Selvarajah D et al. LANCET.August 22, 2022 .

糖尿病周围神经病变性疼痛(DPNP)是一种常见的疼痛性疾病。大多数指南推荐阿米替林、度洛西汀、普瑞巴林或加巴喷丁作为DPNP的初始镇痛治疗，但很少有比较证据表明哪一种是最好的或它们是否应该联合使用。我们的目的是评估不同的一线药物组合治疗DPNP的疗效和耐受性。

研究纳入140例患者，第16周的7天平均NRS评分从基线时的平均6·6 (SD 1.5)下降到第16周时的平均3·3(1.8)。联合治疗组患者NRS平均降低量大于单药治疗组(1.0 [SD 1.3] vs 0.2[1.5])。单药治疗的不良事件是可预测的:我们观察到P-A通路的头晕、D-P通路的恶心和a - p通路的口干显著增加

据我们所知，这是有史以来规模最大、历时最长、面对面、跨界的神经性疼痛试验。研究表明，所有三种治疗途径和单一治疗有相似的镇痛效果。联合治疗的耐受性良好，并能改善疼痛控制欠佳的患者的疼痛缓解

Abstract

Background

Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP.

Methods

OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0–10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443.

Findings

Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was –0·1 (98·3% CI –0·5 to 0·3) for D-P versus A-P, –0·1 (–0·5 to 0·3) for P-A versus A-P, and 0·0 (–0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway.

Interpretation

To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy.

Funding

National Institute for Health Research (NIHR) Health Technology Assessment programme.

文章连接：

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01472-6/fulltext

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