Impact of changes in opioid funding and clinical policies on rapid tapering of opioids in Ontario, Canada.

ABSTRACT: Reports have emerged of abrupt tapering among recipients of long-term prescription opioids to conform new prescribing guidelines. We conducted a population-based, repeated cross-sectional time-series study among very high-dose (≥200 MME) opioid recipients in Ontario, Canada, to examine changes in the monthly prevalence of rapid tapering from 2014 to 2018, defined as recipients experiencing either a ≥50% reduction in daily doses or abrupt discontinuation sustained for 30 days. Interventional autoregressive integrated moving average models were used to test for significant changes following key guidelines and drug policies and programs. A sensitivity analysis examined rapid tapering sustained for 90 days. The monthly prevalence of rapid tapering events was stable from January 2014 to September 2016 (average monthly prevalence: 1.4%) but increased from 1.4% in October 2016 to 1.8% in April 2017 (P = 0.001), coincident with Ontario's Fentanyl Patch-for-Patch Return Program implementation. Transient spikes in the prevalence of rapid tapering also occurred 2 months after Ontario's delisting of publicly funded high-strength opioids and the release of updated Canadian Opioid Prescribing Guideline for Chronic Pain, reaching 2.3% in March 2017 and July 2017, respectively. However, this prevalence decreased to 1.2% in December 2018 (P < 0.0001). Although the prevalence of abrupt opioid discontinuation was lower, similar trends were observed. Our sensitivity analysis examining long-lasting rapid tapering found similar trends but lower prevalence, with no changes in complete discontinuation. These temporary increases in rapid tapering events highlight the need for improved communication and evidence-based resources for prescribers to minimize negative consequences of evolving policies and guidelines.

Adverse event rates associated with oral anticoagulant treatment early versus later after hospital discharge in older adults: a retrospective population-based cohort study.

BACKGROUND: Oral anticoagulants are commonly used high-risk medications, but little is known about their safety in transition from hospital to home. Our objective was to measure the rates of hemorrhage and thromboembolic events among older adults receiving oral anticoagulant treatment early after hospital discharge compared to later. METHODS: We conducted a retrospective population-based cohort study among Ontario residents aged 66 years or more who started, continued or resumed oral anticoagulant therapy at hospital discharge between September 2010 and March 2015. We calculated the rates of hemorrhage and thromboembolic events requiring hospital admission or an emergency department visit over a 1-year follow-up period, stratified by the first 30 days after discharge and the remainder of the year. We used multivariable regression models, adjusting for covariates, to estimate the effect of sex, prevalent versus incident use, and switching anticoagulants on events. RESULTS: A total of 123 139 patients (68 408 women [55.6%]; mean age 78.2 yr) were included. About one-quarter (32 563 [26.4%]) had a Charlson Comorbidity Index score of 2 or higher. The rates of hemorrhage and thromboembolic events per 100 person-years were highest during the first 30 days after hospital discharge (25.8, 95% CI 24.8-26.8 and 19.3, 95% CI 18.4-20.2, respectively), falling to 15.7 (95% CI 15.3-16.1) and 6.9 (95% CI 6.6-7.1), respectively, during the subsequent 11 months. Multivariable analysis showed that patients whose anticoagulant was switched in hospital and men had more hemorrhages and thromboembolic events in follow-up. INTERPRETATION: The first few weeks following hospital discharge represent a very high-risk period for adverse events related to oral anticoagulant treatment among older adults. The results support an intervention trial addressing anticoagulation management in the early postdischarge period.

Oxycodone, Hydromorphone, and the Risk of Suicide: A Retrospective Population-Based Case-Control Study.

INTRODUCTION: Opioids have been increasingly associated with suicide, but whether they are independent contributors is unclear. Oxycodone and hydromorphone are commonly prescribed high-potency opioids that can differentially affect mood. OBJECTIVE: The objective of this study was to explore whether oxycodone and hydromorphone are differentially associated with suicide. METHODS: We conducted a retrospective population-based case-control study in Ontario, Canada, from 1992 to 2014. Using coronial data, we defined case subjects as individuals who died by suicide involving an opioid overdose. Each of these was matched with up to four controls who died of accidental opioid overdose. We ascertained exposure to oxycodone, hydromorphone, and other opioids from postmortem toxicology testing. We used odds ratios and 95% confidence intervals to examine whether opioid-related suicide was disproportionately associated with oxycodone relative to hydromorphone. RESULTS: We identified 438 suicides and 1212 accidental deaths, each of which involved either oxycodone or hydromorphone but not both. The median age at death was 49 years and 51% were men. After adjusting for a history of self-harm, psychiatric illness, and exposure to other opioids, we found that oxycodone was more strongly associated with suicide than hydromorphone (adjusted odds ratio 1.59; 95% confidence interval 1.20-2.11). In a secondary analysis, we observed a trend of similar magnitude in which combined exposure to oxycodone and hydromorphone was more strongly associated with suicide than hydromorphone alone (adjusted odds ratio 1.68; 95% confidence interval 0.92-3.09). CONCLUSIONS: While preliminary, these findings support the possibility that some high-potency opioids might independently influence the risk of suicide in susceptible individuals.

Association Between Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, and Suicide.

Importance: The renin-angiotensin system has been implicated in mood disorders. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the most commonly used medications, yet their effects on mental health outcomes, particularly suicide, are poorly understood. This study examined the association between suicide and exposure to ACEIs and ARBs. Because of differences in their mode of action, it was speculated that ARBs would be associated with a higher risk of suicide than ACEIs. Objective: To examine the association between suicide and exposure to ARBs compared with ACEIs. Design, Setting, and Participants: This population-based nested case-control study of individuals aged 66 years and older used administrative claims databases in Ontario, Canada, from January 1, 1995, to December 31, 2015. Data analysis was performed from January to April 2019. Cases were individuals who died by suicide within 100 days of receiving an ACEI or ARB. The date of death served as the index date. For each case, 4 controls were identified and matched by age (within 1 year), sex, and presence of hypertension and diabetes. All individuals received an ACEI or ARB within 100 days before the index date. Exposures: Use of an ACEI or ARB. Main Outcomes and Measures: Conditional logistic regression was used to estimate odds ratios for the association between suicide and exposure to ARBs compared with ACEIs. Results: Nine hundred sixty-four cases were matched to 3856 controls. The median (interquartile range) age of cases and controls was 76 (70-82) years. Most cases (768 [79.7%]) and controls (3068 [79.6%]) were men. Among cases, 260 (26.0%) were exposed to ARBs, and 704 (18.4%) were exposed to ACEIs. Among controls, 741 (74.0%) were exposed to ARBs, and 3115 (81.6%) were exposed to ACEIs. Compared with ACEI exposure, ARB exposure was associated with higher risk of death by suicide (adjusted odds ratio, 1.63; 95% CI, 1.33-2.00). The findings were consistent in a sensitivity analysis excluding individuals with a history of self-harm (odds ratio, 1.60; 95% CI, 1.29-1.98). Conclusions and Relevance: The use of ARBs may be associated with an increased risk of suicide compared with ACEIs. Preferential use of ACEIs over ARBs should be considered whenever possible, particularly in patients with severe mental health illness.

Evaluation of the fentanyl patch-for-patch program in Ontario, Canada.

BACKGROUND: Rising use of prescription opioids is a major public health concern associated with increased risk of mortality worldwide. Fentanyl, a synthetic opioid available in patch form, is particularly concerning given its high potency. To curb the misuse and diversion of fentanyl patches, a Patch-for-Patch (P4P) program was implemented in some counties in Ontario between 2012 and 2015. The program requires that patients prescribed fentanyl must return used patches to the pharmacy before receiving more patches. OBJECTIVE: To evaluate the impact of the P4P program on fentanyl and non-fentanyl dispensing and opioid-related hospitalizations and deaths. METHODS: We conducted a repeated cross-sectional time-series analysis among counties that implemented the P4P program using Ontario administrative claims data. Because intervention dates varied by county due to staggered program initiation, we aligned all intervention months and examined outcome rates in the 5 years preceding and 12 and 24 months following implementation. We explored the monthly rate of prescriptions dispensed for fentanyl and non-fentanyl opioids, opioid toxicity-related hospital and emergency department visits, and opioid-related deaths. We modeled each outcome using an interventional autoregressive integrated moving average (ARIMA) model and tested the impact of the P4P program using a ramp function. RESULTS: We analyzed 16 counties that implemented the P4P program and had at least 12 months of follow-up. The introduction of the P4P program was associated with a 30.5% decline in the volume of fentanyl patches dispensed at 24 months (from 1,277-888 patches per 10,000 population; p = 0.04). In contrast, there was no significant change in the rate of non-fentanyl opioid dispensing (p = 0.32), opioid toxicity related hospitalizations and emergency department visits (p = 0.4) or opioid-related deaths (p = 0.96) in the 12 months following implementation of the program. CONCLUSIONS: We found that the implementation of a P4P program in select counties in Ontario was associated with a lower volume of fentanyl patches dispensed by pharmacies, without an increase in use of other opioids. The program had no measurable impact on rates of opioid toxicity-related hospital visits or deaths. Policymakers should consider the use of P4P programs as part of larger opioid strategy.

Impact of timing of methadone initiation on perinatal outcomes following delivery among pregnant women on methadone maintenance therapy in Ontario.

BACKGROUND AND AIMS: Methadone maintenance therapy (MMT) is associated with improved outcomes for children exposed to maternal opioid dependence in utero. We examined Ontario's population of pregnant women on MMT and determined the impact of timing of MMT initiation on perinatal outcomes. DESIGN: Cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Women eligible for public drug benefits and on MMT during pregnancy between 2005 and 2015. MEASUREMENTS: We stratified women based on their timing of MMT initiation: (1) stabilized prior to conception, (2) newly initiated prior to conception, (3) initiation in trimester 1, (4) initiation in trimester 2 or (5) initiation in trimester 3. The primary outcomes in the multivariable logistic regression analysis were key perinatal health indicators: small for gestational age, preterm birth, congenital anomalies, severe maternal morbidity, caesarean section and induced labor. Secondary outcomes were specific to maternal opioid dependence: neonatal abstinence syndrome (NAS), admission to a neonatal intensive care unit (NICU), NAS treatment, removal from mother's custody at hospital discharge and neonatal death. FINDINGS: Among 1842 women on MMT during pregnancy, 87.6% (n = 1614) initiated MMT before conception. Almost a quarter of their infants (22.2%; n = 408) were born small for gestational age, 17.5% (n = 323) were preterm and 5.9% (n = 109) were born with a congenital anomaly. The odds of primary outcomes occurring did not differ based on timing of methadone initiation; however, infants of mothers who initiated methadone during pregnancy had up to a fourfold increase in the odds of social services removal at the hospital [adjusted odds ratio (aOR) range = 3.70-4.19] compared with those whose mothers were stabilized on MMT prior to conception. CONCLUSIONS: Later initiation of methadone maintenance therapy among pregnant women in Ontario, Canada has not been found to be clearly related to most key perinatal adverse health outcomes.

Catastrophic drug coverage: utilization insights from the Ontario Trillium Drug Program.

BACKGROUND: Catastrophic drug coverage programs help those with high drug-costs to reduce the burden of out-of-pocket expenses. We set out to measure changes in utilization, spending and demographic profiles of people accessing Ontario's catastrophic drug program, the Trillium Drug Program. METHODS: We conducted a cross-sectional time-series analysis examining quarterly utilization and spending trends among medications reimbursed by the Trillium Drug Program in Ontario, Canada from Jan. 1, 2000, to Dec. 31, 2016. In each of 2000, 2005, 2010 and 2015, we described the population of beneficiaries, including demographic information, health care utilization and medication utilization. RESULTS: Over our study period, use of the Trillium Drug Program increased threefold from 3.6 beneficiaries per 1000 to 10.9 beneficiaries per 1000 Ontarians, and total government spending on the program increased by over 700%, reaching $487 million in 2016. Between 2000 and 2015, there was an increase in the number of beneficiaries who were under the age of 35 years (19.6% to 25.3%; p < 0.0001), did not have a hospital admission (68.3% to 80.5%; p < 0.0001) and had medium to high deductibles (2.3% to 8.0%; p < 0.0001). Further, there was a large increase in the percentage of users with drug claims greater than $1000 (3.4% to 10.4%; p < 0.0001) and those dispensed a high-cost biologic drug (1.6% to 5.5%; p < 0.0001). INTERPRETATION: Increasing use of Ontario's catastrophic drug program highlights the growing burden of high drug prices for Canadians. With a growing number of expensive drugs being approved in Canada, we anticipate that spending and use of the catastrophic drug program will continue to expand.

Survival rates of biological therapies for psoriasis treatment in real-world clinical practice: A Canadian multicentre retrospective study.

BACKGROUND/OBJECTIVES: Data on biologic drug survival in real-world psoriasis treatment are limited. There is a need to evaluate long-term trends of biologic use outside the realm of clinical trials. METHODS: A multicentre chart review was conducted with patients' data from September 2005 to September 2014. Kaplan-Meier plot analysis was used to determine 5-year drug survival rates. A log-rank test was used to compare the rates of drug survival between the studied biologics. RESULTS: For the 398 patients and 545 treatment series analysed, 1, 2, 3, 4 and 5-year survival rates were 0.826, 0.687, 0.563, 0.475 and 0.420 with etanercept; 0.804, 0.648, 0.553, 0.508 and 0.508 with adalimumab; 0.838, 0.664, 0.554, 0.485 and 0.382 with infliximab; and 0.914, 0.856, 0.800, 0.755 and 0.755 with ustekinumab, respectively. A statistically significant difference was seen between ustekinumab and the other three biologics. CONCLUSION: A progressive decrease in treatment adherence was seen with all four biologics, as expected, but the survival rate of ustekinumab was highest.

Changes in the dispensing of opioid medications in Canada following the introduction of a tamper-deterrent formulation of long-acting oxycodone: a time series analysis.

BACKGROUND: In February 2012, a reformulated tamper-deterrent form of long-acting oxycodone, OxyNeo, was introduced in Canada. We investigated the impact of the introduction of OxyNeo on patterns of opioid prescribing. METHODS: We conducted population-based, cross-sectional analyses of opioid dispensing in Canada between 2008 and 2016. We estimated monthly community pharmacy dispensing of oral formulations of codeine, morphine, hydromorphone and oxycodone, and a transdermal formulation of fentanyl, and converted quantities to milligrams of morphine equivalents (MMEs) per 1000 population. We used time series analysis to evaluate the effect of the introduction of OxyNeo on these trends. RESULTS: National dispensing of long-acting opioids fell by 14.9% between February 2012 and April 2016, from 36 098 MMEs to 30 716 MMEs per 1000 population (p < 0.01). This effect varied across Canada and was largest in Ontario (reduction of 22.8%) (p = 0.01) and British Columbia (reduction of 30.0%) (p = 0.01). The national rate of oxycodone dispensing fell by 46.4% after the introduction of OxyNeo (p < 0.001); this was partially offset by an increase of 47.8% in hydromorphone dispensing (p < 0.001). Although dispensing of immediate-release opioids was a substantial contributor to overall population opioid exposure across Canada, it was unaffected by the introduction of OxyNeo (p > 0.05 in all provinces). INTERPRETATION: The findings suggest that the introduction of a tamper-deterrent formulation of long-acting oxycodone in Canada, against a background of changing public drug benefits, was associated with sustained changes in selection of long-acting opioids but only small changes in the quantity of long-acting opioids dispensed. This illustrates the limited effect a tamper-deterrent formulation and associated coverage policy can have when other, non-tamper-deterrent alternatives are readily available.

Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study.

BACKGROUND: Safety profiles of biologics for treatment of psoriasis are limited to data from randomized controlled trials. There is a need for comparative safety reports of biologics based on data from clinical practice. OBJECTIVE: We sought to estimate and compare the incidence of adverse events (AEs) leading to withdrawal of biologics (etanercept, infliximab, adalimumab, and ustekinumab) in the treatment of psoriasis. METHODS: We conducted a multicenter retrospective chart review from September 2005 to September 2014. Incidence proportion and rate of AEs leading to withdrawal by biologic agent and AE were calculated. RESULTS: For 545 treatments administered in 398 patients, 22 (4.04%) AEs were associated with withdrawal, for a rate of 1.97/100 patient-years (95% confidence interval [CI] 1.32-2.94). Common AEs were injection-/infusion-site reactions (0.55%, 0.92%, 0%, and 0% for etanercept, infliximab, adalimumab, and ustekinumab, respectively); infections (0%, 0.18%, 0.55%, 0.18%); and malignancies (0.18%, 0.18%, 0%, 0.37%). LIMITATIONS: Possible incompleteness of chart details and small study population limit the conclusiveness of findings. CONCLUSION: Biologic agents for treatment of psoriasis are safe; AEs associated with withdrawal occurred in 4% of all administered biologic therapies. It does not appear that real-world patients encounter more AEs with biologics than patients in clinical trials.

Tabaquismo, Glutation S-Transferasa, N-Acetiltransferasa 2 y riesgo de cáncer de vejiga / Tabaquism, S-Transferase Glutation, N-Acetiltrasferase 2 and bladder cancer risk

El hábito tabáquico es el factor de riesgo más conocido para cáncer de vejiga. Ciertas arilaminas presentes en el cigarrillo han sido identificadas como carcinógenos para la vejiga en humanos. El objetivo de nuestro estudio es establecer el riesgo de padecer de cáncer de vejiga en individuos fumadores, acetiladores lentos para NAT2 y genotipos nulos de GSTM1 y GSTT1. Materiales y métodos: Se reunieron en total 150 pacientes, 75 pertenecientes al grupo de carcinoma urotelial de vejiga y 75 del grupo control, en este último no se incluyeron pacientes con enfermedad neoplásica de ninguna índole. El ADN se aisló de la muestra de sangre a partir de linfocitos utilizando un kit disponible comercialmente (QIAmp DNA Blood Mini and Maxi Kit, QIAGen GMBH). Mediante el uso de técnicas de reacción en cadena de polimerasa y de restricción/ fragmentación se determinaron los polimorfismos de las enzimas: NAT2, GSTT1 y GSTM1.Resultados: Se incluyeron un total de 150 pacientes, de los cuales 75 pertenecían al grupo controly 75 al grupo de cáncer de vejiga, la media de edad del grupo de cáncer de vejiga fue 60,5 +/-11,4 y del grupo control fue 51,3 +/- 11,4. En cuanto al género en grupo de cáncer de vejiga 64 por ciento pertenecían al sexo masculino. En el grupo control 41 por ciento pertenecían al sexo masculino. Al estudiar el hábito tabáquico se halló que 51 por ciento de los pacientes del grupo de cáncer de vejiga continuaban siendo fumadores, mientras que sólo 21 por ciento fumaba en el grupo control. En el análisis de los genotipos de la enzima NAT2 en el grupo de los pacientes con cáncer de vejiga 52 por ciento resultaron acetiladores lentos, y 4 por ciento acetiladores rápidos. En el grupo control 45 por ciento de los pacientes eran acetiladores lentos y 12 por ciento acetiladores rápidos. En cuanto a la determinación de GSTT1 19 por ciento de los pacientes del grupo de cáncer de vejiga y 24 por ciento del grupo control exhibieron el genotipo nulo...

Introduction: Smoking is the most studied risk factor for bladder cancer. Certain arilamines present in cigarettes have been identified as carcinogenic for the bladder in humans. The purpose of this study is to establish the risk of bladder cancer in smokers, slow acetilators for NAT2 and none active genotypes for GSTM1 and GSTT1. Material and methods: 150 patients were studied, 75 in the group of urothelial carcinoma of the bladder and 75 in the control group. The DNA was isolated from lymphocytes of blood samples using commercially available kit (QIAmp DNA Blood Mini and Maxi Kit, QIAG en GMBH). Enzyme polymorphisms of NAT2, GSTT1 and GSTM1 were determined using techniques of polymerase chain reaction and restriction/fragmentation. Results: 150 patients were included, of who 75 belonged to the control group and 75 had bladder cancer, the average of age of the bladder cancer group was 60.5 +/- 11.4 and of the control group 51.3 +/- 11.4. Regarding gender, in the bladder cancer group 64 percent were males. In the control group 41percent were males. 51 percent of the patients in the bladder cancer group continued being smokers, whereas only 21 percent smoked in control group. In NAT2 enzyme genotype analysis the bladder cancer group 52 percent were slow acetilators, and 4 percent fast acetilators. In the control group 45 percent were slow acetilators and 12 percent fast acetilators. Regarding GSTT1 determination, 19 percent of the bladder cancer group and 24 percent of the control group showed the non-active genotype. GSTM1 showed its non-active form in 44 percent of the bladder cancer group and 48 percent of the control group. Discussion: Bladder cancer is clearly related with smoking habit. We observed a very significant relationship when evaluating smoking habit, slow acetilators for NAT2, and none-active genotypes of GSTM1 and bladder cancer...