A randomised, double-blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial
A randomised, double-blind, placebo-controlled crossover trial of the influence of the HCN channel blocker ivabradine in a healthy volunteer pain model: an enriched population trial
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DOI：
10.1097/j.pain.0000000000001638
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发表时间：
2019-11-01
期刊：
影响因子：
7.4
通讯作者：
Menon, David
中科院分区：
文献类型：
--
作者：
Lee, Michael C.;Bond, Simon;Menon, David
临床前研究表明，2型超极化激活的环核苷酸门控离子通道(HCN2)是神经病理性疼痛所必需的。这项试验评估了非选择性HCN通道阻滞剂伊夫拉定对健康受试者辣椒素引起的痛觉过敏和疼痛的影响。一个丰富的人群包括那些从局部辣椒素(0.5%乳膏涂抹在9厘米(2)区域)产生20厘米(2)点状痛觉过敏的受试者。在一项交叉研究中，这些受试者在使用辣椒素之前1小时按随机分配的顺序服用伊夫拉定(15毫克)或安慰剂，每次使用乳膏时，前臂部位交替使用辣椒素。从筛查到第一次和第二次治疗的间隔时间分别至少为3周和5周，以将遗留影响降至最低。对55名参与者进行了筛查，其中25人完成了至少一次治疗访问。意向治疗分层分析显示，该药物对初步试验结果没有显著影响，定义为安慰剂和伊夫拉定对点状痛觉过敏区域的影响差异(伊夫拉定-安慰剂：平均值=3.22 cm(2)，95%可信区间：=-4.04至10.48，P=0.37)。然而，伊夫拉定导致心率减慢(每分钟差10.10次[95%可信区间-6.48至-13.73；P值
Preclinical studies suggest that type 2 hyperpolarization-activated cyclic nucleotide gated ion channels (HCN2) are necessary for neuropathic pain. This trial assessed the influence of ivabradine, a nonselective HCN channel blocker, on capsaicin-induced hyperalgesia and pain in healthy human subjects. An enriched population comprising subjects who developed >20 cm(2) of punctate hyperalgesia from topical capsaicin (0.5% cream applied onto 9 cm(2) area) was identified. These subjects then received ivabradine (15 mg) or placebo 1 hour before capsaicin application in randomly allocated order in a crossover study, The forearm site for capsaicin alternated with each application of the cream. The interval of time from screening to the first and to the second treatment visits was at least 3 and 5 weeks, respectively, to minimize carryover effects. Fifty-five participants were screened, of which 25 completed at least 1 treatment visit. Intention-to-treat hierarchical analysis revealed no significant effects of the drug on primary trial outcome, defined as a difference in effects of placebo and ivabradine on the area of punctate hyperalgesia (ivabradine - placebo: mean = 3.22 cm(2), 95% confidence interval: = -4.04 to 10.48, P = 0.37). However, ivabradine caused a slowing of heart rate (difference of 10.10 beats per minute [95% confidence interval -6.48 to -13.73; P-value