Predictors of Opioid Analgesic Responses and Common Endogenous Opioid Mechanisms

阿片类镇痛反应的预测因素和常见的内源性阿片类药物机制

• 批准号: 9249839
• 负责人: Stephen Bruehl
• 金额: $ 29.85万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249839
• 关键词: Predictors; Opioid; Analgesic; Responses; Common

DESCRIPTION (provided by applicant): Chronic nonmalignant pain is highly prevalent, and is associated with substantial personal suffering, lost productivity, and healthcare costs. Use of opioid analgesics for management of nonmalignant chronic pain has increased dramatically, yet is fraught with controversy due to associated side effects and abuse potential. Moreover, the analgesic efficacy of opioid analgesics can vary widely between individuals. Given the increasing use of opioid analgesics for the management of chronic pain, we aim in this project to improve understanding of factors that influence opioid analgesic effectiveness, and which may have relevance to understanding opioid risks. Possible predictors of individual differences in responses to opioid analgesics include traits of negative affect and emotion regulation, sex, experimental acute pain sensitivity, circulating levels of the endogenous opioid agonist beta-endorphin (BE), and efficiency of conditioned pain modulation (CPM). A common mechanism that may explain how these diverse factors could all predict opioid analgesic responses is endogenous opioid system function. We propose that traits of negative affect and emotion regulation, sex, acute pain sensitivity, plasma BE levels, and CPM may reveal direct effects on opioid analgesic responses, but may also exert influence indirectly via associations with functioning of endogenous opioid antinociceptive systems. We will use controlled laboratory methods to assess acute pain responses in 120 chronic low back pain (LBP) patients and 120 healthy controls across three sessions using a randomized, counterbalanced design: under placebo, opioid blockade (naloxone), and opioid agonist (morphine). Aim1 is to determine the degree to which an index of endogenous opioid function (opioid blockade effects on pain responses) is related to exogenous opioid analgesic effects, and to compare these associations in LBP patients to those shown in healthy people. This will be an innovative test of the hypothesis that better endogenous opioid function (larger opioid blockade effects) predict greater exogenous opioid analgesia. Aim 2 is to determine: a) the degree to which negative affect and emotion regulation traits, sex, acute pain sensitivity, resting plasma BE levels, and CPM are related to exogenous opioid analgesic effects (total effect); and b) the degree to which these factors are related indirectly to exogenous opioid analgesic effects via differences in endogenous opioid function (blockade effects) (mediation). Aim 3 will explore relationships among opioid side effects, indicators of opioid abuse potential, opioid analgesic efficacy, and endogenous opioid function. Results could improve not only theoretical understanding of how these potential markers for poor opioid analgesic response may operate directly versus through a common endogenous opioid mechanism, but eventually permit clinical characterization of likely costs/benefits of opioid-based pain management a priori for a given patient. In addition, results may suggest interventions that could directly target common pain modulatory mechanisms underlying these predictive factors.

描述（由申请人提供）：慢性非恶性疼痛非常普遍，并且与大量的个人痛苦、生产力损失和医疗保健费用相关。阿片类镇痛药用于非恶性慢性疼痛的管理已显着增加，但由于相关的副作用和滥用的可能性充满了争议。此外，阿片类镇痛剂的镇痛功效在个体之间可能差异很大。鉴于越来越多地使用阿片类镇痛药来治疗慢性疼痛，我们在本项目中的目标是提高对影响阿片类镇痛药有效性的因素的理解，这些因素可能与理解阿片类药物的风险有关。对阿片类镇痛药反应的个体差异的可能预测因素包括负面情绪和情绪调节、性别、实验性急性疼痛敏感性、内源性阿片激动剂β-内啡肽（BE）的循环水平和条件性疼痛调节（CPM）的效率。一个共同的机制，可以解释如何这些不同的因素都可以预测阿片类镇痛反应是内源性阿片系统的功能。我们认为，负面情绪和情绪调节，性别，急性疼痛敏感性，血浆BE水平和CPM的特点可能揭示阿片类镇痛反应的直接影响，但也可能通过与内源性阿片类镇痛系统的功能间接施加影响。我们将使用对照实验室方法评估120名慢性腰痛（LBP）患者和120名健康对照者的急性疼痛反应，采用随机、平衡设计：安慰剂、阿片类药物阻滞剂（纳洛酮）和阿片类药物激动剂（吗啡）。目的1是确定内源性阿片功能指数（阿片类药物对疼痛反应的阻滞作用）与外源性阿片类药物镇痛作用的相关程度，并将LBP患者的这些相关性与健康人的相关性进行比较。这将是一个创新的测试的假设，更好的内源性阿片功能（更大的阿片阻滞作用）预测更大的外源性阿片镇痛。目标2是确定：a）负面情绪和情绪调节特征、性别、急性疼痛敏感性、静息血浆BE水平和CPM与外源性阿片类镇痛作用相关的程度（总效应）;和B）这些因素通过内源性阿片类功能（阻断效应）（中介）的差异与外源性阿片类镇痛作用间接相关的程度。目的3探讨阿片类药物副作用、阿片类药物滥用可能性指标、阿片类药物镇痛疗效和内源性阿片功能之间的关系。结果不仅可以提高对这些阿片类镇痛反应不良的潜在标志物如何直接与通过常见的内源性阿片类机制起作用的理论理解，而且最终可以对给定患者先验地进行基于阿片类药物的疼痛管理的可能成本/获益的临床表征。此外，研究结果可能表明，干预措施可以直接针对这些预测因素的共同疼痛调节机制。