Opioid/Benzodiazepine Polydrug Abuse: Aim 3

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.

• Symbol matching performance task [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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]