Brain Mechanisms of Pharmacotherapy in Opioid Use Disorder

Study Overview
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Brief Summary
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This study will investigate the mechanisms of cognitive-behavioral response to medications used for relapse prevention in opioid use disorder (opioid addiction, OUD), through investigation of the neural circuits underlying key cognition functions. The study will use previously validated cognitive probes, functional Magnetic Resonance Imaging (fMRI), and novel extended-release injectable preparations of opioid partial agonist buprenorphine and antagonist naltrexone, in OUD patients to explain the individual heterogeneity of OUD treatment response.

Detailed Description
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This proposal seeks to identify the neural circuits underlying the cognitive effects of medication assisted therapy (MAT) for OUD. The study will examine the neurocognitive effects of MAT by comparing two preparations with different pharmacodynamic properties (extended release buprenorphine and naltrexone, XRBUP, XRNTX) in three key domains (incentive salience, executive functioning, and emotion processing) using task functional Magnetic Resonance Imaging (MRI). In the 1st phase of the study, forty treatment-seeking OUD patients will be randomized to XRNTX or XRBUP groups after detoxification. Participants will undergo medication induction followed by monthly injections and urine toxicology monitoring for 120 days. Neuroimaging will follow completion of detoxification (pre-treatment) and 15 days after the second injection (on-treatment). The second study phase will extend the paradigm to an independent sample of 160 additional participants and test the explanatory value of MAT-induced changes in the neuroimaging signal in the classification of OUD treatment outcomes.

Official Title
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Brain Mechanisms of Cognitive Response to Pharmacotherapy in Opioid Use Disorder

Conditions
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Opioid Dependence

Intervention / Treatment
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* Drug: Brixadi
* Drug: Vivitrol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and Females 18-65 Years old OUD by DSM5 Criteria, confirmed by history and physical examination including urine toxicology, medical records and self-report Opioids are the drug of choice Interested in injectable extended release agonist or antagonist treatment Have a stable address, working command of English language, and telephone access. Women of childbearing age must use an effective contraceptive Exclusion Criteria: Psychiatric Co-morbidities: Lifetime diagnoses of any psychotic disorder, e.g. schizophrenia, schizoaffective disorder, bipolar disorder type 1. Psychiatric Co-morbidities: Psychiatric disorders requiring current medication treatment, e.g. moderate to severe depression. Mild to moderate Depressive and Anxiety disorders and Attention Deficit Hyperactivity Disorder that do not require prescription stimulants and DSM5 Cluster B and C personality disorders are also allowed. Polysubstance users whose drug of choice is not opioids. Contraindications for XRNTX or XRBUP e.g. active liver disease. Medical and surgical conditions such as malignancy that may affect patients' ability to receive XRNTX or XRBUP treatment because it may interfere with opioid analgesia Contraindications for MRI, e.g. claustrophobia, indwelling foreign magnetic agents.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Buprenorphine<br>Participants assigned to treatment with extended-release buprenorphine | Drug: Brixadi<br>* Extended release injectable Buprenorphine<br>* Other names: Buprenorphine Injectable Product;|
| Active Comparator: Naltrexone<br>Participants assigned to treatment with extended-release naltrexone | Drug: Vivitrol<br>* Extended release injectable Naltrexone<br>* Other names: Naltrexone Injectable Product;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Magnetic Resonance Imaging (fMRI) signal | Brain fMRI response to neurocognitive probes | up to 90 days | 
| Urine Toxicology: opioid | Rapid semi-quantitative ELISA urine drug screen test for morphine, oxycodone and methadone, followed by (cut off levels): Methadone (MTD) Methadone 300 ng/mL Opiates (OPI 300) Morphine Morphine **300 ng/mL Oxycodone (OXY) Oxycodone 100 ng/mL | Through the study completion, up to 120 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anxiety | Hamilton Anxiety Rating Scale (HAM-A) (Hamilton, 1967). The HAM-A is a 15-minute, 14-item, clinician-administered instrument that measures current anxiety and changes in anxiety symptoms. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where <17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. | Through the study completion, up to 120 days | 
| Depression | Hamilton Depression Rating Scale (HAM-D) (Hamilton, 1959 #2497). The HAM-D is a 20-minute, 24-item interview that measures the severity of depression and changes in depressive symptoms. HAM-D form includes 21 items, however the scoring is based on the first 17. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine are scored from 0-2. The HAM-D score level corresponds to the clinical severity of depression as follows: 10 - 13 mild; 14-17 mild to moderate; >17 moderate to severe. | Through the study completion, up to 120 days | 
| Non-opioid Urine Toxicology | Rapid semi-quantitative ELISA urine drug screen test for amphetamine/methamphetamine, benzodiazepines, cocaine, phencyclidine, cannabinoids and cotinine, with cut off levels: Amphetamine/Methamphetamine 500/1000ng/ml Benzodiazepines Enzyme Immunoassay (EIA) 200 ng/mL Cocaine Metabolite (Benzoylecgonine) EIA 150/300 ng/mL Cotinine EIA 250 ng/mL Phencyclidine EIA 25 ng/mL THC (Cannabinoids) EIA 20/50 ng/mL* | Through the study completion, up to 120 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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naltrexone, buprenorphine, neuroimaging