Al-Karagholi Mohammad Al-Mahdi, Ghanizada Hashmat, Kokoti Lili, Paulsen Joachim S, Hansen Jakob Møller, Ashina Messoud
Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.
Danish Headache Knowledge Center, Rigshospitalet Glostrup, Glostrup, Denmark.
Cephalalgia. 2020 Sep;40(10):1045-1054. doi: 10.1177/0333102420949863. Epub 2020 Aug 17.
Administration of ATP-sensitive potassium channel opener levcromakalim triggers headache in healthy volunteers and migraine attacks in migraine patients. Here, we investigated the effect of ATP-sensitive potassium channel blocker glibenclamide on levcromakalim-induced headache in healthy volunteers.
In a randomized, double-blind, placebo-controlled, three-way cross-over study, 15 healthy volunteers aged 18-40 years were randomly allocated to receive glibenclamide and levcromakalim (day 1), glibenclamide and placebo (day 2), and placebo and placebo (day 3) on three different days separated by at least 1 week. The primary endpoints were the difference in incidence of headache and the difference in area under the curve for headache intensity scores (0-12 hours) between the days.
Fifteen healthy volunteers completed the 3 days of the study. More participants (12/15, 80%) developed headache on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day (5/15, 33%) ( = 0.01; mean difference 47%; 95% confidence interval 18-75%) and compared to the placebo-placebo day (1/15, 7%) ( = 0.001; mean difference 73%; 95% confidence interval 48-99%). We found no difference in headache incidence between glibenclamide-placebo day and placebo-placebo day ( = 0.12; mean difference 27%; 95% confidence interval 1.3-52%). The area under the curve for headache intensity was significantly larger on the glibenclamide-levcromakalim day compared to the glibenclamide-placebo day ( = 0.003); and compared to the placebo-placebo day ( = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day ( = 0.07). The median time to onset for headache after levcromakalim infusion with glibenclamide pretreatment was delayed (180 min) compared to levcromakalim without pretreatment (30 min) from a previously published study.
Glibenclamide administration did not cause headache, and glibenclamide pretreatment did not prevent levcromakalim-induced headache. However, glibenclamide delayed the onset of levcromakalim-induced headache. More selective blockers are needed to further elucidate the role of the ATP-sensitive potassium channel in headache initiation. ClinicalTrials.gov NCT03886922.
给予三磷酸腺苷敏感性钾通道开放剂左旋克罗卡林会在健康志愿者中引发头痛，并在偏头痛患者中诱发偏头痛发作。在此，我们研究了三磷酸腺苷敏感性钾通道阻滞剂格列本脲对左旋克罗卡林诱发健康志愿者头痛的影响。
在一项随机、双盲、安慰剂对照、三交叉研究中，15名年龄在18至40岁的健康志愿者被随机分配，在至少间隔1周的三个不同日期分别接受格列本脲和左旋克罗卡林（第1天）、格列本脲和安慰剂（第2天）以及安慰剂和安慰剂（第3天）。主要终点是各日之间头痛发生率的差异以及头痛强度评分（0至12小时）曲线下面积的差异。
15名健康志愿者完成了为期3天的研究。与格列本脲 - 安慰剂日（5/15，33%）相比，更多参与者（12/15，80%）在格列本脲 - 左旋克罗卡林日出现头痛（P = 0.01；平均差异47%；95%置信区间18 - 75%），与安慰剂 - 安慰剂日（1/15，7%）相比也是如此（P = 0.001；平均差异73%；95%置信区间48 - 99%）。我们发现格列本脲 - 安慰剂日与安慰剂 - 安慰剂日之间头痛发生率无差异（P = 0.12；平均差异27%；95%置信区间1.3 - 52%）。与格列本脲 - 安慰剂日相比，格列本脲 - 左旋克罗卡林日头痛强度的曲线下面积显著更大（P = 0.003）；与安慰剂 - 安慰剂日相比也是如此（P = 0.001）。我们发现格列本脲 - 安慰剂日与安慰剂 - 安慰剂日之间曲线下面积无差异（P = 0.07）。与先前发表的研究中未用预处理的左旋克罗卡林（30分钟）相比，用格列本脲预处理后输注左旋克罗卡林引发头痛的中位发作时间延迟（180分钟）。
给予格列本脲不会引起头痛，且格列本脲预处理不能预防左旋克罗卡林诱发的头痛。然而，格列本脲延迟了左旋克罗卡林诱发头痛的发作。需要更具选择性的阻滞剂来进一步阐明三磷酸腺苷敏感性钾通道在头痛发作中的作用。ClinicalTrials.gov NCT03886922。
