The epidemiology of benzodiazepine-related toxicity in Ontario, Canada: a population-based descriptive study.

OBJECTIVES: Despite the widespread use of prescription benzodiazepines, there are few studies examining trends and patterns of benzodiazepine-related toxicity. We describe the epidemiology of benzodiazepine-related toxicity in Ontario, Canada. METHODS: We conducted a population-based, cross-sectional study of Ontario residents who had an emergency department visit or hospitalization for benzodiazepine-related toxicity between January 1, 2013 and December 31, 2020. We reported annual crude and age-standardized rates of benzodiazepine-related toxicity overall, by age, and by sex. In each year, we characterized the history of benzodiazepine and opioid prescribing among people who experienced benzodiazepine-related toxicity, and reported the percentage of encounters with opioid, alcohol, or stimulant co-involvement. RESULTS: Between 2013 and 2020, there were 32,674 benzodiazepine-related toxicity encounters among 25,979 Ontarians. During this period, the crude rate of benzodiazepine-related toxicity declined overall, from 28.0 to 26.1 per 100,000 population (age-standardized rate: 27.8 to 26.4 per 100,000), but increased among young adults aged 19 to 24 (39.9 to 66.6 per 100,000 population). Moreover, by 2020, the percentage of encounters associated with active benzodiazepine prescriptions had declined to 48.9%, while the percentage of encounters that had opioid, stimulant, or alcohol co-involvement rose to 28.8%. CONCLUSION: Benzodiazepine-related toxicity has declined in Ontario overall, but has increased among youth and young adults. Furthermore, there is growing co-involvement of opioids, stimulants, and alcohol, which may reflect the recent emergence of benzodiazepines in the unregulated drug supply. Multifaceted public health initiatives comprising harm reduction, mental health supports, and promotion of appropriate prescribing are needed to reduce benzodiazepine-related harm.

RéSUMé: OBJECTIFS: Malgré l'utilisation généralisée des benzodiazépines sur ordonnance, peu d'études portent sur les tendances et les schémas de toxicité de ces médicaments. Nous décrivons l'épidémiologie de la toxicité liée aux benzodiazépines en Ontario, au Canada. MéTHODE: Nous avons mené une étude populationnelle transversale des résidentes et résidents de l'Ontario ayant visité le service des urgences ou été hospitalisés pour toxicité liée aux benzodiazépines entre le 1er janvier 2013 et le 31 décembre 2020. Nous avons rapporté globalement, par âge et par sexe les taux annuels de toxicité liée aux benzodiazépines, bruts et standardisés pour l'âge. Pour chaque année, nous avons caractérisé les antécédents de prescription de benzodiazépines et d'opioïdes chez les personnes ayant présenté une toxicité liée aux benzodiazépines, et rapporté le pourcentage de rencontres présentant une co-implication avec les opioïdes, l'alcool ou les stimulants. RéSULTATS: Entre 2013 et 2020, il y a eu 32 674 rencontres pour toxicité liée aux benzodiazépines avec 25 979 Ontariens et Ontariennes. Durant cette période, le taux brut de toxicité liée aux benzodiazépines a baissé dans l'ensemble, passant de 28 à 26,1 pour 100 000 habitants (taux standardisé pour l'âge : 27,8 à 26,4 p. 100 000), mais il a augmenté chez les jeunes adultes de 19 à 24 ans (de 39,9 à 66,6 p. 100 000). De plus, en 2020, le pourcentage de rencontres associées à des ordonnances actives de benzodiazépines avait baissé à 48,9 %, tandis que le pourcentage de rencontres présentant une co-implication avec les opioïdes, les stimulants ou l'alcool avait augmenté à 28,8 %. CONCLUSION: La toxicité liée aux benzodiazépines a diminué en Ontario dans l'ensemble, mais elle a augmenté chez les jeunes et les jeunes adultes. De plus, cette toxicité présente une co-implication croissante avec les opioïdes, les stimulants ou l'alcool, ce qui peut refléter l'émergence récente des benzodiazépines dans l'approvisionnement non réglementé en drogues. Des initiatives de santé publique multidimensionnelles incluant la réduction des méfaits, le soutien en santé mentale et la promotion de la prescription appropriée sont nécessaires pour réduire les méfaits liés aux benzodiazépines.

Changing patterns of opioid initiation for pain management in Ontario, Canada: A population-based cross-sectional study.

INTRODUCTION: The recent publication of a national guideline and quality standards in Canada have provided clinicians with new, evidence-based recommendations on safe, appropriate opioid use. We sought to characterize how well opioid initiation practices aligned with these recommendations before and following their release. METHODS: We conducted a population-based study among people initiating opioids prior to the release of national guidelines (April 2015-March 2016; fiscal year [FY] 2015) and in the most recent year available (January-December 2019) in Ontario, Canada. We used linked administrative claims data to ascertain the apparent indication for opioid therapy, and characterized the initial daily dose (milligrams morphine or equivalent; MME) and prescription duration for each indication. RESULTS: In FY2015, 653,885 individuals commenced opioids, compared to 571,652 in 2019. Over time, there were small overall reductions in the prevalence of initial daily doses exceeding 50MME (23.9% vs. 20.1%) and durations exceeding 7 days (17.4% vs. 14.8%); but the magnitude of the reductions varied widely by indication. The prevalence of high dose (>50MME) initial prescriptions reduced significantly across all indications, with the exception of dentist-prescribed opioids (13.6% vs. 12.1% above 50MME). In contrast, there was little change in initial durations exceeding 7 days across most indications, with the exception of some surgical indications (e.g. common excision; 9.3% vs. 6.2%) and among those in palliative care (35.2% vs. 29.2%). CONCLUSION: Despite some modest reductions in initiation of high dose and long duration prescription opioids between 2015 and 2019, clinical practice is highly variable, with opioid prescribing practices influenced by clinical indication. These findings may help identify medical specialties well-suited to targeted interventions to promote safer opioid prescribing.

New opioid use and risk of opioid-related adverse events among adults with intellectual and developmental disabilities in Ontario, Canada.

BACKGROUND: Individuals with intellectual and developmental disability (IDD) can have a high prevalence of pain, which can be managed with prescription opioids. However, the prevalence of substance use disorder is also high in this population, raising concern about opioid-related adverse events. AIMS: To assess the risk of opioid-related adverse events following opioid initiation among adults with versus without IDD. METHOD: We conducted a population-based, propensity score matched cohort study on all adults starting prescription opioid therapy in Ontario, Canada, between January 2013 and December 2018. The outcomes of interest were opioid toxicity, new opioid use disorder (OUD) diagnosis and dose escalation (≥90 mg morphine or equivalent) in the year after opioid initiation. We used Cox proportional hazards models to assess the association between IDD diagnosis and each outcome. RESULTS: The hazards of opioid toxicity and OUD were significantly higher in those with IDD compared with those without IDD in unmatched analyses (opioid toxicity hazard ratio 3.19, 95% CI 2.81-5.18; OUD hazard ratio 2.36, 95% CI 2.10-2.65), whereas the hazard of dose escalation was significantly lower (hazard ratio 0.76, 95% CI 0.66-0.88). Findings were no longer significant in propensity score matched models for opioid toxicity and dose escalation, whereas the hazard of OUD diagnosis was attenuated substantially in those with IDD (hazard ratio 0.79, 95% CI 0.68-0.91). CONCLUSIONS: IDD diagnosis is not a driver of opioid-related harm. The increased risk we observed is likely driven by various risk factors often present in this population.

Risk of SARS-CoV-2 infection following initial COVID-19 vaccination: Population-based cohort study.

BACKGROUND: Anecdotally there are reports of newly diagnosed SARS-CoV-2 infection shortly after vaccination. This has led some to speculate that vaccination itself might inadvertently increase the short-term risk of COVID potentially due to airborne spread at mass vaccination clinics or relaxation of precautions following vaccination. We explored whether receipt of vaccination was associated with a short-term increase in the risk of being diagnosed with COVID-19 and if differences exist between vaccination settings. METHODS: We conducted a cohort study in Ontario, Canada to compare the risk of SARS-CoV-2 infection within 21 days of receiving a first vaccination, according to the setting in which vaccines were administered between March 1, 2021 and May 6, 2021. We used linked population-wide vaccination, laboratory testing, and health administrative databases. We created a 1:1 matched comparison group of unexposed individuals. We reported the overall risk of infection calculated at 3, 7, 10, 14, 18, and 21 days. This was completed overall and by setting of vaccine receipt. RESULTS: We identified 4,798,430 Ontario residents who received their first dose of a COVID-19 vaccine. In the primary analysis, the rate of SARS-CoV-2 infection was significantly lower among vaccine recipients vs non-recipients at all the post-vaccination time points. Analysis stratified by vaccination setting found that mass vaccination clinics, pharmacies, and physician offices were consistent with the main findings. Individuals who received their first vaccine dose in congregate residential settings had a higher rate of SARS-CoV-2 infection at 7 days (HR 1.35, 95% CI 1.00-1.83) and 10 days (HR 1.49, 95% CI 1.03-2.15). CONCLUSION: In this population-based cohort study, we found that there was no increased risk of SARS-CoV2 infection after vaccination suggesting no broad transmission of disease at time of vaccination. Some evidence of increased risk among those vaccinated in congregate settings, highlighting the need to consider opportunities for supporting safe vaccine administration in these settings. Given ongoing and future immunization programs, the results support the need for continued vigilance during any mass vaccination processes and education regarding the delayed nature of protection following vaccination.

Prescribing Characteristics Associated With Opioid Overdose Following Buprenorphine Taper.

Importance: Retention in buprenorphine therapy is associated with a lower risk of opioid overdose. Nevertheless, many patients discontinue treatment, and there is limited evidence to guide buprenorphine tapering. Objective: To understand what prescribing characteristics are associated with opioid overdose following buprenorphine taper. Design, Setting, and Participants: This is a population-based, retrospective, cohort study of adults who were maintained on buprenorphine for at least 60 days and underwent a buprenorphine taper. The study was conducted in the Canadian province of Ontario, using linked administrative health data. New buprenorphine treatment episodes were accrued between January 1, 2013, and January 1, 2019, and the maximum follow-up was April 30, 2020. Data analysis was performed from December 2020 to August 2022. Exposures: The primary exposure of interest was time to taper initiation (≤1 year vs >1 year). Secondary exposures included mean rate of taper, percentage days during which the dose was decreasing, and taper duration. Main Outcomes and Measures: The primary outcome measure was time to fatal or nonfatal opioid overdose within 18 months following treatment discontinuation. Results: Among 5774 individuals, the median (IQR) age at index date was 34 (28-44) years, and 3462 individuals (60.0%) were male. Time to taper initiation longer than 1 year vs 1 year or less (6.73 vs 10.35 overdoses per 100 person-years; adjusted hazard ratio [aHR], 0.69; 95% CI, 0.48-0.997), a lower mean rate of taper (≤2 mg per month, 6.95 overdoses per 100 person-years; >2 to ≤4 mg per month, 11.48 overdoses per 100 person-years; >4 mg per month, 17.27 overdoses per 100 person-years; ≤2 mg per month vs >4 mg per month, aHR, 0.65; 95% CI, 0.46-0.91; >2 to ≤4 mg per month vs >4 mg per month, aHR, 0.69; 95% CI, 0.51-0.93), and dose decreases in 1.75% or less of days vs more than 3.50% of days during the taper period (5.87 vs 13.87 overdoses per 100 person-years; aHR, 0.64; 95% CI, 0.43-0.93) were associated with reduced risk of opioid overdose; however, taper duration was not. Conclusions and Relevance: In this retrospective cohort study, buprenorphine tapers undertaken after at least 1 year of therapy, a slower rate of taper, and a lower percentage of days during which the dose was decreasing were associated with a significantly lower risk of opioid overdose, regardless of taper duration. These findings underscore the importance of a carefully planned taper and could contribute to reduction in opioid-related overdose death.

Opioid Initiation and the Hazard of Falls or Fractures Among Older Adults with Varying Levels of Central Nervous System Depressant Burden.

BACKGROUND: Co-prescription of opioids with other central nervous system (CNS) depressants is common but the combination may increase the risk for adverse events such as falls and fractures, particularly among older adults. We explored the risk of fall- or fracture-related hospital visits after opioid initiation among older adults with varying degrees of concomitant CNS depressant burden. METHODS: We used population-based administrative health data from Ontario, Canada, to examine the relationship between hospital visits for falls or fractures at different levels of CNS burden among individuals aged 66 and older who started prescription opioids between March 1, 2008, and March 31, 2019. For comparison, we identified individuals starting prescription non-steroidal anti-inflammatory drugs (NSAIDs). The outcome was a hospital visit for falls or fractures within 14 days after starting analgesic therapy. We stratified the cohort according to additional CNS burden: none, low (one concurrent CNS depressant drug class) and high (≥ 2 concurrent CNS depressant classes) on the index date. We balanced opioid and NSAID recipients using inverse probability of treatment weighting and reported weighted hazard ratios from Cox proportional hazards models. We then used pairwise comparisons to determine differences between hazard ratios at different levels of CNS burden. RESULTS: The cohort included 1,066,692 older adults, with 562,692 new opioid recipients and 504,000 new NSAID recipients. Among opioid recipients, 83 % had no additional CNS burden, 13 % had low burden and 4 % had high burden. The short-term rate of falls or fractures for new opioid recipients increased by CNS burden from 97 per 1000 person-years (no burden) to 233 per 1000 person-years (high CNS burden). Opioid recipients had a similarly elevated hazard of falls or fractures within each CNS burden level compared to NSAID recipients (adjusted hazard ratio [aHR] 1.62, 95 % CI 1.50-1.76 for no burden; aHR 1.69, 95 % CI 1.45-1.97 for low burden; aHR 1.40, 95 % CI 1.08-1.82 for high burden). CONCLUSION: Among older adults, initiation of opioids is associated with an increased hazard of falls; however, this hazard is not modified by different levels of CNS depressant burden. This suggests that it remains important for physicians, patients, and caregivers to be vigilant when starting new opioid therapy regardless of other CNS medications taken concurrently.

Impact of a publicly funded pharmacy-dispensed naloxone program on fatal opioid overdose rates: A population-based study.

BACKGROUND: Studies examining the impact of pharmacy-dispensed naloxone programs on fatal opioid overdose rates are lacking. We examined the impact of the publicly funded Ontario Naloxone Program for Pharmacies (ONPP), implemented in June 2016, on provincial rates of opioid overdose deaths. METHODS: We conducted a population-based interrupted time-series study between July 1, 2012 and December 31, 2018. We considered a parsimonious model with terms for time, ONPP implementation, and time following the ONPP implementation. Models were adjusted for population characteristics, number of pharmacies and rate of naloxone distributed through non-pharmacy sites within provincial public health units. RESULTS: In the parsimonious model, the ONPP was associated with a non-significant 9% reduction in the level of fatal opioid overdoses (rate ratio [RR] 0.91; 95% confidence interval [CI] 0.79-1.06), a finding that was most pronounced in regions in the lowest tertile of implementation (RR 0.75; 95% CI 0.62-0.91). Following multivariable adjustment, there was an increase in the level (RR 1.06; 95% CI 0.94-1.19) and slope change (RR 1.06; 95% CI 1.02-1.10) of fatal overdose rates. CONCLUSION: The ONPP is insufficient as a single intervention to meaningfully reduce rates of fatal opioid overdoses during a period in which the cause of these deaths shifted from prescription opioids to highly potent fentanyl analogs. Access to additional harm reduction, treatment, and other interventions is necessary to prevent deaths and optimize the health of people who use drugs.

Impact of the COVID-19 pandemic on the prevalence of opioid agonist therapy discontinuation in Ontario, Canada: A population-based time series analysis.

BACKGROUND: We assessed the impact of COVID-19, which includes the declaration of a state of emergency and subsequent release of pandemic-specific OAT guidance (March 17, 2020 to March 23, 2020) on the prevalence of OAT discontinuation. METHODS: We conducted a population-based time series analysis using interventional autoregressive integrated moving average models among Ontario residents who were stable (>60 days of continuous use) and not yet stable on OAT. Specifically, we examined whether COVID-19 impacted the weekly percentage of individuals who discontinued OAT, overall and stratified by treatment type (methadone vs. buprenorphine/naloxone). Additionally, we compared demographic characteristics and patient outcomes among people stable on OAT who discontinued treatment during (March 17, 2020 to November 30, 2020) and prior (July 3, 2019 to March 16, 2020) to the pandemic. RESULTS: The weekly prevalence of OAT discontinuation across the study period ranged between 0.6% and 1.1%, among those stable on treatment compared to 7.3% and 16.6%, among those not stable on treatment. Following COVID-19, there was no significant change in the percentage of Ontarians who discontinued OAT, regardless of whether they were stabilized on treatment. Among those stable on OAT, a similar proportion of patients restarted therapy and experienced opioid-related harm following an OAT discontinuation. However, mortality following OAT discontinuation must be noted, as approximately 1.4% and 0.8% of people who discontinued methadone and buprenorphine/naloxone respectively, died within 30 days of discontinuation. CONCLUSIONS: Trends in the prevalence of OAT discontinuation did not significantly change during the first eight months of the COVID-19 pandemic.

Impact of the COVID-19 pandemic on the provision of take-home doses of opioid agonist therapy in Ontario, Canada: A population-based time-series analysis.

BACKGROUND: In March 2020, the Ontario government declared a state of emergency due to the growing risk of COVID-19. In response, new guidance for the management of opioid agonist therapy (OAT) was released, which included the expansion of eligibility for take-home doses. We investigated the impact of these changes on trends in the distribution of take-home doses of OAT. METHODS: We conducted a population-based time series analysis among residents of Ontario, Canada who were dispensed OAT between June 25, 2019 and November 30, 2020. For each week of the study period, we calculated the percentage of people dispensed (a) methadone and (b) buprenorphine/naloxone by the number of take-home doses received. We used interventional autoregressive integrated moving average models to estimate changes in the percentage of people dispensed each category of take-home doses in the weeks following the declaration of the state of emergency and release of the OAT dispensing guidance. RESULTS: Following the state of emergency and release of the OAT dispensing guidance, there was a significant increase in the percentage of Ontarians dispensed 7 to 13 (3.6% increase; p = 0.033) and 14 or more (0.8% increase; p<0.001) take-home doses of methadone, and in the percentage of people dispensed 7 to 13 (4.3% increase; p = 0.001), 14 to 27 (2.8% increase; p<0.001), and 28 or more (0.3% increase; p = 0.008) take-home doses of buprenorphine/naloxone. There were significant decreases in the percentage of Ontarians receiving daily dispensed buprenorphine/naloxone (-3.1%; p = 0.001), as well as the percentage dispensed 1 to 6 take-home doses of methadone (-4.5%; p = 0.001) and buprenorphine/naloxone (-4.9%; p = 0.001). CONCLUSION: The new guidance for dispensing OAT in Ontario resulted in increases in the duration of take-home doses of methadone and buprenorphine/naloxone supplied. However, given that changes were small, strategies to improve retention in OAT and ensure equitable access to take-home dosing should continue.

Association Between Increased Dispensing of Opioid Agonist Therapy Take-Home Doses and Opioid Overdose and Treatment Interruption and Discontinuation.

Importance: During the COVID-19 pandemic, modified guidance for opioid agonist therapy (OAT) allowed prescribers to increase the number of take-home doses to promote treatment retention. Whether this was associated with an increased risk of overdose is unclear. Objective: To evaluate whether increased take-home doses of OAT early in the COVID-19 pandemic was associated with treatment retention and opioid-related harm. Design, Setting, and Participants: A retrospective propensity-weighted cohort study of 21 297 people actively receiving OAT on March 21, 2020, in Ontario, Canada. Changes in OAT take-home dose frequency were assessed between March 22, 2020, and April 21, 2020, and individuals were observed for up to 180 days to assess outcomes (last date of follow-up, October 18, 2020). Exposures: Exposure was defined as extended take-home doses in the first month of the pandemic within each of 4 cohorts based on OAT type and baseline take-home dose frequency (daily dispensed methadone, 5-6 take-home doses of methadone, daily dispensed buprenorphine/naloxone, and 5-6 take-home doses of buprenorphine/naloxone). Main Outcomes and Measures: Primary outcomes were opioid overdose, interruption in OAT, and OAT discontinuation. Results: Among 16 862 methadone and 4435 buprenorphine/naloxone recipients, the median age ranged between 38 and 42 years, and 29.1% to 38.2% were women. Among individuals receiving daily dispensed methadone (n = 5852), initiation of take-home doses was significantly associated with lower risks of opioid overdose (6.9% vs 9.5%/person-year; weighted hazard ratio [HR], 0.73 [95% CI, 0.56-0.96]), treatment discontinuation (51.0% vs 63.6%/person-year; weighted HR, 0.80 [95% CI, 0.72-0.90]), and treatment interruption (19.0% vs 23.9%/person-year; weighted HR, 0.80 [95% CI, 0.67-0.95]) compared with no change in take-home doses. Among individuals receiving daily dispensed buprenorphine/naloxone (n = 662), there was no significant difference in any outcomes between exposure groups. Among individuals receiving weekly dispensed OAT (n = 11 010 for methadone; n = 3773 for buprenorphine/naloxone), extended take-home methadone doses were significantly associated with lower risks of OAT discontinuation (14.1% vs 19.6%/person-year; weighted HR, 0.72 [95% CI, 0.62-0.84]) and interruption in therapy (5.1% vs 7.4%/person-year; weighted HR, 0.69 [95% CI, 0.53-0.90]), and extended take-home doses of buprenorphine/naloxone were significantly associated with lower risk of interruption in therapy (9.5% vs 12.9%/person-year; weighted HR, 0.74 [95% CI, 0.56-0.99]) compared with no change in take-home doses. Other primary outcomes were not significantly different between groups. Conclusions and Relevance: In Ontario, Canada, during the COVID-19 pandemic, dispensing of increased take-home doses of opioid agonist therapy was significantly associated with lower rates of treatment interruption and discontinuation among some subsets of patients receiving opioid agonist therapy, and there were no statistically significant increases in opioid-related overdoses over 6 months of follow-up. These findings may be susceptible to residual confounding and should be interpreted cautiously.

Trends in Hospitalizations for Serious Infections Among People With Opioid Use Disorder in Ontario, Canada.

OBJECTIVES: Opioid use among people who inject drugs can lead to serious complications, including infections. We sought to study trends in rates of these complications among people with an opioid use disorder (OUD) and the sequelae of those hospitalizations. METHODS: We analyzed all inpatient hospitalizations for serious infections (infective endocarditis [IE], spinal infections, nonvertebral bone infections, and skin or soft tissue infections) among people with OUD in Ontario between 2013 and 2019. We reported the population adjusted rate of hospitalizations for serious infections annually, stratified by type of infection and prevalence of prior opioid agonist therapy and hydromorphone prescribing. We reported characteristics of hospitalizations and 30-day mortality in the most recent 2 years. RESULTS: Among people with OUD there was a 167% increase in rates of IE (7.7-20.6 per million residents; P < 0.01), a 394% increase in rates of spinal infections (3.4-16.8 per million residents; P < 0.01), a 191% increase in rates of nonvertebral bone infections (8.9 to 25.9 per million residents; P < 0.01), and a 147% increase in infections of the skin or soft tissue (32.1-79.4 per million residents; P < 0.01) over 7 years in Ontario. Death in-hospital and within 30 days of discharge was highest among those with IE (11.5% and 15.9%, respectively), and lower among those with other infections (<5%). CONCLUSIONS: Rates of serious infections among people with OUD are rising, placing a significant burden on patients. These findings suggest that early intervention and treatment of infections in this population are needed to prevent downstream harm.