Neurobiology of Placebo Effects in Fibromyalgia

描述(由申请人提供)：在临床试验中，安慰剂反应是“噪音”的主要来源。检查安慰剂反应机制和潜在替代物(生物标志物)的功能的个体间差异将有助于以客观、机械的方式告知临床研究中的可变性来源。Biologica安慰剂效应的形成也代表了一种弹性机制，揭示了治疗环境创造的预期的认知情感整合。因此，对这些过程的描述将指向传统药物或治疗开发中没有考虑到的生物靶点。三十多年来，内源性阿片类药物机制一直集中参与安慰剂止痛效果的形成，但其作用尚未在临床样本中得到系统研究。这项应用检查了诊断为纤维肌痛(FM)的患者的内源性阿片系统的完整性，FM是一种具有中度安慰剂反应的持续性疼痛综合征。我们将利用正电子发射断层扫描和选择性μ-阿片受体放射性示踪剂来获得已知与临床和实验样本中安慰剂止痛效果形成相关的客观分子测量。μ-阿片受体(μOR)可获得性的测量以及对释放挑战(预期止痛的静脉注射安慰剂)的神经递质系统的激活将与治疗反应措施进行对照，这实际上代表了一项有活性和无活性预期的受试者内随机交叉安慰剂试验。我们将采用非欺骗性同意方法，遵循当前的伦理建议，并与我们实验室正在进行的研究保持一致。研究建议，在扫描期间和试验期间服用安慰剂的试验中产生的改善的积极预期的背景下，基线μ或在体内的可用性以及激活这一神经递质系统的能力将与FM患者的治疗反应相关。本着临床可应用性的精神，这些对FM治疗反应预测因素的机械性、分子成像研究将得到更简单的生物标志物检查的补充。选定的标志物已被发现与内源性阿片系统功能有关，它们的预测价值将单独和联合作为所谓的“非特异性”治疗反应的潜在预测因子进行审查。这项建议汇集了一支全面的临床医生和科学家团队，他们拥有专门和互补的专业知识，在分子成像、慢性疼痛、FM和临床试验方面有着丰富的记录，这是管理和完成所建议研究的独特地位。它解决了一个严重的健康问题，慢性疼痛，以及临床研究中一个重要的变异性来源-生物安慰剂效应，这一效应尚未在临床样本中进行机械层面的系统研究。获得的数据还将指向新的治疗靶点 在传统的药物发现策略中没有涉及到。

DESCRIPTION (provided by applicant): Placebo responses represent a substantial source of "noise" in clinical trials. Examination of inter-individual differences in the function of placebo responsive mechanisms, and potential surrogates (biomarkers) would help inform the sources of variability in clinical studies in an objective, mechanistic fashion. The formation of biologica placebo effects also represents a resiliency mechanism, uncovered by the cognitive emotional integration of the expectations created by the treating environment. As such, delineation of these processes would point to biological targets that have not been contemplated in traditional drug or treatment development. Endogenous opioid mechanisms have been centrally implicated in the formation of placebo analgesic effects for more than three-decades, but their function has not been systematically studied in clinical samples. This application examines the integrity of the endogenous opioid system in a sample of patients diagnosed with fibromyalgia (FM), a persistent pain syndrome with moderate placebo responses. We will utilize positron emission tomography (PET) and a selective μ-opioid receptor radiotracer to acquire objective molecular measures known to be associated with the formation of placebo analgesic effects in clinical and experimental samples. Measures of μ-opioid receptor (μOR) availability at baseline and the activation of this neurotransmitter system in response to a releasing challenge (intravenous placebo with expectation of analgesia) will be examined against treatment response measures in what effectively represents a within- subject, randomized, cross-over trial of placebo pills wit and without expectations of activity. We will utilize non-deceptive consent methodology, following current ethical recommendations and consistent with ongoing studies in our laboratory. It is proposed that baseline μOR availability in vivo and the capacity to activate this neurotransmitter system in the context of positive expectations of improvement experimentally created during scanning and by the administration of placebo during the trial, will be associated with treatment response in FM patients. In the spirit of clinical applicability, these mechanistic, molecular imaging studies of predictors of treatment response in FM will be complemented by the examination of simpler biomarkers. The selected markers have been found associated with endogenous opioid system function, and their predictive value, alone and in combination, will be examined as potential predictors of so-called "non-specific" treatment responses. This proposal assembles a comprehensive team of clinicians and scientists with specialized and complementary expertise, and substantial track records in molecular imaging, chronic pain, FM and clinical trials that is uniquely positioned to manage and complete the studies proposed. It addresses a severe health problem, chronic pain, and a substantial source of variability in clinical studies, biological placebo effects, which has not been systematically studied at a mechanistic level in clinical samples. The data acquired will also point to novel treatment targets not addressed in traditional drug discovery strategies.