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

项目总结/摘要 意义：苯二氮卓类（BZD）/阿片类多种物质滥用（PSA）具有显著的药物过量风险， 残疾和死亡;然而，很少有人知道表型，可以有针对性地降低这些风险。我们 将在人口、临床和人类实验室分析水平上解决这一多方面的问题， PAR-16-291的整合和翻译焦点。该项目的统一假设是BZD/阿片类PSA 是由情感调节的双重缺陷维持的（表型：高焦虑敏感性/痛苦耐受性 和享乐缺陷/强化病理学，建立在Koob的奖励缺陷/压力过度模型上）， 与单独使用BZD或阿片类药物相比，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学专家 药理学）将使用严格和互补的混合方法来测试我们在这方面的统一假设。 顺序R21/R33方法。目标1（R21）：从行为健康治疗记录中确定 阿片类药物、BZD或BZD/阿片类药物PSA患者的患病率以及药物使用的相关性 情感症状（主要是焦虑和抑郁）、身体合并症（主要是慢性 疼痛）、药物、人口统计学和治疗结果。这一分析将提供一个背景， 目标2（深入临床评估）和目标3（人体实验室）结果的普遍性。目的2 (R21)：在一个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/阿片类药物PSA的跨领域（情感、神经认知、行为）和 物质使用（尤其是同时vs同时使用BZD/阿片类PSA、酒精）。目标3（R33）： 近期有BZD/阿片类PSA病史的社区招募研究志愿者（非寻求治疗者），检测 是否：（3a）BZD/阿片类PSA中的药物滥用严重程度影响情感、神经认知和 行为测量（使用目标2中的精确评估组合），包括更多的终生药物使用 后果，以及使用行为经济学模拟的阿片类药物和BZD的更大价格无弹性;以及 (3b)阿普唑仑/吗啡与单独药物或安慰剂的实验药物给药（剂量- 反应评估）将在三种不同的行为选择中差异性地改变情感/享乐表型 程序：㈠增加药物需求的价格弹性，㈡改变偏好，避免厌恶性药物， 刺激正向强化，（iii）增加货币延迟折扣。总体影响： 多水平的综合方法将检验我们的统一假设，即BZD/阿片类PSA是由一种双重的 情感/享乐调节缺陷，伴有相关的神经认知和行为障碍。通过平移 从人群和临床水平到基于实验室的方法，该项目将开始解决 BZD/阿片类PSA的复杂性和有害性，其长期目标是促进机制 理解，改善治疗结果，以及减少过量，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.