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).