Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-analysis

Background.-CGRP Antibodies are high-cost newly licensed migraine preventatives. Objective To calculate the overall reduction in monthly migraine days and the proportion contextual effect (PCE) using meta-analysis. The PCE is the ratio between the reduction in Monthly Migraine Days in the placebo group and the reduction in Monthly Migraine Days in the CGRP-Ab group after 3 months of treatment. Methods.-Meta-analysis of randomized double-blind placebo-controlled trials of anti-CGRP antibodies in people with episodic migraine (EM) or chronic migraine (CM) in persons aged 18 or over. Non-randomized trials and trials in persons under 18 years excluded. Search of National Clinical Trials Register 2000-2019, MEDLINE to September 2019, Hand search of major headache conference abstract books 2012-2019. Two investigators used standard proforma to reach consensus. Trial quality assessed using Cochrane Collaboration risk of bias tool. PRISMA guidelines followed. Results.-21 completed trials with 13367 participants (8075 EM, 5292 CM). Compared to placebo, pooled reduction in MMD was 1.50 days in 15 EM trials (95%CI 1.16, 1.84; I-2 = 69%, P-hetereogeneity < .001) and 2.24 days in 7 CM trials (95%CI 1.82, 2.65, I-2 = 15%, P-hetereogeneity = .320). In EM trials, pooled PCE was 0.66 (95%CI 0.59, 0.75; I-2 = 64%, P-hetereogeneity = .001). In CM trials the PCE was .68 (95%CI 0.61, 0.75; I-2 = 20%, P-hetereogeneity = .280). Industry funded every study, but risk of bias was low. Conclusions.-CGRPAbs are effective but sixty-six percent of the benefit is from contextual effects, including placebo effect. Contextual effects merit further scrutiny as a means of improving migraine headache.