Anti-CGRP receptor antibodies do not modulate trigeminal pain processing: indication for distinct mechanisms of CGRP pathway blockade.

BACKGROUND: Monoclonal antibodies (mAbs) targeting calcitonin gene-related peptides (CGRP) are established therapies for migraine. There are currently four CGRP-mAbs available on the market: one targets the CGRP receptor, and the other three target the CGRP ligand. Despite the initial comparability of the two groups regarding efficacy, real-life data demonstrate that up to 30% of non-responders to one class exhibit a positive response to switching classes, indicating different mechanisms. The ligand-mAb, galcanezumab, has previously demonstrated a trigeminal dermatome-specific pain modulatory effect. The present study aims to evaluate the sensory modulatory effect of the receptor-mAb, erenumab. METHODS: Migraine patients were recruited in two phases. In the first phase of the study, 40 patients were included and randomly assigned to receive either erenumab 70 mg (21 patients) or a placebo (19 patients) in a double-blind manner. In the second phase of the study, 46 patients were included and received erenumab 140 mg in an open-label manner. Quantitative sensory testing (QST) parameters were measured on the right forehead (V1 dermatome) and on the forearm prior to and after treatment. A repeated-measures analysis of variance (ANOVA) was used for the statistical analysis. RESULTS: All three study cohorts (placebo, erenumab 70 mg, and erenumab 140 mg) were comparable in terms of demographics, including age, sex ratio, and baseline headache frequency, and showed no statistically significant differences in QST parameters. Subsequent to the administration of the treatment, no changes or discernible trends were observed in any of the QST parameters in any study cohort. CONCLUSIONS: The findings of this study suggest that the receptor-mAb, erenumab, did not modify the sensory thresholds following treatment. This finding is in contrast with the results of galcanezumab in the literature, which demonstrated a trigeminal sensory modulatory effect after treatment. This outcome indicates a different mechanism of action between the anti-CGRP receptor versus ligand mAbs and provides a scientific basis for the rationale of class switching, which aims to achieve additional clinical benefits in patients who are non-responders to anti-CGRP treatment. PREREGISTRATION: The study was preregistered at the Open Science Framework (https://osf.io/ygf3t).