Centralized Pain Phenotype as a Predictor of Opioid Non-responsiveness

 描述(由申请人提供)：手术后的中度到重度疼痛很常见，即使在手术后也是如此。尽管阿片类药物的副作用和相关不良事件已知，但它仍是术后急性疼痛护理的主要药物。到目前为止，大多数研究都集中在麻醉和手术因素与较高的急性疼痛相关，因此在很大程度上忽略了患者之间在疼痛敏感度上的差异。因此，阿片类药物和区域麻醉药的药理辅助药物已被广泛应用于全有或无的方式，而不是根据患者的特征进行个性化。越来越多的人认识到改变中枢神经系统(CNS)处理慢性疼痛状态下疼痛和其他症状的重要性。广泛的躯体疼痛、痛觉过敏和集中性疼痛状态的共病症状在纤维肌痛中得到了最好的研究。纤维肌痛症状并不是存在或不存在的，而是以一种被称为“纤维肌痛”的连续体出现，并可作为集中化程度的粗略替代。阿片类药物被认为对集中性疼痛患者效果较差。我们的基本假设是，尽管外周伤害性信息的输入在急性疼痛反应中很重要，但一些患者具有不同程度的中枢神经系统放大(较高的纤维肌痛)，在疼痛和阿片类药物的消费中发挥着同等甚至更突出的作用。因此，我们假设，疼痛患者更“集中”，因为通过提供内源性阿片类药物音调的替代测量，简单的自我报告测量的疼痛集中程度强烈预测急性阿片类疼痛反应。为了验证我们的假设，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时间进行前瞻性评估。这些数据将被用来评估纤维肌痛是否预示着服用阿片类药物的人急性疼痛更严重，阿片类药物消耗更多，疼痛反应更少。为了评估这些临床发现的机制基础，我们将对200名膝关节置换术患者中的60名进行术前功能成像(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的脑成像结果。然后，阿片类药物的消费和疼痛报告将与大脑成像结果进行分析。与我们个性化止痛药的长期目标一致，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哪些人将是非阿片类药物或减少阿片类药物急性止痛方案的有力候选者。

 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.