Analgesia

Although opioids are not typically very effective in neuropathic pain, recent preclinical data has shown that ultra-low-dose naltrexone enhances the antihyper-algesic and antiallodynic effects of morphine (49) or oxycodone (30) in the L5/L6 spinal nerve ligated rats. The antihyperalgesic effects of intrathecal delivery of these opioids combined with naltrexone at 0.33 ng were complete, though some tolerance developed after 10 days of twice daily administration. Further, while intrathecal morphine did not elicit any antiallodynic effect in this model, its com-bination with ultra-low-dose naltrexone produced a moderate though transient

1 Low-Dose Naltrexone Improves Opioid Analgesia 9

antiallodynic effect. With twice daily oral delivery in this rat model of neuropathic pain, ultra-low-dose naltrexone (0.3–3 μg/kg) combined with oxycodone produced strong antihyperalgesic and antiallodynic effects. Tolerance to these effects was dramatically reduced compared to the more rapid tolerance that developed with oral oxycodone alone. The oral 0.3 μg/kg naltrexone dose combination produced an antihyperalgesic effect that showed no tolerance over this time period. Notably, the enhanced antihypersensitivity effects of the opioids in these studies occurred at slightly higher doses of naltrexone than those shown to enhance antinociception in intact rats. Moreover, these preclinical data suggest that ultra-low-dose naltrexone may augment opioid effects in neuropathic pain and minimize the development of tolerance to them.

Further extending the area of research with ultra-low-dose opioid antagonists, a recent study showed ultra-low-dose naltrexone to enhance cannabinoid-induced analgesia (35). This finding may reflect the well-established interaction of the opi-oid and cannabinoid systems (32), rather than a specific interaction of naltrexone’s binding site on filamin A with cannabinoid receptors. The complete abolition of the analgesic effect of the cannabinoid agonist/naltrexone combination by a cannabinoid antagonist suggests that this analgesia is dependent on the cannabinoid system with any opioid effects upstream. The fact that a high dose of naltrexone only slightly (and nonsignificantly) enhanced here the cannabinoid-induced analgesia suggests that that the potentiation of cannabinoid analgesia by ultra-low-dose naltrexone has some opioid component but does not exclusively rely on opioid receptors.

1.5 Clinical Studies of Ultra-Low-Dose Opioid Antagonist Effects in Analgesia

Clinical experience with ultra-low-dose opioid antagonists has grown from case reports and small clinical studies to blinded, randomized, controlled clinical trials. In contrast to preclinical reports that mostly use naltrexone, clinical studies have reported benefits with ultra-low-doses of naloxone, naltrexone, and also nalmefene. In addition, “ultra-low” doses, dosing schedules, and settings have varied along with results. Most small clinical studies assessed postoperative analgesia and used i.v. (intravenous) administration, while current clinical trials have examined analgesia and dependence and have used oral delivery over 3 weeks or 3 months. While no pub-lished clinical studies or clinical trials have been able to assess ultra-low-dose opioid antagonist effects on analgesic tolerance, a case report noted strong analgesia in a severely opioid tolerant diabetic neuropathy patient from ultra-low-dose naltrexone (1 μg orally, b.i.d.) combined with methadone (16). This patient reported a pain inten-sity reduction from 9 to 3 within 24 h that persisted through a 1-month follow-up.

In a postoperative setting, the first clinical study showed that ultra-low-dose naloxone in a continuous i.v. infusion of 0.25 μg/kg/h, but not 1 μg/kg/h, produced an opioid-sparing effect of morphine delivered by patient-controlled analgesia (PCA) following hysterectomy (18). In another study in women undergoing lower

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abdominal surgery, a single dose of 15 or 25 μg nalmefene administered before morphine PCA decreased severity of pain 24 h later and also decreased the need for antiemetics and antipruritics (26).

A subsequent study using morphine PCA with or without naloxone at an estimated dose of 0.57 followed by 0.19 μg/kg/h failed to demonstrate enhanced analgesia or opioid-sparing effects (4). Reducing the i.v. naloxone dose tenfold in a later study to an estimated 0.05 followed by 0.006 μg/kg/h, Cepeda again did not demonstrate opioid-sparing effects or enhanced morphine analgesia but reported decreased nausea and pruritis (5). It should be noted that in both studies, PCA doses were increased by 20% when pain intensity exceeded 4 and again at 6 on a 0–10 scale, and a rescue dose 2.5 times the PCA solution was administered when pain intensity reached 6, so accurate assessment of doses is difficult. However, the PCA solution contained 6 μg/cc in the first study and 0.6 μg/cc in the second.

A small randomized, double-blind clinical trial of 156 patients presenting to the emergency department with acute, severe pain did not demonstrate any greater analgesic efficacy of a single i.v. bolus of morphine (0.1 mg/kg) combined with one of three different doses of naloxone (0.1, 0.01, or 0.001 ng/kg) compared to the mor-phine alone (1). In contrast to the only other study that used a single i.v. bolus of an ultra-low-dose opioid antagonist, that is nalmefene administered prior to morphine PCA postoperatively and assessed pain scores 24 h later (26), the present study gave one combined bolus and assessed pain intensity over the next 4 h. Possibly refers to confounding the results of the study were additional doses of morphine or other opio-ids administered within the 4 h period. While 13 patients in the morphine-only group received additional morphine, 8, 10, and 14 patients in the 0.1, 0.01, and 0.001 ng/kg naloxone groups required additional morphine, respectively. Although, this data may suggest an opioid-sparing effect at the 0.1 ng/kg naltrexone level these differ-ences were not significant due to the small group sizes. Besides the small group sizes in this study, the diversity of pain conditions and changing rates of pain in patients presenting to the emergency department may have hindered this trial. Nevertheless, this study was unable to demonstrate an effect of ultra-low-dose naloxone in the dose range of 0.001–0.1 ng/kg in augmenting opioid analgesia in acute, severe pain.

The first large, randomized, double-blind clinical trial assessed oxycodone and ultra-low-dose naltrexone (Oxytrex™) versus oxycodone alone delivered orally in 350 osteoarthritis patients with pain ≥5 on a 0–10 scale for 3 weeks (7). Naltrexone was formulated with oxycodone at 1 μg per tablet, so that the Oyxtrex b.i.d. dose group received 2 μg/day while the Oxytrex q.i.d. group received 4 μg/day. Both were compared to placebo and oxycodone alone administered q.i.d. in an immediate-release formulation. All active treatment groups received the same daily dose of oxycodone escalating from a starting dose of 10–40 mg/day in the final week. The Oxytrex b.i.d. treatment, with 2 μg/day naltrexone, provided significantly greater analgesia than both placebo and oxycodone by the end of week 2, with the strongest differences seen at the end of week 3. Neither oxycodone itself nor Oxytrex q.i.d., with 4 μg/day naltrexone, separated from placebo in reduction of pain intensity, a result not inconsistent with prior clinical trials of oxycodone at these doses (37, 33). Although this trial included mostly female patients, a sub-analysis by gender illustrated a stronger treatment effect in males, and a stronger separation

1 Low-Dose Naltrexone Improves Opioid Analgesia 11

of Oxytrex b.i.d. from placebo in males and a statistical separation of Oxytrex b.i.d. only from oxycodone in females, possibly due to a greater placebo effect in females (Fig. 1.3). Moreover, this first clinical trial demonstrated both enhanced analgesia and the ability to dose b.i.d. without any extended release mechanism, illustrat-ing the prolonged duration of effect seen preclinically. In addition, the enhanced analgesic efficacy of the treatment regimen containing 2 but not 4 μg/patient/day of naltrexone, combined with its ∼20% bioavailability by oral delivery, may shed light on earlier studies using i.v. naloxone at higher doses.

A subsequent clinical trial in 750 low-back pain patients showed that Oxytrex b.i.d. provided equivalent analgesia from a significantly lower total average daily dose compared to oxycodone q.i.d. (54). In this trial, patients titrated their dose to a pain score ≤2 or to tolerable side effects up to a maximum of 80 mg/day before being fixed for 12 weeks on their individual doses. Oxytrex b.i.d. also significantly reduced the number of moderate-to-severe events of constipation, somnolence, and pruritis seen with oxycodone alone.

To summarize clinical experience with ultra-low-dose opioid antagonists, some studies may have failed due to “ultra-low” doses that are too high, possibly imped-ing the effect of the opioid by classical receptor antagonism. In addition, differ-ences in efficacy were observed between studies in postoperative or acute pain and chronic pain populations, possibly suggesting greater efficacy in chronic pain, though one demonstrated enhanced efficacy of morphine intra-operatively. Gender differences in sensitivity to ultra-low-dose opioid antagonists have not emerged clinically, though two positive studies were performed in females. Finally, while some positive studies noted enhanced analgesia, others noted opioid-sparing effects or decreased side effects.

Fig. 1.3 Reduction in pain intensity in males and females. Oxytrex b.i.d. provided the greatest reduction in pain intensity scores in both males and females. At week 3, Oxytrex b.i.d. was significantly better than placebo in males and significantly better than oxycodone in females. Reprinted from Chindalore et al. (7) with permission from American Pain Society