Opioid Overdose Research Articles

Implementation Documentation and Process Assessment of the PharmNet Intervention: Observational Report.

The number of overdose deaths in the United States involving opioids continues to exceed 100,000 per year. This has precipitated ongoing declarations of a public health emergency. Harm reduction approaches, such as promoting awareness of, ensuring access to, and fostering willingness to use naloxone to reverse opioid overdose, are a key component of a larger national strategy to address the crisis. In addition, overdose reversal with naloxone directly and immediately saves lives. Because of pharmacies' ubiquity and pharmacists' extensive clinical training, community pharmacies are well-positioned, in principle, to facilitate naloxone access and education. In 2022, a single-site pilot study of PharmNet, a community pharmacy intervention incorporating naloxone distribution, awareness building, and referral, showed promising outcomes for both naloxone and resource distribution in the community. As a next step, this study was intended to be a pilot randomized controlled trial of PharmNet in 7 pharmacies. However, due to circumstances outside of the study team's control, data collection was unable to be fully completed as planned. In keeping with open research standards, we transparently report all available data from the study and discuss trial barriers and processes. We do so both to provide insights that may inform similar studies and to avoid the "file-drawer" (publication bias) problem, which can skew the aggregated scholarly literature through nonpublication of registered trial results or selective publication of findings affirming authors' hypotheses. This paper reports an in-depth implementation study assessment, provides the available observational data, and discusses implementation considerations for similar studies in independent (eg, nonchain) community pharmacies. Retrospective assessment of study outcomes and fidelity data provided for robust discussion around how resource differences in independent community pharmacies (vs well-resourced chain pharmacies), as well as high demands on staff, can affect intervention implementation, even when leadership is highly supportive. Community pharmacies, particularly independent community pharmacies, may require more support than anticipated to be successful when implementing a new intervention into practice, even if it might affect estimates of real-world effectiveness. Further implementation science research is needed specific to independent community pharmacies. All study elements are outlined in the International Registered Report Identifier (IRRID) PRR1-10.2196/42373. Although this paper reports results associated with that registration, results and conclusions should not be given the weight assigned to findings from a preregistered study. RR2-10.2196/42373.

Association Between Self-Reported Opioid Use and Behavioral/Social Health Characteristics—Arizona, 2020

Abstract Background Arizona observed a sharp increase in opioid overdose deaths between 2017 and 2021. Our objective was to better understand the relationship between behavioral/ social characteristics and self-reported opioid misuse among Arizona adults. Methods A cross-sectional study design was done using data from the Arizona 2020 Behavioral Risk Factor Surveillance System (BRFSS) (N = 10,291). Confidence intervals and p-values were found using chi-square for respondents with and without a self-reported opioid misuse. Logistic regression models were developed for the association between adverse childhood experiences (ACEs), mental health, and risk-taking behaviors (RTBs) and opioid misuse. Results Respondents who reported 2–3 ACEs (ORadjusted: 4.7; 95% CI: [2.8, 7.9]) and who reported 4 or more ACEs (ORadjusted: 8.3; 95% CI: [5.0, 13.6]); respondents who reported poor mental health (ORadjusted: 3.3; 95% CI: [2.1, 5.2]); and respondents who reported two or more RTBs (ORadjusted: 3.9; 95% CI: [2.5, 6.1]) had higher odds of self-reported opioid misuse compared to those without self-reported opioid misuse. Discussion Opioid misuse was found to be associated with poor mental and physical health, increased RTBs, and history of at least two ACEs among Arizona adults in this study. These findings stress the importance of opportunities for targeted prevention in both Arizona adults and youth, including screening for ACEs and RTBs, in early stages of life.

The Salience of Social Context, Opioid Antagonist Use, and Prior Opioid Exposure as Determinants of Fatal and Non-fatal Opioid Overdoses

The Salience of Social Context, Opioid Antagonist Use, and Prior Opioid Exposure as Determinants of Fatal and Non-fatal Opioid Overdoses

Nalmefene study: A faster alternative to naloxone

In the first head‐to‐head study of nalmefene nasal spray (OPVEE is the trade name) vs. naloxone to reverse opioid overdose conducted in volunteers, researchers found that nalmefene worked faster than a 4 milligram (mg) dose of naloxone. It worked much faster, in fact, 2.7 mgs of OPVEE reversed respiratory depression within five minutes, compared to 20 minutes for 4 mgs of naloxone. The study, “Reversal of Opioid‐Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone,” was published March 11 in the Journal of Clinical Pharmacology. The opioid that was given to the volunteers was remifentanil, a synthetic opioid.

RREACT: A mobile multidisciplinary response to overdose.

Opioid overdose is a leading cause of death in the United States, and engaging with patients following overdose to provide harm reduction and recovery resources can prove difficult. Quick response models use mobile, multidisciplinary teams to establish a time-sensitive connection between individuals who overdosed and harm reduction and recovery resources that improve outcomes. These quick response models are consistent with the broader field of mobile-integrated health programs that are growing in number and acceptability, though the literature base is sparse and programs vary. We describe the 5-year reach, effectiveness, adoption, implementation and maintenance (RE-AIM) framework of the Rapid Response Emergency Addiction and Crisis Team (RREACT), a fire/emergency medical services-led, multidisciplinary (firefighter/paramedic, law enforcement officer, social worker) mobile outreach team. RREACT provides harm reduction, linkage/transportation to care and wrap-around services to individuals following a nonfatal opioid overdose that resulted in an emergency response in Columbus, Franklin County, Ohio, United States. Between 2018 and 2022, RREACT made 22,157 outreach attempts to 11,739 unique patients. RREACT recorded 3,194 direct patient contacts during this time, resulting in 1,200 linkages to care: 799 direct transports to opioid use disorder treatment and 401 warm handoffs to community treatment agencies. Furthermore, RREACT's staffing increased from 4 full-time equivalent staff in 2018 to 15.5 in 2022 and was supported by the surrounding community through 287 community outreach events and the development of an alumni program. These preliminary results further support the deployment of multidisciplinary mobile outreach teams to increase access to harm reduction and recovery resources following opioid overdose.

Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.

Naloxone is a World Health Organization (WHO)-listed essential medicine and is the first choice for treating the respiratory depression of opioids, also by lay-people witnessing an opioid overdose. Naloxone acts by competitive displacement of opioid agonists at the μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics of the opioid agonist, such as dissociation rate from the MOR receptor and constitution of the victim. Aim of treatment is a balancing act between restoration of respiration (not consciousness) and avoidance of withdrawal, achieved by titration to response after initial doses of 0.4-2 mg. Naloxone is rapidly eliminated [half-life (t1/2) 60-120 min] due to high clearance. Metabolites are inactive. Major routes for administration are intravenous, intramuscular, and intranasal, the latter primarily for take-home naloxone. Nasal bioavailability is about 50%. Nasal uptake [mean time to maximum concentration (Tmax) 15-30 min] is likely slower than intramuscular, as reversal of respiration lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual and between-study variability in pharmacokinetics in volunteers are large. Variability in the target population is unknown. The duration of action of 1 mg intravenous (IV) is 2 h, possibly longer by intramuscular and intranasal administration. Initial parenteral doses of 0.4-0.8 mg are usually sufficient to restore breathing after heroin overdose. Fentanyl overdoses likely require higher doses of naloxone. Controlled clinical trials are feasible in opioid overdose but are absent in cohorts with synthetic opioids. Modeling studies provide valuable insight in pharmacotherapy but cannot replace clinical trials. Laypeople should always have access to at least two dose kits for their interim intervention.

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP.

Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects. Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO2) challenged with 0.1 mg/kg SC fentanyl and 15min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone. While both NLX and NLMF rapidly reversed %SaO2 to baseline within 1min, rats that received cNLX-NP did not return to >90% SaO2 levels until 9min after administration. Similarly, heart and breath rates returned to baseline within 1min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute. While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.

Varying circumstances surrounding opioid toxicity deaths across ethno-racial groups in Ontario, Canada: a population-based descriptive cross-sectional study

IntroductionThe North American toxic drug crisis has been framed as an epidemic primarily affecting white people. However, evidence suggests that deaths are rising among racialised people. Accordingly, we sought to...

Effects of the Communities that Heal (CTH) intervention on perceived opioid-related community stigma in the HEALing Communities Study: results of a multi-site, community-level, cluster-randomized trial

Community stigma against people with opioid use disorder (OUD) and intervention stigma (e.g., toward naloxone) exacerbate the opioid overdose crisis. We examined the effects of the Communities that HEAL (CTH) intervention on perceived opioid-related community stigma by stakeholders in the HEALing Communities Study (HCS). We collected three surveys from community coalition members in 66 communities across four states participating in HCS. Communities were randomized into Intervention (Wave 1) or Wait-list Control (Wave 2) arms. We conducted multilevel linear mixed models to compare changes in primary outcomes of community stigma toward people treated for OUD, naloxone, and medication for opioid use disorder (MOUD) by arm from time 1 (before the start of the intervention) to time 3 (end of the intervention period in the Intervention arm). Intervention stakeholders reported a larger decrease in perceived community stigma toward people treated for OUD (adjusted mean change (AMC)-3.20 [95% C.I.-4.43,-1.98]) and toward MOUD (AMC-0.33 [95% C.I.-0.56,-0.09]) than stakeholders in Wait-list Control communities (AMC-0.18 [95% C.I.-1.38, 1.02], p=0.0007 and AMC 0.11 [95% C.I.-0.09, 0.31], p=0.0066). The relationship between intervention status and change in stigma toward MOUD was moderated by rural-urban status (urban AMC-0.59 [95% CI,-0.87,-0.32], rural AMC not sig.) and state. The difference in stigma toward naloxone between Intervention and Wait-list Control stakeholders was not statistically significant (p=0.18). The CTH intervention decreased stakeholder perceptions of community stigma toward people treated for OUD and stigma toward MOUD. Implementing the CTH intervention in other communities could decrease OUD stigma across diverse settings nationally. US National Institute on Drug Abuse.

Peer Recovery Specialists and Referrals to Treatment: Clinical Correlates Among Patients of an Opioid Overdose Recovery Program in New Jersey.

Peer recovery programs increase recovery support and treatment engagement among individuals with opioid use disorder. Peer recovery specialists (PRS) are critical in the cascade of care of treating addiction and related conditions. Work remains to help identify the benefits of PRS, particularly time spent with a PRS as a clinical indicator associated with referral to substance use treatment services. Gaps in the literature do not consider the nested hierarchical intercorrelations of opioid recovery data within multiple emergency departments. The current study examined demographic and clinical correlates with referral to substance use treatment services including prior engagement within an opioid overdose recovery program, mental health diagnosis, the number of naloxone administrations, prior overdoses, and hospital-level variability of PRS time associated with treatment referrals. This study used data collected by providers among patients who engaged in an opioid overdose recovery program. Data were collected between January 2016 and September 2020. Generalized linear mixed effect multilevel regression analyses tested the associations on clinical referral to substance use services. A total of 5655 patients participated in the study (male: 68.91%; age: mean = 37.75 ± 12.43; White non-Hispanic: 62.48%). Significant individual-level associations were identified between demographic and clinical variables and referral to substance use treatment services. At the hospital level, recovery specialist time spent with the patient also showed a positive and significant association with referral to substance use treatment services. The cross-level interaction effect displayed that any period of time spent with PRS played an important role for those patients with a greater number of prior overdoses on referral to treatment. Results provide important information on the role of PRS in the cascade of care, as well as the time spent with those in this role for both individuals with varying number of prior overdoses.

Architecture and Development Framework for a Web-Based Risk Assessment and Management Platform Developed on WordPress to Address Opioid Overdose.

The number of overdose-related fatalities continues to reach historic levels across Canada, despite ongoing efforts by authorities. To reduce mortality, a clinical trajectory ranging from preventative measures to crisis intervention, skill training to treatment, and risk assessment to risk management needs to be supported. The web-based Risk Assessment and Management Platform (RAMP) was developed to realize this concept and to empower people who use drugs through an integrated tool that allows them to better understand and manage their risk of overdose. This paper outlines the architecture and development of RAMP, which is built on the WordPress platform. WordPress components are mapped onto a 3-tier architecture that consists of presentation, application, and database layers. The architecture facilitates the development of a modular software that includes several features that are independent in functionality but interact with each other in an integrated platform. The relatively low coupling and high coherence of the features may reduce the cost of maintenance and increase flexibility of future developments. RAMP's architecture comprises a user interface, conceptual framework, and backend layers. The RAMP front end effectively uses some of the WordPress' features such as HTML5, CSS, and JavaScript to create a mobile, friendly, and scalable user interface. The RAMP backend uses several standard and custom WordPress plug-ins to support risk assessment and monitoring, with the goal of mitigating the impacts and eliminating risks together. A rule-based decision support system has been hard-coded to suggest relevant modules and goals to complement each user's lifestyle and goals based on their risk assessment. Finally, the backend uses the MySQL database management system and communicates with the RAMP framework layer via the data access layer to facilitate a timely and secure handling of information. Overall, RAMP is a modular system developed to identify and manage the risk of opioid overdose in the population of people who use drugs. Its modular design uses the WordPress architecture to efficiently communicate between layers and provide a base for external plug-ins. There is potential for the current system to adopt and address other related fields such as suicide, anxiety, and trauma. Broader implementation will support this concept and lead to the next level of functionality.

Decreasing Opioid Addiction and Diversion Using Behavioral Economics Applied Through a Digital Engagement Solution: Protocol for a Randomized Controlled Trial.

Despite strong and growing interest in ending the ongoing opioid health crisis, there has been limited success in reducing the prevalence of opioid addiction and the number of deaths associated with opioid overdoses. Further, 1 explanation for this is that existing interventions target those who are opiate-dependent but do not prevent opioid-naïve patients from becoming addicted. Leveraging behavioral economics at the patient level could help patients successfully use, discontinue, and dispose of their opioid medications in an acute pain setting. The primary goal of this project is to evaluate the effect of the 3 versions of the Opioid Management for You (OPY) tool on measures of opioid use relative to the standard of care by leveraging a pragmatic randomized controlled trial (RCT). A team of researchers from the Center for Learning Health System Sciences (CLHSS) at the University of Minnesota partnered with M Health Fairview to design, build, and test the 3 versions of the OPY tool: social influence, precommitment, and testimonial version. The tool is being built using the Epic Care Companion (Epic Inc) platform and interacts with the patient through their existing MyChart (Epic Systems Corporation) personal health record account, and Epic patient portal, accessed through a phone app or the MyChart website. We have demonstrated feasibility with pilot data of the social influence version of the OPY app by targeting our pilot to a specific cohort of patients undergoing upper-extremity procedures. This study will use a group sequential RCT design to test the impact of this important health system initiative. Patients who meet OPY inclusion criteria will be stratified into low, intermediate, and high risk of opiate use based on their type of surgery. This study is being funded and supported by the CLHSS Rapid Prospective Evaluation and Digital Technology Innovation Programs, and M Health Fairview. Support and coordination provided by CLHSS include the structure of engagement, survey development, data collection, statistical analysis, and dissemination. The project was initially started in August 2022. The pilot was launched in February 2023 and is still running, with the data last counted in August 2023. The actual RCT is planned to start by early 2024. Through this RCT, we will test our hypothesis that patient opioid use and diverted prescription opioid availability can both be improved by information delivery applied through a behavioral economics lens via sending nudges directly to the opioid users through their personal health record. ClinicalTrials.gov NCT06124079; https://clinicaltrials.gov/study/NCT06124079. PRR1-10.2196/52882.

Perception and Correlates of Opioid Overdose Risk Among Overdose Survivors Who Use Nonprescribed Opioids in San Francisco and Boston.

Understanding opioid overdose risk perception may inform overdose prevention strategies. We used baseline data from a randomized overdose prevention trial, in San Francisco, CA, and Boston, MA, among people who used nonprescribed opioids, survived an overdose in the past 3 years, and had received naloxone. Participants were asked how likely they were to overdose in the next 4 months. We combined "extremely likely" and "likely" (higher risk perception) and "neutral," "unlikely," and "extremely unlikely" (lower risk perception). We performed bivariate analyses and separate multivariable logistic regression models of risk perception across (1) sociodemographic, (2) substance use, and (3) overdose risk behavior measures. Covariates were selected a priori or significant in bivariate analyses. Among 268 participants, 88% reported at least 1 overdose risk behavior; however, only 21% reported higher risk perception. The adjusted odds ratio (AOR) of higher risk perception was 2.41 (95% confidence interval [CI]: 1.10-5.30) among those unhoused in the past 4 months, 2.06 (95% CI: 1.05-4.05) among those using opioids in a new place, and 5.61 (95% CI: 2.82-11.16) among those who had overdosed in the past 4 months. Living in Boston was associated with higher risk perception in all 3 models (AOR = 2.00-2.46, 95% CI: 1.04-4.88). Despite prevalent risk behaviors, a minority of participants perceived themselves to be at higher risk of overdose. Nonetheless, some known risk factors for overdose were appropriately associated with risk perception. Fentanyl has been prevalent in Boston for longer than San Francisco, which may explain the higher risk perception there.

Adverse Effects After Prehospital Administration of Naloxone by Bystanders: A Preliminary Study.

Opioid use disorder is a cause of significant morbidity and mortality. In order to reverse opioid overdose as quickly as possible, many institutions and municipalities have encouraged people with no professional medical training to carry and administer naloxone. This study sought to provide preliminary data for research into the rates of adverse effects of naloxone when administered by bystanders compared to Emergency Medical Services (EMS) personnel, since this question has not been studied previously. This was a retrospective cohort study performed at an urban, tertiary, academic medical center that operates its own EMS service. A consecutive sample of patients presenting to EMS with opioid overdose requiring naloxone was separated into two groups based on whether naloxone was administered by bystanders or by EMS personnel. Each group was analyzed to determine the incidence of four pre-specified adverse events. There was no significant difference in the rate of adverse events between the bystander (19%) and EMS (16%) groups (OR = 1.23; 95% CI, 0.63 - 2.32; P = .499) in this small sample. Based on these initial results, a study would need a sample size of 6,188 in order to reach this conclusion with 80% power. Similarly, there were no significant differences in the rates of any of the individual adverse events. Secondary analysis of patients' demographics showed differences between the two groups which generate hypotheses for further investigation of disparities in naloxone administration. This preliminary study provides foundational data for further investigation of naloxone administration by bystanders. Adverse events after the prehospital administration of naloxone are rare, and future studies will require large sample sizes. These preliminary data did not demonstrate a statistically significant difference in adverse event rates when comparing naloxone administration by bystanders and EMS clinicians. This study provides data that will be useful for conducting further research on multiple facets of this topic.

Acute opioid overdose in pediatric patients.

Recent increases in pediatric and adolescent opioid fatalities mandate an urgent need for early consideration of possible opioid exposure and specific diagnostic and management strategies and interventions tailored to these unique populations. In contrast to adults, pediatric methods of exposure include accidental ingestions, prescription misuse, and household exposure. Early recognition, appropriate diagnostic evaluation, along with specialized treatment for opioid toxicity in this demographic are discussed. A key focus is on Naloxone, an essential medication for opioid intoxication, addressing its unique challenges in pediatric use. Unique pediatric considerations include recognition of accidental ingestions in our youngest population, critical social aspects including home safety and intentional exposure, and harm reduction strategies, mainly through Naloxone distribution and education on safe medication practices. It calls for a multifaceted approach, including creating pediatric-specific guidelines, to combat the opioid crisis among children and to work to lower morbidity and mortality from opioid overdoses.

Perceived stigma toward naloxone among overdose education and naloxone distribution program participants: Implications for opioid overdose response.

Perceived stigma toward naloxone among overdose education and naloxone distribution program participants: Implications for opioid overdose response.

Estimation of the prevalence of opioid misuse in New York State counties, 2007-2018: a bayesian spatiotemporal abundance model approach.

An important challenge to addressing the opioid overdose crisis is the lack of information on the size of the population of people who misuse opioids (PWMO) in local areas. This estimate is needed for better resource allocation, estimation of treatment and overdose outcome rates using appropriate denominators (ie, the population at risk), and proper evaluation of intervention effects. In this study, we used a bayesian hierarchical spatiotemporal integrated abundance model that integrates multiple types of county-level surveillance outcome data, state-level information on opioid misuse, and covariates to estimate the latent (hidden) numbers of PWMO and latent prevalence of opioid misuse across New York State counties (2007-2018). The model assumes that each opioid-related outcome reflects a partial count of the number of PWMO, and it leverages these multiple sources of data to circumvent limitations of parameter estimation associated with other types of abundance models. Model estimates showed a reduction in the prevalence of PWMO during the study period, with important spatial and temporal variability. The model also provided county-level estimates of rates of treatment and opioid overdose using the numbers of PWMO as denominators. This modeling approach can identify the sizes of hidden populations to guide public health efforts in confronting the opioid overdose crisis across local areas. This article is part of a Special Collection on Mental Health.

Knowledge, experiences, and perceptions of medications for opioid use disorder among Black Kentuckians

Background Opioid overdoses have continued to increase at higher rates among Black Americans compared to people from other racial groups. Despite demonstrated effectiveness of MOUD in reducing risk of opioid overdose, Black Americans face decreased access to and uptake of MOUD. The current study aimed to examine the knowledge, perceptions, and experiences with MOUD among a sample of Black adults who use prescription opioids nonmedically in order to inform tailored efforts to improve MOUD uptake. Methods Data were derived from a larger study assessing cultural and structural influences on drug use and drug treatment among people who use prescription opioids nonmedically. Semi-structured qualitative interviews were conducted with 34 Black men and women across four generational cohorts: born 1955–1969; 1970–1979; 1980–1994; and 1995–2001. Participant responses were analyzed using thematic analysis. Results Nearly half of participants (44.1%) reported no knowledge or experience with MOUD. Among participants who had any knowledge about MOUD, four major themes regarding their perceptions emerged: MOUD Helps with Recovery; Not Needed for Level of Drug Use; Side Effects and Withdrawal; Equivalence with Illicit Drug Use. The majority reported negative perceptions of MOUD (52.6%), and the youngest cohort (born 1995–2001) had a higher proportion of negative perceptions (80%) relative to other age cohorts (born 1980–1994: 50%; 1970–1979: 75%; 1955–1969: 16.6%). Discussion Findings indicate a significant knowledge gap and clear points of intervention for improving MOUD uptake. Interventions to improve communication of health information in ways that are culturally relevant and tailored by age group can be used in conjunction with efforts to improve MOUD access among Black individuals who use opioids nonmedically.

Genetic mouse models in opioid research: current status and future directions.

Synthetic and semi-synthetic opioids are prescribed for the management of severe pain conditions, but their long-term use is often leading to physical dependence and addiction disorders. Understanding the complex neurobiology of the opioid system in preclinical models will be essential for the development of safe and efficacious analgesics. With rising numbers of synthetic opioid users and overdose cases, a better understanding of the neuroanatomical and cellular pathways associated with physical dependence and addiction is expected to guide treatment approaches for opioid use disorders. In this commentary, we highlight the importance of advanced genetic mouse models for studying the regional effects of opioid receptors, and we discuss the need of genetic mouse models for the investigation of the regional, circuit and cell compartment-specific role of intracellular mediators of opioid actions.

Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone.

An open-label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil-induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight-fitting mask for an initial period of 46 min prior to a series of mask "holidays" introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time-dependent reversal of remifentanil-induced reductions in MV measured 2.5-20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P < .0009); the point estimate favors nalmefene, demonstrating non-inferiority and superiority. In this model of opioid-induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose.