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Open Access 01-12-2024 | Headache | Research

Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling

Authors: Haidar M. Al-Khazali, Rune H. Christensen, Basit Ali Chaudhry, Anna G. Melchior, Messoud Ashina, Rami Burstein, Håkan Ashina

Published in: The Journal of Headache and Pain | Issue 1/2024

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.

Available only for authorised users

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Title: Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling
Authors: Haidar M. Al-Khazali
Rune H. Christensen
Basit Ali Chaudhry
Anna G. Melchior
Messoud Ashina
Rami Burstein
Håkan Ashina
Publication date: 01-12-2024
Publisher: Springer Milan
Keywords: Headache
Migraine
Sumatriptan
Published in: The Journal of Headache and Pain / Issue 1/2024
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-024-01762-x

At a glance: The STEP trials

Springer Medicine

Effects of PDE-3 inhibition in persistent post-traumatic headache: evidence of cAMP-dependent signaling

Abstract

Background

Methods

Results

Conclusions

ClinicalTrials.gov Identifier

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

ClinicalTrials.gov Identifier

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