Pregabalin Plus Lofexidine for the Outpatient Treatment of Opioid Withdrawal (UH3)

Inclusion Criteria: Male and/or female subjects ≥ 18 years of age Meet DSM-5 criteria for an Opioid Use Disorder with physiologic features. Have met 2 or more of the 11 criteria for an OUD including tolerance and withdrawal within the last 12 months Interested in opioid antagonist treatment Used opioids in 20 or more of the last 30 days A stable address in the local area; not planning to move in the next 60 days. Have documents for ID check Absence of medical or psychiatric conditions that are likely to interfere with study participation Has 12 lead ECG demonstrating a QTc ≤450 msec and a QRS ≤120 msec. Site PI has final determination for study inclusion if readings exceed these limits. The PENN cardiologists and medical monitor are available for consultation when needed Negative pregnancy test and using adequate contraception if of childbearing potential. Exclusion Criteria: Current psychotic disorder (bipolar I, schizophrenia, major depression that is not in remission Alcohol, benzodiazepine, or other sedative use disorder with physiological features that require medication for detoxification Allergy or other serious adverse event due to treatment with pregabalin, XR-NTX, or lofexidine Pending incarceration or plans to leave the immediate area in the next 30 days Homicidal or otherwise behaviorally disturbed requiring immediate attention High risk for suicide as determined by answering 'yes' to questions 4 and/or 5 on C-SSRS Blood pressure <90 mm Hg (systolic) or <60 mm Hg (diastolic). If value out of normal range, the investigator and study Clinician will decide subject inclusion/exclusion on case-by-case basis Heart rate and/or pulse<50 bpm at screening-sitting An Estimated Glomerular Filtration Rate eGFR<70 mL/min/1.73m2 A History of, or current Seizure disorder (excluding childhood febrile seizures) Inability to read and/or understand English. For example, unable to understand the informed consent as demonstrated by failing to answer 9/10 questions correctly on the quiz 12. Pregnant or breastfeeding 13. Currently taking sympathomimetic drugs, or a thiazolidinedione antidiabetic ALT and/or AST >4X upper limit of normal A Child-Pugh score >7 Currently receiving opioids for pain management In a treatment study where medication was administered in the last 30 days Currently using medications that are known to be strong or moderate inhibitors of CYP2D6 such as fluoxetine, paroxetine, mirabegron, bupropion, quinidine, terbinafine, cimetidine, cinacalcet, duloxetine, or fluvoxamine In a methadone maintenance or buprenorphine treatment program within the last 30 days