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，并且与实质性的个人痛苦，生产力失去和医疗保健成本有关。使用阿片类镇痛药来治疗非恶性慢性疼痛，但由于相关的副作用和滥用潜力而引起争议。此外，在个体之间，阿片类镇痛药的镇痛功效可能会差异很大。鉴于阿片类镇痛药越来越多地用于治疗慢性疼痛，我们的目标是提高对影响阿片类镇痛有效性的因素的理解，并可能与理解阿片类药物的风险有关。对阿片类镇痛药的反应中个体差异的可能预测因素包括负面影响和情绪调节的特征，性别，实验性急性疼痛敏感性，内源性阿片类动力学β-内啡肽（BE）的循环水平以及条件疼痛调节的效率（CPM）。一种常见的机制，可以解释这些不同因素如何预测阿片类镇痛反应是内源性阿片类药物系统功能。我们提出，负面影响和情绪调节，性别，急性疼痛敏感性，血浆BE水平和CPM的特征可能会揭示对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药物抗脑膜炎感性系统的功能而间接发挥影响。我们将使用受控的实验室方法评估120例慢性腰痛患者（LBP）患者的急性疼痛反应，并使用随机，平衡的设计在三个课程中进行120个健康对照：安慰剂下，阿片类药物阻滞（Naloxone）和阿片类动物（Morphine）。 AIM1是确定内源性阿片类药物功能指数（阿片类药物阻断对疼痛反应的影响）与外源性阿片类镇痛作用有关的程度，并将LBP患者中的这些关联与健康人员进行比较。这将是对更好的内源性阿片类药物功能（较大的阿片类药物阻滞作用）预测较大的外源性阿片类镇痛的假设的创新检验。目的2是确定：a）负面影响和情绪调节性状，性别，急性疼痛敏感性，静息等离子体的水平以及CPM与外源性阿片类镇痛作用有关（总效应）的程度； b）这些因素与内源性阿片类药物功能的差异（封闭效应）（介导）间接与外源阿片类镇痛作用间接相关的程度。 AIM 3将探索阿片类药物副作用，阿片类药物滥用潜力，阿片类镇痛功效和内源性阿片类药物功能之间的关系。结果不仅可以改善对这些潜在的阿片类镇痛反应的潜在标志物如何直接通过常见的内源性阿片类药物来直接起作用，而且最终允许临床表征给定患者的基于阿片类药物的疼痛管理的可能成本/益处。此外，结果可能表明可以直接针对这些预测因素的基础的常见疼痛调节机制的干预措施。