The Science of the Placebo Toward an interdisciplinary research agenda Edited by Harry A Guess Arthur Kleinman John W Kusek Linda W Engel BMJ Books 2002 Chapter 3 Sissela Bok Chapter 14 Robert Levine BMJ Books is an imprint of the BMJ Publishing Group All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording and/or otherwise, without the prior written permission of the publishers. First published in 2002 by BMJ Books, BMA House, Tavistock Square, London WC1H 9JR www.bmjbooks.com British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0 7279 1594 0 Typeset by SIVA Math Setters, Chennai, India Printed and bound in Spain by GraphyCems, Navarra Contents Contributors v Foreword ix 1 An overview 1 Arthur Kleinman, Harry A Guess, Joan S Wilentz Section 1: Historical and ethical perspectives 33 2 “Seeing” the placebo effect: historical legacies and present opportunities 35 Anne Harrington 3 Ethical issues in use of placebo in medical practice and clinical trials 53 Sissela Bok Section 2: Elucidating placebo effects: explanatory mechanisms 75 4 Explanatory mechanisms for placebo effects: cultural influences and the meaning response 77 Daniel E Moerman 5 Explanatory mechanisms for placebo effects: cognition, personality and social learning 108 Richard R Bootzin, Opher Caspi 6 Explanatory mechanisms for placebo effects: Pavlovian conditioning 133 Shepard Siegel 7 Regression to the mean or placebo effect? 158 Clarence E Davis Section 3: Elucidating placebo effects: intervening psychophysiology 167 8 Neuroendocrine mediators of placebo effects on immunity 169 Farideh Eskandari, Esther M Sternberg iii CONTENTS 9 Endogenous opioid and non-opioid pathways as mediators of placebo analgesia 183 Donald D Price, Lene Vase Soerensen Section 4: Use of placebo groups in clinical trials – methodological and ethical issues 207 10 Placebo controlled trials and active controlled trials: ethics and inference 209 Robert J Temple 11 When is it appropriate to use a placebo arm in a trial? 227 Kenneth J Rothman, Karin B Michels 12 The pros and cons of non-inferiority (equivalence) trials 236 Stuart J Pocock 13 Use of placebo in large-scale, pragmatic trials 249 Robert M Califf, Sana M Al-Khatib 14 Placebo controls in clinical trials of new therapies for conditions for which there are known effective treatments 264 Robert J Levine Section 5: Priorities for future research 281 15 The research and ethical agenda 283 Joan S Wilentz, Linda W Engel Part I: Recommendations for research to further elucidate the nature of the placebo effect 286 Fabrizio Benedetti, Susan M Czajkowski, Cheryl A Kitt, Michael Stefanek, Esther M Sternberg Part II: Recommendations for research on applying placebo effects in clinical practice 293 Ruth L Fischbach, David Spiegel Part III: Recommendations for research concerning the use of placebos in clinical trials to test pharmacological and procedural interventions 300 David W Feigal, Jr, Kathleen J Propert, David S Wendler Part IV: Recommendations for research concerning the use of placebos in clinical trials to test behavioral interventions 306 Thomas D Borkovec, Lisa S Onken Section 6: Conclusions and future directions 311 16 Conclusions and future directions 313 Stephen E Straus, Josephine P Briggs Appendix 317 Index 323 iv Contributors Sana M Al-Khatib, Associate in Medicine, Department of Medicine, Duke University Medical Center, Durham, NC, USA Fabrizio Benedetti, Professor of Physiology and Neuroscience, Department of Neuroscience, University of Turin Medical School, Turin, Italy Sissela Bok, Senior Visiting Fellow, Harvard Center for Population and Development Studies, Harvard School of Public Health, Cambridge, MA, USA Richard R Bootzin, Professor, Department of Psychology, University of Arizona, Tucson, AZ, USA Thomas D Borkovec, Distinguished Professor of Psychology, Department of Psychology, Pennsylvania State University, University Park, PA, USA Josephine P Briggs, Director, Division of Kidney, Urologic and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA Robert M Califf, Professor of Medicine, Associate Vice Chancellor for Clinical Research, Director, Duke Clinical Research Institute, Durham, NC, USA Opher Caspi, Research Assistant Professor, Program in Integrative Medicine, University of Arizona College of Medicine, Tucson, AZ, USA Susan M Czajkowski, Social Scientist Analyst, Division of Epidemiology and Clinical Applications, Behavioral Medicine Scientific Research Group, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Clarence E Davis, Professor and Chair, Department of Biostatistics, University of North Carolina School of Public Health, Chapel Hill, NC, USA Linda W Engel, Special Assistant to the Director for Program Development, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD, USA v CONTRIBUTORS Farideh Eskandari, Research Fellow, Department of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA David W Feigal, Jr, Director, Center for Devices and Radiological Health, US Food and Drug Administration, Rockville, MD, USA Ruth L Fischbach, Senior Advisor for Medical Ethics, National Institutes of Health, Bethesda, MD, USA (currently Professor of Bioethics, Columbia University, College of Physicians and Surgeons, New York, NY, USA) Harry A Guess, Vice President, Epidemiology, Merck Research Laboratories, West Point, PA, USA; Adjunct Professor of Epidemiology and Biostatistics, University of North Carolina, Chapel Hill, NC, USA Anne Harrington, Professor of the History of Science, Harvard University, Cambridge, MA, USA Cheryl A Kitt, Program Director for Pain Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA Arthur Kleinman,Professor of Social Anthropology, Harvard University; Maude and Lillian Presley Professor of Medical Anthropology and Psychiatry, Harvard Medical School, Cambridge, MA, USA John W Kusek, Clinical Trials Program Director, Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA Robert J Levine, Professor, Department of Medicine; Lecturer, Department of Pharmacology; Co-Chairperson, Yale University Interdisciplinary Program for Bioethics; Yale University, New Haven, CT, USA Karin B Michels, Assistant Professor of Epidemiology, Harvard School of Public Health; Assistant Professor of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, USA Daniel E Moerman, William E Stirton Professor of Anthropology, Department of Behavioral Sciences, University of Michigan-Dearborn, Dearborn, MI, USA Lisa S Onken, Associate Director for Behavioral Treatment Research; Chief, Behavioral Treatment Development Branch, Division of Treatment Research and Development, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA Stuart J Pocock, Professor of Medical Statistics, London School of Hygiene and Tropical Medicine, London, England vi CONTRIBUTORS Donald D Price, Professor, Department of Oral and Maxillofacial Surgery, College of Dentistry; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA Kathleen J Propert, Associate Professor of Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA Kenneth J Rothman, Professor, Department of Epidemiology and Biostatistics, Boston University School of Public Health, and Section of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA Shepard Siegel, University Professor, Department of Psychology, McMaster University, Hamilton, Ontario, Canada Lene Vase Soerensen, Department of Psychology, University of Aarhus, Denmark David Spiegel, Professor and Associate Chair of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA Michael Stefanek, Chief, Basic Biobehavioral Research Branch, Behavioral Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Esther M Sternberg, Chief, Section on Neuroendocrine Immunology and Behavior; Director, Integrative Neural Immune Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA Stephen E Straus, Director, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD, USA Robert J Temple, Associate Director for Medical Policy, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD, USA David S Wendler, Head, Unit on Vulnerable Populations, Section on Human Subjects Research, Department of Clinical Bioethics, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD, USA Joan S Wilentz, Senior Science Writer, Bethesda, MD, USA vii Foreword These proceedings grew from parallel discussions among staff of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and members of the National Center for Complementary and Alternative Medicine (NCCAM) that reflected the somewhat different perspectives of each organization. The first perspective is that of clinical scientists who design and oversee studies aimed at providing rigorous evaluations of unproven therapies – placebos are generally seen as indispensable in many such studies. The second perspective is that of biologists and behavioral scientists who are fascinated by what might be the basis of the placebo effect, what it tells us about how people experience illness and recover from it, and whether placebo mechanisms could be harnessed to facilitate healing. It was only after each group of discussants learned that others at the National Institutes of Health (NIH) shared their interests in the placebo, that a plan began to unfold to collaborate on a broad-based multidisciplinary meeting. Part of our charge at the NIH is to oversee research that aims to build the evidence base for the treatment or prevention of disease. At NIDDK, for example, we are concerned with burdensome chronic illnesses such as diabetes, urologic disease, progressive kidney diseases, and inflammatory bowel disease. We mount major clinical trials aiming to advance the state-of-the-art approaches to these diseases. When we in NIDDK began to think about convening a meeting on the placebo and started to plan it, the dominant issues were whether placebos are truly needed, how large their effects can be, how long they last – practical issues of the sort that dog the design of randomized clinical trials. The randomized placebo controlled clinical trial has emerged over the past half century as a critical tool for evidence-based medicine for many good reasons. Hunches about what is good for patients commonly prove wrong, preliminary studies are often misleading, and unexpected harmful effects can overwhelm benefits, problems that become apparent through rigorous and unbiased evaluation with a randomized and blinded design. This must be balanced, however, with the ethical imperative of equipoise, which demands assurance that treatments being offered to participants are equally valuable. Yet, a treatment that is plausible enough to justify a large-scale trial has, quite inevitably, both its advocates and its detractors. Often what we call equipoise reflects a kind of truce between the believers and the skeptics, the enthusiasts and the nihilists. Sometimes new therapies ix