Inclusion Criteria:
* Individuals between the ages of 18-65 (inclusive) interested in antagonist-based relapse prevention treatment
* Meets current DSM-5 criteria for current opioid use disorder of at least six months duration supported by urine toxicology positive for opioids OR positive naloxone challenge (defined by 3-point increase in COWS) if seeking detoxification and XR-NTX induction OR confirmed recent detoxification treatment for opioids.
* In otherwise good health based on complete medical history, physical examination, vital signs measurement, ECG, and laboratory tests (hematology, blood chemistry, urinalysis) with no clinically significant abnormalities
* Participants who completed detoxification and received XR-NTX are eligible for the study. Participants may be enrolled up to 2 weeks following an initial XR-NTX injection given in any outside research or community-based treatment setting (inpatient, outpatient residential).
* Seeking treatment for opioid use disorder, willing to accept treatment with XR-NTX and, in the judgment of the treating physician, is a good candidate for naltrexone-based treatment.
* Voluntarily seeking treatment for opioid use disorder.
* Able to give written informed consent to participate in the study and showing a thorough understanding of the difference between agonist and antagonist-based treatment.
Exclusion Criteria:
* Methadone maintenance within 2 weeks of XR-NTX induction or any use of methadone in the week prior to XR-NTX induction
* Maintenance on buprenorphine or frequent buprenorphine use in the week prior to XR-NTX induction (must be using no more than 8 mg of buprenorphine per day for no more than 3 days per week). If consenting after initial XR-NTX injection, any use of buprenorphine since XR-NTX induction is exclusionary.
* Serious medical, psychiatric or substance use disorder that, in the opinion of the study physician, would make a detoxification and naltrexone initiation, or maintenance treatment with XR-NTX in combination with buprenorphine, hazardous (relative contraindications) or requires a different level of care. Examples include:
1. Disabling or terminal medical illness (e.g., uncompensated heart failure, severe acute hepatitis, cirrhosis or end-stage liver disease) as assessed by medical history and/or review of systems.
2. Severe, untreated or inadequately treated mental disorder (e.g., active psychosis, uncontrolled manic-depressive illness) as assessed by history and/or clinical interview.
3. Current severe alcohol, benzodiazepine, or other depressant or sedative hypnotic use likely to require a complicated medical detoxification (routine alcohol and sedative detoxifications may be included).
4. Suicidal or homicidal
* AST/ALT \> 3x normal limit
* Pregnancy, lactation, or a plan of becoming pregnant. Women need to have negative blood pregnancy test at screening and agree to practice dual contraceptives.
* Physiological dependence on alcohol or sedative-hypnotics with impending withdrawal. Other substance use diagnoses are not exclusionary.
* History of allergic or adverse reaction to buprenorphine, naltrexone, naloxone, clonidine, or clonazepam.
* Painful medical condition that requires ongoing opioid analgesia or anticipated surgery necessitating opioid medications.
* Individuals above 60 with possible early cognitive decline or other neurodegenerative conditions as evidenced by a score of less than 25 on a Mini Mental Status Exam screen.
* Participants who had 30 or more opioid-free days prior to randomization will not be eligible.
* Participants more than 2 weeks following an initial XR-NTX injection (given in any outside research or community-based treatment setting, for example inpatient, outpatient residential).
