Clinical trial NCT05006079: Opioid/Benzodiazepine Polydrug Abuse: Aim 3
Official title: Opioid/Benzodiazepine Polydrug Abuse: Integrating Research on Mechanisms, Treatment and Policies - Study 3
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Opioid Abuse
Benzodiazepine Abuse
Polysubstance Abuse
Lead sponsor: Wayne State University
Sponsor class: OTHER
Collaborators: name: Henry Ford Health System
First posted: 2021-08-16
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Repeated measures, placebo-controlled, randomized crossover
Primary purpose: BASIC_SCIENCE

Brief summary: In this study, the investigators will measure affective, neurocognitive and behavioral outcomes related to chronic use of opioids and benzodiazepines (screening phase), and in response to the administration of the opioid morphine, the benzodiazepine alprazolam, morphine then alprazolam, alprazolam then morphine, morphine+alprazolam simultaneously, and placebo (laboratory pharmacology experiment). The latter will enable the investigators to assess the effects of an opioid alone, benzodiazepine alone, concurrent and simultaneous administration of opioid+benzodiazepine, relative to a placebo control.

Detailed description: The investigators propose that benzodiazepine/opioid polysubstance abuse is perpetuated by a dual-deficit in affective/hedonic regulation (difficulties modulating emotional reactions relative to the context and the person's long-term goals). Furthermore, the investigators propose that this dual-deficit biases neurocognition (interferes with executive function) and behaviors (guided by negative reinforcement processes such that polysubstance use acutely blunts aversive states and directs actions away from natural rewards). The scientific premise for this project builds on George Koob's foundational concept that addiction is a 'reward-deficit/stress-surfeit disorder'. There is an urgent need to obtain clinical pharmacology and mechanistic data to test this hypothesis of dual-deficit in affective/hedonic regulation. This study will use human laboratory methods to test affective, neurocognitive and behavioral mechanisms that maintain benzodiazepine/opioid polysubstance abuse.

The screening phase of this human laboratory study will include measures of affective dysregulation related to benzodiazepine/opioid polysubstance use behaviors. These include distress tolerance, pain sensitivity and nocebo responding, and biomarkers (e.g. plasma cortisol). Also, the investigators will include behavioral measures of drug and non-drug reinforcement (e.g. economic simulations of price elasticity of alprazolam and morphine) and neurocognition (e.g. drug attentional bias, response inhibition, cognitive flexibility).

During the pharmacology study the investigators will administer oral placebo, morphine alone and alprazolam doses alone, as well as morphine and alprazolam sequentially (in counterbalanced order) and simultaneously. Following each drug administration, the investigators will measure responses in affective (e.g. anxiety levels, distress tolerance), neurocognitive (e.g. executive function, learning) and behavioral domains (e.g. impulsivity, psychomotor function, reinforcer preferences). The lab study is highly significant because we lack prospective, controlled, dose-response studies that identify whether opioids, benzodiazepines, and their combination modulate core phenotypes that underlie this harmful polysubstance abuse. Testing effects of both sequential and simultaneous benzodiazepine/opioid administration within the same individuals will establish a firm foundation for understanding which phenotypes are sensitive to disruption and may respond to treatment.

Findings from this study will help to focus clinical assessment and identify mechanisms that maintain benzodiazepine/opioid polysubstance abuse, toward the development of novel medication-assisted, evidence-based psychosocial interventions.

Eligibility criteria: Inclusion Criteria:

* must self-report past 10-year experience taking opioid and sedative drugs (for therapeutic or non-therapeutic reasons), but not necessarily at the same time. As an alternative to the sedative drug exposure requirement, participants must have used alcohol on at least 3 separate days during the past month. Participants may have current mild- or moderate-severity Opioid Use Disorder or current mild- or moderate-severity Sedative Use Disorder;
* must not be seeking treatment for their substance use problems;
* must be in current good overall health

Exclusion Criteria:

* meet DSM-5 criteria for current psychosis, bipolar disorder, or severe depression (i.e. severe psychiatric disorder);
* meet DSM-5 criteria for severe substance use disorder for any substance (e.g. Sedative, Opioid, Alcohol);
* past-month benzodiazepine or opioid prescription (which would suggest daily use, tolerance, or withdrawal upon cessation);
* report of past-year any-drug overdose or suicide attempt/ideation;
* exhibit cognitive impairment (IQ \< 80 on the Shipley Institute of Living Scale);
* neurological, cardiovascular, pulmonary, or systemic diseases (see specific exclusionary conditions under Protection of Human Subjects);
* body mass index \> 38 kg/m2;
* females who are pregnant (urine), lactating or heterosexually active (self-report) and not using medically approved birth control;
* treatment with methadone, buprenorphine or naltrexone;
* past 30-day use of contraindicated medications;
* alcohol-positive breath sample (\>.02% breath alcohol concentration);
* urine sample positive for methadone, cocaine, amphetamines, or barbiturates (\<300 ng/ml)
* intolerance of lactose

Primary outcomes:
measure: State anxiety
timeFrame: within-session peak change from pre-drug baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Positive affect
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Negative affect
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
Secondary outcomes:
measure: Symbol matching performance task
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Impulsivity performance task accuracy
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Cognitive flexibility performance task
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Cognitive inhibition performance task
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Vigilance performance task
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Hypothetical drug purchasing questionnaire
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Preference for natural reinforcement choice procedure
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Monetary delay discounting questionnaire
timeFrame: difference from placebo condition, measured within each session at 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Respiration rate
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Oxygen saturation
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Heart rate
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Blood pressure
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Pupil diameter
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Drug effect visual analog scale (VAS) ratings
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Drug craving visual analog scale (VAS) ratings
timeFrame: within-session peak change from baseline to 15-120 min post-drug 1 and 15-240 min post-drug 2 administration; measured in each of the 6 laboratory sessions over about 3 weeks
measure: Sleep efficiency
timeFrame: difference from placebo condition, measured on an outpatient basis during the evening after each laboratory drug administration; measured after each of the 6 laboratory sessions over about 3 weeks
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Tolan Park Medical Building
state: Michigan
Study officials:
affiliation: Wayne State University
name: Mark K Greenwald, PhD
role: PRINCIPAL_INVESTIGATOR
References: