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

Opioid-use Disorder Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04893525
• Other study ID #: H20-03698
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: July 23, 2021
• Est. completion date: June 2025

Study information

• Verified date: February 2024
• Source: University of British Columbia
• Contact: Seth Long, MPH
• Phone: 236-863-1168
• Email: seth.long[@]ubc.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 658
• Est. completion date: June 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Emergencies
• Opioid-Related Disorders
• Opioid-use Disorder

Intervention

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.

Locations

Country	Name	City	State
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Northeast Community Health Centre	Edmonton	Alberta
Canada	Royal Alexandra Hospital	Edmonton	Alberta
Canada	St. Paul's Hospital	Vancouver	British Columbia
Canada	University of British Columbia Hospital	Vancouver	British Columbia
Canada	Vancouver General Hospital	Vancouver	British Columbia

Sponsors (1)

Lead Sponsor	Collaborator
University of British Columbia

Country where clinical trial is conducted

Canada, 

References & Publications (3)

Moe J, Badke K, Pratt M, Cho RY, Azar P, Flemming H, Sutherland KA, Harvey B, Gurney L, Lockington J, Brasher P, Gill S, Garrod E, Bath M, Kestler A. Microdosing and standard-dosing take-home buprenorphine from the emergency department: A feasibility study. J Am Coll Emerg Physicians Open. 2020 Oct 20;1(6):1712-1722. doi: 10.1002/emp2.12289. eCollection 2020 Dec. — View Citation

Moe J, Doyle-Waters MM, O'Sullivan F, Hohl CM, Azar P. Effectiveness of micro-induction approaches to buprenorphine initiation: A systematic review protocol. Addict Behav. 2020 Dec;111:106551. doi: 10.1016/j.addbeh.2020.106551. Epub 2020 Jul 11. — View Citation

Moe J, O'Sullivan F, Hohl CM, Doyle-Waters MM, Ronsley C, Cho R, Liu Q, Azar P. Short communication: Systematic review on effectiveness of micro-induction approaches to buprenorphine initiation. Addict Behav. 2021 Mar;114:106740. doi: 10.1016/j.addbeh.2020.106740. Epub 2020 Nov 25. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients who have filled a prescription for buprenorphine/naloxone within two weeks of their ED visit.	Number of patients who have filled a prescription for buprenorphine/naloxone within two weeks of their ED visit.	14 days
Secondary	Number of patients retained in Opioid agonist therapy (OAT) following the ED visit	Number of patients retained in Opioid agonist therapy (OAT) following the ED visit	30, 90, and 365 days
Secondary	Number of fatal or non-fatal overdose events, mortality, ED visits, physician visits, admissions, and days admitted to hospital for patients following ED visit.	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.