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

项目摘要/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， 这很难治疗。需要有效的预防战略。预防慢性疼痛的一个主要障碍是 关于急性关节疼痛如何导致中枢神经系统(CNS)通路改变的认识差距 负责感知、传递和调节疼痛。这一过程导致了广泛的痛苦 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 以防止类风湿性关节炎(RA)的疼痛集中，从而防止慢性疼痛。其目标是确定 导致早期慢性疼痛发生的可改变的临床因素和神经生物学途径 拉。此应用程序的重点是早期RA，因为RA诊断后的前12个月可能代表 防止急性疼痛向慢性疼痛过渡的关键时刻。加拿大早盘的初步数据 关节炎队列(CATCH)显示，纤维肌痛的发生率，典型的集中性疼痛状况， 在RA确诊后的第一年是最高的。中心假设是睡眠问题，心理社会问题 因素和异常的中枢神经系统(如大脑、脊髓)调节机制预测疼痛的发展 类风湿性关节炎确诊后第一年集中。核心假说将通过追求 以下三个具体目标：1)确定预测疼痛集中症状的可修改因素 早期类风湿关节炎；2)确定增强的中枢神经系统疼痛处理的定量感觉测试(QST)证据 预测疼痛集中的症状；以及3)确定脑功能和解剖通路 早期类风湿关节炎潜在的疼痛集中。对于第一个目标，534名早期类风湿关节炎患者来自Catch和Catch- 美国(美国推广CATCH)将完成对睡眠、疼痛、心理社会因素的测量，并 在进入队列后0、3、6和12个月进行残疾治疗。对于第二个目标，125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个月和12个月时接受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的组织体积)， 以前被证明与疼痛集中有关。建议的研究具有创新性。 因为它代表着与现状的实质性背离：1)专注于早期RA，2)纳入 两个多部位早期RA登记中疼痛相关结构的评估，以及3)采用多模式 方法，包括患者报告的疼痛测量，QST和神经成像，以评估疼痛路径。这个 拟议的研究具有重要意义，因为它将为干预设计(例如，认知行为)奠定基础 治疗睡眠问题，加巴喷丁早期治疗疼痛)，以及未来预防慢性 疼痛，最终导致全身性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.