Dual-mechanism preventive therapy in chronic migraine: an exploratory meta-analysis of onabotulinumtoxinA and anti-CGRP monoclonal antibody combination

BACKGROUND: Dual targeting with onabotulinumtoxinA and anti-CGRP monoclonal antibodies has emerged as a potential option for patients with chronic migraine who respond incompletely to single-agent preventive therapy. Evidence from individual observational reports suggests benefit, but the magnitude, consistency, and methodological quality of available studies remain unclear. METHODS: A systematic search identified observational studies evaluating combination therapy with onabotulinumtoxinA plus an anti-CGRP monoclonal antibody. Ten studies met inclusion criteria, of which six provided extractable quantitative data for meta-analysis. Outcomes included monthly headache days (MHD), ≥ 50% and ≥ 75% responder rates, headache-related disability (MIDAS, HIT-6), and acute medication use. Random-effects models were applied, and heterogeneity, subgroup patterns, and publication bias were assessed. Of the ten eligible studies, only six provided extractable quantitative data for combination therapy and were included in pooled analyses. RESULTS: Across six studies, combination therapy reduced MHD by a pooled - 7.9 days (95% CI - 10.2 to - 5.7). The pooled ≥ 50% responder rate was 0.51 (95% CI 0.37-0.66), and the ≥ 75% responder rate was 0.19 (95% CI 0.10-0.34). Disability measures improved, with MIDAS decreasing by - 47.4 points (95% CI - 65.7 to - 29.1) and HIT-6 by - 8.2 points (95% CI - 10.9 to - 5.5). Acute medication use declined by - 4.3 days per month (95% CI - 6.1 to - 2.5). Heterogeneity across outcomes was moderate to high. Subgroup analyses by age and sex showed generally consistent directionality, though several strata were represented by only one or two studies. Funnel plot inspection and Egger testing did not indicate marked publication bias. CONCLUSIONS: Combination therapy with onabotulinumtoxinA and an anti-CGRP monoclonal antibody demonstrates clinically meaningful reductions in headache frequency, disability, and medication use across observational cohorts. Interpretation should remain cautious given high heterogeneity, the absence of controlled comparative designs, and limited subgroup data. Because dispersion measures were imputed in several studies, statistical precision may be overestimated, and effect sizes should be interpreted as approximate rather than definitive. Larger prospective studies are needed to clarify patient selection, durability of benefit, cost-effectiveness, and equity of access.