Fentanyl Induction for Opioid Use Disorder

(SIFI Trial)

Overseen By Marianne Harris, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Pouya Azar

Must be taking: Opioid agonist therapy

Must not be taking: Prescribed fentanyl, Buprenorphine-naloxone

Disqualifiers: Pregnancy, Breast-feeding, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

50 Participants Needed

Trial Summary

What is the purpose of this trial?

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?

Will I have to stop taking my current medications?

If you are taking prescribed opioids for safer supply or risk mitigation, you will need to stop them starting on the first day of the study and for the first 7 days. If you are currently receiving prescribed fentanyl, you cannot participate in the trial.

What data supports the effectiveness of the drug for opioid use disorder?

Research suggests that slow-release oral morphine (SROM) can be as effective as methadone in helping people with opioid use disorder, especially for those who have not responded well to other treatments. A case report also showed that SROM helped a patient stop using opioids after a fentanyl overdose when other treatments had failed. ^{1 2 3 4 5}

Is slow-release oral morphine safe for treating opioid use disorder?

Research shows that slow-release oral morphine (SROM) is generally well tolerated and has a better safety profile compared to methadone, especially regarding heart-related effects. It is considered a safe option for long-term maintenance treatment in opioid dependence. ^{1 4 6 7 8}

How is the drug used in the Fentanyl Induction for Opioid Use Disorder trial different from other treatments?

The trial explores using methadone and slow-release oral morphine to adapt induction schedules for patients using fentanyl, which is more potent than traditional opioids. This approach aims to address the unique challenges of treating opioid use disorder in the fentanyl era by potentially allowing for more rapid and aggressive methadone inductions compared to conventional methods. ^{9 10 11 12 13}

Research Team

Pouya Azar, MD

Principal Investigator

University of British Columbia

Eligibility Criteria

This trial is for individuals with opioid use disorder who have used fentanyl intentionally, confirmed by a urine test. They must meet the clinical criteria for OUD and be ready to start treatment with methadone or slow-release oral morphine. Participants need to consent in writing to join the study.

Inclusion Criteria

Opioid use disorder (OUD) of any severity by DSM-5 Clinical Diagnostic criteria

My recent drug test showed positive for fentanyl.

Willing and able to provide written informed consent for study participation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Induction

Participants undergo symptom-inhibited fentanyl induction under medical supervision

1 day

Multiple visits (in-person) within a single day

Initial Treatment

Participants receive opioid agonist therapy (OAT) daily for 7 days with monitoring

7 days

Daily visits (in-person)

Follow-up

Participants are monitored for safety, effectiveness, and satisfaction with OAT

12 months

Visits at 7 days, 1, 3, 6, and 12 months

Treatment Details

Interventions

• Methadone
• Slow-release oral morphine

Trial Overview The study tests if giving IV fentanyl until withdrawal symptoms stop, followed by daily oral treatments (methadone or slow-release morphine), is safe and effective in a clinic setting. It also checks if this leads to higher starting doses of these medications and helps patients stay on treatment longer.

Participant Groups

Group I: Symptom-inhibited IV fentanyl induction Experimental Treatment 3 Interventions

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

Methadone is already approved in United States, European Union, Canada, Japan, Switzerland for the following indications:

Approved in United States as Dolophine for:

• Pain management
• Opioid use disorder

Approved in European Union as Methadose for:

• Pain management
• Opioid dependence

Approved in Canada as Physeptone for:

• Pain management
• Opioid use disorder

Approved in Japan as Heptadon for:

• Pain management

Approved in Switzerland as Heptanon for:

• Pain management
• Opioid dependence

Who Is Running the Clinical Trial?

Pouya Azar

Lead Sponsor

Trials

1

Recruited

50+

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Findings from Research

The pRESTO study is a 24-week randomized controlled trial involving 298 adults with opioid use disorder, comparing the effectiveness of slow-release oral morphine (SROM) to methadone in suppressing illicit opioid use, particularly in the context of fentanyl contamination.

This research aims to fill a critical gap in understanding how SROM performs relative to methadone, with a focus on various outcomes such as treatment retention, safety, and patient satisfaction, which are essential for developing effective treatment strategies for those affected by the opioid crisis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): Protocol for a non-inferiority randomized clinical trial. Socias, ME., Wood, E., Dong, H., et al.[2021]

In a study of 62 hospitalized patients with opioid use disorder, 82% successfully transitioned to buprenorphine using a low dose induction method while still on full opioid agonists, indicating this approach can be effective for managing OUD in a hospital setting.

Factors such as older age, the need for discharge placement, and withdrawal symptoms were associated with a lower likelihood of successfully leaving the hospital with a buprenorphine prescription, highlighting areas for improvement in patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Dose Buprenorphine Induction With Full Agonist Overlap in Hospitalized Patients With Opioid Use Disorder: A Retrospective Cohort Study. Bhatraju, EP., Klein, JW., Hall, AN., et al.[2022]

In an open-label crossover study involving 18 patients, switching from methadone to slow-release oral morphine (SROM) resulted in mild withdrawal symptoms and a favorable dose ratio of 4.6:1, indicating a manageable transition between medications.

Patients reported improved social functioning, reduced heroin cravings, and fewer side effects with SROM compared to methadone, with 78% of participants preferring SROM, suggesting it may be a promising alternative for opioid dependence treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Mitchell, TB., White, JM., Somogyi, AA., et al.[2013]

A case study of a 48-year-old male with severe opioid use disorder (OUD) showed that slow-release oral morphine (SROM) effectively reduced opioid cravings and illicit drug use after previous treatments with methadone and buprenorphine/naloxone failed.

This case suggests that SROM may be a promising second-line treatment option for individuals with OUD, particularly those who have not responded to standard opioid agonist therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment with slow-release oral morphine following afentanyl-related overdose: A case report. Prinsloo, G., Ahamad, K., Socías, ME.[2020]

A study involving 67 opioid addicts in Slovenia found that switching from methadone to slow-release oral morphine (SROM) significantly reduced side effects and improved withdrawal symptoms and cravings for those who were intolerant to methadone or had inadequate withdrawal suppression.

After four weeks of SROM treatment, participants reported significant improvements in both physical and psychological well-being, indicating that SROM is a well-tolerated and effective alternative for maintenance therapy in opioid addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slow-release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression. Kastelic, A., Dubajic, G., Strbad, E.[2013]

In a study involving 211 patients, slow-release oral morphine (SROM) was found to be well tolerated and associated with higher treatment satisfaction, fewer cravings for heroin, and lower mental stress compared to methadone.

SROM demonstrated a better safety profile than methadone, as it resulted in a significantly shorter QTc-interval, indicating a lower risk of cardiac issues, making it a promising long-term maintenance treatment for opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence. Hämmig, R., Köhler, W., Bonorden-Kleij, K., et al.[2015]

In a study of 504 advanced cancer patients, those using transdermal fentanyl reported higher overall satisfaction with their pain management compared to those using sustained-release oral morphine.

Patients on transdermal fentanyl experienced significantly fewer and less impactful side effects from their pain medication, which may contribute to their greater satisfaction, despite being older and having lower functioning and well-being scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. Payne, R., Mathias, SD., Pasta, DJ., et al.[2022]

In a study of 100 patients post-orthopedic surgery, MS Contin (MSC) 60 mg demonstrated superior analgesic efficacy compared to Oramorph SR (OSR) 60 mg, achieving significant pain relief within the first three hours after administration.

MSC 60 mg not only provided faster pain relief but also resulted in fewer adverse effects, with the OSR group experiencing nearly double the number of side effects, including increased somnolence and dizziness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic efficacy and safety of two oral controlled-release morphine preparations in orthopedic postoperative pain. Cooper, SA., Fitzmartin, R., Slywka, J., et al.[2013]

Conventional methods for starting buprenorphine treatment for opioid use disorder, which require patients to be in withdrawal, are inadequate in the current fentanyl crisis, leading to challenges like precipitated withdrawal.

Involving people who use drugs in the development of new strategies for buprenorphine initiation is crucial, as their experiences can inform more effective and life-saving treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprenorphine Are Urgently Needed in the Fentanyl Era. Sue, KL., Cohen, S., Tilley, J., et al.[2023]

In a case series involving four patients, three successfully transitioned from fentanyl to buprenorphine using a low-dose induction method, demonstrating the potential effectiveness of this approach for those averse to withdrawal.

One patient also transitioned from methadone to buprenorphine, highlighting the safety and feasibility of low-dose buprenorphine induction in treating opioid use disorder (OUD) in outpatient settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose buprenorphine initiation in the era of fentanyl and fentanyl analogs: A case series of outpatient inductions. Ahmed, S., Faruqui, Z., Poddar, K., et al.[2023]

Fentanyl and its analogs are now more common in the opioid supply, necessitating changes in methadone dosing protocols at opioid treatment programs (OTPs) to better address the needs of patients.

Current methadone induction schedules are outdated and conservative, and there is a call for more aggressive induction practices and updated research to ensure safety and efficacy in treating opioid use disorder in the context of fentanyl prevalence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapting methadone inductions to the fentanyl era. Buresh, M., Nahvi, S., Steiger, S., et al.[2022]

The micro-induction method for starting buprenorphine in patients with Opioid Use Disorder is effective and can be done in an outpatient setting without reducing methadone doses, as demonstrated in two case studies.

Both patients successfully transitioned to buprenorphine without experiencing precipitated withdrawal, even one who was using fentanyl, highlighting the method's potential for safely managing complex opioid use situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Community based buprenorphine micro-induction in the context of methadone maintenance treatment and fentanyl - Case report. Kaliamurthy, S., Jegede, O., Hermes, G.[2023]

A systematic review of 47 studies involving 924 patients found that both traditional initiation and microdosing strategies for transitioning to buprenorphine were highly effective, with over 95% success rates in both groups.

Novel microdosing strategies allow for the safe initiation of buprenorphine without the withdrawal symptoms typically associated with starting this medication, offering a promising alternative for patients with opioid use disorder or pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine initiation strategies for opioid use disorder and pain management: A systematic review. Spreen, LA., Dittmar, EN., Quirk, KC., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Slow release oral morphine versus methadone for opioid use disorder in the fentanyl era (pRESTO): Protocol for a non-inferiority randomized clinical trial. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Low Dose Buprenorphine Induction With Full Agonist Overlap in Hospitalized Patients With Opioid Use Disorder: A Retrospective Cohort Study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Successful treatment with slow-release oral morphine following afentanyl-related overdose: A case report. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Slow-release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence. [2015]

7. United States pubmed.ncbi.nlm.nih.gov

Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Analgesic efficacy and safety of two oral controlled-release morphine preparations in orthopedic postoperative pain. [2013]

9. Netherlands pubmed.ncbi.nlm.nih.gov

A Plea From People Who Use Drugs to Clinicians: New Ways to Initiate Buprenorphine Are Urgently Needed in the Fentanyl Era. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

Low-dose buprenorphine initiation in the era of fentanyl and fentanyl analogs: A case series of outpatient inductions. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Adapting methadone inductions to the fentanyl era. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Community based buprenorphine micro-induction in the context of methadone maintenance treatment and fentanyl - Case report. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Buprenorphine initiation strategies for opioid use disorder and pain management: A systematic review. [2022]