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.
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
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
24
Tolan Park Medical Building
Detroit, Michigan, United States
RECRUITINGState anxiety
State Trait Anxiety Inventory - state anxiety scale total score
Time frame: 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
Time frame: 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
Time frame: 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
Symbol matching performance task
Digit Symbol Substitution Task (DSST) symbol matching total score
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
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