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

摘要 阿片类药物用于慢性疼痛管理的不分青红皂白的处方导致了目前的阿片类药物 危机虽然阿片类药物在稳定剂量下对一些患者效果良好，但其他患者的疼痛缓解效果较差， 发生医源性阿片类药物使用障碍（OUD）的重大风险。类似的风险可能发生在以下情况下： 大手术后使用阿片类药物进行术后疼痛管理。预测这一点的能力 个体患者的风险/获益平衡受到对影响机制的不充分理解的限制 阿片类药物的反应和风险。为了弥补这一差距，我们先前资助的工作系统地评估了 导致阿片类药物反应差异的机制。我们已经表明：1）慢性疼痛患者在 阿片类药物滥用的风险增加，阿片类药物的镇痛作用和主观强化作用更强 止痛药（例如，药物喜好，再次服用药物的愿望），2）低内源性阿片样物质（EO）功能预测 对阿片类镇痛药的镇痛反应更大（在两项研究中重复），3）EO功能降低 和内源性大麻素（EC）水平共同预测更大的主观阿片类药物强化作用。我们的数据是 与强化模型一致，其中差异阿片样物质反应与低EO和EC功能相关 可能会增加OUD的风险。压力是OUD风险的已知预测因子，但机制尚不清楚。 明白然而，已知EO和EC活性都抑制应激反应。该项目整合了 将在120名慢性腰痛患者中测试一种新的机制模型， 升高的压力，通过与低EO和EC活性的联系，有助于不同阿片样物质反应的模式， 将通过升高阿片类药物强化特性增加OUD风险。主要目的是：（1）确定是否 与压力相关的测量与安慰剂的镇痛和误用相关的主观反应相关- 控制羟考酮给药，和2）评估压力相关措施和两者之间的关联 EO功能和EC水平，并测试EO和EC机制是否介导压力- 相关措施和羟考酮反应。该项目将在多个层面上评估压力（主观， 对两种受控应激源的心血管反应性和疼痛相关心率变异性（HRV）应激 标记物）与EC水平的定量评估，以及EO功能和阿片激动剂的评估 基于随机、安慰剂对照交叉给药的主观和镇痛反应 纳洛酮（用于EO）和羟考酮（阿片类药物反应）。实验室应力测量将使用以下方法进行验证： EMA电子日记压力评估。结果将提供独特的机械知识， 有助于压力和OUD风险之间已知关联的机制，符合PAS的目标， 18 - 624，并强调一种新颖的和临床实用的HRV测量，可能预测风险增强 在开始阿片类药物治疗之前的阿片类药物反应差异。

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.