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

项目摘要/摘要 意义：苯二氮卓类(BZD)/阿片类多物质滥用(PSA)会带来严重的服药过量风险， 残疾和死亡；然而，人们对可用于降低这些风险的表型知之甚少。我们 将在人口、临床和人体实验室分析水平上解决这个多方面的问题，使用 PAR-16-291的综合和翻译焦点。该项目的统一假设是BZD/阿片类PSA 由情感调节的双重缺陷维持(表型：高度焦虑-敏感/痛苦-不耐受 和享乐缺陷/强化病理学，建立在Koob的奖励-缺陷/压力-过量模型基础上)，相关 神经认知和行为功能受损，相对于单独使用BZD或阿片类药物。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方面的专家 药理学)将使用严格和互补的混合方法来测试我们的统一假设 顺序R21/R33进场。目标1(R21)：从行为健康治疗记录中确定 患者出现阿片类药物、BZD或BZD/阿片类PSA的患病率及其与药物使用的关系 有情感症状(主要是焦虑和抑郁)、身体并存(主要是慢性 疼痛)、药物、人口统计学和治疗结果。这一分析将为评估 目标2(深入临床评估)和目标3(人体实验室)结果的概括性。目标2 (R21)：在新入院的行为健康患者样本中，严格评估和描述缺陷 阿片类药物、BZD和BZD/阿片类PSA的跨域(情感、神经认知、行为)和模式 药物使用(特别是同时使用BZD/阿片类PSA和酒精)。目标3(R33)：在 社区招募的研究志愿者(非治疗寻求者)，最近有BZD/阿片类PSA病史，测试 (3A)BZD/阿片类PSA中药物滥用的严重程度是否会影响情感、神经认知和 行为测量(使用目标2中改进的评估单元)，包括更多终生吸毒 使用行为经济模拟，阿片类药物和BZD的后果和更大的价格弹性；以及 (3B)阿普唑仑/吗啡实验用药与单独用药或安慰剂(剂量- 反应评估)会在三种不同的行为选择中不同地改变情感/享乐的表型 程序：(一)增加药品需求的价格弹性，(二)从避免厌恶转向偏爱 刺激向正强化，以及(Iii)增加货币延迟贴现。总体影响：这 多层次、综合的方法将检验我们的统一假设，即BZD/阿片类PSA由双重- 情感/享乐调节缺陷，伴有相关的神经认知和行为障碍。通过翻译 从人口和临床层面到基于实验室的方法，这个项目将开始解决 BZD/阿片类PSA的复杂性和危害性，其长期目标是推进机制 了解、改善治疗结果以及降低服药过量、残疾和死亡风险的政策。

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.