Hypersensitivity to Phosphodiesterase 5 Inhibition in Post-Traumatic Headache

To investigate whether sildenafil (phosphodiesterase 5 inhibitor) induces migraine-like headache in people with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (mTBI).

Inclusion Criteria:Age 18 to 65 years of age upon entry into screeningHistory of persistent headache attributed to mild traumatic injury to the head for ≥ 12 months and in accordance with the International Classification of Headache Disorders, 3rd Edition (ICHD-3)≥ 4 monthly headache days on average across the 3 months prior to screeningProvision of informed consent prior to initiation of any study-specific activities/proceduresExclusion Criteria:> 1 mild traumatic injury to the headHistory of any primary or secondary headache disorder prior to mild traumatic injury to the head (except for infrequent episodic tension-type headache)History of moderate or severe injury to the headHistory of whiplash injuryHistory of craniotomyHistory or evidence of any other clinically significant disorder, condition or disease (except for those outlined above) than, in the opinion of the site investigator, would pose a risk to subject safety or interfere with study evaluation, procedures or completionThe subject is at risk of self-harm or harm to others as evidenced by past suicidal behaviorFemale subjects of childbearing potential with a positive pregnancy test during any study visitCardiovascular disease of any kind, including cerebrovascular diseasesHypertension (systolic blood pressure of ≥150 mmHg and/or diastolic blood pressure of ≥100 mmHg) prior to the start of infusion on the experimental dayHypotension (systolic blood pressure of ≤90 mmHg and/or diastolic blood pressure of ≤50 mmHg)Initiation, discontinuation, or change of dosing of prophylactic medications within 2 months prior to study inclusionIntake of acute medications (e.g. analgesics, triptans) within 48 hours of infusion startBaseline headache intensity of >3 on an 11-point numeric rating scale (0 being no headache, 10 being the worst imaginable headache)Baseline headache with migraine-like features or self-reported baseline headache that mimics the subjects' usual headache with migraine-like features