Centralized Pain Phenotype as a Predictor of Opioid Non-responsiveness

 描述（由申请人提供）：手术后中度至重度疼痛很常见，即使在被认为是“轻微”的手术后也是如此。“阿片类药物是急性术后疼痛护理的支柱，尽管它们具有已知的副作用和相关的不良事件。迄今为止，大多数研究都集中在与更高的急性疼痛相关的麻醉和手术因素上，从而在很大程度上忽略了疼痛敏感性的患者间差异。因此，对阿片类药物和区域麻醉剂的药理学抑制剂已经以全或无的方式广泛应用，而不是基于患者特征进行个性化。在慢性疼痛状态下，中枢神经系统（CNS）对疼痛和其他症状的处理改变的重要性越来越受到重视。广泛的身体疼痛，痛觉过敏和共病的中枢性疼痛状态已在纤维肌痛研究最好。而不是存在或不存在，纤维肌痛症状发生在连续体上，被称为“纤维肌痛”，可以作为集中程度的粗略替代。阿片类药物被认为对集中性疼痛患者的疗效较低。我们的主要假设是，虽然外周伤害性输入在急性疼痛反应中很重要，但有些患者具有不同程度的CNS放大（较高的纤维肌痛），在疼痛和阿片类药物消耗的表达中发挥着同等或甚至更突出的作用。因此，我们假设，患者的疼痛是更“集中”的疼痛集中的程度上测量一个简单的自我报告的措施，强烈预测急性阿片类药物疼痛反应，通过提供一个替代措施的内源性阿片紧张。为了检验我们的假设，我们将对接受全膝关节置换术的患者（n=200）的疼痛、阿片类药物消耗和不良急性术后期进行前瞻性评估。这些数据将用于评估纤维肌痛是否预示着更高的急性疼痛、更多的阿片类药物消耗以及对阿片类药物给药的疼痛反应较低。为了评估这些临床结果的机制基础，我们将在200例膝关节置换术患者中的60例纤维肌痛患者中进行术前功能成像（fMRI和PET扫描），以确定术前阿片类药物张力和先前描述的痛觉过敏脑成像结果。阿片类药物的消耗和疼痛报告将与脑成像结果进行分析。与我们个性化疼痛医学的长期目标一致，拟议的研究可能会对临床实践产生重大影响，因为可以很容易地确定一部分人是非阿片类或减少阿片类急性镇痛方案的强有力候选人。

 DESCRIPTION (provided by applicant): Moderate to severe pain following surgery is common, even after surgeries thought of as "minor." Opioids are the mainstay for acute postoperative pain care despite their known side effects and related adverse events. Most research to date has focused on the anesthetic and surgical factors associated with higher acute pain, thereby largely ignoring the inter-patient variability in pain sensitivity. As such, pharmacological adjuncts to opioids and regional anesthetics have been broadly applied in an all or none fashion rather than personalized based on patient characteristics. There is a growing appreciation of the importance of altered central nervous system (CNS) processing of pain and other symptoms in chronic pain states. The widespread body pain, hyperalgesia and comorbid symptomatology of centralized pain states has been best studied in fibromyalgia. Rather than being present or absent, fibromyalgia symptoms occur on a continuum that has been termed "fibromyalgianess" and can serve as a crude surrogate of the degree of centralization. Opioids are thought to be less effective in centralized pain patients. Our primary hypothesis is that although peripheral nociceptive input is important in the acute pain response, some patients possess varying degrees of CNS amplification (higher fibromyalgianess) that plays an equally or even more prominent role in the expression of pain and opioid consumption. Thus, we hypothesize that the patients with pain that is more "centralized" in that the degree of pain centralization as measured on a simple self-report measure strongly predicts acute opioid pain responsiveness by providing a surrogate measure of endogenous opioid tone. To test our hypothesis, we will conduct a prospective assessment of pain, opioid consumption and adverse acute postoperative period in patients undergoing total knee arthroplasty (n=200). These data will be used to assess whether fibromyalgianess predicts higher acute pain, more opioid consumption, and a lesser response of pain for the opioids administered. To assess the mechanistic underpinnings of these clinical findings, we will conduct preoperative functional imaging (fMRI and PET scanning) in 60 of the 200 knee arthroplasty patients across the continuum of fibromyalgianess to determine preoperative opioid tone and previously described brain imaging findings of hyperalgesia. The opioid consumption and pain reports will then be analyzed with the brain imaging findings. Consistent with our long term goal of personalized pain medicine, the proposed research could have a major impact on clinical practice because a subset of individuals could be easily identified who would be strong candidates for non- or reduced opioid acute analgesic regimens.