Headache caused immediately, or after a delay, by acute exposure to a nitric oxide donor.
8.1.1 Nitric oxide (NO) donor-induced headache is typically frontotemporal and pulsating. All NO donors (eg, amyl nitrate, erythrityl tetranitrate, pentaerythrityl tetranitrate, glyceryl trinitrate [GTN], isosorbide mono- or dinitrate, sodium nitroprusside, mannitol hexanitrate) can cause headache of this subform.
GTN induces immediate headache in most normal people, but can also cause a delayed headache in migraineurs which fulfils the diagnostic criteria for 1.1 Migraine without aura. In people with 2.3 Chronic tension-type headache, GTN has been shown to induce a delayed headache which has the characteristics of 2. Tension-type headache (the effect is unknown in those with 2.1 Infrequent episodic tension-type headache or 2.2 Frequent episodic tension-type headache).
These delayed headaches occur, on average, 5-6 hours after exposure. People with 3. Cluster headache develop delayed headache only during cluster periods: GTN usually induces a cluster headache attack 1-2 hours after intake.
Headache is a side-effect of therapeutic use of nitroglycerine. With chronic use, tolerance develops within a week, and GTN-induced headache disappears in most patients within that time. Other NO donors used therapeutically may also produce headache. Isosorbide mononitrate has been the subject of one formal double-blind placebo-controlled study, and causes a much longer-lasting headache than GTN owing to its slow release of NO.