Symptom-inhibited Fentanyl Induction

Study Overview
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Brief Summary
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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?

Detailed Description
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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 after the final fentanyl dose (or until the first dose of OAT), 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 their clinical addictions management team. The total cumulative dose of IV fentanyl administered during the induction phase (the loading dose) x 4 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. 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 1 hour after the first dose of SROM. Vital signs, POSS, and COWS will be monitored 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 vital signs, POSS, and COWS. An ECG will be performed on OAT Days 3 and 7 for participants receiving methadone. Methadone will be maintained at the same dose for the first 7 days. 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) 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, 1 month, 3 months, 6 months, and 12 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

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

Conditions
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Opioid Use Disorder

Intervention / Treatment
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* Drug: Fentanyl
* Drug: Methadone
* Drug: Slow-release oral morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Opioid use disorder (OUD) of any severity by DSM-5 Clinical Diagnostic criteria Intentional use of unregulated fentanyl by any route (injection and/or inhalation) by participant self-report Urine drug test (UDT) positive for fentanyl at screening or within 7 days prior to date of screening visit Clinical indication to start OAT with methadone or SROM Willing and able to provide written informed consent for study participation Exclusion Criteria: Individuals who are pregnant or breast-feeding Currently receiving prescribed fentanyl in any form, e.g. fentanyl patch Previous participation in this study

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Symptom-inhibited IV fentanyl induction<br>Symptom-inhibited IV fentanyl induction followed by opioid agonist therapy (OAT) with either oral methadone or slow-release oral morphine (SROM) | Drug: Fentanyl<br>* Symptom-inhibited IV fentanyl induction<br>* Other names: Fentanyl injection;Drug: Methadone<br>* Opioid agonist therapy (OAT) with methadone at starting doses established by symptom-inhibited IV fentanyl induction<br>* Other names: Methadone oral product;Drug: Slow-release oral morphine<br>* Opioid agonist therapy (OAT) with SROM at starting doses established by symptom-inhibited IV fentanyl induction<br>* Other names: Kadian;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fentanyl, Methadone, Morphine, Opioid agonist therapy