title: Induction of nitrate tolerance is not a useful treatment in cluster headache.
abstract: The aims of the present study were to investigate whether induction of nitrate tolerance is a useful treatment in cluster headache and to correlate any changes in attack frequency of cluster headache and nitrate-induced headache to the vascular adaptation during continuous nitrate administration. The results were compared to results obtained from studies of nitrate tolerance in healthy subjects.
  
  
  METHODS
  5-isosorbide-mononitrate (5-ISMN) 30 mg was administered orally three times daily for 4 weeks in nine sufferers 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 and radial arteries were measured with high frequency ultrasound. The haemodynamic data were compared to changes in the frequency of cluster headache attacks and interval headaches over time.
  
  
  RESULTS
  Tolerance was complete within 24 h in the middle cerebral arteries and after 7 days in the symptomatic temporal artery, while tolerance of the radial artery was not observed within this period. The time profiles of tolerance were almost identical to the 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 headache attack frequency.
  
  
  CONCLUSIONS
  Induction of tolerance to nitrates cannot be used to treat cluster headache. If pain is related to arterial dilatation 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.
authors.affiliation: Department of Neurology, Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.
authors.forename: I
authors.initials: I
authors.lastname: Christiansen
authors.forename: H K
authors.initials: HK
authors.lastname: Iversen
authors.forename: J
authors.initials: J
authors.lastname: Olesen
mesh_terms: D000328:Adult; D000368:Aged; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002536:Cerebral Arteries / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D003027:Cluster Headache / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D017534:Radial Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D013699:Temporal Arteries / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology; D017211:Treatment Failure; D014463:Ultrasonography; D014664:Vasodilation; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D014665:Vasodilator Agents; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate