Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial

Brain, 2024 · DOI: https://doi.org/10.1093/brain/awad367 · Published: October 21, 2023

Simple Explanation

This study explores the role of PACAP-38 in post-traumatic headache (PTH), noting similarities between PTH and migraine. The trial involved participants with persistent PTH who received either PACAP-38 or a placebo, and researchers observed if they developed migraine-like headaches. The results showed that most participants developed migraine-like headaches after receiving PACAP-38, suggesting that targeting PACAP-38 signaling could be a new treatment avenue for PTH.

Study Duration

June 2022 to September 2022

Participants

21 adults with persistent post-traumatic headache

Evidence Level

Level 1, Randomized, double-blind, placebo-controlled, two-way crossover trial

Key Findings

1
Intravenous infusion of PACAP-38 induced migraine-like headache in 95% of participants with persistent PTH, compared to 10% after placebo.
2
The baseline-corrected AUC for median headache intensity scores was significantly higher after PACAP-38 compared to placebo.
3
Most participants reported adverse events like palpitations, flushing, and warm sensations after PACAP-38 infusion.

Research Summary

This study investigated the role of PACAP-38 in post-traumatic headache (PTH) by conducting a randomized, double-blind, placebo-controlled trial. The results demonstrated that PACAP-38 infusion induced migraine-like headache in people with persistent PTH, suggesting a hypersensitivity to PACAP-38 in this population. The study supports the hypothesis that PACAP signalling plays a significant role in the genesis of migraine-like headache in PTH, potentially opening a novel therapeutic avenue.

Practical Implications

Novel Drug Target

Targeting PACAP signalling might be a promising therapeutic approach for treating PTH.

Differentiated Approach

Drugs targeting PACAP signalling might offer a differentiated approach compared with existing drugs targeting CGRP signalling.

Potential for New Drugs

Elucidating the involvement of PACAP in PTH holds promise for the development of novel drugs that can address the unmet needs of those affected.

Study Limitations

1
The in-hospital observational period was limited to 1-h post-infusion, which might have influenced the incidence of migraine-like headache due to environmental factors.
2
The inclusion of participants with a mild headache at the time of infusion start might be perceived as a confounder.
3
The study did not investigate the specific sites and mechanisms of action by which PACAP-38 induces migraine-like headache.

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