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Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality. We conducted a population-based nested case-control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose-response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p = 0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias. In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.

London InterCommunity Health Centre (LIHC) launched a safer opioid supply (SOS) program in 2016, where clients are prescribed pharmaceutical opioids and provided with comprehensive health and social supports. We sought to evaluate the impact of this program on health services utilization and health care costs. We conducted an interrupted time series analysis of London, Ontario, residents who received a diagnosis of opioid use disorder (OUD) and who entered the SOS program between January 2016 and March 2019, and a comparison group of individuals matched on demographic and clinical characteristics who were not exposed to the program. Primary outcomes were emergency department (ED) visits, hospital admissions, admissions for infections and health care costs. We used autoregressive integrated moving average (ARIMA) models to evaluate the impact of SOS initiation and compared outcome rates in the year before and after cohort entry. In the time series analysis, rates of ED visits (−14 visits/100, 95% confidence interval [CI] −26 to −2; p = 0.02), hospital admissions (−5 admissions/100, 95% CI −9 to −2; p = 0.005) and health care costs not related to primary care or outpatient medications (−$922/person, 95% CI −$1577 to −$268; p = 0.008) declined significantly after entry into the SOS program (n = 82), with no significant change in rates of infections (−1.6 infections/100, 95% CI −4.0 to 0.8; p = 0.2). In the year after cohort entry, the rate of ED visits (rate ratio [RR] 0.69, 95% CI 0.53 to 0.90), hospital admissions (RR 0.46, 95% CI 0.29 to 0.74), admissions for incident infections (RR 0.51, 95% CI 0.27 to 0.96) and total health care costs not related to primary care or outpatient medications ($15 635 v. $7310/person-year; p = 0.002) declined significantly among SOS clients compared with the year before. We observed no significant change in any of the primary outcomes among unexposed individuals (n = 303). Although additional research is needed, this preliminary evidence indicates that SOS programs can play an important role in the expansion of treatment and harm-reduction options available to assist people who use drugs and who are at high risk of drug poisoning.

The majority of people with hypertension require more than one medication to achieve blood pressure control. Many patients are prescribed multipill antihypertensive regimens rather than single-pill fixed-dose combination (FDC) treatment. Although FDC use may improve medication adherence, the impact on patient outcomes is unclear. We compared clinical outcomes and medication adherence with FDC therapy versus multipill combination therapy in a real-world setting using linked clinical and administrative databases. We conducted a population-based retrospective cohort study of 13,350 individuals 66 years and older in Ontario, Canada with up to 5 years of follow-up. We included individuals who were newly initiated on one angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II-receptor blocker (ARB) plus one thiazide diuretic. High-dimensional propensity score matching was used to compare individuals receiving FDC versus multipill therapy. The primary outcome was a composite of death or hospitalization for acute myocardial infarction (AMI), heart failure, or stroke. We conducted 2 analyses to examine the association between adherence and patient outcomes. First, we performed an on-treatment analysis to determine whether outcomes differed between groups while patients were on treatment, censoring patients when they first discontinued treatment, defined as not receiving medications within 150% of the previous days' supply. Second, we conducted an intention-to-treat analysis that followed individuals allowing for breaks in treatment to quantify the difference in drug adherence between groups and assess its impact on clinical outcomes. As expected, there was no significant difference in the primary outcome between groups in the on-treatment analysis (HR 1.06, 95% CI 0.86-1.31, P = 0.60). In the intention-to-treat analysis, the proportion of total follow-up days covered with medications was significantly greater in the FDC group (70%; IQR 19-98) than in the multipill group (42%, IQR 11-91, P < 0.01), and the primary outcome was less frequent in FDC recipients (3.4 versus 3.9 events per 100 person-years; HR 0.89, 95% CI 0.81-0.97, P < 0.01). The main limitations of this study were the lack of data regarding cause of death and blood pressure measurements and the possibility of residual confounding. Among older adults initiating combination antihypertensive treatment, FDC therapy was associated with a significantly lower risk of composite clinical outcomes, which may be related to better medication adherence.

A randomized controlled trial involving a high-risk, unvaccinated population that was conducted before the Omicron variant emerged found that nirmatrelvir–ritonavir was effective in preventing progression to severe COVID-19. Our objective was to evaluate the effectiveness of nirmatrelvir–ritonavir in preventing severe COVID-19 while Omicron and its subvariants predominate. We conducted a population-based cohort study in Ontario that included all residents who were older than 17 years of age and had a positive polymerase chain reaction test for SARS-CoV-2 between Apr. 4 and Aug. 31, 2022. We compared patients treated with nirmatrelvir–ritonavir with patients who were not treated and measured the primary outcome of hospital admission from COVID-19 or all-cause death at 1–30 days, and a secondary outcome of all-cause death. We used weighted logistic regression to calculate weighted odds ratios (ORs) with confidence intervals (CIs) using inverse probability of treatment weighting (IPTW) to control for confounding. The final cohort included 177 545 patients, 8876 (5.0%) who were treated with nirmatrelvir–ritonavir and 168 669 (95.0%) who were not treated. The groups were well balanced with respect to demographic and clinical characteristics after applying stabilized IPTW. We found that the occurrence of hospital admission or death was lower in the group given nirmatrelvir–ritonavir than in those who were not (2.1% v. 3.7%; weighted OR 0.56, 95% CI 0.47–0.67). For death alone, the weighted OR was 0.49 (95% CI 0.39–0.62). Our findings were similar across strata of age, drug–drug interactions, vaccination status and comorbidities. The number needed to treat to prevent 1 case of severe COVID-19 was 62 (95% CI 43–80), which varied across strata. Nirmatrelvir–ritonavir was associated with significantly reduced odds of hospital admission and death from COVID-19, which supports use to treat patients with mild COVID-19 who are at risk for severe disease.

Long-term opioid use is an increasingly important problem related to the ongoing opioid epidemic. The purpose of this study was to identify patient, hospitalization and system-level determinants of long term opioid therapy (LTOT) among patients recently discharged from hospital. To be eligible for this study, patient needed to have filled at least one opioid prescription three-months post-discharge. We retrieved data from the provincial health insurance agency to measure medical service and prescription drug use in the year prior to and after hospitalization. A multivariable Cox Proportional Hazards model was utilized to determine factors associated with time to the first LTOT occurrence, defined as time-varying cumulative opioid duration of ≥ 60 days. Overall, 22.4% of the 1,551 study patients were classified as LTOT, who had a mean age of 66.3 years (SD = 14.3). Having no drug copay status (adjusted hazard ratio (aHR) 1.91, 95% CI: 1.40-2.60), being a LTOT user before the index hospitalization (aHR 6.05, 95% CI: 4.22-8.68) or having history of benzodiazepine use (aHR 1.43, 95% CI: 1.12-1.83) were all associated with an increased likelihood of LTOT. Cardiothoracic surgical patients had a 40% lower LTOT risk (aHR 0.55, 95% CI: 0.31-0.96) as compared to medical patients. Initial opioid dispensation of > 90 milligram morphine equivalents (MME) was also associated with higher likelihood of LTOT (aHR 2.08, 95% CI: 1.17-3.69). Several patient-level characteristics associated with an increased risk of ≥ 60 days of cumulative opioid use. The results could be used to help identify patients who are at high-risk of continuing opioids beyond guideline recommendations and inform policies to curb excessive opioid prescribing.

ABSTRACTBackgroundThe drug toxicity crisis continues to accelerate across Canada, with rapid increases in opioid-related harms following the onset of the COVID-19 pandemic. We sought to describe trends in the burden of opioid-related deaths across Canada throughout the pandemic, comparing these trends by province or territory, age, and sex. MethodsWe conducted a repeated cross-sectional analysis of accidental opioid-related deaths between Jan. 1, 2019, and Dec. 31, 2021, across 9 Canadian provinces and territories using aggregated national data. Our primary measure was the burden of premature opioid-related death, measured by potential years of life lost. Our secondary measure was the proportion of all deaths attributable to opioids; we used the Cochrane–Armitage test for trend to compare proportions. ResultsBetween 2019 and 2021, the annual number of opioid-related deaths increased from 3007 to 6222 and years of life lost increased from 126 115 to 256 336 (from 3.5 to 7.0 yr of life lost per 1000 population). In 2021, the highest number of years of life lost was among males (181 525 yr) and people aged 30–39 years (87 045 yr). In 2019, we found that 1.7% of all deaths among those younger than 85 years were related to opioids, rising to 3.2% in 2021. Significant increases in the proportion of deaths related to opioids were observed across all age groups ( p < 0.001), representing 29.3% and 29.0% of deaths among people aged 20–29 and 30–39 years in 2021, respectively. InterpretationAcross Canada, the burden of premature opioid-related deaths doubled between 2019 and 2021, representing more than one-quarter of deaths among younger adults. The disproportionate loss of life in this demographic group highlights the critical need for targeted prevention efforts.

Naloxone is a life-saving antidote for opioid overdoses. In June 2016, the Ontario government implemented the Ontario Naloxone Program for Pharmacies (ONPP) to enhance access to naloxone. We examined the initial uptake of naloxone through the ONPP and characteristics of the individuals receiving and pharmacies dispensing naloxone kits. We conducted a population-based study of all Ontario residents who received a naloxone kit between July 1, 2016 and March 31, 2018. This involved 1) a cross-sectional analysis of monthly rates of kits dispensed; and 2) a descriptive analysis of all individuals and pharmacies who accessed and dispensed naloxone, respectively. We stratified individuals according to their opioid exposure as: prescription opioid agonist therapy (OAT) recipients, prescription opioid recipients, those with past opioid exposure and those with no/unknown opioid exposure. We calculated a Lorenz curve comparing the cumulative percent of naloxone-dispensing pharmacies and cumulative percent of naloxone kits dispensed and the corresponding Gini coefficient. Naloxone dispensing through the ONPP increased considerably from 1.9 to 54.3 kits per 100,000 residents over the study period. In this time, 2,729 community pharmacies dispensed 91,069 kits to 67,910 unique individuals. Uptake was highest among prescription OAT recipients (40.7% of OAT recipients dispensed at least one kit), compared with 1.6% of prescription opioid recipients, 1.0% of those with past opioid exposure and 0.3% with no/unknown opioid exposure. Naloxone dispensing was highly clustered among pharmacies (Gini = 0.78), with 55.6% of Ontario pharmacies dispensing naloxone, and one-third (33.7%) of kits dispensed by the top 1.0% of naloxone-dispensing pharmacies. The ONPP launch led to a rapid increase in the number of naloxone kits dispensed in Ontario. Although the program successfully engaged people prescribed OAT, efforts to increase uptake among others at risk of opioid overdose appear warranted. Opportunities for expanding pharmacy participation should be identified and pursued.

Diabetes mellitus is characterized by insulin deficiency or resistance. The two main types of diabetes mellitus are type 1 (T1DM) and type 2 (T2DM). Insulin is the mainstay of therapy for T1DM and often the last-line therapy for T2DM. Biosimilar insulins are cost-saving alternatives to reference products that may improve access for patients and sustainability for healthcare systems. Despite supporting evidence from randomized controlled trials, biosimilar insulin uptake is poor, and real-world evidence of their safety and effectiveness is limited. Our objective is to compare the real-world effectiveness and safety of insulin biosimilars versus reference products in adults with diabetes mellitus. We will include observational studies and open-label pragmatic randomized controlled trials. We will exclude other randomized controlled trials, literature reviews, meta-analyses, case series, case reports, study protocols, opinion pieces, and conference abstracts. Our primary effectiveness outcome will be glycated hemoglobin (HbA1c) and our primary safety outcome will be hypoglycemia. Our secondary outcomes will include fasting plasma glucose; time in range; microvascular complications; health-related quality of life; physician visits, emergency department visits, and hospital admissions for hypoglycemia, hyperglycemia, and diabetic ketoacidosis; weight gain; immunogenicity; injection site reactions; and incident cancers. The search strategy combines three key concepts: diabetes, insulin, and biosimilars. We will conduct a structured search in MEDLINE, EMBASE, and International Pharmaceutical Abstracts. We will also search in grey literature databases, targeted websites, and the Google search engine. Finally, we will scan forward and backward citations. Articles will be screened, extracted, and appraised independently by two reviewers. Data will be descriptively summarized. Our systematic review of the real-world evidence on biosimilar insulins can help support clinical and policy decisions that impact the care of patients with T1DM or T2DM.

Accidental acetaminophen overdoses are associated with substantial morbidity and health care costs. In Canada, updated labelling standards were implemented in October 2009 and September 2016, with the intent of communicating risks of overdose and facilitating product identification and safe use, respectively. Full compliance with the 2016 standards was expected by March 2018. We sought to explore whether these changes affected rates of hospital admission for accidental acetaminophen overdose. We conducted a population-based study of hospital admissions for accidental acetaminophen overdose in 9 Canadian provinces and 3 Canadian territories between Apr. 1, 2004, and Mar. 31, 2020. We used interventional autoregressive integrated moving average (ARIMA) models to evaluate the impact of the updated labelling standards on rates of hospital admission for accidental acetaminophen overdose. In secondary analyses, we studied intensive care unit (ICU) admissions and hospital admissions for accidental acetaminophen overdose involving opioids. Monthly rates of hospital admission for accidental acetaminophen overdose were essentially unchanged over the study period (0.21 and 0.22 cases per 100 000 population in April 2004 and March 2020, respectively). We found no association between changing labelling standards and trends in rates of hospital admission for accidental acetaminophen overdose (October 2009 p = 0.2, September 2016 p = 0.7 and March 2018 p = 0.2). Similarly, labelling changes did not have an impact on admissions involving ICU admission and concomitant opioid poisoning. Modifications to product labels did not reduce the rate of acetaminophen-related harm. Additional measures to reduce the burden of accidental acetaminophen overdose are required.

The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated.