Gilron Ian, Xiao Maggie Z X, Carley Meg, Salter Michael W, Hutchinson Mark R, Moulin Dwight E, Moore R Andrew, Ross-White Amanda
Department of Anesthesiology & Perioperative Medicine, Kingston Health Sciences Centre, Queen's University, Kingston, ON, Canada.
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, ON, Canada.
Pain. 2025 May 1;166(5):1030-1049. doi: 10.1097/j.pain.0000000000003447. Epub 2024 Oct 15.
Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other comparators. The primary outcomes included validated participant-reported measures of pain intensity or relief and, in studies of opioid administration, measures of opioid consumption and/or opioid-related adverse effects. Twenty-six trials (2132 participants) of glial modulators (12 minocycline, 11 pentoxifylline, and 3 ibudilast) were included. Because of clinical heterogeneity related to study drug, participant population, outcome measures, and trial design, no meta-analysis was possible. Only 6 trials reported a positive effect of the treatment (pentoxifylline-4 trials; minocycline-2 trials), whereas 11 trials reported mixed results and 9 trials reported no effect. This review does not provide convincing evidence of efficacy of current pharmacological targets of nervous system glial function for pain treatment or prevention. However, in light of ample preclinical evidence of the importance of neuroimmune signalling and glial functions in pain pathophysiology, continued strategic human research is anticipated to identify (1) drugs with maximal activity as selectively targeted glial modulators, (2) the necessary timing and duration of pharmacological glial modulation needed for pain prevention or treatment for specific injuries or pain conditions, and (3) the best design of future clinical trials of glial-targeted drugs for pain treatment and/or prevention.
临床前研究支持神经系统胶质细胞在疼痛病理生理学中起关键作用。本系统评价对用于预防或治疗疼痛的潜在胶质细胞调节药物的人体试验进行了预定义的检索策略和方案注册。我们检索了比较假定的胶质细胞调节药物与安慰剂或其他对照的英文随机双盲试验。主要结局包括经过验证的参与者报告的疼痛强度或缓解程度测量指标，以及在阿片类药物给药研究中，阿片类药物消耗量和/或阿片类药物相关不良反应的测量指标。纳入了26项胶质细胞调节剂试验（2132名参与者）（12项米诺环素试验、11项己酮可可碱试验和3项异丁司特试验）。由于与研究药物、参与者群体、结局测量指标和试验设计相关的临床异质性，无法进行荟萃分析。只有6项试验报告了治疗的积极效果（己酮可可碱4项试验；米诺环素2项试验），而11项试验报告了混合结果，9项试验报告无效果。本评价未提供令人信服的证据表明目前针对神经系统胶质细胞功能的药理学靶点对疼痛治疗或预防有效。然而，鉴于神经免疫信号传导和胶质细胞功能在疼痛病理生理学中的重要性有充分的临床前证据，预计持续的战略性人体研究将确定：（1）作为选择性靶向胶质细胞调节剂具有最大活性的药物；（2）针对特定损伤或疼痛状况预防或治疗疼痛所需的药理学胶质细胞调节的必要时机和持续时间；（3）未来针对疼痛治疗和/或预防的胶质细胞靶向药物临床试验的最佳设计。
