Ostenfeld Thor, Krishen Alok, Lai Robert Y, Bullman Jonathan, Green Joanne, Anand Praveen, Scholz Joachim, Kelly Madeline
*Neurosciences Discovery Medicine Unit ‡Clinical Pharmacokinetics, Modelling and Simulation §Clinical Pharmacology Discovery Medicine #Neurosciences Medicines Development Centre, GlaxoSmithKline R&D, Harlow ∥Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College, London, UK †Quantitative Data Sciences, GlaxoSmithKline R&D, Research Triangle Park, NC ¶Departments of Anesthesiology and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY.
Clin J Pain. 2015 Apr;31(4):283-93. doi: 10.1097/AJP.0000000000000122.
Preclinical studies have demonstrated involvement of p38 mitogen-activated protein kinase signaling pathways in the development of persistent pain after peripheral nerve injury. A double-blind, randomized, placebo-controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38α/β inhibitor, in patients with chronic neuropathic pain due to lumbosacral radiculopathy.
A total of 144 patients with at least moderate baseline pain intensity (average daily score of ≥4 on an 11-point pain intensity numeric rating scale) were randomized to receive losmapimod, 7.5 mg bid orally or placebo. All patients underwent a blinded placebo run-in period for 7 days before receiving losmapimod/placebo for 28 days. Efficacy and safety evaluations were undertaken weekly.
The adjusted mean treatment difference for the change from baseline to week 4 in numeric rating scale was -0.36 U (95% confidence interval, -0.84, 0.13; P=0.149) in favor of losmapimod over placebo; this was not considered clinically meaningful. Statistically significant differences in favor of losmapimod were observed, however, for several secondary endpoints of emotional, physical, and social functioning: Oswestry Disability Index; Profile of Mood States total score; Short-Form 36 Health Survey physical functioning, bodily pain, general health, role emotional, social functioning, and vitality domains; and Short-Form 36 physical, and mental components. There were no unexpected findings related to safety or tolerability following treatment with losmapimod.
Losmapimod could not be differentiated from placebo in terms of analgesia. The lack of response could reflect insufficient losmapimod levels in the spinal cord or differences between lumbosacral radiculopathy and animal models of neuropathic pain.
临床前研究已证明p38丝裂原活化蛋白激酶信号通路参与外周神经损伤后持续性疼痛的发展。开展了一项双盲、随机、安慰剂对照研究，以评估新型p38α/β抑制剂洛索匹莫德（GW856553）对腰骶神经根病所致慢性神经性疼痛患者的镇痛效果。
总共144例基线疼痛强度至少为中度（11点疼痛强度数字评定量表上平均每日评分≥4分）的患者被随机分组，接受口服洛索匹莫德7.5mg每日两次或安慰剂治疗。所有患者在接受洛索匹莫德/安慰剂治疗28天之前，先进行为期7天的双盲安慰剂导入期。每周进行疗效和安全性评估。
数字评定量表上从基线到第4周变化的调整后平均治疗差异为-0.36单位（95%置信区间，-0.84，0.13；P=0.149），表明洛索匹莫德优于安慰剂；但这在临床上不具有意义。然而，在情绪、身体和社会功能的几个次要终点方面观察到了有利于洛索匹莫德的统计学显著差异：Oswestry功能障碍指数；情绪状态剖面图总分；简明健康调查36项身体功能、身体疼痛、总体健康、角色情绪、社会功能和活力领域；以及简明健康调查36项身体和心理成分。洛索匹莫德治疗后未发现与安全性或耐受性相关的意外发现。
在镇痛方面，洛索匹莫德与安慰剂无法区分。缺乏反应可能反映脊髓中洛索匹莫德水平不足，或腰骶神经根病与神经性疼痛动物模型之间的差异。
