Reducing Perioperative Oxidative Stress to Prevent Postoperative Chronic Pain Following Total Knee Arthroplasty

摘要 美国每年进行大约100万例全膝关节置换术（TKA）， 解决膝关节疼痛和骨关节炎导致的功能限制的病理基础。TKA是 主要在老年人中进行，虽然在许多TKA患者中有效减轻疼痛，但在15%或以上的TKA患者中有效减轻疼痛 尽管手术在技术上是成功的，但患者报告的长期疼痛结果并不令人满意。TKA术后疼痛 据报道，在长达4年的随访中，7%的TKA患者的疼痛比术前更严重。 虽然导致TKA术后长期疼痛的机制还不清楚，但我们先前的纵向研究表明， 项目（R01AG048915）发现证据表明，氧化应激（OS）可能是TKA后慢性 痛苦术中切口前F2-异前列烷和异呋喃水平升高（体内最敏感 OS生物标志物）和标准TKA中止血带应用期间这些生物标志物的表达增加 手术预测TKA术后6个月时的TKA术后疼痛强度更大（过去24小时和过去一周）。的 拟议的项目建立在这一先前的工作，并将回答一个关键的临床问题： 术前和围手术期改善TKA术后长期疼痛结局？我们提出了一个前瞻性的 随机安慰剂对照试验，将检查术前、围手术期和长期OS;疼痛;以及 功能结果并首次测试了有效的抗氧化剂干预（大豆加）的假设 N-乙酰半胱氨酸[GlyNAC]）降低了接受TKA的患者的OS和慢性术后疼痛。GlyNAC 已显示在初始试验中显著减少F2-异前列烷，支持其作为 抗氧化剂干预改善TKA术后疼痛结局。考虑到大量的老年人 每年经历不良的TKA后慢性疼痛结果（每年150，000英镑）， 可能会改变临床实践我们将招募老年骨关节炎患者， 接受初次单侧TKA，并随机接受GlyNAC（n = 74）或安慰剂（丙氨酸; n = 74） 从TKA前4周开始，持续至TKA后6周。基线疼痛和心理社会 将在TKA前4周（T0）在患者家中进行表型分析并评估OS， 在干预4周后再次[TKA前3天]（T1）;围手术期切口前[T2]，45 止血带应用后15分钟[T3]和止血带移除后15分钟[T4];以及TKA后， ups.将在6周、6个月和12个月随访时评估疼痛、功能和阿片类药物使用结局。 我们将检验GlyNAC降低OS和疼痛强度、改善功能并减少阿片类药物的假设。 与安慰剂相比，6周和6个月（主要）随访时的镇痛剂使用情况。我们还将测试 6个月随访时GlyNAC相关的疼痛强度降低在12个月随访时得以维持， GlyNAC治疗前基线OS水平是否为GlyNAC改善长期疼痛结局的中度疗效。

Abstract Approximately 1 million total knee arthroplasty (TKA) procedures are carried out in the U.S. annually to address pathology underlying knee joint pain and functional limitations resulting from osteoarthritis. TKAs are conducted primarily in older adults, and while effective for pain reduction in many, 15% or more of TKA patients report unsatisfactory long-term pain outcomes despite a technically successful surgery. Post-TKA pain at up to 4-year follow-up has been reported to be worse than the preoperative pain in 7% of TKA patients. While mechanisms contributing to long-term pain post-TKA are not well-understood, our prior longitudinal project (R01AG048915) found evidence that oxidative stress (OS) may be one contributor to post-TKA chronic pain. Elevated intraoperative pre-incision levels of F2-isoprostanes and isofurans (the most sensitive in vivo OS biomarkers) and increased expression of these biomarkers during tourniquet application in standard TKA procedures predicted greater post-TKA pain intensity (past 24 hour and past week) at 6-months post-TKA. The proposed project builds on this prior work and will answer a critical clinical question: does reducing OS in the preoperative and perioperative period improve long-term post-TKA pain outcomes? We propose a prospective randomized placebo-controlled trial that will examine preoperative, perioperative, and long-term OS; pain; and functional outcomes and test for the first time the hypothesis that a potent antioxidant intervention (Glycine plus N-acetylcysteine [GlyNAC]) reduces OS and chronic postsurgical pain in patients undergoing TKA. GlyNAC has been shown to dramatically decrease F2-isoprostanes in initial trials, supporting its potential utility as an antioxidant intervention for improving post-TKA pain outcomes. Given the large number of older adults experiencing adverse post-TKA chronic pain outcomes each year (≈150,000 annually), the proposed project could potentially have practice-changing clinical implications. We will enroll older adult osteoarthritis patients undergoing primary unilateral TKA and randomize them to receive GlyNAC (n=74) or placebo (alanine; n = 74) beginning 4 weeks prior to TKA with continuation until 6 weeks post-TKA. Baseline pain and psychosocial phenotyping will be carried out and OS will be assessed in the patient’s home at 4 weeks pre-TKA (T0) and again after 4 weeks of the intervention [3 days prior to TKA] (T1); perioperatively at pre-incision [T2], 45 minutes after tourniquet application [T3], and 15 minutes post-tourniquet removal [T4]; and at post-TKA follow- ups. Pain, function, and opioid use outcomes will be assessed at 6-week, 6-month, and 12-month follow-up. We will test the hypothesis that GlyNAC reduces OS and pain intensity, improves function, and reduces opioid analgesic use at 6-week and 6-month (primary) follow-up compared to placebo. We will also test whether GlyNAC-related reductions in pain intensity at 6-month follow-up are maintained at 12-month follow-up, and whether pre-GlyNAC baseline OS levels moderate efficacy of GlyNAC for improving long-term pain outcomes.