Buprenorphine for Opioid Use Disorder

(ROLDI Trial)

Overseen By Ashish P Thakrar, MD, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Benzodiazepines, Methadone, Azole antifungals, others

Disqualifiers: Pregnancy, Other substance use disorder, 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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 1-2 days

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to learn if buprenorphine can be started for opioid use disorder with fentanyl use without requiring or precipitating opioid withdrawal. To be eligible, participants must have moderate or severe opioid use disorder and must have fentanyl detected on a urine drug test. Participants will be admitted to a monitored research unit for the trial. They will be randomized to start buprenorphine with either standard initiation or with a new approach called rapid outpatient low-dose initiation (ROLDI). For standard initiation, participants will be instructed to arrive to the unit with at least 8 hours since last fentanyl use. Once they have at least moderately severe opioid withdrawal (Clinical Opiate Withdrawal Scale \[COWS\] 11 or higher), participants will receive 2 mg, 2 mg, 4 mg, and then 8 mg sublingual buprenorphine, with doses every 2 hours. They will then continue 8 mg twice daily (or up to three times daily). This is the current standard of care. For ROLDI, participants will not be required to have a period abstinence, they will have no or minimal withdrawal (COWS 4 or less) when starting buprenorphine, and participants will take 0.5 mg, 0.5 mg, 1 mg, 1 mg, 1 mg, and then 4 mg sublingual buprenorphine with dosing every two hours. They will then continue 8mg twice daily (or up to three times daily). The main aim of this clinical trial is to assess whether ROLDI is safe, feasible, acceptable to patients, and worthwhile to study in a larger trial. The secondary aim is to describe fentanyl and norfentanyl pharmacokinetics (that is to say, fentanyl and norfentanyl concentration in blood and urine) during early abstinence to understand why some people using fentanyl develop precipitated withdrawal with standard initiation.

Will I have to stop taking my current medications?

The trial requires that you stop using certain medications, such as benzodiazepines and drugs metabolized by CYP3A4 (like some antifungals and antibiotics). If you're using these, you may need to stop them before participating.

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 helping people reduce or stop their opioid use. However, its success can be limited by issues like low adherence to the medication, especially early in treatment. ^{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. ^{3 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 might be taken orally or intravenously. ^{10 11 12 13 14}

Eligibility Criteria

This trial is for adults with moderate to severe opioid use disorder who have used fentanyl, as confirmed by a urine test. Participants must understand English well enough to give informed consent. It's not suitable for those under 18 or unable to consent.

Inclusion Criteria

I have a moderate to severe opioid addiction.

I can read and sign the consent form in English.

My urine test was positive for fentanyl.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants are admitted to a monitored research unit and randomized to either standard initiation or rapid outpatient low-dose initiation (ROLDI) of buprenorphine.

1-2 days

Continuous monitoring in research unit

Follow-up

Participants are monitored for safety and effectiveness after buprenorphine initiation, focusing on the absence of precipitated withdrawal.

4 weeks

Treatment Details

Interventions

• Buprenorphine

Trial Overview The study tests if buprenorphine can be started in patients using fentanyl without causing withdrawal. One group follows standard care, waiting until experiencing withdrawal symptoms before starting treatment. The other uses a rapid low-dose method without waiting.

Participant Groups

Group I: Rapid outpatient low-dose initiation Experimental Treatment 1 Intervention

Participants randomized to low-dose initiation will be instructed to arrive to the research unit without withdrawal. Participants with COWS \<4 will be admitted to the research unit to begin induction. They will be administered 0.5, 0.5, 1, 1, 1, 4, and then 8 mg as sublingual buprenorphine films with doses scheduled every 2 hours. They will then continue 8mg twice daily (or up to three times daily) as maintenance treatment.

Group II: Standard initiation Active Control 1 Intervention

Participants randomized to standard induction will be instructed to arrive to the research unit with mild withdrawal and to have abstained from opioids for at least 8 hours, per ASAM Guidelines. Participants with COWS 4 or higher on initial assessment will be admitted to the research unit to begin induction. Standard initiation will follow guidelines from the 2020 Focused Update of the ASAM National Practice Guidelines. Once participants have had at least 8 hours of abstinence and have reached COWS 11 or greater, they will be given 2 mg sublingual buprenorphine, followed 2 hours later by 2 mg, followed 2 hours later by 4 mg, followed 2 hours later by 8 mg. They will then continue 8 mg twice (or up to three times) daily as maintenance treatment.

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?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

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]

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 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]

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]

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 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 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, 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]

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]

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]

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]

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]

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]

References

1. 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]

2. 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]

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

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

7. 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]

8. Singapore pubmed.ncbi.nlm.nih.gov

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

9. Australia pubmed.ncbi.nlm.nih.gov

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

10. Hungary pubmed.ncbi.nlm.nih.gov

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

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

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

13. England pubmed.ncbi.nlm.nih.gov

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

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

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