Naloxone, which reverses the effects of opioids, was synthesized in 1960, though the hunt for opioid antagonists began a half-century earlier. The history of this quest reveals how cultural and medical attitudes toward opioids have been marked by a polarization of discourse that belies a keen ambivalence. From 1915 to 1960, researchers were stymied in seeking a “pure” antidote to opioids, discovering instead numerous opioid molecules of mixed or paradoxical properties. At the same time, the quest for a dominant explanatory and therapeutic model for addiction was likewise unsettled. After naloxone’s discovery, new dichotomizing language arose in the “War on Drugs,” in increasingly divergent views between addiction medicine and palliative care, and in public debates about layperson naloxone access. Naloxone, one of the emblematic drugs of our time, highlights the ambivalence latent in public and biomedical discussions of opioids as agents of risk and relief.

Deaths due to opioid overdose have reached unprecedented levels in Canada; over 12,800 opioid-related deaths occurred between January 2016 and March 2019, and overdose death rates increased by approximately 50% from 2016 to 2018.1 In 2016, Health Canada declared the opioid epidemic a national public health crisis,2 and life expectancy increases have halted in Canada for the first time in decades.3 Children are not exempt from this crisis, and the Chief Public Health Officer of Canada has recently prioritized the prevention of problematic substance use among Canadian youth.4

Introduction: Naloxone is recommended for reversing opioid-associated respiratory depression. There is wide variability in emergency department (ED) practice patterns regarding naloxone use, dosing, and observation time post-administration. This study describes the naloxone practice patterns of ED physicians managing suspected opioid overdose patients. Methods: A retrospective chart review was conducted of adult patients (≥ 18 years) presenting to an academic tertiary care centre (consisting of two EDs with an annual census 150,000 visits) in 2017 with suspected opioid overdose who were administered naloxone in the ED. Patients were identified electronically and the following information was abstracted from patient charts: demographics, naloxone dosage and infusion initiation, disposition data, indications for naloxone administration, response to therapy, and adverse effects. Variability in initial and total dose was examined. Initial dose was also compared in those with cardiorespiratory compromise (CPR given, respiratory rate < 8, or desaturation below 89%) using independent samples median tests. Data was analyzed using standard descriptive statistics. Results: 113 patients met inclusion criteria. Indications for naloxone administration were: level of consciousness (50.5%), respiratory depression (4.0%), miosis (1.0%), a combination of factors (19.8%), or undocumented (24.8%). Median initial dose was 0.40 mg (IQR: 0.20-0.40 mg). Median total naloxone administered in the ED was 0.48 mg (IQR: 0.35-1.2 mg). The initial dose resulted in a response in 43.1% of patients, with 36.0% of responding patients later experiencing subsequent respiratory depression. 31% of patients received a naloxone infusion. Initial dose in patients with cardiopulmonary compromise was significantly different only comparing patients who received CPR versus those who did not (median 0.40 mg; IQR: 0.20-0.80 mg; P = 0.019). Four patients experienced emesis following naloxone. Median length of ED stay was 7.0 hours (IQR: 4.0-9.5 hours), and median hospital length of stay was 3.0 days (IQR: 1.0-5.0 days). Median ED observation time prior to discharge was 4.0 hours (IQR: 2.0-8.0 hours). Ultimate disposition home, to the ward, or to the intensive care unit was 47.1%, 42.2%, and 9.8% respectively (1.0% deceased). Conclusion: The dose and usage of naloxone by ED physicians in this study is variable. Further prospective studies are needed to determine the effective naloxone dosing strategy.

Introduction: Distributing take-home naloxone (THN) kits from Emergency Departments (EDs) is an important strategy for preventing opioid overdose deaths. However, there is a lack of clear operational guidance for implementing ED-based THN programs. This scoping review had two objectives: 1) identify key strategies for THN distribution in EDs, and 2) develop a theory-informed implementation model that can be used to optimize the effectiveness of ED-based THN programs. Methods: We systematically searched health science databases through April 18, 2019. The search strategy combined terms representing the ED, naloxone, and take-home kits/bystander administration. Two reviewers independently screened the search results. We included all peer-reviewed articles that described THN distribution within EDs. A standardized form was used for data extraction. Included studies were coded by two reviewers and mapped to domains of the Consolidated Framework for Implementation Research (CFIR). A third reviewer with content expertise adjudicated disagreements in record screening and data coding. Results: Database searching retrieved 717 records after duplicates were removed. 87 full-text studies were assessed for eligibility. Two studies were added through other sources, resulting in a total of 21 studies included in the final review. Of note, 14 studies evaluated existing ED-based THN programs. We synthesized themes that emerged within each CFIR domain and identified four key implementation strategies: 1) develop ED policies on opioid harm reduction; 2) collaborate with community and government partners to ensure programs meet patient needs; 3) address provider attitudes and knowledge gaps through dedicated training; and 4) establish guidelines to identify patients who are at risk of opioid overdose, and engage at-risk patients to maximize THN acceptance. Conclusion: ED-based THN programs must be tailored to local community needs and available hospital resources. Innovative implementation strategies are needed to promote ED provider engagement, and reduce barriers to patient acceptance of THN in the ED. This scoping review highlights key considerations for ED-THN implementation that can guide EDs to establish new programs, or refine existing programs to maximize their effectiveness.

There is currently no simple and morbidity-free procedure available to determine opiate dependence in patients. There is preliminary evidence, however, that the naloxone conjunctival test may be useful in this regard. This test consists of instilling a drop of saline solution of naloxone hydrochloride (an opiate-receptor antagonist) into the subject's eye. This causes significant homolateral mydriasis (anisocoria) in the eye of a chronic opioid-dependent subject and not in that of a non-dependent subject. We reviewed the international literature on the naloxone conjunctival test using the Medline database and a manual search of major scientific journals specialized in the field of substance abuse. Up to March 1995, we identified six articles dealing specifically with the use of opiate antagonist ophthalmic solutions in populations of chronic opioid addicts. Four of the articles reported the occurrence of mydriasis when a solution of naloxone is used in opioid addicts. Two of the articles reported that there was no differential change in pupil size when the naloxone solution is used; however, one study used a much weaker and the other a much stronger solution of naloxone than reported in the other studies. From our review of the literature, it appears that the naloxone conjunctival test holds great promise as a simple and morbidity-free method of testing for chronic opioid addiction and, therefore, it should be studied further and its usage eventually developed.

The influence of an adrenal medullary transplant into the lumbar subarachnoid space on learned helplessness, an animal model of depression, was examined. The transplanted rats were found to be less susceptible than sham-operated animals to become helpless after administration of inescapable shocks. The effect was attributed to release of opioid peptides by chromaffin cells as it was reversed by naloxone. The viability of the transplanted tissue was verified by electron microscopy.

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.

Background: In Alberta in 2016 more people died from an opioid overdose than from motor vehicle crashes. Naloxone is an opioid antagonist - it can reverse an opioid overdose for a period of 30 to 60 minutes. Naloxone kits are available free at emergency departments and community organizations around the province with training provided at the point of pickup. It is possible that training may be refused or may be forgotten and people are often left to rely solely on the instructions included in the kit. Human centred design can improve the way people interact with overdose instructions. Aim Statement: This study will measure the effectiveness and usefulness of prototype community naloxone kit instructions over a six month period of time (2018) in Calgary and Edmonton with the aim to use human centred design principles to improve the way people interpret emergency overdose response directions. Measures & Design: Information design experts engaged people with lived experience to provide a process map outlining the current role that educational materials and instructions for community naloxone kits play in responding to an opioid overdose. Alberta Health Services (AHS) Human Factors, in collaboration with AHS harm reduction developed the protocol and administered pre- and post-questionnaire and specific ‘performance checkpoints’ intended to measure effectiveness and usefulness. A simulated overdose including a mannequin, injection trainer and anatomical paper diagram was designed and a community naloxone kit with instructions setting was provided. Participants were recruited through harm reduction nurses with pre-existing clinical relationships (experienced group), family and friends of people who use opioids and general public (non-experienced) through the University of Alberta Faculty of Art and Design. Evaluation/Results: A total of 30 voluntary participants provided their informed consent and engaged in a simulated overdose scenario using a set of prototype instructions developed by a professional information designer. Through repeated data sampling, the following points were observed and will be integrated in the next iteration of design: It isn't clear to people what opioids are. It isn't clear to people that giving a dose of naloxone will not harm a person, especially if they have not overdosed. Almost none of the participants called 911. People seem to read pictures and text equally in the non-experienced group, but in the experienced group, typically read the pictures. Many participants stated that they knew how to do rescue breaths, but did not perform them correctly. Performing the procedure is a not the same as being asked about how to perform the procedure. Discussion/Impact: Even with new instructional prototypes, many participants identified components that were unclear or confusing. The experienced group made less mistakes than the non-experienced group. They seemed to be more invested or interested in saving a friend's life. These instructions will go through another round of design to incorporate feedback from end users. The final product will be part of a larger provincial emergency medicine initiative that includes participant led design and education around emergency response in opioid overdose settings.

Introduction: Introduction: Paramedics frequently make immediate life-altering decisions with minimal clinical information. This applies to their decision to treat an unconscious patient with naloxone when the history of an opioid overdose cannot be readily established. Among patients treated by paramedics with naloxone, our objective was to compare patient demographics, treatment interventions and clinical response between patients with and without a confirmed history of an opioid overdose. Methods: Methods: This was a retrospective cohort study design of consecutive patients treated with naloxone by paramedics between January 1, 2016, and June 30, 2017. Patients were classified based on whether paramedics did or did not document a history of an opioid overdose. Baseline characteristics, treatment interventions, and response to naloxone were compared between groups. Comparisons were done using a chi-squared or Fishers exact test. Results: Results: We identified 294 patients of whom 113 (38%) did not have a confirmed history of an opioid overdose. The groups were similar in gender, bystander CPR, and bystander administration of naloxone. There were no differences in the presence of pinpoint pupils, initial oxygen saturation, initial Glasgow Coma Score (GCS), respiratory rate, or time on scene. Both patient groups were managed similarly with respect to route of naloxone administration and the use of a bag valve mask. All patients who were intubated were in the no confirmed history group (n=5; p=.003). Post naloxone there were no differences in last recorded vital signs except the no confirmed history group was less likely to achieve a GCS 10 (57% versus 89%; p<.001). The overall post-naloxone development of agitation (9%) was moderate while the need for physical/chemical restraint (2%) was low with no differences between groups. All patients were transported to the hospital. Conclusion: Conclusion: A substantial proportion of patients who received naloxone did not have a confirmed history of an opioid overdose. These patients closely resembled those with a confirmed history with respect to demographics and physical characteristics. The primary difference was a lower proportion of patients with no confirmed history who achieved a post naloxone GCS 10. Despite a moderate development of post naloxone agitation, paramedics were able to manage most of these patients without the use of physical/chemical restraints.