Opioid misuse/abuse remains at unprecedented levels and is a major public health burden. Stress-reactivity interferes with opioid abstinence and increase risks of relapse and adverse outcomes. We have shown that the pharmacological stressor yohimbine + hydrocortisone (YOH/CORT) increases opioid seeking in buprenorphine (BUP)-stabilized volunteers. Prior studies suggest maintenance on methadone (MTD) and BUP can attenuate stress-reactivity, but those studies have several limitations. BUP is effective via opioid substitution (withdrawal suppression) and cross-tolerance (blockade); another important but poorly understood mechanism is that BUP might afford stress-protection. In our studies, reactivity to YOH/CORT (which co-activates noradrenaline and glucocorticoid systems) was found for some measures but not others; this suggests moderate-dose BUP has a partial blocking effect on stress reactivity. Although stress plays a role in drug seeking/relapse, one research gap is that no studies have examined whether BUP (or MTD) dose-dependently attenuates stress reactivity in subjects with opioid use disorder. Improving treatment outcomes requires that we identify opioid-abusing patients with elevated relapse risk to address their susceptibility. Yet, few studies have examined whether chronic stress biomarker levels or acute stress-reactivity predicts relapse and consequences in subjects with opioid use disorder. In this project, we will determine whether maintenance on varying buprenorphine/naloxone (BUP/NAL) doses reduces YOH/CORT dose-related reactivity (phase 1: within-subject crossover), then use these data to predict opioid relapse and consequences during a standardized outpatient BUP/NAL dose taper paired with opioid abstinence-contingent reinforcement, and at 1, 2 and 3 months follow up (phase 2: intent-to- treat). We predict: (1a) YOH/CORT will increase opioid price-inelasticity (greater economic demand), elevate acute stress biomarkers (e.g. blood pressure, plasma noradrenaline, saliva cortisol, negative mood) and novel indices predicted to be sensitive based on non-opioid studies (e.g. blood levels of BDNF and pro-inflammatory cytokines; saliva ?-amylase); (1b) BUP/NAL will dose-dependently block YOH/CORT stress-reactivity; (2a) stress-reactivity at lower-dose BUP/NAL will predict more opioid use and adverse consequences during and after BUP/NAL dose tapering; and chronic stress indices (e.g. hair cortisol level, questionnaire responses) will modulate YOH/CORT reactivity (1c) and relapse (2b). Impact of this project will be exceptional because: opioid use problems remain at critical levels and stress-related opioid use is poorly understood, posing a major clinical challenge; the highly innovative idea that BUP affords stress protection will be tested using rigorous methods (placebo controlled, dose-response drug-interaction design) with established and novel biomarkers, and mediators/moderators of stress-reactivity will be used to predict relapse potential to bridge a large translational gap. This project offers a novel template to examine effects of stressors on drug seeking and relapse biomarkers, and to develop treatment approaches to reduce stress-potentiated drug use.
Opioid use disorder remains highly prevalent and burdensome, and stress-reactivity is a major barrier to opioid abstinence and a risk factor for relapse. In this competing renewal application, we propose a highly innovative and significant direction to investigate: (1) whether buprenorphine/naloxone (BUP/NAL) maintenance produces dose-related stress protection, as measured by attenuation of experimental pharmacological stressor dose- related reactivity (opioid demand elasticity, novel biomarkers, subjective and cognitive effects), and (2) whether stress-reactivity measures predict opioid use (relapse) and related adverse consequences during BUP/NAL dose tapering and at 1, 2 and 3 months follow up. This project will improve scientific and clinical understanding of a major cause of drug abuse/relapse, and may guide development of novel therapeutics for opioid use disorder.
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