Introduction: Optimizing naloxone dosing in the context of increasing fentanyl and ultra-potent opioid (UPO) prevalence is an important consideration for emergency health care providers. The goal of this systematic review was to evaluate the association between initial and cumulative naloxone doses on effective reversal and adverse events in undifferentiated and fentanyl/UPO overdoses. Methods: We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings from July to October 2018 and back to 1972. Our search included pertinent indexing terms for UPOs. We included interventional and observational studies reporting on naloxone administration for opioid toxicity reversal in people ≥12 years old. Additionally, we accessed non-traditional evidence sources (case reports and series) given this rapidly changing field. We conducted inclusion screens, data extraction and quality assessments in duplicate. We summarized study characteristics and where reported, analyzed number of patients with clinical response. Response was defined as not receiving further naloxone doses and remaining alive. Results: We included 174 studies (108 case reports and series, 55 observational, 9 interventional) with 26,660 subjects (median age 35.1; 74.2% male). We observed lower response among patients exposed to fentanyl/UPO versus heroin for initial naloxone doses ≤0.4mg (56.8% versus 80.2%) and > 0.4mg (27.0% versus 82.1%). Mean cumulative doses were higher for fentanyl/UPO (2.10 mg, SD 1.80 mg) versus heroin (1.48 mg, SD 1.68 mg) overdoses. In North American studies the median cumulative dose used was higher for fentanyl/UPO versus heroin overdoses. A dose-response curve for fentanyl/UPO studies showed marked variability in doses among responders, indicating heterogeneity. Adverse events reporting was inconsistent; 10% of subjects experienced withdrawal based on studies in which they were reported. Conclusion: This is the first systematic review to summarize proportion of patients with clinical response by naloxone dose provided. While variable reporting, study quality, heterogeneity, and our outcome definitions limit the conclusions we can draw, it appears that higher initial doses and in some cases, higher cumulative naloxone doses were used and may be necessary to reverse toxicity due to fentanyl/UPO compared to other opioids. High-quality prospective studies assessing effectiveness and safety are needed.

Introduction: Substance and opioid misuse present significant illness burdens in Emergency Departments (EDs). Understanding risk factors for mortality in these patients is urgently needed to allow targeted prevention. This studys objective was to determine whether frequent ED use is independently associated with mortality among patients with substance and opioid misuse, and secondarily, whether degree of frequent use influences mortality risk. Methods: This is a retrospective cohort study in Alberta, Canada. National Ambulatory Care Reporting System ED data was linked to Vital Statistics mortality data using postal code, birthdate, and sex. All adults (18 years old at index visit, i.e. first visit made in the study year) with substance or opioid misuse (defined by ICD-10 codes) from April 1, 2012 to March 31, 2013 were included. Frequent use was defined by 5 ED visits in the 12 months prior to index visit. The primary outcome was mortality within 90 days, and secondarily, within 30 days, 365 days, and 2 years post-index visit. Mortality was compared using Kaplan-Meier curves and Cox regression adjusting for age, sex and income. Degree was examined by subcategorizing frequent use into 5-10, 11-15, 16-20, and >20 visits. Results: Overall, 16,389 patients made 24,880 visits for substance misuse, and 1787 patients made 2241 visits for opioid misuse. Frequent vs. non-frequent substance misusers were older, more often female, lower income, more often of rural residence, and arrived more by ambulance for lower acuity visits that were hospitalized less often. Compared to frequent substance misusers, frequent opioid misusers were more often female, of non-rural residence, arrived less often by ambulance, and made higher acuity visits that were hospitalized more often. Among substance misuse patients, 97.1% (95% CI: 96.6, 97.7) of frequent users vs. 98.0% (95% CI: 97.7, 98.2) of non-frequent users were alive at 2 years. Frequent use was significantly associated with mortality at 365 days (HR 1.36 [95% CI: 1.04, 1.77]) and 2 years (HR 1.32 [95% CI: 1.04, 1.67]) but not at 90 or 30 days. Subcategorized by degree, frequent use was significantly associated with mortality only for patients with >20 visits/year at 365 days (HR 1.88 [1.03, 3.44]) and 2 years (HR 1.89 [1.10, 3.22]). Among opioid misuse patients, there was no difference in mortality between frequent and non-frequent ED users at any time point. However, subcategorized by degree, a significant association was seen for those with 16-20 visits/year at 365 days (HR 3.62 [95% CI:1.13, 11.66]), and 2 years (HR 3.37 [95% CI: 1.05, 10.81]). Conclusion: In substance misuse patients, frequent ED use was significantly associated with long-term but not short-term mortality. Mortality risk for substance and opioid misuse patients was concentrated in extremely frequent users suggesting that the highest frequency presenters should be targeted for prevention.

Introduction: Substance and opioid misuse are growing public health concerns in Canada. Substance use disorders affect 21.6% of Canadians and accounted for $267 million in healthcare costs in 2011. Opioid misuse is a current public health crisis. The extent of the rise in substance and opioid misuse-related Emergency Department (ED) visits in Canada and the demographic groups in which the rise is concentrated have not been elaborated. Alberta has one of the most complete provincial ED visit records and provides an important understanding of national trends. The objective of this study was to evaluate trends in substance and opioid misuse-related ED visits in Alberta from 2010/11 to 2014/5 within demographic cross-sections of the population using administrative ED visit data from the National Ambulatory Care Reporting System (NACRS). Methods: All visits made by adult patients (18 years old) to any of more than 100 Albertan EDs for a substance misuse-related presentation between 2010/11 and 2014/15 were analyzed. Visits were classified as being related to substance or opioid misuse if the primary and/or secondary visit diagnoses were among an a priori determined group of ICD-10 codes. Annual substance misuse-related visits were compared as visits per 100,000 adult population in Alberta to standardize for population growth. Linear regression was used to assess whether ED visits increased significantly over time. A cross-sectional time-series analysis was employed to examine trends within subgroups defined by sex and age categories (18-29, 30-39, 40-49, 50-59, and 60 years) over a 60-month period. Results: 149,719 substance misuse-related visits were made by 65,089 patients and 8768 opioid misuse-related visits were made by 5763 patients. From 2010/11 to 2014/15, substance misuse-related ED visits in Alberta increased by 38% from 811 to 1119 visits per 100,000 population. Opioid misuse-related ED visits increased significantly (64%) from 44 to 72 per 100,000 population. Conversely, total ED visits per 100,000 population did not increase significantly. Substance and opioid misuse-related visits rose more in non-rural than rural areas. Cross-sectional time-series analysis showed that the greatest increase in substance and opioid misuse-related ED visits occurred in males and in the 18-29 year age category, in which visit increases for opioid misuse appeared exponential. Conclusion: Substance and opioid misuse-related ED visits increased significantly from 2010/11 to 2014/15 in Alberta, with the most dramatic increases occurring in young patients and males. These findings have important implications for targeting urgent preventative public health interventions to stem the rise of this epidemic.