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

1 Citation (Scopus)


INTRODUCTION: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Original languageEnglish
JournalCephalalgia : an international journal of headache
Issue number7
Pages (from-to)598-607
Number of pages10
Publication statusPublished - Jun 2022


  • isosorbide-5-mononitrate
  • migraine
  • never had headache
  • pathway
  • protective mechanisms
  • Provocation study


Dive into the research topics of 'Headache provocation by nitric oxide in men who have never experienced a headache'. Together they form a unique fingerprint.

Cite this