Placebo response in chronic peripheral neuropathic pain trials: systematic review and meta-analysis

ObjectiveTo estimate the magnitude of the placebo and nocebo responses in chronic peripheral neuropathic pain (CNP) and explore possible associations with trial characteristics. MethodsWe searched CENTRAL, MEDLINE, and Embase for randomized controlled trials (RCTs) from inception to May 2020. We included placebo-controlled RCTs of [≥]8 weeks investigating first-line pharmacological interventions for CNP. Primary endpoints were the placebo response, the proportion of patients receiving placebo with pain intensity reduction (PIR) [≥]30% from baseline, and the nocebo response, the proportion of patients receiving placebo experiencing adverse events (AEs). Screening, data extraction, and bias assessment (with the Cochrane risk of bias tool) were conducted by independent reviewers. We pooled data using a random-effects model. ResultsWe included 50 trials, with a combined 5,693 participants allocated to placebo, conducted between 1998 and 2020. Overall, 38% of patients receiving placebo reported PIR[≥]30% (95% CI 34 to 42, I2=86%); 23% reported PIR[≥]50% (95% CI 20 to 26; I2=81%). 50% of patients receiving placebo reported AEs (95% CI 0.43 to 0.58; I2=97%); 2% reported serious AEs (95% CI 2 to 3; I2=58%). In patients receiving active interventions, the placebo response accounts for 75% of the treatment effect on PIR[≥]30%, and the nocebo response accounts for 75% of the AEs. Interpreted inversely, only 25% of responses and 25% of adverse events can be attributed to the intervention. Publication year positively correlated with PIR[≥]30% and negatively correlated with AEs. Female sex negatively correlated with AEs. ConclusionsThe placebo and nocebo responses in parallel-designed RCTs in CNP are substantial and should be considered in trial interpretation and in the design of future trials.