Dataset Information

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

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.

SUBMITTER: Al-Khazali HM

PROVIDER: S-EPMC10994530 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Al-Khazali Haidar M HM Christensen Rune H RH Dodick David W DW Chaudhry Basit Ali BA Amin Faisal Mohammad FM Burstein Rami R Ashina Håkan H Ashina Håkan H

Brain : a journal of neurology 20240401 4

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 i ...[more]

PMID: 37864847

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Project description:BackgroundCurrently, there are no FDA approved therapies for persistent post-traumatic headache (PPTH) secondary to traumatic brain injury (TBI). As such neither headache nor TBI specialists have an effective means to manage PPTH. Thus, the objective of the present pilot trial was to evaluate the feasibility and preliminary efficacy of a four-week at-home remotely supervised transcranial direct current stimulation (RS-tDCS) intervention for veterans with PPTH.MethodsTwenty-five (m = 46.6 ± 8.7 years) veterans with PPTH were randomized into two groups and received either active (n = 12) or sham (n = 13) RS-tDCS, with anodal stimulation over left dlPFC and cathodal over occipital pole. Following a four-week baseline, participants completed 20-sessions of active or sham RS-tDCS with real-time video monitoring over a period of four-weeks. Participants were assessed again at the end of the intervention and at four-weeks post-intervention. Primary outcomes were overall adherence rate (feasibility) and change in moderate-to-severe headache days per month (efficacy). Secondary outcomes were changes in total number of headache days, and PPTH-related functional outcomes.ResultsAdherence rate was high with 88% of participants (active = 10/12; sham = 12/13) fully completing tDCS interventions. Importantly, there was no significant difference in adherence between active and sham groups (p = 0.59). Moderate-to-severe headache days were significantly reduced within the active RS-tDCS group (p = 0.004), compared to sham during treatment (-2.5 ± 3.5 vs. 2.3 ± 3.4), and 4-week follow-up (-3.9 ± 6.4 vs. 1.2 ± 6.5). Total number of headache days was significantly reduced within the active RS-tDCS (p = 0.03), compared to sham during-treatment (-4.0 ± 5.2 vs. 1.5 ± 3.8), and 4-week follow-up (-2.1 ± 7.2 vs. -0.2 ± 4.4).ConclusionThe current results indicate our RS-tDCS paradigm provides a safe and effective means for reducing the severity and number of headache days in veterans with PPTH. High treatment adherence rate and the remote nature of our paradigm indicate RS-tDCS may be a feasible means to reduce PPTH, especially for veterans with limited access to medical facilities.Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT04012853].

Project description:ObjectiveTo examine whether sensory hypersensitivity contributes to headache-related disability in a secondary analysis of patients with post-traumatic headache.BackgroundUp to one-third of individuals with traumatic brain injuries report persistent headache 3 months post-injury. High rates of allodynia and photophobia have been observed in clinical studies and animal models of post-traumatic headache, but we do not fully understand how sensory amplifications impact post-traumatic headache-related disability.MethodsWe identified a cross-sectional sample of patients from the American Registry for Migraine Research database with new or worsening headaches post-head injury from 2016 to 2020 and performed a secondary analysis of those data. We modeled the relationship between sensory sensitivity and Migraine Disability Assessment scores using questionnaires. Candidate variables included data collection features (study site and year), headache-related and general clinical features (headache frequency, migraine diagnosis, abuse history, sex, age, cognitive and affective symptom scores), and sensory symptoms (related to light, sound, and touch sensitivity).ResultsThe final sample included 193 patients (median age 46, IQR 22; 161/193, 83.4% female). Migraine Disability Assessment scores ranged from 0 to 260 (median 47, IQR 87). The final model included allodynia, hyperacusis, photosensitivity, headache days per month, abuse history, anxiety and depression, cognitive dysfunction, and age (R2 = 0.43). An increase of one point in allodynia score corresponded to a 3% increase in headache disability (95% CI: 0%-7%; p = 0.027), an increase of one-tenth of a point in the photosensitivity score corresponded to a 12% increase (95% CI: 3%-25%; p = 0.002), and an increase of one point in the hyperacusis score corresponded to a 2% increase (95% CI: 0%-4%; p = 0.016).ConclusionsIncreased photosensitivity, allodynia, and hyperacusis were associated with increased headache-related disability in this sample of patients with post-traumatic headache. Symptoms of sensory amplification likely contribute to post-traumatic headache-related disability and merit an ongoing investigation into their potential as disease markers and treatment targets.

Dataset Information

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

Publications

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

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