Defining opioid naïve and implications for monitoring opioid use: A population-based study in Alberta, Canada.

PURPOSE: Reducing initial exposure of "opioid naïve" patients to opioids is a public health priority. Identifying opioid naïve patients is difficult, as numerous definitions are used. The objective is to summarize current definitions and evaluate their impact on opioid naïve measures in Alberta. METHODS: An exploratory data analysis of the literature was conducted over the last 10 years to identify definitions commonly used in the literature to define opioid naïve. Then, using these definitions as a guide, we descriptively report the proportion of patients in Alberta between 2017 and 2021 who would be considered as opioid naïve using these definitions and all opioid dispensing data. RESULTS: Three categories of definitions were broadly identified: (1) no opioid use within the previous 30 days/6 months/1 year, based on dispensation date; (2) no opioid use based on dispensation date plus days of supply; and, (3) exclusion of codeine from Definitions 1 and 2. Applying these definitions to the Alberta population showed a very wide range in the proportion who would be considered as opioid naïve. Overall, 36.4% of Albertans (n = 1 551 075) had an opioid dispensation in 2017-2021. The average age was 46.6 ± 18.8 and 52.8% were female. The proportion of opioid naïve were most affected by the "opioid free" period, with 97.4%, 83.2%, and 65.6% being classified as opioid naïve using time windows from Definition 1 (30 days, 6 months, 1 year of no prior opioid use). Definitions 2 and 3 did not materially change the results. Further extending the "opioid free" period to 2 years showed only 35% were opioid naïve. CONCLUSIONS: The most convenient definition for "opioid naïve" was the use of an "opioid free" period. The choice of window would depend on how the information may be used to assistant in clinical decisions with longer windows more likely to reflect true opioid naïve patients. Irrespective of definition used, a large proportion of opioid users would be considered opioid naïve in Alberta.

Adding pharmacists to primary care teams increases guideline-concordant antiplatelet use in patients with type 2 diabetes: results from a randomized trial.

BACKGROUND: Antiplatelet therapy is recommended as part of a strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. However, compliance with these guideline-recommended therapies appears to be less than ideal. OBJECTIVE: To assess the effect of adding pharmacists to primary care teams on initiation of guideline-concordant antiplatelet therapy in type 2 diabetic patients. METHODS: Prespecified secondary analysis of randomized trial data. In the main study, the pharmacist intervention included a complete medication history, limited physical examination, provision of guideline-concordant recommendations to the physician to optimize drug therapy, and 1-year follow-up. Controls received usual care without pharmacist interactions. Patients with an indication for antiplatelet therapy, but not using an antiplatelet drug at randomization were included in this substudy. The primary outcome was the proportion of patients using an antiplatelet drug at 1 year. RESULTS: At randomization, 257 of 260 study patients had guideline-concordant indications for antiplatelet therapy, but less than half (121; 47%) were using an antiplatelet drug. Overall, 136 patients met inclusion criteria for the substudy (71 intervention and 65 controls): 60% were women, with mean (SD) age 58.0 (11.9) years, diabetes duration 5.3 (6.0) years, and hemoglobin A(1c) 7.6% (1.5). Sixteen (12%) had established cardiovascular disease at enrollment. At 1 year, 43 (61%) intervention patients and 15 (23%) controls were using an antiplatelet drug (38% absolute difference; number needed to treat, 3; relative increase, 2.6; 95% CI 1.5-4.7; p < 0.001). Of these 58 patients, 52 (90%) were using aspirin 81 mg daily. CONCLUSIONS: Adding pharmacists to primary care teams significantly and substantially increased the proportion of type 2 diabetic patients using guideline-concordant antiplatelet therapy.

Cross-sectional study of rapid tapering of opioid prescriptions following medical regulatory intervention in Alberta from 2013 to 2020.

OBJECTIVE: To determine if inappropriate tapering/discontinuation of opioids to Alberta patients occurred from mid-2013-2020, as unintended consequences of prescribing guidelines, regulations and policies in response to the North American opioid crisis. DESIGN: A population-based, repeated cross-sectional time-series study. SETTING: Alberta, Canada. PARTICIPANTS: Residents of Alberta, Canada aged 18 and older who received an opioid dispense from a community pharmacy from 2013 to 2020. MAIN OUTCOME MEASURES: The prevalence of potential rapid tapering was measured at a given date (reference day), enveloped by a data window. Dose changes were measured as oral morphine equivalents (OME) per patient, at multiple time points ('data window' around a reference day). Chronic recipients were identified, and their prescriptions were contrasted 90 days before and after the reference day to measure OME/day changes. RESULTS: Approximately 9000 dispenses (totalling ~6 million OME) per day were analysed from 2013 to 2020. The total number of opioid recipients was highly cyclic in nature (peaking in winter). The number of chronic opioid recipients remained somewhat stable from ~70K in 2013 to ~86K at the end of 2020. The number of chronic high and very high dose recipients presented a significant decrease after 2017. Approximately 11%-12% of chronic high-dose recipients experienced potential rapid dose tapering at a rate of 50% or more prereference to postreference day at any given point of time. For chronic very high dose recipients, approximately 11.5% experience potential rapid dose tapering at a rate of 50% or more prereference to postreference day at any given point of time. Potential discontinuation remained constant and the interventions did not have a significant impact on the trend. CONCLUSION: The evidence suggests that changes in prescribing guidelines were not associated with an increase of rapid opioid tapering/discontinuation in Alberta.

Development and Validation of a Machine Learning Model to Estimate Risk of Adverse Outcomes Within 30 Days of Opioid Dispensation.

Importance: Machine learning approaches can assist opioid stewardship by identifying high-risk opioid prescribing for potential interventions. Objective: To develop a machine learning model for deployment that can estimate the risk of adverse outcomes within 30 days of an opioid dispensation as a potential component of prescription drug monitoring programs using access to real-world data. Design, Setting, and Participants: This prognostic study used population-level administrative health data to construct a machine learning model. This study took place in Alberta, Canada (from January 1, 2018, to December 31, 2019), and included all patients 18 years and older who received at least 1 opioid dispensation from a community pharmacy within the province. Exposures: Each opioid dispensation served as the unit of analysis. Main Outcomes and Measures: Opioid-related adverse outcomes were identified from administrative data sets. An XGBoost model was developed on 2018 data to estimate the risk of hospitalization, an emergency department visit, or mortality within 30 days of an opioid dispensation; validation on 2019 data was done to evaluate model performance. Model discrimination, calibration, and other relevant metrics are reported using daily and weekly predictions on both ranked predictions and predicted probability thresholds using all data from 2019. Results: A total of 853 324 participants represented 6 181 025 opioid dispensations, with 145 016 outcome events reported (2.3%); 46.4% of the participants were men and 53.6% were women, with a mean (SD) age of 49.1 (15.6) years for men and 51.0 (18.0) years for women. Of the outcome events, 77 326 (2.6% pretest probability) occurred within 30 days of a dispensation in the validation set (XGBoost C statistic, 0.82 [95% CI, 0.81-0.82]). The top 0.1 percentile of estimated risk had a positive likelihood ratio (LR) of 28.7, which translated to a posttest probability of 43.1%. In our simulations, the weekly measured predictions had higher positive LRs in both the highest-risk dispensations and percentiles of estimated risk compared with predictions measured daily. Net benefit analysis showed that using machine learning prediction may not add additional benefit over the entire range of probability thresholds. Conclusions and Relevance: These findings suggest that prescription drug monitoring programs can use machine learning classifiers to identify patients at risk of opioid-related adverse outcomes and intervene on high-risk ranked predictions. Better access to available administrative and clinical data could improve the prediction performance of machine learning classifiers and thus expand opioid stewardship efforts.

Pharmacokinetics of Efavirenz 600 mg Once Daily During Pregnancy and Post Partum in Ghanaian Women Living With HIV.

PURPOSE: The updated World Health Organization guidelines recommend efavirenz (EFV) 400 mg as the preferred alternate first-line antiretroviral therapy to dolutegravir, with EFV 600 mg recommended only in special situations. We examined the pharmacokinetic (PK) properties of EFV 600 mg/d during pregnancy and post partum to inform EFV dosing decisions in pregnant women. METHODS: Ghanaian pregnant women with HIV infection initiating tenofovir disoproxil fumarate 300 mg/lamivudine 300 mg/EFV 600 mg fixed-dose combination tablet once daily were enrolled. Efavirenz concentrations were measured at 4 weeks of antiretroviral therapy initiation during pregnancy and 6 weeks post partum using validated LC-MS/MS assays. Efavirenz PK parameters were calculated using noncompartmental analysis, and within-group parameters between the 2 periods were compared. FINDINGS: Of 25 enrolled women, 19 completed PK sampling during pregnancy and post partum. The Cmax, Cmin, AUC0-24h, and CL/F for EFV during pregnancy were similar to values at 6 weeks post partum. The pregnancy/postpartum geometric mean ratios for EFV Cmax, Cmin, AUC0-24, and CL/F were 1.10 (95% CI, 0.93-1.31), 0.88 (95% CI, 0.67-1.17), 0.84 (95% CI, 0.71-0.98), and 1.20 (95% CI, 1.02-1.40), respectively. Viral load suppression (HIV RNA <200 copies/mL) was achieved in 16 of 17 participants (94%) by the time of delivery. There was 1 maternal-to-child transmission. IMPLICATIONS: We found that the PK parameters of EFV 600 mg once daily during pregnancy were similar to those in the postpartum period. Our findings suggest that EFV dose adjustment during pregnancy is not necessary in our study population.

Characterisation of concurrent use of prescription opioids and benzodiazepine/Z-drugs in Alberta, Canada: a population-based study.

OBJECTIVE: The objective of this study is to characterise concurrent use of benzodiazepine receptor modulators and opioids among prescription opioid users in Alberta in 2017. DESIGN: A population based retrospective study. SETTING: Alberta, Canada, in the year 2017. PARTICIPANTS: All individuals in Alberta, Canada, with at least one dispensation record from a community pharmacy for an opioid in the year 2017. EXPOSURE: Concurrent use of a benzodiazepine receptor modulator and opioid, defined as overlap of supply for both drugs for at least 1 day. MAIN OUTCOME MEASURES: Prevalence of concurrency was estimated among subgroups of patient characteristics that were considered clinically relevant or associated with inappropriate medication use. RESULTS: Among the 547 709 Albertans who were dispensed opioid prescriptions in 2017, 132 156 (24%) also received prescriptions for benzodiazepine receptor modulators. There were 96 581 (17.6%) prescription opioid users who concurrently used benzodiazepine receptor modulators with an average of 98 days (SD=114, 95% CI 97 to 99) of total cumulative concurrency and a median of 37 days (IQR 10 to 171). The average longest duration of consecutive days of concurrency was 45 (SD=60, 95% CI 44.6 to 45.4) with a median of 24 days (IQR 8 to 59). Concurrency was more prevalent in females, patients using an average daily oral morphine equivalent >90 mg, opioid dependence therapy patients, chronic opioid users, patients utilising a high number of unique providers, lower median household incomes and those older than 65 (p value<0.001 for all comparisons). CONCLUSIONS: Concurrent prescribing of opioids and benzodiazepine receptor modulators is common in Alberta despite the ongoing guidance of many clinical resources. Older patients, those taking higher doses of opioids, and for longer durations may be at particular risk of adverse outcomes and may be worthy of closer follow-up for assessment for dose tapering or discontinuations. As well, those with higher healthcare utilisation (seeking multiple providers) should also be closely monitored. Continued surveillance of concurrent use of these medications is warranted to ensure that safe drug use recommendations are being followed by health providers.

Benzodiazepine receptor agonist dispensations in Alberta: a population-based descriptive study.

BACKGROUND: There is increasing concern over the use of benzodiazepine receptor agonists (BZRAs). The objective of this study was to describe BZRA dispensations in the province of Alberta in 2015 according to age, sex and appropriateness. METHODS: A population-based descriptive study of people 10 years of age or older with at least 1 BZRA dispensation in Alberta, Canada, between Jan. 1 and Dec. 31, 2015, was conducted. Prevalence of BZRA use, characteristics of BZRAs dispensations, use at the individual level and appropriateness were determined. RESULTS: A total of 372 870 people received 2 463 585 BZRA dispensations in Alberta in 2015. Prevalence of use at the population level was 10% overall, increased with age (p value for trend < 0.001) and was consistently highest among females. Twenty percent of patients used both Z-drugs and benzodiazepines. BZRA users had an average of 7 dispensations (standard deviation [SD] 20), 137 days of use overall (SD 123) and a maximum period of consecutive use of 90 days (SD 95). Days of consecutive use were highest among those aged 65 years or older (126 d). A total of 62 795 (17%) people used more than 1 distinct BZRA ingredient concurrently and 10% had 3 or more distinct prescribers. INTERPRETATION: The prevalence of BZRA use was high and a substantial proportion of use appeared to be potentially inappropriate. This study supports the need for continued monitoring for the prescribing and use of these medications at the population level.