Abstract：
Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25-75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300-5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72-0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71-0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60-0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.
摘要：
疼痛在糖尿病和慢性肾脏病(CKD)患者中普遍存在。这些患者的慢性疼痛的管理受到常用药物(包括非甾体抗炎药(NSAID)和阿片类药物)的肾毒性的限制。由于先前的研究暗示内皮素-1参与疼痛伤害感受，我们对SONAR试验的事后分析评估了内皮素受体拮抗剂阿曲生坦与疼痛和镇痛药处方之间的关联.SONAR是随机的，双盲,安慰剂对照临床试验招募2型糖尿病和CKD参与者(估计肾小球滤过率25-75ml/min/1.73m2;尿白蛋白/肌酐比值300-5000mg/g).参与者被随机分配接受阿曲生坦或安慰剂（每组1834人）。主要结局是研究者报告的疼痛相关不良事件（AE）。我们应用Cox回归评估阿曲生坦与安慰剂相比对首次报告的疼痛相关不良事件风险的影响，其次,镇痛药的第一个处方。我们使用Anderson-Gill方法评估对所有（第一次和随后的）疼痛相关AE的影响。在2.2年的中位随访期间，发生1183例疼痛相关AE。阿曲生坦和安慰剂组首次疼痛相关事件发生率分别为138.2和170.2/1000人年(风险比0.82[95%置信区间0.72-0.93])。阿曲生坦还降低了所有（第一次和随后的）疼痛相关的AE的发生率（比率为0.80[0.70-0.91]。在考虑了竞争性死亡风险后，这些发现是相似的（亚风险比0.81[0.71-0.92]）。与安慰剂相比，使用阿曲生坦治疗的患者在随访期间开始使用更少的镇痛药，包括NSAIDs和阿片类药物（风险比=0.72[0.60-0.88]）。因此，在精心选择的2型糖尿病和CKD患者中,阿曲生坦与疼痛相关事件和疼痛相关镇痛药使用减少相关.
