Calcitonin gene-related peptide induces headache attacks in people with idiopathic intracranial hypertension

Calcitonin gene-related peptide (CGRP) is a key mediator in migraine pathophysiology. Idiopathic intracranial hypertension (IIH) headache phenotype is now understood to be typically migraine-like, but it is unclear whether CGRP directly provokes IIH headaches or alters intracranial pressure (ICP) dynamics. We conducted a randomized, double-blind, placebo-controlled, two-way crossover trial to address this. Twenty women with IIH and no prior migraine were randomly assigned to receive a 20-min continuous intravenous infusion of CGRP (1.5 μg/min) or placebo (isotonic saline). The primary outcome was the difference in the proportion of participants who developed a provoked headache attack between CGRP and placebo during the 12 h observation after infusion. Secondary outcomes included the area under the curve (AUC) for headache intensity from -10 min to 12 h, the timing and duration of headache features, and baseline-adjusted changes for vital signs, cerebrovascular haemodynamics and ICP. Seventeen participants with mean age (standard deviation) 26.7 (6.4) years completed both visits. Twelve (71%) participants developed a typical IIH headache attack with migraine-like features after CGRP compared with three (18%) after placebo (risk difference 53%; 95% confidence interval, 26-79; P = 0.004). The AUC-10min-12h for headache intensity was higher after CGRP than after placebo (P = 0.016). The mean ICP remained unchanged, whereas ICP amplitude increased significantly after CGRP (P = 0.005). Vital signs and cerebrovascular haemodynamics AUC-10min-90min were significantly altered after CGRP [increased: heart rate (P < 0.001), tissue oxygenation index (P = 0.041), and oxygenated haemoglobin (P < 0.001); decreased: mean arterial pressure (P = 0.010) and middle cerebral artery blood velocity (P = 0.006)]. CGRP reliably provoked typical IIH headache attacks (which have migraine-like features) and increased ICP pulse amplitude, as a measure of intracranial compliance, without altering mean pressure. These findings provide mechanistic support for CGRP involvement in headache attributed to IIH and justify prospective evaluation of CGRP pathway blockade in this population.