Opioid/Benzodiazepine Polydrug Abuse: Aim 3 (MAP)

Opioid/Benzodiazepine Polydrug Abuse: Integrating Research on Mechanisms, Treatment and Policies - Study 3

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.

Study Overview

• Status: Recruiting
• Conditions: Opioid Abuse; Benzodiazepine Abuse; Polysubstance Abuse
• Intervention / Treatment: Drug: Placebo; Drug: Morphine; Drug: Alprazolam

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Mark K Greenwald, PhD; Phone Number: 313-993-3965; Email: mgreen@med.wayne.edu
• Study Contact Backup: Name: Heidi Aguas; Phone Number: 313-993-3960; Email: gh7962@wayne.edu

Study Locations

• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Tolan Park Medical Building
      • Contact: Mark Greenwald, PhD; Phone Number: 313-993-3965; Email: mgreen@med.wayne.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo drug; Lactose, administered both at 9:30 am and 12:00 pm	Drug: Placebo; Lactose
Active Comparator: Morphine alone; 15mg immediate-release oral morphine, administered both at 9:30 am and 12:00 pm	Drug: Morphine; immediate release oral 15mg dose
Active Comparator: Alprazolam alone; 0.25mg oral alprazolam, administered at both 9:30 am and 12:00 pm	Drug: Alprazolam; oral 0.25mg dose
Active Comparator: Morphine then alprazolam; 15mg oral morphine administered at 9:30 am, then 0.25mg oral alprazolam administered at 12:00 pm	Drug: Morphine; immediate release oral 15mg dose; Drug: Alprazolam; oral 0.25mg dose
Active Comparator: Alprazolam then morphine; 0.25mg oral alprazolam administered at 9:30 am, then 15mg oral morphine administered at 12:00 pm	Drug: Morphine; immediate release oral 15mg dose; Drug: Alprazolam; oral 0.25mg dose
Active Comparator: Morphine+alprazolam simultaneously; morphine 15mg + 0.25mg alprazolam at 9:30 am, then morphine 15mg + 0.25mg alprazolam at 12:00 pm	Drug: Morphine; immediate release oral 15mg dose; Drug: Alprazolam; oral 0.25mg dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
State anxiety	State Trait Anxiety Inventory - state anxiety scale total score	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
Positive affect	Positive and Negative Affect Scale-Short Form (PANAS-SF) positive affect scale score	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
Negative affect	Positive and Negative Affect Scale-Short Form (PANAS-SF) negative affect scale score	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symbol matching performance task	Digit Symbol Substitution Task (DSST) symbol matching total score	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
Impulsivity performance task accuracy	Go/No task percentage of trials correct	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
Cognitive flexibility performance task	Wisconsin Card Sorting Task (WCST) percentage of trials correct	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
Cognitive inhibition performance task	Addiction Stroop Task, reaction time to drug vs. neutral words presented in different colors	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
Vigilance performance task	Psychomotor Vigilance Task (PVT) average reaction time	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
Hypothetical drug purchasing questionnaire	Intensity and elasticity of drug demand. This is measured by having the participant make a series of independent choices as to how many drug units s/he will purchase across a range of (low to high) unit prices. Demand intensity is the drug purchase amount at the lowest non-zero price. Demand intensity is the calculated point on the price/purchasing curve where the slope (in log/log space) equals -1 (i.e. 'tipping point' where purchasing decreases more rapidly than the rate of increase in drug price).	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
Preference for natural reinforcement choice procedure	Number of choices for money vs. avoiding listening to soundtrack of crying babies	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
Monetary delay discounting questionnaire	Participants are asked to make a series of independent choices (preferences) for delayed larger amounts of money vs. smaller immediate amounts of money. The outcome is the rate at which future choice value is discounted, measured by area under the time-delay curve	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
Respiration rate	Breaths per minute, measured by behavioral observation	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
Oxygen saturation	Percentage oxygen saturation, measured by photoplethysmograph	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
Heart rate	Pulse rate (beats per minute), measured by photoplethysmograph	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
Blood pressure	Systolic and diastolic blood pressure (mm Hg)	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
Pupil diameter	Pupil size (mm), measured by digital photography	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
Drug effect visual analog scale (VAS) ratings	0-100 scale ratings of alert, difficulty concentrating, clumsy, confused, forgetful, blurred vision, dizzy, heaviness in limbs, mellow, yawning, stimulated, sedated, sleepy, tired, energetic, self-confident, dreamy, floating, sluggish, tingling, high, liking, good drug effect, bad drug effect	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
Drug craving visual analog scale (VAS) ratings	0-100 scale rating of "want to take drug again", "desire to use", and "craving" for opioids, sedatives, alcohol, cigarettes, marihuana, and cocaine	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
Sleep efficiency	Percentage of sleep time (time asleep divided by time in bed), measured using WatchPat device	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

Collaborators and Investigators

• Sponsor: Wayne State University
• Collaborators: Henry Ford Health System
• Investigators: Principal Investigator: Mark K Greenwald, PhD, Wayne State University

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: August 4, 2021
• First Submitted That Met QC Criteria: August 6, 2021
• First Posted (Actual): August 16, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Narcotic-Related Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Morphine; Alprazolam
• Other Study ID Numbers: IRB-21-07-3844

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes