Physiologic oxygen responses to smoking opioids: an observational study using continuous pulse oximetry at overdose prevention services in British Columbia, Canada.

BACKGROUND: In British Columbia, Canada, smoking is the most common modality of drug use among people who die of opioid toxicity. We aimed to assess oxygen saturation (SpO2) while people smoked opioids during a pilot study that introduced continuous pulse oximetry at overdose prevention services (OPS) sites. METHODS: This was an observational cohort study, using a participatory design. We implemented our monitoring protocol from March to August 2021 at four OPS. We included adults (≥ 18 years) presenting to smoke opioids. A sensor taped to participants' fingers transmitted real-time SpO2 readings to a remote monitor viewed by OPS staff. Peer researchers collected baseline data and observed the timing of participants' inhalations. We analyzed SpO2 on a per-event basis. In mixed-effects logistic regression models, drop in minimum SpO2 ≤ 90% in the current minute was our main outcome variable. Inhalation in that same minute was our main predictor. We also examined inhalation in the previous minute, cumulative inhalations, inhalation rate, demographics, co-morbidities, and substance use variables. RESULTS: We recorded 599 smoking events; 72.8% (436/599) had analyzable SpO2 data. Participants' mean age was 38.6 years (SD 11.3 years) and 73.1% were male. SpO2 was highly variable within and between individuals. Drop in SpO2 ≤ 90% was not significantly associated with inhalation in that same minute (OR: 1.2 [0.8-1.78], p = 0.261) or inhalation rate (OR 0.47 [0.20-1.10], p = 0.082). There was an association of SpO2 drop with six cumulative inhalations (OR 3.38 [1.04-11.03], p = 0.043); this was not maintained ≥ 7 inhalations. Demographics, co-morbidities, and drug use variables were non-contributory. CONCLUSIONS: Continuous pulse oximetry SpO2 monitoring is a safe adjunct to monitoring people who smoke opioids at OPS. Our data reflect challenges of real-world monitoring, indicating that greater supports are needed for frontline responders at OPS. Inconsistent association between inhalations and SpO2 suggests that complex factors (e.g., inhalation depth/duration, opioid tolerance, drug use setting) contribute to hypoxemia and overdose risk while people smoke opioids.

How do we understand the value of drug checking as a component of harm reduction services? A qualitative exploration of client and provider perspectives.

BACKGROUND: Mortality related to opioid overdose in the U.S. has risen sharply in the past decade. In California, opioid overdose death rates more than tripled from 2018 to 2021, and deaths from synthetic opioids such as fentanyl increased more than seven times in those three years alone. Heightened attention to this crisis has attracted funding and programming opportunities for prevention and harm reduction interventions. Drug checking services offer people who use drugs the opportunity to test the chemical content of their own supply, but are not widely used in North America. We report on qualitative data from providers and clients of harm reduction and drug checking services, to explore how these services are used, experienced, and considered. METHODS: We conducted in-depth semi-structured key informant interviews across two samples of drug checking stakeholders: "clients" (individuals who use drugs and receive harm reduction services) and "providers" (subject matter experts and those providing clinical and harm reduction services to people who use drugs). Provider interviews were conducted via Zoom from June-November, 2022. Client interviews were conducted in person in San Francisco over a one-week period in November 2022. Data were analyzed following the tenets of thematic analysis. RESULTS: We found that the value of drug checking includes but extends well beyond overdose prevention. Participants discussed ways that drug checking can fill a regulatory vacuum, serve as a tool of informal market regulation at the community level, and empower public health surveillance systems and clinical response. We present our findings within three key themes: (1) the role of drug checking in overdose prevention; (2) benefits to the overall agency, health, and wellbeing of people who use drugs; and (3) impacts of drug checking services at the community and systems levels. CONCLUSION: This study contributes to growing evidence of the effectiveness of drug checking services in mitigating risks associated with substance use, including overdose, through enabling people who use and sell drugs to test their own supply. It further contributes to discussions around the utility of drug checking and harm reduction, in order to inform legislation and funding allocation.

Use of Intravenous Lipid Emulsion Therapy and Insulin in a Case of Tarka Intoxication.

INTRODUCTION: Tarka (trandolapril/verapamil hydrohloride extended-release) is a fixed-dose combination antihypertensive drug formed from verapamil hydrochloride and trandolapril. Toxicologic manifestations of Tarka overdose are altered mental status, bradycardia, hypotension, atrioventricular block (first-degree), hyperglycemia, metabolic acidosis, and shock. CASE PRESENTATION: We report a case of Tarka toxicity in a 2-year-old girl who presented with altered mental status, cardiogenic shock, hypotension, bradycardia, severe metabolic acidosis, hyperglycemia, and first-degree atrioventricular block. We started fluid resuscitation, epinephrine, norepinephrine, and insulin. Because of the patient's hyperlactatemia and hypotension despite standard therapies, we initiated intravenous lipid emulsion (ILE) therapy, after which her condition improved promptly. DISCUSSION: Tarka overdose may be life-threatening as it can cause cardiogenic shock. In our patient, the regression of lactate elevation in a short time with ILE therapy and the improvement of her general condition highlight the importance of ILE. CONCLUSIONS: ILE is an alternative treatment method for acute lipophilic drug intoxications, such as Tarka.

Understanding and Addressing Widening Racial Inequalities in Drug Overdose.

The fourth wave of the United States overdose crisis-driven by the polysubstance use of fentanyl with stimulants and other synthetic substances-has driven sharply escalating racial/ethnic inequalities in drug overdose death rates. Here the authors present a detailed portrait of the latest overdose trends and synthesize the literature to describe where, how, and why these inequalities are worsening. By 2022 overdose deaths among Native and Black Americans rose to 1.8 and 1.4 times the rate seen among White Americans, respectively. This reflects that Black and Native Americans have been disproportionately affected by fentanyl and the combination of fentanyl and stimulants at the national level and in virtually every state. The highest overdose deaths rates are currently seen among Black Americans 55-64 years of age as well as younger cohorts of Native Americans 25-44 years of age. In 2022-the latest year of data available-deaths among White Americans decreased relative to 2021, whereas rates among all other groups assessed continued to rise. Moving forward, Fundamental Cause Theory shows us a relevant universal truth of implementation science: in socially unequal societies, new technologies typically end up favoring more privileged groups first, thereby widening inequalities unless underlying social inequalities are addressed. Therefore, interventions designed to reduce addiction and overdose death rates that are not explicitly designed to also improve racial/ethnic inequalities will often unintentionally end up worsening them. Well-funded community-based programs, with Black and Native leadership, providing harm reduction resources, naloxone, and medications for opioid use disorder in the context of comprehensive, culturally appropriate healthcare and other services, represent the highest priority interventions to decrease inequalities.

Paracetamol overdose in Danish children and adolescents during the Covid-19 restrictions.

INTRODUCTION: To assess the effect of long-term isolation on the mental state of Danish youth. This study aimed to investigate trends in paracetamol overdoses among people under 18 years of age in Denmark during Covid-19 restrictions as an indicator of mental health. METHODS: All patients under the age of 18 years presenting with paracetamol overdose at one of the 18 paediatric departments in Denmark from 2016 to 2021 were included. They were identified in all Danish hospital databases using specific diagnostic codes. RESULTS: From 2016 to 2021, a total of 3,217 people under 18 years of age were admitted for paracetamol overdose. Among these, 86% (n = 2,755) were girls and 14% (n = 462) were boys. During 2020, a slight (7%) decrease in admissions was observed among both boys and girls compared with the preceding four-year mean value. In 2021, the number of overdoses among girls exceeded by 35% the former all-time high from 2016. Furthermore, the number of overdoses among girls exceeded the pre-four-year period mean value by 43%. Among boys, an 8% increase was seen from the highest ever previous value recorded in 2019 and a 23% increase compared with the previous four-year mean value. CONCLUSIONS: During the first year of restrictions, a slight decrease in paracetamol overdoses was observed, possibly associated with limited accessibility. The second year showed a considerable increase in paracetamol overdoses, which may imply an affected mental state among youth during the prolonged lockdown restrictions as seen in previous epidemics. Therefore, further studies are warranted to develop a pandemic preparedness plan to protect general mental health. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Ambulance Services Attendance for Mental Health and Overdose Before and During COVID-19 in Canada and the United Kingdom: Interrupted Time Series Study.

BACKGROUND: The COVID-19 pandemic impacted mental health and health care systems worldwide. OBJECTIVE: This study examined the COVID-19 pandemic's impact on ambulance attendances for mental health and overdose, comparing similar regions in the United Kingdom and Canada that implemented different public health measures. METHODS: An interrupted time series study of ambulance attendances was conducted for mental health and overdose in the United Kingdom (East Midlands region) and Canada (Hamilton and Niagara regions). Data were obtained from 182,497 ambulance attendance records for the study period of December 29, 2019, to August 1, 2020. Negative binomial regressions modeled the count of attendances per week per 100,000 population in the weeks leading up to the lockdown, the week the lockdown was initiated, and the weeks following the lockdown. Stratified analyses were conducted by sex and age. RESULTS: Ambulance attendances for mental health and overdose had very small week-over-week increases prior to lockdown (United Kingdom: incidence rate ratio [IRR] 1.002, 95% CI 1.002-1.003 for mental health). However, substantial changes were observed at the time of lockdown; while there was a statistically significant drop in the rate of overdose attendances in the study regions of both countries (United Kingdom: IRR 0.573, 95% CI 0.518-0.635 and Canada: IRR 0.743, 95% CI 0.602-0.917), the rate of mental health attendances increased in the UK region only (United Kingdom: IRR 1.125, 95% CI 1.031-1.227 and Canada: IRR 0.922, 95% CI 0.794-1.071). Different trends were observed based on sex and age categories within and between study regions. CONCLUSIONS: The observed changes in ambulance attendances for mental health and overdose at the time of lockdown differed between the UK and Canada study regions. These results may inform future pandemic planning and further research on the public health measures that may explain observed regional differences.

Perspectives of people experiencing homelessness with recent non-fatal street drug overdose on the Pharmacist and Homeless Outreach Engagement and Non-medical Independent prescribing Rx (PHOENIx) intervention.

INTRODUCTION: In Scotland, a third of all deaths of people experiencing homelessness (PExH) are street-drug-related, and less than half of their multiple physical- and mental health conditions are treated. New, holistic interventions are required to address these health inequalities. PHOENIx (Pharmacist Homeless Outreach Engagement and Non-medical Independent prescribing Rx) is delivered on outreach by National Health Service (NHS) pharmacist independent prescribers in partnership with third sector homelessness charity workers. We describe participant's perspectives of PHOENIx. METHODS: This study aims to understand experiences of the PHOENIx intervention by participants recruited into the active arm of a pilot randomised controlled trial (RCT). Semi-structured in-person interviews explored participants' evaluation of the intervention. In this study, the four components (coherence, cognitive participation, collective action, reflexive monitoring) of the Normalisation Process Theory (NPT) framework underpinned data collection and analyses. RESULTS: We identified four themes that were interpreted within the NPT framework that describe participant evaluation of the PHOENIx intervention: differentiating the intervention from usual care (coherence), embedding connection and consistency in practice (cognitive participation), implementation of practical and emotional operational work (collective action), and lack of power and a commitment to long-term support (reflexive monitoring). Participants successfully engaged with the intervention. Facilitators for participant motivation included the relationship-based work created by the PHOENIx team. This included operational work to fulfil both the practical and emotional needs of participants. Barriers included concern regarding power imbalances within the sector, a lack of long-term support and the impact of the intervention concluding. CONCLUSIONS: Findings identify and describe participants' evaluations of the PHOENIx intervention. NPT is a theoretical framework facilitating understanding of experiences, highlighting both facilitators and barriers to sustained engagement and investment. Our findings inform future developments regarding a subsequent definitive RCT of PHOENIx, despite challenges brought about by challenging micro and macro-economic and political landscapes.

How Ohio public library systems respond to opioid-related substance use: a descriptive analysis of survey results.

BACKGROUND: Public libraries in the United States have experienced increases in opioid-related substance use in their communities and on their premises. This includes fatal and non-fatal overdose events. Some libraries have adopted response measures in their branches to deter substance use or prevent overdose. A small number of libraries around the nation have decided to stock the opioid antagonist naloxone (Narcan) for staff to administer to patrons who experience overdose. This response measure has generated extensive media attention. Although Ohio ranks fourth in age-adjusted drug mortality rate in the United States, there has been no investigation of whether Ohio libraries are observing opioid-related transactions, consumption, and/or overdose events, or which measures they have adopted in response to these activities. We conducted a multimethod survey with Ohio public library directors to identify the response measures they have adopted. We present descriptive findings from the quantitative and qualitative items in our survey. METHODS: We conducted a cross-sectional 54-item multimethod survey of public library system directors (one per system) in Ohio. Directors of each of Ohio's public library systems were invited to participate via email. RESULTS: Of 251 library systems, 56 responded (22.3% response rate), with 34 respondents (60.7%) indicating awareness of opioid-related transactions, consumption, and/or overdose on their premises. Most (n = 43, 76.8%) did not stock naloxone in their buildings. Over half (n = 34, 60.7%) reported implementing one or more non-naloxone response measures. These measures focus on improving security for staff and patrons, deterring opioid-related transactions (purchases and exchanges) and consumption, and providing educational events on substance use. Nearly half (n = 25, 47.2%) partner with community organizations to provide opioid response measures. A similar proportion reported adequate funding to respond to opioid-related substance use (n = 23, 45.1%), and most (n = 38, 74.5%) reported adequate support from their boards and communities. Few respondents have implemented evaluations of their response measures. CONCLUSIONS: Ohio public libraries are responding to evidence of opioid-related transactions, consumption, and/or overdose on their premises with a range of measures that focus on substance use prevention and deterrence. Most Ohio library systems do not stock naloxone. Respondents indicated they prefer to call 911 and let first responders handle overdose events. The majority of respondents indicated their library systems have political capacity to respond to evidence of opioid-related substance use on their premises, but have limited operational and functional capacity. Findings suggest the need to revisit assumptions that public libraries are willing to stock naloxone to respond to overdose events, and that libraries have the resources to respond robustly to opioid-related transactions, consumption, and/or overdose on their premises.

Brexpiprazole toxicity in a paediatric patient.

Brexpiprazole is a relatively new drug that has no published research or applications within the paediatric population. Brexpiprazole targets multiple receptors and can manifest as multisystem symptoms when ingested in supratherapeutic quantities. In this report, we discuss the case of a child in early childhood who presented with delayed neurological and cardiac symptoms 24 hours after accidental ingestion of brexpiprazole. Due to delayed onset, this case highlights that a high index of suspicion and prolonged observation are necessary to appropriately manage brexpiprazole overdose or accidental ingestion.

Vaccines as Immunotherapies for Substance Use Disorders.

Substance use disorders (SUD) present a worldwide challenge with few effective therapies except for the relative efficacy of opioid pharmacotherapies, despite limited treatment access. However, the proliferation of illicit fentanyl use initiated a dramatic and cascading epidemic of lethal overdoses. This rise in fentanyl overdoses regenerated an interest in vaccine immunotherapy, which, despite an optimistic start in animal models over the past 50 years, yielded disappointing results in human clinical trials of vaccines against nicotine, stimulants (cocaine and methamphetamine), and opioids. After a brief review of clinical and selected preclinical vaccine studies, the "lessons learned" from the previous vaccine clinical trials are summarized, and then the newest challenge of a vaccine against fentanyl and its analogs is explored. Animal studies have made significant advances in vaccine technology for SUD treatment over the past 50 years, and the resulting anti-fentanyl vaccines show remarkable promise for ending this epidemic of fentanyl deaths.

Clinical and healthcare use outcomes after cessation of long term opioid treatment due to prescriber workforce exit: quasi-experimental difference-in-differences study.

OBJECTIVE: To examine the association between prescriber workforce exit, long term opioid treatment discontinuation, and clinical outcomes. DESIGN: Quasi-experimental difference-in-differences study SETTING: 20% sample of US Medicare beneficiaries, 2011-18. PARTICIPANTS: People receiving long term opioid treatment whose prescriber stopped providing office based patient care or exited the workforce, as in the case of retirement or death (n=48 079), and people whose prescriber did not exit the workforce (n=48 079). MAIN OUTCOMES: Discontinuation from long term opioid treatment, drug overdose, mental health crises, admissions to hospital or emergency department visits, and death. Long term opioid treatment was defined as at least 60 days of opioids per quarter for four consecutive quarters, attributed to the plurality opioid prescriber. A difference-in-differences analysis was used to compare individuals who received long term opioid treatment and who had a prescriber leave the workforce to propensity-matched patients on long term opioid treatment who did not lose a prescriber, before and after prescriber exit. RESULTS: Discontinuation of long term opioid treatment increased from 132 to 229 per 10 000 patients who had prescriber exit from the quarter before to the quarter after exit, compared with 97 to 100 for patients who had a continuation of prescriber (adjusted difference 1.22 percentage points, 95% confidence interval 1.02 to 1.42). In the first quarter after provider exit, when discontinuation rates were highest, a transient but significant elevation was noted between the two groups of patients in suicide attempts (adjusted difference 0.05 percentage points (95% confidence interval 0.01 to 0.09)), opioid or alcohol withdrawal (0.14 (0.01 to 0.27)), and admissions to hospital or emergency department visits (0.04 visits (0.01 to 0.06)). These differences receded after one to two quarters. No significant change in rates of overdose was noted. Across all four quarters after prescriber exit, an increase was reported in the rate of mental health crises (0.39 percentage points (95% confidence interval 0.08 to 0.69)) and opioid or alcohol withdrawal (0.31 (0.014 to 0.58)), but no change was seen for drug overdose (-0.12 (-0.41 to 0.18)). CONCLUSIONS: The loss of a prescriber was associated with increased occurrences of discontinuation of long term opioid treatment and transient increases in adverse outcomes, such as suicide attempts, but not other outcomes, such as overdoses. Long term opioid treatment discontinuation may be associated with a temporary period of adverse health impacts after accounting for unobserved confounding.

Public stigma against fentanyl overdose decedents in the United States: A conjoint vignette experiment.

The United States is facing a drug overdose crisis, and stigma against people who use drugs is a major roadblock to implementing solutions. Despite the public health importance of understanding and mitigating substance use stigma, prior research has focused mainly on perceptions of individuals with substance use disorders and a limited set of demographic traits. This leaves critical gaps in our understanding of stigma against fentanyl overdose decedents, who represent a much broader group, including people who use substances recreationally. This study develops a more robust understanding of these attitudes through an experimental vignette survey fielded to a national sample of American adults (n = 1432). Respondents were shown two fictional fentanyl overdose obituaries where a complex suite of decedent characteristics-including demographic traits and contexts of substance use-were randomly varied in a conjoint design. Respondents then endorsed one of the two decedents for each of several attitudinal outcomes, including blameworthiness and support for various interventions, and justified their choices in an open-ended format. Results indicate that the public assesses victims of fentanyl overdose meritocratically, making judgments based on personal history and life experience rather than traditional race, class, and gender status beliefs. While certainly a signal of progress on some fronts, this meritocratic lens conflicts with the public health model of addressing the overdose crisis and exposes the alarming persistence of explicit stigma against people who use drugs.

"Fighting demons": Stigma and shifting norms in explicit mention of overdose in obituaries, 2010-2019.

Obituaries are often the only published record of an individual's life and elicit community reactions, including stigmatization. Because obituaries are typically written by the bereaved, their content reflects the writer's perceptions of mores governing the social context of the next-of-kin and decedent. When a cause of death is stigmatized, it can influence the way the bereaved write the obituary. However, what constitutes a stigmatized cause of death may change as larger societal discourses of morality shift and conditions or events become framed differently. Using a sample of obituaries (N = 210) from obituary aggregator Legacy.com of "off-time," or premature, deaths in West Virginia from 2010, 2015, 2017, and 2019, this article explores whether the presentation of overdose deaths in obituaries changes alongside the shift in the public framing of the opioid crisis as medical rather than criminal. I find obituaries including terms associated with drug use and overdose become both more common and explicit over the course of the study period. This suggests that the shift in public framing of the opioid crisis from criminalization to medicalization corresponds with a decrease in drug stigmatization in obituaries. Obituary analysis can be a useful means of exploring the stigmatization of other controversial causes of death, such as suicide, cirrhosis, and lung cancer.

The impact of the COVID-19 pandemic on people who use drugs in three Canadian cities: a cross-sectional analysis.

BACKGROUND: The COVID-19 pandemic had a disproportionate impact on the health and wellbeing of people who use drugs (PWUD) in Canada. However less is known about jurisdictional commonalities and differences in COVID-19 exposure and impacts of pandemic-related restrictions on competing health and social risks among PWUD living in large urban centres. METHODS: Between May 2020 and March 2021, leveraging infrastructure from ongoing cohorts of PWUD, we surveyed 1,025 participants from Vancouver (n = 640), Toronto (n = 158), and Montreal (n = 227), Canada to describe the impacts of pandemic-related restrictions on basic, health, and harm reduction needs. RESULTS: Among participants, awareness of COVID-19 protective measures was high; however, between 10 and 24% of participants in each city-specific sample reported being unable to self-isolate. Overall, 3-19% of participants reported experiencing homelessness after the onset of the pandemic, while 20-41% reported that they went hungry more often than usual. Furthermore, 8-33% of participants reported experiencing an overdose during the pandemic, though most indicated no change in overdose frequency compared the pre-pandemic period. Most participants receiving opioid agonist therapy in the past six months reported treatment continuity during the pandemic (87-93%), however, 32% and 22% of participants in Toronto and Montreal reported missing doses due to service disruptions. There were some reports of difficulty accessing supervised consumption sites in all three sites, and drug checking services in Vancouver. CONCLUSION: Findings suggest PWUD in Canada experienced difficulties meeting essential needs and accessing some harm reduction services during the COVID-19 pandemic. These findings can inform preparedness planning for future public health emergencies.

Excess Fatal Overdoses in the United States During the COVID-19 Pandemic by Geography and Substance Type: March 2020-August 2021.

Objectives. To assess heterogeneity in pandemic-period excess fatal overdoses in the United States, by location (state, county) and substance type. Methods. We used seasonal autoregressive integrated moving average (SARIMA) models to estimate counterfactual death counts in the scenario that no pandemic had occurred. Such estimates were subtracted from actual death counts to assess the magnitude of pandemic-period excess mortality between March 2020 and August 2021. Results. Nationwide, we estimated 25 668 (95% prediction interval [PI] = 2811, 48 524) excess overdose deaths. Specifically, 17 of 47 states and 197 of 592 counties analyzed had statistically significant excess overdose-related mortality. West Virginia, Louisiana, Tennessee, Kentucky, and New Mexico had the highest rates (20-37 per 100 000). Nationally, there were 5.7 (95% PI = 1.0, 10.4), 3.1 (95% PI = 2.1, 4.2), and 1.4 (95% PI = 0.5, 2.4) excess deaths per 100 000 involving synthetic opioids, psychostimulants, and alcohol, respectively. Conclusions. The steep increase in overdose-related mortality affected primarily the southern and western United States. We identified synthetic opioids and psychostimulants as the main contributors. Public Health Implications. Characterizing overdose-related excess mortality across locations and substance types is critical for optimal allocation of public health resources. (Am J Public Health. 2024;114(6):599-609. https://doi.org/10.2105/AJPH.2024.307618).

Efficacy of human prothrombin complex concentrate in the treatment of warfarin overdose in patients receiving warfarin for mechanical heart valve replacement.

Warfarin, a widely utilized anticoagulant, is paramount for preventing thromboembolic events in patients with mechanical heart valve replacements. However, its narrow therapeutic index can lead to over-anticoagulation and overdose, resulting in serious health risks. This study examines the efficacy of human prothrombin complex concentrate (PCC) in managing warfarin overdose, in comparison with traditional treatments. A retrospective analysis was conducted on 162 adults who presented with warfarin overdose (INR > 5.0) at a tertiary care hospital between 2016 and 2020. Participants were divided into 2 groups-those treated with PCC (n = 57) and those treated with conventional methods (n = 105), including vitamin K and fresh frozen plasma. The primary outcome was the rate of reaching the target (International Normalized Ratio) INR within 24 hours. Secondary outcomes included transfusion requirements, thromboembolic events, adverse reactions, 30-day mortality, and length of hospital stay. PCC demonstrated significant efficacy, with 89.5% of patients achieving the target INR within 24 hours, compared to 64.8% in the control group (P < .05). The PCC group also had reduced transfusion requirements and a shorter average hospital stay. There was no significant difference in thromboembolic events or adverse reactions between the 2 groups, and the reduced 30-day mortality in the PCC group was not statistically significant. Human prothrombin complex concentrate is associated with rapid reaching the target INR, decreased transfusion needs, and shortened hospitalization, making it a promising option for warfarin overdose management. While the results are encouraging, larger, multicenter, randomized controlled trials are necessary to further validate these findings and optimize PCC administration protocols.

High-dose naloxone formulations are not as essential as we thought.

Naloxone is an effective FDA-approved opioid antagonist for reversing opioid overdoses. Naloxone is available to the public and can be administered through intramuscular (IM), intravenous (IV), and intranasal spray (IN) routes. Our literature review investigates the adequacy of two doses of standard IM or IN naloxone in reversing fentanyl overdoses compared to newer high-dose naloxone formulations. Moreover, our initiative incorporates the experiences of people who use drugs, enabling a more practical and contextually-grounded analysis. The evidence indicates that the vast majority of fentanyl overdoses can be successfully reversed using two standard IM or IN dosages. Exceptions include cases of carfentanil overdose, which necessitates ≥ 3 doses for reversal. Multiple studies documented the risk of precipitated withdrawal using ≥ 2 doses of naloxone, notably including the possibility of recurring overdose symptoms after resuscitation, contingent upon the half-life of the specific opioid involved. We recommend distributing multiple doses of standard IM or IN naloxone to bystanders and educating individuals on the adequacy of two doses in reversing fentanyl overdoses. Individuals should continue administration until the recipient is revived, ensuring appropriate intervals between each dose along with rescue breaths, and calling emergency medical services if the individual is unresponsive after two doses. We do not recommend high-dose naloxone formulations as a substitute for four doses of IM or IN naloxone due to the higher cost, risk of precipitated withdrawal, and limited evidence compared to standard doses. Future research must take into consideration lived and living experience, scientific evidence, conflicts of interest, and the bodily autonomy of people who use drugs.