Tara Gomes

With Canadian provinces expanding investments for bed-based inpatient (i.e., residential) substance use treatment, it’s important to understand who accesses these programs and their treatment outcomes. Therefore, the aim of our study was to describe admissions to publicly-funded residential treatment for opioid use disorder (OUD) and opioid toxicities rates following discharge. We conducted a population-based repeated cross-sectional study of publicly-funded residential treatment for OUD in Ontario, Canada, between July 1, 2013 and June 30, 2022. We calculated population-adjusted residential treatment admission rates and used joinpoint regression models to assess significant changes in monthly percent changes (MPC). We reported characteristics of discharged clients and weekly rates of fatal or non-fatal opioid toxicity 1-year post-discharge. Among the first identified residential treatment episode for each client, we determined the proportion who had an opioid toxicity event within 28-days post-discharge, overall and stratified by admission date, age, sex, mandated treatment, and discharge reason. Over the study period, admissions fluctuated monthly (from 1.5 [N = 18] to 11.9 [N = 136] per 1,000,000), declining gradually until December 2019 (MPC: -0.3%; p-value = 0.0009) before dropping abruptly between January and April 2020 (MPC: -20.3%; p-value = 0.44) and then rising soon thereafter (MPC, 2.5%; p-value = 0.0001). Overall, 60.8% of clients (N = 9,388; mean age, 33.1 + 10.2 years; 64.1% male) completed their treatment program. Within 28 days post-discharge, 1.4% experienced an opioid toxicity, with higher rates among clients who were male (1.7%), mandated to treatment (2.1%), and discharged early, both voluntarily (2.0%) and involuntarily (2.8%). Despite rising investments into residential treatment programs, our findings showed admissions for OUD dropped substantially early in the COVID-19 pandemic and remained below pre-pandemic levels in the subsequent two years. Importantly, high rates of early discharge and opioid toxicity soon thereafter underscore the need to implement quality standards for residential treatment programs in Ontario and throughout Canada.

Objectives: The unregulated drug supply in Canada increasingly contains benzodiazepines, particularly those not approved for medical use, raising concerns about toxicity risk, especially when combined with opioids. Therefore, we aimed to describe trends in benzodiazepine-related toxicity deaths and compare their characteristics and circumstances by benzodiazepine type. Methods: We conducted a descriptive cross-sectional study of accidental benzodiazepine-related toxicity deaths in Ontario between January 1, 2018 and June 30, 2022, using linked administrative healthcare at ICES including coroner’s investigation records from the Drug and Drug/Alcohol Related Death Database. We measured monthly crude rates of benzodiazepine toxicity deaths and summarized characteristics (age, sex, region of residence, etc.) and circumstances (number and types of substances involved, healthcare encounters for toxicities and substance use disorders, etc.) of decedents and compared these by benzodiazepine type (approved vs. not approved for medical use in Canada). Results: Between January 2018 and June 2022, 782 Ontarians died of benzodiazepine-related toxicity (median age of 40 years), of which 70.5% were male and 88.6% resided in Southern Ontario The rate of benzodiazepine toxicity death peaked in December 2020 (0.27 per 100,000; N = 40). Overall, 98.1% of benzodiazepine deaths involved another substance, most commonly opioids (91.2%). Moreover, one-fifth (22.6%) of decedents had experienced a hospital-treated substance toxicity in the year prior to death, and almost two-thirds (64.1%) had a healthcare encounter with a substance use disorder diagnosis in the prior five years. Conclusion: Benzodiazepines remain an important contributor to substance-related mortality in Ontario, with nearly 800 benzodiazepine-related toxicity deaths observed over a four-and-a-half-year period. As almost all deaths involved multiple substances, most commonly opioids, harm reduction and treatment programs must adapt to the evolving needs of people who use drugs who may experience both intentional and unintentional benzodiazepine exposure.

IntroductionOpioid agonist therapy (OAT) is central to treating opioid use disorder, and its benefits depend on continuous engagement in care. This study used a provincial administrative cohort to examine sociodemographic and clinical factors associated with longitudinal OAT adherence, measured by proportion of days covered (PDC), across Ontario, Canada.MethodsWe conducted a retrospective cohort study using linked health administrative and pharmacy dispensing data for Ontario residents aged ≥15 years who initiated OAT between 2014 and 2022. We calculated PDC as monthly OAT coverage during the follow-up period using the Narcotics Monitoring System. We fitted a population-averaged model using generalized estimating equations (GEE) to repeated PDC observations. Covariates included age, sex, region (Northern vs Southern Ontario), neighborhood deprivation and marginalization, rurality, homelessness, mental illness, HIV, and hepatitis C.ResultsThe cohort comprised 48,547 patients, of whom 82.5% resided in Southern Ontario and 17.5% in Northern Ontario. Mean monthly PDC was 0.58 (range: 0.01–0.81). No significant difference in PDC was observed between patients residing in Northern Ontario and those living in Southern Ontario. Female sex and older age were associated with modestly higher PDC, whereas homelessness, greater neighborhood marginalization, and mental illness were associated with lower PDC. Income-based deprivation was associated with adherence after adjustment. Associations were generally consistent across OAT medications, although patients receiving buprenorphine formulations had slightly lower PDC than those receiving methadone.Conclusion In this large provincial OAT cohort, adherence, measured by PDC, was associated with several structural, clinical, and regional factors. Homelessness, neighborhood marginalization, mental illness, and regional context were important correlates of adherence, highlighting the need for targeted strategies that address social and geographic barriers to sustained OAT engagement.

Background: In 2022, Canada experienced a shortage of pediatric acetaminophen and ibuprofen, raising concerns that reduced availability could increase emergency department use for febrile illness or acetaminophen-related poisoning in children. Objective: To evaluate the impact of the pediatric antipyretic shortage on pediatric health service use and outcomes. Methods: We conducted a population-based ecological time-series study using administrative health data from Ontario and Alberta, Canada, including national and provincial hospitalization and respiratory virus databases. We used generalized additive models and segmented negative binomial regression to estimate immediate and postshortage changes in rates of ED visits for fever and acetaminophen poisoning among children aged 0 to 11 years between the pre- (January 2018 to July 2022) and post- (August 2022 to March 2023) shortage periods. Results: We identified 163,396 fever-related ED visits in Ontario and 58,070 visits in Alberta. The shortage was not associated with an immediate [Ontario rate ratio (RR) 1.08: 95% CI: 0.72-1.63] or trend change in Ontario (RR: 0.98; 95% CI: 0.92-1.04). Similar findings were observed in Alberta (RR: 0.88; 95% CI: 0.56-1.38 and RR: 0.99; 95% CI: 0.93-1.05, respectively). We identified 1998 ED visits for acetaminophen poisoning in Ontario and 906 visits in Alberta. In Alberta, the shortage was associated with an immediate decline in visits for acetaminophen poisoning (RR: 0.76; 95% CI: 0.67-0.87), followed by an increasing trend (RR: 1.04; 95% CI: 1.03-1.05). No such changes were observed in Ontario (RR: 0.98; 95% CI: 0.92-1.05 and RR: 1.01; 95% CI: 0.99-1.02, respectively). Conclusion: The 2022 pediatric antipyretic shortage was not associated with increased febrile illness-related ED visits in Ontario or Alberta. Interprovincial differences in the association between the shortage and ED visits for acetaminophen poisoning may reflect variation in mitigation strategies.

Background: Long-term benzodiazepine use has been associated with increased risk of morbidity and mortality. Preventing long-term use through safer prescribing practices has received little attention to date. We sought to better understand associations between initial prescription characteristics and duration of benzodiazepine use. Methods and findings: This was a retrospective population-based cohort study of 1,820,808 adults in Ontario with incident benzodiazepine prescriptions between January 1, 2013 and December 31, 2020, with follow-up to December 31, 2021. The primary exposure was duration of the index prescription (≤7 days—referent group, 8–14 days, 15–30 days, or >30 days). Secondary exposures were: (a) duration of action of index benzodiazepine(s) prescription (short-acting, long-acting or both); (b) number of benzodiazepine dispensed on index (1 or 2+); and (c) mean daily dose of the index prescription in Diazepam Milligram Equivalents (DMEs). The primary outcome was time to benzodiazepine discontinuation in days. Multivariable models were adjusted for age, sex, anxiety, insomnia, and substance use disorders as well as other important comorbidities and socio-demographic characteristics. The median age at index was 53 years (Interquartile Range (IQR) 38–67), and 62.6% were women. The median time to discontinuation in women was 16 days (IQR: 6–29) while the median time to discontinuation in men was 19 days (IQR: 6–29). Lorazepam was the most commonly prescribed benzodiazepine on index (63.9%), followed by clonazepam (17.3%) and diazepam (5.8%). In multivariable Cox Proportional Hazards Models, longer index prescriptions were associated with a lower likelihood of benzodiazepine discontinuation (adjusted Hazard Ratio (aHR) 0.54 (95% Confidence Interval (CI) [0.54,0.54]) for 8–14 days; aHR 0.26 (95% CI [0.25,0.26] for 15–30 days and aHR 0.14 (95% CI [0.14,0.14]) for >30 days, compared to ≤7 days, respectively). Being prescribed two or more benzodiazepines versus 1 was also associated with a reduced likelihood of discontinuation (aHR 0.59 (95% CI [0.57,0.61])), as was being prescribed long-acting benzodiazepines (aHR 0.80 (95% CI [0.80,0.80])) or a combination of short and long acting benzodiazepine (aHR 0.84 (95% CI [0.80,0.88])) versus short-acting benzodiazepines alone. Mean daily doses of >5 to ≤10 DME and >10 to ≤20 DME were associated with an increased likelihood of discontinuation (aHR 1.03 (95% CI [1.03,1.03]); aHR: 1.03 (95% CI [1.03,1.04])), whereas doses >20 DME were associated with a reduced likelihood of discontinuation (aHR 0.98 (95% CI [0.97,0.98])) compared with ≤5 DME. Findings may be subject to bias from unmeasured confounding. Conclusion: This large population-based cohort study found that prescribing shorter courses of benzodiazepines, use of a single benzodiazepine, use of a short-acting agent, were associated with reduced likelihood of long-term benzodiazepine use. Findings suggest that simple changes to prescribing practices could reduce prolonged benzodiazepine use and the morbidity and mortality associated with long-term use of these medications.

Background and Aims: In 2019, British Columbia (BC) became the first jurisdiction in North America to introduce a mandatory non‐medical switching (NMS) policy requiring patients with Crohn's disease (CD) and ulcerative colitis (UC) to be switched from originator biologics to biosimilar equivalents. This study examines the influence of the BC Biosimilars Initiative NMS policy on the longer‐term infliximab and adalimumab biosimilar utilization and patterns of continuation/discontinuation of biosimilars. Methods: We used health administrative data from BC to study drug utilization trends between 2015 and 2022. We used an interrupted time series design with segmented regression analysis to evaluate the impact of the Biosimilars Initiative on the utilization of biosimilars for infliximab and adalimumab and marginal Cox regression models to explore predictors of discontinuation of biosimilars post NMS. Results: The Biosimilars Initiative was associated with an increase in the proportion of biosimilars within the anti‐TNF market of 29.3% (95% CI: 28.6%, 29.9%) in Phase 1 (infliximab) and 49.5% (95% CI: 48.4%, 50.7%) in the adalimumab phase; thereafter, biosimilar use increased by 1.5% per year (95% CI: 0.3%, 2.7%). After the NMS, by the end of 2022, 13.5% ( n = 4648) had switched from a biosimilar to an originator or a biologic in a different class. Female patients and biologic‐naive patients starting on a biosimilar were more likely to switch from a biosimilar to another drug. Conclusions: Our results suggest that the Biosimilars Initiative NMS in BC was successful in switching patients to biosimilars and that most patients remained on biosimilar versions.

Background: Clinical guidance in Canada and the United States recommends faster methadone dose titration for individuals using fentanyl. An initial dose increase is recommended between days 4 and 6, but the impact on patient outcomes remains unclear, particularly when provided in an outpatient setting. Therefore, we evaluated the association between early methadone dose titration (i.e., within treatment days 4–6) and treatment discontinuation and opioid toxicity. Methods and findings: We conducted a retrospective propensity-score weighted cohort study of Ontario residents who initiated methadone in an outpatient setting between January 2017 and December 2022. Exposure was defined as provision of a dose titration between treatment days 4–6, with the index date defined as the first date of dose increase. For unexposed individuals, the index date was randomly assigned and followed the same distribution as those exposed. Individuals were followed for up to 181 days following index date for study outcomes. Primary outcomes included methadone discontinuation and opioid toxicity, using an intention-to-treat approach. Secondary outcomes included methadone versus non-methadone-related toxicity while on treatment. We fit a propensity-score model to estimate the probability of dose titration, conditional on baseline demographic and clinical (e.g., comorbidities, past medication use) variables. Propensity score weighted Cox proportional hazard models were then estimated to determine the association between early dose titration and study outcomes. Among 13,560 incident methadone recipients (61.4% [ N = 8,322] provided early dose titration), the mean age was 36.5 years old, and approximately one-third were female. Individuals who received an early dose titration had a lower weighted hazard of discontinuation, which was most pronounced during the first seven days of follow-up (weighted hazard ratio [wHR]: 0.55; 95% confidence interval [CI]: 0.51, 0.60), with attenuation towards the null over time. The observed weighted rate of opioid toxicity was lower among those exposed versus unexposed (10.1 versus 12.3 per 100 person-years; wHR: 0.82; [95% CI: 0.69, 0.97]). Early dose titration was not associated with opioid toxicity while on treatment. Most toxicities were attributed to non-methadone opioids (exposed: 3.89 per 100 person-years versus unexposed: 4.06 per 100 person-years; wHR: 1.00; [95% CI: 0.70, 1.44]). Methadone-related toxicity while on treatment remained low and comparable between exposed and unexposed groups (2.02 versus 2.65 per 100 person-years; wHR: 0.80; [95% CI: 0.46, 1.41]). The main study limitation is the lack of information on drug use history and time-varying clinical factors that may influence both dose titration and subsequent outcomes, introducing the potential for residual confounding. Conclusions: This population-based analysis demonstrated that early methadone dose titration was associated with improved treatment retention and lower hazard of opioid toxicity. Logistical barriers that hinder timely provision of dose increases must be addressed to improve methadone retention among people who use fentanyl.

Fentanyl, hydromorphone, and oxycodone are metabolized by cytochrome P450 3A4 (CYP3A4). Co‐administration with CYP3A4‐inhibiting macrolides (clarithromycin or erythromycin) may increase opioid concentrations and overdose risk, but the clinical impact of these interactions is unknown. We conducted three population‐based nested case‐control studies of Ontario residents aged 15 years or older who were prescribed transdermal fentanyl, oral hydromorphone, or oral oxycodone between 1997 and 2023. We defined cases as individuals who died of or were hospitalized with opioid toxicity and matched each case to up to four controls on age, sex, calendar year, and a disease risk score. We assigned controls random index dates based on the distribution among cases and estimated adjusted odds ratios (aOR) and 95% confidence intervals (CIs) for the association between opioid toxicity and macrolide use in the preceding 14 days. We matched 735 fentanyl‐treated (45.3% of eligible cases), 2,506 hydromorphone‐treated (64.5%), and 678 oxycodone‐treated (50.1%) individuals with opioid toxicity to at least one control. Across all studies, 70 cases and 120 controls were exposed to a macrolide. CYP3A4‐inhibiting macrolide exposure was associated with an increased risk of opioid toxicity among patients treated with fentanyl (aOR 3.80, 95% CI: 1.36–11.56), hydromorphone (aOR 3.38, 95% CI: 1.28–8.97), and oxycodone (aOR 3.11, 95% CI: 1.05–9.51). We observed no associations with azithromycin, a non‐CYP3A4 inhibiting macrolide. There was no significant effect modification by study period, and findings were robust in bias analyses. These findings likely extend to individuals exposed to clandestinely produced fentanyl and to other CYP3A4 inhibitors.