Department of Health Sciences, Centre for Health and Wellbeing Across the Lifecourse, Brunel University London, Uxbridge, UK.
Centre for Pain IMPACT, Neuroscience Research Australia, Sydney, Australia.
Cochrane Database Syst Rev. 2021 Dec 2;12(12):CD013756. doi: 10.1002/14651858.CD013756.pub2.
Implanted spinal neuromodulation (SNMD) techniques are used in the treatment of refractory chronic pain. They involve the implantation of electrodes around the spinal cord (spinal cord stimulation (SCS)) or dorsal root ganglion (dorsal root ganglion stimulation (DRGS)), and a pulse generator unit under the skin. Electrical stimulation is then used with the aim of reducing pain intensity.
To evaluate the efficacy, effectiveness, adverse events, and cost-effectiveness of implanted spinal neuromodulation interventions for people with chronic pain.
We searched CENTRAL, MEDLINE Ovid, Embase Ovid, Web of Science (ISI), Health Technology Assessments, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry from inception to September 2021 without language restrictions, searched the reference lists of included studies and contacted experts in the field.
We included randomised controlled trials (RCTs) comparing SNMD interventions with placebo (sham) stimulation, no treatment or usual care; or comparing SNMD interventions + another treatment versus that treatment alone. We included participants ≥ 18 years old with non-cancer and non-ischaemic pain of longer than three months duration. Primary outcomes were pain intensity and adverse events. Secondary outcomes were disability, analgesic medication use, health-related quality of life (HRQoL) and health economic outcomes.
Two review authors independently screened database searches to determine inclusion, extracted data and evaluated risk of bias for prespecified results using the Risk of Bias 2.0 tool. Outcomes were evaluated at short- (≤ one month), medium- four to eight months) and long-term (≥12 months). Where possible we conducted meta-analyses. We used the GRADE system to assess the certainty of evidence.
We included 15 unique published studies that randomised 908 participants, and 20 unique ongoing studies. All studies evaluated SCS. We found no eligible published studies of DRGS and no studies comparing SCS with no treatment or usual care. We rated all results evaluated as being at high risk of bias overall. For all comparisons and outcomes where we found evidence, we graded the certainty of the evidence as low or very low, downgraded due to limitations of studies, imprecision and in some cases, inconsistency. Active stimulation versus placebo SCS versus placebo (sham) Results were only available at short-term follow-up for this comparison. Pain intensity Six studies (N = 164) demonstrated a small effect in favour of SCS at short-term follow-up (0 to 100 scale, higher scores = worse pain, mean difference (MD) -8.73, 95% confidence interval (CI) -15.67 to -1.78, very low certainty). The point estimate falls below our predetermined threshold for a clinically important effect (≥10 points). No studies reported the proportion of participants experiencing 30% or 50% pain relief for this comparison. Adverse events (AEs) The quality and inconsistency of adverse event reporting in these studies precluded formal analysis. Active stimulation + other intervention versus other intervention alone SCS + other intervention versus other intervention alone (open-label studies) Pain intensity Mean difference Three studies (N = 303) demonstrated a potentially clinically important mean difference in favour of SCS of -37.41 at short term (95% CI -46.39 to -28.42, very low certainty), and medium-term follow-up (5 studies, 635 participants, MD -31.22 95% CI -47.34 to -15.10 low-certainty), and no clear evidence for an effect of SCS at long-term follow-up (1 study, 44 participants, MD -7 (95% CI -24.76 to 10.76, very low-certainty). Proportion of participants reporting ≥50% pain relief We found an effect in favour of SCS at short-term (2 studies, N = 249, RR 15.90, 95% CI 6.70 to 37.74, I 0% ; risk difference (RD) 0.65 (95% CI 0.57 to 0.74, very low certainty), medium term (5 studies, N = 597, RR 7.08, 95 %CI 3.40 to 14.71, I = 43%; RD 0.43, 95% CI 0.14 to 0.73, low-certainty evidence), and long term (1 study, N = 87, RR 15.15, 95% CI 2.11 to 108.91 ; RD 0.35, 95% CI 0.2 to 0.49, very low certainty) follow-up. Adverse events (AEs) Device related No studies specifically reported device-related adverse events at short-term follow-up. At medium-term follow-up, the incidence of lead failure/displacement (3 studies N = 330) ranged from 0.9 to 14% (RD 0.04, 95% CI -0.04 to 0.11, I 64%, very low certainty). The incidence of infection (4 studies, N = 548) ranged from 3 to 7% (RD 0.04, 95%CI 0.01, 0.07, I 0%, very low certainty). The incidence of reoperation/reimplantation (4 studies, N =5 48) ranged from 2% to 31% (RD 0.11, 95% CI 0.02 to 0.21, I 86%, very low certainty). One study (N = 44) reported a 55% incidence of lead failure/displacement (RD 0.55, 95% CI 0.35, 0 to 75, very low certainty), and a 94% incidence of reoperation/reimplantation (RD 0.94, 95% CI 0.80 to 1.07, very low certainty) at five-year follow-up. No studies provided data on infection rates at long-term follow-up. We found reports of some serious adverse events as a result of the intervention. These included autonomic neuropathy, prolonged hospitalisation, prolonged monoparesis, pulmonary oedema, wound infection, device extrusion and one death resulting from subdural haematoma. Other No studies reported the incidence of other adverse events at short-term follow-up. We found no clear evidence of a difference in otherAEs at medium-term (2 studies, N = 278, RD -0.05, 95% CI -0.16 to 0.06, I 0%) or long term (1 study, N = 100, RD -0.17, 95% CI -0.37 to 0.02) follow-up. Very limited evidence suggested that SCS increases healthcare costs. It was not clear whether SCS was cost-effective.
AUTHORS' CONCLUSIONS: We found very low-certainty evidence that SCS may not provide clinically important benefits on pain intensity compared to placebo stimulation. We found low- to very low-certainty evidence that SNMD interventions may provide clinically important benefits for pain intensity when added to conventional medical management or physical therapy. SCS is associated with complications including infection, electrode lead failure/migration and a need for reoperation/re-implantation. The level of certainty regarding the size of those risks is very low. SNMD may lead to serious adverse events, including death. We found no evidence to support or refute the use of DRGS for chronic pain.
植入式脊髓神经调节（SNMD）技术用于治疗难治性慢性疼痛。它们涉及在脊髓（脊髓刺激（SCS））或背根神经节（背根神经节刺激（DRGS））周围植入电极，以及一个皮下脉冲发生器单元。然后使用电刺激来减轻疼痛强度。
评估植入式脊髓神经调节干预措施治疗慢性疼痛的疗效、有效性、不良事件和成本效益。
我们检索了 CENTRAL、MEDLINE Ovid、Embase Ovid、Web of Science（ISI）、卫生技术评估、ClinicalTrials.gov 和世界卫生组织国际临床试验注册平台，检索时间截至 2021 年 9 月，无语言限制，检索了纳入研究的参考文献列表，并联系了该领域的专家。
我们纳入了比较 SNMD 干预与安慰剂（假刺激）、无治疗或常规护理；或比较 SNMD 干预+另一种治疗与单独该治疗的随机对照试验（RCT）。我们纳入了年龄≥18 岁、疼痛持续时间超过三个月的非癌症和非缺血性疼痛患者。主要结局是疼痛强度和不良事件。次要结局是残疾、镇痛药使用、健康相关生活质量（HRQoL）和健康经济学结局。
两位综述作者独立筛选数据库检索结果，以确定纳入标准，提取数据，并使用风险偏倚 2.0 工具评估预设结果的风险偏倚。在短期（≤1 个月）、中期（4 至 8 个月）和长期（≥12 个月）评估结果。在可能的情况下，我们进行了荟萃分析。我们使用 GRADE 系统评估证据的确定性。
我们纳入了 15 项已发表的研究，共纳入 908 名参与者，还有 20 项正在进行的研究。所有研究都评估了 SCS。我们没有发现符合条件的已发表的 DRGS 研究，也没有比较 SCS 与无治疗或常规护理的研究。我们发现所有结果的总体风险偏倚都很高。对于我们发现证据的所有比较和结局，我们都将证据的确定性评为低或非常低，降级的原因是研究的局限性、不精确性，以及在某些情况下的不一致性。
主动刺激与安慰剂 SCS 与安慰剂（假刺激）：只有短期随访的结果可用。疼痛强度：六项研究（N=164）表明 SCS 在短期随访时有较小的效果（0 到 100 分，分数越高表示疼痛越严重，平均差异（MD）-8.73，95%置信区间（CI）-15.67 至-1.78，非常低的确定性）。该点估计值低于我们预定的有临床意义的效果（≥10 分）。没有研究报告该比较的 30%或 50%疼痛缓解的参与者比例。不良事件（AE）：由于这些研究中不良事件报告的质量和不一致性，我们无法进行正式分析。
主动刺激+其他干预与其他干预单独 SCS+其他干预与其他干预单独（开放标签研究）：疼痛强度：三项研究（N=303）表明 SCS 在短期随访时有潜在的有临床意义的平均差异，有利于 SCS 的为-37.41（95%CI-46.39 至-28.42，非常低的确定性），以及中短期随访（5 项研究，635 名参与者，MD-31.22，95%CI-47.34 至-15.10，低确定性），以及长期随访（1 项研究，44 名参与者，MD-7，95%CI-24.76 至 10.76，非常低的确定性）。报告≥50%疼痛缓解的参与者比例：我们发现 SCS 在短期随访时有效果（两项研究，N=249，RR 15.90，95%CI 6.70 至 37.74，I 0%；风险差异（RD）0.65，95%CI 0.57 至 0.74，非常低的确定性）、中期随访（5 项研究，N=597，RR 7.08，95%CI 3.40 至 14.71，I=43%；RD 0.43，95%CI 0.14 至 0.73，低确定性证据）和长期随访（1 项研究，N=87，RR 15.15，95%CI 2.11 至 108.91；RD 0.35，95%CI 0.2 至 0.49，非常低的确定性）。不良事件（AE）：设备相关：没有研究在短期随访时专门报告与设备相关的不良事件。在中期随访时，导线故障/移位的发生率（三项研究，N=330）为 0.9%至 14%（RD 0.04，95%CI-0.04 至 0.11，I 64%，非常低的确定性）。感染发生率（四项研究，N=548）为 3%至 7%（RD 0.04，95%CI 0.01 至 0.07，I 0%，非常低的确定性）。再手术/重新植入的发生率（四项研究，N=548）为 2%至 31%（RD 0.11，95%CI 0.02 至 0.21，I 86%，非常低的确定性）。一项研究（N=44）报告了 55%的导线故障/移位发生率（RD 0.55，95%CI 0.35 至 0 至 75，非常低的确定性）和 94%的再手术/重新植入率（RD 0.94，95%CI 0.80 至 1.07，非常低的确定性）在五年随访时。没有研究提供长期随访时感染率的数据。我们发现了一些作为干预结果的严重不良事件的报告。这些包括自主神经病、延长住院时间、延长单瘫、肺水肿、伤口感染、器械脱出和 1 例因硬膜下血肿导致的死亡。其他：没有研究报告短期随访的其他不良事件发生率。我们发现中短期随访（两项研究，N=278，RD-0.05，95%CI-0.16 至 0.06，I 0%）或长期随访（一项研究，N=100，RD-0.17，95%CI-0.37 至 0.02）的其他不良事件没有明显差异。非常有限的证据表明 SCS 增加了医疗成本。目前尚不清楚 SCS 是否具有成本效益。
我们发现 SCS 与安慰剂刺激相比，可能不会提供有临床意义的疼痛缓解。我们发现 SNMD 干预措施与常规药物治疗或物理治疗相结合时，可能会为疼痛强度提供有临床意义的益处。SCS 与感染、电极导线故障/迁移和需要再次手术/重新植入有关。这些风险的确定性水平非常低。SNMD 可能导致严重的不良事件，包括死亡。我们没有发现支持或反驳使用 DRGS 治疗慢性疼痛的证据。
