Induction of nitrate tolerance is not a useful treatment in cluster headache

The aims of the present study were to investigate whether induction of nitr ate tolerance is a useful treatment in cluster headache and to correlate an y changes in attack frequency of cluster headache and nitrate-induced heada che to the vascular adaptation during continuous nitrate administration. Th e results were compared to results obtained from studies of nitrate toleran ce in healthy subjects. Materials and methods: 5-isosorbide-mononitrate (5- ISMN) 30 mg was administered orally three times daily for 4 weeks in nine s ufferers of chronic cluster headache in a double-blind, randomized placebo- controlled cross-over design. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and the diameters of the temporal an d radial arteries were measured with high frequency ultrasound. The haemody namic data were compared to changes in the frequency of cluster headache at tacks and interval headaches over time. Results: Tolerance was complete wit hin 24 h in the middle cerebral arteries and after 7 days in the symptomati c temporal artery, while tolerance of the radial artery was not observed wi thin this period. The time profiles of tolerance were almost identical to t he time profiles observed in healthy subjects. A close temporal association between the disappearance of nitrate-induced headache and tolerance of the temporal artery was observed but tolerance had no effect on cluster headac he attack frequency. Conclusions: Induction of tolerance to nitrates cannot be used to treat cluster headache. If pain is related to arterial dilatati on the results point to extracerebral rather than cerebral arteries as the site of nociception. However, other peripheral and central pain-modulating effects of nitric oxide, the time courses of which are unknown, should also be taken into consideration.