Stress and Opioid Misuse Risk: The Role of Endogenous Opioid and Endocannabinoid Mechanisms

压力和阿片类药物滥用风险：内源性阿片类药物和内源性大麻素机制的作用

• 批准号: 10399520
• 负责人: Stephen Bruehl
• 金额: $ 55.48万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399520
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Acute Pain; Address; Algorithms; Analgesics; Anxiety; Back Pain; Benefits and Risks; Cardiovascular system; Chronic low back pain; Clinical; Crossover Design; Data; Development; Dose; Double-Blind Method; Drug Exposure; Elements; Endocannabinoids; Equilibrium; Exposure to; Funding; Goals; Iatrogenesis; Impairment; Individual; Knowledge; Laboratories; Link; Literature; Low Back Pain; Measures; Mediating; Medicine; Mental Depression; Modeling; Morphine; Naloxone; Operative Surgical Procedures; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid agonist; Oral; Outcome Study; Oxycodone; Pain; Pain Measurement; Pain intensity; Pain management; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiological; Placebo Control; Placebos; Plasma; Play; Postoperative Pain; Property; Psychological reinforcement; Psychosocial Stress; Randomized; Rest; Risk; Risk Marker; Role; Standardization; Stimulus; Stress; System; Testing; Time; Weight; Work; base; biological adaptation to stress; chronic pain management; chronic pain patient; clinically relevant; design; diaries; disorder risk; endogenous cannabinoid system; endogenous opioids; experience; heart rate variability; indexing; individual patient; innovation; negative affect; non-drug; novel; opioid epidemic; opioid misuse; opioid therapy; opioid use; opioid use disorder; pain patient; pain relief; perceived stress; precision medicine; prescription opioid; psychosocial; response; response biomarker; sex; stressor

Abstract Indiscriminate prescribing of opioids for chronic pain management has contributed to the current opioid crisis. While opioids work well at stable doses for some patients, others experience poor pain relief with significant risks of developing iatrogenic opioid use disorder (OUD). Similar risks may occur in the context of extended postoperative pain management using opioids following major surgery. Ability to predict this risk/benefit balance for individual patients is limited by inadequate understanding of mechanisms influencing opioid responses and risks. To address this gap, our prior funded work has systematically evaluated mechanisms contributing to differential opioid responses. We have shown that: 1) chronic pain patients at increased risk of opioid misuse experience greater analgesia and subjective reinforcing effects of opioid analgesics (e.g., drug liking, desire to take the drug again), 2) low endogenous opioid (EO) function predicts greater analgesic responses to opioid analgesics (replicated across two studies), and 3) that low EO function and endocannabinoid (EC) levels together predict greater subjective opioid reinforcing effects. Our data are consistent with a reinforcement model in which differential opioid responding related to low EO and EC function may enhance risk of OUD. Stress is a known predictor of risk for OUD, but mechanisms are not well understood. EO and EC activity are however both known to inhibit stress responses. This project integrates diverse literatures and will test in 120 chronic low back pain patients a novel mechanistic model in which elevated stress, via links to low EO and EC activity, contributes to patterns of differential opioid responding that will enhance OUD risk via elevated opioid reinforcing properties. Primary aims are: 1) to determine whether stress-related measures are associated with analgesic and misuse-relevant subjective responses to placebo- controlled oxycodone administration, and 2) evaluate associations between stress-related measures and both EO function and EC levels, and test whether EO and EC mechanisms mediate associations between stress- related measures and oxycodone responses. This project will assess stress at multiple levels (subjective, cardiovascular reactivity to two controlled stressors, and pain-relevant heart rate variability [HRV] stress markers) with quantitative assessment of EC levels, and assessment of EO function and opioid agonist subjective and analgesic responses based on randomized, placebo-controlled crossover administration of naloxone (for EO) and oxycodone (opioid responses). Laboratory stress measures will be validated using EMA electronic diary assessment of stress. Results will provide unique mechanistic knowledge of mechanisms contributing to known associations between stress and OUD risk, in line with the goals of PAS- 18-624, and highlight a novel and clinically-pragmatic HRV measure that might predict risk-enhancing differential opioid responses before initiating opioid therapy.

摘要 不分青红皂白地开阿片类药物来治疗慢性疼痛是造成目前阿片类药物的原因之一 危机。虽然阿片类药物在稳定剂量下对一些患者效果很好，但其他患者使用阿片类药物缓解疼痛效果不佳 发生医源性阿片使用障碍(OUD)的重大风险。类似的风险可能在以下情况下发生 大手术后延长使用阿片类药物的术后疼痛管理。预测这一点的能力 个体患者的风险/收益平衡受到对影响机制的不充分理解的限制 阿片类药物反应和风险。为了解决这一差距，我们先前资助的工作已经系统地评估了 不同的阿片类药物反应的机制。我们已经证明：1)慢性疼痛患者在 阿片类药物滥用风险增加阿片类药物具有更强的止痛和主观强化作用 止痛剂(例如，对药物的喜好、再次服药的愿望)，2)内源性阿片(EO)功能低下预示 对阿片类镇痛剂的止痛反应更强(在两项研究中重复)，以及3)低EO功能 和内源性大麻素(EC)水平一起预测更大的主观阿片类药物强化效应。我们的数据是 与强化模型一致，在该模型中，差异阿片反应与低EO和EC功能有关 可能会增加OUD的风险。压力是已知的预测OUD风险的指标，但机制不是很好。 明白了。然而，EO和EC活性都被认为可以抑制应激反应。该项目集成了 并将在120名慢性下腰痛患者中测试一种新的机制模型，在该模型中 压力升高，通过与低EO和EC活性的联系，促进了不同的阿片类药物反应模式， 将通过提高阿片类药物的强化特性来增加OUD的风险。主要目标是：1)确定是否 应激相关措施与止痛药和滥用安慰剂相关的主观反应有关- 受控羟考酮给药，以及2)评估应激相关措施和两者之间的相关性 EO功能和EC水平，并测试EO和EC机制是否在应激-内分泌之间的联系中起中介作用。 相关措施和羟考酮反应。这个项目将评估多个层面的压力(主观的， 心血管对两种受控应激源的反应性以及与疼痛相关的心率变异性(HRV)应激 标记物)，定量评估EC水平，评估EO功能和阿片类激动剂 基于随机、安慰剂对照交叉给药的主观和止痛反应 纳洛酮(用于EO)和羟考酮(阿片类药物反应)。实验室压力测量将使用以下工具进行验证 EMA电子日记压力评估。结果将提供独特的机械知识 根据PAS的目标，促进压力和OUD风险之间已知关联的机制-- 18-624，并强调了一种新的、临床实用的HRV测量方法，可以预测风险增加 开始阿片类药物治疗前的不同阿片反应。