Placebo responses in non-surgical trials for knee osteoarthritis: A systematic review and meta-analysis

Background Previous reviews have demonstrated notable placebo responses in placebo-controlled clinical trials assessing osteoarthritis treatments; however, there is limited consensus regarding the relative importance of factors influencing these responses. This review and meta-analysis aimed to (1) evaluate effect sizes observed in the placebo arms of knee osteoarthritis trials published since 2008, and (2) identify factors contributing to explained variance through meta-regression analysis. Methods Outcome data at baseline and follow-up were extracted, and Hedges’ g was calculated as a measure of effect size for each study using a random effects model. Heterogeneity was quantified using the I² statistic. Sources of variance were investigated through multivariate meta-regression involving 16 clinically relevant covariates. The Cochrane RoB-2 tool was used to assess risk of bias. Results Searches provided 179 trials that met inclusion criteria. Of these, 109 trials (60%) reported Hedges’ g values ≥ 0.5. Substantial heterogeneity was observed (I² = 89%, p < 0.0001), with a broad prediction interval (-0.30 to 1.63). In multivariate meta-regression two-thirds of the variance remained unexplained, while the covariates baseline pain, commercial funding, effect size in active treatment arms and geographical region together accounted for 33% of explained variance. Risk of bias, duration of follow-up, year of publication, and method of placebo administration were not found to significantly influence the outcomes. Conclusion : Most trials demonstrated moderate to large placebo effect sizes, but there was marked between-trial statistical heterogeneity and a substantial proportion of the variance remained unexplained. An important limitation is the lack of data regarding psychological variables, such as participant expectations and the patient–provider relationship, which are recognized as major determinants of placebo effects.