Symptom-inhibited Fentanyl Induction (SIFI)

Rapid IV Symptom-inhibited Fentanyl Induction (SIFI) to Facilitate Rotation Onto Oral Opioid Agonist Therapy (OAT)

The goal of this clinical trial is to test a treatment strategy for individuals with opioid use disorder (OUD) who use fentanyl. Participants will receive medically-administered doses of intravenous (IV) fentanyl at intervals until they are comfortable and do not have withdrawal symptoms. They then will be given opioid agonist therapy (OAT) once daily by mouth, which is the current standard treatment for OUD. In this trial, each participant's starting dose of OAT will be tailored to meet their opioid needs, based on the amount of IV fentanyl they received.

The main questions this trial aims to answer are:

• Is the IV fentanyl protocol feasible and safe for use in a community clinic setting?
• Will the protocol result in higher-than-standard starting doses of OAT? Are these doses safe, and will they enable participants to stay on OAT for a longer time?

Study Overview

• Status: Completed
• Conditions: Opioid Use Disorder
• Intervention / Treatment: Drug: Fentanyl; Drug: Methadone; Drug: Slow-release oral morphine

Detailed Description

This is an open-label, single arm, prospective clinical trial involving 50 individuals with opioid use disorder (OUD) who use illicit fentanyl and for whom opioid agonist therapy (OAT) with either methadone or slow-release oral morphine (SROM) is clinically indicated. Participants who provide informed consent and are found to be eligible will undergo a "symptom-inhibited" fentanyl induction procedure under close medical supervision in a community clinic. A study doctor or nurse will administer intravenous (IV) fentanyl at 5-minute intervals until the participant indicates comfort and their opioid withdrawal symptoms are minimized, or until their sedation level is 2 on the Pasero Opioid-induced Sedation Scale (POSS). Immediately before the first dose of fentanyl, after each dose during the induction procedure, and every 5 minutes for 15 minutes (or until stable) after the final fentanyl dose, study staff will monitor the participants' level of sedation (POSS), withdrawal symptoms (Clinical Opiate Withdrawal Scale, COWS), and vital signs (heart rate, respiratory rate, blood pressure, oxygen saturation).

Selection of the appropriate OAT agent for each participant will be done in advance by the clinical addictions management team. Participants with a QTc interval >500 msec on screening ECG will not be eligible to receive methadone, and will be offered SROM if clinically appropriate. Participants with known chronic kidney disease will have serum creatinine tested for calculation of estimated glomerular filtration rate (eGFR) if they are to receive SROM; if eGFR is between 15 and 60 mL/min, SROM doses will be adjusted according to current recommendations [Lexicomp 2021]; if eGFR<15 mL/min, the participant will not be eligible to receive SROM.

The total cumulative dose of IV fentanyl administered during the induction phase (the loading dose) x 8 will be used as a proxy for the individual's 24-hour opioid tolerance, which in turn will be converted to oral morphine equivalents and used to calculate the appropriate starting dose of methadone or SROM, up to a maximum daily dose of 200 mg for methadone or 2000 mg for SROM. The first OAT dose will be administered under observation in the clinic, preferably on the same day and 15-30 minutes after the completion of the induction procedure. Participants will remain in the clinic under observation for 3 hours after the first dose of methadone or SROM. Vital signs, POSS, and COWS will be monitored before the first OAT dose, then hourly and prior to discharge. Study staff will assess the participants' satisfaction with the symptom-inhibited fentanyl induction process, using the single item Medication Satisfaction Questionnaire (MSQ) and 3-open ended questions. Participants will be discharged from the clinic when medically stable.

Participants will return to the study clinic once daily for 7 days for OAT dispensing and assessment of activity level in the previous 24 hours, vital signs, POSS, and COWS. An ECG will be performed on OAT Days 3 (+/- 2 days) and 7 (+/- 2 days) for participants receiving methadone. Methadone will be preferentially be maintained at the same dose for the first 7 days; however, methadone dose may be adjusted (up to a maximum daily dose of 200 mg) if felt to be safe and clinically indicated. SROM doses may be increased by 100 mg every 24-48 hours (consistent with current clinical guidelines from the British Columbia Centre on Substance Use) up to a maximum daily dose of 2000 mg if clinically indicated (presence of cravings or withdrawal symptoms, and absence of SROM-related adverse events and opioid toxicity).

After Day 7, OAT will be dispensed through a community pharmacy according to standard procedure. Participants will return to the study clinic for the following assessments at 7 days (up to +2 days) , 1 month (+/- 2 weeks), 3 months (+/- 1 month), 6 months (+/- 2 months), and 12 months (+/- 3 months) post-induction:

• Participant satisfaction with their current OUD treatment (single-item MSQ)
• Whether maintained on oral OAT and, if so, current dose
• Whether on prescribed opioids for risk mitigation, and if so, type and dose
• Self-reported illicit opioid use - type, route, amount, frequency
• Self-reported use of other substances - type, route, amount, frequency
• Withdrawal symptoms (COWS score)
• Urine drug test

At the same time points, additional information will be obtained from the clinic's electronic medical record (EMR) database:

• Overdose events requiring intervention (acute care or hospitalization)
• Hospitalizations, including diagnosis, route of admission, dates, duration
• Survival; if deceased, cause of death

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6A 1H2
      • Hope to Health Research & Innovation Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Opioid use disorder (OUD) of any severity by DSM-5 Clinical Diagnostic criteria
2. Intentional use of unregulated fentanyl by any route (injection and/or inhalation) by participant self-report
3. Urine drug test (UDT) positive for fentanyl at screening or within 7 days prior to date of screening visit
4. Clinical indication to start OAT with methadone or SROM
5. Willing and able to provide written informed consent for study participation
6. If taking prescribed opioids for safer supply/risk mitigation, willing to discontinue them starting on study Day 1 and for the first 7 days of the study

Exclusion Criteria:

1. Individuals who are pregnant or breast-feeding
2. Currently receiving prescribed fentanyl in any form, e.g. fentanyl patch
3. Previous participation in this study
4. Current use of methadone >150mg/day or SROM >1300mg/day or buprenorphine extended-release in any dose
5. Use of buprenorphine-naloxone within the previous 3 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Symptom-inhibited IV fentanyl induction; Symptom-inhibited IV fentanyl induction followed by opioid agonist therapy (OAT) with either oral methadone or slow-release oral morphine (SROM)

Drug: Fentanyl; Symptom-inhibited IV fentanyl induction; Other Names: Fentanyl citrate; Fentanyl injection; Drug: Methadone; Opioid agonist therapy (OAT) with methadone at starting doses established by symptom-inhibited IV fentanyl induction; Other Names: Methadone hydrochloride; Methadone oral product; Drug: Slow-release oral morphine; Opioid agonist therapy (OAT) with SROM at starting doses established by symptom-inhibited IV fentanyl induction; Other Names: Kadian; SROM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of clinically significant study drug-related adverse events requiring intervention	Total number of clinically significant study drug-related adverse events (e.g. sedation, respiratory depression, hypoxia, QT prolongation) requiring intervention, occurring during the first week	Count starting from the beginning of the IV fentanyl induction procedure up to the end of Day 7 on OAT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Starting doses of oral OAT	Starting doses of methadone or slow-release oral morphine (SROM)	Immediately after IV fentanyl induction
OAT retention	Proportion of participants who are retained on OAT	Days 1-7 and 1, 3, 6, and 12 months after IV fentanyl induction
Participant satisfaction with fentanyl induction	Qualitative interview and single-item Medication Satisfaction Questionnaire (MSQ)	First 1 to 3 hours after IV fentanyl induction
Participant satisfaction with current OAT	Single-item MSQ	Before IV fentanyl induction, and at Day 7 and 1, 3, 6, and 12 months after IV fentanyl induction
Withdrawal symptoms	Clinical Opiate Withdrawal Scale (COWS) score	Before, during, and during 1-3 hours after IV fentanyl induction; daily during first week on OAT; and at 1, 3, 6, and 12 months
Overdose events	Opioid overdose events requiring Intervention (acute care or hospitalization)	Day 7 and 1, 3, 6, and 12 months
Hospitalizations	Inpatient hospital admissions for any cause	Day 7 and 1, 3, 6, and 12 months
Death	Death	Day 7 and 1, 3, 6, and 12 months

Collaborators and Investigators

• Sponsor: Pouya Azar
• Investigators: Principal Investigator: Pouya Azar, MD, University of British Columbia

Publications and helpful links

General Publications

• Azar P, Ignaszewski MJ, Harris M, Barazanci Z, Davison R, Wong JSH, Maharaj A, Mathew N, Hall D, Guillemi SA, Foreman J, Barrios R, Montaner JSG. Rapid intravenous symptom-inhibiting fentanyl induction (SIFI) to optimize rotation onto oral opioid agonist therapy among individuals who use unregulated fentanyl: protocol for an open-label, single arm clinical trial. Addict Sci Clin Pract. 2025 Jul 29;20(1):58. doi: 10.1186/s13722-025-00586-7.

Study record dates

Study Major Dates

• Study Start (Actual): January 29, 2024
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: May 30, 2023
• First Submitted That Met QC Criteria: June 7, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 12, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Methadone; Morphine; Fentanyl; Opioid agonist therapy
• Additional Relevant MeSH Terms: Narcotic-Related Disorders; Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Opioid-Related Disorders; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Piperidines; Heterocyclic Compounds, 4 or More Rings; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Phenanthrenes; Morphine Derivatives; Ketones; Morphine; Fentanyl; Methadone
• Other Study ID Numbers: H23-00111

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.: No