Opioid/benzodiazepine polydrug abuse: Integrating research on mechanisms, treatment and policies

阿片类药物/苯二氮卓类多种药物滥用：整合机制、治疗和政策研究

• 批准号: 10443186
• 负责人: CYNTHIA L ARFKEN
• 金额: $ 65.52万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443186
• 关键词: Opioid; benzodiazepine; polydrug; abuse; Integrating

PROJECT SUMMARY / ABSTRACT Significance: Benzodiazepine (BZD)/opioid polysubstance abuse (PSA) confers significant risks of overdose, disability and death; yet, little is known about phenotypes that could be targeted to decrease these risks. We will address this multi-faceted problem at population, clinical and human laboratory levels of analysis, using the integrative and translational focus of PAR-16-291. This project’s unifying hypothesis is that BZD/opioid PSA is maintained by a dual-deficit in affective regulation (phenotypes: high anxiety-sensitivity/distress-intolerance and hedonic deficit/reinforcement pathology, building on Koob’s reward-deficit/stress-surfeit model), associated with impaired neurocognitive and behavioral functions, relative to BZD or opioid use alone. Goals: Our interdisciplinary team (experts in epidemiology, biostatistics, clinical assessment, and human behavioral pharmacology) will use rigorous and complementary mixed methods to test our unifying hypothesis in this sequential R21/R33 approach. Aim 1 (R21): Determine from behavioral health treatment records the prevalence of patient presentation with opioid, BZD or BZD/opioid PSA and associations of substance-use patterns with affective symptoms (primarily anxiety and depression), physical comorbidities (primarily chronic pain), medications, demographics, and treatment outcomes. This analysis will provide a context for assessing generalizability of findings from Aim 2 (in-depth clinical assessment) and Aim 3 (human laboratory). Aim 2 (R21): In a sample of newly admitted behavioral health patients, rigorously evaluate and characterize deficits across domains (affective, neurocognitive, behavioral) in opioid, BZD and BZD/opioid PSA and pattern of substance use (especially simultaneous vs concurrent BZD/opioid PSA, alcohol use). Aim 3 (R33): Among community-recruited research volunteers (non-treatment seekers) with a recent history of BZD/opioid PSA, test whether: (3a) substance abuse severity among BZD/opioid PSA influences affective, neurocognitive and behavioral measures (using the refined assessment battery from Aim 2) including more lifetime drug-use consequences, and greater price-inelasticity for opioid and BZD using behavioral economic simulations; and (3b) experimental drug administration of alprazolam/morphine vs. either drug alone or placebo (with dose- response evaluation) will differentially alter affective/hedonic phenotypes in three different behavioral choice procedures: (i) increase price-elasticity of drug demand, (ii) shift preference away from avoiding aversive stimulation toward positive reinforcement, and (iii) increase monetary delay discounting. Overall impact: This multi-level, integrated approach will test our unifying hypothesis that BZD/opioid PSA is maintained by a dual- deficit in affective/hedonic regulation, with related neurocognitive and behavioral impairments. By translating findings from population and clinical levels to laboratory-based approaches, this project will begin to address the complex and harmful nature of BZD/opioid PSA with longer-term objectives of advancing mechanistic understanding, improving treatment outcomes, and policies to reduce risks of overdose, disability and death.

项目摘要 /摘要 意义：苯二氮卓（BZD）/阿片类药物多刺激滥用（PSA）承认过量的重大风险， 残疾与死亡；但是，对于可以降低这些风险的表型知之甚少。我们 将在人口，临床和人类实验室分析水平上解决这个多方面的问题，使用 PAR-16-291的综合和翻译重点。该项目的统一假设是BZD/阿片类药物PSA 由情感调节中的双重缺陷维持（表型：高动画敏感/遇险intermantance 以及基于KOOB的奖励缺陷/压力造成模型的享乐国防/增强病理学，相关 仅相对于BZD或单独使用阿片类药物，神经认知和行为功能受损。目标：我们的 跨学科团队（流行病学，生物统计学，临床评估和人类行为的专家 药理学）将使用严格和互补的混合方法来检验我们的统一假设 顺序R21/R33方法。目标1（R21）：从行为健康治疗记录中确定 患者使用阿片类药物，BZD或BZD/阿片类药物PSA的患病率以及物质使用的关联 具有情感症状的模式（主要是焦虑和抑郁），身体合并症（主要是慢性病 疼痛），药物，人口统计和治疗结果。该分析将提供评估的背景 AIM 2（深入临床评估）和AIM 3（人类实验室）的发现的普遍性。目标2 （R21）：在新入院的行为健康患者样本中，严格评估和表征缺陷 阿片类药物，BZD和BZD/阿片类药物的跨域（情感，神经认知，行为）以及模式 药物使用（尤其是同时发生的BZD/阿片类药物PSA，饮酒）。目标3（R33）： 社区招募的研究志愿者（非治疗者）具有BZD/阿片类药物PSA的历史，测试 是否：（3a）BZD/阿片类药物PSA之间的药物滥用严重程度会影响情感，神经认知和 行为措施（使用AIM 2的精制评估电池），包括更多终身药物使用 使用行为经济模拟的后果和更高的阿片类药物和BZD价格；和 （3B）单独使用阿普唑仑/吗啡的实验药物给药或单独的药物或安慰剂（用剂量 - 响应评估）将在三种不同的行为选择中改变情感/享乐表型 程序：（i）增加药品需求的价格弹性，（ii）转移优先避免避免厌恶 刺激阳性强化，（iii）增加货币延迟折现。总体影响：这 多层次的综合方法将检验我们的统一假设，即BZD/阿片类药物PSA由双重 - 情感/享乐调节的赤字以及相关的神经认知和行为障碍。通过翻译 从人口和临床水平到基于实验室的方法的结果，该项目将开始解决 BZD/阿片类药物PSA的复杂和有害性质具有延长机械性的长期目标 理解，改善治疗结果以及减少过量，残疾和死亡风险的政策。