Science of the Placebo: Toward an Interdisciplinanary Research Agenda (Evidence-Based Medicine Workbks.)

332 Pages·2002·1.71 MB·English

by  Harry Guess

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