A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain
A randomized, phase 2 study investigating TRV130, a biased ligand of the μ-opioid receptor, for the intravenous treatment of acute pain
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DOI：
10.1097/j.pain.0000000000000363
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发表时间：
2016-01-01
期刊：
影响因子：
7.4
通讯作者：
Skobieranda, Franck
中科院分区：
文献类型：
--
作者：
Viscusi, Eugene R.;Webster, Lynn;Skobieranda, Franck
常规阿片类药物的疗效可能受到不良事件（AE）的限制。TRV 130是一种结构新颖的m-阿片受体的偏向性配体，其激活G蛋白信号传导而几乎没有β-抑制蛋白募集。在这项2期、随机、安慰剂和活性对照研究中，我们研究了TRV 130在拇囊炎切除术后急性疼痛中的疗效和耐受性。我们采用了一种适应性研究设计，其中144例拇囊炎切除术后出现中度至重度急性疼痛的患者在试验阶段随机接受双盲TRV 130、安慰剂或吗啡。初步分析后，195例患者随机接受双模拟TRV 130 0.5、1、2或3 mg每3小时（q3 h）;安慰剂;或吗啡4 mg q4 h静脉注射。主要终点是48小时治疗期间数字评定量表疼痛强度的时间加权平均变化。次要终点包括秒表和疼痛缓解的分类评估。还评估了安全性和耐受性。TRV 130 2和3 mg q3 h和吗啡4 mg q4 h在48小时内产生的疼痛强度的平均降低在统计学上大于安慰剂（P < 0.005）。在第一次给药后，2和3 mg的TRV 130产生比吗啡显著更大的分类疼痛缓解（P < 0.005），在5分钟内发生有意义的疼痛缓解。TRV 130未产生严重AE，耐受性与吗啡相似。这些结果表明，TRV 130在中度至重度急性疼痛中迅速产生深刻的镇痛作用，表明G蛋白偏向的m-阿片受体活化是开发新型镇痛药的有希望的靶点。
Efficacy of conventional opioids can be limited by adverse events (AEs). TRV130 is a structurally novel biased ligand of the m-opioid receptor that activates G protein signaling with little beta-arrestin recruitment. In this phase 2, randomized, placebo-and active-controlled study, we investigated the efficacy and tolerability of TRV130 in acute pain after bunionectomy. We used an adaptive study design in which 144 patients experiencing moderate-to-severe acute pain after bunionectomy were randomized to receive double-blind TRV130, placebo, or morphine in a pilot phase. After pilot phase analysis, 195 patients were randomized to receive double-dummy TRV130 0.5, 1, 2, or 3 mg every 3 hours (q3h); placebo; or morphine 4 mg q4h intravenously. The primary end point was the time-weighted average change in numeric rating scale pain intensity over the 48-hour treatment period. Secondary end points included stopwatch and categorical assessments of pain relief. Safety and tolerability were also assessed. TRV130 2 and 3 mg q3h, and morphine 4 mg q4h produced statistically greater mean reductions in pain intensity than placebo over 48 hours (P < 0.005). TRV130 at 2 and 3 mg produced significantly greater categorical pain relief than morphine (P < 0.005) after the first dose, with meaningful pain relief occurring in under 5 minutes. TRV130 produced no serious AEs, with tolerability similar to morphine. These results demonstrate that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased m-opioid receptor activation is a promising target for development of novel analgesics.