Headache characteristics during the development of tolerance to nitrates: pathophysiological implications

Area of Science:

• Pharmacology
• Neurology
• Vascular Biology

Background:

• Nitric oxide (NO) is implicated in both nitrate-induced headaches and spontaneous migraine attacks.
• Organic nitrates are prodrugs for NO, with headache being a common adverse effect that can diminish with continuous use.
• Understanding headache tolerance to nitrates may offer insights into general vascular headache mechanisms.

Purpose of the Study:

• To characterize headache and associated symptoms during continuous nitrate administration until headache tolerance develops.
• To investigate the relationship between hemodynamic changes and headache severity/tolerance.

Main Methods:

• A double-blind, randomized placebo-controlled cross-over study involving 11 healthy subjects.
• Oral administration of 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily for 7 days.
• Comparison of hemodynamic data with headache development and tolerance over time.

Main Results:

• Headache during 5-ISMN administration was more severe and longer-lasting than placebo (P<0.004).
• Migraine criteria were met by 10 subjects for pain and 5 subjects for full diagnosis (migraine without aura).
• Intravenous glyceryl trinitrate infusion caused milder headaches and no migraine.
• Tolerance to headache correlated with reduced dilation of the superficial temporal artery.
• Tolerance in the middle cerebral artery occurred earlier (24h) than headache tolerance.

Conclusions:

• Sufficiently high doses of NO administered over hours can trigger migraine attacks in healthy individuals.
• The findings suggest extracerebral arteries may be involved if vasodilation causes headache.
• Central nervous system effects of NO, including cytotoxic and pain modulation, could also contribute to headache mechanisms.