Overdose Reversal Research Articles

Characterizing and combating the opioid epidemic in the Los Angeles County jail system

IntroductionOpioid overdose-related morbidity and mortality is a pressing public health crisis. Successful overdose reversal through bystander administration of naloxone is well documented, but there is an absence of literature on the implementation and impact of widespread naloxone access in a correctional setting during incarceration. The objective of this study was to describe our efforts to combat opioid overdose, prevent deaths, and examine and identify opioid use and predictors of opioid use through factors including age, sex assigned at birth, and ethnicity among the incarcerated population within the Los Angeles County jail system. MethodsWe retrospectively analyzed self-reported substance use information from all newly incarcerated persons from September 2018 to December 2020 to characterize opioid use in the Los Angeles County Jail system and used multivariable logistic regression analysis to determine predictors of substance use. We analyzed data on all cases of naloxone administration by custody personnel (i.e., all correctional officers) during the same period by examining patient demographic information, hospital discharge diagnosis, and patient outcome information. To describe naloxone training and access for incarcerated persons as an overdose prevention strategy, we reviewed electronic health record data on patient health outcomes for all cases of naloxone administration by an incarcerated person. ResultsA total of 6.4 % (11,881 of 187,528) of incarcerated persons reported opioid use. In the multivariable analysis, reported substance use was most significantly associated with any ethnicity other than Black (aOR for White =11.2; 95 % CI 10.4, 12.0, aOR for Hispanic/Latinx 3.0; 95 % CI 2.8, 3.2, aOR for All Others; 5.2 95 % CI 4.6, 5.8) and being <65 years old. Naloxone was administered by custody personnel to a total of 129 patients, where 122 (94.6 %) survived and 7 (5.4 %) died. After the deployment of naloxone in jail housing units, there were two instances of bystander naloxone administration by incarcerated persons that led to successful opioid overdose reversal and survival. ConclusionsThe expansion of naloxone availability to both custody personnel and incarcerated persons is an effective and warranted method to ensure timely naloxone administration and successful overdose reversal in a correctional setting.

Implementation of a Leave-behind Naloxone Program in San Francisco: A One-year Experience

In response to the ongoing opioid overdose crisis, US officials urged the expansion of access to naloxone for opioid overdose reversal. Since then, emergency medical services' (EMS) dispensing of naloxone kits has become an emerging harm reduction strategy. We created a naloxone training and low-barrier distribution program in San Francisco: Project FRIEND (First Responder Increased Education and Naloxone Distribution). The team assembled an advisory committee of stakeholders and subject-matter experts, worked with local and state EMS agencies to augment existing protocols, created training curricula, and developed a naloxone-distribution data collection system. Naloxone kits were labeled for registration and data tracking. Emergency medical technicians and paramedics were asked to distribute naloxone kits to any individuals (patient or bystander) they deemed at risk of experiencing or witnessing an opioid overdose, and to voluntarily register those kits. Training modalities included a video module (distributed to over 700 EMS personnel) and voluntary, in-person training sessions, attended by 224 EMS personnel. From September 25, 2019-September 24, 2020, 1,200 naloxone kits were distributed to EMS companies. Of these, 232 kits (19%) were registered by EMS personnel. Among registered kits, 146 (63%) were distributed during encounters for suspected overdose, and 103 (44%) were distributed to patients themselves. Most patients were male (n = 153, 66%) and of White race (n = 124, 53%); median age was 37.5 years (interquartile range 31-47). We describe a successful implementation and highlight the feasibility of a low-threshold, leave-behind naloxone program. Collaboration with multiple entities was a key component of the program's success.

The PharmNet Harm Reduction Intervention for Community Pharmacies: Protocol for a Pilot Randomized Controlled Trial.

The overdose epidemic in the United States has continued to worsen despite substantial efforts to mitigate its harms. The opioid antagonist naloxone has been identified as a key means of reducing the prevalence of fatal overdoses. An important evidence-based approach to optimizing naloxone's impact is to seed it throughout the community, because bystanders are often able to reverse overdoses more quickly than first responders and sometimes are the only possible means of overdose reversal. As part of a multipronged approach to distributing naloxone nationwide, community pharmacies have been identified as ideal venues for naloxone dispensing, especially under standing orders. However, dispensing rates remain surprisingly low, and there is a need to understand how best to engage community pharmacies in naloxone-based harm reduction services. The objective of this trial is to determine whether a tailored, pragmatic pharmacy intervention (PharmNet) results in greater naloxone dispensing relative to baseline (the prior 3 months) compared to a control condition. This pilot trial is intended to determine whether it is appropriate to invest the substantial resources that would be required to conduct a full-scale, randomized controlled study of PharmNet. We will conduct a 3-month randomized controlled pilot trial consisting of 2 parallel groups with a 4:3 allocation ratio. A group of 7 independent pharmacies from rural areas in Indiana will be randomly assigned to either the PharmNet intervention arm (n=4) or the control arm (n=3). The primary outcome will be overall naloxone dispensing (both at cost and free), and secondary outcomes will include the distribution of referral cards and multiple variables at the level of individual staff members. Dispensing data will be collected for the 3 months prior to the intervention and the 3 months of the intervention, and all other data will be collected using a pretest-posttest design. The primary analysis will be a generalized linear mixed model with a Poisson distribution with fixed effects for group, time, and their interaction and a random effect for pharmacy ID to account for repeated measures within pharmacies. This study was approved by the Indiana University institutional review board in 2 phases (August 2, 2021, and April 26, 2022) and was funded by the Indiana University Grand Challenge: Responding to the Addictions Crisis. If this study produces evidence that the PharmNet intervention results in increased naloxone dispensing relative to control pharmacies, it will be both appropriate and important to study it in a large, full-scale randomized controlled trial. PRR1-10.2196/42373.

Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose.

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects. The orvinol series of ligands are known for their high-affinity binding to opioid receptors and often extended duration of action; generally, compounds on this scaffold show agonist activity at the kappa and the mu-opioid receptor. Diprenorphine is an unusual member of this series being an antagonist at mu and only a partial agonist at kappa-opioid receptors. In this study, an orvinol antagonist, 14, was designed and synthesized that shows no agonist activity in vitro and is at least as good as naloxone at reversing the effects of mu-opioid receptor agonists in vivo.

“I don’t go to funerals anymore”: how people who use opioids grieve drug-related death in the US overdose epidemic

BackgroundOpioid-related overdose death is a public health epidemic in much of the USA, yet little is known about how people who use opioids (PWUO) experience overdose deaths in their social networks. We explore these experiences through a qualitative study of opioid-related overdose death bereavement among PWUO.MethodsWe recruited 30 adults who inject opioids from a syringe service program in the Midwestern USA and interviewed them using a semi-structured guide that addressed experiences of opioid use, opioid-related overdose, and overdose reversal via the medication naloxone. Interviews were transcribed verbatim and analyzed thematically.FindingsParticipants described overdose death as ever-present in their social worlds. Most (approximately 75%) reported at least one overdose death in their social network, and many came to consider death an inevitable end of opioid use. Participants described grief shaped by complex social relations and mourning that was interrupted due to involvement with social services and criminal legal systems. They also reported several ways that overdose deaths influenced their drug use, with some increasing their use and others adopting safer drug use practices. Despite the high prevalence of overdose deaths in their social networks, only one participant reported receiving grief support services.DiscussionFindings underscore the need for interventions that not only maintain life, such as naloxone distribution, but also improve quality of life by attending to grief related to overdose death bereavement. We discuss policies and practices with the potential to address the unique psychological, social, and structural challenges of grief for this population.

Evaluating the Use of Parenteral Naloxone in the Emergency Department of a Community Hospital.

Background:Thousands of patients die every year from opioid overdose. Naloxone is a lifesaving medication FDA approved for opioid overdose reversal. Many patients may present to the emergency department (ED) and require naloxone administration. The purpose of this study was to evaluate parenteral naloxone usage in the ED. It assessed parenteral naloxone indication of use and the patient population requiring its administration in order to support the need of a take home naloxone distribution program. Methods: This study was a retrospective, randomized, single center, chart review that took place at a community hospital ED. A computerized report was generated to identify all patients 18 years of age or older who were administered naloxone in the ED from June 2020 to June 2021. The charts of 100 patients randomly selected from the generated report were reviewed to collect the following information: gender, age, indication for use, dosing, drug being reversed, risk factors for overdose, ED revisits within 1 year. Results: Out of the 100 patients randomly reviewed, 55 (55%) patients were administered parenteral naloxone for overdose indication. Eighteen (32%) of overdose patients revisited the hospital within 1 year for overdose. Thirty-six (65%) of patients administered naloxone for overdose had history of substance abuse with 45 (82%) being under the age of 65 years. Conclusion: These results support the need for a take home naloxone distribution program to be implemented for patients at risk for opioid overdose or individuals at risk of witnessing a drug overdose.

Naloxone administration by law enforcement officers in New York State (2015–2020)

BackgroundThe COVID-19 pandemic has amplified the need for wide deployment of effective harm reduction strategies in preventing opioid overdose mortality. Placing naloxone in the hands of key responders, including law enforcement officers who are often first on the scene of a suspected overdose, is one such strategy. New York State (NYS) was one of the first states to implement a statewide law enforcement naloxone administration program. This article provides an overview of the law enforcement administration of naloxone in NYS between 2015 and 2020 and highlights key characteristics of over 9000 opioid overdose reversal events.MethodsData in naloxone usage report forms completed by police officers were compiled and analyzed. Data included 9133 naloxone administration reports by 5835 unique officers located in 60 counties across NYS. Descriptive statistics were used to examine attributes of the aided individuals, including differences between fatal and non-fatal incidents. Additional descriptive analyses were conducted for incidents in which law enforcement officers arrived first at the scene of suspected overdose. Comparisons were made to examine year-over-year trends in administration as naloxone formulations were changed. Quantitative analysis was supplemented by content analysis of officers’ notes (n = 2192).ResultsIn 85.9% of cases, law enforcement officers arrived at the scene of a suspected overdose prior to emergency medical services (EMS) personnel. These officers assessed the likelihood of an opioid overdose having occurred based on the aided person’s breathing status and other information obtained on the scene. They administered an average of 2 doses of naloxone to aided individuals. In 36.8% of cases, they reported additional administration of naloxone by other responders including EMS, fire departments, and laypersons. Data indicated the aided survived the suspected overdose in 87.4% of cases.ConclusionsWith appropriate training, law enforcement personnel were able to recognize opioid overdoses and prevent fatalities by administering naloxone and carrying out time-sensitive medical interventions. These officers provided life-saving services to aided individuals alongside other responders including EMS, fire departments, and bystanders. Further expansion of law enforcement naloxone administration nationally and internationally could help decrease opioid overdose mortality.

Student pharmacists' attitudes, perceptions, and knowledge regarding opioid use, misuse, and overdose: Four years of data

IntroductionThe American Association of Colleges of Pharmacy has urged pharmacy faculty to commit to actions to reduce the public health threat from opioid use and misuse. Optimizing student pharmacist training necessitates understanding changes in their attitudes and perceptions over time. This study assessed student attitudes, perceptions, and understanding of addiction, opioid use and misuse, and opioid overdose over four sequential years, from 2016 to 2019. MethodsThe participants were third-professional year doctor of pharmacy students enrolled in a required course. Participants voluntarily completed a 27-statement survey to determine student attitudes, perceptions, and understanding. ResultsA total of 452 participants completed the survey (response rate = 76.5%). Of the 27 survey items, five survey statements showed year on year positive increases in specific student attitudes towards addiction, hopefulness for its treatment, and confidence to use and train opioid overdose reversal agents. These yearly changes did not appear to be related to any changes in the academic aptitude of the students. The 22 remaining statements showed positive and stable attitudes towards self-perceived understanding of opioid use and misuse, hopefulness for its treatment, and the role of pharmacists. ConclusionTo our knowledge, this is the first large multiyear assessment of student pharmacists' attitudes, perceptions, and understanding of opioid use, misuse, and overdose. The data indicate favorable and improving attitudes. Knowledge of student attitudes, perceptions, and understanding regarding opioid use, misuse, and overdose will aid in the development of effective training programs for students in our, and other colleges of pharmacy.

Development of Cross-Reactive Antibodies for the Identification and Treatment of Synthetic Cannabinoid Receptor Agonist Toxicity.

Synthetic cannabinoid receptor agonists (SCRAs) are compounds that mimic the pharmacology of the psychoactive components in cannabis. These compounds are structurally diverse, inexpensive, commercially available, and difficult to identify with modern analytical methods, making them highly accessible for recreational use. Suspected SCRA toxicity, which can present with a breadth of cardiovascular, gastrointestinal, and neurological disturbances, is currently addressed through symptom management followed by a toxicological screening that often occurs long after patient discharge. Here, we report the development of four cross-reactive anti-SCRA bioconjugate vaccines as a platform for developing improved diagnostic and therapeutic interventions against SCRA intoxication, using SCRA-resembling small molecule haptens that combine common subregional motifs occurring within and across different generations of SCRA molecules. Using a combination of multiplexed competitive ELISA screening and chemoinformatic analyses, it was found that the antibodies resulting from vaccination with these bioconjugates demonstrated their ability to detect multiple SCRAs with a Tanimoto minimum common structure score of 0.6 or greater, at concentrations below 8 ng/mL. The scope of SCRAs detectable using these haptens was found to include both bioisosteric and non-bioisosteric variants within the core and tail subregions, as well as SCRAs bearing valine-like head subregions, which are not addressed by commercially available ELISA screening approaches. Vaccination with these bioconjugates was also found to prevent the changes in locomotion and body temperature that were induced by a panel of SCRAs at doses of 1 and 3 mg/kg. Further refinement of this genericized hapten design and cross-reactivity-prioritizing approach may enable the rapid detection of otherwise cryptic SCRAs that arise during overdose outbreaks, and could ultimately lead to identification of monoclonal antibody species applicable for overdose reversal.

Spatial and neighborhood-level correlates of lay naloxone reversal events and service availability.

The opioid epidemic in the United States continues to surge, reaching record deaths from opioid and fentanyl overdoses in 2020. This study analyzes spatial and neighborhood correlates of free naloxone distribution sites as well as overdose and naloxone reversal events in Baltimore, Maryland, which has one of the highest overdose rates in the country. Using data from a randomized clinical trial on HIV prevention among people using substances in Baltimore, Maryland, as well as demographic data from the US Census Bureau, we conducted: (1) exploratory spatial visualizations of census tracts' minimum distance to naloxone distribution sites, (2) univariable Wilcoxon rank-sum tests to compare census tracts on demographic metrics, and (3) bivariable and multivariable negative binomial regression models to assess associations between census tract characteristics and naloxone reversal events. Valid geographic data were provided for 518 overdose events involving either fentanyl or heroin in this study. Of these, 190 (37%) attempted naloxone reversal events were reported. Exploratory spatial visualization techniques suggest that most distribution sites are appropriately located near populations at high risk of overdose, but study findings also identify areas where drug use and overdoses occur that are located farther from distribution sites. In multivariable analyses, naloxone administration was significantly and inversely associated with distance to the nearest distribution site (incidence rate ratio (IRR)=0.72 per 1000m increase, 95% CI 0.59-0.89, p=0.002). Study findings emphasize the correlation between proximity to naloxone sites and utilization of resources, highlighting that physical proximity to harm reduction resources may contribute to uptake. Results further underscore that research on service accessibility and utilization must consider the spatial distribution of health services.

Patient perceptions of higher-dose naloxone nasal spray for opioid overdose.

Higher-dose formulations of naloxone were recently approved by the FDA for the treatment of opioid overdose. These products were developed based on projected saturation of high-potency fentanyl analogues in the illicit marketplace although the evidence base for their necessity is still under scrutiny. Concern has been raised that unintended reductions in patient acceptance of naloxone may occur due to increased precipitated withdrawal risk associated with higher naloxone doses. A well-founded and time-sensitive call for representation of people who use drugs in this decision-making process has been made. This study provides the first data on patient perceptions of higher-dose formulations to inform this scientific debate and distribution efforts. Patients (N=1152) entering treatment for opioid use disorder at one of 49 addiction treatment facilities located across the United States completed a preference assessment of naloxone nasal spray formulations. Patients selected a formulation preference across three scenarios (administration for self, administration to others, community responder administration). A majority of respondents that had been administered naloxone previously reported that their most recent overdose reversal included two or more naloxone administrations (59.9%). Most respondents either had no preference (48.4%) or preferred a higher-dose formulation (35.9%) if personally experiencing an overdose. Similar preference distributions were observed for administration to others and by community responders. Relative to standard-dose preference, respondents preferring higher-dose formulations had a greater odds of recent suspected fentanyl exposure. These data inform patients, advocates, and policy-makers considering distribution and utilization of naloxone formulations by reporting perspectives of patients with opioid use and overdose experience. Limited evidence for widespread avoidance of higher-dose formulations was found. As real-world evidence of acceptability and effectiveness emerges, either supporting or refuting the widespread need for higher-dose naloxone formulations, it is the responsibility of the scientific and public health community to be responsive to those data.

Management of opioid use disorder, opioid withdrawal, and opioid overdose prevention in hospitalized adults: A systematic review of existing guidelines.

Hospitalizations related to the consequences of opioid use are rising. National guidelines directing in-hospital opioid use disorder (OUD) management do not exist. OUD treatment guidelines intended for other treatment settings could inform in-hospital OUD management. Evaluate the quality and content of existing guidelines for OUD treatment and management. OVID MEDLINE, PubMed, Ovid PsychINFO, EBSCOhost CINHAL, ERCI Guidelines Trust, websites of relevant societies and advocacy organizations, and selected international search engines. Guidelines published between January 2010 to June 2020 addressing OUD treatment, opioid withdrawal management, opioid overdose prevention, and care transitions among adults. We assessed quality using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Nineteen guidelines met the selection criteria. Most recommendations were based on observational studies or expert consensus. Guidelines recommended the use of nonstigmatizing language among patients with OUD; to assess patients with unhealthy opioid use for OUD using the Diagnostic Statistical Manual of Diseases-5th Edition criteria; use of methadone or buprenorphine to treat OUD and opioid withdrawal; use of multimodal, nonopioid therapy, and when needed, short-acting opioid analgesics in addition to buprenorphine or methadone, for acute pain management; ensuring linkage to ongoing methadone or buprenorphine treatment; referring patients to psychosocial treatment; and ensuring access to naloxone for opioid overdose reversal. Included guidelines were informed by studies with various levels of rigor and quality. Future research should systematically study buprenorphine and methadone initiation and titration among people using fentanyl and people with pain, especially during hospitalization.

A longitudinal study of naloxone opioid overdose awareness and reversal training for first-year medical students: specific elements require reinforcement

BackgroundThe opioid epidemic is a progressively worsening public health crisis that continues to impact healthcare system strategies such as overdose reversal and destigmatization. Even among healthcare professionals, there remains a lack of confidence in naloxone administration and a prevalence of stigma. While training can play a major impact in reducing these shortcomings, the long-term effectiveness has yet to be characterized in training healthcare professionals. This study examined the long-term retention of opioid overdose awareness and reversal training (OOART) by evaluating performance at two-time intervals, immediately post-training and at a 3-month follow-up.MethodsVoluntary training was offered to first-year (M1) medical students at the Drexel University College of Medicine in 2021. At this training, 118 students completed training, 95 completed the post-training survey, and 42 completed the 3-month follow-up.ResultsOpioid reversal knowledge questions assessed significantly increased scores post-training and at the 3-month follow-up. In three of the attitude questions, scores were improved at both follow-up timepoints. In addition, three attitude questions indicating a participant’s confidence to respond to an opioid overdose situation increased directly after the training, but regressed at the 3-month follow-up. The remaining questions did not show any statistical difference across the survey intervals.ConclusionsThis study establishes that while OOART provides participants with the knowledge of how to respond to an opioid overdose, the retention of this knowledge at a 3-month interval is reduced. The results were mixed for longitudinal assessment of participant’s attitudes toward people with opioid use disorder. Some positive increases in attitudes were retained at the 3-month interval, while others trended back toward pre-training levels. These results support the effectiveness of the training but also provide evidence that OOART must be reinforced often.

Real-world study of multiple naloxone administration for opioid overdose reversal among bystanders

BackgroundThe increasing prevalence of highly potent, illicitly manufactured fentanyl and its analogues (IMF) in the USA is exacerbating the opioid epidemic which has worsened during the COVID-19 pandemic. Narcan® (naloxone HCl) Nasal Spray has been approved by the US Food and Drug Administration as a treatment for opioid-related overdoses. Due to the high potency of IMF, multiple naloxone administrations (MNA) may be needed per overdose event. It is essential to determine the patterns of naloxone use, including MNA, and preferences among bystanders who have used naloxone for opioid overdose reversal.MethodsA cross-sectional web-based survey was administered to 125 adult US residents who administered 4 mg Narcan® Nasal Spray during an opioid overdose in the past year. The survey asked about the most recent overdose event, the use of Narcan® during the event and the associated withdrawal symptoms, and participant preferences regarding dosages of naloxone nasal spray. An open-ended voice survey was completed by 35 participants.ResultsParticipants were mostly female (70%) and white (78%), while reported overdose events most frequently occurred in people who were males (54%) and white (86%). Most events (95%) were successfully reversed, with 78% using ≥ 2 doses and 30% using ≥ 3 doses of Narcan® Nasal Spray. Over 90% were worried that 1 Narcan® box may not be enough for a successful future reversal. Reported withdrawal symptoms were similar in overdose events where 1 versus ≥ 2 sprays were given. Eighty-six percent of participants reported more confidence in an 8 mg versus a 4 mg naloxone nasal spray and 77% reported a stronger preference for 8 mg over 4 mg.ConclusionsMNA occurred in most overdose events, often involving more sprays than are provided in one Narcan® nasal spray box, and participants predominantly expressed having a stronger preference for and confidence in an 8 mg compared to a 4 mg nasal spray. This suggests the need and desire for a higher dose naloxone nasal spray formulation option. Given that bystanders may be the first to administer naloxone to someone experiencing an opioid overdose, ensuring access to an adequate naloxone supply is critical in addressing the opioid overdose epidemic.

Pharmacology and pharmacokinetics of fentanyl toxicity reversal by anti‐fentanyl monoclonal antibodies in combination with naloxone

AIMWidespread access to illicit fentanyl has contributed to an ongoing epidemic of fatal drug overdoses in the United States. The incidence of fatal overdoses in the United States accelerated during the COVID‐19 pandemic, with over 100,000 deaths recorded by April 2021. Fentanyl‐specific monoclonal antibodies (mAb) offer a prophylactic and therapeutic intervention against opioid overdose by binding and sequestering fentanyl in serum, and reducing distribution to the brain. Here, the kinetics of overdose reversal by anti‐fentanyl mAb alone or in combination with naloxone were explored, and the dose‐response relationship between naloxone and high doses of fentanyl in the presence of mAb was evaluated.METHODSTo evaluate the kinetics of fentanyl reversal, fentanyl 0.1 mg/kg was administered to male Sprague‐Dawley rats, and mAb or naloxone was administered fifteen minutes after exposure. Oxygen saturation was monitored constantly for ten minutes following administration of reversal agent. To evaluate duration and extent of protection from further fentanyl exposures, rats were pre‐treated with mAb, naloxone, or a combination, and challenged with increasing doses of fentanyl up to 0.5 mg/kg. Finally, to determine whether the presence of mAb would increase efficacy of naloxone against a lethal dose of fentanyl, 2.25 mg/kg fentanyl was administered, followed by naloxone 0.01 to 1.0 mg/kg.RESULTSThe most rapid reversal of fentanyl toxicity was achieved by intravenous administration of a combination of anti‐fentanyl mAb and naloxone (&lt;1 min). Intravenous naloxone reversed fentanyl toxicity more quickly than subcutaneous naloxone, and intravenous mAb was effective against fentanyl within 4 minutes, similar to subcutaneous NLX. Against further challenges of fentanyl, both mAb and 0.1 mg/kg naloxone were effective against 0.1‐0.2 mg/kg fentanyl, and the combination of mAb and naloxone was effective against doses of 0.5 mg/kg fentanyl or higher. Prophylactic administration of mAb enhanced efficacy of naloxone in reversing a potentially lethal challenge of 2.25 mg/kg fentanyl. Finally, mAb sequestered high concentrations of both fentanyl and its metabolite norfentanyl in serum, and reduced brain concentrations of fentanyl in pre‐exposure scenarios.CONCLUSIONSThese results support translation of mAb as medical countermeasures to prevent and reverse opioid overdose related to fentanyl and its analogs.

Treatment of opioid overdose: current approaches and recent advances.

BackgroundThe USA has recently entered the third decade of the opioid epidemic. Opioid overdose deaths reached a new record of over 74,000 in a 12-month period ending April 2021. Naloxone is the primary opioid overdose reversal agent, but concern has been raised that naloxone is not efficacious against the pervasive illicit high potency opioids (i.e., fentanyl and fentanyl analogs).MethodsThis narrative review provides a brief overview of naloxone, including its history and pharmacology, and the evidence regarding naloxone efficacy against fentanyl and fentanyl analogs. We also highlight current advances in overdose treatments and technologies that have been tested in humans.Results and conclusionsThe argument that naloxone is not efficacious against fentanyl and fentanyl analogs rests on case studies, retrospective analyses of community outbreaks, pharmacokinetics, and pharmacodynamics. No well-controlled studies have been conducted to test this argument, and the current literature provides limited evidence to suggest that naloxone is ineffective against fentanyl or fentanyl analog overdose. Rather a central concern for treating fentanyl/fentanyl analog overdose is the rapidity of overdose onset and the narrow window for treatment. It is also difficult to determine if other non-opioid substances are contributing to a drug overdose, for which naloxone is not an effective treatment. Alternative pharmacological approaches that are currently being studied in humans include other opioid receptor antagonists (e.g., nalmefene), respiratory stimulants, and buprenorphine. None of these approaches target polysubstance overdose and only one novel approach (a wearable naloxone delivery device) would address the narrow treatment window.

Characteristics of and Experience Among People Who Use Take-Home Naloxone in Skåne County, Sweden.

BackgroundOpioid overdose related injury or death can be prevented by bystander naloxone administration. For naloxone to be present when and where overdoses occur, opioid prevention education and naloxone distribution (OPEND) must be established on a broad level. This is the 30-month follow-up of the first multi-site naloxone project in Sweden, implemented at 31 sites in the County of Skåne 2018.AimTo address participant characteristics and factors associated with returning for naloxone refill and with having used naloxone for overdose reversal. An additional aim was to describe self-reported reasons for naloxone refill and overdose experiences.MethodsData were collected during June 2018—December 2020 through questionnaires at baseline and upon naloxone refill of the initial and subsequent naloxone kit. Descriptive statistics was used to address participant characteristics, those returning for naloxone refill and reporting overdose reversal. Chi-2 test was used for variable comparison between groups. Factors associated with overdose reversals were examined by logistic regression analysis. Reasons for naloxone refill, overdose situation and management were presented descriptively.ResultsAmong 1,079 study participants, 22% (n = 235) returned for naloxone refill, of which 60% (n = 140) reported a total of 229 overdose reversals. Reversals were more likely to be reported by participants trained at needle exchange programs (NEPs) [adjusted odds ratio (AOR) = 5.18, 95% Confidence interval (CI) = 3.38–7.95)], with previous experience of own (AOR = 1.63, 95% CI = 1.03–2.58) or witnessed (AOR = 2.12, 95% CI = 1.05–4.29) overdose, or who had used sedatives during the last 30 days before initial training (AOR = 1.56, 95% CI = 1.04–2.33). A majority of overdoses reportedly occurred in private settings (62%), where the victim was a friend (35%) or acquaintance (31%) of the rescuer.ConclusionParticipants with own risk factors associated with overdose (e.g., injection use, concomitant use of benzodiazepines and previous experience of own overdose) were more likely to report administering naloxone for overdose reversal. Overdose management knowledge was high. The findings indicate that implementation of multi-site OPEND reaches individuals at particularly high risk of own overdose in settings with limited previous harm reduction strategies and favors a further scaling up of naloxone programs in similar settings.

Pharmacological Profiling of Antifentanyl Monoclonal Antibodies in Combination with Naloxone in Pre- and Postexposure Models of Fentanyl Toxicity.

The incidence of fatal drug overdoses in the United States is an alarming public health threat that has been exacerbated by the COVID-19 pandemic, resulting in over 100,000 deaths between April 2020 and April 2021. A significant portion of this is attributable to widespread access to fentanyl and other synthetic opioids, alone or in combination with heroin or psychostimulants, such as cocaine or methamphetamine. Monoclonal antibodies (mAb) offer prophylactic and therapeutic interventions against opioid overdose by binding opioids in serum, reducing distribution of drug to the brain and other organs. Here, we investigated the efficacy of a leading antifentanyl mAb, clone HY6-F9, in reversal and prevention of fentanyl-induced toxicity compared with the opioid receptor antagonist naloxone (NLX) in rats. In postexposure models, rats were challenged with fentanyl, followed by HY6-F9, NLX, or both. HY6-F9 reversed fentanyl-induced antinociception, respiratory depression, and bradycardia, and rats retained protection against additional challenges for at least 1 week. Although intravenous NLX reversed fentanyl-induced respiratory depression more rapidly than mAb alone, kinetics of reversal by intravenous mAb were similar to subcutaneous NLX. Coadministration of mAb and NLX provided greater protection than individual treatments against high doses of fentanyl. Prophylactic administration of mAb reduced the ED50 of NLX approximately twofold against 2.25 mg/kg of fentanyl. Finally, mAb sequestered fentanyl and its metabolite norfentanyl in serum and reduced brain concentrations of fentanyl. These results support the translation of mAb as medical interventions alone or in combination with NLX to prevent and reverse fentanyl-related overdose. SIGNIFICANCE STATEMENT: Fentanyl-related overdoses have increased dramatically in the US and worldwide. Currently, approved pharmacotherapies for treatment of opioid use disorder and reversal of overdose are not sufficient to curb the incidence of opioid-related deaths. Additionally, fentanyl and its potent analogs present a potential risk from use in deliberate poisoning or chemical attacks. This study demonstrates the use of monoclonal antibodies as a countermeasure to fentanyl-induced toxicity in pre- and postexposure scenarios, supporting their use in combination with the opioid antagonist naloxone.

A qualitative examination of responses from a survey of pharmacy staff in Georgia regarding access to Narcan®.

Georgia state lawmakers enacted legislation designed to reduce opioid overdose deaths by increasing public access to rescue products, such as Narcan®. This article explores whether pharmacy employees have effectively adopted such changes into pharmacy practice. We analyzed unsolicited remarks noted during a parent telephone survey of 120 Georgia pharmacy staff regarding price, availability and barriers to layperson purchase of Narcan®. Comments regarding dispensing requirements and challenges in obtaining inventory and changes in communication style were recorded. Around 15% were unfamiliar with Narcan® as an opioid overdose reversal agent or were unaware of their pharmacy's policies governing its sale. Nearly half of those contacted did not have Narcan® in stock with some reporting that receiving Narcan® would take several days after placing an order. Over half specified requirements for purchasing Narcan® not required by law. Fewer than 15% had Narcan® available and imposed no unnecessary requirements for its purchase. During approximately 10% of the survey calls, respondents used a tone of voice or made comments suggestive of bias. We conclude that non-compliance with current laws, lack of familiarity with Narcan® and negative communication tendencies that suggest implicit bias and stigmatizing behaviors could ultimately inhibit access to opioid overdose treatment.

Reducing the stigma surrounding opioid use disorder: evaluating an opioid overdose prevention training program applied to a diverse population

BackgroundThe opioid epidemic is a rapidly growing public health concern in the USA, as the number of overdose deaths continues to increase each year. One strategy for combating the rising number of overdoses is through opioid overdose prevention programs (OOPPs).ObjectiveTo evaluate the effectiveness of an innovative OOPP, with changes in knowledge and attitudes serving as the primary outcome measures.MethodsThe OOPP was developed by a group of medical students under guidance from faculty advisors. Training sessions focused on understanding stigmatizing factors of opioid use disorder (OUD), as well as protocols for opioid overdose reversal through naloxone administration. Pre- and post-surveys were partially adapted from the opioid overdose attitudes and knowledge scales and administered to all participants. Paired t-tests were conducted to assess differences between pre- and post-surveys.ResultsA total of 440 individuals participated in the training; 381 completed all or the majority of the survey. Participants came from a diverse set of backgrounds, ages, and experiences. All three knowledge questions showed significant improvements. For attitude questions, significant improvements were found in all three questions evaluating confidence, two of three questions assessing attitudes towards overdose reversal, and four of five questions evaluating stigma and attitudes towards individuals with OUD.ConclusionsOur innovative OOPP was effective not only in increasing knowledge but also in improving attitudes towards overdose reversal and reducing stigma towards individuals with OUD. Given the strong improvements in attitudes towards those with OUD, efforts should be made to incorporate the unique focus on biopsychosocial and sociohistorical components into future OOPPs.