The extended-release formulation of buprenorphine (brand name Sublocade) is administered monthly via abdominal subcutaneous injection for the management of moderate to severe opioid use disorder. Extended-release buprenorphine may reduce patients’ medication burden, as it is administered monthly rather than daily. It is currently indicated for patients who have been clinically stabilized on 8mg to 24mg of sublingual buprenorphine-naloxone for a minimum of seven days.

Extended-release buprenorphine is associated with significantly higher treatment retention (close to 100%) and mean abstinence percentages (over 40%) compared to placebo (5%) in individuals with moderate to severe opioid use disorder.125 A follow-up study included both roll-over patients (n=113) and de novo patients (n=112) whose first exposure to extended-release buprenorphine was in this phase III open-label long-term study.126 At 12 months of treatment, approximately 60% of rollover and 76% of de novo patients had ceased unregulated opioid use. Both rollover and de novo patients had similar retention rates (~51%) and similar participant satisfaction scores.126 A 2020 longitudinal study found that participants who received 12 months of extended-release buprenorphine were significantly more likely to be abstinent at the 12-month follow-up than those who received 2 or less months of this medication (75.3% vs 24.1%; P=0.001).127  Overall, 51% of all participants remained abstinent for 12 months. An open-label randomized clinical trial (n=119) in Australia comparing patient-reported outcomes for individuals prescribed a different formulation of extended-release buprenorphine (brand name Brixadi/Buvidal) compared to sublingual buprenorphine/naloxone found that extended-release buprenorphine was associated with higher treatment satisfaction (p=0.002), convenience (p<0.001), and overall quality of life (p=0.03) with no significant difference in unregulated opioid use measured by self-report or urine drug tests.128 It should be noted that extended-release buprenorphine and sublingual buprenorphine/naloxone have not yet been compared in a clinical trial. The evidence outlining the characteristics of patients who benefit from transitioning to extended-release buprenorphine is limited and continues to evolve.127,129 Discussion of potential risks and benefits, informed consent, and regular follow-up including monitoring for cravings and withdrawal symptoms following initiation of extended-release buprenorphine should be considered key components of care.

See Appendix 3 for guidance on the titration and dosing of these buprenorphine formulations. 

Subdermal buprenorphine implant (Probuphine)

A subdermal buprenorphine implant (Probuphine) allows for continuous blood levels of buprenorphine for up to 6 months following implantation.130 According to available evidence, this formulation is superior to placebo at reducing unregulated opioid use over a 6-month period, and non-inferior to sublingual buprenorphine at preventing unregulated opioid use over a 4–6 month period.130 

A subdermal buprenorphine implant (80mg) is currently approved for use in patients who have sustained stability on sublingual buprenorphine/naloxone at doses of no more than 8mg.130,131 However, this formulation is being phased out in Canada and will no longer be available in BC.

Buprenorphine/naloxone film

Buprenorphine/naloxone film is a buccal film available in BC in 3 dosages132; however, this formulation is not currently covered by BC PharmaCare (including Plan C, G, and W), the Non-Insured Health Benefit (NIHB), or Veteran Affairs Canada. 

In a randomized controlled trial, no significant differences in dose effects, adverse effects, or treatment outcomes were identified between Suboxone film and sublingual tablets.133 Some patients may prefer the taste or faster dissolving time of the Suboxone film compared to the sublingual tablet.134 Suboxone film produces higher bioavailability of buprenorphine compared to the same dose of the sublingual tablet; as such, switching between the two forms could theoretically lead to inadvertent over- or underdosing,134 although actual dose changes have not been required in head-to-head trials. For this reason, switching between formulations should be done only with appropriate monitoring for symptoms of over- or under-dosing of buprenorphine.134 Consult the product monograph for further information on switching from tablet to film.135

Buprenorphine/naloxone treatment can be initiated through traditional induction and low-dose induction methods, both of which can be conducted at different speeds and in a range of settings, including primary care, emergency department, inpatient settings, and at home or other unobserved settings. This section provides an overview of the evidence supporting available induction methods. Detailed guidance on buprenorphine induction and dosing is provided in Appendix 3.

The traditional induction schedules provided in the buprenorphine/naloxone product monograph are approved by Health Canada136 and have been widely used in BC. However, growing clinical and research experience indicate that more flexible induction dosing approaches—such as more rapid titration schedules—are associated with increased patient comfort and improved treatment outcomes. In keeping with the therapeutic range described in the Suboxone Product Monograph, Health Canada currently recommends a maximum starting dose of 12mg/3mg and a maximum total daily dose of 24mg/6mg of buprenorphine/naloxone; the Suboxone product monograph suggests that daily doses greater than 24mg/6mg have not been demonstrated to provide clinical advantage. However, this recommendation is based on data collected before the infiltration of fentanyl into the unregulated drug market. More recent data suggests that a daily dose of up to 32mg/8mg buprenorphine/naloxone may be reasonable and can be provided safely to address the high opioid tolerance of patients who use fentanyl.137

The NIDA-funded START trial (n=740)138 allowed a flexible approach to dosing, with minimal instructions to study clinicians (e.g., maximum upper limit of 16mg/4mg buprenorphine/naloxone on Day 1, and 32mg/8mg buprenorphine/naloxone on Days 2–168). Other than recommending dose adjustment to address participant symptoms, dose escalation rates were not explicitly outlined in the START protocol, and study clinicians employed a range of induction trajectories. The analysis explored higher versus lower dose trajectories during the first three days of induction and latency to achieve a stable dose.138 The authors found that participants who were started at a moderate dose (16mg/4mg buprenorphine/naloxone) and shifted quickly over 3 days to a high dose (16mg/4mg–32mg/8mg buprenorphine/naloxone) were three times less likely to drop out in the first 7 days than participants who were started and maintained at a low dose (8mg/2mg–16mg/4mg buprenorphine/naloxone). Participants who were stabilized at an optimal dose quickly had less opioid use in the last 28 days of treatment than those who were slowly titrated to their optimal dose, without an increase in adverse events in the first or last 28 days of treatment.138 

Early studies examining the efficacy of buprenorphine have been critiqued for employing relatively low buprenorphine doses and slower induction protocols than current practice standards.139 A 2014 Cochrane review found low doses of buprenorphine (2–6mg/day) were not as effective at retaining people in treatment compared to low doses of methadone (<40mg/day), although any dose of buprenorphine greater than 2mg/day had higher rates of retention compared to a placebo.116 

A multi-site 2008 retrospective observational study in Italy (n=979) examined different treatment protocols across 32 treatment centres. During the induction phase, protocols indicated a first dose between 2mg and 4mg with subsequent doses ranging from 2mg–4mg. While some protocols did not impose a limit on maximum dose during the first three days of induction, others limited doses to 8mg on the first day, 16mg on the second day, and 24–32mg on the third day. Participants who received lower induction doses had significantly higher relapse rates, with 51.2% of those induced on 2mg of buprenorphine experiencing a relapse, compared to 39.2% of those induced with 4mg, 31.5% of those induced on 8mg, and 20.6% of those induced on 10mg. Nearly all participants who received an induction dose of 16mg or greater successfully completed induction. In addition, reductions in positive urine screens for cocaine and cannabis were observed as buprenorphine doses increased, with the greatest reductions seen at doses greater than 16mg.140 

A 2022 systematic review (N=9 studies) seeking to determine factors associated with longer retention in buprenorphine treatment also found that higher doses  of buprenorphine/naloxone were associated with significantly higher rates of treatment retention (p<0.01).141 Sub-optimal doses of opioid agonist treatment medications should be avoided, as they are a commonly cited reason for treatment disengagement.142 An optimal dose of opioid agonist treatment medications should be understood as a dose that reduces the discomfort of withdrawal symptoms, overcomes drug cravings, reduces the use of unregulated drugs in accordance with the patient’s treatment goals, and causes minimal adverse reactions in patients without inducing toxicity.142

Traditionally, buprenorphine induction has required a period of abstinence from opioids to ensure that withdrawal is not precipitated. This period can be both time-consuming and challenging for patients,116,143 as it requires patients to be in moderate withdrawal prior to induction. If insufficient time has passed since last opioid use,  the introduction of buprenorphine, a partial agonist with high affinity for the opioid receptor, may cause precipitated withdrawal. A low-dose  induction that slowly up-titrates small doses of buprenorphine without cessation of all other opioids until a therapeutic dose has been reached was first described in the literature in 2016, with growing numbers of cases described since then.144 A 2021 systematic review included 19 case studies/series and 1 feasibility study (n=57).145 All 57 patients were able to reach a maintenance dose, and 95% (54/57) did not report precipitated withdrawal during the induction process. Twenty-six patients (46%) were co-prescribed full agonists (including methadone, fentanyl, hydromorphone, and morphine), with the rest continuing to use unregulated opioids during the induction period. Although all included patients achieved a maintenance dose, some patients required multiple attempts, and return to unregulated opioid use was reported for 5 patients. The median starting dose for studies that did not report precipitated withdrawal was 0.5mg, median duration was 6 days, median maintenance dose was 16mg, and mean rate of dose change to 8mg was 1.36mg/day.145 While the findings are promising, the overall quality of included studies was rated as poor, and the lack of standardized outcome measures and comparative effectiveness studies limit conclusions regarding effectiveness. There is significant variability and a lack of standardization in the low-dose induction protocols reported.145

Several case studies and case series have also reported findings in favour of the use of low-dose inductions in a variety of settings. These include successfully transitioning patients (n=6) onto extended-release buprenorphine,146,147 a low-dose induction paired with assertive community outreach to successfully initiate a patient with multiple past treatment attempts and complex medical comorbidities onto buprenorphine/naloxone,148 and low-dose inductions for individuals prescribed opioids for analgesia.149,150

Research is ongoing to produce high-quality evidence of the efficacy of low-dose induction compared to standard buprenorphine induction; two randomized controlled trials are planned to compare low-dose inductions with traditional buprenorphine/naloxone inductions, one at Vancouver General Hospital,151 and one with four sites in BC and Alberta.152 

Although research evidence is limited, clinical practice in many parts of BC now commonly includes using low-dose inductions as they reduce the risk of precipitated withdrawal and do not require the patient to abstain from the use of other opioids for a prolonged period. This may increase the likelihood of patient retention and satisfaction. Low-dose inductions may be especially helpful for individuals using fentanyl, as emerging evidence and clinical experience suggests that the risk of precipitated withdrawal is higher for these individuals, likely due to the unique pharmacokinetics of fentanyl.153,154 Considerably more research is needed to compare traditional inductions to low-dose inductions in order to determine comparative efficacy and to identify specific factors that support the tailored selection of the appropriate induction approach. More research is also needed to determine optimal low-dose induction protocols. 

See Appendix 3 for clinical guidance for conducting low-dose inductions based on protocols commonly utilized in BC.

Individuals with opioid use disorder have high rates of emergency department (ED) utilization.155 Data from the 2005–2014 National Surveys on Drug Use and Health in the U.S. showed that 58.2% of individuals with prescription opioid use disorder reported past-year ED utilization, with 45.1% reporting 2-4 visits.156 Data from the BC Provincial Overdose Cohort, which examined 10,455 overdose events between January 1, 2015 and November 30, 2016, found that over half (60.4%) visited the emergency department in the year prior to overdose.157 These high rates of ED utilization suggest that ED visits may be an opportunity to engage individuals in OUD care. A small but growing body of evidence suggests that ED-based initiation of buprenorphine/naloxone increases engagement and retention in treatment.158-160 

A 2015 RCT (n=329) randomized participants to one of three conditions: screening and referral to treatment; screening, brief intervention, and facilitated referral to community-based treatment services; or screening, brief intervention, ED-initiated buprenorphine/naloxone, and referral to primary care for 10-week follow up.158 The initiation group had significantly higher treatment engagement and significantly fewer days of self-reported unregulated opioid use after 30 days, compared to the other two groups.158 At two months, the initiation group continued to have significantly higher treatment engagement and fewer days of self-reported unregulated opioid use; however, this difference between groups did not persist at 6 or 12 months.161 A cost-effectiveness evaluation of this study found that ED-initiated buprenorphine/naloxone is most likely to be cost-effective relative to both referral and brief-intervention.162 

A small (n=26) 2019 study randomized patients presenting to the ED in opioid withdrawal (or soon to be) to either a clonidine or buprenorphine/naloxone group. The clonidine group were provided with clonidine in the ED and provided a 5-day discharge prescription along with a flyer and map to a rapid access addiction clinic, while the buprenorphine/naloxone group was administered up to 12mg/3mg buprenorphine/naloxone and given a prescription for a 5-day supply of buprenorphine/naloxone, a map to the nearest outpatient pharmacy, and printed information and a map for the rapid access addiction clinic.159 At 1 month, the buprenorphine/naloxone group was significantly more likely to be receiving OAT (62% vs. 8%). In addition, more than double the number of buprenorphine/naloxone participants went for follow-up within five days at the rapid access addiction clinic (77% vs. 38%); however, this difference was not statistically significant.159 A small number of case studies (n=3) from the California Bridge Program have shown that individuals can be rapidly inducted onto buprenorphine/naloxone in the ED following naloxone reversal of an opioid overdose, without serious adverse event.163

A 2019 retrospective chart review of four community hospitals in Ontario evaluated 49 patients who were eligible to receive ED-initiated buprenorphine/naloxone treatment followed by a discharge prescription of up to three daily witnessed doses and a referral to the rapid access addiction clinic; 88% (n=43) consented to the intervention.160 Approximately 54% of those initiated on buprenorphine/naloxone attended their initial appointment at the rapid access addiction clinic. At six months, 35% remained on buprenorphine/naloxone-based OAT and 2.3% had successfully transitioned off of buprenorphine/naloxone treatment.160 In addition, those patients in the ongoing treatment group had significantly lower ED utilization in the 6 months following initiation onto buprenorphine/naloxone. 

Several programs for ED-initiation of buprenorphine/naloxone are currently in existence, in both Canada and the United States. To facilitate engaging ED patients with OUD in OAT, the BCCSU and BC Patient Safety and Quality Council worked together to launch the Learning about Opioid Use Disorder in the Emergency Department Collaborative (LOUD in the ED). The program developed three key resources: a Tool for Emergency Department Buprenorphine/naloxone Induction, a webinar series,  and two new modules (modules 23 and 24) of the Provincial Opioid Addiction Treatment Support Program (POATSP).

See Appendix 4 for guidance on ED buprenorphine/naloxone induction.