Efficacy and safety of calcitonin gene-related peptide monoclonal antibodies for cluster headache: a systematic review and frequentist-Bayesian meta-analysis.

BACKGROUND

Calcitonin gene-related peptide (CGRP) monoclonal antibodies have transformed migraine prevention, but their efficacy in cluster headache remains uncertain.

METHODS

We searched PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov through February 28, 2026, for trials of CGRP monoclonal antibodies in cluster headache. The primary outcome was weekly cluster headache attack frequency, quantified as mean difference (MD) with 95% confidence intervals. Bayesian meta-analysis with five prior specifications and trial sequential analysis were conducted as prespecified sensitivity analyses.

RESULTS

Four trials (655 participants) were included. The pooled MD was - 0.81 attacks per week (95%CI - 2.24 to 0.62; P = 0.265; I2 = 8%). Neither episodic (MD - 1.21; 95%CI - 5.20 to 2.78) nor chronic (MD - 0.93; 95%CI - 2.89 to 1.03) subgroups reached significance (P = 0.90). The odds ratio for 50% or greater responder rate was 1.39 (95%CI 0.88-2.19; P = 0.159); risk ratios reached significance (1.25; 95%CI 1.04-1.49; P = 0.017), a discrepancy driven by high placebo rates (27-53%). Bayesian analysis showed an 81.1% posterior probability of any benefit, but only 17.9% probability that the true reduction reached 2 or more attacks per week. Trial sequential analysis indicated that for an assumed effect of 2.5 attacks per week, accrued information exceeded the required information size (135.6%) without the cumulative Z-statistic crossing the efficacy boundary; for an assumed effect of 2.0, evidence remained inconclusive.

CONCLUSION

Current evidence is insufficient to determine significant benefit of CGRP monoclonal antibodies in cluster headache. Modest benefit cannot be excluded, but clinically meaningful efficacy remains uncertain.