Headache provocation by nitric oxide in men who have never experienced a headache

In the general population 4% have never experienced a headache. Freedom from headache could be due to distinctive protective mechanisms or a lack of environmental risk factors for headache. Isosorbide-5-mononitrate is an organic nitrate which in the body is metabolised to nitric oxide. The nitric oxide pathway plays a crucial role in the primary headaches. We hypothesized that people who are free from headache are protected by distinctive mechanisms in the nitric oxide pathway.

We performed an observer blinded case-control study using nitric oxide to provoke a headache. 32 headache free male participants and 26 randomly selected male controls received 60 mg Isosorbide-5-mononitrate orally on the study day. Participants fill out a headache diary with headache intensity and characteristics until 12 hours after administration of Isosorbide-5-mononitrate. Primary endpoint were areas under the curve of headache intensity score.

All 58 participants completed the study. There was no significant difference in headache incidence, headache intensity score or migraine-like attack between headache free participants and controls.

We show that men who have never experienced a headache develop a headache when provoked with Isosorbide-5-mononitrate. This indicates that freedom from headache in men is not related to the nitric oxide pathway which is involved in the primary headache disorders.