Predictors of Opioid Analgesic Responses and Common Endogenous Opioid Mechanisms

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治疗已急剧增加，但由于相关的副作用和滥用潜力而充满争议。此外，阿片类镇痛药的镇痛效果在个体之间差异很大。鉴于阿片类镇痛药越来越多地用于慢性疼痛的治疗，我们在这个项目的目的是提高对影响阿片类镇痛药有效性的因素的理解，这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可能的预测因素包括负面情绪和情绪调节的特征、性别、实验性急性疼痛敏感性、内源性阿片类激动剂β -内啡肽（BE）的循环水平和条件疼痛调节（CPM）的效率。可能解释这些不同因素如何预测阿片镇痛反应的共同机制是内源性阿片系统功能。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等特征可能揭示了对阿片镇痛反应的直接影响，但也可能通过与内源性阿片抗感觉系统功能的关联间接施加影响。我们将采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，分三个阶段：安慰剂、阿片阻断剂（纳洛酮）和阿片激动剂（吗啡）。目的1是确定内源性阿片功能指数（阿片对疼痛反应的阻断作用）与外源性阿片镇痛作用的关系程度，并将LBP患者与健康人的相关性进行比较。这将是对更好的内源性阿片功能（更大的阿片阻断效应）预测更大的外源性阿片镇痛的假设的创新检验。目的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（总效应）的关系程度；b)这些因素通过内源性阿片功能的差异（阻断效应）（中介）间接与外源性阿片镇痛作用相关的程度。目的3将探讨阿片类药物副作用、阿片类药物滥用潜力指标、阿片类药物镇痛疗效和内源性阿片类药物功能之间的关系。结果不仅可以提高对阿片类药物不良镇痛反应的这些潜在标志物如何直接作用而不是通过共同的内源性阿片类药物机制的理论理解，而且最终可以先验地对给定患者的阿片类药物疼痛管理的可能成本/收益进行临床表征。此外，结果可能表明干预措施可以直接针对这些预测因素背后的常见疼痛调节机制。

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. PUBLIC HEALTH RELEVANCE: Use of opioid analgesics for management of nonmalignant chronic pain has increased, but is fraught with controversy because of risk of abuse, dependence and side effects, and because analgesic efficacy can vary widely between individuals. It is crucial that we identify ways of discriminating patients who will achieve optimal benefit from opioid analgesics from those who may experience few treatment benefits yet still run the risk of side effects. This project will test several potential predictors of poor opioid analgesic responsiveness, and will seek to understand common endogenous opioid mechanisms that may underlie these predictive effects.