Glyceryl trinitrate triggers premonitory symptoms in migraineurs

Abstract

Studying attacks of migraine is considerably hampered by its fundamentally episodic nature. Developing approaches to triggering migraine reliably is important for advancing understanding of the disorder by facilitating its study. Based on the work of the Copenhagen Group we administered an intravenous infusion of 0.5 microg/kg/min glyceryl trinitrate (GTN) to 44 migraineurs, 23 migraine without aura, 21 migraine with aura, and to 12 healthy controls. We sought to characterise the GTN-induced migraine in terms of the clinical features of the attacks and reproducibility of triggering, and included a non-migraine control group for the purpose of comparing any effects to exclude an ordering effect. Of the 44 patients administered GTN, 33 had a migraine attack fulfilling International Headache Society criteria. Thirty-two attacks were of migraine without aura and one of migraine with aura. Twelve patients described typical premonitory symptoms, which have not been previously documented with GTN-induced migraine. A repeat attack was triggered in all subjects but one. In one case a visual aura was also triggered both times. Our study shows that GTN-induced triggering is common in our patients, and remarkably reproducible. The data will facilitate the use of the GTN model in studies requiring extensive planning, such as brain imaging, or where preventive questions are at issue. We also report the first patient with a reproducible GTN-triggered migraine with aura.

Nitric Oxide-Related Drug Targets in Headache

“…Aura symptoms were not elicited in any subject, but have subsequently been observed by others in rare instances after GTN. 36 However, an attack fulfilling criteria for migraine without aura developed in 6 of 12 patients. 35 This was significantly more than in the normal controls in which no one developed a migraine attack.…”

“…These proportions were based on small numbers, but subsequent studies have demonstrated almost identical figures in large numbers of patients. 36,37 The migraine aura is probably caused by a so-called cortical spreading depression, 38 which is a slowly spreading depolarization of all cellular elements of the cerebral cortex; this phenomenon is associated with the production of NO. Indeed, the GTN experiments previously described herein suggest that the aura may produce headache via the production of NO.…”

“…Subsequently, Afridi et al 36 performed a large study of GTN in migraine patients. They confirmed previous observations and also, for the first time, demonstrated premonitory symptoms just before GTN-induced migraine.…”

Premonitory-like Symptomatology in Migraine

“…Nitroglycerin (NTG) and pituitary adenylate-cyclase activating protein (PACAP) have been shown to be able to trigger premonitory symptoms in migraineurs, similar to those experienced with spontaneous attacks. 34,35 NTG is a well-established migraine-triggering model in the literature, 36 but it has not been used extensively yet to study premonitory-like symptomatology. PACAP is newer in migraine research 37 and its ability to trigger migraine 38 has led to interest in agents targeted against the PAC1 receptor as a possible treatment for migraine.…”

Modulatory effect of synthetic kynurenic acid derivatives on the nitroglycerin-induced trigeminal activation and sensitization in rats

“…NTG can trigger migraine with aura as well, during which activation in the primary visual area of the occipital cortex was demonstrated (Afridi et al, 2005). NTG induced premonitory symptoms (yawning, tiredness, irritability, neck stiffness, frequency of urination, hunger and low mood) in migraineurs, who have usually these symptoms before spontaneous migraine attack (Afridi et al, 2004). Both during genuine migraine attack (Weiller et al, 1995) and after taking of NTG by migraine patients, significant activation in the dorsal rostral brain stem and dorsal lateral pons can be observed during the pain, which was ipsilateral to the site of headache (Afridi et al, 2005).…”