TY - JOUR

T1 - Hypersensitivity to PACAP-38 in post-traumatic headache

T2 - a randomized clinical trial

AU - Al-Khazali, Haidar M.

AU - Christensen, Rune H.

AU - Dodick, David W.

AU - Chaudhry, Basit Ali

AU - Amin, Faisal Mohammad

AU - Burstein, Rami

AU - Ashina, Håkan

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PY - 2024

Y1 - 2024

N2 - 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, 2-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-minute continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week wash-out period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-hour 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-hour 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 women. Most of them (19 [90%] of 21) had a migraine-like phenotype. During the 12-hour observational period, 20 (95%) of 21 participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with 2 (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-hour 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.

AB - 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, 2-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-minute continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week wash-out period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-hour 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-hour 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 women. Most of them (19 [90%] of 21) had a migraine-like phenotype. During the 12-hour observational period, 20 (95%) of 21 participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with 2 (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-hour 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.

U2 - 10.1093/brain/awad367

DO - 10.1093/brain/awad367

M3 - Journal article

C2 - 37864847

VL - 147

SP - 1312

EP - 1320

JO - Brain

JF - Brain

SN - 0006-8950

IS - 4

ER -