Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain.
Role of hyperpolarization-activated cyclic nucleotide-gated ion channels in neuropathic pain: a proof-of-concept study of ivabradine in patients with chronic peripheral neuropathic pain.
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DOI：
10.1097/pr9.0000000000000967
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发表时间：
2021-11
期刊：
影响因子：
4.8
通讯作者：
Lee MC
中科院分区：
文献类型：
--
作者：
Bernard Healey SA;Scholtes I;Abrahams M;McNaughton PA;Menon DK;Lee MC
超极化激活的环核苷酸门控（HCN）通道受体在临床前模型中介导神经病理性疼痛。在此，探索性分析揭示了在神经性疼痛患者中使用HCN阻断剂的剂量依赖性疼痛减轻。超极化激活的环核苷酸门控（HCN）离子通道介导心脏和神经系统中的重复动作电位放电。HCN 2亚型在伤害感受器中表达，临床前研究表明在神经性疼痛中起关键作用。伊伐布雷定是目前可用于心脏适应症处方的非选择性HCN阻滞剂。小鼠数据表明，高浓度伊伐布雷定的镇痛作用与加巴喷丁相同。我们试图将这些发现转化为慢性周围神经性疼痛患者。我们试图将这些发现转化为慢性周围神经性疼痛患者。我们采用开放标签设计，给予递增剂量的伊伐布雷定，以达到50 - 60 BPM的心率目标，最高剂量为7.5 mg，每日两次。所有参与者在11分数字评分量表（NRS）上对他们的疼痛进行评分。7例受试者接受了药物并完成了研究。对主要终点（基线和最大剂量时平均评分之间的差异）无显著治疗效应（平均降低= 0. 878，95% CI =-2. 07至0. 31，P = 0. 1）。然而，使用线性混合模型的探索性分析显示伊伐布雷定剂量与疼痛评分之间存在高度显著相关性（χ2（1）= 74.6，P < 0.001），每毫克减少0.12 ± 0.01（SEM）NRS点。2名患有疼痛性糖尿病神经病变的参与者反应特别好。这表明伊伐布雷定在较高剂量下可能有效，尤其是在糖尿病神经性疼痛患者中。重要的是，参与者没有报告任何不良影响。这些数据表明，伊伐布雷定是一种外周限制性药物（无中枢神经系统副作用），在慢性神经性疼痛患者中耐受良好。伊伐布雷定目前已失效，其镇痛潜力值得在临床试验中进一步研究。
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel receptors mediate neuropathic pain in preclinical models. Here, exploratory analysis reveals a dose-dependent reduction in pain with HCN blockade in patients with neuropathic pain. Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels mediate repetitive action potential firing in the heart and nervous system. The HCN2 isoform is expressed in nociceptors, and preclinical studies suggest a critical role in neuropathic pain. Ivabradine is a nonselective HCN blocker currently available for prescription for cardiac indications. Mouse data suggest that ivabradine in high concentrations is equianalgesic with gabapentin. We sought to translate these findings to patients with chronic peripheral neuropathic pain. We sought to translate these findings to patients with chronic peripheral neuropathic pain. We adopted an open-label design, administering increasing doses of ivabradine to target a heart rate of 50 to 60 BPM, up to a maximum of 7.5 mg twice daily. All participants scored their pain on an 11-point numerical rating scale (NRS). Seven (7) participants received the drug and completed the study. There was no significant treatment effect on the primary endpoint, the difference between the mean score at baseline and at maximum dosing (mean reduction = 0.878, 95% CI = −2.07 to 0.31, P = 0.1). Exploratory analysis using linear mixed models, however, revealed a highly significant correlation between ivabradine dose and pain scores (χ2(1) = 74.6, P < 0.001), with a reduction of 0.12 ± 0.01 (SEM) NRS points per milligram. The 2 participants with painful diabetic neuropathy responded particularly well. This suggests that ivabradine may be efficacious at higher doses, particularly in patients with diabetic neuropathic pain. Importantly, participants reported no adverse effects. These data suggest that ivabradine, a peripherally restricted drug (devoid of central nervous system side effects), is well tolerated in patients with chronic neuropathic pain. Ivabradine is now off-patent, and its analgesic potential merits further investigation in clinical trials.