CNS Pain Mechanisms in Early Rheumatoid Arthritis: Implications for the Acute to Chronic Pain Transition

项目总结/摘要 数以百万计的美国人每天都在与关节炎相关的剧烈疼痛中度过。疼痛持续的时间越长， 更难治疗。需要有效的预防策略。预防慢性疼痛的主要障碍是 关于急性关节疼痛如何导致中枢神经系统（CNS）通路变化的知识缺口 负责感知，传递和调节疼痛这个过程会导致广泛的疼痛 敏感性，被称为疼痛集中。这项研究计划的长期目标是设计干预措施， 以防止疼痛集中，从而防止类风湿性关节炎（RA）中的慢性疼痛。目标是确定 可改变的临床因素和神经生物学途径，导致慢性疼痛的发展， RA.本申请的重点是早期RA，因为RA诊断后的前12个月可能代表了早期RA。 这是防止急性疼痛转变为慢性疼痛的关键时间。加拿大早期的初步数据 关节炎队列（CATCH）显示，纤维肌痛的发病率，典型的集中性疼痛状况， 在RA诊断后的第一年最高。中心假设是睡眠问题，心理社会 因素和异常CNS（例如，脑、脊髓）调节机制预测疼痛的发展 在RA诊断后的第一年集中。中心假设将通过以下方式进行检验： 以下三个具体目标：1）确定可改变的因素，预测疼痛集中的症状， 早期RA; 2）确定定量感觉测试（QST）增强CNS疼痛处理的证据， 预测疼痛集中的症状; 3）确定功能和解剖脑通路 早期RA的潜在疼痛集中。对于第一个目标，来自CATCH和CATCH的534名早期RA患者- 将入组US（CATCH的US扩展），以完成睡眠、疼痛、心理社会因素和 在进入队列后0、3、6和12个月进行残疾评估。对于第二个目标，125例早期RA 患者将接受QST，这是一种测试，涉及评估对定义明确、可量化的 疼痛刺激（例如，压力和寒冷），在0，3和12个月。对于第三个目标，来自目标2的95名患者将 在0和12个月时进行磁共振成像以评估神经成像标记物（例如，相关性 在不同脑区之间的活动中，由神经细胞体组成的脑区中的组织体积）， 之前已经被证明与疼痛集中有关。建议的研究是创新的 因为它代表了一个实质性的偏离现状：1）专注于早期RA，2）纳入 两个多中心早期RA登记处的疼痛相关结构评估，以及3）采用多模式 方法，包括患者报告的疼痛测量、QST和神经影像学，以评估疼痛通路。的 拟议的研究是重要的，因为它将为干预设计奠定基础（例如，认知行为 治疗睡眠问题的治疗，加巴喷丁早期治疗疼痛）和未来的试验，以防止慢性 疼痛，最终导致全身炎症性疾病疼痛管理的范式转变。

PROJECT SUMMARY/ABSTRACT Millions of Americans spend each day in severe pain associated with arthritis. The longer the pain persists, the harder it is to treat. Efficacious prevention strategies are needed. A major barrier to chronic pain prevention is a gap in knowledge about how acute joint pain leads to changes in central nervous system (CNS) pathways responsible for sensing, transmitting and regulating pain. This process, which results in widespread pain sensitivity, is termed pain centralization. The long-term goal of this research program is to design interventions to prevent pain centralization, and hence chronic pain, in rheumatoid arthritis (RA). The objective is to identify modifiable clinical factors and neurobiological pathways that lead to the development of chronic pain in early RA. The focus of this application is early RA because the first 12 months after RA diagnosis likely represents a critical time in which to prevent the acute to chronic pain transition. Preliminary data from the Canadian Early Arthritis Cohort (CATCH) showed that the incidence of fibromyalgia, the prototypical centralized pain condition, is highest during the first year after RA diagnosis. The central hypothesis is that sleep problems, psychosocial factors, and abnormal CNS (e.g., brain, spinal cord) regulatory mechanisms predict the development of pain centralization in the first year after RA diagnosis. The central hypothesis will be tested by pursuing the following three specific aims: 1) to identify modifiable factors that predict symptoms of pain centralization in early RA; 2) to identify quantitative sensory testing (QST) evidence of augmented CNS pain processing that predict symptoms of pain centralization; and 3) to define the functional and anatomic brain pathways underlying pain centralization in early RA. For the first aim, 534 early RA patients from CATCH and CATCH- US (US extension of CATCH) will be enrolled to complete measures of sleep, pain, psychosocial factors, and disability administered at 0, 3, 6 and 12 months after entry into the cohorts. For the second aim, 125 early RA patients will undergo QST, a type of testing that involves assessing response to well-defined, quantifiable painful stimuli (e.g., pressure and cold), at 0, 3 and 12 months. For the third aim, 95 patients from Aim 2 will undergo magnetic resonance imaging at 0 and 12 months to assess neuroimaging markers (e.g., correlations in activity between different brain regions, volume of tissue in brain areas consisting of nerve cell bodies) that have previously been shown to be involved in pain centralization. The proposed research is innovative because it represents a substantive departure from the status quo by: 1) focusing on early RA, 2) incorporating assessments of pain-related constructs into two multi-site early RA registries, and 3) employing a multimodal approach, including patient-reported measures of pain, QST, and neuroimaging, to assess pain pathways. The proposed research is significant because it will set the stage for intervention design (e.g., cognitive behavioral therapy to treat sleep problems, early treatment of pain with gabapentin) and future trials to prevent chronic pain, ultimately leading to a paradigm shift in the management of pain in systemic inflammatory diseases.