The voltage-gated sodium channel NaV1.7 plays an important role in pain processing according to genetic data. Those data made NaV1.7 a popular drug target, especially since its relatively selective expression in nociceptors promised pain relief without the adverse effects associated with broader sodium channel blockade. Despite encouraging preclinical data in rodents, NaV1.7-selective inhibitors have not yet proven effective in clinical trials. Discrepancies between preclinical and clinical results should raise alarms. We reviewed preclinical and clinical reports on the analgesic efficacy of NaV1.7-selective inhibitors and found critical differences in several factors. Putting aside species differences, most preclinical studies tested young male rodents with limited genetic variability, inconsistent with the clinical population. Inflammatory pain was the most common preclinical chronic pain model whereas nearly all clinical trials focused on neuropathic pain despite some evidence suggesting NaV1.7 channels are not essential for neuropathic pain. Preclinical studies almost exclusively measured evoked pain whereas most clinical trials assessed average pain intensity without distinguishing between evoked and spontaneous pain. Nearly all preclinical studies gave a single dose of drug unlike the repeat dosing used clinically, thus precluding preclinical data from demonstrating whether tolerance or other slow processes occur. In summary, preclinical testing of NaV1.7-selective inhibitors aligned poorly with clinical testing. Beyond issues that have already garnered widespread attention in the pain literature, our results highlight the treatment regimen and choice of pain model as areas for improvement.

中文翻译：

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NaV1.7 选择性疼痛抑制剂的临床前和临床测试不一致。


根据遗传数据，电压门控钠通道 NaV1.7 在疼痛处理中起重要作用。这些数据使 NaV1.7 成为一种流行的药物靶点，特别是因为它在伤害感受器中的相对选择性表达有望缓解疼痛，而不会产生与更广泛的钠通道阻断相关的不良反应。尽管在啮齿动物中获得了令人鼓舞的临床前数据，但 NaV1.7 选择性抑制剂尚未在临床试验中证明有效。临床前和临床结果之间的差异应该引起警惕。我们回顾了 NaV1.7 选择性抑制剂镇痛效果的临床前和临床报告，并发现几个因素存在关键差异。撇开物种差异不谈，大多数临床前研究测试了遗传变异有限的年轻雄性啮齿动物，与临床人群不一致。炎症性疼痛是最常见的临床前慢性疼痛模型，而几乎所有临床试验都集中在神经性疼痛上，尽管一些证据表明 NaV1.7 通道对于神经性疼痛不是必需的。临床前研究几乎只测量诱发性疼痛，而大多数临床试验评估平均疼痛强度，而不区分诱发性疼痛和自发性疼痛。与临床上使用的重复给药不同，几乎所有的临床前研究都给出了单剂量的药物，因此排除了临床前数据证明是否发生耐受性或其他缓慢过程。总之，NaV1.7 选择性抑制剂的临床前测试与临床测试的一致性不佳。除了在疼痛文献中已经引起广泛关注的问题外，我们的结果还强调了治疗方案和疼痛模型的选择作为需要改进的领域。