Psychosocial and Oxidative Stress Mechanisms of Post-Surgical Chronic Pain

全膝关节置换术（TKA）是老年人越来越常见的外科手术。虽然 对于许多患者有效，15%或更多的患者经历不满意的疼痛结果。虽然仅限于后- 在一些患者的手术慢性疼痛中，其他患者也会出现局部异常性疼痛和痛觉过敏、水肿， 自主神经功能表明复杂性局部疼痛综合征（CRPS），一种特别难以治疗的慢性 疼痛状况。TKA术后慢性疼痛和CRPS的机制尚不清楚。最 常见的TKA手术包括将止血带应用于手术肢体持续较长时间（最多 2小时）。动物模型表明，当血流阻断时，延长止血带应用后再灌注， 止血带被移除导致缺血再灌注损伤，其通过增加氧化应激可导致 持续神经病理性疼痛和CRPS的临床特征。该项目的一个关键目标是检查 第一次在人类中基线和围手术期氧化应激的影响，如F2- 异前列腺素对TKA术后长期疼痛、CRPS和功能结局的影响。一个已知的预测后- TKA慢性疼痛是更大的术前负面影响（特别是抑郁和焦虑）。新兴 文献表明，抑郁和焦虑的升高可能与氧化应激的升高有关， 程度.拟议中的项目将测试一个新的理论模型，整合这些不同的研究领域 通过确定抑郁和焦虑对TKA术后慢性疼痛结局的影响， 部分通过氧化应激机制传递。如果假设得到支持，结果将突出显示 手术后慢性疼痛和CRPS的新机制，可能适合先发制人 干预，并加强对心理社会因素影响的机制的理解， 随后的术后疼痛相关和功能结局。项目小组将由以下人员组成： 在慢性疼痛、CRPS、测量和健康方面具有互补多学科专业知识的研究人员 氧化应激、TKA手术和前瞻性研究设计的影响。这项研究将招募150名 单侧TKA患者在手术过程中均经历了类似的组织创伤。疼痛，CRPS 精神病学（使用经验证的连续CRPS严重程度评分），抑郁和焦虑症状， 在TKA前基线时系统评估F2-异前列腺素的功能和血浆水平， 术中、术后2天以及6周和6个月随访时。分析将利用 前瞻性的数据，以检查基线和围手术期氧化应激对 随后的慢性疼痛、CRPS和功能结局。调解分析将用于测试是否 抑郁和焦虑部分通过氧化应激对TKA术后长期疼痛、CRPS和功能产生影响 机制等结果有可能提高对手术后慢性炎症机制的理解。 疼痛和CRPS，并指导基于机制的预防干预措施的发展。

Total knee arthroplasty (TKA) is an increasingly common surgical procedure in older adults. Although effective for many patients, 15% or more experience unsatisfactory pain outcomes. While limited to post- surgical chronic pain in some patients, others also develop regional allodynia and hyperalgesia, edema, and autonomic features indicating Complex Regional Pain Syndrome (CRPS), a particularly difficult to treat chronic pain condition. The mechanisms of post-TKA chronic pain and CRPS are not well understood. The most common TKA procedure involves application of a tourniquet to the operated limb for extended periods (up to ≈2 hours). Animal models indicate that extended tourniquet application followed by reperfusion when the tourniquet is removed leads to ischemic reperfusion injury, which via increased oxidative stress, can result in prolonged neuropathic pain and clinical features of CRPS. One key objective of this project is to examine for the first time in humans the impact of baseline and perioperative oxidative stress, as indexed by F2- isoprostanes, on long-term pain, CRPS, and functional outcomes following TKA. One known predictor of post- TKA chronic pain is greater preoperative negative affect (specifically, depression and anxiety). Emerging literature suggests that elevated depression and anxiety may be associated with elevated oxidative stress levels. The proposed project will test a novel theoretical model that integrates these disparate research areas by determining whether the influence of depression and anxiety on post-TKA chronic pain outcomes is conveyed in part through oxidative stress mechanisms. If hypotheses are supported, results will highlight a novel mechanism of post-surgical chronic pain and CRPS that is potentially amenable to pre-emptive intervention, and enhance understanding of mechanisms through which psychosocial factors impact on subsequent postsurgical pain-related and functional outcomes. The project team will be comprised of investigators with complementary multidisciplinary expertise in chronic pain, CRPS, measurement and health effects of oxidative stress, TKA procedures, and prospective study designs. The proposed study will enroll 150 unilateral TKA patients all experiencing similar tissue trauma during the course of surgery. Pain, CRPS symptomatology (using a validated continuous CRPS severity score), depression and anxiety symptoms, function, and plasma levels of F2-isoprostanes will be systematically assessed at pre-TKA baseline, intraoperatively, for two days post-surgically, and at 6 week and 6 month follow-up. Analyses will utilize the prospective nature of the data to examine the impact of baseline and perioperative oxidative stress on subsequent chronic pain, CRPS, and functional outcomes. Mediation analyses will be used to test whether depression and anxiety impact on long-term post-TKA pain, CRPS, and function in part via oxidative stress mechanisms. Results have the potential to enhance understanding of the mechanisms of post-surgical chronic pain and CRPS, and guide development of mechanism-based preventive interventions for both.