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

基本信息

批准号：
10685979
负责人：
CYNTHIA L ARFKEN
金额：
$ 60.68万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10685979
关键词：
Adaptive Behaviors Address Admission activity Affective Affective Symptoms Alcohol consumption Alprazolam Anhedonia Anxiety Behavioral Benzodiazepines Biometry Cessation of life Clinical Clinical assessments Communities Complex County Distress Dose Drug usage Elasticity Electronic Health Record Epidemiology Evaluation Exhibits Functional disorder Goals Human Impairment Impulsivity Individual Laboratories Link Measures Memory Mental Depression Methods Modeling Morphine Nature Neurocognition Neurocognitive Neurocognitive Deficit Occupational Opioid Opioid abuser Pathology Patients Pattern Persons Pharmaceutical Preparations Phase Phenotype Physical activity Placebo Control Placebos Policies Population Positive Reinforcements Prevalence Price Procedures Psychological reinforcement Recording of previous events Records Regulation Research Resources Rewards Risk Risk Reduction Sampling Severities Stress Substance abuse problem Testing Translating Treatment Failure Treatment outcome affective disturbance anxiety sensitivity anxiety symptoms attentional bias behavior measurement behavioral economics behavioral health behavioral impairment behavioral pharmacology behavioral phenotyping chronic pain comorbidity demographics depressive symptoms design disability discounting executive function hedonic improved multidrug abuse neurobehavioral opioid abuse opioid use overdose risk polysubstance abuse preference premature recruit response simulation substance use theories volunteer

项目摘要

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。