Introduction

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.

Methods

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.

Results

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%) (p = 0.01; mean difference 47%; 95% confidence interval 18–75%) and compared to the placebo-placebo day (1/15, 7%) (p = 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 (p = 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 (p = 0.003); and compared to the placebo-placebo day (p = 0.001). We found no difference in the area under the curve between the glibenclamide-placebo day compared to the placebo-placebo day (p = 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.

Conclusion

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.

Trial Registration: ClinicalTrials.gov NCT03886922.

中文翻译：

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KATP 通道阻滞剂格列本脲对左旋卡林引起的头痛的影响。

介绍

服用 ATP 敏感性钾通道开放剂 levcromakalim 会引发健康志愿者的头痛和偏头痛患者的偏头痛发作。在这里，我们研究了 ATP 敏感的钾通道阻滞剂格列本脲对健康志愿者中左旋卡林引起的头痛的影响。

方法

在一项随机、双盲、安慰剂对照、三向交叉研究中，15 名 18-40 岁的健康志愿者被随机分配接受格列本脲和左旋卡林（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）在相隔至少 1 周的三个不同的日子。主要终点是头痛发生率的差异和头痛强度评分（0-12 小时）曲线下面积的差异。

结果

15 名健康志愿者完成了为期 3 天的研究。与格列本脲-安慰剂治疗日 (5/15, 33%) 相比，更多的参与者 (12/15, 80%) 在格列本脲-左旋卡林日出现头痛（p  = 0.01；平均差异 47%；95% 置信区间 18-75 %) 并与安慰剂安慰剂日 (1/15, 7%) 相比（p  = 0.001；平均差异 73%；95% 置信区间 48-99%）。我们发现格列本脲-安慰剂日和安慰剂-安慰剂日头痛发生率没有差异（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-左旋卡林日的头痛强度曲线下面积显着更大（p = 0.003); 并与安慰剂安慰剂日相比（p  = 0.001）。我们发现格列本脲-安慰剂日与安慰剂-安慰剂日之间的曲线下面积没有差异（p  = 0.07）。从先前发表的研究中，与没有预处理的 levcromakalim (30 分钟) 相比，在 levcromakalim 输注与格列本脲预处理后头痛发作的中位时间 (180 分钟)。

结论

格列本脲给药不会引起头痛，格列本脲预处理也不能预防左旋卡林引起的头痛。然而，格列本脲延缓了左旋卡林引起的头痛的发作。需要更多选择性阻滞剂来进一步阐明 ATP 敏感钾通道在头痛发生中的作用。

试验注册： ClinicalTrials.gov NCT03886922。