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

Abstract

Prophylactic drug trials in migraine are long-lasting and expensive and require long-term toxicology information. A human migraine model would therefore be helpful in testing new drugs. Immediate headache and delayed migraine after glyceryltrinitrate (GTN) has been well characterized. We have recently shown that sodium valproate has prophylactic effect in the GTN model. Here we report our experience with propranolol in this model. Nineteen subjects with migraine without aura and 16 sex- and aged-matched healthy subjects were included in a two-centre randomized double-blind cross-over study. Fourteen migraine subjects and 14 healthy subjects completed the study and results from comparison of the 28 subjects are reported. Randomly propranolol 160 mg or placebo were each given daily for 14 days to both migraine and healthy subjects. A 20-min intravenous infusion of GTN 0.25 microg/kg per min was administered on a study day at the end of both pretreatment periods. Headache was registered for 12 h after GTN infusions. Its intensity was scored on a numerical verbal rating scale from 0 to 10. Fulfilment of International Headache Society (HIS) criteria was recorded for 24 h. Radial and superficial temporal artery diameters and blood velocity of both middle cerebral arteries were measured. All migraine subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 5, range 0-7) compared with placebo (median 5, range 0-10) (P = 0.441). Eight of the 14 completing migraine subject developed IHS 1.1 migraine after GTN, two subjects on both days, three subjects only after placebo, and three subjects only after propranolol. No reduction of GTN-induced migraine was found after propranolol compared with placebo (5 vs. 5, P = 1.000). All healthy subjects developed headache after GTN. No reduction of overall peak headache was found after propranolol (median 2, range 1-5) compared with placebo (median 1, range 1-7) (P = 0.315). Two subjects fulfilled IHS criteria 1.1 for migraine without aura after propranolol but not after placebo. The fulfilment was short lasting and did not require rescue medication. Headache after GTN was more pronounced in migraine subjects than in healthy subjects both with (P = 0.003) and without pretreatment with propranolol (P = 0.017). We found that 2 weeks of propranolol constricted the radial artery in healthy subjects but not in migraine subjects. GTN-induced vasodilatation abolished this difference. Mean maximum blood flow velocity in the middle cerebral artery was higher in healthy subjects than in migraine patients (P = 0.003-0.033) and unaffected by propranolol. We observed no effect of propranolol on GTN-induced headache and migraine. This could indicate that GTN induces migraine at a deeper level of the pathophysiological cascade of migraine than the prophylactic effect of propranolol. Propranolol does not constrict cerebral arteries, which therefore cannot be part of its mechanism of action in migraine.

“The Efficacy Of Combined Low-Doses Of Propranolol And Flunarizine In Episodic Migraine”

“…This was in fact study of add-on efficacy of propranolol with flunarizine. It is also to be noted that the dosages of propranolol 20 mg and 40 mg used for the prophylaxis are much lower than those commonly used as 80-160 mg daily of propranolol (17)(18)(19)(20). This was to show whether a very low dosage combination of long-acting propranolol and flunarizine was effective or no in the prophylaxis of episodic migraine without aura.…”

Effect of genetic deletion and pharmacological antagonism of P2X7 receptors in a mouse animal model of migraine

“…Several reports show that the clinical use of NTG induces delayed spontaneous headache in migraine patients [7-9] coupled with accompanying symptoms. NTG-derived nitric oxide (NO) activates brainstem regions and neuronal populations which are involved in environmentally triggered migraine attacks [10] and prophylactic agents can block NTG-induced headaches in human [11,12]. Furthermore, NTG can provoke cutaneous allodynia in migraine sufferers [13] including in non-cranial regions [4,5].…”

Über die Rolle der Phosphodiesterasen in der Pathophysiologie der Migräne

“…Neben den PDE−Inhibitoren wurde auch das Migräneprophylak− tikum Propranolol im humanen GTN−induzierten Migränemo− dell untersucht. Nach Einnahme des Propranolols in therapeuti− scher Dosierung über mehrere Wochen fand sich nach GTN−Ex− position keine Reduktion der Migräneattacken, weder in ihrer Stärke noch in der Häufigkeit[16].Zusammenfassend konnte sowohl im Tierversuch als auch beim Menschen für NO, CGRP und für die in den jeweiligen Signalwe− gen nachgeschalteten PDE 3 und 5 eine besondere Bedeutung im trigeminovaskulären Modell der Migränepathophysiologie nachgewiesen werden. Unklar ist in den humanen Kopfschmerz− modellen die Ursache sowohl des Zeitintervalls zwischen Been− digung der Infusion und dem Auftreten des Kopfschmerzes als auch der unterschiedlichen Wirkung auf die zerebralen Gefäße.Für eine Expressionsänderung der cGMP−abhängigen PDE 2, 3 oder 5 durch NO spricht zum einen das mehrere Stunden dau− ernde Zeitintervall zwischen Applikation des GTN und dem Auf− treten der Migräneattacke.…”