Neurobiology of Placebo Effects in Fibromyalgia

纤维肌痛安慰剂效应的神经生物学

• 批准号: 9352267
• 负责人: Jon-Kar Zubieta
• 金额: $ 59.65万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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/9352267
• 关键词: Absence of pain sensation; 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; Endocannabinoids; Environment; Enzymes; Ethics; Experimental Models; Fibromyalgia; Genes; Genetic Polymorphism; Health; Hydrocortisone; Individual; Individual Differences; Inflammatory; Interleukin-1 beta; Intervention; Intravenous; Laboratories; Literature; Measurement; Measures; Mediating; Medical; Methodology; Molecular; Nature; Neurobiology; Neurotic Disorders; Neurotics; Neurotransmitters; Noise; Nucleus Accumbens; Opioid; Pain; Patients; Persistent pain; Personality inventories; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Placebo Effect; Placebos; Plasma; Positioning Attribute; Positron-Emission Tomography; Predictive Value; Process; Psychophysics; Randomized; Receptor Activation; 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; chronic pain; clinical application; clinical practice; conditioning; cytokine; drug development; drug discovery; endogenous cannabinoid system; endogenous opioids; expectation; fatty acid amide hydrolase; healthy volunteer; imaging study; in vivo; inter-individual variation; molecular imaging; mu opioid receptors; neurochemistry; neuroimaging; neuroregulation; neurotransmission; novel; patient stratification; pill; potential biomarker; predictive of treatment response; psychosocial; public health relevance; radiotracer; randomized trial; receptor; resilience; response; symptomatic improvement; therapy development; trait; treatment response; week trial

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.

描述（由申请方提供）：安慰剂反应是临床试验中“噪音”的主要来源。检查安慰剂反应机制功能的个体间差异和潜在的替代物（生物标志物）将有助于以客观、机械的方式告知临床研究中的变异性来源。生物安慰剂效应的形成也代表了一种弹性机制，通过治疗环境所产生的期望的认知情感整合来揭示。因此，这些过程的描述将指向传统药物或治疗开发中未考虑的生物靶点。内源性阿片类药物机制在安慰剂镇痛作用的形成中起着重要作用，但其功能尚未在临床样本中进行系统研究。本申请检查了被诊断为纤维肌痛（FM）的患者样本中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（PET）和选择性μ-阿片受体放射性示踪剂，以获得已知与临床和实验样本中安慰剂镇痛作用形成相关的客观分子测量。在有效代表有和无预期活性的安慰剂片剂的受试者内、随机、交叉试验中，将对照治疗反应指标检查基线时μ-阿片受体（μOR）可用性的指标和该神经递质系统对释放激发（静脉注射安慰剂，预期镇痛）的激活。我们将使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一致。建议在扫描期间和试验期间通过安慰剂给药实验性改善的积极预期背景下，体内基线μOR可用性和激活该神经递质系统的能力将与FM患者的治疗反应相关。本着临床适用性的精神，这些机制，分子成像研究的预测治疗反应的FM将补充检查更简单的生物标志物。已发现所选标志物与内源性阿片系统功能相关，将检查其单独和组合的预测值作为所谓的“非特异性”治疗反应的潜在预测因子。该提案汇集了一个由临床医生和科学家组成的综合团队，他们具有专业和互补的专业知识，以及在分子成像，慢性疼痛，FM和临床试验方面的大量跟踪记录，具有独特的优势来管理和完成拟议的研究。它解决了严重的健康问题，慢性疼痛，以及临床研究中变异性的重要来源，生物安慰剂效应，尚未在临床样本中进行系统的机制研究。获得的数据还将指向新的治疗目标 传统的药物发现策略中没有提到。