Nitroglycerin provocation in normal subjects is not a useful human migraine model?

Abstract

Provoking delayed migraine with nitroglycerin in migraine sufferers is a cumbersome model. Patients are difficult to recruit, migraine comes on late and variably and only 50-80% of patients develop an attack. A model using normal volunteers would be much more useful, but it should be validated by testing the response to drugs of known efficacy in acute migraine. Furthermore, treatment during headache rather than pretreatment is the most naturalist method. To fulfil these requirements we used continuous long-lasting infusion of glyceryl trinitrate (GTN) 0.2 microg kg-1 min-1 for 140 min and gave aspirin 1000 mg, zolmitriptan 5 mg or placebo to normal healthy volunteers. The design was double-blind, placebo-controlled three-way crossover. Our hypothesis was that these drugs would be effective in the treatment of the mild constant headache induced by long-lasting GTN infusion. The headaches did not fulfil the International Headache Society diagnostic criteria for migraine without aura. Moreover, there was no effect on headache of either zolmitriptan or aspirin. Thus our hypothesis was disproved and we conclude that our model is not valid for the testing of new acute antimigraine drugs. Our experiment suggests that headache caused by direct nitric oxide (NO) action in the continued presence of NO is very resistance to analgesics and to specific acute migraine treatments. This suggests that NO works very deep in the cascade of events associated with vascular headache, whereas tested drugs work higher in the cascade. The model suggested here should therefore be tested with other headache/migraine-provoking agents that supposedly work higher in the cascade of events. The need for human models persists, but the solution to this problem is still pending.

Towards a pragmatic human migraine model for drug testing: 2. Isosorbide-5-mononitrate in healthy individuals

“…Previous studies have shown that neither zolmitriptan nor aspirin, nor olcegepant, have an effect on headache induced by long-lasting glyceryl trinitrate (GTN) infusion (17,18). The present results are in agreement as 5-ISMN releases NO continuously over many hours and we saw no effect of sumatriptan.…”

TNFα Levels and Macrophages Expression Reflect an Inflammatory Potential of Trigeminal Ganglia in a Mouse Model of Familial Hemiplegic Migraine

“…In particular, FHM-1 patients are not hypersensitive to CGRP [47] and nitric oxide [48], by contrast with patients with migraine with or without aura [49]. Since administration of CGRP or of a nitric oxide donor does not induce migraine in healthy subjects [50] it is likely that the hypersensitivity of migraineurs to these substances implies abnormal signaling downstream of the primary mechanism of CGRP and nitric oxide activities.…”

Functional Neuroimaging in Migraine: Chances and Challenges

“…It is therefore understandable that some studies resolve to investigating pharmacologically provoked migraine like headache or try to trigger attacks using natural stimuli . Both approaches are problematic: at the moment we do not know whether the migraine like headache experienced by migraine patients following NO‐ or pituitary adenylate cyclase activating peptide (PACAP)‐administration is pathophysiologically identical to spontaneous migraine attacks . A crucial point in imaging studies using pharmacological induction of headaches is to separate the headache‐specific signal changes, ie, the condition of interest, from general drug effects.…”

“…5,12,[24][25][26][27][28] Both approaches are problematic: at the moment we do not know whether the migraine like headache experienced by migraine patients following NO 29,30 -or pituitary adenylate cyclase activating peptide (PACAP) 31 -administration is pathophysiologically identical to spontaneous migraine attacks. [32][33][34][35][36][37] A crucial point in imaging studies using pharmacological induction of headaches is to separate the headachespecific signal changes, ie, the condition of interest, from general drug effects. It is thus necessary during piloting to exclude any such changes or, if they exist, to control them via an apt control group.…”