Magnitude and Determinants of Placebo Response in Acute Migraine Trials: A Systematic Review and Meta-Analysis.

Abstract

Migraine is a highly prevalent and disabling neurologic disorder. Beyond drug-specific mechanisms, the role of contextual, individual-related, and disease-related factors remains poorly characterized. We quantified placebo response in randomized controlled trials (RCTs) of acute migraine treatments and identified patient-level, drug-level, and study-level determinants. This meta-analytic review searched PubMed, Embase, Cochrane Central, ClinicalTrials.gov, and the European and Japanese Trial Registers from inception to November 2025 for published/unpublished, double-blind, parallel-group, phase 2 or 3 RCTs evaluating acute pharmacologic migraine treatments. Placebo rates with 95% CIs and prediction intervals (PIs) were pooled using random-effects models. Subgroup analyses and meta-regressions explored potential drivers. The primary outcome was 2-hour pain freedom after placebo administration. Secondary outcomes included 2-hour pain relief, sustained pain freedom, rescue medication use, global impression of improvement, and most bothersome symptom (MBS) freedom. We analyzed 126 RCTs published between 1991 and 2025, comprising 24,614 placebo-treated participants (mean age range, 34.8-45.2 years; female, 65.2%-96.9%). The pooled 2-hour pain freedom rate was 11% (95% CI 10%-12%; PI: 4%-27%). The highest estimates were observed for intranasal (14%; 95% CI 12%-16%) and subcutaneous (13%; 95% CI 8%-20%) administration, compared with oral (10%; 95% CI 9%-12%) (<i>p</i> < 0.05). A lower proportion of patients with severe baseline headache and a lower probability of receiving an active treatment were associated with greater responsiveness (β -1.38; 95% CI -2.37 to -0.38; <i>p</i> < 0.01 and β -1.20; 95% CI -2.02 to -0.38; <i>p</i> < 0.005, respectively). Placebo response increased significantly over time (β 0.03; 95% CI 0.01-0.04; <i>p</i> < 0.001), even after multivariable adjustment. Placebo rates were 34% for 2-hour pain relief, 9% for sustained pain freedom, 52% for rescue medication use, 24% for positive global impression, and 34% for MBS freedom. Exploratory analyses of pain relief showed high placebo responses among non-Caucasian individuals, in Asian countries, and in gepant RCTs. Placebo response represents a substantial and increasing component of outcomes in acute migraine RCTs. Improved trial design, standardized communication, and transparent reporting may enhance effect-size interpretation and preserve assay sensitivity in future trials.