糖尿病神经病变的系统评价和荟萃分析（三）

 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。

Data Synthesis and Analysis

For RCTs, quantitative meta-analysis was performed on RevMan 5.3 (The Cochrane Collaboration), calculating mean difference using random effects modeling to compare best medical therapy (BMT) to neuromodulation for RCTs. Other studies were pooled for similar likelihood of bias and post-operative follow-up, then means and 95% CI calculated (z-distribution: n ≥ 30, t-distribution: n < 30) for improvement of pain from baseline. Otherwise, a narrative synthesis was carried out. For purposes of meta-analysis, 10-point scores were converted to 100-point scores, day pain scores were used when both day and night scores were reported, and peak pain scores were used when both background and peak scores were reported. Visual analogue scale (VAS), numerical rating scale (NRS), and pain severity scores from the brief pain inventory for diabetic peripheral neuropathy (BPI-DPN) were used. Authors were contacted when desired data were omitted. Distinction was made between intention to treat (ITT), modified-ITT (mITT), and per protocol analysis (PPA). There is no consensus definition of mITT. For the setting of invasive neuromodulation, we defined mITT as attempted analysis of everyone who received a permanent implant following trial stimulation. PPA is defined as attempted analysis of everyone with an implant at a given time point.

数据合成与整合分析

对于随机对照试验，定量荟萃分析于RevMan 5.3（Cochrane协作）网络 平台上进行，使用随机效应模型计算平均差，比较最佳药物治疗（best medical therapy，BMT）和神经调节的RCT治疗结果。其他研究合并后计算类似的或然比偏倚，再行术后随访，然后计算疼痛治疗结果的平均值和95%可信区间（z分布：n≥ 30，t分布：n<30）。另外，文献还记录了整合后的陈述部分。为了方便进行荟萃分析，将10分的分数一律转换为100分，白天和晚上的分数皆有记录时统一使用白天的疼痛分值，背景和峰值分数都有记录时统一使用峰值疼痛分数。视觉模拟量表（VAS）、数字评分量表（NRS）和糖尿病患者简明疼痛量表中的疼痛严重程度评分采用周围神经病变（BPI-DPN）。当缺失需要的数据时，我们联系了原作者。对于每个具体治疗方案（per-protocol analysis PPA）的意向治疗（intention to treat，ITT）、改良ITT（mITT）分别进行分析。对于改良ITT的定义没有一致尚未形成共识。针对有创性神经调节的特定情形，我们将mITT定义为在试验刺激后对接受永久性植入物的所有人对手术接受程度的意向分析。PPA的定义是在给定的时间点每个植入者对手术接受程度的意向分析。

RESULTS

The search strategy retrieved 180 and 456 results from MEDLINE and Embase, respectively (Fig. 1). Following deduplication, 480 abstracts were reviewed, with 72 publications proceeding to full-text evaluation. Thirty-two publications (including seven conference abstracts) remained after full-text screening (Supporting Information Table S2), including reports of t-SCS (n = 21), high-frequency spinal cord stimulation (hf-SCS) (n = 2), burst spinal cord stimulation (b-SCS) (n = 2), dorsal root ganglion stimulation (DRGS) (n = 5), deep brain stimulation (DBS) (n =1) and selective nerve root stimulation (n = 1). Among these, there was one erratum, and 13 single cases (Supporting Information Table S3 for summary). 17 publications were inappropriate for meta-analysis.

结果

按设定检索方法分别从MEDLINE和Embase中检索到文献180篇和456篇（图1）。在删除重复数据之后，对480篇摘要进行了审查，筛选出72篇文献进一步做全文评估。全文筛选后保留32篇文章（包括7篇会议摘要）（详细信息见表S2），主要刺激模式包括t-SCS（n=21）、高频电刺激（hf-SCS）（n=2）、爆发电刺激（b-SCS）（n=2）、背根神经节刺激（DRGS）（n=5），深部脑刺激（DBS）（n=1）和选择性神经根电刺激（n=1）。另外，还有一个勘误表，和13篇个案报道（详细信息见表S3摘要）。17篇文章不适合进行荟萃分析。

Meta-Analysis

Quantitative meta-analysis of t-SCS RCTs showed superiority to BMT at six-month follow-up by ITT (Fig. 2). Likewise, meta-analysis demonstrated significant improvement in pain from baseline at 6-and 12-month post-operative follow-up in t-SCS case series by mITT and PPA, respectively (Table 1). Long-term case follow-up demonstrates that clinical benefit appears to continue for many years (Fig. 3). DRGS showed significant pain improvement from baseline at 1-, 6- and 12-month follow-up by PPA (Table 1). Mean improvement was similar for DRGS and t-SCS by PPA, however very broad 95% CIs, due to the small number of patients, limit the comparison.

meta分析

随机对照试验ITT的定量meta分析结果显示，治疗后6个月随访，t-SCS优于BMT（图2）。同样，meta分析显示，在mITT和PPA分别对t-SCS病例系列进行术后6个月和12个月随访时，疼痛较基线水平有显著改善（表1）。长期的病例随访表明，临床受益似乎持续多年（图3）。在PPA随访1、6和12个月时，DRG显示疼痛较基线显著改善（表1）。PPA对DRGS和t-SCS的平均改善率相似，但由于患者数量较少，95%的顺式反应非常广泛，限制了比较。

Tonic Spinal Cord Stimulation

Controlled Trials

Two unblinded multicenter RCTs compare t-SCS to BMT at six months. Both reported outcomes on an intention-to-treat (ITT) basis. de Vos et al. (n = 40) used a primary outcome of >50% VAS reduction, and Slangen et al. (n = 19) used a broader primary outcome of “treatment success”: >50% pain relief during daytime or night-time on an NRS scale, or “(very) much improved” for pain and sleep on the patient global impression of change (PGIC) scale. de Vos et al. reported 93% having successful trial stimulation and implantation, with 60% having a > 50% VAS reduction compared to 5% for BMT (p < 0.001) at six months. Slangen et al. reported 77% having successful trial stimulation and implantation, with 59% having treatment success at six months, compared to 7% for BMT (p < 0.01). Follow-up of the successfully implanted patients (mITT) showed treatment success decrease from 76% at six months to 65% at 24 months.

张力型脊髓电刺激

对照研究

两项非盲法多中心随机对照研究比较了6个月时t-SCS和BMT的治疗结果。两个报道结果均以意向治疗（ITT）为主要指标。de Vos等人（n=40）将VAS减少>50%定义为有效，Slangen等人（n=19）定义的“治疗有效”则复杂得多：白天或夜间疼痛缓解NRS评分>50%，或患者总体印象变化（PGIC）量表的疼痛和睡眠（明显）改善。de Vos等报告，93%的患者成功地进行了试验刺激和植入手术，其中60%的患者在6个月时VAS降低>50%，而BMT患者的VAS降低为5%（p<0.001）。Slangen等报道，77%的患者成功地进行了试验刺激和植入手术，其中59%的患者在6个月时治疗有效，而BMT患者的治疗有效率为7%（p<0.01）。对成功植入患者（mITT）的随访显示，治疗有效率从6个月时的76%下降到24个月时的65%。

Prospective Case Series

Pluijms et al. (n = 15) reported 73% having successful trial stimulation and implantation. Treatment was successful (>50% pain relief) in 82% of patients at six months, 91, 55, and 64% at one, two, and three years follow-up (mITT). The cohorts of Slangen et al. (including cross-over patients from medical arm) and Pluijms et al. (n = 48) have combined longer-term follow-up, following 83% trial success. Treatment success was achieved in 87, 71, 77, 67, and 55% at one, two, three, four, and five years follow-up (PPA). At five years, 80% of patients implanted were still using their device. Tesafye et al. (n = 10) reported eight patients undergoing permanent implantation after trial, all reporting >50% relief during active stimulation. Peak pain improved from a baseline mean VAS of 64.5 (SD = 12.2) to 35.6 (SD = 32.6) at six months, while 72.3 (SD = 15.5) with stimulation off. VAS was 27 (SD = 22.5, n = 6) at 3.3 years and 42.3 (SD = 11.3, n = 4) at 7.5 years (43). De Vos et al. (n = 11) reported 82% having successful trial stimulation (44). Implanted patients improved from 77.2 (SD = 9.4) to 34.4 (SD = 16.5), 22.8 (SD = 24.4) and 22.5 (SD = 19.8) at 6, 12, 30 months follow-up. Munteanu (n = 50) reports success rates of 85% at one year, 69% at two years, 75% at three years, and 55% at four years follow-up.

前瞻性病例报道

Pluijms等报道73%的患者（n=15）成功进行了试验刺激和植入手术，在6个月随访有效率（>50%的疼痛缓解）为82%，1年、2年、3年随访（mITT）分别为82%、91%、55%和64%中。Slangen等和Pluijms等合作的队列研究（n=48）（包括交叉至治疗组的患者）在83%的患者试验成功后结合了长期随访。在1年、2年、3年、4年和5年的随访（PPA）中，治疗有效率分别为87%、71%、77%、67%和55%。5年后，80%的植入患者仍在使用他们的设备。Tesafye等报道8名患者（n=10）在试验后接受永久性植入手术，所有8例患者在主动刺激期间疼痛缓解程度均>50%。6个月随访时，峰值疼痛从基线平均VAS的64.5（SD=12.2）降低至35.6（SD=32.6），而在停止刺激后升至72.3（SD=15.5）。3.3年随访时VAS为27（SD=22.5，n=6），7.5年时VAS为42.3（SD=11.3，n=4）。De Vos等报告道82%的患者（n=11）成功进行了试验刺激。第6、12、30个月随访时，接受植入手术患者疼痛VAS从77.2（SD=9.4）降低到34.4（SD=16.5）、22.8（SD=24.4）和22.5（SD=19.8）。Munteanu（n=50）报道1年的有效率为85%，2年的有效率为69%，3年的有效率为75%，4年的成功率为55%。

Quality of Life

One trial was significant for improvement of quality of life, with EQ-5D increasing by 11 with t-SCS and decreasing by four with BMT (p < 0.01). McGill Pain Questionnaire Quality of Life decreased by 8 for t-SCS and by 1 for BMT (p < 0.001) and satisfaction with treatment was significantly higher with t-SCS: 8 vs. 4/10 (p < 0.001). Another trial was not significant for t-SCS improving quality of life (EQ-5D) or perceived health (EQ-VAS, Medical Outcomes Study SF-36). Pluijms et al. also did not show improvement of quality of life (EQ-5D, SF-36) at six months, only the physical component of SF-36 at 12 months (p < 0.01) (mITT).

生活质量评分

其中1项研究显示生活质量改善有显著差异，t-SCS组EQ-5D增加11分，BMT组减低4分（p<0.01）。McGill疼痛问卷t-SCS患者的生活质量降低了8分，BMT患者的生活质量下降了1分（p<0.001），t-SCS患者对治疗的满意度显著提高：8/10比4/10（p<0.001）。另一项研究则显示t-SCS对于生活质量（EQ-5D）或感知健康（EQ-VAS，医学研究专用SF-36）的改善程度没有显著意义。Pluijms等在随访6个月时也没有显示出生活质量的改善（EQ-5D，SF-36），在12个月时只有SF-36的体能成分有所改善（p<0.01）（mITT）。