An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee
An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee
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DOI：
10.1016/j.pain.2012.04.020
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发表时间：
2012-09-01
期刊：
影响因子：
7.4
通讯作者：
Young, Tim
中科院分区：
文献类型：
--
作者：
Huggins, John P.;Smart, Trevor S.;Young, Tim
在一项随机安慰剂和活性对照临床试验中，研究了PF-04457845（一种强效选择性脂肪酸酰胺水解酶-1（FAAH 1）抑制剂）对膝关节骨关节炎所致疼痛的影响。试验包括2个阶段（间隔2周洗脱期），包括1周洗脱期和2周双盲治疗。患者在整个洗脱期和洗脱期接受单盲安慰剂。患者随机接受4 mg q.d. PF-04457845，随后安慰剂（反之亦然）或500 mg b.i.d.萘普生，然后是安慰剂（或反之亦然）。主要终点是西安大略和麦克马斯特大学骨关节炎指数（WOMAC）疼痛评分。该试验基于PF-04457845优于或劣于标准治疗的可能性（认为与安慰剂相比，WOMAC疼痛评分降低1.8），制定了预定义的决策规则。共74例患者被随机分配至4个治疗序列之一。PF-04457845与安慰剂相比，WOMAC疼痛评分的平均差异（80%置信区间）为0.04（-0.63至0.71），萘普生为-1.13（-1.79至-0.47），这表明虽然萘普生似乎有效，但PF-04457845与安慰剂没有区别。在中期分析时因无效而停止研究。PF-04457845使FAAH活性降低>96%，并显著增加4种内源性底物（脂肪酸酰胺）。PF-04457845在骨关节炎患者中耐受性良好，无大麻素类不良事件的证据。FAAH 1抑制在人体中缺乏镇痛作用与来自动物模型的数据相反。物种之间的这种明显脱节需要进一步研究。(C)2012年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
The effect of PF-04457845, a potent and selective fatty acid amide hydrolase-1 (FAAH1) inhibitor, on pain due to osteoarthritis of the knee was investigated in a randomised placebo and active-controlled clinical trial. The trial involved 2 periods (separated by a 2-week washout) consisting of a 1-week wash-in phase followed by 2 weeks double-blind treatment. Patients received single-blind placebo throughout the wash-in and washout periods. Patients were randomised to receive either 4 mg q.d. PF-04457845 followed by placebo (or vice versa), or 500 mg b.i.d. naproxen followed by placebo (or vice versa). The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. The trial had predefined decision rules based on likelihood that PF-04457845 was better or worse than the standard of care (considered to be a 1.8 reduction in WOMAC pain score compared to placebo). A total of 74 patients were randomised to 1 of 4 treatment sequences. The mean differences (80% confidence intervals) from placebo in WOMAC pain score were 0.04 (-0.63 to 0.71) for PF-04457845 and -1.13 (-1.79 to -0.47) for naproxen, indicating that whilst naproxen seemed efficacious, PF-04457845 was not differentiated from placebo. The study was stopped at the interim analysis for futility. PF-04457845 decreased FAAH activity by >96% and substantially increased 4 endogenous substrates (fatty acid amides). PF-04457845 was well tolerated in osteoarthritis patients, and there was no evidence of cannabinoid-type adverse events. The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models. This apparent disconnect between species needs further study. (C) 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.