This is a two phase study investigating combinations of pharmacological and behavioral interventions to optimize the treatment of Opioid Use Disorder (OUD). The Retention Phase will assess strategies for improving retention on buprenorphine (BUP) and extended-release injectable naltrexone (XR-NTX). The Discontinuation Phase will assess which approaches are most likely to lead to long-term success (absence of relapse), and what characteristics of participants distinguish those who can safely discontinue Medications for Opioid Use Disorder (MOUD) from those who remain at risk of relapse and should not discontinue.

The main objectives of this study are:

1. To test strategies to improve retention in treatment on medications for opioid use disorder (MOUD), among patients initiating treatment for OUD.
2. To test strategies to improve outcomes among patients who have achieved stable remission on MOUD and want to discontinue MOUD.
3. To develop models to predict who is able to discontinue MOUD without relapse, based on patient characteristics, including duration of MOUD prior to discontinuation.

The study will have a multicenter, randomized, pragmatic non-blinded design. The study has two phases, a Retention Phase and a Discontinuation Phase.

Inclusion Criteria for Retention Phase:

1. 18 years of age or older;
2. Meet DSM-5 criteria for current opioid use disorder (heroin, fentanyl or other synthetic opioids, and/or prescription opioids);
3. Seeking treatment for opioid use disorder and choosing either buprenorphine (BUP) or extended-release injection naltrexone (XR-NTX);
4. If choosing buprenorphine, willing to be randomized to SL-BUP-16mg, SL-BUP-32mg, or XR-BUP;
5. Willing to be randomized to either MM (standard Medical Management plus counseling treatment as usual available at the site) or MMR (MM plus usual counseling and access to an app delivering CM + CBT);
6. In good-enough general health (meaning good enough health to be in outpatient treatment) as determined by the study medical clinician on the basis of medical history, review of systems, and physical/mental status exam, to permit treatment with XR-NTX or BUP;
7. Willing and able to provide written informed consent;
8. Able to speak English sufficiently to understand the study procedures;
9. If female of childbearing potential, willing to practice an effective method of birth control for the duration of participation in the study (participants who become pregnant during the study will continue to be followed; treatment may be modified consistent with pregnancy).

Exclusion Criteria for Retention Phase:

1. Serious medical, psychiatric, or co-occurring substance use disorder or concomitant medication that, in the opinion of the study medical clinician, makes the patient not appropriate for outpatient treatment with buprenorphine or XR-NTX, but instead requires a higher or different level of care. Examples include:

   1. Disabling or terminal medical illness (e.g., uncompensated heart failure, cirrhosis or end-stage liver disease) as assessed by medical history, review of systems, physical exam and/or laboratory assessments;
   2. Severe, untreated or inadequately treated psychiatric condition (e.g., active psychosis, uncontrolled bipolar disorder) as assessed by history and/or clinical interview, requiring a different level of care (e.g., hospitalization);
   3. Current severe alcohol, benzodiazepine, or other depressant or sedative hypnotic use, requiring a different level of care (e.g., hospitalization);

2. Suicidal or homicidal ideation or behavior requiring a different level of care (e.g., hospitalization);

3. Known allergy or sensitivity to preferred medication or its components;

4. Maintenance on methadone at the time of signing consent;

5. For those preferring XR-NTX, presence of pain of sufficient severity as to require ongoing pain management with opioids;

6. For those preferring XR-NTX, body habitus that, in the judgment of the study physician, precludes safe intramuscular injection of XR-NTX (e.g., BMI>40, excess fat tissue over the buttocks, emaciation);

7. If female, currently pregnant or breastfeeding or planning on conception;

8. Are currently in jail, prison or other overnight facility as required by court of law or have pending legal action that could prevent participation in study activities;

9. Have used the reSET-O or CHESS Connections mHealth apps in the 3 months prior to consent;

10. Other major reasons that might prevent an individual from participating in the study (e.g., a planned move out of the area).

Inclusion Criteria for Discontinuation Phase:

1. 18 years of age or older;
2. Have been receiving buprenorphine for OUD for at least the past year or XR-NTX pharmacotherapy for OUD for at least the past 6 months prior to consent for the Discontinuation Phase;
3. Express the desire to discontinue MOUD after a shared decision-making discussion with the treating provider;
4. Meet stability criteria, i.e., have abstained from opioids (other than buprenorphine), cocaine, methamphetamine, and non-prescribed benzodiazepines for the past ≥12 weeks, and do not meet DSM-5 criteria for current (≥12 weeks) alcohol use disorder (participants with cannabis use will be eligible);
5. If currently taking buprenorphine, are willing to take either SL-BUP or XR-BUP if randomized to that condition;
6. Willing to be randomized to either MM or to MMD;
7. Able to provide written informed consent after discussion with their provider regarding the risks of discontinuation;
8. Able to speak English sufficiently to understand the study procedures;
9. If female of childbearing potential, willing to practice an effective method of birth control while in the study and taking study medication (participants who become pregnant during the study will continue to be followed; treatment may be modified consistent with pregnancy).

Exclusion Criteria for Discontinuation Phase:

1. Serious medical or psychiatric disorder or concomitant medication that, in the opinion of the study medical clinician, would make study participation hazardous to the participant or compromise study findings or would prevent the participant from completing the study. Examples include:

   1. Disabling or terminal medical illness (e.g., uncompensated heart failure, cirrhosis or end-stage liver disease) as assessed by medical history, review of systems, physical exam and/or laboratory assessments;
   2. Severe, untreated, or inadequately treated psychiatric condition (e.g., active psychosis, uncontrolled bipolar disorder) as assessed by history and/or clinical interview, requiring a different level of care (e.g., hospitalization);

2. Suicidal or homicidal ideation or behavior requiring a different level of care (e.g., hospitalization);

3. For participants entering the study taking buprenorphine, presence of pain requiring or likely requiring ongoing pain management with buprenorphine or other opioids;

4. If female, currently pregnant or breastfeeding or planning on conception;

5. Use of opioids (other than buprenorphine), cocaine, methamphetamine, or non-prescribed benzodiazepines in the past 12 weeks;

6. Meets current DSM-5 criteria for any current alcohol use disorder;

7. Are currently in jail, prison or other overnight facility as required by court of law or have pending legal action that could prevent participation in study activities;

8. Have used the Connections mHealth app in the 3 months prior to consent (other than Connections in the Retention Phase);

9. Other major reasons that might prevent an individual from participating in the study (e.g., a planned move out of the area.

This study will comply with the NIH Data Sharing Policy and Implementation Guidance (https://grants.nih.gov/grants/policy/data\_sharing/data\_sharing\_guidance.htm) and (for HEAL-funded studies) the HEAL Public Access and Data Sharing Policy (https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative/research/heal-public-access-data-sharing-policy).

Primary data for this study will be available to the public in the NIDA data repository. For more details on data sharing please visit https://datashare.nida.nih.gov/.

The primary outcome(s) publication will be included along with study underlying primary data in the data share repository, and it will also be deposited in PubMed Central http://www.pubmedcentral.nih.gov/ per NIH Policy (http://publicaccess.nih.gov/).

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.