【晨读】有创性电神经调节治疗疼痛性糖尿病神经病变的系统评价和荟萃分析（一）

 英语晨读 ·

山东省立医院疼痛科英语晨读已经坚持10余年的时间了，每天交班前15分钟都会精选一篇英文文献进行阅读和翻译。一是可以保持工作后的英语阅读习惯，二是可以学习前沿的疼痛相关知识。我们会将晨读内容与大家分享，助力疼痛学习。

本次文献选自Raghu ALB, Parker T, Aziz TZ, et al. Invasive Electrical Neuromodulation for the Treatment of Painful Diabetic Neuropathy: Systematic Review and Meta-Analysis. Neuromodulation, 2021; 24: 13–21。本次学习由谢珺田副主任医师主讲。

ABSTRACT

Objectives: Neuromodulation is a treatment option for people suffering from painful diabetic neuropathy (PDN) unresponsive to conventional pharmacotherapy. We systematically examined the pain outcomes of patients with PDN receiving any type of invasive neuromodulation for treatment of neuropathic pain.

Materials and Methods: MEDLINE and Embase were searched through 10 January 2020, without language restriction. All study types were included. Two reviewers independently screened publications and extracted data. Quantitative meta-analysis was performed with pain scores converted to a standard 100-point scale. Randomized controlled trial (RCT) scores were pooled using the inverse variance method and expressed as mean differences.

Results: RCTs of tonic spinal cord stimulation (t-SCS) showed greater pain improvement than best medical therapy at six months (intention-to-treat: 38/100, 95% CI: 29–47). By per-protocol analysis, case series of t-SCS and dorsal root ganglion stimulation (DRGS) showed improvement by 56 (95% CI: 39–73) and 55 (22–87), respectively, at 12 months. For t-SCS, the rate of failing a therapeutic stimulation trial was 16%, the risk of infection was 4%, and the rate of lead problems requiring surgery to resolve was 4% per year of follow-up. High-frequency SCS and burst SCS both showed efficacy, with few patients studied.

Conclusion: Efficacious, lasting and safe surgical pain management options are available to diabetic patients suffering from PDN. Tonic-SCS is the established standard of treatment; however, other SCS paradigms and DRGS are emerging as promising treatments offering comparable pain benefits, but with few cases published to date. Randomized controlled trials are ongoing to assess their relative merits.

Keywords: Chronic pain, meta-analysis, neuropathic pain, neurostimulation, peripheral neuropathy, SCS

摘要

目的：神经调节是对传统药物治疗无效的疼痛性糖尿病神经病变（PDN）患者的一种治疗选择。我们系统地研究了接受各种不同类型的有创性神经调节治疗PDN患者的疼痛缓解情况。

材料与方法：检索MEDLINE和Embase数据库，发表截止日期为2020年1月10日，无语言限制。包括所有研究方法。两位研究者独立筛选出版物并提取数据。采用连续变量量荟萃分析方法，将疼痛评分转换为标准的100分评估量表。随机对照试验（RCT）疼痛评分采用反向方差法汇总分析，结果以平均差值表示。

结果：6个月时，强直性脊髓电刺激（t-SCS）的随机对照试验显示疼痛改善程度优于最佳药物治疗（意向治疗：38/100，95%可信区间：29-47）。区分不同治疗方式进行独立分析，12个月时t-SCS和背根神经节刺激（DRGS）的病例组分别改善56（95%CI:39-73）和55（22-87）。对于t-SCS，治疗性刺激试验失败率为16%，感染风险为4%，需要手术解决的电极故障发生率为每年4%。高频SCS和爆发SCS均显示有效，但纳入研究的病例数很少。

结论：对糖尿病合并PDN患者进行有效、持久、安全的手术治疗是可行的。强直性SCS是公认的标准治疗模式；然而，其他SCS模式和背根节电刺激亦成为具有较高效价比的有希望的治疗方法，但迄今为止很少有病例报道发表。确切评估其优势的随机对照试验尚在研究之中。

关键词：慢性疼痛，荟萃分析，神经病理性疼痛， 神经调节，周围神经病变，脊髓电刺激

INTRODUCTION

Diabetic neuropathy is the most common peripheral neuropathy in the United States and globally. With the prevalence of diabetes in adults rising to 10.8% in the United States and 4.3% in the United Kingdom, improving the management of peripheral neuropathy has never been more important.

概述

糖尿病神经病变是美国和全球最常见的周围神经病变类型。随着美国和英国成人糖尿病患病率分别上升到10.8%和4.3%，改善周围神经病变的治疗变得前所未有的重要。

The principal pathology is a length-dependent neuropathy, estimated to affect around 30% of people with diabetes and more than half of those 60 years or older. It involves distal autonomic and sensory dysfunction, predominantly affecting the feet, but often progressing proximally and/or involving the upper limbs as time passes. The process initially affects small fibers (protopathic, autonomic: C, Aδ) and progresses to involve large fibers (epicritic: Aα, Aβ) to generate a classic pan-modal pathological pattern. Clinically, damage can lead to symptoms of neuropathic pain, paraesthesia, and numbness, which can progress to further complications such as neuropathic arthropathy and ulceration.

主要的病理变化是一种病程相关性神经病变，估计约有30%的糖尿病患者和超过一半的60岁以上的人受到影响。它涉及远端自主神经和感觉功能障碍，主要影响足部，但随着时间的推移，通常进展到近端和/或累及上肢。这一过程最初影响细纤维（本体感觉、自主神经：C纤维，Aδ纤维），并逐渐累及大纤维（精细感觉：Aα，Aβ），形成典型的肢体远端末梢神经病变。临床上，损伤可导致神经病理性疼痛、感觉异常和麻木症状，进而发展为神经性关节病和溃疡等并发症。

Painful diabetic neuropathy (PDN) affects around 26% of people with diabetes, resulting in significant physical and social morbidity and impairing quality of life. PDN has escaped categorization to specific pathomorphological findings, however, neurophysiologically is likely to involve dysfunctional processing at multiple levels including the dorsal root ganglia (DRG), ventrolateral periaqueductal gray, and autonomic nervous system.

疼痛性糖尿病神经病变（PDN）累及约26%的糖尿病患者，导致严重的生理残疾和社交障碍，生活质量明显下降。PDN尚缺乏特定类型的病理形态变化，然而，神经生理功能障碍可累及多个环节，包括背根神经节（DRG）、腹外侧导水管周围灰质和自主神经系统。

Patients are typically managed with anticonvulsant analgesic medications such as gabapentin or pregabalin and/or antidepressants such as amitriptyline or duloxetine. However, around 50% of patients are refractory, resulting in prescriptions of opioid analgesics and patients seeking alternative therapies.

患者通常使用抗惊厥镇痛药物（如加巴喷丁或普瑞巴林）和/或抗抑郁药物（如阿米替林或度洛西汀）进行治疗。然而，大约50%的患者难以奏效，需要开具阿片类镇痛药及寻求其它替代疗法。

Noninvasive and minimally invasive neuromodulation techniques may benefit some patients, but their analgesia is very limited and of short duration. Invasive neuromodulation with an implanted stimulator device may offer longer-term relief to refractory patients with poorly controlled pain. Given the prevalence of PDN, it has the potential to be one of the commonest indications for such treatments. The neurophysiology of chronic stimulation and how it achieves analgesia is poorly understood. The classic treatment, tonic spinal cord stimulation (t-SCS), involves regular electrical pulses (50 Hz) delivered to the dorsal columns through epidural electrodes. Tonic stimulation evokes paraesthesia in the area of pain, traditionally thought to function through a gate control mechanism to compete out pain signals. However, multiple stimulation methods that can achieve analgesia, but without generating paraesthesia, are now available, casting doubt on these long-held beliefs. The field continues to evolve. New stimulation methods including burst spinal cord stimulation (b-SCS), high-frequency spinal cord stimulation (HF-SCS), and dorsal root ganglion stimulation (DRGS), have all been shown to be highly effective as treatments for pain within the last decade.

无创和微创神经调节技术可以使一些患者受益，但其镇痛作用非常有限，持续时间亦较短暂。植入刺激器的侵入性神经调节可以为疼痛控制不佳的难治性患者提供长期缓解。鉴于PDN的较高的罹患率，它有可能成为此类治疗技术最常用的适应证之一。长期电刺激治疗的神经生理改变及其镇痛机制，目前还知之甚少。经典的刺激模式，强直性脊髓刺激（t-SCS），作用原理都是通过硬膜外电极将电脉冲（50hz）信号传递到脊髓背柱。强直刺激引起疼痛区域的感觉异常，传统上认为是通过门控制机制阻断疼痛信号传导引起的。然而，目前采用的一些新型刺激方法，既可以达到镇痛作用，又不产生麻木不适，对传统的门控镇痛机制理论提出了挑战。这些刺激治疗模式还在继续发展之中。在过去的十年里，新的刺激方法包括突发性脊髓刺激（b-SCS）、高频脊髓刺激（HF-SCS）和背根神经节刺激（DRGS）都被证明是非常有效的电刺激治疗模式。

There is growing evidence to suggest that invasive neuromodulation may be an effective therapy for patients with debilitating PDN. We therefore performed a systematic review and meta-analysis of all original published literature on the outcomes of invasive neuromodulation for the treatment of PDN.

有越来越多的证据表明，有创性神经调节是一种有效改善PDN患者症状的治疗技术。因此，我们对所有关于有创性神经调节治疗PDN的原始文献进行了系统回顾和荟萃分析。