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情况的患病率急剧上升。从历史上看，骨性关节炎的“疾病”主要被视为软骨和骨的损伤。因此，这些结构的损伤或炎症程度可以预测症状。基于人群的研究表明并非如此；30- 50%患有中度至重度骨关节炎的患者无症状，约10%患有中度至重度膝关节疼痛的患者x线片正常2,3。在疼痛和其他症状的差异中，心理因素确实占了大约4.5%，但只是很小的一部分。外周损伤、炎症甚至心理因素都不能解释慢性疼痛的存在、缺失或严重程度，这不足为奇。迄今为止，没有慢性疼痛状态涉及外周因素和疼痛水平之间的强烈关系。我们假设，虽然外周伤害性输入和较小程度的心理因素在导致KOA的疼痛和症状表达中起重要作用，但一些患者具有不同程度的非心理中枢神经系统（CNS）因素，这些因素在疼痛和共病症状的表达中发挥同等甚至更突出的作用6-8。广泛地说，在慢性疼痛状态下，已经确定的患者亚群具有突出的中枢神经系统机制（与外周损伤相反或除了外周损伤外），在疼痛感知中起重要作用。这些因素包括弥漫性痛觉过敏或异常性疼痛，和/或缺乏内源性降压镇痛活性6,8,9。到目前为止，对这些中枢神经系统因素在OA中的探索还比较有限，但越来越多的证据支持OA患者亚群确实具有这些有效机制的假设10-12。我们的假设进一步得到了一些研究的支持，这些研究已经确定了与中枢性疼痛状况（如疲劳、睡眠问题）相关的共病躯体症状在OA中普遍存在13,14。最后，最近的随机对照试验表明，中枢改变疼痛神经递质的化合物，如15、16血清素和去甲肾上腺素（如度洛西汀、三环类药物）对OA有效。我们将确定中枢神经系统因素在KOA中发挥的作用，首先显示患者亚群具有症状模式和实验性感觉测试异常，与疼痛的“中枢”成分一致。然后，我们将通过显示患有中枢性疼痛的KOA患者对膝关节置换术的反应不佳来证明这些措施的效用。鉴于膝关节置换术的高“失败率”，该研究具有17个高公共卫生影响。如果KOA的现状保持不变，预计在未来20年内，膝关节置换术的需求将增加700%。因此，除了本研究为我们关于OA“疾病”的思维提供了潜在的范式转变之外，本研究还开发了实用的临床工具，用于识别OA中中枢增强型疼痛的存在。

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. PUBLIC HEALTH RELEVANCE: This study aims to examine why individuals with osteroarthritis of the knee respond poorly to knee arthroplasty. With demand for this procedure increasing, and an aging population, it is important to examine why there is such a high failure rate in this population.