Neurobiology of Placebo Effects in Fibromyalgia

纤维肌痛安慰剂效应的神经生物学

基本信息

批准号：
8893900
负责人：
Jon-Kar Zubieta
金额：
--
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8893900
关键词：
Absence of pain sensation Accounting Acute Address Affect Affective Amygdaloid structure Analgesics Anterior Biological Biological Markers Brain Brain region Cholecystokinin Clinical Clinical Medicine Clinical Research Clinical Trials Cognitive Complement Consent Cross-Over Trials Crossover Design Data Decision Making Diagnosis Disclosure Dopamine Dorsal Ego Emotional Environment Enzymes Ethics Experimental Models Fibromyalgia Genes Genetic Polymorphism Health Hydrocortisone Individual Individual Differences Inflammatory Intervention Intravenous Laboratories Literature Measurement Measures Mediating Medical Methodology Molecular Nature Neurobiology Neurotic Disorders Neurotransmitters Noise Nucleus Accumbens Opioid Opioid Receptor Pain Patients Persistent pain Personality inventories Pharmaceutical Preparations Pilot Projects Placebo Effect Placebos Plasma Positioning Attribute Positron-Emission Tomography Predictive Value Process Psychophysics Randomized Recommendation Records Recovery Regulation Reporting Rewards Sampling Scanning Science Scientist Sensory Social Environment Source Structure Surrogate Markers Syndrome System Technology Testing Thalamic structure Therapeutic Therapeutic Intervention Time Translating Variant Wit body mechanics chronic pain clinical application clinical practice conditioning cytokine drug development drug discovery endogenous cannabinoid system endogenous opioids expectation fatty acid amide hydrolase healthy volunteer in vivo inter-individual variation midbrain central gray substance molecular imaging neurochemistry neuroimaging neuroregulation neurotransmission novel patient stratification pill potential biomarker psychosocial radiotracer randomized trial receptor response symptomatic improvement therapy development trait treatment response week trial

项目摘要

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 �-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 �-opioid receptor (�OR) 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 �OR 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.

描述（由应用程序提供）：安慰剂反应代表了临床试验中“噪声”的大量来源。检查安慰剂反应机制和潜在替代物（生物标志物）功能的个体间差异将有助于以客观的机械方式为临床研究中的可变性提供信息。生物安慰剂效应的形成也代表了一种弹性机制，这是由于治疗环境所产生的期望的认知情绪整合所揭示的。因此，对这些过程的描述将指出传统药物或治疗开发中未考虑的生物学靶标。内源性阿片类药物机制已在三个以上以上的安慰剂镇痛作用形成中被集中隐含，但是在临床样品中，它们的功能尚未系统地研究。本申请考试的完整性诊断为纤维肌痛（FM）的患者样本中的内源性阿片类药物系统，这是一种具有现代安慰剂反应的持续性疼痛综合征。我们将利用阳性发射断层扫描（PET）和选择性 - 阿片受体放射性示例来获取已知与临床和实验样品中安慰剂镇痛作用相关的已知分子测量。基线时的 - 阿片受体（或）可用性的措施以及该神经递质系统的激活，以应对释放挑战（静脉内安慰剂和镇痛的期望）的响应，以实现治疗反应度量，这有效地代表了一项内部主题，随机，随机，随机，随机的，无需预期的次要剂量的，而无需预期的活动。根据当前的道德建议，我们将利用非欺骗性的同意方法，并与我们实验室正在进行的研究一致。有人提出，在扫描过程中对改善的积极预期和试验期间的安慰剂给药的积极期望，基线或在体内的可用性以及激活该神经递质系统的能力将与FM患者的治疗反应有关。本着临床适用性的精神，这些机制， FM治疗反应预测指标的分子成像研究将通过检查更简单的生物标志物来完成。已经发现所选标记与内源性阿片类药物系统功能相关，并且它们的预测值单独和组合将被检查为所谓“非特异性”治疗反应的潜在预测指标。该提案组成了一个由专业和互补专业知识组成的综合团队和科学家团队，并在分子成像，慢性疼痛，FM和临床试验方面进行了实质性的记录，这些记录旨在管理和完成所提出的研究。它解决了严重的健康问题，慢性疼痛以及临床研究，生物安慰剂效应的大量可变性来源，在临床样品中，在机械水平上尚未系统地研究。获取的数据还将指向新的治疗目标没有在传统的药物发现策略中解决。