Raveendhara R. Bannuru, MD, PhD; Timothy E. McAlindon, MD; Matthew C. Sullivan, BA; John B. Wong, MD; David M. Kent, MD; Christopher H. Schmid, PhD
This article was published online first at www.annals.org on 28 July 2015.
Grant Support: By the Agency for Healthcare Research and Quality.
Disclosures: Dr. Bannuru reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and grants and personal fees from the American College of Rheumatology and Sanofi outside the submitted work. Dr. McAlindon reports grants from Croma, Flexion Therapeutics, the National Institutes of Health, the Agency for Healthcare Research and Quality, Fidia, Sanofi-Aventis, Samumed, and AbbVie and personal fees from Novartis, McNeil, Bioventus, and the Federal Trade Commission outside the submitted work. Dr. Wong reports grants from the Patient-Centered Outcomes Research Institute and National Institutes of Health National Center for Complementary and Alternative Medicine and nonfinancial support from the European League Against Rheumatism outside the submitted work. Dr. Kent reports grants from the National Institutes of Health during the conduct of the study. Dr. Schmid reports grants from Brown University during the
conduct of the study and personal fees from Pfizer outside the submitted work. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0623.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Raveendhara R. Bannuru, MD, PhD, Center for Treatment Comparison and Integrative Analysis (CTCIA), Tufts Medical Center, 800 Washington Street, Box #406, Boston, MA 02111; e-mail, email@example.com.
Current Author Addresses: Drs. Bannuru and McAlindon and Mr. Sullivan: Division of Rheumatology, Tufts Medical Center, 800 Washington Street, Box 406, Boston, MA 02111.
Dr. Kent: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.
Dr. Wong: Division of Clinical Decision Making, Tufts Medical Center, 800 Washington Street, Boston, MA 02111.
Dr. Schmid: Brown University School of Public Health, 121 South Main Street, Providence, RI 02912.
Author Contributions: Conception and design: R.R. Bannuru, T.E. McAlindon, D.M. Kent, C.H. Schmid.
Analysis and interpretation of the data: R.R. Bannuru, T.E. McAlindon, J.B. Wong, D.M. Kent, C.H. Schmid.
Drafting of the article: R.R. Bannuru, M.C. Sullivan, J.B. Wong, D.M. Kent, C.H. Schmid.
Critical revision of the article for important intellectual content: R.R. Bannuru, T.E. McAlindon, M.C. Sullivan, J.B. Wong, D.M. Kent, C.H. Schmid.
Final approval of the article: R.R. Bannuru, T.E. McAlindon, M.C. Sullivan, J.B. Wong, D.M. Kent, C.H. Schmid.
Provision of study materials or patients: R.R. Bannuru, D.M. Kent.
Statistical expertise: R.R. Bannuru, C.H. Schmid.
Obtaining of funding: R.R. Bannuru, D.M. Kent.
Administrative, technical, or logistic support: R.R. Bannuru.
Collection and assembly of data: R.R. Bannuru, M.C. Sullivan, D.M. Kent.
Bannuru RR, McAlindon TE, Sullivan MC, Wong JB, Kent DM, Schmid CH. Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials. Ann Intern Med. 2015;163:365-372. doi: 10.7326/M15-0623
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Published: Ann Intern Med. 2015;163(5):365-372.
Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials.
To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.
MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.
149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos.
Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.
Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.
Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos.
All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results.
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