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- Title
Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling.
- Authors
Al-Khazali, Haidar M.; Christensen, Rune H.; Chaudhry, Basit Ali; Melchior, Anna G.; Ashina, Messoud; Burstein, Rami; Ashina, Håkan
- Abstract
Background: Phosphodiesterase 3 (PDE-3) inhibition have been implicated in the neurobiologic underpinnings of migraine. Considering the clinical similarities between migraine and persistent post-traumatic headache (PPTH), we aimed to ascertain whether PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Methods: We tested cilostazol, which inhibits PDE-3, in a randomized, double-blind, placebo-controlled, two-way crossover study involving persons with PPTH attributed to mild traumatic brain injury. The randomized participants were allocated to receive oral administration of either 200-mg cilostazol or placebo (calcium tablet) on two separate experiment days. The primary end point was the incidence of migraine-like headache during a 12-hour observation window post-ingestion. The secondary endpoint was the area under the curve (AUC) for reported headache intensity scores during the same observation window. Results: Twenty-one persons underwent randomization and completed both experiment days. The mean participants' age was 41.4 years, and most (n = 17) were females. During the 12-hour observation window, 14 (67%) of 21 participants developed migraine-like headache post-cilostazol, in contrast to three (14%) participants after placebo (P =.003). The headache intensity scores were higher post-cilostazol than after placebo (P <.001). Conclusions: Our results provide novel evidence showing that PDE-3 inhibition can elicit migraine-like headache in persons with PPTH. Given that PDE-3 inhibition increases intracellular cAMP levels, our findings allude to the potential therapeutic value of targeting cAMP-dependent signaling pathways in the management of PPTH. Further investigations are imperative to substantiate these insights and delineate the importance of cAMP-dependent signaling pathways in the neurobiologic mechanisms underlying PPTH. ClinicalTrials.gov Identifier: NCT05595993.
- Subjects
PROTEIN metabolism; CYCLIC adenylic acid; RESEARCH funding; PLACEBOS; RECEIVER operating characteristic curves; HEADACHE; TETRAZOLES; STATISTICAL sampling; BLIND experiment; QUESTIONNAIRES; TREATMENT effectiveness; CELLULAR signal transduction; RANDOMIZED controlled trials; DESCRIPTIVE statistics; PHOSPHODIESTERASE inhibitors; CROSSOVER trials; DISEASE incidence; NOCICEPTIN; PHARMACODYNAMICS
- Publication
Journal of Headache & Pain, 2024, Vol 25, p1
- ISSN
1129-2369
- Publication type
Article
- DOI
10.1186/s10194-024-01762-x