UCSF Pain Clinical Research Center, University of California, San Francisco, CA, USA Abbott Laboratories, 200 Abbott Park Rd., Abbott Park, IL, USA University of Wisconsin, Madison, WI, USA.
Pain. 2009 Dec;146(3):245-252. doi: 10.1016/j.pain.2009.06.013. Epub 2009 Jul 24.
ABT-594 is a neuronal nicotinic acetylcholine receptor (NNR) agonist that exhibits potent analgesic activity in preclinical models of acute, chronic, and neuropathic pain. The purpose of this phase 2, randomized, multicenter, double-blind, placebo-controlled study was to evaluate the safety and analgesic efficacy of ABT-594 in patients with diabetic peripheral neuropathic pain (DPNP). A total of 266 DPNP patients were randomized 1:1:1:1 to receive placebo, ABT-594 150 microg BID, ABT-594 225 microg BID, or ABT-594 300 microg BID. Patients were titrated to a fixed-dose of ABT-594 over 7 days and remained at this dose for another 6 weeks. Compared to placebo, all three ABT-594 treatment groups showed significantly greater decreases on the average diary-based 0-10 Pain Rating Scale (PRS) score from baseline to final evaluation, the primary efficacy measure (placebo, -1.1; 150 microg BID, -1.9; 225 microg BID, -1.9; 300 microg BID, -2.0). The proportion of patients achieving at least a 50% improvement in the average diary-based PRS was greater in all three ABT-594 treatment groups. However, adverse event (AE) dropout rates were significantly higher in all three ABT-594 treatment groups (28% for 150 microg BID, 46% for 225 microg BID, and 66% for 300 microg BID) than for the placebo group (9%). Consistent with the expected side-effect profile of NNR agonists, the most frequently reported AEs were nausea, dizziness, vomiting, abnormal dreams, and asthenia. This study establishes proof of concept for NNR agonists as a new class of compounds for treating neuropathic pain.
ABT-594 是一种神经元烟碱型乙酰胆碱受体（NNR）激动剂，在急性、慢性和神经性疼痛的临床前模型中表现出强大的镇痛活性。这项 2 期、随机、多中心、双盲、安慰剂对照研究的目的是评估 ABT-594 在糖尿病周围神经病理性疼痛（DPNP）患者中的安全性和镇痛疗效。共有 266 名 DPNP 患者按 1:1:1:1 的比例随机分配至安慰剂组、ABT-594 150μg，每日两次（BID）组、ABT-594 225μg，BID 组或 ABT-594 300μg，BID 组。患者在 7 天内滴定至固定剂量的 ABT-594，并在接下来的 6 周内保持该剂量。与安慰剂相比，所有三种 ABT-594 治疗组在从基线到最终评估的平均基于日记的 0-10 疼痛评分量表（PRS）评分上均显示出显著更大的降低，这是主要疗效测量指标（安慰剂组，-1.1；150μg BID 组，-1.9；225μg BID 组，-1.9；300μg BID 组，-2.0）。在所有三种 ABT-594 治疗组中，达到平均基于日记的 PRS 至少改善 50%的患者比例更高。然而，所有三种 ABT-594 治疗组的不良事件（AE）退出率明显高于安慰剂组（150μg BID 组为 28%，225μg BID 组为 46%，300μg BID 组为 66%）。与 NNR 激动剂的预期副作用特征一致，最常报告的 AE 是恶心、头晕、呕吐、异常梦境和乏力。这项研究确立了 NNR 激动剂作为治疗神经性疼痛的一类新化合物的概念验证。
