Prevention of Opioid Overdose

This review explains harm-reduction strategies for three groups of patients: those who have not received previous opioid therapy, those receiving long-term opioid therapy, and those with an opioid use disorder. It explains both risk assessment and the current approach to the use of medications for opioid use disorder

Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4

Background: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liverspecific organic anion-transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. Methods: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n = 51 523) or azithromycin (n = 52 518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and allcause mortality. All outcomes were assessed within 30 days after co-prescription. Results: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. Interpretation: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes

Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study

Objective To compare the risk of acute myocardial infarction, heart failure, and death in patients with type 2 diabetes treated with rosiglitazone and pioglitazone

The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis

Objective To examine the safety of using aliskiren combined with agents used to block the renin-angiotensin system

Multiplying the serum aminotransferase by the acetaminophen concentration to predict toxicity following overdose The APAP × AT multiplication product

Context. The first available predictors of hepatic injury following acetaminophen (APAP) overdose are the serum APAP and aminotransferases [AT, i.e., aspartate (AST) aminotransferase or alanine (ALT) aminotransferase]. Objective. We describe the initial value, rate of change, and interrelationship between these biomarkers in patients who develop hepatotoxicity despite treatment following acute overdose. A new parameter, the APAP × AT multiplication product, is proposed for early risk stratification. Methods. We conducted a descriptive study of individuals selected from a multicenter retrospective cohort of patients hospitalized for APAP poisoning. We selected those acute APAP overdose patients who subsequently developed AT >1,000 IU/L. Rising serum AT values were compared to simultaneously measured (or estimated) falling serum APAP. The APAP × AT was expressed relative to initiation of acetylcysteine therapy and grouped by time to meeting hepatotoxicity criteria. Results. In the 94 cases studied, serum APAP concentrations were still appreciable Because serum AT rose rapidly (doubling time 9.5 h ) and APAP fell slowly (half-life 4.8 h), the multiplication product remained elevated during the first 12-24 h of antidotal therapy, especially among patients who developed earlier hepatotoxicity (AT > 1,000 IU/L). Discussion and conclusions. The APAP × AT multiplication product, calculated at the time of presentation and after several h of antidotal therapy, holds promise as a new risk predictor following APAP overdose. It requires neither graphical interpretation nor accurate time of ingestion, two limitations to current risk stratification

Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study

Objective To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen’s effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6)

Characteristics of Opioid-Related Deaths in Ontario, Canada: Leveraging the Drug and Drug/Alcohol Related Death (DDARD) Database

Introduction Review of post-mortem toxicological results is the gold standard for identifying whether a death is opioid-related. The Drug and Drug/Alcohol Related Death (DDARD) database contains abstracted information from the Office of the Chief Coroner of Ontario, for all opioid-related deaths that occurred in Ontario, Canada between 1991 and 2016. Objectives and Approach The DDARD, which contains manner of death and drug concentrations from post-mortem toxicology results for opioids-related deaths in Ontario, was linked to the data repository housed at ICES. The objective of this project was to examine demographic characteristics and the type of opioid contributing to opioid-related deaths in FY2015/16. Individuals identified within DDARD who died from an opioid-related cause were linked to demographic, hospitalization and prescription drug databases to report on age, gender, neighbourhood income quintile, past health services utilization for opioid-toxicity, alcohol use disorders (AUD), mental health emergency department (ED) visits, and opioid(s) present at time of death. Results We identified 737 opioid-related deaths in FY2015/16, the majority of which involved men (n=497; 67.4%), those living in lower socioeconomic status areas (n=395; 53.6%), and those residing in urban regions (n=655; 88.9%). Nearly half (n=325; 44.1%) of opioid-related deaths occurred among those aged 45 to 65 years. We found 9.5% (n=70) of individuals had a previous hospital visit for opioid toxicity, 25.4% (n=187) had previously diagnosed AUD, and 42.5% (n=313) had a previous mental health ED visit. Overall, 250 (33.9%) individuals had an active opioid prescription at time of death with oxycodone (n=92; 36.8%) the most commonly dispensed. Among those who didn’t have an active opioid prescription at time of death (n=484; 66%), fentanyl (n=184; 37.8%) was the most commonly found opioid on post-mortem toxicology. Conclusion/Implications This project demonstrates how data obtained through chart abstractions can be used to enhance existing administrative health datasets. Given the concern around the safety of opioids, it is important to examine the characteristics and type of opioid(s) involved at time of opioid-related death in order to develop targeted preventative strategies

Hospitalization for Hemorrhage Among Warfarin Recipients Prescribed Amiodarone

Amiodarone inhibits the hepatic metabolism of warfarin, potentiating its anticoagulant effect. However, the clinical consequences of this are not well established. Our objective in this study was to characterize the risk of hospitalization for a hemorrhage associated with the initiation of amiodarone within a cohort of continuous warfarin users in Ontario. We conducted a population-based retrospective cohort study among Ontario residents aged ≥66 years receiving warfarin. Among patients with at least 6 months of continuous warfarin therapy, we identified those who were newly prescribed amiodarone and an equal number who were not, matching on age, gender, year of cohort entry, and a high-dimensional propensity score. The primary outcome was hospitalization for hemorrhage within 30 days of amiodarone initiation. Between July 1, 1994, and March 31, 2009, we identified 60,497 patients with at least 6 months of continuous warfarin therapy, of whom 11,665 (19%) commenced amiodarone. For 7,124 (61%) of these, we identified a matched control subject who did not receive amiodarone. Overall, 56 (0.8%) amiodarone recipients and 23 (0.3%) control patients were hospitalized for hemorrhage within 30 days of initiating amiodarone (adjusted hazard ratio 2.45; 95% confidence interval, 1.49–4.02). Seven of 56 (12.5%) patients hospitalized for a hemorrhage after starting amiodarone died in hospital. In conclusion, initiation of amiodarone among older patients receiving warfarin is associated with a more than twofold increase in the risk of hospitalization for hemorrhage, with a relatively high fatality rate. Physicians should closely monitor patients who initiate amiodarone while receiving warfarin