Look Inside Systematic Reviews by IASP

Systematic Reviews in Pain Research: Methodology Reﬁned Henry J. McQuay • Eija Kalso • R. Andrew Moore Editors

International Association for the Study of Pain®

Mission Statement of IASP Press速 IASP brings together scientists, clinicians, health care providers, and policy makers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide. IASP Press publishes timely, high-quality, and reasonably priced books relating to pain research and treatment.

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Systematic Reviews in Pain Research: Methodology Refined

Editors

Henry J. McQuay, DM, FRCA, FRCP(Edin) Oxford Pain Relief Unit, Churchill Hospital, Headington, Oxford, United Kingdom; University of Oxford, Oxford, United Kingdom

Eija Kalso, MD, PhD Institute of Clinical Medicine, University of Helsinki; Pain Center, Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain Medicine, Helsinki University General Hospital, Helsinki, Finland

R. Andrew Moore, DSc, FRCS Nuffield Department of Anaesthetics, University of Oxford, Oxford, United Kingdom; Pain Research, Churchill Hospital, Headington, Oxford, United Kingdom

IASP PRESSÂŽ â&#x20AC;˘ SEATTLE

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© 2008 IASP Press® International Association for the Study of Pain® 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, or otherwise, without the prior written permission of the publisher. Timely topics in pain research and treatment have been selected for publication, but the information provided and opinions expressed have not involved any verification of the findings, conclusions, and opinions by IASP®. Thus, opinions expressed in Systematic Reviews in Pain Research: Methodology Refined do not necessarily reflect those of IASP or of the Officers and Councilors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in the medical sciences, the publisher recommends that there should be independent verification of diagnoses and drug dosages. Library of Congress Cataloging-in-Publication Data International Association for the Study of Pain. Research Symposium (6th : 2006 : Alicante, Spain) Systematic reviews in pain research : methodology refined / editors, Henry J. McQuay, Eija Kalso, R. Andrew Moore. p. ; cm. Includes bibliographical references and index. Summary: “Presents invited papers from the 6th IASP Research Symposium, Systematic Reviews and Meta-Analyses in Pain, held in Spain in September 2006, organized by the International Collaboration on Evidence-Based Critical Care, Anaesthesia and Pain (ICECAP). Describes systematic reviews and meta-analyses that estimate the efficacy and harm of interventions in clinical trials of pain medications”--Provided by publisher. ISBN 978-0-931092-69-5 (softcover : alk. paper) 1. Pain--Chemotherapy--Evaluation-Congresses. 2. Analgesics--Evaluation--Congresses. 3. Systematic reviews (Medical research)--Congresses. 4. Meta-analysis--Congresses. I. McQuay, H. J. (Henry J.) II. Kalso, Eija, 1955- III. Moore, R. Andrew (Robert Andrew), 1947- IV. Title. [DNLM: 1. Pain--drug therapy. 2. Analgesics--therapeutic use. 3. Clinical Trials. 4. Meta-Analysis. 5. Review Literature. WL 704 I604s 2008] RB127.I55 2006 616’.0472--dc22 2007028392 Published by: IASP Press International Association for the Study of Pain 111 Queen Anne Ave N, Suite 501 Seattle, WA 98109-4955, USA Fax: 206-283-9403 www.iasp-pain.org Printed in the United States of America

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Contents List of Contributing Authors Preface

ix xiii

Part I Systematic Reviews and Meta-Analyses 1. 2. 3. 4. 5. 6. 7. 8.

Systematic Reviews: Are We Getting It Right Yet? R. Andrew Moore

Managing Potential Publication Bias R. Andrew Moore, Jodie Barden, Sheena Derry, and Henry J. McQuay

Individual Patient Meta-Analysis R. Andrew Moore

Industry Bias Sheena Derry

Placebo and Control Event Rate Henry J. McQuay

Adverse Events Sheena Derry

Guidelines, Guidance, and Evidence Kate Seers

Basic Science Systematic Reviews Vesa K. Kontinen

Part II Acute Pain 9.

Treatment of Postoperative Pain: By Procedure Or by Patient Factors? Francis Bonnet

109

10. Is Opioid Sparing Clinically Relevant? Nadia Elia and Martin R. TramĂ¨r

119

11. Challenges in Practicing Evidence-Based Perioperative Medicine Using Systematic Reviews: What We Know, What Is Uncertain, and What We Need to Know Peter Kranke

133

12. What Can We Learn from Evidence on the Use of NSAIDs, Coxibs, and Paracetamol (Acetaminophen) for Acute Pain? Emmanuel Marret and Francis Bonnet

151

13. Dose Response Henry J. McQuay

163

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CONTENTS

Part III Chronic Pain 14. Defining the Importance of Change in Clinical Trials of Acute Pain Jodie Barden

175

15. Chronic Nonmalignant Pain in the Elderly: Do Opioids Cause Cognitive Impairment? Helen Gaskell

185

16. Clinical Trials in Pediatric Pain Katri Hamunen

195

17. Opioids in Chronic Noncancer Pain: Systematic Reviews of Efficacy and Safety—What More Is Needed? Eija Kalso

207

18. Trial Design of Psychological Treatments in Chronic Pain: What Can We Tell Patients? Stephen Morley

217

19. Cannabinoids and Analgesia, with Special Reference to Neuropathic Pain Andrew S.C. Rice, Isobel Lever, and Roxaneh Zarnegar

233

20. Epidemiology of Chronic Pain Blair H. Smith and Nicola Torrance

247

21. Cognitive-Behavioral Pain Management: Lessons Learned Amanda C. de C. Williams

275

Part IV Cancer Pain 22. Trial Design in Cancer Pain: Oral Opioids and the Missing Placebo Rae F. Bell, Torbjørn Wisløff, Christopher Eccleston, and Eija Kalso

287

23. What Evidence Do We Have That the WHO Ladder Is Effective in Cancer Pain? Michael I. Bennett

303

Part V From Evidence to Practice 24. What We Have Learned about Trials from Systematic Reviews Henry J. McQuay

317

25. Risk: Presentation and Systematic Reviews R. Andrew Moore

327

26. Randomized Controlled Trials for Complex Interventions? Kate Seers

339

27. Evidence-Based Decision Making: Why Is It So Difficult to Get from Evidence to Practice? Steen Møiniche

349

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CONTENTS

vii

28. Economics: Delivering Better Health Care? Ceri J. Phillips

359

29. Pain Ladders, Systematic Reviews, and Trials Henry J. McQuay

373

30. Research Translation for Systematic Reviews into Community Practice: The Alberta HTA Chronic Pain Ambassador Program Paul Taenzer, Saifudin Rashiq, Donald Schopflocher, Pamela Barton, Ann Scott, Carmen Moga, and Christa Harstall

381

Index

395

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408

INDEX

Henry J. McQuay, DM, FRCA, FRCP (Edin), is Nuffield Professor of Clinical Anaesthetics at the Oxford Pain Relief Unit, University of Oxford, and a Professorial Fellow at Balliol College. His clinical expertise is in the management of chronic pain, both cancer and noncancer. His research interests have included bench studies of analgesics, primary clinical trials of analgesic interventions, and using systematic review techniques to work out the relative efficacy and safety of analgesics. He is a member of the IASP Council and has served as clinical section editor for IASP’s journal PAIN. He is co-editor of the evidence-based medicine publication Bandolier.

R. Andrew Moore, MA, DPhil, CChem, FRSC, DSc, is Director of Research at Pain Research, University of Oxford, and is Honorary Professor, School of Health Sciences, University of Wales at Swansea. He is co-editor of Bandolier and author of Bandolier’s Little Book of Pain and Bandolier’s Little Book of Understanding the Medical Evidence. With more than 30 years’ experience in biomedical research, he has over 400 scientific and clinical publications. He founded a diagnostics company making drug and cancer tests, expanding in the United Kingdom from a staff of 6 to over 300 in less than a decade. He has written over 100 systematic reviews, including over 20 Cochrane reviews written or in progress.

Eija Kalso, MD, DMedSci, is Professor of Pain Research and Management at the University of Helsinki. Her main research interests include pharmacology of opioids, cancer pain, chronic postinjury pain and clinical trial design. She is section editor for clinical research in IASP’s journal PAIN and a member of the IASP Council.

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Contributing Authors Jodie Barden, DPhil Balliol College, University of Oxford, Oxford, United Kingdom Pamela Barton, MD, FRCPC Calgary Health Region Chronic Pain Centre and Division of Physical Medicine and Rehabilitation, University of Calgary, Calgary, Alberta, Canada Rae F. Bell, MD, PhD Pain Clinic/Regional Center of Excellence in Palliative Care, Haukeland University Hospital, Bergen, Norway Michael I. Bennett, MB ChB, MD, FRCP Palliative Medicine, University of Leeds, and St Gemmaâ&#x20AC;&#x2122;s Hospice, Leeds, United Kingdom; currently Department of Palliative Medicine, International Observatory on End of Life Care, Institute for Health Research, Lancaster University, Lancaster, United Kingdom Francis Bonnet, MD, FRCA Department of Anesthesia, Tenon University Hospital, Paris, France; Saint Antoine Faculty of Medicine, Pierre and Marie Curie University, Paris, France; Procedure Specific Postoperative Pain Management (PROSPECT) Group Sheena Derry, MA Pain Research, Churchill Hospital, Oxford, United Kingdom Christopher Eccleston, PhD Department of Psychology, University of Bath, Bath, United Kingdom Nadia Elia, MD Division of Anesthesiology, Geneva University Hospitals, Geneva, Switzerland Helen Gaskell, BM BCh, DPhil Department of Clinical Geratology, John Radcliffe Hospital, Oxford, United Kingdom; Pain Research, Churchill Hospital, Oxford, United Kingdom; Katri Hamunen, MD, DMedSci Department of Anesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland Christa Harstall, MLS, MHSA Institute of Health Economics, University of Alberta, Edmonton, Alberta, Canada Eija Kalso, MD, PhD Institute of Clinical Medicine, University of Helsinki; Pain Center, Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain Medicine, Helsinki University General Hospital, Helsinki, Finland Vesa K. Kontinen, MD, PhD Department of Pharmacology, Institute of Biomedicine, University of Helsinki; Department of Anaesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland

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CONTRIBUTING AUTHORS

Peter Kranke, MD, MBA Department of Anesthesiology, University Hospitals of Würzburg, Würzburg, Germany Isobel Lever, PhD Pain Research Group, Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, United Kingdom Emmanuel Marret, MD Department of Anesthesiology and Critical Care, Tenon University Hospital, Paris, France Henry J. McQuay, DM, FRCA, FRCP(Edin) Oxford Pain Relief Unit, Churchill Hospital, Oxford, United Kingdom; University of Oxford, Oxford, United Kingdom Carmen Moga, MD, MSc Institute of Health Economics, University of Alberta, Edmonton, Alberta, Canada Steen Møiniche, MD Department of Anesthesiology, Glostrup University Hospital, Glostrup, Copenhagen, Denmark R. Andrew Moore, DSc, FRCS Nuffield Department of Anaesthetics, University of Oxford, Oxford, United Kingdom; Pain Research, Churchill Hospital, Oxford, United Kingdom Stephen Morley, PhD Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom Ceri J. Phillips, MSc(Econ), PhD Institute for Health Research, Swansea University, Swansea, United Kingdom Saifudin Rashiq, BM BS, MSc(Epid), DA(UK), FRCPC Division of Pain Medicine, Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada Andrew S.C. Rice, MB BS Pain Research Group, Department of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, United Kingdom Donald Schopflocher, PhD Institute of Health Economics, University of Alberta, Edmonton, Alberta, Canada Ann Scott, PhD Institute of Health Economics, University of Alberta, Edmonton, Alberta, Canada Kate Seers, PhD RCN Institute, John Radcliffe Hospital, Oxford, United Kingdom; currently RCN Research Institute, School of Health and Social Studies, Warwick University, United Kingdom Blair H. Smith, MD, MEd, FRCGP Aberdeen Pain Research Collaboration, Department of General Practice and Primary Care, University of Aberdeen, Aberdeen, United Kingdom Paul A. Taenzer, PhD Calgary Health Region Chronic Pain Centre, Calgary, Alberta, Canada

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CONTRIBUTING AUTHORS

Nicola Torrance, MPH, PhD Aberdeen Pain Research Collaboration, Department of General Practice and Primary Care, University of Aberdeen, Aberdeen, United Kingdom Martin R. Tramèr, MD, DPhil Division of Anesthesiology, Geneva University Hospitals, Geneva, Switzerland Amanda C. de C. Williams, PhD Department of Clinical Health Psychology, University College London, London, United Kingdom Torbjørn Wisløff, MSc Norwegian Knowledge Center for the Health Services, Oslo, Norway Roxaneh Zarnegar, MB BS, FRCA Department of Anaesthesia, Royal National Orthopaedic Hospital, Stanmore, Middlesex, United Kingdom

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Preface The past decade has seen a proliferation of clinical trials for interventions for pain relief, as well as systematic reviews and meta-analyses of these trials. It has been a period of great change in our understanding of what makes for good evidence, so that we are better able to sift the good from the not-so-good. This book was inspired by presentations by international experts at the 6th IASP Research Symposium organized by the International Collaboration on Evidence-Based Critical Care, Anaesthesia and Pain (ICECAP). The symposium created a unique opportunity to take stock of what we have learned from systematic reviews in pain research and learn some lessons from the past to guide us on pathways to the future. The first lesson is most appropriate, and is one of humility. Collectively, we have recognized that, when it comes to interventions such as those for pain relief, where we are seeking substantial changes in a small number of people, the rules and outputs of systematic review and meta-analysis are different from when we are looking for small changes in large numbers of people. Researchers have progressively ditched obscure and unusable statistical outcomes (e.g., odds ratios), progressing through relative risks into numbers needed to treat, until we feel confident about talking about the simple percentage of people who will benefit from treatment. Such simplification has empowered many of us to reach out and try to understand clinical research and, more important, to question it — especially the practical relevance of outcomes chosen by academics or regulatory authorities. Increasingly, we are striving to incorporate and understand evidence about harm. We also now have systematic reviews that concentrate on adverse events, such as Moore et al.’s review of tolerability and adverse events in clinical trials of celecoxib in arthritis (Arthritis Res Ther 2005; 7:R644–R665). Adverse events — whether common but mild and reversible, or rare, more serious, and frequently irreversible — have developed from an aside to a major and crucial interest in clinical research. Indeed, more patients have participated in studies to investigate harm than efficacy in recent years, such as with the major studies of gastrointestinal and cardiovascular effects of coxibs (selective cyclooxygenase-2 inhibitors). The limited information we have tells us that this issue is of fundamental interest to patients, and that goals of therapy are changing: not just efficacy is needed, but efficacy in the absence of harm (Dahlöf CG et al., Cephalalgia 2005; 26:400–408). This insight imposes new, more stringent requirements on clinical research. xiii

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xiv

PREFACE

This is where systematic review comes into its own, as it allows us to look at the way in which we have done trials in the past and ask whether this is how we should be doing them in the future. Systematic review is now an integral part of the ongoing quality control process for any clinical research — part of the quest to make things better. The ideal is that we should have information available at the level of the individual patient, because we know that averages from clinical trials infrequently reflect the real result. Some patients do well, and some do poorly, but few occupy the middle ground between these extremes. Obtaining individual patient data allows us to do two things. First, we can question our outcomes, as Moore et al. have described with regard to acute pain (Pain 2005; 116:322–331), and ask whether different outcomes would better reflect what patients want or find acceptable. Second, we can pose a far more interesting and practical question, which is not whether interventions work on average, but in which patients do these interventions work, perhaps aiding real-world decisions. Even without the ideal of individual patient data, systematic reviews allow us to take a fresh look at the trials we are doing and ask whether they are good enough. An example is Bjordal et al.’s meta-analysis of interventions for knee osteoarthritis (Eur J Pain 2007; 11:125–138), which showed that no intervention provided much more than 10 mm difference more than placebo on a 100-mm pain intensity scale after about four weeks. This finding raises all sorts of interesting questions, especially whether the interventions are relatively ineffective or the trial methods are insensitive and fail to capture the full effects of really useful therapies (McQuay H, Moore A, Eur J Pain 2007; 11:123–124). In one sense, it does not matter what the answer is, because the systematic review has forced us to question whether our intervention and trial design are sufficient. Asking this question makes it likely that we will have an answer that will eventually yield better results in the future. The ultimate lesson is that systematic reviews should provoke us to look beyond the bounds of traditional research methodology. Systematic reviews and meta-analyses are not just for pointy-headed academics. They are powerful tools that can help incorporate the best evidence of the effectiveness of different treatments into health care policy and clinical decisions about individual patients. Knowing something is often easier than doing it, and the business of constructing care pathways built on the foundation of good evidence is complex, or so it seems. There are certainly few examples of clinical pathways constructed and tested in a literature that is replete with clinical trials, observational studies, audits, and opinion. Taking a fresh look at where we have been points out these deficiencies, and perhaps indicates changing priorities and approaches for the future.

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PREFACE

We are delighted that IASP has been able to resource this book, and we sincerely hope this book will prod and provoke others to question and test the evidence and push for something better. Our collaborators in the ad hoc group of people who form ICECAP have been inspirational, as has the IASP Special Interest Group on systematic reviews. HENRY J. MCQUAY, DM, FRCA, FRCP(EDIN) EIJA KALSO, MD, PHD R. ANDREW MOORE, DSC, FRCS

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Systematic Reviews in Pain Research: Methodology Refined, edited by Henry J. McQuay, Eija Kalso, and R. Andrew Moore, IASP Press, Seattle, ÂŠ 2008.

3 Individual Patient Meta-Analysis R. Andrew Moore Nuffield Department of Anaesthetics, University of Oxford; Pain Research, Churchill Hospital, Headington, Oxford, United Kingdom

In February 1993, The Lancet published a paper by Lesley Stewart and Mahesh Parmar that asked if there was a difference whether we combined data acquired from published papers or from individual patients. Using randomized trials of cisplatin-based therapy in ovarian cancer, the authors concluded that there was a difference: meta-analysis of the literature showed that the absolute difference between platinum and nonplatinum regimens was 7.5% and statistically significant, whereas meta-analysis using individual patient data showed a nonsignificant 2.5%. Although the authors used different data sets, with relatively small patient numbers, and these effects were seen over only a small part of the overall survival curve, the authors interpreted their findings as proof that meta-analysis of individual patients was superior to combining data from individual trials. Further â&#x20AC;&#x153;proofâ&#x20AC;? came from a study of paternal cell immunization for recurrent miscarriage (Jeng et al. 1995). The authors found that an analysis of four published studies gave a different, better, result with 202 patients than when data from 183 more patients were added from unpublished studies. This finding was taken to confirm the superiority of individual patient meta-analysis over meta-analysis of data combined from published studies (Oxman et al. 1995), despite the very small numbers of patients, and despite the fact that the original finding of statistical significance had a lower confidence interval for relative risk of 1.03. Somewhat unfortunately for the idea that individual patient analysis is better than analyzing data from published studies, some U.S. authors performing a meta-analysis of the influence of oral contraceptives on ovarian cancer risk were able to use the two different methods of meta-analysis on the same data set (Steinberg et al. 1997). They found excellent quantitative agreement using the two methods to analyze 10 observational studies with many thousands of patients and events. 25

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H.J. MCQUAY

PLACEBO RESPONSE OR PLACEBO EFFECT

Placebo response or effect is perhaps one of the most difficult of all topics, especially with subjective outcomes such as pain or depression. If we were discussing a topic such as myocardial infarction and our outcome measure was death, then we might be reasonably sure that a placebo would have no effect on the outcome. But with subjective outcomes such as pain, we might guess that patients would feel better after placebo, and consequently would have less pain if the doctor or nurse was nice to them or appeared authoritative, or if the placebo was given as a big red capsule instead of a tiny white pill or as an injection and not a tablet. Whatever we think, proving that any or all of these influences had an effect would be difficult because very large trials would be necessary to show any effect independent of random chance. Table I summarizes effects that we might expect to find in various control groups (Kalso and Moore 2000). It is all very complicated, and is made more so by the difficulty in proving that “negativity” or “interaction” or “expectation” contribute anything at all to the actual perception of pain as it is measured. We don’t help ourselves by using lax, if understandable, shorthand. When we want to discuss the effect that we observe when patients are given a placebo, we call it the placebo effect or placebo response. Immediately, that can be retranslated as “the effect caused by placebo.” Indirectly, of course, administration of placebo can and does result in an effect, such as analgesia in a pain study. The pitfall is that we jump to a simplistic causal connection and then in turn jump to conclusions about the mechanism of the effect. Ideas about how placebo has its effect will be discussed later. COMMON MISCONCEPTIONS ABOUT THE RESPONSE TO PLACEBO

There are a number of misconceptions about placebo, and they are worth examining because they are highly instructive. Table I Effects in control groups Control

Effects

Waiting list

Natural course of disease minus the negativity from nothing being done Natural course of disease plus doctor/nurse/patient interaction Natural course of disease plus interaction plus expectation that there will be an effect Natural course of disease plus interaction plus expectation plus actual effect

Visits without treatment Placebo Active control

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S. DERRY Table III Study designs suitable for examining associations for adverse events

Incidence of Event

Background Incidence Ease of Proving the Association

Common Rare Common Uncommon Rare

Rare Rare Common Moderately common Common

Easy: direct clinical observation Difficult: observational study Difficult: large trial Very difficult: large observational study Almost impossible (perhaps n-of-1 trial)

ADVERSE EVENTS IN CLINICAL TRIALS

Clinical trials are probably our best source of information for adverse events that are relatively common and occur soon after exposure. Trials need to be large to minimize chance findings, of good quality to minimize the effects of bias, and valid to be sure they are clinically relevant. Ideally they should report as a minimum: • number of patients with one or more adverse event • number of patients with any serious adverse event • number of patients with a treatment-related adverse event • number of patients withdrawing because of an adverse event • number of patients with individual/specific adverse events • severity of specific adverse events • details of all serious adverse events, including possible causation A number of reviews have shown that reporting of adverse events in published clinical trials is generally poor, across a wide range of specialities, including pain, and for both drug and other types of interventions (Edwards et al. 1999; Ioannidis and Lau 2001; Loke and Derry 2001; Papanikolaou and Ioannidis 2004). On average between 0.1 and 0.3 of a page, or less than 6% of the total results and discussion sections, was devoted to safety, which was frequently less than was devoted to authors’ details and contributions. There were inadequacies in reporting of clinical adverse events, laboratory-determined toxicity, and numbers and reasons for withdrawals due to adverse events. Such limitations can make interpretation of the individual trial, and comparison with other trials, difficult or impossible. In 2004, in response to these concerns, an extension to the CONSORT statement was published (Ioannidis et al. 2004), providing new recommendations to improve reporting of adverse events in clinical trials. If fully implemented, these recommendations should make things better in the future, but clinicians and researchers need now to use information from clinical trials already published.

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Systematic Reviews in Pain Research: Methodology Refined, edited by Henry J. McQuay, Eija Kalso, and R. Andrew Moore, IASP Press, Seattle, ÂŠ 2008.

13 Dose Response Henry J. McQuay Oxford Pain Relief Unit, Churchill Hospital, Headington, Oxford, United Kingdom; University of Oxford, Oxford, United Kingdom

Using systematic review and meta-analytic methods to investigate dose response of either efficacy or safety of interventions can be a very powerful tool. Dose response in some ways is just a special case of comparing the relative efficacy or safety of interventions; with dose response it is the comparison of efficacy or safety of two or more doses, whereas usually we are concerned with one dose level of each of two or more different drugs. What the meta-analysis should bring to the analysis if dose response is compared with individual trial data is size, potentially allowing us to be more certain of differences in efficacy or adverse effect incidence between different doses. Size alone does not quite capture what is needed, because, particularly for adverse effects, we need a sufficient number of events to allow us to reach robust conclusions. By event is meant occurrence of the outcome of interest, which could be either an efficacy outcome or the occurrence of an adverse event. One example of a situation in which insufficient events led to an incorrect conclusion is the meta-analysis of magnesium in myocardial infarction (Teo et al. 1991). In the seven trials in the analysis there were 25 (3.8%) deaths among 657 patients given magnesium and 53 (8.2%) deaths among 644 patients given a control. This statistically significant difference was rebutted by subsequent large trials, and this false-positive result is attributable to the low number of events in the pooled patient population. More relevant to dose response are the problems with nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 inhibitors (coxibs) over the past 5 years. Think of the issues around aspirin for secondary prevention in cardiovascular disease. In a 6300-patient meta-analysis with aspirin doses in the range of 50â&#x20AC;&#x201C;325 mg/day (Weisman and Graham 2002), there were significantly fewer deaths, combined vascular events, and myocardial infarctions, but more gastrointestinal bleeds. Of the 41 gastrointestinal bleeds with aspirin 24 were severe, and of the 17 bleeds with placebo 9 were severe. No deaths were caused by 163

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H.J. MCQUAY

bleeding. The results indicated that if 1,000 patients were treated with aspirin prophylactically as secondary prevention instead of not being treated, there would be 55 fewer vascular events (including 27 myocardial infarctions and 11 strokes) and 15 fewer deaths. Offset against this benefit would be 8 more episodes of bleeding, of which about half would be severe. Clearly, it would be helpful to have a better grip on the dose response, both for efficacy and adverse effects. Across a bigger range of doses than 50 to 325 mg of aspirin daily, the gastrointestinal bleed dose response is clear (TramĂ¨r 2000). Just what is the minimum effective dose for secondary prevention, and precisely what is the incidence of gastrointestinal bleeding and cerebral bleeding at that dose? Think, too, of the lack of certainty about the extent of the reduction in gastrointestinal bleeding with coxibs, and consider the real difficulties in determining whether or not the increased risk of heart attacks is greater with higher doses of coxibs than with lower doses, is a class phenomenon, or indeed happens with NSAIDs as well. For serious adverse effects, such as heart attacks with NSAIDs or coxibs, the increase in risk may be an additional 1% on top of the 1% baseline risk without the drug. Unless we use meta-analytic techniques it is difficult to see how we can get a robust grasp of the problem, particularly if the increased risk is dose-related, because of the huge data sets needed to have enough events (heart attacks) to allow for meaningful analysis. A third general comment about meta-analysis and dose response is obvious but necessary, and that is the need for the different doses to have been tested in similar settings and similar patient populations. Investigating aspirin gastrointestinal bleeding rates at low doses in high-risk patients and high doses in low-risk patients would minimize any true underlying dose response. This type of clinical heterogeneity is a potential problem for all meta-analysis, but it is perhaps more of a danger in dose-response because of the risk that high and low doses of the intervention drug may be studied in different contexts. Another example would be antiemetics in postoperative nausea and vomiting (PONV). If the low dose is studied in patients at low baseline risk of PONV and the high dose in patients at higher baseline risk of PONV, then the net result of a dose-response meta-analysis will be to minimize any true underlying dose response. We have surprisingly few examples of dose response in the analgesic world. The last time we searched for randomized controlled trials (RCTs) of injected morphine in postoperative pain there was just one trial, which compared 10 and 20 mg of morphine (Norholt et al. 1996). When a single dose of 10 mg intramuscular morphine was compared with a dose of 20 mg in 74 patients in a single trial, 31% and 62% of patients achieved at least 50% pain relief over 4 hours, respectively. The results at least went in the â&#x20AC;&#x153;correctâ&#x20AC;? direction, with a number needed to treat (NNT) of just under 4 on 10 mg of morphine improving to 1.7 on 20 mg of morphine.

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EVIDENCE BASE FOR SPECIFIC ASPECTS OF THE WHO ANALGESIC LADDER “BY THE MOUTH” (USE ORAL ROUTE)

Oral analgesia is recommended because it is generally easier to manage and allows rapid titration to adequate doses. A Cochrane review of oral morphine for cancer pain found that the clinical trial evidence was meager in support of this approach and that many studies lacked sufficient statistical power to determine clinical differences between morphine and comparators (Wiffen et al. 2003). In the last 10 years, transdermal delivery systems have been introduced for fentanyl and buprenorphine. Clinical observational trials have shown that opioid-naive patients randomized to transdermal fentanyl or sustained-release oral morphine experienced similar analgesic efficacy, but the fentanyl group experienced fewer adverse effects and rated their treatment more highly than the morphine group (Ahmedzai and Brooks 1997; van Seventer et al. 2003). Whether this finding reflects the actions of the specific opioid or merely the delivery system is not clear. It does suggest, however, that while oral morphine may be cost-effective, it is not necessarily the most clinically effective analgesic. “BY THE CLOCK” (START WITH NORMAL-RELEASE REGULAR OPIOIDS)

Regular dosing with analgesics appears to be a sensible approach to managing continuous pain, but few studies have examined dosing schedules in detail. One study compared a continuous subcutaneous infusion of hydromorphone with patient-controlled subcutaneous injections in 22 patients with cancer pain (Bruera et al. 1988). Patients crossed over to the alternate treatment after 3 days; the total study period was 6 days. Twice-daily measurements of pain intensity and adverse effects did not differ between groups, and daily opioid consumption was similar. Equal numbers of patients chose each method, suggesting that “as needed” dosing may be as effective as regular dosing in short-term management of cancer pain, provided that patients have good access to analgesia. Other studies have compared normal-release morphine with sustainedrelease morphine (given once daily) when commencing and titrating strong opioids for cancer pain. Klepstad et al. (2003) demonstrated that in 40 patients randomized to either method (previously treated with weak opioids), both groups achieved adequate pain relief in a similar time (means of 1.7 and 2.1 days for sustained- and normal-release groups, respectively), but patients who received sustained-release morphine reported significantly less tiredness. Other adverse effects were similar in both groups.

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EVIDENCE FOR THE WHO LADDER

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One further study tested the EAPC recommendation to take a double dose of normal-release opioid at bedtime (Todd et al. 2002). The authors randomized 20 patients in a crossover design to take either a double dose of their scheduled normal release opioid at bedtime (DD group), or to take a single dose and be awakened 4 hours later (SD group). The study demonstrated that the SD group required less breakthrough analgesia and reported better pain control and less severe adverse effects than the DD group. In summary, evidence from small randomized studies suggests that the recommendations on dosing can be challenged. “BY THE LADDER” (USE MORPHINE AS THE PREFERRED STRONG OPIOID)

Probably the most debated aspect of the WHO analgesic ladder is the role of the second step, i.e., the role of weak opioids in cancer pain management. A frequent argument in support of this step is that it allows a wider range of choices and avoids the stigma of being treated with morphine, which is important for some patients and clinicians. However, a growing counter-argument claims that step 2 is redundant. From a theoretical basis, it is argued that codeine and related compounds are less potent entities of morphine (approximately one-fifth to one-tenth as potent), and therefore low doses of morphine offer equivalent analgesia with potentially less troublesome adverse effects. Meta-analyses and systematic reviews have assessed the effects of NSAIDs, either alone or in combination with weak opioids, for managing cancer pain. One review (Eisenberg et al. 1994) found that weak opioids did not produce greater analgesia than NSAIDs alone, either in combination or alone. A later review (McNicol et al. 2004) demonstrated that NSAIDs were significantly more effective for cancer pain than placebo, with no difference in adverse effects. The review also showed the lack of clear evidence to support the superiority of combinations of an NSAID with weak opioid over either alone. Of 14 trials identified that met inclusion criteria, 4 showed no difference and 9 showed only a slight, but statistically significant, advantage for the combination. In summary, this work suggests that if pain is unrelieved by a non-opioid (step 1) analgesic, there is a lack of evidence to support a significant improvement in pain when moving to a step 2 analgesic. If step 2 is not supported by a good evidence base, what trial evidence is there to show that progression from step 1 to step 3 is effective and safe? Two randomized clinical trials have examined the use of strong opioids as a first-line treatment. Marinangeli et al. (2004) recruited 100 patients with mild to moderate cancer pain (defined as pain rated less than 6 on a 0–10 VAS) who had not been treated previously with opioids. Patients were openly randomized to either

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the standard WHO approach or to treatment with strong opioids. Non-opioid analgesics and adjuvants were given to both groups as required. The authors reported significantly improved pain relief in both groups over a mean of 75 days of treatment, compared to baseline. The strong opioid group experienced greater pain relief (a reduction of 2.61 versus 1.92 on a 0–10 VAS, P = 0.041) and greater satisfaction with care, but also reported a greater incidence of nausea (P < 0.001). The study provides evidence that strong opioids are safe and well tolerated. However, the open randomization and the authors’ interpretation that the WHO recommends strong opioids only as third-line treatment (which it does not) suggests caution when applying this evidence to clinical practice. A later clinical trial, also from Italy, used similar methodology (Maltoni et al. 2005). Over a mean study period of 42 days following randomization, 24 patients received analgesics according to the WHO analgesic ladder while 30 were treated directly with strong opioids. Pain intensity was significantly better for the strong opioid group; worst pain was present on only 22.8% of days compared to 28.6% of days in the WHO group (P < 0.001). Satisfaction with treatment was also greater for the strong opioid group, but so also was the incidence of anorexia and constipation. In addition, baseline pain intensity scores showed that more patients in the WHO group had severe pain (and fewer had mild pain) compared to the strong opioid group. Both trials suggest that progression from step 1 to step 3 (strong opioids) might offer better pain control, but at the expense of gastrointestinal adverse effects. Further validation studies of this two-step approach are needed before recommending changes to the WHO analgesic ladder. “INDIVIDUALIZED TO THE PATIENT” (USE ALTERNATIVE OPIOIDS IF ADVERSE EFFECTS PERSIST)

Not all patients are able to tolerate morphine. In some patients, pain may be controlled by morphine, but adverse effects (such as nausea or hallucinations) persist. In others, opioid titration to a dose that provides good pain control may be prevented by adverse effects. In these circumstances, other analgesic approaches are needed, which may necessitate a change of opioid (opioid switching). Mercadante and Bruera (2006) undertook a systematic literature review and identified 31 studies that described opioid switching. Studies were predominantly observational and contained small numbers of patients, making meta-analysis impossible. Overall, around 50% of patients appeared to benefit following an opioid switch, but the authors stressed that the process of reaching an optimal dose for a patient should be highly individualized. Clearly, 50% of patients did not benefit from switching.

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25 Risk: Presentation and Systematic Reviews R. Andrew Moore Nuffield Department of Anaesthetics, University of Oxford; Pain Research, Churchill Hospital, Headington, Oxford, United Kingdom

The last decade has seen a major change in the way in which the developed world looks at medicines and medical interventions. Medical treatments are now portrayed as “risky,” and some, at least, of our societies have become risk averse. There are three major influences in this process. First, it is increasingly easy to initiate legal proceedings, often at no cost. Legal firms actively trawl for cases using websites and advertisements. Second, clinical trials conducted by industry are heavily monitored and record every adverse event that occurs. Small numbers of major events may occur with numerical or statistical differences in individual trials because of the play of chance, or with real differences seen in meta-analyses. Third, the use of large databases covering millions of people allows unprecedented opportunities to explore otherwise unconsidered relationships between disease, therapy, and serious but rare adverse consequences. The consequences of these changes are significant. They have generated a certain lack of trust in medicine, generally stemming from the question of why medicines are not safe, while conveniently ignoring the fact that nothing is safe. Discussing risk with patients is difficult, because we often have little in the way of numbers we can use, we have real problems in how we use those numbers—or words—to describe risk, and we are largely without evidence about how to communicate risk effectively. Let’s start with a definition of risk. Risk has two main meanings. One is that of chance, the pure statistical likelihood of any event, good or bad, happening (probability). The other is that of danger, injury, harm, or loss, together with an indication of severity. There is a tendency to confuse these meanings; to some extent risk is used commonly to process or communicate the product of probability and severity. 327

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27 Evidence-Based Decision Making: Why Is It So Difficult to Get from Evidence to Practice? Steen Møiniche Department of Anaesthesiology, Glostrup University Hospital, Glostrup, Copenhagen, Denmark

This chapter presents my thoughts and opinions about implementation of evidence, care pathways, and evidence-based policy making. The chapter draws heavily on views and citations from papers located on Bandolier and elsewhere.

DECISION MAKING

One of the major tasks every health professional faces is the need to make decisions—lots and lots of decisions, which must be made every day, all year round. Decisions concerning the care and handling of our patients’ well-being, as well as decisions of a structural, organizational, and financial nature. The basis on which we make these decisions depends on our educational background, the immediate context, the economic framework, the patients’ preferences, our previous experience, personal attitudes, and many other variables. The literature on this issue is vast and cannot be fully explored here. However, most readers would agree that one major key element in decision making should be “knowledge,” of which “evidence” is one factor. And this is where the challenge begins—keeping up with medical knowledge has become an increasingly difficult task because the amount of medical literature is expanding exponentially. A Medline search using the terms “postoperative pain” and “postoperative analgesia” reveals more than 15,000 articles. The volume of published medical information has become almost impossible for the average clinician to review. Concise summaries of information, for example on the treatment of postoperative pain, are thus becoming an increasingly important element in decision making. 349

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Recent Publications from IASP Press: Immune and Glial Regulation of Pain Joyce A. DeLeo, Linda S. Sorkin, and Linda R. Watkins, Editors November 2007 Sleep and Pain Gilles Lavigne, Barry J. Sessle, Manon ChoiniĂ¨re, and Peter J. Soja, Editors June 2007 Central Neuropathic Pain: Focus on Poststroke Pain James L. Henry, Akbar Panju, and Kiran Yashpal, Editors April 2007 For detailed information on these and other IASP Press publications, visit the IASP website at www.iasp-pain.org/IASPPress.

IASP brings together scientists, clinicians, health care providers and policymakers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide. IASP Press publishes timely, high-quality, and reasonably priced books relating to pain research and treatment.

INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN 111 Queen Anne Avenue N., Suite 501 Seattle, WA 98109-4955 USA www.iasp-pain.org