Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College, London, UK.
Eur J Pain. 2011 Nov;15(10):1040-8. doi: 10.1016/j.ejpain.2011.04.005. Epub 2011 May 14.
Current treatments of neuropathic pain arising from conditions such as nerve injury/compression are only partially effective, and limited in their use by side-effects. p38 mitogen-activated protein kinase (MAPK) is involved in the regulation and synthesis of inflammatory mediators, and is the target for a novel class of cytokine-suppressive anti-inflammatory drugs. p38 inhibitors may reduce neuronal sensitisation in preclinical models of neuropathic pain, particularly where there is a substantial inflammatory component. An exploratory, multicentre, double-blind, placebo-controlled, two-period, cross-over trial was undertaken to evaluate the effect of dilmapimod (SB-681323), a selective p38 MAPK inhibitor, on neuropathic pain symptoms and signs. Fifty patients with nerve trauma, radiculopathy or carpal tunnel syndrome were randomised; 43 patients completed the study. Eligible patients received oral dilmapimod and placebo twice daily for 2 weeks, with an intervening washout period of 2-4 weeks. Subjects attended weekly for efficacy and safety assessments, which included evaluation of daily and current pain intensity using an 11-point numerical rating scale (NRS), quantitative sensory testing, allodynia and global impression of change. There was a statistically significant reduction in the primary endpoint of average daily pain score during the second week of treatment among patients treated with dilmapimod (15 mg/day) compared to placebo using NRS [0.80; 95% CI (0.28, 1.33); p=0.0034]. A similar trend for effect was seen in some secondary endpoints. Dilmapimod was well tolerated, with no clinically relevant safety findings. p38 MAPK inhibitors merit further evaluation for neuropathic pain in larger clinical trials, particularly for clinically meaningful analgesic effect size.
目前，针对神经损伤/压迫等疾病引起的神经性疼痛的治疗方法仅部分有效，并且由于副作用限制了其使用。p38 有丝分裂原活化蛋白激酶（MAPK）参与炎症介质的调节和合成，是一类新型细胞因子抑制性抗炎药物的作用靶点。p38 抑制剂可能会减少神经性疼痛的临床前模型中的神经元敏化，尤其是在存在大量炎症成分的情况下。进行了一项探索性、多中心、双盲、安慰剂对照、两期交叉试验，以评估选择性 p38 MAPK 抑制剂（SB-681323，即 dilmapimod）对神经性疼痛症状和体征的影响。将 50 名患有神经创伤、神经根病或腕管综合征的患者随机分组；43 名患者完成了该研究。符合条件的患者接受每日两次口服 dilmapimod 和安慰剂治疗，为期 2 周，其间有 2-4 周的洗脱期。患者每周进行一次疗效和安全性评估，包括使用 11 点数字评分量表（NRS）评估每日和当前疼痛强度、定量感觉测试、感觉异常和总体变化印象。与安慰剂相比，接受 dilmapimod（15mg/天）治疗的患者在治疗的第二周，NRS 评估的平均每日疼痛评分的主要终点显著降低[0.80；95%置信区间（0.28，1.33）；p=0.0034]。一些次要终点也显示出类似的效果趋势。dilmapimod 耐受性良好，无临床相关安全性发现。p38 MAPK 抑制剂在更大的临床试验中值得进一步评估神经性疼痛，特别是在具有临床意义的镇痛效果大小方面。
