Comparing Rapid Micro-Induction and Standard Induction of Buprenorphine/Naloxone for Treatment of Opioid Use Disorder

Comparing Rapid Micro-Induction and Standard Induction of Buprenorphine/Naloxone for Treatment of Opioid Use Disorder: A Randomized Controlled Trial

The current first-line treatment for opioid use disorder (OUD) in Canada is buprenorphine/naloxone (bup/nx). The standard induction method of bup/nx requires patients to be abstinent from opioids and thereby experience withdrawal symptoms prior to induction, which can be a major barrier in starting treatment. Rapid micro-induction (also known as micro-dosing, low-dose induction) involves the administration of small, frequent does of bup/nx and removes the need for a period of withdrawal prior to the start of treatment. This study aims to compare the effectiveness and safety of rapid micro-induction versus standard induction of bup/nx in patients with OUD.

Study Overview

• Status: Recruiting
• Conditions: Opioid Use Disorder
• Intervention / Treatment: Drug: Buprenorphine/naloxone; Drug: Hydromorphone

Detailed Description

This is a randomized, controlled, open-label superiority trial involving 50 individuals with OUD. Participants will be randomized into two arms: rapid micro-induction and standard induction (based on the American Society of Addiction Medicine Practice Guidelines and product monograph) of bup/nx.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pouya Azar, MD, FRCPC, DABAM; Phone Number: 54788 604-875-4111; Email: pouya.rezazadeh-azar@ubc.ca
• Study Contact Backup: Name: James Wong, MSc; Phone Number: 604-875-5823; Email: james.wong@vch.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Recruiting
      • Vancouver General Hospital
      • Contact: Pouya Azar, MD, FRCPC, DABAM; Phone Number: 54788 604-875-4111; Email: pouya.rezazadeh-azar@ubc.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Opioid Use Disorder (OUD) as defined by the Diagnostic and Statistical Manual of Mental Disorders-5 diagnostic criteria;
2. Individuals seeking Opioid Agonist Treatment (OAT);
3. Be 19 years of age or older;
4. Be willing and able to adhere to the study protocol and follow-up schedule;
5. Be able to provide written informed consent to participate in the clinical trial.
6. If female and of childbearing potential, agree to use an effective method of birth control approved by the study investigators throughout the study.

Exclusion Criteria:

1. Diagnosis of severe medical or psychiatric conditions contraindicated for buprenorphine/naloxone or hydromorphone treatment;
2. Anticipated deterioration of health due to discontinuation of medications that are contraindicated with buprenorphine/naloxone and/or hydromorphone;
3. Positive pregnancy test for women of childbearing potential;
4. Methadone use in the past 5 days;
5. Buprenorphine use in the past 5 days;
6. Known allergy or sensitivity to buprenorphine/naloxone and/or hydromorphone;
7. Anticipation that the patient may need to initiate pharmacological treatment during the trial that is deemed unsafe by the study physician or could prevent study completion;
8. Unwilling or unable to use an effective method of birth control approved by the study investigators throughout the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapid Micro-Induction; On Day 1, participants will receive 0.5mg bup/nx sublingually (SL) every 3 hours (Q3H) - total daily dose of 4mg. On Day 2, they will receive 1mg bup/nx SL Q3H - total daily dose of 8mg. On Day 3, they will receive 8mg bup/nx SL once and 1-4mg bup/nx SL Q3H as needed (PRN) for withdrawal symptoms and/or craving and/or pain - maximum daily dose of 32mg. Afterwards, their day 3 total dose will be consolidated to once daily dosing - maximum daily dose of 32mg. On Days 1 and 2, participants will concurrently receive 1-48mg hydromorphone orally, intravenously, subcutaneously, or intramuscularly (PO/IV/SC/IM) Q1 to 3H PRN for withdrawal symptoms and/or craving and/or pain, titrated to effect (start at lower end of dosing range). Hydromorphone will be discontinued on Days 3 onwards.	Drug: Buprenorphine/naloxone; Buprenorphine/naloxone is an opioid agonist treatment for opioid use disorder. It is administered via sublingual tablet form.; Other Names: Suboxone; Drug: Hydromorphone; Hydromorphone is an opioid used for managing pain, craving, and withdrawal. It is administered orally via tablet or liquid form; or administered intravenously, subcutaneously, or intramuscularly via liquid form.; Other Names: Dihydromorphinone, Dilaudid
Active Comparator: Standard Induction; Day 1 is initiated when participants score 11 or above on the Clinical Opiate Withdrawal Scale (COWS), and when they have been abstinent from short-acting opioids for at least 6-12 hours or from long-acting opioids for 24-72 hours. On Day 1, participants will start with 2 or 4mg bup/nx SL. If their COWS score increases, bup/nx will be held. If their COWS score remains the same or decreases, additional dosing can be done in increments of 2mg bup/nx SL every 2 hours (Q2H) as needed (PRN). On Day 2, dosing will be consolidated to once daily dosing. The maximum total daily dose for Day 1 and 2 is 32mg.	Drug: Buprenorphine/naloxone; Buprenorphine/naloxone is an opioid agonist treatment for opioid use disorder. It is administered via sublingual tablet form.; Other Names: Suboxone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Successful induction of bup/nx with low levels of withdrawal	This is defined as the following: participants who remain in treatment until they have received a total daily dose of ≥ 8mg of bup/nx (successful induction), and score ≤ 12 on the COWS (low levels of withdrawal) from baseline to when they reach that dose.	Baseline to Day 1 (Standard Induction Arm) or Day 2 (Rapid Micro-Induction Arm)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Illicit drug use	Assessed by urine drug screens (UDS) and Treatment Outcomes Profile (TOP).	Baseline to Day 1 (Standard Induction Arm) or Day 2 (Rapid Micro-Induction Arm)
Drug use behaviour	Assessed by the Treatment Outcomes Profile (TOP).	Baseline to Day 1 (Standard Induction Arm) or Day 2 (Rapid Micro-Induction Arm)
Treatment retention	Participants who pick up their prescription of bup/nx on Day 7. Assessed via the pharmacy database.	Day 7
Craving	Assessed by the numeric craving scale.	Baseline to Day 1 (Standard induction Arm) or Day 2 (Rapid Micro-Induction Arm)
Pain	Assessed by the numeric pain scale.	Baseline to Day 1 (Standard induction Arm) or Day 2 (Rapid Micro-Induction Arm)
Physical health	Assessed by the health section of the Opiate Treatment Index (OTI).	Baseline (both arms)
Client satisfaction	Assessed by the Treatment Perceptions Questionnaire (TPQ).	Day 1 (Standard induction Arm) or Day 2 (Rapid Micro-Induction Arm)
Appearance of adverse events	Assessed by an adverse events report form.	Baseline to Day 1 (Standard induction Arm) or Day 2 (Rapid Micro-Induction Arm)

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: Vancouver Coastal Health
• Investigators: Principal Investigator: Pouya Azar, MD, FRCPC, DABAM, University of British Columbia; Principal Investigator: Nickie Mathew, MD, MSc, FRCPC, ABPN, ABPM, University of British Columbia

Publications and helpful links

General Publications

• Sandhu R, Zivanovic R, Klaire S, Nikoo M, Rozylo J, Azar P. Buprenorphine/naloxone induction for treatment of acute on chronic pain using a micro-dosing regimen: A case report. Can J Pain. 2019 Apr 25;3(1):79-84. doi: 10.1080/24740527.2019.1599279. eCollection 2019.
• Klaire S, Zivanovic R, Barbic SP, Sandhu R, Mathew N, Azar P. Rapid micro-induction of buprenorphine/naloxone for opioid use disorder in an inpatient setting: A case series. Am J Addict. 2019 Jul;28(4):262-265. doi: 10.1111/ajad.12869. Epub 2019 Mar 22.
• Hammig R, Kemter A, Strasser J, von Bardeleben U, Gugger B, Walter M, Dursteler KM, Vogel M. Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. Subst Abuse Rehabil. 2016 Jul 20;7:99-105. doi: 10.2147/SAR.S109919. eCollection 2016.
• Vogel M, Kock P, Strasser J, Wiesbeck G, Walter M, Dursteler KM. Chronic High-Dose Buprenorphine Does Not Block Subjective High from Diacetylmorphine in a Patient in Heroin-Assisted Treatment. J Psychoactive Drugs. 2019 Sep-Oct;51(4):377-382. doi: 10.1080/02791072.2019.1610200. Epub 2019 May 2.
• Kampman K, Jarvis M. American Society of Addiction Medicine (ASAM) National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. J Addict Med. 2015 Sep-Oct;9(5):358-67. doi: 10.1097/ADM.0000000000000166.
• Wong JSH, Nikoo M, Westenberg JN, Suen JG, Wong JYC, Krausz RM, Schutz CG, Vogel M, Sidhu JA, Moe J, Arishenkoff S, Griesdale D, Mathew N, Azar P. Comparing rapid micro-induction and standard induction of buprenorphine/naloxone for treatment of opioid use disorder: protocol for an open-label, parallel-group, superiority, randomized controlled trial. Addict Sci Clin Pract. 2021 Feb 12;16(1):11. doi: 10.1186/s13722-021-00220-2.

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2021
• Primary Completion (Estimated): January 1, 2025
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: January 13, 2020
• First Submitted That Met QC Criteria: January 15, 2020
• First Posted (Actual): January 21, 2020

Study Record Updates

• Last Update Posted (Actual): June 11, 2024
• Last Update Submitted That Met QC Criteria: June 10, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Suboxone; Buprenorphine/naloxone; Opioid agonist treatment; Micro-induction; Microdosing; Withdrawal Management
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Narcotic-Related Disorders; Substance-Related Disorders; Opioid-Related Disorders; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Buprenorphine; Naloxone; Buprenorphine, Naloxone Drug Combination; Hydromorphone
• Other Study ID Numbers: H19-03254

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
• product manufactured in and exported from the U.S.: Yes