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

摘要 在美国，每年大约有100万例全膝关节置换术(TKA)手术 阐述膝关节疼痛和骨性关节炎引起的功能受限的病理基础。将军澳是 主要在老年人中进行，虽然对许多、15%或更多的TKA患者有效减轻疼痛 尽管手术技术上取得了成功，但患者报告的长期疼痛结果并不令人满意。全膝关节置换术后疼痛 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TKA术后长期疼痛的机制尚不清楚，但我们之前的纵向 项目(R01AG048915)发现证据表明，氧化应激(OS)可能是TKA后慢性疾病的一个因素 疼痛。术中切开前F2-异前列腺素和异氟醚水平升高(体内最敏感) OS生物标志物)以及在标准全膝关节置换术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个月的疼痛强度(过去24小时和过去一周)更大。这个 拟议的项目建立在这项先前工作的基础上，并将回答一个关键的临床问题：在 术前和围手术期改善TKA术后长期疼痛结果？我们提出了一个预期的 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 功能结果和首次测试假设一种有效的抗氧化剂干预(甘氨酸加 N-乙酰半胱氨酸[GlyNAC])可减少接受全膝关节置换术的患者的OS和慢性术后疼痛。GlyNAC 在初步试验中已被证明可显著减少F2-异前列腺素，支持其作为 用于改善TKA术后疼痛结局的抗氧化剂干预。考虑到大量的老年人 每年经历TKA后的不良慢性疼痛结局(每年≈150,000)，拟议的项目 可能会有改变临床实践的潜在影响。我们将招收老年骨性关节炎患者 接受单侧TKA，随机分为GlyNAC组(n=74)或安慰剂组(n=74)。 从全膝关节置换术前4周开始，持续至术后6周。基线疼痛与心理社会 将在TKA(T0)前4周在患者家中进行表型鉴定和OS评估。 再次干预4周后[TKA前3天](T1)；围手术期切开前[T2]，45 使用止血带后几分钟[T3]，拆除止血带后15分钟[T4]；在TKA术后随访- UPS。疼痛、功能和阿片类药物的使用结果将在6周、6个月和12个月的随访中进行评估。 我们将验证GlyNAC降低OS和疼痛强度、改善功能和减少阿片类药物的假设 与安慰剂相比，在6周和6个月(主要)随访时使用止痛药。我们还将测试 与GlyNAC相关的疼痛强度在6个月的随访中保持在12个月的随访期内，并且 GlyNAC治疗前的基线OS水平是否适中于GlyNAC改善长期疼痛结果的疗效。

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.