Evaluating Buprenorphine/Naloxone Microdosing vs. Standard Dosing in Emergency Departments

February 27, 2024 updated by: Jessica Moe, University of British Columbia

Evaluating Microdosing in Emergency Departments: A Randomized Controlled Trial Comparing the Effectiveness of Buprenorphine/Naloxone Microdosing vs. Standard Dosing (EMED Study)

This is a multi-centre, open-label RCT at four Emergency Departments (EDs) in British Columbia and Alberta. The purpose of the current study is to compare the effectiveness of buprenorphine/naloxone microdosing and standard dosing take-home induction regimens at enabling patients to successfully complete the induction regimen, and at retaining patients on opioid agonist therapy.

We will randomize our enrolled patients to receive take-home microdosing or standard dosing packages of buprenorphine/naloxone. For the microdosing arm, patients immediately start taking low doses that increase to effective levels without requiring them to go into withdrawal.

We hypothesize that ED patients provided buprenorphine/naloxone microdosing packages will be more likely to successfully complete the induction period compare to patients provided standard dosing packages. We furthermore hypothesize that those provided microdosing will be more likely to be retained in opioid agonist therapy, and will experience lower overdose, mortality, and healthcare utilization subsequent to their ED visit.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This multi-centered, open-label RCT will be carried out at four emergency departments (EDs) across Canada, two in British Columbia (Vancouver General Hospital and St. Paul's Hospital) and two in Alberta (Royal Alexandra Hospital and Northeast Health Centre). The investigators will randomize the selected patients to receive take-home microdosing or standard dosing packages. These will include a five-day regimen in a bubble package, along with over-the-counter adjunctive medication. The details of the different regimens are outlined in the "Study Arms" section of this page, and the adjunctive medication regimen is highlighted below.

The primary objective of the current study is to compare the effectiveness of ED-initiated buprenorphine/naloxone take-home standard dosing and microdosing interventions for patients with opioid use disorder identified at the four study ED's, with regard to a) successful completion of the induction period (primary outcome) and b) retention on opioid agonist therapy at 30, 90, and 365 days following ED visit, or decreasing overdose, mortality and healthcare utilization (secondary outcomes).

The primary outcome measure will be whether the patient filled a prescription for buprenorphine/naloxone within two weeks of their ED visit (binary variable). If this occurs, the investigators presume that the patient successfully completed the induction regimen provided, followed up with a healthcare provider able to prescribe buprenorphine/naloxone, and was subsequently prescribed ongoing buprenorphine/naloxone therapy. The investigators chose a two-week period, recognizing that patients receiving take-home packages from the ED may not start taking the induction regimen immediately after the ED visit, but instead may decide to delay the start of their regimen to a time that is more convenient to them. The investigators hypothesize that most patients would decide to start within two weeks of their ED visit. This hypothesis is supported by peer advisors on the study team.

Secondary outcomes will include retention on OAT, which will be assessed using provincial pharmacy records (PharmaNet and PIN) up to 30, 90 and 365 days.

The investigators will also examine fatal or non-fatal overdose, mortality, ED visits, physician visits, admissions, and days admitted within 30, 90 and 365 days (timeframes plausibly attributable to ED interventions). The investigators expect that successful OAT initiation would lead to decreased healthcare use, consistent with our previous work indicating high admissions among persons with recent OUD diagnoses and OAT discontinuation. The investigators will also assess patients' self-reported experiences with study regimens, withdrawal, precipitated withdrawal, and comfort via participant surveys.

The study will offer co-interventions to both the intervention and control groups that will be outlined in study-related pre-printed clinical ordersets. This will include symptomatic treatment of nausea/vomiting (dimenhydrinate: 50 mg PO q6h prn - 6 doses), and pain or myalgias (acetaminophen: 975 mg po q6h prn - 6 doses) (ibuprofen: 400 mg po q6h prn - 6 doses), to use in the first two days of inductions, when the investigators expect withdrawal symptoms to be most challenging, especially for standard dosing. Those receiving microdosing may experience breakthrough withdrawal if they do not take an adequate dose of overlapping opioid. Of note, enrolled patients will also be offered counselling with ED social workers to aid with social or other patient needs (e.g., housing, transportation).

This RCT builds on interventions, recruitment, and follow-up procedures successfully tested in a feasibility study. The study team has expertise in emergency and addictions medicine, peer engagement, community overdose prevention, biostatistics, health economics, and RCT implementation, including the high-profile SALOME trial comparing heroin and hydromorphone treatments in our target population. Knowledge users from provincial health ministry and regions will ensure scale-up. The study team are engaging people with lived experience throughout study design, implementation, and interpretation to ensure relevance.

The investigators will ascertain our primary and secondary outcome measures relating to completion of induction and retention on OAT, on records of prescriptions filled in provincial pharmacy databases: PharmaNet in BC, and the Pharmaceutical Information Network in Alberta. The investigators specifically selected partner sites in BC and Alberta to allow our team to access these provincial administrative databases for outcome ascertainment, which will minimize losses to follow-up and strengthen the reliability of our results. The investigators will assess secondary outcomes of overdose and mortality by linking our study cohort to the BC Centre for Disease Control Overdose Cohort (for patients enrolled in BC), and to provincial Vital Statistics data (Alberta and BC). The investigators will assess secondary outcomes related to healthcare utilization by linking our study cohort to provincial databases on emergency department visits (National Ambulatory Care Reporting System) and hospitalizations (Discharge Abstract Data) in Alberta and BC. We will access all administrative databases through Population Data BC (PopData BC) and Alberta Health Services.

This trial will inform urgent development of effective ED buprenorphine/naloxone programs to improve OAT access for people at high risk of overdose. The investigators will leverage our networks of policy makers, public health leaders, and health providers to enable rapid dissemination of findings in guidelines and policies across Canada.

Study Type

Interventional

Enrollment (Estimated)

658

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N2T9
      • Edmonton, Alberta, Canada, T5H 3V9
      • Edmonton, Alberta, Canada, T5A 5E4
    • British Columbia
      • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • Recruiting
        • Vancouver General Hospital
        • Contact:
        • Principal Investigator:
          • Jessica Moe, MD
      • Vancouver, British Columbia, Canada, V6T2B5
        • Recruiting
        • University of British Columbia Hospital
        • Principal Investigator:
          • Jessica Moe, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

We will include ED patients ≥18 years of age with opioid use disorder who are being discharged from the ED. We will define opioid use disorder as non-medical opioid use in the previous 30 days and a positive score for opioid dependency based on the validated Rapid Opioid Dependence Screen (RODS).

All patients will also be assessed by the treating physician or degree of clinical opioid withdrawal, based on the clinical opiate withdrawal scale (COWS) score. Patients will be eligible for the take-home study interventions if they have a COWS score <=12, as a score greater than 12 would mean the patient is a candidate for standard buprenorphine induction in the ED at that moment in time, and would therefore not be eligible for outpatient study interventions.

Exclusion Criteria:

  • Active withdrawal at time of ED assessment (Clinical Opiate Withdrawal Score [COWS] >12)
  • Admitted to hospital
  • Severe communication barriers that inhibit patients' understanding of study procedures and interventions
  • Are taking opioids for cancer or palliative-care related indications
  • Are deemed unsafe to approach by ED providers
  • Incarceration
  • Not a resident of the province in which they are seeking care (BC or Alberta)
  • Actively receiving OAT, defined as having filled a prescription for one of the following medications in the 5 days prior to ED presentation: buprenorphine/naloxone, methadone, sustained release morphine, injectable hydromorphone, injectable diacetylmorphine
  • Prior enrollment in the study
  • Known or suspected mechanical gastrointestinal obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type).
  • Suspected surgical abdomen (e.g., acute appendicitis or pancreatitis).
  • Severe respiratory insufficiency.
  • Severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury.
  • Complicating patient factors that make home inductions from the ED unsafe and/or that require expert consultation for consideration of induction in an observed setting.

These factors include:

  • Allergy to buprenorphine/naloxone
  • Severe respiratory or liver dysfunction
  • Concurrent withdrawal or intoxication from sedatives (e.g., alcohol, benzodiazepines)
  • Active prescription for sedative medications (e.g., benzodiazepines, opioids)
  • Use of monoamine oxidase inhibitors within the past 14 days
  • Concerns that the patient is unable to safely store medications
  • Pregnancy (we will obtain a point-of-care urine pregnancy test on all women of child-bearing age prior to enrollment)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Buprenorphine/naloxone Microdosing

Participants with Opioid use disorder will receive a Buprenorphine/naloxone microdosing package from the ED. This will consist of a five-day take-home packages with gradually increasing doses of 2mg/0.5mg buprenorphine/naloxone tablet employing a four times daily dosing schedule over five days.

Day 1: Buprenorphine 0.5 mg-naloxone 0.125 mg SL* QID** (One quarter tablet),

Day 2: Buprenorphine 1 mg-naloxone 0.25 mg SL QID (One half tablet),

Day 3: Buprenorphine 2 mg-naloxone 0.5 mg SL QID (1 tablet),

Day 4: Buprenorphine 3 mg-naloxone 0.75 mg SL QID (1.5 tablets)

Day 5: Buprenorphine 16 mg-naloxone 4 mg SL once daily (8 tablets).

*SL: Sublingual

** QID: four times daily
Drug: Buprenorphine/naloxone
Buprenorphine/naloxone is a first line, evidence-based opioid agonist therapy that improves mortality for people with opioid use disorder, and that has been demonstrated to be effective at retaining people in addictions care and decreasing illicit opioid use when initiated from EDs.
Other Names:
  • Suboxone
Active Comparator: Buprenorphine/naloxone Standard Dosing

The control intervention will be provision of a buprenorphine/naloxone standard dosing package from the ED. This will consist of a five day package with a commonly accepted standard dosing regimen aiming to achieve a therapeutic buprenorphine/naloxone dose within 24 hours of initiation. Standard dosing packages are currently available in EDs in BC and Alberta as standard of care.

Day 1: Buprenorphine 2 mg-naloxone 0.5 mg SL q1h prn to a maximum of 6 tablets in the first 24 hours (1 tablet),

Day 2: Buprenorphine 12 mg-naloxone 3 mg SL once daily (6 tablets),

Day 3: Buprenorphine 16 mg-naloxone 3 mg SL once daily (8 tablets),

Day 4:Buprenorphine 16 mg-naloxone 3 mg SL once daily (8 tablets).

Day 5:Buprenorphine 16 mg-naloxone 3 mg SL once daily (8 tablets).
Drug: Buprenorphine/naloxone
Buprenorphine/naloxone is a first line, evidence-based opioid agonist therapy that improves mortality for people with opioid use disorder, and that has been demonstrated to be effective at retaining people in addictions care and decreasing illicit opioid use when initiated from EDs.
Other Names:
  • Suboxone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients who have filled a prescription for buprenorphine/naloxone within two weeks of their ED visit.
Time Frame: 14 days
Number of patients who have filled a prescription for buprenorphine/naloxone within two weeks of their ED visit.
14 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients retained in Opioid agonist therapy (OAT) following the ED visit
Time Frame: 30, 90, and 365 days
Number of patients retained in Opioid agonist therapy (OAT) following the ED visit
30, 90, and 365 days
Number of fatal or non-fatal overdose events, mortality, ED visits, physician visits, admissions, and days admitted to hospital for patients following ED visit.
Time Frame: 30, 90, and 365 days.
Number of fatal or non-fatal overdose events, mortality, ED visits, physician visits, admissions, and days admitted to hospital for patients following ED visit.
30, 90, and 365 days.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of British Columbia

Investigators

  • Principal Investigator: Jessica Moe, MD, University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 23, 2021

Primary Completion (Estimated)

December 1, 2024

Study Completion (Estimated)

June 1, 2025

Study Registration Dates

First Submitted

May 14, 2021

First Submitted That Met QC Criteria

May 14, 2021

First Posted (Actual)

May 19, 2021

Study Record Updates

Last Update Posted (Estimated)

February 29, 2024

Last Update Submitted That Met QC Criteria

February 27, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H20-03698

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

There is no plan to make individual participant data available to other researchers

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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