The Prophylactic Effect of Valproate on Glyceryltrinitrate induced Migraine

Abstract

In this study the human glyceryltrinitrate (GTN) model of migraine was for the first time used to test the effect of a prophylactic drug. We chose to test valproate due to its well documented effect as a migraine prophylactic drug. Efficacy of this compound would support the usefulness of the model in prophylactic antimigraine drug development. Twelve patients with migraine without aura were included in a randomized double blind crossover study. Valproate 1000 mg or placebo was given daily, each for a minimum of 13 days. On the last treatment day of each arm a 20 min intravenous infusion of GTN (0.25 microg/kg/min) was given. Headache was registered for 12 h after the infusion and headache intensity was scored on a scale from 0 to 10. Fulfillment of IHS criteria was recorded for 24 h. The middle cerebral arteries were evaluated by transcranial Doppler and the diameter of the superficial temporal and radial arteries were measured with high frequency ultrasound. GTN evoked migraine fulfilling IHS criteria 1.1 in 6 patients after placebo and in 2 patients after valproate (P = 0.125). Including additionally 3 patients on placebo and 1 patient on valproate who felt they had suffered a migraine attack, but who had as associated symptoms only photophobia or phonophobia, a significant reduction in the number of patients with induced migraine after valproate was seen (P = 0.031). Median peak headache intensity was 1 (range 0-9) after valproate compared to 4.5 (range 0-8) after placebo (P = 0.120). Pretreatment with valproate as compared to placebo reduced the velocity in both middle cerebral arteries after GTN (left P = 0.021, right P = 0.031). No effect of valproate was seen in the diameter of the superficial temporal artery (P = 0.781) or the radial artery (P = 0.367) before or after GTN. The study indicates that a prophylactic effect of valproate may be demonstrated using the GTN human migraine model. Although, all headache parameters were reduced after valproate compared to placebo, only one parameter was statistically significantly reduced probably because of the small number of patients. The size of the effect was similar to that of valproate in clinical trials. The GTN model may therefore be a valid tool for testing new prophylactic antimigraine drugs.

The Effect of Propranolol on Glyceryltrinitrate-Induced Headache and Arterial Response

“…This could limit the use of the model. In a recent study with the same study design, we found that sodium valproate could prevent GTN‐induced headache/migraine in migraine patients (8). The present study may therefore indicate that propranolol has a different mechanism of action in preventing migraine and that this effect is overruled or bypassed by the nitric oxide (NO) donor GTN.…”

“…The prophylactic effect of propranolol and other β‐adrenoceptor antagonists (β‐blockers) in migraine is well established (7). We have previously shown the efficacy of sodium valproate in preventing GTN‐induced headache and migraine (8). We therefore studied the effect of propranolol prophylaxis on GTN‐induced headache and migraine, in order to validate our model further.…”

Sumatriptan alleviates nitroglycerin-induced mechanical and thermal allodynia in mice

“…However, 30 min to 4 h after administration of NTG, patients with a history of migraine also report the onset of delayed headache symptoms that are indistinguishable from their environmentally triggered migraines (7). Furthermore, experimentally administered NTG induces migrainous headaches that are accompanied by thermal allodynia (8), activate brainstem regions that are also active in a migraine attack (9) and can be blocked by migraine prophylactic agents (10,11). NTG can even trigger aura in some patients with an established history of migraine with aura (12).…”

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device

“…Human models of migraine have been developed to study drug effects under standardised conditions. The glyceryl trinitrate (GTN) model, which uses systemic or sublingual administration of GTN, is the most commonly used to induce neurovascular headaches (cluster headache and migraine) and is considered as safe, reproducible and reliable 10–15 . Sublingual administration of GTN is easier and this modality has been shown to reproduce the main features of spontaneous headache attacks experienced by patients with migraine without aura and cluster headaches 13 .…”