Efficacy and safety of CGRP monoclonal antibodies for cluster headache: a systematic review and network meta-analysis of randomized controlled trials.

INTRODUCTION

Cluster headache (CH) is a severe unilateral trigeminal autonomic cephalalgia with limited well tolerated therapies. Calcitonin gene related peptide monoclonal antibodies, including galcanezumab, fremanezumab, and eptinezumab, have established efficacy in migraine and are under evaluation in CH. This study assesses their efficacy and safety using pairwise and network meta analysis.

METHODS

PubMed, Embase, Scopus, and ClinicalTrials.gov were searched through April 2025. Randomized controlled trials enrolling adults with episodic or chronic CH were included. The primary endpoint was change in weekly attack frequency. Secondary outcomes included subtype specific effects and adverse events. Frequentist random effects network meta analysis and pairwise meta analysis were performed in R.

RESULTS

Five trials with approximately 1,000 participants were included. No agent demonstrated statistically significant reduction in weekly attack frequency versus placebo, although consistent numerical improvements were observed. Dose specific network estimates showed mean differences of - 0.81 for galcanezumab 300 mg, - 0.17 for eptinezumab 400 mg, 0.71 for fremanezumab 675/225 mg, and - 1.27 for fremanezumab 900/225 mg. Pooled dose estimates were - 0.81 for galcanezumab, - 0.27 for fremanezumab, and - 0.17 for eptinezumab. Pairwise meta analysis yielded a pooled mean difference of - 0.41. Subgroup analysis indicated minimal change in chronic CH and greater numerical reduction in episodic CH.

CONCLUSION

CGRP monoclonal antibodies demonstrate modest directional reductions in attack frequency without statistical significance. Signals appear more pronounced in episodic CH, supporting the need for adequately powered, subtype specific trials.