Are some people more susceptible to placebos? A systematic review and meta-analysis of inter-individual variability in musculoskeletal pain

Abstract

Existing data suggest placebo responses to treatments are small, but some people may be more likely to respond. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) on interindividual variability in response to placebo interventions MEDLINE, EMBASE, CINAHL, Web of Science Core Collection, CENTRAL, and SPORTDiscus were searched from inception to September 2023. Trial registry searches, citation tracking, and searches for prior systematic reviews were completed. The PEDro scale assessed study quality. Random effects robust variance estimation estimated the log variability ratio (VR), identifying subgroups with varying responses. Twenty-six studies were included, comprising various musculoskeletal pain conditions. Analysis of pain intensity (VR: 1.06, 95%-confidence interval (CI):[0.97; 1.16], 95%-prediction interval (PI):[0.75; 1.51], p = 0.17, k = 26 studies, N = 52 outcomes, GRADE: low), physical function (VR: 1.14, 95%-CI:[0.97; 1.34], 95%-PI:[0.62; 2.11], p = 0.11, k = 19, N = 40, GRADE: low), and health-related quality of life (VR: 1.14, 95%-CI:[0.91; 1.41], 95%-PI:[0.72; 1.80], p = 0.19, k = 7, N = 13, GRADE: low) outcomes revealed minimal, non-statistically significant variability in placebo response compared to control. However, wide prediction intervals suggest uncertainty regarding individual response patterns. There are likely no distinct subgroups of people who are more likely to respond to placebo interventions in musculoskeletal pain; although the available data limits the certainty of this assessment. Future work should consider individual participant data meta-analyses to better elucidate potential responder subgroups and optimize treatment strategies for musculoskeletal pain. PERSPECTIVE: This study systematically reviewed and analyzed RCTs to assess interindividual variability in placebo responses for musculoskeletal pain. Findings suggest minimal variability in placebo response, with no distinct subgroups more likely to respond. Wide prediction intervals indicate uncertainty, highlighting the need for future individual participant data meta-analyses to better elucidate potential responder subgroups.

Keywords: Contextual effects; Meta-analysis; Musculoskeletal pain; Placebo responder; RCTs; Systematic review.