Hypersensitivity to Calcitonin Gene–Related Peptide in Post‐Traumatic Headache

Objective To demonstrate that calcitonin gene–related peptide (CGRP) induces headache exacerbation with migraine‐like features in patients with persistent post‐traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). Methods A randomized, double‐blind, placebo‐controlled, two‐way crossover study was conducted. Analyses were intention‐to‐treat. Eligible patients were aged 18 to 65 years and had a history of persistent PTH after mild TBI for at least 12 months. Patients were randomized to receive an intravenous infusion of 1.5μg/min of CGRP or placebo (isotonic saline) over 20 minutes on two separate experimental days. A 12‐hour observational period was used to evaluate the following outcomes: (1) difference in incidence of headache exacerbation with migraine‐like features and (2) difference in area under the curve for headache intensity scores. Results Thirty patients (mean age = 37 years, 25 women [83%]) were randomized and completed the study. During the 12‐hour observational period, 21 of 30 patients (70%) developed headache exacerbation with migraine‐like features after CGRP, compared with 6 patients (20%) after placebo ( p < 0.001). The baseline‐corrected area under the curve for headache intensity scores was significantly larger after CGRP, compared with placebo ( p < 0.001). Interpretation Patients with persistent PTH are hypersensitive to CGRP, which underscores its pathophysiological importance. Furthermore, CGRP‐targeted therapies might provide a novel mechanism‐based treatment option for patients with persistent PTH. ANN NEUROL 2020;88:1220–1228