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，与严重的个人痛苦、生产力丧失和医疗费用有关。阿片类镇痛剂用于治疗非恶性慢性疼痛的数量急剧增加，但由于相关的副作用和滥用可能性，仍充满争议。此外，阿片类镇痛剂的止痛效果在不同个体之间可能存在很大差异。鉴于越来越多的阿片类镇痛剂用于慢性疼痛的治疗，我们在这个项目中的目的是提高对影响阿片类止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。阿片类镇痛剂反应的个体差异可能的预测因素包括负性情绪和情绪调节的特征、性别、实验性急性疼痛敏感性、内源性阿片激动剂β-内啡肽(BE)的循环水平以及条件性疼痛调制(CPM)的效率。一个共同的机制可以解释这些不同的因素如何都可以预测阿片类止痛反应是内源性阿片系统功能。我们认为负性情绪和情绪调节的特征、性别、急性疼痛敏感性、血浆BE水平和CPM可能直接影响阿片类药物的镇痛反应，但也可能通过与内源性阿片类药物抗伤害感受系统的功能相关来间接影响。我们将使用对照实验室方法，使用随机平衡设计，在三个疗程中评估120名慢性下腰痛(LBP)患者和120名健康对照的急性疼痛反应：在安慰剂、阿片类阻滞剂(纳洛酮)和阿片类激动剂(吗啡)下。目的1确定内源性阿片类药物功能指标(阿片类药物对疼痛反应的阻断效应)与外源性阿片类药物止痛效应之间的关系，并比较LBP患者和健康人的这种相关性。这将是对内源性阿片类药物功能更好(阿片类药物阻断效果更大)预示外源性阿片类药物镇痛效果更好的假设的创新检验。目的2是确定：a)负性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与外源性阿片类药物镇痛效应(总效应)的相关程度；以及b)这些因素通过内源性阿片类药物功能(阻断效应)(中介)的差异间接与外源性阿片类药物镇痛效应相关的程度。目的3探讨阿片类药物副作用、阿片类药物滥用潜能指标、阿片类药物镇痛效果和内源性阿片类药物功能之间的关系。这些结果不仅可以提高对这些阿片类止痛反应差的潜在标记物如何直接起作用而不是通过常见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特定患者进行基于阿片类药物的疼痛治疗的可能成本/收益的临床表征。此外，结果可能建议直接针对这些预测因素背后的常见疼痛调节机制进行干预。 公共卫生相关性：用于治疗非恶性慢性疼痛的阿片类镇痛剂的使用有所增加，但由于滥用、依赖和副作用的风险，以及因为止痛效果在个体之间可能存在很大差异，因此充满了争议。至关重要的是，我们要找出方法，区分那些将从阿片类止痛药中获得最佳益处的患者和那些可能获得很少治疗好处但仍有副作用风险的患者。该项目将测试阿片类药物镇痛反应性差的几个潜在预测因素，并将寻求了解可能支持这些预测效应的常见内源性阿片类药物机制。

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.