Central Sensitization in Post-Knee Replacement Pain and Relation to OA Pathology

描述(由申请人提供)：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)是目前治疗膝骨性关节炎的唯一有效方法。反映这一点的是，2004年进行了约50万个KR，预计到2030年将进行约350万个KR。尽管置换了患病的关节，20%-30%的患者在这项可能是决定性的旨在改善疼痛的主要外科手术中没有足够的疼痛缓解。疼痛缓解效果不佳的原因尚不完全清楚。中枢敏感化是中枢神经系统神经元的一种异常兴奋性，导致疼痛敏感性增强，因此可能是KR后持续疼痛的一个因素。中枢敏感化的发生有多种原因，包括病变组织和其他全身来源的炎症输入(例如肥胖，这是与低度炎症相关的OA的主要风险因素)，以及手术本身。初步的先导数据支持KR术后剧烈疼痛的中枢敏化与放射学膝关节骨关节炎的横断面关系，提示骨关节炎的病理可能有助于敏化。这项研究的目的是全面研究两者之间的关系 1)KR后对疼痛的中枢敏感化；2)KR后疼痛的持续时间和严重程度 OA(滑膜炎、积液)以及可能在局部或全身起作用的炎性介质(肿瘤坏死因子、脂联素、瘦素)，以达到中枢敏感化。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，以及中枢敏感化的发生。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，该研究是一组约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，到目前为止，他们已经对疾病、疼痛和功能进行了长达7年的标准化评估。这项研究将创建一个新的KR后队列，以实现对KR前后中枢敏感化的更大评估，因为这些测量以前并不是在所有KR患者中获得的，并将能够评估神经病理性疼痛作为KR后疼痛的一个因素。将评估两种中枢敏感化指标：1)时间总和和2)压力痛阈值，这是疾病部位的外周和/或中枢敏感化的标志，或当在其他正常区域评估时是中枢敏感化的标志。这些评估将在这个队列中全面收集的与不良KR疼痛结果相关的其他相关因素的背景下进行。深入了解中枢敏化在膝关节骨性关节炎后疼痛中的作用，以及可能有助于中枢敏化的骨关节炎或其他全身性炎症介质的炎症病理，将提供机会开发合理的新靶点，以改善膝关节骨性关节炎疾病过程中早期的疼痛结局，以及改善膝关节骨性关节炎后疼痛结局，这是目前唯一可用于膝关节骨性关节炎的权威治疗方法。 公共卫生相关性：膝关节置换手术是治疗骨性关节炎的唯一权威治疗方法，骨性关节炎是美国老年人腿部疼痛和残疾的主要原因，但有相当数量的人在膝关节置换后仍有疼痛。因此，迫切需要了解哪些因素可以解释为什么一些人在膝关节置换后没有获得足够的疼痛缓解，特别是因为如此大量的此类手术是在美国进行的。这项研究将提供有关神经系统改变(敏化)作为膝关节置换术后疼痛持续的潜在危险因素的重要信息，以及炎症是否可能导致这些改变，从而增加我们对骨关节炎和膝关节置换术后疼痛的潜在原因和治疗目标的了解。

DESCRIPTION (provided by applicant): Knee osteoarthritis (OA) is the leading cause of lower extremity disability among older adults in the United States. Knee replacement (KR) is the only definitive treatment available for knee OA presently. Reflecting this, ~0.5 million KRs were performed in 2004, with ~3.5 million projected by the year 2030. Despite replacement of the diseased joint, 20-30% of patients have inadequate pain relief from this presumably definitive major surgical procedure aimed at improving pain. The reason for suboptimal pain relief is not entirely clear. Central sensitization, which is an abnormal excitability of neurons in the central nervous system, causes heightened pain sensitivity and is therefore a plausible contributing factor to ongoing pain after KR. Central sensitization can occur for a variety of reasons, including inflammatory inputs from diseased tissue and other systemic sources (such as obesity, a major risk factor for OA, which is associated with low-grade inflammation), and the surgery itself. Preliminary pilot data support the cross-sectional relation of central sensitizatio to severe pain post-KR and radiographic knee OA, suggesting the possibility of OA pathology contributing to sensitization. The objective of this study is to comprehensively study the relation of: 1) central sensitization to pain post-KR; 2) the duration and severity inflammatory features of OA (synovitis, effusion) as well as inflammatory mediators that may act locally or systemically (TNF-¿, adiponectin, leptin) to central sensitization. These studies will provide insight into potential pathophysiologic mechanisms underlying post-KR and knee OA pain, and occurrence of central sensitization. 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. This study will create a new post-KR cohort to enable greater assessments of central sensitization pre- and post-KR as these measures were not obtained in all those with KR previously, and will enable assessment of neuropathic pain as a contributor to post-KR pain. Two measures of central sensitization 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, or of central sensitization when assessed at an otherwise normal area. These evaluations 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 central sensitization in pain post-KR, and the inflammatory pathology of OA or other systemic inflammatory mediators that may contribute to central sensitization will offer opportunities to develop rational new targets fo 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. PUBLIC HEALTH RELEVANCE: Knee replacement surgery is the only definitive treatment available for osteoarthritis, the leading cause of lower extremity pain and disability among older adults in the United States, yet a substantial number of people continue to have pain after knee replacement. Accordingly, there is a vital need to understand what factors may explain why some people do not achieve adequate pain relief post-knee replacement, particularly since such a large number of such surgeries are performed in the United States. This research will provide important information regarding nervous system alterations (sensitization) as a potential risk factor for pain persistence post-knee replacement, and whether inflammation may contribute to these alterations, thereby increasing our understanding of potential causes of and treatment targets for pain in osteoarthritis and post-knee replacement.