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

基本信息

批准号：
10574596
负责人：
Stephen Bruehl
金额：
$ 55.83万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10574596
关键词：
2-arachidonylglycerol Absence of pain sensation Acute pain management 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 Combinations Electronics 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 Postoperative Period Property Psychological reinforcement Psychosocial Stress Randomized Rest Risk Risk Marker Role Standardization Stimulus Stress System Testing Time Weight Work 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 risk prediction sex stressor

项目摘要

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.

抽象的阿片类药物的不分青红皂白，用于慢性疼痛管理有助于当前的阿片类药物危机。虽然阿片类药物适合某些患者的稳定剂量效果很好，但另一些人则疼痛缓解发展医源性阿片类药物使用障碍（OUD）的重大风险。在大手术后使用阿片类药物使用阿片类药物进行扩展术后疼痛。能够预测这一点单个患者的风险/福利平衡受到对影响机制的理解不足的限制阿片类药物的反应和风险。为了解决这一差距，我们先前的资助工作已系统评估有助于差异阿片类药物反应的机制。我们已经表明：1）慢性疼痛患者阿片类药物滥用的风险增加经历更大的镇痛和阿片类药物的主观增强作用镇痛药（例如，药物喜欢，渴望再次服用药物），2）低内源性阿片类药物（EO）功能预测对阿片类镇痛药的镇痛反应更大（在两项研究中复制），3）较低的EO功能内源性大麻素（EC）水平共同预测了更大的主观阿片类药物增强作用。我们的数据是与增强模型一致，其中差异阿片类药物与低EO和EC功能有关可能会增加OUD的风险。压力是OUD风险的已知预测指标，但机制不好理解。但是，EO和EC活性都抑制压力反应。该项目集成了多样的文献，将在120名慢性下腰痛患者中测试一种新型机械模型通过与低EO和EC活性的链接，压力升高有助于差异阿片类药物的模式，从而做出反应将通过升高的阿片类药物增强特性来提高OUD风险。主要目的是：1）确定是否与压力相关的措施与对安慰剂的镇痛和滥用主观反应有关控制的羟考酮给药，2）评估与压力相关的措施和两者之间的关联 EO功能和EC水平，并测试EO和EC机制是否介导应力之间的关联相关措施和羟考酮反应。该项目将评估多个级别的压力（主观，对两个受控压力源的心血管反应性和与疼痛相关的心率变异性[HRV]应力[HRV] 标志物）对EC水平进行定量评估，并评估EO功能和阿片类药物激动剂基于随机，安慰剂对照的跨界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）。实验室压力指标将通过 EMA电子日记评估应力。结果将提供独特的机械知识与PAS- 18-624，突出显示了一种新颖且临床上的HRV措施，该测量可能预测风险增强启动阿片类药物疗法之前，阿片类药物反应差异。