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

膝关节骨关节炎（OA）是美国老年人下肢残疾的主要原因。膝关节置换术（KR）是膝关节OA的唯一确定性治疗，约20-30%的患者发生疼痛缓解不足。中枢敏感化（CS）是中枢神经系统神经元的异常兴奋性，会导致疼痛敏感性升高，因此可能导致KR后持续疼痛。CS的发生可能有多种原因，包括来自病变组织的机械和炎症输入，例如可以在膝关节OA中看到，因此OA本身可能是CS的风险因素。初步数据支持CS与KR后重度疼痛和影像学膝关节OA相关。本研究的目的是全面研究：1）CS与KR后疼痛的相关性; 2）放射学膝关节OA的持续时间和严重程度，以及炎症（滑膜炎、积液）和机械负荷（骨髓病变）与CS的具体特征。这些研究将深入了解KR后和膝关节OA疼痛以及CS发生的潜在病理生理机制。该研究将在NIH资助的多中心骨关节炎（MOST）研究中进行，该研究是一项约3000名患有不同严重程度和持续时间的膝关节OA的老年人以及膝关节OA高风险人群的队列研究，这些人群迄今为止已进行了7年以上的疾病、疼痛和功能的纵向标准化评估，迄今为止的KR>600。本研究将扩展对KR患者的评价，以更好地评估KR前后的CS。将评价CS的两个指标：1）时间总和和2）压痛阈值，这是疾病/炎症部位的外周和/或中枢致敏的标志物，或在其他正常区域评估时的CS标志物。将在该队列中全面收集的与不良KR疼痛结局相关的其他相关因素的背景下对这些相关性进行评价。深入了解CS在KR后疼痛中的作用，以及可能导致CS的OA病理学，将为开发合理的新目标提供机会，以改善疾病过程早期膝关节OA的疼痛结局，以及改善KR后的疼痛结局，这是目前唯一可用于膝关节OA的明确治疗方法。

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.