Buprenorphine/Naloxone Dosing Strategies for Opioid Use Disorder

Recruiting at 5 trial locations

Overseen By Elle Wang, MSc

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

Trial Summary

What is the purpose of this trial?

This is a multi-centre, open-label RCT at four Emergency Departments (EDs) in British Columbia and Alberta. The purpose of the current study is to compare the effectiveness of buprenorphine/naloxone microdosing and standard dosing take-home induction regimens at enabling patients to successfully complete the induction regimen, and at retaining patients on opioid agonist therapy. We will randomize our enrolled patients to receive take-home microdosing or standard dosing packages of buprenorphine/naloxone. For the microdosing arm, patients immediately start taking low doses that increase to effective levels without requiring them to go into withdrawal. We hypothesize that ED patients provided buprenorphine/naloxone microdosing packages will be more likely to successfully complete the induction period compare to patients provided standard dosing packages. We furthermore hypothesize that those provided microdosing will be more likely to be retained in opioid agonist therapy, and will experience lower overdose, mortality, and healthcare utilization subsequent to their ED visit.

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.

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

Buprenorphine/naloxone is shown to improve outcomes for people seeking treatment for opioid use disorder, although its effectiveness can be limited by low adherence to the medication, especially early in treatment. Additionally, micro-dosing strategies may help overcome challenges related to starting the medication. ^{1 2 3 4 5}

Is Buprenorphine/Naloxone safe for humans?

Buprenorphine/naloxone is generally considered safe for treating opioid use disorder and chronic pain, with mild and rare adverse effects due to the naloxone component. It has been used safely in clinical settings, although some concerns about side effects and patient-provider relationships have been noted. ^{4 6 7 8 9}

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

Buprenorphine/naloxone is unique because it combines buprenorphine, which helps reduce cravings and withdrawal symptoms, with naloxone, which discourages misuse by blocking opioid effects if injected. This combination is available in a sublingual (under the tongue) tablet form, offering flexibility in dosing schedules and reducing the risk of abuse compared to other treatments. ^{1 3 5 10 11}

Research Team

Jessica Moe, MD

Principal Investigator

University of British Columbia

Eligibility Criteria

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

I am over 18 and have an opioid use disorder, being discharged from the ED.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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. Ireland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, bioavailability and opioid effects of liquid versus tablet buprenorphine. [2013]

2. Australia 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. [2021]

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

Outcomes associated with once-daily versus multiple-daily dosing of buprenorphine/naloxone for opioid use disorder. [2022]

4. 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]

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

Evaluation of opioid use disorder treatment outcomes in patients receiving split daily versus once daily dosing of buprenorphine-naloxone. [2023]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Sublingual Buprenorphine/Naloxone and Multi-Modal Management for High-Risk Chronic Pain Patients. [2021]

7. Ireland 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. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The Naloxone Component of Buprenorphine/Naloxone: Discouraging Misuse, but at What Cost? [2023]

9. England 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. [2023]

10. Ireland 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. [2018]

11. Ireland pubmed.ncbi.nlm.nih.gov

Buprenorphine: how to use it right. [2019]