High Dose Buprenorphine for Opioid Use Disorder

Recruiting at 3 trial locations

Overseen By Ethan Cowan, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Icahn School of Medicine at Mount Sinai

Must be taking: Buprenorphine

Must not be taking: Methadone

Disqualifiers: Pregnancy, Unstable condition, Legal issues, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

140 Participants Needed

Trial Summary

What is the purpose of this trial?

This project, involving two distinct clinical trials, tests whether induction to a higher than currently recommended buprenorphine (BUP) induction dose is safe and can improve the proportion of patients who engage in comprehensive addiction services within 7-day of induction. Trial 1 is a head-to-head comparison of the safety, tolerability and feasibility of high dose BUP induction (32 mg). The study involves two cohorts, (1) a 12mg cohort (standard) to determine baseline data and (2) a 32 mg (high dose) cohort. If the 32mg is intolerable, a 24 mg dose may be evaluated. Trial 2 is a small pilot multicenter randomized, double blinded, clinical trial in 80 participants (randomized 1:1) that will provide preliminary information on efficacy with the primary outcome being engagement in comprehensive addiction treatment 7-days post BUP induction. In collaboration with National Institute on Drug Abuse (NIDA), the research team have determined that there must be a minimum increase in engagement in comprehensive addiction treatment of 15% at 7-days in the high dose induction group to justify a larger future clinical trial.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are taking methadone, you would not be eligible to participate.

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

Research shows that Buprenorphine is a highly effective medication for treating opioid use disorder, helping to improve outcomes for individuals seeking treatment. It has a high safety profile, with a low level of physical dependence and mild withdrawal symptoms, making it a valuable option for managing opioid addiction. ^{1 2 3 4 5}

Is high dose buprenorphine generally safe for humans?

Buprenorphine is considered safe for treating opioid dependence, with a low risk of overdose and abuse, especially when combined with naloxone. However, there are risks of abuse and serious side effects, such as tissue damage from improper use and potential danger when mixed with other drugs like benzodiazepines. ^{6 7 8 9 10}

How is the drug buprenorphine unique for treating opioid use disorder?

Buprenorphine is unique because it is a partial opioid agonist, meaning it activates opioid receptors in the brain but to a lesser extent than full agonists, which helps reduce cravings and withdrawal symptoms with a lower risk of misuse. It also has a 'ceiling effect' that limits its potential for causing respiratory depression, making it safer than other opioids. ^{2 5 11 12 13}

Research Team

Ethan Cowan, MD, MS

Principal Investigator

Icahn School of Medicine

Eligibility Criteria

This trial is for adults in the emergency department with moderate to severe opioid use disorder, showing withdrawal symptoms and a positive test for fentanyl. They must understand the study and agree to participate. Excluded are those with legal issues, no additional contact point, unwillingness to follow procedures, recent naloxone use, pain management opioids need, methadone presence in tests, pregnancy, unstable conditions requiring hospitalization or current/formal addiction treatment.

Inclusion Criteria

Urine toxicology positive for fentanyl

Evidence of a personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study

Meet DSM-5 diagnostic criteria for moderate to severe OUD

Exclusion Criteria

Engaged in formal addiction treatment in the 30-days prior to the ED visit (excluding addiction treatment or residential programs where MOUD is not given e.g. behavioral counseling, abstinence programs, NA)

Pending legal status or pending legal action that could prohibit full participation in or compliance with study procedures

My drug screen tested positive for methadone.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Induction

Participants receive either a standard or high dose of buprenorphine in the Emergency Department, followed by a 4-hour observation period

1 day

1 visit (in-person)

Immediate Follow-up

Participants are monitored daily for 7 days post-induction to assess drug use and opioid craving

7 days

Daily follow-up (virtual or phone)

Extended Follow-up

Participants are assessed for engagement in comprehensive addiction treatment and healthcare utilization

30 days

2 visits (in-person or virtual)

Treatment Details

Interventions

• Buprenorphine

Trial Overview The trial compares two doses of Buprenorphine: a standard dose (12mg) versus a high dose (32mg), which can be reduced to 24mg if necessary. The goal is to see if higher doses are safe and increase engagement in addiction treatment after one week. It includes an initial head-to-head comparison followed by a small pilot randomized double-blinded trial.

Participant Groups

Group I: Buprenorphine High Dose Experimental Treatment 1 Intervention

The experimental arm tests the safety and tolerability of 32mg of BUP split as 16mg at time=0 and 16mg at time=30-60 min as an induction dose.

Group II: Buprenorphine Standard Dose Active Control 1 Intervention

The standard arm will receive an induction dose of 12mg of buprenorphine (BUP) split as 8mg at time=0 and 4mg at time=30-60 min.

Buprenorphine is already approved in United States, European Union for the following indications:

Approved in United States as Buprenorphine for:

• Moderate to severe opioid addiction (dependence)

Approved in European Union as Buprenorphine for:

• Opioid dependence

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

A cohort study involving 24 hospitalized patients with opioid use disorder demonstrated that a rapid low-dose buprenorphine initiation protocol is feasible and well-tolerated, with 79% of patients completing the initiation within an average of 72 hours.

Importantly, no patients experienced precipitated withdrawal during the transition from full-agonist opioids to buprenorphine, indicating the safety of this rapid initiation approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid Low-dose Buprenorphine Initiation for Hospitalized Patients With Opioid Use Disorder. Sokolski, E., Skogrand, E., Goff, A., et al.[2023]

In a study of 17,158 individuals aged 18-64 initiating buprenorphine treatment for opioid use disorder, over half (55%) discontinued treatment within 180 days, indicating a significant challenge in treatment retention.

Lower initial doses (≤4 mg) and fewer days of supply (≤7 days) were linked to higher odds of treatment discontinuation, emphasizing the need for careful prescribing practices to improve retention in buprenorphine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescribing decisions at buprenorphine treatment initiation: Do they matter for treatment discontinuation and adverse opioid-related events? Meinhofer, A., Williams, AR., Johnson, P., et al.[2020]

The study will involve 280 adults with opioid use disorder and aims to improve adherence to buprenorphine-naloxone treatment through two psychological interventions: contingency management (CM) and brief motivational interviewing plus substance-free activities and mindfulness (BSM).

The primary goal is to assess which intervention is more effective in promoting medication adherence, measured by attendance at physician appointments and the presence of buprenorphine in urine toxicology, with follow-up occurring 8 months after randomization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder. Peter, SC., Murphy, JG., Witkiewitz, K., et al.[2023]

Buprenorphine, particularly the brand-name formulations like Suboxone, has been significantly more utilized and reimbursed in Medicaid compared to other formulations, with brand-name versions dispensed 2.7 times more and costing 4.4 times more than all other formulations combined from 2002 to 2018.

Delays in the availability of generic buprenorphine formulations due to market and regulatory factors contributed to increased costs and may have hindered access to treatment for opioid use disorder during the opioid crisis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors Affecting Buprenorphine Utilization and Spending in Medicaid, 2002-2018. Barenie, RE., Sinha, MS., Kesselheim, AS.[2021]

Buprenorphine, a partial micro opioid agonist, has a high safety profile due to its 'ceiling effect,' which limits respiratory depression and physical dependence, making it a suitable option for treating opioid addiction.

The combination of buprenorphine and naloxone in Suboxone is designed to discourage misuse, while buprenorphine alone (Subutex) will be used for initial dosing; however, patients with recent opioid use may experience mild withdrawal symptoms upon starting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine: a primer for emergency physicians. Sporer, KA.[2013]

A study analyzing abuse trends of sublingual buprenorphine products from 2003 to 2005 found that Subutex accounted for only 7.8% of reported abuse cases, while Suboxone made up 92.2%.

The overall rate of abuse for both products was low, with an average quarterly abuse rate of 0.08 cases per 1,000 prescriptions for Subutex and 0.16 for Suboxone, indicating that these medications are relatively safe in terms of abuse potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abuse of buprenorphine in the United States: 2003-2005. Smith, MY., Bailey, JE., Woody, GE., et al.[2013]

Buprenorphine (Subutex) is recognized for its improved safety profile in treating opioid dependence, particularly by reducing the risk of overdose compared to other opioids.

Despite its safety advantages, there are still risks associated with the diversion of buprenorphine for misuse, as evidenced by cases of attempted intravenous injection, highlighting the need for strict dispensing protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Groin tissue necrosis requiring skin graft following parenteral abuse of buprenorphine tablets. Feeney, GF., Fairweather, P.[2013]

Buprenorphine is a safe and effective treatment for opioid dependence, particularly when combined with naloxone, which reduces its potential for abuse.

New regulations enable certified physicians to prescribe buprenorphine in their offices, significantly improving patient access to this important treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine maintenance: a new treatment for opioid dependence. Collins, GB., McAllister, MS.[2019]

Buprenorphine, approved for treating opiate dependence, has been found to have an abuse potential similar to that of traditional opioids like morphine, despite initial beliefs of its low abuse risk.

A study of 120 buprenorphine abusers revealed that the majority were middle-aged males with a significant history of early illicit drug use, highlighting a concerning trend of prescription medication abuse that requires increased awareness and vigilance among healthcare professionals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Socio-demographic profile and help-seeking behaviour of buprenorphine abusers in Singapore. Winslow, M., Ng, WL., Mythily, S., et al.[2020]

In a study investigating six drug abusers who died, all cases involved a combination of buprenorphine and benzodiazepines, indicating a dangerous interaction between these substances.

The findings suggest that the tissue concentrations of these drugs were significantly higher than blood levels, raising concerns about the safety of buprenorphine when used in conjunction with benzodiazepines, which may warrant a review of its dispensing practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Six deaths linked to concomitant use of buprenorphine and benzodiazepines. Reynaud, M., Petit, G., Potard, D., et al.[2022]

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]

Buprenorphine is an opioid medication used for treating opioid dependence and managing moderate to severe pain, and it can be prescribed to pregnant women as part of their treatment for opioid addiction.

The chapter details a method for quantifying buprenorphine and its metabolite norbuprenorphine in meconium using liquid chromatography tandem mass spectrometry (LC-MS/MS), which is important for monitoring drug exposure in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitation of Total Buprenorphine and Norbuprenorphine in Meconium by LC-MS/MS. Marin, SJ., McMillin, GA.[2016]

Buprenorphine has a favorable safety profile and low potential for physical dependence, making it a suitable option for treating opioid dependence.

The combination tablet of buprenorphine and naloxone has been shown to be effective in reducing the potential for abuse while maintaining similar clinical effects to buprenorphine alone, allowing for flexible dosing schedules.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine: how to use it right. Johnson, RE., Strain, EC., Amass, L.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Rapid Low-dose Buprenorphine Initiation for Hospitalized Patients With Opioid Use Disorder. [2023]

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

Prescribing decisions at buprenorphine treatment initiation: Do they matter for treatment discontinuation and adverse opioid-related events? [2020]

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

Use of a sequential multiple assignment randomized trial to test contingency management and an integrated behavioral economic and mindfulness intervention for buprenorphine-naloxone medication adherence for opioid use disorder. [2023]

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

Factors Affecting Buprenorphine Utilization and Spending in Medicaid, 2002-2018. [2021]

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

Buprenorphine: a primer for emergency physicians. [2013]

6. England pubmed.ncbi.nlm.nih.gov

Abuse of buprenorphine in the United States: 2003-2005. [2013]

7. Australia pubmed.ncbi.nlm.nih.gov

Groin tissue necrosis requiring skin graft following parenteral abuse of buprenorphine tablets. [2013]

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

Buprenorphine maintenance: a new treatment for opioid dependence. [2019]

9. Singapore pubmed.ncbi.nlm.nih.gov

Socio-demographic profile and help-seeking behaviour of buprenorphine abusers in Singapore. [2020]

10. England pubmed.ncbi.nlm.nih.gov

Six deaths linked to concomitant use of buprenorphine and benzodiazepines. [2022]

11. 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]

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

Quantitation of Total Buprenorphine and Norbuprenorphine in Meconium by LC-MS/MS. [2016]

13. Ireland pubmed.ncbi.nlm.nih.gov

Buprenorphine: how to use it right. [2019]