Hypersensitivity to phosphodiesterase-5 inhibition in post-traumatic headache: evidence of cGMP-dependent signaling

BackgroundPhosphodiesterase‐5 (PDE‐5) inhibition increases intracellular cyclic guanosine monophosphate (cGMP), a second messenger molecule implicated in migraine pathogenesis. Given the clinical overlap between migraine and post‐traumatic headache (PTH), we investigated whether pharmacologic elevation of cGMP induces migraine‐like headache in individuals with persistent PTH.MethodsAdults with persistent PTH and no pre‐trauma history of migraine were enrolled in a randomized, double‐blind, placebo‐controlled, 2‐way crossover study. Each participant received a single 100‐mg oral dose of sildenafil or placebo on two experimental days, separated by a 1‐week washout interval. Headache outcomes were assessed using structured diaries over 12 h post‐ingestion. The primary outcome was the incidence of migraine‐like headache during this observation window. The secondary outcome was the baseline‐corrected area under the curve (AUC) for headache intensity scores over the same period.ResultsA total of 21 participants (mean age 42.3 years; 57% female) with persistent PTH completed both experimental days. Migraine‐like headache occurred in 15 participants (71%) after sildenafil administration, compared with 4 (19%) following placebo (P = 0.003). Headache intensity scores, as quantified by the AUC, were significantly higher after sildenafil than after placebo (P < 0.001).ConclusionsPharmacologic elevation of cGMP via PDE‐5 inhibition elicits migraine‐like headache in individuals with persistent PTH, despite no pre‐trauma history of migraine. These findings provide the first experimental evidence linking intracellular cGMP‐dependent signaling to headache provocation in this patient population. The observed response implicates cGMP‐dependent mechanisms in the pathogenesis of PTH and identifies this pathway as a potential target for future therapeutic development.Trial registration: ClinicalTrials.gov (Identifier: NCT05669885).