Effectiveness and Implications of Alternative Placebo Treatments: A Systematic Review and Network Meta-analysis of Osteoarthritis Trials

Ann Intern Med. 2015 Sep 1;163(5):365-72. doi: 10.7326/M15-0623.


Background: 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.

Objective: To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.

Data sources: MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.

Study selection: 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.

Data extraction: Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.

Data synthesis: 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.

Limitations: 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.

Conclusion: 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.

Primary funding source: Agency for Healthcare Research and Quality.

Publication types

  • Meta-Analysis
  • Research Support, U.S. Gov't, P.H.S.
  • Review
  • Systematic Review

MeSH terms

  • Adrenal Cortex Hormones / therapeutic use
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Cyclooxygenase 2 / therapeutic use
  • Humans
  • Hyaluronic Acid / therapeutic use
  • Osteoarthritis, Knee / drug therapy*
  • Pain / drug therapy
  • Placebo Effect*
  • Randomized Controlled Trials as Topic / standards*


  • Adrenal Cortex Hormones
  • Anti-Inflammatory Agents, Non-Steroidal
  • Hyaluronic Acid
  • Cyclooxygenase 2