Symptom-Inhibited Naloxone Induction (SINI) for Buprenorphine Initiation: A Feasibility Trial

Symptom-inhibited Naloxone Induction (SINI) to Initiate Buprenorphine/Naloxone and Buprenorphine Extended-release for Opioid Use Disorder: A Single-arm Feasibility Trial

The goal of this clinical study is to evaluate a new treatment approach called symptom inhibited naloxone induction (SINI) for people with opioid use disorder. In this study, participants will receive small doses of intravenous (IV) naloxone at intervals until they feel mild opioid withdrawal symptoms. At this point, they will be given buprenorphine/naloxone under the tongue to help with the withdrawal symptoms. One hour after, they will receive a injection of long acting buprenorphine under the skin if they choose to.

The main questions this study aims to answer are:

Is it feasible to use the SINI protocol in inpatient and outpatient settings? Is the SINI protocol safe and tolerable for individuals with opioid use disorder?

This is a prospective, single arm, open label, feasibility study involving 12 participants with opioid use disorder who have a clinical indication to start opioid agonist therapy with buprenorphine. Eligible participants provide informed consent will undergo buprenorphine induction using the symptom inhibited naloxone induction protocol (SINI). A study doctor or nurse will administer 0.1 - 0.2 mg of intravenous naloxone every 2 minutes until the patient is in mild opioid withdrawal, defined as a Clinical Opiate Withdrawal Scale (COWS) score of ≥8 and at least two objective withdrawal signs not attributable to other causes. Once this is level of opioid withdrawal is achieved, ≥ 8 mg of sublingual buprenorphine/naloxone (BUP/NLX) will be administered consistent with the recommended minimum induction dose in the product monograph and published high dose induction strategies.

If the patient opts for extended release buprenorphine treatment (BUP-XR) and their COWS score has not increased by more than 5 points one hour after sublingual buprenorphine/naloxone administration, a 300 mg dose of BUP-XR will be administered subcutaneously one hour after their sublingual BUP/NLX.

The following information will the collected

• Substance use history
• Substance use treatment utilization
• Harm reduction service utilization
• Clinical Opiate Withdrawal Scores / Subjective Opiate Withdrawal Scores
• Vital Signs (Heart rate, blood pressure, respiratory rate, oxygen saturation)
• Adverse events
• Treatment satisfaction questionnaire for medication (TSQM)

Following the SINI protocol, participants receiving sublingual BUP/NLX treatment, ongoing medication dispensing will transition to a community pharmacy in accordance with standard clinical practice. Participants receiving subcutaneous BUP/XR treatment, subsequent doses will be administered either at a CPAS physician's office, clinic, or pharmacy, as per standard clinical practice. Participants will be followed for 28 days, during which the information listed below will be collected.

• Retention on BUP/NLX or BUP-XR, or other forms of OAT
• Unregulated opioid use
• Rates of overdose and hospitalization
• Adverse events

Inclusion Criteria:

To be eligible for this study, participants must fulfill all the following inclusion criteria:

• 19 years of age or older.

• Opioid use disorder as confirmed by DSM 5 diagnostic criteria.

• Clinical indication to start OAT with buprenorphine.

• Willingness to tolerate mild opioid withdrawal precipitated by naloxone, expected to last less than 20 minutes.

• Willing and able to have and maintain IV access for the duration of the SINI

• If of childbearing potential and elected BUP-XR, agree to use an effective method of birth control.

  o Highly effective methods of birth control include hormonal contraceptives (e.g., combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or intrauterine system (IUS); vasectomy and tubal ligation. Effective methods include barrier methods of contraception (e.g., male condom, female condom, cervical cap, diaphragm, contraceptive sponge).

• Willing and able to provide written informed consent for study participation.

Exclusion Criteria:

If participants meet any of the following exclusion criteria, they will be excluded from participation in the study:

• Diagnosis of severe medical or psychiatric conditions contraindicated for naloxone or buprenorphine.

• Concomitant use of medications with drug-drug interactions with buprenorphine, unless alternative treatment options are less appropriate and a risk-benefit assessment has been discussed and recommended by the participant's healthcare team.

  o Examples include, but are not limited to: benzodiazepines and non-benzodiazepine central nervous system depressants, naltrexone, CYP3A4 inhibitors and inducers, serotonergic drugs, monoamine oxidase inhibitors, QTc interval-prolonging drugs, diuretics, anticholinergics, and antiretrovirals.

• Known allergy or sensitivity to naloxone or buprenorphine.

• Use of BUP/NLX within the past 9 days.

• Use of BUP-XR within the past 43 weeks.

• Previous participation in this study (previous receipt of SINI in a clinical setting is not exclusionary).

• Currently pregnant or breastfeeding.

• COWS ≥ 8