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

减少围术期氧化应激以预防全膝关节置换术后慢性疼痛

• 批准号: 10793361
• 负责人: Frederic Tremaine Billings
• 金额: $ 87.46万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793361
• 关键词: Acetylcysteine; Address; Adverse event; Affect; Alanine; Antioxidants; Arthralgia; Automobile Driving; Biological Markers; Chronic; Clinical; Degenerative polyarthritis; Elderly; Enrollment; Excision; F2-Isoprostanes; Free Radicals; Glycine; Home; Home environment; Hour; Intervention; Knee joint; Limb structure; Link; Mediating; Nociceptors; Operative Surgical Procedures; Opioid; Opioid Analgesics; Outcome; Oxidative Stress; Pain; Pain Research; Pain intensity; Pathology; Patients; Perioperative; Phenotype; Placebo Control; Placebos; Postoperative Pain; Postoperative Period; Procedures; Randomized; Randomized, Controlled Trials; Reperfusion Injury; Reporting; Risk; Subgroup; Surgical incisions; Testing; Time; Tourniquets; Work; chronic pain; design; experience; follow-up; functional improvement; functional outcomes; improved; in vivo; innovation; knee replacement arthroplasty; nerve injury; opioid use; pain outcome; pain reduction; precision medicine; prevent; prospective; psychosocial; randomized placebo controlled trial; stress reduction; success

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.

抽象的 美国每年进行约 100 万例全膝关节置换术 (TKA) 手术， 解决骨关节炎引起的膝关节疼痛和功能限制的病理学问题。 TKA 是 主要针对老年人进行，同时对许多 TKA 患者（15% 或更多）的疼痛减轻有效 尽管手术在技术上是成功的，但患者报告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 后长期疼痛的机制尚不清楚，但我们之前的纵向研究 项目 (R01AG048915) 发现证据表明氧化应激 (OS) 可能是 TKA 后慢性病的诱因之一 疼痛。术中切口前 F2-异前列腺素和异呋喃（体内最敏感的物质）水平升高 OS 生物标志物）以及在标准 TKA 中使用止血带期间这些生物标志物的表达增加 手术预测 TKA 后 6 个月的疼痛强度（过去 24 小时和过去一周）会更高。这 拟议的项目建立在先前的工作基础上，并将回答一个关键的临床问题：减少 OS 术前和围手术期可改善 TKA 术后长期疼痛结果吗？我们提出一个前瞻性的 随机安慰剂对照试验，将检查术前、围手术期和长期 OS；疼痛;和 功能结果并首次测试了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 TKA 的患者的 OS 和慢性术后疼痛。甘氨酸NAC 在初步试验中已被证明可显着减少 F2-异前列腺素，支持其作为一种药物的潜在用途 抗氧化干预可改善 TKA 后疼痛结果。鉴于老年人数量众多 每年经历 TKA 后慢性疼痛不良后果（每年约 150,000 例），拟议项目 可能会产生改变实践的临床意义。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，一直持续到 TKA 后 6 周。基线疼痛和心理社会 TKA 前 4 周 (T0) 将在患者家中进行表型分析并评估 OS 干预 4 周后再次【TKA 前 3 天】（T1）；围手术期切开前 [T2]，45 使用止血带后几分钟 [T3]，以及去除止血带后 15 分钟 [T4]；在 TKA 术后， UPS。将在 6 周、6 个月和 12 个月的随访中评估疼痛、功能和阿片类药物使用结果。 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，在 6 周和 6 个月（主要）随访中使用镇痛剂。我们还将测试是否 6 个月随访时 GlyNAC 相关的疼痛强度降低在 12 个月随访中得以维持，并且 GlyNAC 前基线 OS 水平是否会调节 GlyNAC 改善长期疼痛结果的功效。