Pregabalin Plus Lofexidine for the Outpatient Treatment of Opioid Withdrawal

A placebo-controlled trial in which male and female outpatients with an opioid use disorder who express interest in extended-release injectable naltrexone (XR-NTX) are randomized 1:1 to lofexidine/pregabalin or lofexidine/pregabalin placebo for withdrawal management and offered XR-NTX if after completing withdrawal. It follows a UG3 study in which 90 inpatients with an OUD who expressed interest in XR-NTX were randomized 2:1 to withdrawal management with lofexidine/pregabalin or lofexidine/placebo pregabalin. Results were that the conditions were equally safe, and that lofexidine/pregabalin was more effective in reducing subjective withdrawal and keeping patients in treatment than lofexidine/placebo pregabalin.

The objectives are to study the safety and effectiveness of lofexidine/pregabalin compared to lofexidine/placebo for managing opioid withdrawal and transitioning to XR-NTX in outpatient settings.

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