Central Nervous System Mechanisms in Knee Osteoarthritis (KOA)

描述(由申请人提供)：最近的研究表明，有症状的膝骨性关节炎(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，骨性关节炎的“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的程度应该可以预测症状。基于人群的研究表明并非如此：30-50%的人有中度到重度的骨性关节炎放射学改变是没有症状的，而大约10%的中度到重度膝关节疼痛的人有正常的X光片2，3。心理因素确实在疼痛和其他症状的变化中解释了大约4，5，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、缺失或严重程度，这并不令人惊讶。到目前为止，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是导致膝关节骨性关节炎疼痛和症状表达的重要因素，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，已发现具有显著的中枢神经系统机制(与外周损伤相反或除此之外)在疼痛感知中发挥重要作用的患者亚群。这些因素包括弥漫性痛觉过敏或痛觉异常，和/或缺乏内源性下行止痛活性6，8，9。到目前为止，对这些中枢神经系统因素的探索在一定程度上局限于骨性关节炎，但正在出现的证据支持这样的假设，即骨性关节炎患者的亚组确实具有这些机制10-12。我们的假设进一步得到了研究的证实，已知与中枢疼痛状况(例如，疲劳、睡眠问题)有关的共病躯体症状通常出现在OA 13、14中。最后，最近的随机对照试验证明，在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(例如，度洛西汀，三环素)在OA中是有效的。我们将确定中枢神经系统因素在膝关节骨性关节炎中所起的作用，首先显示部分患者有症状模式和实验感觉测试异常，这些异常与他们疼痛的“中心”成分一致。然后，我们将通过展示患有中枢性疼痛的膝关节骨性关节炎患者对膝关节置换术的不良反应来证明这些措施的有效性。鉴于膝关节置换术的“失败率”很高，这项研究对公众健康有17项重大影响。如果膝关节骨性关节炎的实践现状保持不变，膝关节置换术的需求将在未来20年18增长700%。因此，除了这项研究提供了我们对骨性关节炎“疾病”思维的潜在范式转变外，这项研究还开发了实用的临床工具来识别骨性关节炎中是否存在中心性增强性疼痛。

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.