Central Nervous System Mechanisms in Knee Osteoarthritis (KOA)

描述（由申请人提供）：最近的研究表明，症状性膝关节骨性关节炎（KOA）的终生风险为45%1。人口老龄化和肥胖率的增加导致这种疾病的患病率急剧增加。从历史上看，OA的“疾病”主要被视为对软骨和骨骼的损伤。因此，这些结构的损伤或炎症程度应该可以预测症状。以人群为基础的研究表明并非如此; 30- 50%的中重度OA影像学改变的个体无症状，约10%的中重度膝关节疼痛患者影像学正常2，3。心理因素确实可以解释疼痛和其他症状的这种差异，但程度很小。外周损伤、炎症甚至心理因素无法解释慢性疼痛的存在、不存在或严重程度，这并不奇怪。迄今为止，没有慢性疼痛状态涉及外周因素和报告的疼痛水平之间的密切关系。我们假设，尽管外周伤害性输入和较小程度的心理因素在导致KOA疼痛和症状表达方面很重要，但一些患者具有不同程度的非心理性中枢神经系统（CNS）因素，这些因素在KOA疼痛和共病症状的表达中发挥着同样或甚至更突出的作用6-8。广泛地在慢性疼痛状态中，已经确定了具有在疼痛感知中发挥重要作用的突出CNS机制（与外周损伤相反或除了外周损伤之外）的患者子集。这些因素包括弥漫性痛觉过敏或异常性疼痛，和/或缺乏内源性下行镇痛活性6，8，9。迄今为止，对这些中枢神经系统因素的探索在OA中受到一定的限制，但正在出现的证据支持这样的假设，即OA患者的亚群确实具有这些机制10-12。我们的假设进一步得到了研究的加强，这些研究已经确定了已知与中枢性疼痛病症相关的共病躯体症状（例如，疲劳，睡眠问题）是常见的OA 13，14。最后，最近的随机对照试验表明，改变中枢疼痛神经递质的化合物，如15，16血清素和去甲肾上腺素（例如，度洛昔单抗、三环类）在OA中有效。我们将确定的作用，中枢神经系统的因素在KOA中发挥的作用，首先表明，患者的子集有症状模式和实验感觉测试异常一致，有一个“中央”的组成部分，他们的疼痛。然后，我们将证明这些措施的效用，显示与中央疼痛的KOA的个人将对膝关节置换术反应不佳。鉴于膝关节置换术的高“失败”率，此类研究具有较高的公共卫生影响。如果KOA的实践现状得以维持，膝关节置换术的需求将在未来20年内增加700%。因此，除了这项研究提供了一个潜在的范式转变，我们的思维有关的“疾病”的OA，这项研究还开发了实用的临床工具，以确定存在的中枢增强疼痛的OA。

DESCRIPTION (provided by applicant): Recent studies suggest the lifetime risk for symptomatic knee OA (KOA) is 45%1. An aging population and increasing rates of obesity contribute to dramatic increases in the prevalence of this condition. Historically, the "disease" of OA is viewed primarily as damage to the cartilage and bone. As such, the magnitude of damage or inflammation of these structures should predict symptoms. Population-based studies suggest otherwise; 30- 50% of individuals with moderate to severe radiographic changes of OA are asymptomatic, and approximately 10% with moderate to severe knee pain have normal radiographs2,3. Psychological factors do account for some 4,5 of this variance in pain and other symptoms, but only to a small degree . This failure of peripheral damage, inflammation, or even psychological factors to explain the presence, absence, or severity of chronic pain should not be surprising. To date, no chronic pain state involves a strong relationship between peripheral factors and the level of pain reported. We hypothesize that, although peripheral nociceptive input and to a lesser extent psychological factors are important in leading to pain and symptom expression in KOA, some patients possess varying degrees of non-psychological central nervous system (CNS) factors which play an equally or even more prominent role in the expression of pain and co-morbid symptoms 6-8. Broadly within chronic pain states, subsets of patients have been identified that have prominent CNS mechanisms (as opposed or in addition to, peripheral damage) playing important roles in pain perception. Such factors include diffuse hyperalgesia or allodynia, and/or a lack of endogenous descending analgesic activity 6,8, 9 . The exploration of these CNS factors has been somewhat limited to date in OA, but evidence is emerging that supports the hypothesis that subsets of OA patients do indeed have these mechanisms operative 10-12. Our hypothesis is further strengthened by studies that have identified co-morbid somatic symptoms known to be associated with central pain conditions (e.g., fatigue, sleep problems) to be commonly present in OA 13, 14. Finally, recent RCTs have demonstrated that compounds that alter pain neurotransmitters centrally such as 15,16 serotonin and norepinephrine (e.g., duloxetine, tricyclics) are efficacious in OA . We will identify the role that CNS factors are playing in KOA by first showing that subsets of patients have symptom patterns and experimental sensory testing abnormalities consistent with having a "central" component to their pain. We will then demonstrate the utility of these measures by showing that individuals with KOA with central pain will respond poorly to knee arthroplasty. Such a study possesses 17 high public health impact given the high "failure" rate of knee arthroplasty . If the status quo in practice for KOA is maintained, demand for knee arthroplasty will increase by an expected 700% in the next 20 years 18. Thus, in addition to this study providing a potential paradigm shift in our thinking regarding the "disease" of OA, this study also develops practical clinical tools for identifying the presence of centrally-enhanced pain in OA.