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: 8159687
• 负责人: Stephen Bruehl
• 金额: $ 58.95万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8159687
• 关键词: Absence of pain sensation; Acute Pain; Adverse effects; Affect; Agonist; Analgesics; Chronic; Chronic low back pain; Clinical; Constipation; Costs and Benefits; Data; Dependence; Effectiveness; Equilibrium; Health Care Costs; Individual; Individual Differences; Intervention; Laboratories; Low Back Pain; Measures; Mediation; Medication Management; Methods; Morphine; Naloxone; Non-Malignant; Opioid; Opioid Analgesics; Pain; Pain management; Patients; Pharmaceutical Preparations; Placebos; Plasma; Predictive Factor; Productivity; Protocols documentation; Public Health; Randomized; Research; Rest; Risk; Running; Sedation procedure; Severities; System; Testing; Validity and Reliability; Ventilatory Depression; base; beta-Endorphin; chronic pain; design; diffuse noxious inhibitory control; emotion regulation; endogenous opioids; experience; improved; indexing; innovation; opioid abuse; response; sex; tool; trait

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.

描述（由申请人提供）：慢性非恶性疼痛非常普遍，并且与巨大的个人痛苦、生产力损失和医疗费用相关。阿片类镇痛药用于治疗非恶性慢性疼痛的使用急剧增加，但由于相关的副作用和滥用可能性而充满争议。此外，阿片类镇痛药的镇痛功效在个体之间可能存在很大差异。鉴于阿片类镇痛药越来越多地用于治疗慢性疼痛，我们在该项目中的目标是提高对影响阿片类镇痛药效果的因素的了解，这些因素可能与了解阿片类药物的风险相关。阿片类镇痛药反应个体差异的可能预测因素包括负面情绪和情绪调节特征、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）的循环水平以及条件性疼痛调节（CPM）的效率。可以解释这些不同因素如何预测阿片类镇痛反应的一个常见机制是内源性阿片类系统功能。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镇痛系统功能的关联而间接产生影响。我们将使用受控实验室方法来评估 120 名慢性腰痛 (LBP) 患者和 120 名健康对照者在三个疗程中的急性疼痛反应，使用随机、平衡的设计：安慰剂、阿片类药物阻断（纳洛酮）和阿片类药物激动剂（吗啡）。目的1是确定内源性阿片类药物功能指数（阿片类药物对疼痛反应的阻断作用）与外源性阿片类药物镇痛作用的相关程度，并将 LBP 患者与健康人中显示的这些关联进行比较。这将是对以下假设的创新测试：更好的内源性阿片类药物功能（更大的阿片类药物阻断作用）预示着更强的外源性阿片类药物镇痛作用。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效果（总效果）的相关程度； b) 这些因素通过内源性阿片类药物功能的差异（阻断效应）（介导）与外源性阿片类药物镇痛作用间接相关的程度。目标 3 将探讨阿片类药物副作用、阿片类药物滥用潜力指标、阿片类药物镇痛功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这些阿片类药物镇痛反应不佳的潜在标志物如何直接发挥作用与通过常见的内源性阿片类药物机制发挥作用的理论理解，而且最终可以对特定患者基于阿片类药物的疼痛管理的可能成本/收益进行临床表征。此外，结果可能表明可以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。 公共健康相关性：阿片类镇痛药用于治疗非恶性慢性疼痛的使用有所增加，但由于滥用、依赖性和副作用的风险，而且个体之间的镇痛效果差异很大，因此充满争议。至关重要的是，我们必须找到区分那些将从阿片类镇痛药中获得最佳益处的患者与那些可能体验到很少治疗益处但仍面临副作用风险的患者的方法。该项目将测试阿片类药物镇痛反应不佳的几种潜在预测因素，并将寻求了解可能构成这些预测效果的常见内源性阿片类药物机制。