Chaudhry, Basit Ali

Objective To investigate whether levcromakalim (a K ATP channel opener) induces migraine-like headache in people with persistent post-traumatic headache who had no known history of migraine. Methods In a randomized, double-blind, placebo-controlled, 2-way crossover trial, participants were randomly assigned to receive a 20-minute continuous intravenous infusion of levcromakalim (50 µg/mL) or placebo (isotonic saline) on two separate experimental days with a 1-week wash-out period in between. The primary endpoint was the difference in incidence of migraine-like headache between levcromakalim and placebo during a 12-hour observational period after infusion start. The secondary endpoint was the difference in area under the curve for baseline-corrected median headache intensity scores between levcromakalim and placebo during the 12-hour observational period. Results A total of 21 participants with persistent post-traumatic headache were randomized and completed the trial. During the 12-hour observational period, 12 (57%) of 21 participants reported experiencing migraine-like headache following the levcromakalim infusion, compared with three after placebo ( P = 0.013). Moreover, the baseline-corrected median headache intensity scores were higher following the levcromakalim infusion than after placebo ( P = 0.003). Conclusion Our findings suggest that K ATP channels play an important role in the pathogenesis of migraine-like headache in people with persistent post-traumatic headache. This implies that K ATP channel blockers might represent a promising avenue for drug development. Further research is warranted to explore the potential therapeutic benefits of K ATP channel blockers in managing post-traumatic headache. Trial Registration: ClinicalTrials.gov Identifier: NCT05243953

Abstract Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.