Central sensitization in post-knee replacement pain and relation to OA pathology

膝骨性关节炎(OA)是美国老年人腿部残疾的主要原因。膝关节置换术(KR)是膝骨性关节炎的唯一权威治疗方法，疼痛缓解不足的患者约占20%-30%。中枢敏感化(CS)是中枢神经系统神经元的一种异常兴奋性，导致疼痛敏感性升高，从而可能导致KR后持续疼痛。CS的发生有多种原因，包括病变组织的机械性和炎症性输入，如膝关节骨关节炎，因此骨关节炎本身可能是CS的危险因素。飞行员数据支持CS与KR术后严重疼痛和放射学膝关节骨性关节炎之间的关联。本研究的目的是全面研究CS与KR后疼痛的关系；2)膝关节骨关节炎的持续时间和严重程度，以及炎症(滑膜炎、渗出)和机械负荷(骨髓损害)与CS的特殊特征。这些研究将深入了解KR和膝关节骨性关节炎后疼痛的潜在病理生理机制，以及CS的发生。这项研究将在NIH资助的多中心骨关节炎(MOST)研究范围内进行，该研究是一个队列，包括约3000名患有不同严重程度和持续时间的膝骨性关节炎的老年人，以及膝骨性关节炎的高危人群，他们迄今已对疾病、疼痛和功能进行了纵向标准化评估，迄今已有600 KR。这项研究将扩大对KRS患者的评估，以便能够在KR之前和之后对CS进行更多的评估。CS的两个指标将被评估：1)时间总和和2)压力痛阈值，这是疾病/炎症部位的外周和/或中枢敏化的标志，或者当在其他正常区域评估时，是CS的标志。对这些相关性的评估将在与不良KR疼痛结局相关的其他相关因素的背景下进行，这些因素在该队列中全面收集。深入了解CS在膝关节骨性关节炎术后疼痛中的作用，以及可能导致CS的膝骨性关节炎的病理机制，将为在疾病过程的早期改善膝关节骨性关节炎疼痛结局以及改善膝关节骨性关节炎术后疼痛结局提供机会，这是目前唯一可用于膝关节骨性关节炎的权威治疗方法。

Knee osteoarthritis (OA) is the leading cause of lower extremity disability among older adults in the United States. Inadequate pain relief with knee replacement (KR), the only definitive therapy for knee OA, occurs in ~20-30% of patients. Central sensitization (CS), which is an abnormal excitability of neurons in the central nervous system, causes heightened pain sensitivity and therefore may contribute to ongoing pain after KR. CS can occur for a variety of reasons, including mechanical and inflammatory inputs from diseased tissue, such as may be seen in knee OA, and therefore OA itself may be a risk factor for CS. Pilot data support an association of CS with severe pain post-KR, and with radiographic knee OA. The objective of this study is to comprehensively study the association of: 1) CS with pain post-KR; 2) duration and severity of radiographic knee OA, and specific features of inflammation (synovitis, effusion) and mechanical load (bone marrow lesions) with CS. These studies will provide insight into potential pathophysiologic mechanisms underlying post-KR and knee OA pain, and occurrence of CS. The study will be conducted within the NIH-funded Multicenter Osteoarthritis (MOST) Study, which is a cohort of ~3000 older adults with knee OA of varying severity and duration, as well as persons who are at high risk for knee OA, who have had longitudinal standardized assessments of disease, pain, and function over 7 years to date, with >600 KRs to date. This study will extend the evaluation of persons with KRs to enable greater assessments of CS pre- and post-KR. Two measures of CS will be evaluated: 1) temporal summation and 2) pressure pain threshold, which is a marker of peripheral and/or central sensitization at sites of disease/inflammation, or of CS when assessed at an otherwise normal area. The evaluation of these associations will occur in the context of other pertinent factors associated with poor KR pain outcomes that are comprehensively collected in this cohort. Insight into the role of CS in pain post-KR, and the pathology of OA that may contribute to CS will offer opportunity to develop rational new targets for improving pain outcomes in knee OA earlier in the disease process, as well as improving pain outcomes post-KR, which is currently the only definitive therapy available for knee OA.