Prescribing practices in opioid agonist treatment and changes in compliance to clinical dosing guidelines in British Columbia, Canada

Abstract

Background and aim:

In British Columbia, Canada, clinical guidelines for the treatment of opioid use disorders (OUD) were updated in 2017, during a period in which the potency and composition of the illicit drug supply changed rapidly. We aimed to describe changes in opioid agonist treatment (OAT) prescribing practices at the population level in a setting in which fentanyl and its analogs have become the primary illicit opioid of use.

Design, setting and participants:

This was a population-based retrospective cohort study using three linked health administrative databases in British Columbia (BC), Canada. All individuals with at least one OAT dispensation in BC between 1 January 2014 and 31 August 2021 took part.

Measurements:

To assess changes in OAT prescribing practices over time, we calculated initiation doses, dose titration intervals, maintenance doses and take-home dosing intervals stratified by medication [methadone, buprenorphine–naloxone and slow-release oral morphine (SROM)] according to recommended guidelines.

Findings:

A total of 265 410 OAT episodes (57.5% on methadone, 34.5% on buprenorphine–naloxone and 8.0% on SROM) were initiated during the study period. Compared with the guideline recommendation, observed initiation doses were higher among all medications from 2014 (2017 for SROM) to 2021 (buprenorphine–naloxone: 14–29%; methadone: 53–66%; SROM: 26–55%). Titration intervals were shorter for all medications, consistent with guidelines for buprenorphine–naloxone (26–49%), but shorter than recommended for methadone or SROM (28–51% and 12–41%, respectively). Higher maintenance dosing was observed for methadone (68–78%) and SROM (3–21%). Take-home allowances extending beyond the recommended guideline length increased across medications (buprenorphine–naloxone: 18–35%; methadone: 50–64%; SROM: 34–39%). Changes in prescribing patterns were similar for first-time OAT initiators.

Conclusion:

In British Columbia, Canada, from 2014 to 2021, prescribers of opioid agonist treatment (OAT) appeared to initiate both new and experienced OAT clients at higher doses than guideline recommendations, titrate them more rapidly and maintain clients at higher doses. Take-home dose allowances also gradually increased.

INTRODUCTION

As the prevalence of illicit fentanyl use has increased across North America [1–3], prescribers are frequently challenged to meet the needs of their clients to sustain retention in opioid use disorder (OUD) treatment. Fentanyl and its analogs rapidly overtook the illicit drug supply in British Columbia (BC), prompting a public health emergency declaration in 2016 [4]. As of 2022, overdose deaths have more than doubled since the declaration, with toxicology reports confirming more than 82% of all fatal overdoses contained fentanyl during the past 7 years, a stark increase from 2014 where a quarter of deaths had had fentanyl detected [5].

Revised clinical guidelines for the treatment of OUD in the province were released in 2017 [6], 14 months after the declaration. As well as endorsing buprenorphine–naloxone as a first-line opioid agonist treatment (OAT), recommendations on initial doses, titration, maintenance dose and take-home dosage were revised according to updated evidence on the use of both methadone and buprenorphine–naloxone. In addition, slow-release oral morphine (SROM) was introduced as a second-line treatment (Table 1). However, evidence on the effective clinical management of people primarily using illicit fentanyl is extremely limited [7]. Evidence cited in BC’s OUD guidelines—and current guidelines from American Society of Addiction Medicine and Substance Abuse and Mental Health Services Administration—almost exclusively predate the introduction of fentanyl and its analogs into the illicit drug supply [6, 8, 9]. However, only the American Society of Addiction Medicine suggests the need for further research to address illicit fentanyl use in OUD treatment [9]. Lastly, all guidelines recommend an individualized approach to OUD treatment, with more recent guidelines from the United States [8, 9] emphasizing patient-centered care and shared-decision making.

TABLE 1.

Summary of British Columbia’s 2017 Opioid Use Disorder guideline for the outcomes of interest.

Aspect of treatment	Description	BC OUD guideline dosing recommendations
		Buprenorphine–naloxone	Methadone	Slow-release oral morphine
Initiation dosing	The dose prescribed when an individual initiates OAT allowing them to function adequately without experiencing withdrawal symptoms and at a dose found to be a safe and effective strategy for treatment	Day 1: ≤ 4 mg/1 mg/day up to 12 mg/3 mg/day	• No tolerance/opioid naive: initial dose 5–10 mg/day • Unknown tolerance/other medications or conditions: initial dose 10–20 mg/day • Known tolerance: initial dose 20–30 mg/day • Initial dose should not exceed 30 mg/day	30–60 mg is recommended on day 1 for individuals with daily or lower frequency heroin use
Titration interval	Following initiation, medication titration adjusts treatment dosage to achieve the desired therapeutic effects while minimizing side effects	Dose increased by ≤ 2 mg/1 mg at a time to a maximum of 24 mg/6 mg/day within the first week of treatment	Dose increased by 5–10 mg at a time, ≥ 5 days apart	• Dose increased ≥ 2 days apart within the first week • Dose titration is personalized to the individual.
Maintenance dose	The amount of treatment that an individual requires to prevent withdrawal symptoms without experiencing psychoactive effects	Stable dosing 12 mg/3 mg–24 mg/6 mg per day after week 1	At least 24 hours without withdrawal symptoms or side effects ≥ 60 mg/day	• Average dose ranges from 235 to 791 mg/day • Full range is 60–1200 mg/day
Take-home dosing	Allowing individuals to self-administer treatment instead of having a practitioner or pharmacist witness a client ingest their medication	≤ 2 weeks of take-home dose	One take-home dose per week increased to < 1 week worth of medication at a time	One take-home dose per week increased to < 1 week worth of medication at a time

Abbreviations: BC = British Columbia; OAT = opioid agonist treatment.

Using linked health administrative data, available for the population of people accessing OAT in BC, our aim was to provide a descriptive analysis of changes in OAT prescribing practices during a period of rapid change in the illicit drug supply and the introduction of new clinical guidelines.

METHODS

Study design and data sources

We conducted a population-based retrospective cohort study using a linkage of three provincial health administrative databases to identify all people who had received at least one OAT dispensation in BC between 1 January 2014 and 31 August 2021, comparing between pre- and post-OAT guideline changes in 2017 and periods where fentanyl prevalence was changing. We used the BC PharmaNet database to identify buprenorphine–naloxone, methadone and SROM dispensations in the province, capturing all individuals who had had at least one dispensation at a community-based pharmacy [10] (Supporting information, Table S1). The Discharge Abstract Database captures all hospitalizations [11]. Vital Statistics database captures death records and their underlying cause in the province [12]. The databases were deterministically linked using a unique, individual-level de-identified personal health number [13].

OAT episodes were defined as continuous medication dispensations that had prescribed doses with no interruptions longer than 5 days for methadone or SROM and 6 days for buprenorphine–naloxone. Thresholds were set according to provincial clinical guidelines that recommend reverting to a starting dose after missing medication doses for 5/6 days to account for clients’ loss of tolerance [14]. Individuals may change their medication type during the episode. While OAT dispensations occurring in hospital were not available in our data, we assumed no interruptions in OAT episodes during hospitalizations.

Key measures

The key measures analyzed were population-level changes in OAT prescribing practices, according to four key aspects of treatment, including OAT initiation dosing, dose titration intervals, maintenance dosing and the duration of take-home doses. We defined initiation dose as the first dispensed dose of an OAT episode. The titration interval was defined as the number of days between dose increases within 12 weeks of the start of an OAT episode. The maintenance dose was defined as the highest dosage that has been maintained for at least 4 weeks during an OAT episode. Episodes without stable dosing for at least 4 weeks were excluded. Take-home dosing was defined as the maximum number of days of OAT medication dispensed during a single episode. We then report the percentage of all episodes initiated within a given calendar year that complied with clinical guidelines (Table 1).

Statistical analysis

We have provided a descriptive analysis of all OAT episodes from 2014 to 2021 of buprenorphine–naloxone, methadone, and SROM. We calculated 95% confidence intervals (CI) for the proportions of OAT episodes using normal approximation [15]. We also provided prescriber-level descriptive statistics including urbanicity, prescriber specialty, OAT prescribing history and experience since January 1996 and health authority of practice. Lastly, we described only incident (first-time) users defined as individuals initiating OAT with no prior OAT dispensations in BC to determine whether the observed changes in prescribing practices were consistent for new initiators of OAT.

This analysis was not pre-registered and the results should be considered exploratory.

RESULTS

We identified 54 206 unique individuals with 265 410 OAT episodes (57.5% initiated on methadone, 34.5% on buprenorphine–naloxone, 8.0% on SROM) during the study period. From 2014 to 2021 there was a threefold increase in the number of prescribers and a 17% observed increase in general practitioners (1087–3604 prescribers; 33.8–50.8% general practitioners). By 2021, prescribers were mainly in urban settings (80.4%), practicing in Vancouver Coastal health authority (26.7%), with 73.3% having fewer than 5.5 years of OAT prescribing history (Supporting information, Table S2). There was a 9% observed increase of new OAT prescribers from 2015 to 2016 (22.8–31.9%). Nearly a third of prescribers between 2016 and 2018 had no history of OAT prescription, subsequently declining to 17.5% by 2021.

Higher initiation doses became more common during the study period for all medications (Figure 1a; Supporting information, Tables S3 and S4). We observed an increase in buprenorphine–naloxone initiation doses of at least 12 mg/3 mg/day, from 13.9% in 2014 to 29.4% in 2021. Fifty-three per cent of all methadone episodes were initiated at doses of more than 30 mg in 2014, declining to 42% in 2018 in response to clinical guideline changes, subsequently rising to 66% by 2021. Otherwise, by the end of the study period we observed that 55% of SROM initiation doses were more than three times the recommended dose of less than 60 mg compared to 26.4% in 2014. As such, the percentage of initiation doses that followed guideline recommendations decreased for all medications during the study period, with the steepest declines for methadone (59.3–33.6%) and SROM (29–6%).

FIGURE 1.

Trends in opioid agonist treatment prescription following provincial guidelines recommendation between 1 January 2014 and 31 August 2021 in British Columbia, Canada. Abbreviations: BNX = buprenorphine-naloxone; SROM = Slow-release oral morphine

Titration intervals also declined across medications during the study period (Figure 1b; Supporting information, Tables S3 and S4). One-day buprenorphine–naloxone titration intervals had an observed increase of 23.4% from 2014 to 2021 (25.6–49%). Among methadone recipients, titration intervals under 5 days increased from 27.5 to 51.1% throughout the study period. Finally, daily titration of SROM was observed as 29.4% higher from 2017 to 2021 (12–41.4%). After guideline changes in 2017, titration intervals that followed guideline recommendations were 23.4% higher for buprenorphine–naloxone (25.6–49%), 23.5% lower for methadone (72.5–49%) and 29.4% lower for SROM (88–58.6%), for which slower titration was recommended.

Similar to initiation doses, maintenance doses increased across medications (Figure 1c; Supporting information, Tables S3 and S4). For buprenorphine–naloxone maintenance doses, we observed an increase of 6.5% (1.3–7.8%) for doses greater than 24 mg/6 mg throughout the study period. However, maintenance doses lower than 12 mg/3 mg increased 6.1% (32.7–38.8%) after the guideline was introduced in 2017. Methadone maintenance doses greater than 60 mg were 10.5% higher (67.8–78.2%). Additionally, prescription of SROM maintenance doses greater than 1200 mg increased from 3.1% to 21.1%. Overall, we observed maintenance dose prescriptions that followed guideline recommendations (i.e. dosing exceeded recommendations) decreasing 11.1% for buprenorphine–naloxone (64.5–53.4%) and increasing 4.4% for methadone (73.8–78.2%) and 33.9% for SROM (51.8–85.7%).

Take-home dose durations also increased among all medications during the study period (Figure 1d; Supporting information, Tables S3 and S4). Two-week buprenorphine–naloxone take-home doses had an observed increase of 17.6% between 2014 and 2021 (17.7–35.3%). Similarly, methadone take-home doses extending more than a week increased 14.9% in the same period (49.5–64.4%). SROM take-home doses lasting longer than a week were observed as 4.8% higher (34.1–38.9%). After the 2017 guideline was introduced, take-home doses that followed guideline recommendations decreased across all medications, with methadone having the most considerable reduction (15.2% reduction).

For incident (first-time) individuals on OAT, there were 32 254 episodes (Supporting information, Tables S5 and S6, Figure S1). Prescribing practices that followed clinical guidelines were similar for incident OAT episodes and all episodes for initiation doses, titration lengths, maintenance doses and methadone take-home doses, with marginal differences for take-home doses of buprenorphine–naloxone and SROM.

DISCUSSION

This study provides a descriptive analysis of changes in OAT prescribing practices between 2014 and 2021 in BC. Although health administrative records do not provide information pertaining to clinical decision-making our results suggest that, as a response to client needs and co-occurring influx of fentanyl and its analogs in the illicit drug supply [16], prescribers have initiated both new and experienced OAT clients at higher doses, titrated them more rapidly and maintained clients at higher doses. Take-home dose allowances have also gradually increased across buprenorphine–naloxone, methadone and SROM. Although we cannot draw inferences from our descriptive analysis, these findings may be an indirect result of shared decision-making between clients and prescribers, possibly reflecting increased engagement in patient-centered care [17, 18]. Most of the observed changes in prescribing practices did not follow the recommended ranges for dosing except for an increase of buprenorphine–naloxone titration interval, where a 1-day titration is recommended by the guideline, as well as increases in maintenance dosing for methadone and SROM.

Given the relative novelty of prescribing buprenorphine–naloxone in BC, our findings suggest a growing comfort in rapid dose titration among prescribers over time, consistent with guideline recommendations and the underlying pharmacological profile of buprenorphine–naloxone [19]. Otherwise, starting doses below 4 mg/1 mg increased after 2017, possibly reflecting an increase in the use of micro-induction to overcome the requirements for abstinence and withdrawal symptoms needed to initiate treatment, and to avoid precipitated withdrawal during induction [20]. Additionally, SROM was introduced as a form of OAT in BC from 2017. The novelty in its use as OAT resulted in limited evidence to inform clinical guidelines. The rapid increase in SROM initiation and maintenance doses, particularly from 2017 to 2019, suggests that prescribers adjusted their practices over time according to their clients’ experience. Dosing guidelines have since been revised accordingly in 2023, addressing micro-induction for buprenorphine–naloxone, new formulations for methadone and buprenorphine–naloxone, higher initiation doses for methadone, more flexible take-home doses and new dosing and titration intervals for SROM [21].

Prescribing practices and regulations in Canada differ from other settings in North America, offering a more flexible patient-centered approach. Federal and provincial policies in Canada allow OAT prescription by physicians or nurse practitioners in any clinical setting, and oversight of OAT occurs at a provincial level [22]. In contrast, in the United States, OUD treatment is federally regulated where methadone prescription and dispensation are monitored and allowed in specialized clinics, buprenorphine is available in outpatient settings and SROM is not approved for OUD treatment [23]. The public health emergency declaration in 2016 marked a notable change in OUD treatment in BC. Removal of a requirement for a federal exemption to prescribe buprenorphine–naloxone, adding coverage for buprenorphine–naloxone in the provincial health services plan and allowing nurse practitioners to prescribe [24], all contributed to the increase of new OAT prescribers between 2016 and 2018. The subsequent yearly reductions in new OAT prescribers may have been exacerbated by COVID-19 disruptions on licensing institutions and decreased contact with health-care services.

Concerns that OUD practice standards and guidelines promote an ineffective and standardized approach to patient care have been raised in BC [25], which may create a sense of apprehension among prescribers to follow new clinical practice recommendations. Prescriber uptake of new treatment recommendations may be influenced by stigma, legal constraints, training, logistical factors such as remuneration or time commitment and concerns for diversion [26], where addressing clients’ needs may require a more cautious approach. Nevertheless, emphasizing individualized care, in addition to shared decision-making, has been shown to improve client/prescriber relationships, as well as improved health outcomes such as retention in OAT [27].

Although the results provide indirect evidence that prescribers changed their practices to meet their clients’ needs on their OAT dosing, retention declined during this period [28]. Changes in take-home dosing during COVID-19 were released for BC, Ontario and the United States [29, 30]. However, the changes in BC did not appear to have a population-level impact. Additionally, the evidence available for the 2017 BC guidelines was predominantly generated prior to fentanyl being present in the illicit drug supply. While we present no inferential link between prescribing practices and retention in OAT, it is likely that outcomes would have been further compromised without the prescriber’s apparent response to their clients’ needs.

The opioid overdose epidemic in North America has prompted a public health response to expand OAT access and care delivery through innovations such as hospital initiations, introduction of new treatment modalities (e.g. long-acting OAT), efforts to enhance linkage to care, telehealth and simplified protocols for prescribers to deliver OUD care [31, 32]. As generating experimental evidence may prove too time-consuming to keep pace with the changes in the composition of the drug supply, population-level linked health administrative data provides an opportunity to emulate target trials to determine new OAT dosing strategies in addition to evaluation of these practices [33]. Guideline diffusion and innovation in care require ongoing monitoring alongside health outcomes to determine impactful implementation strategies for clinical practice [34].

Limitations

While all community-based pharmacy dispensations of OAT are captured in our data, hospital dispensations are not observed. Lastly, we are unable to observe the decision-making process at the prescriber level or observe the role of the client in the decision-making process regarding dosing decisions during their treatment course. Ongoing research on effective dosing practices and the decision-making process of prescribers is needed to optimize rapid uptake of new care and treatment recommendations.

CONCLUSION

The increased potency of opioids from the illicit drug supply has led to an increased tolerance in users. Clinical guidelines for people with opioid use disorder need to be responsive to clients’ opioid tolerance to effectively retain clients in treatment, acknowledging potential dangers of rapid titration and high daily dosing while also adapting to the opioids that are present in the current illicit drug supply. Guidelines need to further promote and emphasize shared decision-making and have frequent revisions to accommodate the needs of the population and undergo ongoing, rapid cycle evaluation to define new dosing guidelines as the potency of the composition of the illicit drug supply continues to evolve.

DATA AVAILABILITY STATEMENT

The datasets generated and/or analysed during the current study are not publicly available due to privacy restrictions and concerns on individual level administrative data. Materials and code available on request.