PROSTAGLANDIN-E2 LEVELS OVER THE COURSE OF GLYCERYL TRINITRATE PROVOKED MIGRAINE ATTACKS 99 5 We here aimed to shed light on the mechanistic aspect PGE2 has in migraine attack development, as it might serve as a possible drug target. We measured PGE2 plasma levels in female subjects with migraine and age-matched female healthy controls in the (pre)ictal phases of GTN provoked migraine-like attacks to assess whether PGE2 levels change as part of GTN-induced migraine attacks. Methods Participants This study was conducted as part of an extensive migraine provocation study, described in Onderwater et al.21 In total, 37 female subjects with migraine (without aura) and 25 age-matched female healthy controls were included. Due to the predominance of migraine in females only female subjects were included in the study. Migraine was diagnosed in accordance with the International Classification of Headache Disorders (ICHD-3).3 Participants with migraine experienced one or more migraine attacks per month during the past six months. Subjects with chronic migraine or medication-overuse headache were excluded. Healthy controls were free of (severe) headaches, neurological or psychiatric disorders and had no family history of severe primary headaches, but were allowed to occasionally have tension-type headaches. None of the participants used chronic medication other than oral contraceptives. The study was approved by the ethics committee of the Leiden University Medical Center and in accordance with the World Medical Association Declaration of Helsinki. All participants provided written informed consent prior to the study. Study design During the study day, each participant was subjected to detailed interviews over the course of the day and underwent three blood withdrawals. Samples were drawn by venipuncture from the medial cubital vein. Participants were attack-free at least three days prior to the investigation and had been instructed to refrain from using prophylactic medication for at least four weeks. Apart from abstaining from alcoholic beverages, caffeinated beverages, and smoking for at least 8 hours prior to and during the study day there were no dietary restrictions. Before GTN infusion, all participants underwent a baseline assessment consisting of a neurological examination, headache assessment, and a blood withdrawal in ethylenediaminetetraacetic acid (EDTA)-containing tubes was performed for baseline measurement [T0]. Following the baseline measurement, participants received an intravenous infusion of GTN (0.5 µg/kg/min over 20 minutes) between 9:45 and 10:45 AM, in supine position. After GTN infusion, blood was again drawn from participants at two time points, namely ~140 minutes [T1] and ~320 minutes after the start of GTN infusion [T2]. To avoid biochemical interference in the processes related to the initiation and onset of a migraine-like headache, participants were requested to abstain from using acute migraine attack medication until after the 3rd and final blood measurement [T2]. Blood was centrifuged at room
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