High Dose Buprenorphine (BUP) Induction in the Emergency Department (ED)

The design of Trial 1 and Trial 2 will be described separately. Trial 1 is a prospective test of the safety and tolerability of 32 mg of BUP as an induction dose (split dosing over 30-60 minutes with 4 hours of post-induction monitoring) with the recommended BUP induction dose (12mg, also split over 60 minutes). Dosing for the 12 mg cohort is planned to be 8 mg at t=0 and 4 mg at 30-60 min. The dosing for the 32 mg cohort is planned to be 16 mg at t=0 and 16 mg at 30-60 min.

The frequency of unacceptable dose limiting toxicities is set at \>10%. The study will therefore compare two cohorts of 10 participants, with the potential for 5 extra participants per cohort if 1 dose limiting toxicity is observed in the first 10 subjects in a cohort.

If there are two dose limiting toxicities (DLTs) in the 32mg cohort, that cohort will no longer recruit. A new, 24 mg high dose cohort will be formed. If the 24 mg cohort has 2 DLTs in either 1st 10 patients or when expanded to n=15, it will be concluded that no safe/tolerable high induction dose has been identified and trial 2 will not occur.

If the 12 mg (control) cohort has 2 DLTs, at n=15 the Data and Safety Monitoring Board (DSMB) will be consulted about enlarging the cohort size or other modifications.

Any participants in the 12 mg cohort who choose not to take their full assigned dose will be replaced to ensure the full cohort size. No more than 20% of participants in either 24 mg or 32 mg cohorts who choose not to take their full assigned dose can be replaced.

Trial 1 will only take place in the Emergency Department at Mount Sinai Beth Israel Study participants can only be enrolled if they are active ED patients and only on the day of their ED visits. Patients will be screened by trained research associates (RAs) with a screener that includes questions about illicit opioid use in the past 30 days embedded in a general health and substance use screener that also includes questions about safety, tobacco and alcohol use. The screener will contain questions regarding opioid use and non-medical use of prescription opioids. Potential study patients who report any opioid use in the past month will complete a 7-day recall of such use. If opioid use is reported during the past 7 days a brief (10 minute) structured diagnostic interview with questions on the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) criteria will be used to evaluate the presence of moderate/severe opioid use. Those who meet study criteria will be informed that they may qualify for the study and will be then asked to provide a urine sample. If the urine tests are positive for fentanyl, the patient indicates ability to provide contract information for 1 separate reliable contacts (in addition to their own) and the patient meets all eligibility criteria on the Patient Eligibility Summary form, informed consent will be obtained.

Patients who sign written informed consent will be enrolled in the study and assigned to a dose cohort (either 12 or 32mg). Assignment in Trial 1 is sequential, not randomized. Participants will receive their full dose over 30-60 minutes and be observed for a total of 4-hours in the ED from the time of their first BUP dose. At the time of discharge all participants will receive a prescription for BUP for 7-day (16mg per day), harm reduction counseling that includes the provision of a naloxone rescue kit and fentanyl test strips and a referral for out-patient addiction treatment within 7-days of the ED visit. After discharge, study participants will be followed-up daily for 7 days to assess daily drug use and opioid craving. At 7-days all participants will be asked to return to provide a urine drug screen and be assessed for engagement in comprehensive addiction treatment and healthcare utilization.

Trial 2 is a four-site pilot randomized controlled trial (RCT) (n=20x4) conducted in the ED, that will test the efficacy, safety and tolerability of the high BUP dose (selected in Trial 1) as an induction dose (split dosing over 30-60 min) compared standard BUP induction dose (up to 12mg) also split over 30-60 min. The four sites participating in the Trial 2 RCT are, (1) Mount Sinai Hospital Emergency Department, (2) Mount Sinai Beth Israel Emergency Department, (3) Barnes Jewish Hospital Emergency Department and (4) Rhode Island Hospital Emergency Department.

Eligibility, screening and enrollment procedures are identical to Trial 1. Eligible participants will be randomized 1:1 with stratification by site to receive either standard (12mg) or high dose BUP induction (determined from trial 1 but no more than 32mg). Participants and study personnel will be blinded to group assignment. All participants will be observed in the ED for a total of 4-hours from the time of their first BUP dose. At discharge. all participants will receive a prescription for BUP for 7-day (16mg per day), harm reduction counseling that includes the provision of a naloxone rescue kit and fentanyl test strips and a referral for out-patient addiction treatment within 7-days of the ED visit. Participants will be followed-up at 7 and 14-day to assess the primary outcome (engagement in comprehensive addiction treatment) and multiple secondary outcomes.

• Percentage of days with opioid abstinence (Trial 1) [Срок оценки: at day 7]
• Percentage of days with opioid use (Trial 1) [Срок оценки: 7 days post-ED]
• Percentage of days with opioid use (Trial 2) [Срок оценки: 30 days post-ED]
• Daily assessment of opioid use (Trial 1) [Срок оценки: Days 1-7 after enrollment]
• Change in number of times opioids used (Trial 1) [Срок оценки: induction through 7 days]
• Change in number of times opioids used (Trial 2) [Срок оценки: Baseline and follow-up assessment day 7]
• Change in number of times opioids used (Trial 2) [Срок оценки: Baseline and follow-up assessment day 30]
• Proportion of participants with persistent nausea/vomiting during induction [Срок оценки: at 240 minutes]
• Proportion of participants with a Pasero Opioid-induced Sedation Scale (POSS) score of 3 or higher [Срок оценки: at 240 minutes]
• Proportion of participants with a Mini Mental Status Exam (MMSE) score indicating severe cognitive impairment [Срок оценки: at 240 minutes]
• Proportion of participants with precipitated or worsening withdrawal [Срок оценки: up to 240 minutes]
• Patient Satisfaction Survey [Срок оценки: ED enrollment visit at 240 minutes]