Buprenorphine/Naloxone Dosing Strategies for Opioid Use Disorder

Recruiting at 5 trial locations

Overseen By Cindy Liu, BSc

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of British Columbia

Must not be taking: Opioids, Benzodiazepines

Disqualifiers: Active withdrawal, Cancer opioids, Incarceration, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

658 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new ways to assist people with opioid use disorder by comparing two methods of initiating treatment with buprenorphine/naloxone, a medication that reduces withdrawal symptoms. The study tests whether starting with very low doses (microdosing) and gradually increasing them is more effective than the standard approach, where a full dose is administered quickly. The goal is to determine which method better helps people adhere to their treatment and avoid overdoses after leaving the Emergency Department. Individuals who have used opioids without a prescription in the last 30 days and are not in active withdrawal might be suitable candidates for this trial. As a Phase 2, Phase 3 trial, this research evaluates the treatment's effectiveness in a smaller group and represents the final step before FDA approval, offering participants a chance to contribute to significant advancements in opioid use disorder treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but if you are actively receiving opioid agonist therapy or have an active prescription for sedative medications, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both regular and small doses of buprenorphine/naloxone are generally safe for treating opioid use disorder. Studies have found that regular doses between 16 mg/day and 32 mg/day help people stay in treatment and reduce the use of illegal drugs, with patients typically tolerating these doses well.

The small dose approach, known as microdosing, helps patients start treatment without experiencing withdrawal symptoms. This method has been used successfully, with a lower risk of severe withdrawal compared to traditional methods. Both strategies aim to make starting medication easier and safer.

In this trial, researchers are using both methods to determine the best way to help patients begin and continue their treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the buprenorphine/naloxone dosing strategies for opioid use disorder because they explore new ways to start treatment that could improve patient outcomes. Unlike standard treatments, which may take longer to reach an effective dose, these strategies include a standard dosing method that aims to achieve therapeutic levels within 24 hours and a microdosing method that gradually increases the dose over several days. The microdosing approach is particularly intriguing because it might reduce withdrawal symptoms during the transition to treatment, potentially making it easier for patients to begin and stick with their recovery plan. Overall, these dosing strategies could offer more flexible and patient-friendly options compared to traditional methods.

What evidence suggests that this trial's treatments could be effective for opioid use disorder?

Research has shown that buprenorphine/naloxone effectively treats opioid addiction. It can reduce the risk of death and aid in recovery. In this trial, participants will follow one of two dosing strategies. Some will receive the standard dosing method, which often helps patients quickly reach therapeutic levels and encourages continued treatment. Others will receive the microdosing method, which allows for a gradual increase without withdrawal symptoms and shows promise for better initial success. This approach might help more people remain in treatment and reduce the risk of overdose. Both dosing methods are effective, but microdosing might offer additional benefits. ^{2 4 6 7 8}

Who Is on the Research Team?

Jessica Moe, MD

Principal Investigator

University of British Columbia

Are You a Good Fit for This Trial?

This trial is for adults over 18 in British Columbia or Alberta with opioid use disorder, who have used opioids non-medically in the past month and are not currently hospitalized. They must score positively on a dependency screen but not be in active withdrawal or receiving opioid therapy recently.

Inclusion Criteria

Opioid use disorder defined as non-medical opioid use in the previous 30 days and a positive score for opioid dependency based on the Rapid Opioid Dependence Screen (RODS)

Patients with a Clinical Opiate Withdrawal Scale (COWS) score <=12

Exclusion Criteria

I am currently admitted to a hospital.

Active withdrawal at time of ED assessment (Clinical Opiate Withdrawal Score [COWS] >12)

Actively receiving Opioid Agonist Treatment (OAT) in the 5 days prior to ED presentation

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Induction

Participants receive a five-day take-home package of buprenorphine/naloxone, either microdosing or standard dosing, to initiate opioid agonist therapy.

5 days

Follow-up

Participants are monitored for retention on opioid agonist therapy and healthcare utilization, including overdose and mortality, at 30, 90, and 365 days.

365 days

What Are the Treatments Tested in This Trial?

Interventions

• Buprenorphine/naloxone

Trial Overview The study compares two methods of starting buprenorphine/naloxone treatment for opioid addiction: microdosing without withdrawal symptoms versus standard dosing. Patients leaving emergency departments will receive either method to see which is more effective at keeping them on treatment.

How Is the Trial Designed?

Group I: Buprenorphine/naloxone Standard Dosing Active Control 1 Intervention

The control intervention will be provision of a buprenorphine/naloxone standard dosing package from the ED. This will consist of a five day package with a commonly accepted standard dosing regimen aiming to achieve a therapeutic buprenorphine/naloxone dose within 24 hours of initiation. Standard dosing packages are currently available in EDs in BC and Alberta as standard of care. Day 1: Buprenorphine 2 mg-naloxone 0.5 mg SL q1h prn to a maximum of 6 tablets in the first 24 hours (1 tablet), Day 2: Buprenorphine 12 mg-naloxone 3 mg SL once daily (6 tablets), Day 3: Buprenorphine 16 mg-naloxone 3 mg SL once daily (8 tablets), Day 4:Buprenorphine 16 mg-naloxone 3 mg SL once daily (8 tablets). Day 5:Buprenorphine 16 mg-naloxone 3 mg SL once daily (8 tablets).

Group II: Buprenorphine/naloxone Microdosing Active Control 1 Intervention

Participants with Opioid use disorder will receive a Buprenorphine/naloxone microdosing package from the ED. This will consist of a five-day take-home packages with gradually increasing doses of 2mg/0.5mg buprenorphine/naloxone tablet employing a four times daily dosing schedule over five days. Day 1: Buprenorphine 0.5 mg-naloxone 0.125 mg SL\* QID\*\* (One quarter tablet), Day 2: Buprenorphine 1 mg-naloxone 0.25 mg SL QID (One half tablet), Day 3: Buprenorphine 2 mg-naloxone 0.5 mg SL QID (1 tablet), Day 4: Buprenorphine 3 mg-naloxone 0.75 mg SL QID (1.5 tablets) Day 5: Buprenorphine 16 mg-naloxone 4 mg SL once daily (8 tablets). \*SL: Sublingual \*\* QID: four times daily

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

Approved in European Union as Suboxone for:

• Opioid dependence
• Opioid use disorder

Approved in United States as Suboxone for:

• Opioid dependence
• Opioid use disorder

Approved in Canada as Suboxone for:

• Opioid dependence
• Opioid use disorder

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Published Research Related to This Trial

In a study of 78 patients over six years at the High-Risk Pain Clinic, buprenorphine/naloxone was found to significantly reduce pain scores, indicating its efficacy in managing chronic pain for patients with a history of substance use disorder.

The clinic had a retention rate of 41%, suggesting that while many patients continued treatment, there is still a notable number who may not stay engaged in this multimodal approach to pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual Buprenorphine/Naloxone and Multi-Modal Management for High-Risk Chronic Pain Patients. Kaski, S., Marshalek, P., Herschler, J., et al.[2021]

A retrospective case series involving seven participants demonstrated that micro-dosing buprenorphine/naloxone over a 7-day period allowed for successful induction without precipitated withdrawal, even while participants were still using other opioids.

This approach may provide a promising alternative for individuals with opioid use disorder, potentially eliminating the need for a period of abstinence before starting treatment with buprenorphine/naloxone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of a novel prescribing approach for the treatment of opioid use disorder: Buprenorphine/naloxone micro-dosing - a case series. Brar, R., Fairbairn, N., Sutherland, C., et al.[2021]

In a study of 100 patients with opioid use disorder, those on once-daily buprenorphine/naloxone had significantly more negative urine drug screens (84%) compared to those on multiple-daily dosing (74%), indicating better adherence or effectiveness of the once-daily regimen.

The once-daily cohort also experienced significantly fewer relapses (43 total) compared to the multiple-daily cohort (141 total), suggesting that less frequent dosing may lead to better outcomes in managing opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes associated with once-daily versus multiple-daily dosing of buprenorphine/naloxone for opioid use disorder. Allen, SM., Nichols, TA., Fawcett, J., et al.[2022]

A study of 316 heroin-dependent patients receiving buprenorphine-naloxone treatment identified four distinct profiles based on dosage management, highlighting the importance of individualized treatment plans.

Patients in the 'Clinically Inadequate and Adjusted to Patient Desired Moderate Dosage' cluster experienced worse outcomes, including higher drug use and lower satisfaction with treatment, indicating that proper dosage management is crucial for effective recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A cluster-analytic profiling of heroin-dependent patients based on level, clinical adequacy, and patient-desired adjustment of buprenorphine dosage during buprenorphine-naloxone maintenance treatment in sixteen Spanish centers. Alcaraz, S., González-Saiz, F., Trujols, J., et al.[2018]

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 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]

In a study involving 24 participants with opiate dependence, the 16 mg buprenorphine tablet formulation achieved higher serum concentrations than the 8 mg liquid solution by Day 7, indicating better pharmacokinetics for the tablet.

Despite the higher serum concentration, there were no significant differences in the physiological, subjective, or objective effects of the two formulations, suggesting that clinicians may need to adjust dosing for the tablet to achieve similar effects as the liquid solution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, bioavailability and opioid effects of liquid versus tablet buprenorphine. Compton, P., Ling, W., Moody, D., et al.[2013]

Increasing access to buprenorphine, a treatment for opioid use disorder, is crucial for reducing overdose deaths, but limited availability of buprenorphine monoproduct is a significant barrier.

The requirement to prescribe buprenorphine as a combination product with naloxone may lead to adverse effects that are more serious than previously thought, potentially harming the patient-provider relationship and increasing stigma, which can hinder access to care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Naloxone Component of Buprenorphine/Naloxone: Discouraging Misuse, but at What Cost? Gregg, J., Hartley, J., Lawrence, D., et al.[2023]

In a study involving adults with moderate-to-severe opioid use disorder (OUD), the 300-mg maintenance dose of BUP-XR (SUBLOCADE®) was found to be more effective than the 100-mg dose for opioid-injecting participants, leading to better treatment retention and higher rates of opioid abstinence.

Both the 100-mg and 300-mg doses of BUP-XR had similar safety profiles, indicating that increasing the dose for injecting participants does not compromise safety while enhancing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder. Greenwald, MK., Wiest, KL., Haight, BR., et al.[2023]

A study involving 250 patients with opioid use disorder found that once daily dosing of sublingual buprenorphine-naloxone resulted in similar treatment retention and adherence outcomes compared to split daily dosing over a 12-month period.

There were no significant differences in hospitalization rates or medication adherence between the two dosing regimens, suggesting that both dosing strategies are equally effective for managing opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of opioid use disorder treatment outcomes in patients receiving split daily versus once daily dosing of buprenorphine-naloxone. Borris, JB., Dowd-Green, C., Bowman, LA., et al.[2023]

Buprenorphine (BUP) is effective for treating opioid use disorder, requiring specific levels of mu-opioid receptor (μOR) availability to prevent withdrawal symptoms and block the effects of abused opioids, with optimal dosing often exceeding 16 mg for some patients.

The study suggests that imposing fixed limits on BUP dosing or reimbursement policies is inappropriate, as individual patient needs can vary significantly based on their μOR availability and treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. Greenwald, MK., Comer, SD., Fiellin, DA.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04893525

Evaluating Buprenorphine/Naloxone Microdosing vs. ... The primary objective of the current study is to compare the effectiveness of ED-initiated buprenorphine/naloxone take-home standard dosing and microdosing ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7745932/

Buprenorphine-naloxone microdosing: Tool for opioid agonist ... Abstract. Objective. To raise awareness of alternative techniques that can facilitate buprenorphine-naloxone treatment for opioid use disorder.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1555415524003763

Buprenorphine Microdosing the “Bernese Method”: Patient ... Buprenorphine is increasingly favored over methadone for treating opioid use disorder in Australia due to its superior safety profile.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7919736/

BUPRENORPHINE/NALOXONE MICRO-DOSING ... Buprenorphine/naloxone micro-dosing may offer a promising alternative approach for successful induction for individuals with opioid use disorder who desire ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05644587

NCT05644587 | Novel Induction to Buprenorphine/Naloxone Primary outcomes include effectiveness and safety. Secondary outcomes include treatment retention, self-reported use of opioids during induction, return to ...

6. samhsa.gov samhsa.gov/

Home | SAMHSA - Substance Abuse and Mental Health ... SAMHSA leads efforts to advance behavioral health across the U.S., offering resources for mental health, substance use, and community well-being.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6585403/

Buprenorphine Treatment for Opioid Use Disorder Methadone was studied in order to find a medication to: 1) Prevent opiate withdrawal, 2) Reduce “drug hunger” or craving, and 3) Normalize physiologic functions ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/204242s011lbl.pdf

4150044 This label may not be the latest approved by FDA ... ZUBSOLV sublingual tablet is indicated for treatment of opioid dependence and should be used as part of a complete treatment plan to include counseling and.