Abstract Background and aims Chronic migraine (CM) is a disabling neurological disorder affecting approximately 1.4–2.2% of the population and imposing substantial personal and healthcare burdens. Preventive treatments demonstrate variable efficacy,. The magnitude and variability of the placebo effect across CM trials have not, to date, been characterized. To evaluate the clinical significance and variability of the placebo effect in CM through a systematic meta-analysis of phase III randomized controlled trials (RCTs). Methods We performed a systematic review and meta-analysis in Nested Knowledge, searching PubMed, Ovid, Science Direct and Cochrane through October 2025. Randomized phase III placebo-controlled trials including prophylactic treatment of CM were included. Primary outcomes were Mean Migraine Days (MMDs) and Mean Headache Days (MHDs); secondary outcomes included Migraine disability assessment (MIDAS), 50% reduction of MMDs and reduction in use of Acute medication (AM). Results Of 1,717 screened records, 14 trials met inclusion criteria. Preventive therapies significantly reduced MMDs and MHDs versus placebo from Weeks 4–12 (p0.05), indicating early and sustained benefits. Placebo alone produced significant reductions (~3 days from baseline; p0.05). AM use decreased more with treatment (p0.05). Responder rates were higher with treatment (36.8% vs 21.3%), and MIDAS improved more (18 vs 9 points), though differences were not statistically significant. Safety profiles were comparable. Conclusions Active treatment significantly reduced migraine frequency and AM use, while MIDAS and responder rates showed no significant difference. Placebo yielded clinically meaningful improvements, highlighting its critical role in trial design. Future studies should include placebo arms and closely match procedures to interventions. Conflict of interest Pernelle Guastavino ; nothing to disclose. Michelle Barry; nothing to disclose. Mahmood Mirza; nothing to disclose. Patrick Brouwer; nothing to disclose
Guastavino et al. (Fri,) studied this question.