Placebo response to intra-articular injections in knee osteoarthritis: magnitude, evolution over time, and influencing factors. A systematic review and meta-analysis with meta-regression

Purpose To quantify the response to intra-articular saline administration in terms of pain, function, and quality of life, with a focus on the evolution of placebo response over time and the identification of influencing factors on the placebo response to knee osteoarthritis injections. Methods After registration on PROSPERO, a systematic review was conducted following PRISMA guidelines to identify double-blind, placebo-controlled randomised clinical trials on intra-articular knee injections for knee osteoarthritis. The placebo response was evaluated through meta-analyses of VAS pain, WOMAC, KOOS, and responder rates at 1-, 3-, 6-, and 12-months on placebo arms of included trials. The evolution of placebo response over time was assessed, and meta-regression was conducted. Risk of bias and quality of evidence were assessed following Cochrane guidelines. Results From the initial 2,746 records, 73 articles on 5,895 patients were included. The meta-analysis demonstrated statistically and clinically significant improvements at the 1-, 3-, and 6-month follow-ups. At the 12-month follow-up, placebo response declined and was no longer clinically significant for some sub-scores. Responder rates exceeded 50% at 1-, 3-, and 6-months. The placebo response was stronger in studies with a higher proportion of female participants and in more recently published trials. Conclusions Placebo response to intra-articular injections is statistically and clinically significant in knee osteoarthritis for pain, function improvement, and patients' quality of life, with responses peaking at 4–8 months but evidence up to 12 months. Among influencing factors, female sex and recent publications seem to present stronger placebo responses, emphasising the importance of placebo-controlled trials to evaluate knee osteoarthritis treatments.