Central Pain Mechanisms, Pain Intensity and Drug Response in Rheumatoid Arthritis

描述（由申请方提供）：本提案的总体目标是了解活动性类风湿关节炎（RA）患者的中枢疼痛调节机制、临床疼痛体验（临床疼痛强度、疼痛行为和干扰）与治疗反应之间的关系。慢性疼痛是一种使人衰弱的健康问题，影响超过1.16亿人。慢性疼痛最常见的原因之一是关节炎，影响着22%的成年人。RA疼痛是最常见的全身性炎症性关节炎，历史上认为是由于关节炎症。然而，70%的RA患者将疼痛视为他们的首要任务，尽管使用了疾病缓解抗风湿药物（DMARD）治疗，并且大约三分之一对免疫抑制治疗没有反应。与一般人群相比，RA患者对广泛分布的疼痛更敏感，影响关节和非关节部位。这些观察结果表明，类风湿关节炎患者改变了中枢疼痛机制。尚不清楚反映中枢机制改变的疼痛敏感性增强是否会使RA患者产生更强烈的临床疼痛，超出关节炎症的预期。与作用于中枢疼痛机制的疗法相比，这些患者对作用于外周炎症的DMARD的反应是否较差也尚不清楚。该项目的中心假设是中枢疼痛机制的改变与临床疼痛（疼痛强度，疼痛行为，疼痛干扰）和不良DMARD反应的测量值升高相关。本研究的具体目的是：1）确定RA患者的中枢疼痛机制与疼痛强度、疼痛行为和疼痛干扰之间的关系; 2）评估中枢疼痛机制对治疗反应的影响。这项研究将跟踪272名RA患者开始或转换DMARD治疗超过12周。为了评估总体中枢性疼痛机制，将在关节和非关节部位测量压痛阈值（导致疼痛的压力量）。此外，将评估两种特定类型的中枢疼痛机制，即下行镇痛通路和中枢致敏。下行镇痛通路抑制从大脑延伸到脊髓的疼痛信号，而中枢致敏与传递疼痛的中枢神经系统神经元的兴奋性升高有关。将使用条件性疼痛调节的范例评估下行镇痛机制，其中疼痛条件刺激（冷加压）用于刺激镇痛通路。将使用时间总和的范例评估中枢致敏，其中重复给予有害刺激，并在每个系列的开始和结束时评估疼痛等级。我们将研究中枢性疼痛机制与疼痛强度和治疗反应的主要结局之间的关联。这项研究的结果将通过确定全身炎症性疾病疼痛管理的机制为基础的目标产生重要的积极影响。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to understand the relationship between central pain regulatory mechanisms, the clinical pain experience (clinical pain intensity, pain behaviors and interference) and treatment response in rheumatoid arthritis (RA) patients with active disease. Chronic pain is a debilitating health problem, affectig over 116 million people. One of the most common causes of chronic pain is arthritis, affecting 22% of the adult population. Pain in RA, the most common systemic inflammatory arthritis, is historically thought to be due to joint inflammation. However, 70% of RA patients rate pain as their number one priority, despite treatment with disease-modifying anti-rheumatic drugs (DMARDs), and approximately one-third do not respond to immunosuppressive therapy. Compared to the general population, RA patients are more sensitive to pain in a widespread distribution, affecting joint and non-joint sites. These observations suggest that RA patients have altered central pain mechanisms. It is not known whether enhanced pain sensitivity, reflecting alterations in central mechanisms, predisposes RA patients to more intense clinical pain, beyond what is expected from joint inflammation. It is also not known whether these patients respond less well to DMARDs, which act on peripheral inflammation, compared with therapies that act on central pain mechanisms. The central hypothesis of this project is that alterations in central pain mechanisms are associated with heightened measures of clinical pain (pain intensity, pain behavior, pain interference) and poor DMARD response. The specific aims of this proposal are to: 1) determine the associations between central pain mechanisms and pain intensity, pain behaviors and pain interference among RA patients, and 2) evaluate the effects of central pain mechanisms on treatment response. The proposed study will follow 272 RA patients starting or switching DMARD therapy over 12 weeks. To assess overall central pain mechanisms, pressure pain thresholds (the amount of pressure that causes pain) will be measured at both joint and non-joint sites. In addition, two specific types of central pain mechanisms, the descending analgesic pathways and central sensitization, will be assessed. The descending analgesic pathways dampen pain signals extending from the brain to the spinal cord, whereas central sensitization is associated with heightened excitability of the central nervous system neurons transmitting pain. Descending analgesic mechanisms will be assessed using the paradigm of conditioned pain modulation, whereby a painful conditioning stimulus (cold pressor) is used to stimulate the analgesic pathways. Central sensitization will be assessed using the paradigm of temporal summation, whereby a noxious stimulus is given repeatedly, and pain ratings are assessed at the beginning and end of each series. We will examine the association between central pain mechanisms and the primary outcomes of pain intensity and treatment response. The results of this study will have an important positive impact by identifying mechanism-based targets for pain management in systemic inflammatory diseases.