Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
Department of Oncology and Human Metabolism, Medical School, University of Sheffield, Sheffield, UK.
Health Technol Assess. 2022 Oct;26(39):1-100. doi: 10.3310/RXUO6757.
The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared.
To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain.
A randomised crossover trial with health economic analysis.
Twenty-one secondary care centres in the UK.
Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10).
Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded.
The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory - Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients' preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective.
A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)].
Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable.
Future research should explore (1) variations in diabetic peripheral neuropathic pain management at the practice level, (2) how OPTION-DM (Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus) trial findings can be best implemented, (3) why some patients respond to a particular drug and others do not and (4) what options there are for further treatments for those patients on combination treatment with inadequate pain relief.
The three treatment pathways appear to give comparable patient outcomes at similar costs, suggesting that the optimal treatment may depend on patients' preference in terms of side effects.
The trial is registered as ISRCTN17545443 and EudraCT 2016-003146-89.
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme, and will be published in full in ; Vol. 26, No. 39. See the NIHR Journals Library website for further project information.
糖尿病周围神经病理性疼痛的主要治疗方法是药物治疗，但目前的国家卫生与保健卓越研究所指南不是基于强有力的证据，因为这些治疗方法及其组合尚未进行直接比较。
确定糖尿病周围神经病理性疼痛最具临床益处、最具成本效益和最耐受的治疗途径。
一项具有健康经济分析的随机交叉试验。
英国的 21 个二级保健中心。
7 天平均自评疼痛评分≥4 分（数字评分量表 0-10）的糖尿病周围神经病理性疼痛成人患者。
参与者随机分配至三种常用的治疗途径：（1）阿米替林联合普瑞巴林，（2）度洛西汀联合普瑞巴林，（3）普瑞巴林联合阿米替林。参与者和研究团队对治疗分配进行了盲法，使用了过包衣胶囊和匹配的安慰剂。现场药剂师未进行盲法。
主要结局是在每种途径的最后一周，路径之间 24 小时平均 Numeric Rating Scale 评分的差异，通过 7 天平均每日 Numeric Rating Scale 疼痛评分来衡量，次要终点包括第 6 周单药治疗之间的 7 天平均每日 Numeric Rating Scale 疼痛评分、生活质量（Short Form 问卷-36 项）、医院焦虑和抑郁量表评分、达到 30%和 50%疼痛缓解的患者比例、简短疼痛量表 - 修订后的短表项目评分、失眠严重程度指数评分、神经病理性疼痛症状量表评分、耐受性（0-10 分）、第 16 周患者全球印象变化评分和第 50 周患者首选治疗途径。记录不良事件和严重不良事件。进行了一项试验内成本-效用分析，使用从 NHS 和社会保健角度的增量成本-质量调整生命年来比较治疗途径。
从英国的 13 个中心中招募了 140 名参与者，其中 130 名参与者被纳入分析。第 16 周的疼痛评分在各臂之间相似，与阿米替林联合普瑞巴林相比，度洛西汀联合普瑞巴林的差异为-0.1 分（98.3%置信区间 -0.5 至 0.3 分），与阿米替林联合普瑞巴林相比，普瑞巴林联合阿米替林的差异为-0.1 分（98.3%置信区间 -0.5 至 0.3 分），与度洛西汀联合普瑞巴林相比，普瑞巴林联合阿米替林的差异为 0.0 分（98.3%置信区间 -0.4 至 0.4 分）。在耐受性、停药和生活质量方面的结果相似。每种药物的不良反应都是可以预测的。与单药治疗（6-16 周）相比，联合治疗（普瑞巴林联合阿米替林）进一步降低了 Numeric Rating Scale 疼痛评分（平均 1.0 分，98.3%置信区间 0.6 至 1.3 分）。与那些继续单药治疗的患者相比（平均 0.2 分，98.3%置信区间 -0.1 至 0.5 分）。由于治疗引起的不良事件，普瑞巴林联合阿米替林途径的单药治疗停药率最低，且最常被首选（最常被患者首选的治疗途径：阿米替林联合普瑞巴林，24%；度洛西汀联合普瑞巴林，33%；普瑞巴林联合阿米替林，43%；=0.26）。没有一种途径在成本效益方面具有优势。每种途径比较的质量调整生命年增量增益都很小[阿米替林联合普瑞巴林与度洛西汀联合普瑞巴林相比-0.002（95%置信区间 -0.011 至 0.007）质量调整生命年，阿米替林联合普瑞巴林与普瑞巴林联合阿米替林相比-0.006（95%置信区间 -0.002 至 0.014）质量调整生命年，度洛西汀联合普瑞巴林与普瑞巴林联合阿米替林相比 0.007（95%置信区间 0.0002 至 0.015）质量调整生命年]，且 16 周内的增量成本相似[阿米替林联合普瑞巴林与度洛西汀联合普瑞巴林相比-£113（95%置信区间 -£381 至 £90），阿米替林联合普瑞巴林与普瑞巴林联合阿米替林相比 £155（95%置信区间 -£37 至 £625），度洛西汀联合普瑞巴林与普瑞巴林联合阿米替林相比 £141（95%置信区间 -£13 至 £398）]。
尽管没有安慰剂组，但从随机安慰剂对照试验中可以得到每种研究药物的有力证据。增加安慰剂组将延长这项已经很长且要求很高的试验的时间，并且在伦理上认为这是不合理的。
未来的研究应该探索（1）糖尿病周围神经病理性疼痛管理在实践层面上的差异，（2）如何实施 OPTION-DM（治疗糖尿病周围神经病理性疼痛的最佳途径）试验结果，（3）为什么一些患者对特定药物有反应而另一些患者没有反应，以及（4）对于那些联合治疗疼痛缓解不足的患者，还有哪些进一步的治疗选择。
三种治疗途径在相似的成本下似乎提供了相似的患者结局，这表明最佳治疗可能取决于患者在不良反应方面的偏好。
该试验在 ISRCTN 注册，注册号为 ISRCTN84010044 和 EudraCT 2016-003146-89。
该项目由英国国家卫生与保健卓越研究所（NIHR）卫生技术评估计划资助，将在《 ; 第 26 卷，第 39 期》中全文发表。请访问 NIHR 期刊库网站了解更多项目信息。
