Psychosocial and Oxidative Stress Mechanisms of Post-Surgical Chronic Pain

全膝关节置换术(TKA)是一种越来越常见的老年人外科手术。虽然 对许多患者有效，15%或更多的患者疼痛结果不令人满意。虽然仅限于后- 外科慢性疼痛的一些患者，另一些还发展为局部痛觉异常和痛觉过敏，浮肿，和 表明复杂区域疼痛综合征(CRPS)的自主神经特征，这是一种特别难治疗的慢性 疼痛状况。TKA术后慢性疼痛和CRPS的机制尚不清楚。最多的 常见的TKA手术包括在手术肢体上长时间应用止血带(最多 ≈2小时)。动物模型表明，延长止血带应用后再灌流 取下止血带会导致缺血再灌注损伤，这可能通过增加氧化应激而导致 延迟性神经病理性疼痛与慢性盆腔炎的临床特点。这个项目的一个关键目标是检查 以F2为指标的基线和围手术期氧化应激对人类的影响首次出现-- 异前列腺素对TKA术后长期疼痛、CRPS和功能结果的影响。一个已知的预测后遗症的因素 TKA慢性疼痛是术前较大的负面影响(特别是抑郁和焦虑)。新兴 文献表明，抑郁和焦虑的加剧可能与氧化应激的加剧有关。 级别。拟议的项目将测试一种新的理论模型，该模型整合了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 术后慢性疼痛和CRPS的新机制可能先发制人 干预，并加强对心理社会因素影响的机制的理解 术后疼痛相关的后续结果和功能结果。项目团队将由以下人员组成 在慢性疼痛、CRPS、测量和健康方面具有互补的多学科专业知识的研究人员 氧化应激的影响、TKA程序和前瞻性研究设计。拟议中的研究将招收150名学生 单侧全膝关节置换术患者在手术过程中均经历相似的组织损伤。疼痛，CRPS 症状学(使用经过验证的连续CRPS严重程度评分)、抑郁和焦虑症状、 功能，血浆F2-异前列腺素水平将在TKA前基线进行系统评估， 术中、术后2天、术后6周、6个月随访。分析将利用 检查基线和围手术期氧化应激对患者的影响的数据的前瞻性 随后的慢性疼痛、CRPS和功能结果。将使用调解分析来测试 抑郁和焦虑对TKA术后长期疼痛、CRPS和功能的影响部分是通过氧化应激实现的 机械装置。这一结果有可能加强对手术后慢性疾病机制的理解。 疼痛和CRPS，并指导为两者制定基于机制的预防干预措施。

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.