Derry Sheena, Rice Andrew Sc, Cole Peter, Tan Toni, Moore R Andrew
Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, UK, OX3 7LE.
Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK, SW10 9NH.
Cochrane Database Syst Rev. 2017 Jan 13;1(1):CD007393. doi: 10.1002/14651858.CD007393.pub4.
This review is an update of 'Topical capsaicin (high concentration) for chronic neuropathic pain in adults' last updated in Issue 2, 2013. Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin, capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are 'defunctionalised' quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams. High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, often following local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made.
To review the evidence from controlled trials on the efficacy and tolerability of topically applied, high-concentration (8%) capsaicin in chronic neuropathic pain in adults.
For this update, we searched CENTRAL, MEDLINE, Embase, two clinical trials registries, and a pharmaceutical company's website to 10 June 2016.
Randomised, double-blind, placebo-controlled studies of at least 6 weeks' duration, using high-concentration (5% or more) topical capsaicin to treat neuropathic pain.
Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and numbers needed to treat for one additional event, using standard methods.Efficacy outcomes reflecting long-duration pain relief after a single drug application were from the Patient Global Impression of Change (PGIC) at specific points, usually 8 and 12 weeks. We also assessed average pain scores over weeks 2 to 8 and 2 to 12 and the number of participants with pain intensity reduction of at least 30% or at least 50% over baseline, and information on adverse events and withdrawals.We assessed the quality of the evidence using GRADE and created a 'Summary of findings' table.
We included eight studies, involving 2488 participants, two more studies and 415 more participants than the previous version of this review. Studies were of generally good methodological quality; we judged only one study at high risk of bias, due to small size. Two studies used a placebo control and six used 0.04% topical capsaicin as an 'active' placebo to help maintain blinding. Efficacy outcomes were inconsistently reported, resulting in analyses for most outcomes being based on less than complete data.For postherpetic neuralgia, we found four studies (1272 participants). At both 8 and 12 weeks about 10% more participants reported themselves much or very much improved with high-concentration capsaicin than with 'active' placebo, with point estimates of numbers needed to treat for an additional beneficial outcome (NNTs) of 8.8 (95% confidence interval (CI) 5.3 to 26) with high-concentration capsaicin and 7.0 (95% CI 4.6 to 15) with 'active' placebo (2 studies, 571 participants; moderate quality evidence). More participants (about 10%) had average 2 to 8-week and 2 to 12-week pain intensity reductions over baseline of at least 30% and at least 50% with capsaicin than control, with NNT values between 10 and 12 (2 to 4 studies, 571 to 1272 participants; very low quality evidence).For painful HIV-neuropathy, we found two studies (801 participants). One study reported the proportion of participants who were much or very much improved at 12 weeks (27% with high-concentration capsaicin and 10% with 'active' placebo). For both studies, more participants (about 10%) had average 2 to 12-week pain intensity reductions over baseline of at least 30% with capsaicin than control, with an NNT of 11 (very low quality evidence).For peripheral diabetic neuropathy, we found one study (369 participants). It reported about 10% more participants who were much or very much improved at 8 and 12 weeks. One small study of 46 participants with persistent pain following inguinal herniorrhaphy did not show a difference between capsaicin and placebo for pain reduction (very low quality evidence).We downgraded the quality of the evidence for efficacy outcomes by one to three levels due to sparse data, imprecision, possible effects of imputation methods, and susceptibility to publication bias.Local adverse events were common, but not consistently reported. Serious adverse events were no more common with active treatment (3.5%) than control (3.2%). Adverse event withdrawals did not differ between groups, but lack of efficacy withdrawals were somewhat more common with control than active treatment, based on small numbers of events (six to eight studies, 21 to 67 events; moderate quality evidence, downgraded due to few events). No deaths were judged to be related to study medication.
AUTHORS' CONCLUSIONS: High-concentration topical capsaicin used to treat postherpetic neuralgia, HIV-neuropathy, and painful diabetic neuropathy generated more participants with moderate or substantial levels of pain relief than control treatment using a much lower concentration of capsaicin. These results should be interpreted with caution as the quality of the evidence was moderate or very low. The additional proportion who benefited over control was not large, but for those who did obtain high levels of pain relief, there were usually additional improvements in sleep, fatigue, depression, and quality of life. High-concentration topical capsaicin is similar in its effects to other therapies for chronic pain.
本综述是对《高浓度辣椒素局部用药治疗成人慢性神经性疼痛》的更新，该综述上次更新于2013年第2期。含辣椒素的外用乳膏用于治疗周围神经性疼痛。涂抹于皮肤后，辣椒素会引起敏感性增强，随后是一段敏感性降低的时期，反复涂抹后会出现持续脱敏。高浓度（8%）辣椒素贴片的研发旨在增加辣椒素的给药量；快速给药被认为可以提高耐受性，因为皮肤伤害感受器能迅速“失活”。单次给药可避免患者不依从。目前仅有8%辣椒素贴片制剂，其辣椒素浓度约为传统乳膏的100倍。高浓度局部用辣椒素以单贴片形式应用于患处。由于其会引起初始强烈烧灼感，必须在高度可控的条件下应用，通常在局部麻醉后进行。预期疗效可持续约12周，届时可能需再次给药。
综述关于外用高浓度（8%）辣椒素治疗成人慢性神经性疼痛的疗效和耐受性的对照试验证据。
本次更新中，我们检索了截至2016年6月10日的Cochrane系统评价数据库、医学期刊数据库、荷兰医学文摘数据库、两个临床试验注册库以及一家制药公司的网站。
随机、双盲、安慰剂对照研究，持续时间至少六周，使用高浓度（5%或更高）局部用辣椒素治疗神经性疼痛。
两名综述作者独立检索研究、提取疗效和不良事件数据，并审查研究质量和潜在偏倚问题。在可行的情况下进行汇总分析时，我们使用二分数据计算风险比和需治疗人数以获得一个额外事件，采用标准方法。反映单次用药后长期疼痛缓解的疗效结果来自特定时间点（通常为第8周和第12周）的患者总体印象变化（PGIC）。我们还评估了第2至8周和第2至12周的平均疼痛评分，以及疼痛强度较基线降低至少30%或至少50%的参与者人数，以及不良事件和退出研究的信息。我们使用GRADE评估证据质量并创建了“结果总结”表。
我们纳入了八项研究，涉及2488名参与者，比本综述的上一版本多两项研究和415名参与者。研究的方法学质量总体良好；由于样本量小，我们仅判定一项研究存在高偏倚风险。两项研究使用安慰剂对照，六项研究使用0.04%局部用辣椒素作为“活性”安慰剂以帮助维持盲法。疗效结果报告不一致，导致大多数结果的分析基于不完整数据。
对于带状疱疹后神经痛，我们找到了四项研究（1272名参与者）。在第8周和第12周，报告高浓度辣椒素组比“活性”安慰剂组自我感觉有很大或非常大改善（much or very much improved）的参与者多约10%，高浓度辣椒素组获得额外有益结果的需治疗人数（NNTs）点估计值为8.8（95%置信区间（CI）5.3至26），“活性”安慰剂组为7.0（95%CI 4.6至15）（两项研究，571名参与者；中等质量证据）。与对照组相比，更多参与者（约10%）使用辣椒素后在第2至8周和第2至12周的平均疼痛强度较基线降低至少30%和至少50%，NNT值在10至12之间（两项至四项研究，571至1272名参与者；极低质量证据）。
对于疼痛性HIV神经病变，我们找到了两项研究（801名参与者）。一项研究报告了第12周时自我感觉有很大或非常大改善（much or very much improved）的参与者比例（高浓度辣椒素组为27%，“活性”安慰剂组为10%）。对于两项研究，与对照组相比，更多参与者（约10%）使用辣椒素后在第2至12周的平均疼痛强度较基线降低至少30%，NNT为11（极低质量证据）。
对于糖尿病周围神经病变，我们找到了一项研究（369名参与者）。该研究报告在第8周和第12周自我感觉有很大或非常大改善（much or very much improved）的参与者多约10%。一项针对46名腹股沟疝修补术后持续疼痛患者的小型研究未显示辣椒素与安慰剂在减轻疼痛方面存在差异（极低质量证据）。
由于数据稀疏、不精确、插补方法的可能影响以及易受发表偏倚影响，我们将疗效结果的证据质量下调一至三个等级。局部不良事件很常见，但报告不一致。严重不良事件在活性治疗组（3.5%）中并不比对照组（3.2%）更常见。基于少量事件（六项至八项研究，21至67个事件），不良事件导致的退出研究在两组间无差异，但因缺乏疗效导致的退出研究在对照组中比活性治疗组略多（中等质量证据，因事件数少而降级）。未判定有死亡与研究用药相关。
与使用低得多浓度辣椒素的对照治疗相比，高浓度局部用辣椒素用于治疗带状疱疹后神经痛、HIV神经病变和疼痛性糖尿病神经病变时，有更多参与者获得中度或显著程度的疼痛缓解。由于证据质量为中等或极低，这些结果应谨慎解读。受益于对照治疗的额外比例不大，但对于那些确实获得高水平疼痛缓解的患者，通常在睡眠、疲劳、抑郁和生活质量方面还有额外改善。高浓度局部用辣椒素在治疗慢性疼痛方面的效果与其他疗法相似。
