Brain Mechanisms of Cognitive Response to Pharmacotherapy in Opioid Use Disorder

Relapse prevention is the greatest challenge in opioid use disorder (OUD) treatment. We propose to elucidate the mechanisms of response to OUD by investigating the effects of OUD pharmacotherapy on the neurocognitive domains instrumental to relapse. We shall use previously validated neurocognitive probes, functional Magnetic Resonance Imaging (fMRI), and the novel extended-release injectable preparation (Brixadi ®) of the opioid partial agonist buprenorphine (XRBUP) and approved antagonist naltrexone (XRNTX), in OUD patients. Using two medications with opposing opioid receptor action will allow a comprehensive evaluation of the response mechanisms to relapse prevention medications in OUD. The R61 phase (Aim 1) will search for treatment effects in the domains of executive function, incentive salience and emotion regulation and the interaction that will indicate a difference between the two medications. Differences in at least two domains, with an effect size that is at least small (Cohen's d>0.2), will serve as a milestone for advance to the R33 phase (Aim 2). The R33 phase will test the significance of the interactions examined in the R61 phase and the ability of the brain signal to explain relapse defined by % of opioid-positive urine tests and adherence to the study treatments. Participants will be treatment-seeking OUD patients who will receive three monthly XRNTX or XRBUP injections yielding approximately 100 days of treatment and have weekly urine toxicology monitoring. In the R61 phase, 40 treatment-seeking OUD patients who completed detoxification will be randomly assigned to XRNTX or XRBUP. If the milestone is met, the R33 phase will randomize 160 participants. Logistic regression will be used to test the explanatory value of the brain signal in modeling relapse vulnerability, identify variables that differentiate treatment groups, test the explanatory value of integrated brain- behavior models of relapse vulnerability, identify differences in variable loading between treatment groups, and explore the potential mechanism of individual variability in treatment outcomes. The proposal would be the first neural systems' level investigation of the cognitive effects of the next generation extended-release preparation of buprenorphine and naltrexone to explain the individual heterogeneity of OUD treatment response and failure. This project can advance the theory and personalized treatment of OUD by elucidating the brain mechanisms of vulnerability to relapse in OUD and SUD in general.