INSERM U 987, CETD, Hôpital Ambroise Paré, APHP, 92100 Boulogne-Billancourt, France.
UVSQ, Paris Saclay University, 78000 Versailles, France.
Brain. 2021 Dec 16;144(11):3328-3339. doi: 10.1093/brain/awab208.
Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile.
重复经颅磁刺激 (rTMS) 已被提议用于治疗神经性疼痛，但证据质量仍然较低。我们旨在评估在 25 周内对原发性运动皮层 (M1) 或背外侧前额叶皮层 (DLPFC) 进行神经导航 rTMS 治疗神经性疼痛的疗效和安全性。我们在法国的四个门诊进行了一项随机、双盲、安慰剂对照试验。年龄在 18-75 岁之间的患有周围神经性疼痛的患者按 1:1 的比例随机分为 M1 或 DLPFC-rTMS 组，并按 2:1 的比例再次随机分为活性或假刺激-rTMS 组 (10 Hz，3000 脉冲/session，22 周内 15 次)。患者和研究者对治疗分配均不知情。主要终点是在 25 周的过程中，比较活性 M1-rTMS、活性 DLPFC-rTMS 和假刺激-rTMS 对平均疼痛强度（从 0 无疼痛到 10 最大疼痛）的变化，使用混合模型重复测量分析在接受至少一次 rTMS 治疗的患者中（改良意向治疗人群）。次要结局包括其他疼痛强度和缓解测量、疼痛的感觉和情感维度、疼痛质量、自我报告的疼痛强度和疲劳（患者日记）、患者和临床医生对变化的总体印象 (PGIC、CGIC)、生活质量、睡眠、情绪和灾难化。这项研究在 ClinicalTrials.gov 注册，编号为 NCT02010281。共有 152 名患者被随机分组，149 名患者接受了治疗（49 名 M1；52 名 DLPFC；48 名假刺激）。与假刺激相比，M1-rTMS 降低了疼痛强度（组×会话交互作用的估计值：-0.048±0.02；95%CI：-0.09 至 -0.01；P=0.01）。与假刺激相比，DLPFC-rTMS 并没有更好的效果（估计值：-0.003±0.01；95%CI：-0.04 至 0.03，P=0.9）。M1-rRMS，而不是 DLPFC-rTMS，在疼痛缓解、疼痛的感觉维度、自我报告的疼痛强度和疲劳、PGIC 和 CGIC 方面也优于假刺激。由于所有组在时间上都有相似的改善，因此对疼痛质量、情绪、睡眠和生活质量没有影响。头痛是最常见的副作用，分别发生在 M1、DLPFC 和假刺激组的 17（34.7%）、23（44.2%）和 13（27.1%）名患者中（P=0.2）。我们的结果支持 M1-rTMS 对周围神经性疼痛的临床相关性，而不是 DLPFC-rTMS 的相关性，其安全性良好。
