Buprenorphine for Opioid Use Disorder

(ED-ENVISION Trial)

Recruiting at 4 trial locations

Overseen By Michael Baumann, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Yale University

Must not be taking: Opioid analgesics, Methadone

Disqualifiers: Severe liver failure, Pregnancy, 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: Unknown

Duration: 10 days

360 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a multisite double-blind, double-dummy, randomized clinical trial enrolling ED patients with untreated moderate to severe opioid use disorder (OUD) to compare Standard Dose Induction (SDI) and High Dose Induction (HDI) on rates of participation in OUD treatment within 10 days post randomization, and opioid withdrawal symptoms, opioid craving, and use of illicit and non-prescribed drugs.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you require ongoing prescription opioid painkillers or have used methadone in the past 72 hours.

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

Research shows that Buprenorphine, often combined with Naloxone (as in Suboxone), is effective in treating opioid use disorder by improving treatment outcomes. However, challenges like low adherence and misuse exist, which can be addressed with sustained release formulations. ^{1 2 3 4 5}

Is buprenorphine safe for humans?

Buprenorphine is generally considered safe for treating opioid dependence, with a lower risk of overdose compared to other opioids. However, it can still be abused, especially if not taken as prescribed, and there are risks if it is injected instead of taken as directed. ^{4 6 7 8 9}

What makes the drug Buprenorphine unique for treating opioid use disorder?

Buprenorphine is unique because it combines a partial mu-receptor agonist (buprenorphine) with an antagonist (naloxone) in a 4:1 ratio, which helps reduce the risk of misuse. It is administered sublingually (under the tongue), making it different from other treatments that may require different routes of administration. ^{10 11 12 13 14}

Research Team

Gail D'Onofrio, MD, MS

Principal Investigator

Yale University

Kathryn Hawk

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults over 18 with moderate to severe opioid use disorder (OUD), who have tested positive for opioids and are not currently on opioid withdrawal treatments. Participants must speak English, be able to consent, and commit to the study's follow-up process. Those with ongoing opioid prescriptions, prior study enrollment, in custody, or with conditions needing hospitalization can't join.

Inclusion Criteria

Have a urine toxicology test that is positive for opioids

Be treated in the ED during study screening hours

Meet DSM-5 diagnostic criteria for moderate to severe OUD

Exclusion Criteria

I need a prescription for painkillers.

Have prior enrollment in the current study

Be a prisoner or in police custody at the time of index ED visit

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either Standard Dose Induction (SDI) or High Dose Induction (HDI) of buprenorphine/naloxone

10 days

Daily assessments

Follow-up

Participants are monitored for engagement in OUD treatment and assessed for opioid withdrawal symptoms, cravings, and substance use

30 days

Treatment Details

Interventions

• Buprenorphine

Trial Overview The trial compares two methods of starting Buprenorphine treatment in emergency department patients: a Standard Dose Induction (SDI) versus a High Dose Induction (HDI). It aims to see which method leads to better engagement in OUD treatment after discharge and assesses withdrawal symptoms and drug cravings.

Participant Groups

Group I: High Dose SL-BUP Experimental Treatment 1 Intervention

Participants will receive three 5.7 mg Zubsolv pills; all will be active medication.

Group II: Standard SL-BUP Active Control 1 Intervention

Participants will receive three pills; one 5.7 mg Zubsolv pill with active medication and two placebo pills.

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?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

The Emmes Company, LLC

Industry Sponsor

Trials

149

Recruited

1,052,000+

Peter Ronco

The Emmes Company, LLC

Chief Executive Officer since 2023

BSc from Nottingham University

Dr. Joe Sliman

The Emmes Company, LLC

Chief Medical Officer since 2020

MD from Uniformed Services University of the Health Sciences, MPH from Johns Hopkins University, BSc in Molecular and Cell Biology from Pennsylvania State University

Alameda Health System

Collaborator

Trials

9

Recruited

4,100+

National Drug Abuse Treatment Clinical Trials Network

Collaborator

Trials

7

Recruited

3,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

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]

The novel weekly subcutaneous buprenorphine depot formulation, CAM2038, was found to effectively block the euphoric effects of opioids and suppress withdrawal symptoms in individuals with moderate-to-severe opioid use disorder, based on a study involving 47 participants.

Both doses of CAM2038 (24 mg and 32 mg) were well-tolerated and demonstrated significant efficacy in preventing opioid effects, making it a promising alternative to daily oral formulations that carry risks of misuse and nonadherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial. Walsh, SL., Comer, SD., Lofwall, MR., et al.[2020]

A study of 200 rural residents revealed that motivations for using nonprescribed buprenorphine shifted from initially seeking to avoid withdrawal and get high to maintaining abstinence from other drugs, indicating a complex relationship with self-treatment.

Participants with a history of treatment for opioid use disorder were more likely to use nonprescribed buprenorphine for self-treatment, suggesting that dissatisfaction with existing treatment options may drive individuals to seek alternatives outside of prescribed care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing Motivations for Nonprescribed Buprenorphine Use Among Rural Appalachian Substance Users. McDonald, MJ., DeVeaugh-Geiss, AM., Chilcoat, HD., 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]

In a study of 32 veterans over three years, those receiving buprenorphine/naloxone in a group setting had a significantly higher retention rate in treatment after one year (69%) compared to those treated individually (27%).

The study also found that 94% of urine samples from participants were negative for opioids, indicating effective management of opioid use disorder with buprenorphine/naloxone in a group format.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Group medication management for buprenorphine/naloxone in opioid-dependent veterans. Berger, R., Pulido, C., Lacro, J., et al.[2014]

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]

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 and its combination with naloxone (Suboxone) have been officially added to the list of approved medications for treating opioid dependence in federally certified treatment programs, alongside methadone and ORLAAM.

These medications will be subject to the same federal treatment standards as existing opioid treatments, ensuring consistent safety and efficacy protocols in managing opioid dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Opioid drugs in maintenance and detoxification treatment of opiate addiction; addition of buprenorphine and buprenorphine combination to list of approved opioid treatment medications. Interim final rule. [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]

Zoledronic acid (ZOL), administered as a single intravenous infusion once a year, effectively reduces the risk of vertebral and hip fractures in postmenopausal women with osteoporosis, and also lowers the incidence of future fractures in men and women with recent hip fractures.

ZOL is generally safe and well tolerated, with mild and transient flu-like symptoms occurring after the first infusion, making it a convenient option for patients who may struggle with compliance to oral bisphosphonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoledronic acid for prevention and treatment of osteoporosis. Recknor, C.[2018]

A study analyzing 5,970 emergency department visits in Italy found that benzodiazepines (BZD) and Z-drugs (ZD) are associated with a higher rate of adverse events (AEs) leading to hospitalization compared to opioids, particularly among younger patients and those with a history of substance abuse.

23% of BZD/ZD-related AEs were linked to drug abuse, and these cases often required hospitalization (52%), highlighting the significant health risks associated with the inappropriate use of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hospitalisations related to benzodiazepine, Z-drug, and opioid treatment in Italy: a claim on the risks associated with inappropriate use. Mattioli, I., Bettiol, A., Crescioli, G., et al.[2022]

Intravenous zoledronic acid (Zol) is effective in reducing fracture risk in patients with postmenopausal osteoporosis and recent low-trauma hip fractures, showing improvements in bone mineral density and early reduction of bone remodeling markers.

Zol is generally well tolerated and offers a convenient once-a-year treatment option, making it suitable for older patients with adherence issues to oral medications, although it is not recommended for those with severe renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of zoledronic acid in the prevention and treatment of osteoporosis. Räkel, A., Boucher, A., Ste-Marie, LG.[2023]

Suboxone (buprenorphine/naloxone) is a well-tolerated and effective treatment for opiate addiction, with significant positive psychological and behavioral changes observed in patients during the first month of therapy.

The initial phase of treatment is critical, as nearly 22.5% of patients dropped out within the first month, highlighting the need for thorough patient education about potential withdrawal symptoms to improve retention rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early experience with Suboxone maintenance therapy in Hungary. Demetrovics, Z., Farkas, J., Csorba, J., et al.[2015]

Chronic use of intravenous bisphosphonates, like Zometa, can lead to bisphosphonate-related osteonecrosis of the jaws (BRONJ), which is a serious and painful condition that can have severe consequences for patients.

This case highlights the importance for dentists to recognize the early signs of BRONJ and consider treatment options, including conservative measures and potential jaw resection, to manage this complication effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bisphosphonate-related osteonecrosis of the jaws--a case report. Kamoh, AK., Ogle, O.[2018]

References

1. 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]

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

Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Assessing Motivations for Nonprescribed Buprenorphine Use Among Rural Appalachian Substance Users. [2023]

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

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

Group medication management for buprenorphine/naloxone in opioid-dependent veterans. [2014]

6. Singapore pubmed.ncbi.nlm.nih.gov

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

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

Opioid drugs in maintenance and detoxification treatment of opiate addiction; addition of buprenorphine and buprenorphine combination to list of approved opioid treatment medications. Interim final rule. [2013]

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

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

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

Zoledronic acid for prevention and treatment of osteoporosis. [2018]

11. Germany pubmed.ncbi.nlm.nih.gov

Hospitalisations related to benzodiazepine, Z-drug, and opioid treatment in Italy: a claim on the risks associated with inappropriate use. [2022]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Role of zoledronic acid in the prevention and treatment of osteoporosis. [2023]

13. Hungary pubmed.ncbi.nlm.nih.gov

Early experience with Suboxone maintenance therapy in Hungary. [2015]

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

Bisphosphonate-related osteonecrosis of the jaws--a case report. [2018]