Naloxone’s role in the national opioid crisis— past struggles, current efforts, and future opportunities

Abstract

Over the past 25 years, naloxone has emerged as a critical lifesaving overdose antidote. Public health advocates and community activists established early methods for naloxone distribution to people who inject drugs, but a legacy of stigmatization and opposition to universal naloxone access continues to limit the drug’s full potential to reduce opioid-related mortality. The establishment of naloxone distribution programs under the umbrella of syringe exchange programs faces the same practical, ideological and financial barriers to expansion similar to those faced by syringe exchange programs themselves. The expansion of naloxone from the confines of a few syringe exchange programs to what we see today represents an enormous triumph for the grass-roots activists, service providers, and public health professionals who have fought to guarantee lay access to naloxone. Despite the extensive efforts to expand access to naloxone, naloxone continues to remains a scarce resource in many US localities. Considerable naloxone “deserts” remain and even where there is naloxone access, it does not always reach those at risk. Promising areas for expansion include the development of more robust telehealth methods for naloxone distribution, including subsidized mail delivery programs; lowering barriers to pharmacy access; working with hospitals, ambulances, and law enforcement to expand naloxone “leave behind” programs; providing naloxone co-prescription with medications for opioid use disorder; and working with prisons, shelters, and networks of people who use drugs to increase access to the lifesaving medication. Efforts to ensure over-the-counter and low- or no-cost naloxone are ongoing and stand alongside medication-assisted treatments as efficacious, readily-actionable, and cost-efficient population-level interventions available for combatting opioid-related overdose in the United States. (Translational Research 2021; 000:115)

INTRODUCTION

In response to the public health crisis of overdose (OD) that had been building for over 2 decades,¹ on April 4, 2018, Surgeon General Jerome Adams issued a public health advisory urging more Americans to obtain the overdose reversal drug, naloxone, and be trained in its use. More than ever, the opioid antagonist figures prominently in national and local response efforts designed to reduce overdose mortality, but its current salience within local and national response strategies comes only after a roughly 50-year history characterized by hard fought political struggles. In this article, we briefly review this history with an eye on elucidating areas in which a legacy of stigmatization and opposition to universal naloxone access continues to limit the drug’s full potential to reduce opioid-related morality. In so doing, we highlight the work of advocates, harm reduction service providers, and researchers who have led the way in designing and implementing effective approaches to overdose education and naloxone distribution (OEND) and identify key areas in which additional effort and advocacy are required.

The struggle for community access.

Naloxone was approved by the FDA in 1971 as a prescription medicine for the “reversal” of an opioid overdose,² and its use over roughly the next 2 decades was limited primarily to hospitals and ambulances. As national rates of opioid-involved drug overdose escalated in the 1990s, however, pressure to broaden access began to mount from people who use opioids (PWUO), their friends and family members, as well as community-based service providers who increasingly witnessed people around them overdosing and were motivated to take action. The 1990s represent, in retrospect, a perfect storm of opioid-related risks. Traditional low-potency heroin sources from Central and East Asia were suddenly challenged by new, higher-potency “black tar” preparations, and prescription opioid dispensing reached record highs across the United States as opioids were established as the “gold standard” of pharmacological therapies for chronic, noncancer pain.^3–5 For some pain patients, longer-term use combined with high dosage formations resulted in iatrogenic addiction.

In the context of a rapidly escalating crisis of opioid-related morbidity and mortality, public health advocates and community activists (many working in harm reduction agencies) established early methods for naloxone distribution to PWUO and, in particular, people who inject drugs. Still lacking a medicolegal framework for lay implementation, early innovators and social justice activists worked with local harm reduction organizations and departments of health to distribute naloxone, first in more grassroots settings like the Chicago Recovery Alliance (1996), but soon followed by state and city health agencies, like the San Francisco Department of Public Health (1999) and New Mexico’s State Department of Health (2001).² Two long-term naloxone advocates recently characterized Chicago Recovery Alliance’s community-based naloxone distribution as “an act of liberating a material resource crucial to survival from the control of the health care and criminal justice systems and putting it into the hands of people who use drugs.”⁶ As opioid-related fatalities began to spike in the late 1990s, interviews conducted with early key actors in these initiatives reveal the sense of urgency felt to get naloxone directly to PWUO, even in the absence of clear legal sanctions allowing it.^7–9

Naloxone expansion played out differently in each state as activists had to overcome legal, financial, logistical, and ideological challenges specific to their communities. In Pittsburgh, Pennsylvania, for example, a combination of financial and ideological barriers prevented rapid expansion and scaling up of naloxone distribution, especially in the county jail, despite abundant research showing a clear link between incarceration, release and overdose risk.^10–14 There, a decade of advocacy efforts encouraging the jail to provide naloxone to inmates upon release was met with incredulity from jail administrators and staff who opposed the idea of giving naloxone directly to inmates.⁹ Institutional pushback also came from the Allegheny County Health Department and Department of Human Services, who opposed the idea that they should be giving naloxone directly to people who use drugs.¹⁵ It was not until 2016 that the Pittsburgh jail started to give naloxone to inmates upon release, over a decade after overdose prevention trainings had been established in the jail and extensive advocacy to implement the practice of mass distribution through agencies working directly with people who use drugs to try to blanket the community. Getting naloxone directly to PWUO was a social justice and public health imperative, “an embodiment of the belief that people who use drugs have the right to their own life and survival.”⁶

Overdose education and naloxone distribution (OEND) / Take home naloxone (THN).

Despite obstacles, early programs developed innovative and effective models of naloxone distribution and focused on getting naloxone into the hands of at-risk people who use opioids in community settings where they were likely to be found.¹⁶ Between 1996 and 2010 community-based take-home naloxone (THN) access grew considerably, and an estimated 53,032 persons were trained in overdose response, with laypersons reporting having performed over 10,000 reversals with naloxone in that period.¹⁷ Expanded access to naloxone during this period^18–20 drew scientific scrutiny, and evaluations of THN programs consistently found that providing access to lay overdose responders including PWUO was highly efficacious and cost-effective in reducing overdose mortality and led to few adverse events.^21–24 As PWUO and their friends and family members saved countless lives with THN, the overdose crisis continued largely unabated as new synthetic opioids entered the drug supply. By about 2013, significant amounts of illicitly manufactured fentanyl and fentanyl analogues in the illicit drug supply contributed to what one researcher recently dubbed the “triple wave epidemic,” in reference to the progression from prescription opioids, to heroin, and most recently illicitly manufactured fentanyl.^25,26 The establishment of naloxone distribution programs under the umbrella of syringe exchange programs came with the same practical, ideological and financial barriers to expansion that syringe exchange programs themselves faced. The ban on the use of federal funds for syringe exchange programs between 1988 and 2015²⁷ meant that programs had to carefully distinguish naloxone distribution from syringe distribution and potentially create staff positions solely for naloxone outreach. In terms of the practicalities of securing real estate, numerous stakeholders protested the formation of syringe exchange programs in their neighborhoods, often citing the commonplace claim that they might give the impression of condoning drug use while also bringing greater numbers of PWUO to a neighborhood²⁸ whose syringe waste would create increased risk for nonusers contracting blood-borne infections resulting from needle-stick injuries.²⁹ Naloxone, in many ways, came to occupy the same position as sterile syringes given to people who inject drugs, with opponents to layperson THN arguing that it enabled or even encouraged drug use and represented a defeatist position in the struggle to combat addition. As drug scholars have demonstrated convincingly, providing naloxone to PWUO and recognizing them as active agents in their own lives was thought to be inconsistent with a criminal justice emphasis on supply reduction through law enforcement and DEA interdiction and demand reduction, typically conceived of as abstinence-based therapies.^8,30

Due in part to these numerous barriers, by 2013, only 55% of syringe exchange programs had established naloxone distribution.³¹ In only a few short years, however, the long process of establishing a tenuous foothold in community-based organizations gave way to widespread endorsement, and by 2017 every state in the United States had established some form of naloxone access laws providing access to people at-risk, and federal agencies, including the Centers for Disease Control and Prevention (CDC) and Substance Abuse and Mental Health Service Administration, endorsed THN. Throughout this period, community activists, people who use drugs, academics, researchers, service providers came together and held countless community meetings, drafted legislation, lobbied State and Federal government, the Food and Drug Administration, and created national networks of advocacy and innovation with the common goal of expanding naloxone access and saving lives. Another priority was getting naloxone into the hands of first responders, including police, firefighters, and emergency medical service personnel.^32,33 In some communities, first responders also began providing naloxone to those at risk and their friends and family.³⁴ Naloxone “leave behind programs”³⁵ were also established so naloxone could be officially provided at locations where overdoses had occurred in order to prevent subsequent emergencies.

Community-based clinics and treatment programs, as well as several larger health systems and hospitals, established THN programs which became an integral part of medical practice in many settings. The Veterans Administration, for example, began naloxone distribution programs and THN in 2014, subsequently establishing OEND programs throughout their facilities and effectively translating community-based OEND into a national healthcare system approach, marking the establishment of the largest, national naloxone distribution program to those at risk to date.³⁶ With historically high rates of opioid analgesic use to treat chronic pain, veterans were at heightened risk for OD^37–40 and were a population perceived to be unequivocally deserving of naloxone, and access expansion in the VA faced less backlash than it did among other PWUO populations.

Re-framing people who use drugs.

For many observers and researchers tracking the policy changes that have transpired since the beginning of the current US opioid crisis, a newfound interest in public health approaches (rather than trough-on-crime criminal justice policies characteristic of the War on Drugs) was directly linked to opioid impacts on predominantly white, middleclass communities.^2,41–43 These shifts have ultimately benefited many white, suburban communities, while many low-income, predominantly Black and Latino communities have seen little change in policing or access to prevention and treatment resources.^44,45 Seminal works by historians have traced the emergence of the modern War on Drugs and its disproportionate impact on many poorer people of color,^46–48 especially Black males. Indeed, critics have long identified the resistance to funding and legalizing THN as part of a broader set of punitive policies and criminal justice-oriented ideologies about the importance of waging a drug war on PWUO.^8,30 Critics point out that from the early 2000s to the present, white people not previously thought of as at-risk suddenly emerged as a vulnerable group in need of being “saved,” making political endorsement of OEND/THN suddenly fashionable.^2,41–43

While the shift from criminal justice to a public health framework benefited many white, suburban communities, other communities composed primarily of Black and Latino individuals were missed, continuously burdened by criminal justice rather than therapeutic interventions.^44,49

Despite the ample barriers to naloxone access that continue to exist (and will be reviewed in the following section), the roughly 20-year expansion of naloxone from the confines of a few syringe exchange programs to what we see today represents an enormous triumph for the grass-roots activists, service providers, and public health professionals who have fought not just to guarantee lay access to naloxone but for the protections to assure that fear of reprisals after administering does not unduly deter potential responders. Both naloxone standing orders^50,51 and Good Samaritan Laws have been critical thus far. Naloxone standing orders allow for dispensing of the medication under a blanket directive without the prescriber having examined the patient, a process referred to as “nonpatient specific prescription.”⁵² Overdose Good Samaritan Laws aim to reduce overdose mortality and morbidity associated with the fear of calling 911 by providing at least some legal immunity against prosecution for drug and paraphernalia possession (as well as for parole violations in some jurisdictions) for those calling 911 and present at an OD. Forty-six states had enacted a Good Samaritan Laws as of December 2018.⁴

Current obstacles.

Despite the extensive efforts to expand access to naloxone documented in Section 1, naloxone continues to remain a scarce resource in many US localities. Currently, only 34 states in the United States have syringe exchange programs, leaving many localities with only pharmacy-based access as an option, and even in the presence of ample no-cost supply, other barriers to optimal uptake and intervention durability remain. In this section we review briefly the current challenges facing those working to universalize naloxone access and maximize the likelihood that doses dispensed will be available when overdose events occur.

AVAILABILITY—THE CHALLENGE OF SATURATION

Researchers, health departments, and service providers working on expanding access to naloxone refer to “saturation” as the achievement of adequate numbers of naloxone kits within a community to assure that overdose deaths do not result from a fundamental lack of access to the medication.⁵³ Saturation, in other words, is the point at which providing additional naloxone supplies to a community fails to further reduce overdose mortality rates. While the concept is relatively simple, saturation efforts are complicated by the numerous variables that impact the calculation of how many naloxone kits per 100,000 population are required in any given location. Between 10% and 25% of heroin users overdose annually,^54–57 and most of those events are nonfatal,⁵⁸ but the numbers of PWUO in different localities are hard to estimate, as is the range of illicit opioids being consumed. Areas with greater proportions of illicitly manufactured fentanyl (IMF) products, for example, may experience considerably higher overdose rates than those dominated by black tar heroin.²⁶ Two studies indicate that roughly two-thirds of opioid users sampled in Rhode Island⁵⁹ and NYC⁶⁰ reported having witnessed at least one overdose, but very little is known about the social contexts for illicit opioid use and whether group use in public or semipublic locations like parks, alleys or informal shooting galleries (vs. solitary use in homes and apartments) varies significantly by region and population density. All of these factors influence naloxone saturation calculations, as well as strategies for outreach designed to best reach local populations of PWUO.

What is clear, however, is that across different regional, pharmacological, and cultural contexts, increasing the availability of naloxone, especially to PWUO, results in rapid and dramatic increases in overdose reversals.⁶¹ In a study of Massachusetts naloxone outcomes, 87% of rescue attempts involving naloxone were made by opioid users themselves,²⁰ and a comprehensive examination of community-based naloxone provision in the United States⁶² indicate that naloxone provided to active substance users can result in almost a 1:1 ratio of reversal attempts to kits provided in high risk clusters.^16,62,63 When a more conservative estimate of 1 reversal for every 5 kits provided to users is employed,¹⁷ the number of kits needed to blanket communities is clearly more substantial. According to recent data collected by the CDC, many areas across the United States remain underserved by OEND and undersupplied with naloxone.⁶⁴ In many states, some counties have effectively zero access to naloxone, despite the enormous returns on investments—not simply in terms of lives saved but also as reductions both in medical expenses and the broader economic costs of accidental deaths—when more than 100 kits per 100,000 population are provided.⁶⁵ The CDC points to enormous gaps in access, with highest-dispensing counties in the United States having roughly 25 times the rate of dispensing than in the lowest-dispensing counties.⁶⁴ Even where prescribers in primary care and substance use disorder treatment programs prescribe naloxone for PWUO and local pharmacies stock it, financial barriers may persist for low-income PWUO, as more than half of naloxone prescriptions in 2018 required a copay.⁶⁴ A 2017 assessment found that rural communities are 3 times more likely to be in the lowest dispensing group than metropolitan areas, and a number of high OD mortality counties–many across Appalachia, the South, and Southwest of the United States–were among the 8% of US counties that had no community based OD prevention programs distributing no-cost naloxone.⁶⁶

Barriers to uptake.

Even where ample supplies of naloxone exist within a community, countless dynamics can serve to diminish the impact of the lifesaving medication. Broadly speaking, these barriers fall into 1 of 2 categories—lack of awareness about the medication’s availability or limiting attitudes about the drug’s utility or acceptability, the latter often due to perceived stigma around naloxone and PWUO. Despite the rapid escalation of naloxone distribution outside of professional medical communities in the past decade discussed above, recent research reports suggest that a considerable subpopulation of PWUO continue to not know about naloxone or know about it but not where to get it.^33,67,68 This lack of knowledge is not limited to PWUO. Internal medicine residents in recent research have generally expressed favorable attitudes toward naloxone prescribing, but have very little experience in prescribing, in part because of uncertainty about how and when to do so.⁶⁹ Similarly, pharmacists and pharmacy technicians have reported great support for open access to naloxone in pharmacy settings but are often poorly trained and informed about the particular uses of naloxone.⁷⁰ For those whose access to naloxone exists solely through a traditional healthcare setting, stigma may also create additional obstacles. The “opt-in” structure of prescriptions (usually for PWUO flagged by physicians as “high risk”) has been described as creating unnecessary stigma around accessing naloxone in pharmacies⁷¹ that might be avoided by prescribing naloxone to all persons receiving opioid analgesics, regardless of perceived risk status.

In addition to insufficient awareness among some providers, not all perceptions of naloxone distribution to laypersons among medical personnel and other stakeholder groups are positive. The burden of nonfatal events on hospitals and emergency medical services (EMS) personnel and emergency department staff is pronounced^72,73 and has fed into critical and highly stigmatizing narratives about PWUO in some US towns⁷⁴ and among some professional first responder communities.^75–77 Some health-care providers hold negative views of PWUO due to a perceived overuse of resources and failure to adhere to recommended care.^78,79 Some of the critical discourse is grounded in the aforementioned assumptions about the potential for naloxone to function as a “safety net”.⁸⁰ Some small-scale media coverage about strategic heroin and naloxone mixing among youth^81–83 has potentially motivated clinicians’ concerns about risk compensatory behavior⁸⁴ and the ways in which naloxone is presented to PWUO,⁸⁵ but to date scientific inquiry has tended to suggest that alarmism about naloxone’s potentially disinhibiting effects are inaccurate. A recent study of naloxone recipients found no evidence of compensatory increases in heroin and polydrug use among people currently using heroin,⁸⁶ while participants in other qualitative research have spoken strongly against the safety net hypothesis, arguing that no one with an opioid dependency wants to risk being administered naloxone and experiencing a precipitated withdrawal because they overdosed.⁶⁷

Regardless of whether or not some degree of risk compensatory behavior exists around naloxone,⁸⁷ the evidence of the intervention’s efficacy in combatting overdose mortality far outweighs any negative secondary consequences among a minority of naloxone recipients. Expanded training protocols that go beyond the basic technical overview to overdose reversal provided in most OEND interventions⁸⁸ may prove effective in deterring risk compensatory behavior, but the current evidence strongly suggests the main problems related to naloxone dissemination among PWUO in the US today ultimately derive more from insufficient supply, healthcare provider ignorance and stigma,⁸⁹ and a lack of awareness about naloxone’s purpose and availability among people who use drugs.^90,91

Having vs. holding.

The literature cited above on OEND offers a relatively clear picture of the obstacles limiting the efficacy of OEND in deterring overdose mortality in the United States. The problem with confining the discussion to the topic of saturation, however, is that very little research has actually demonstrated what saturation “looks like” once achieved. A lot of what we know about THN comes from European examples. Scotland was the first to implement a national naloxone distribution program, and both it and Norway are currently at the forefront of evaluating widespread distribution efforts.^2,92 In Norway,⁵³ where efforts to saturate communities with naloxone appear better supported and funded than in many US States, after implementation of take-home naloxone programs in 7 cities, resulting in provision of roughly 500 nasal sprays per 100,000 population on average, researchers found that the program had reached a point at which further naloxone supply was unlikely to improve rates of uptake. Evaluations of Scotland’s national THN program, which was established earlier, in 2011, suggested that for THN to be available at every witnessed opioid-related OD, a national THN-policy should aim to issue between 9 and 20 times as many kits as there are opiate-related deaths annually.^92,93 While supply required for saturation is linked to overdose mortality rates and the size of local at-risk populations, these figures suggest rough benchmarks by which efforts across the United States might be calibrated. Perhaps more importantly, the studies are stark reminders that saturation is only a first step toward realizing the full potential of naloxone to reduce overdose mortality. In the 6 Norwegian cities that had established THN programs, for example, the mean rate of having been trained in naloxone among high-risk individuals was 58%, with only 43% in current possession of naloxone when surveyed by study staff.

As is clear from the European case studies, even when naloxone is readily available in community settings, people at risk for opioid-involved overdose often do not access OEND/THN programs even when they are available in their localities for a complex range of reasons. In our own current work with a sample of 575 people who use illicit opioids in NYC (a city with extensive and relatively longstanding naloxone saturation efforts via OEND/THN and subsidized pharmacy access programs), we find somewhat greater rates of uptake than those in Norway, but other findings indicate we have much more to do to be able to realize the public health benefit of readily available, no-cost naloxone. Of the 575 PWUO, recruited via respondent driven sampling across all 5 city boroughs to create greater representativeness, 66% (379) had ever received OEND and an impressive 80% (302/379) of those who had ever been trained were currently in possession of a naloxone kit. When asked on how many days in the past 30 days naloxone was available for use when consuming opioids, however, 65% (374) of all participants (574) indicated 0 days, and the mean number of days naloxone was reported to be available when using opioids was only 7.9 days. Part of this gap between “possessing” naloxone and “having it available” is attributable to PWUO forgetting to carry it, feeling insecure about their competence to use it,⁶⁸ fear of police involvement,⁹⁴ or finding the standard blue bag “kit” used in many US-based OEND conspicuous or cumbersome.⁶⁷ However, in our own research we found that solitary living and opioid use scenarios—only 20% of the sample reported living with someone else who used opioids, and 38% of the sample lived alone—was the biggest driver of naloxone inutility among even those trained and in possession of it. For solitary users and those without networks of other PWUO with whom to share the responsibility of looking out for others, the potential value of take-home naloxone is effectively negated.

The challenges ahead.

Clearly, saturating communities with naloxone is one of the most salient challenges for naloxone distribution programs in the near future, and this section addresses a number of contexts and stakeholder groups around which considerable efforts are still required. Despite much effort on the part of activists, local health departments and others to expand naloxone into every community, as our review has shown, considerable naloxone “deserts”⁹⁵ remain and even where there is naloxone access, it does not always reach those at risk. As we have written elsewhere, that in at least some localities, it is now appropriate to begin asking how to move “beyond saturation,”⁹⁶ in the sense that providing adequate naloxone to a community is only the groundwork for a fully-realized overdose mortality prevention effort. In this final section, we draw upon our own experience with naloxone distribution as well as the extensive activism and research of others, to begin to define an agenda for OEND for the coming years.

TOWARD UNIVERSAL ACCESS

As we have highlighted in the previous sections, naloxone availability across the United States continues to appear as a patchwork of regional microclimates, ranging from the rainforest-like abundance of left-leaning coastal metropolises, like New York City and San Francisco, to deserts like southern Nevada, or much of Appalachia, where overdose mortality rates have led the nation but failed to prompt the adoption of OEND programs.⁶⁶ In many ways, the absence of OEND follows from the absence of syringe exchange programs, and areas lacking both have historically tended to gravitate toward the political right. In some localities, however, the issues are not so much political opposition to harm reduction interventions and infrastructure, but geographically diffused population bases and limited resources for any public health intervention. While front-line harm reduction workers have developed many effective and radical systems of naloxone delivery to reach many hidden populations of drug users, efforts across rural America cannot easily follow the model set by relatively wealthy population centers.⁹⁷

Telehealth approaches to OEND.

Establishing large scale mechanisms of naloxone delivery is critical, and COVID-19 has brought additional concerns about the limitations of face-to-face delivery mechanisms that have characterized much of the naloxone distribution in the United States, whether via pharmacies, OEND outreach, or prescriptions written in doctors’ offices. Mail-order, on-demand naloxone represents one of the most important and timely interventions to emerge in response to the countless communities underserved by OEND and THN in the United States. Begun by Jamie Favaro and collaborators and inspired by the grassroots naloxone distribution of Tracey Helton, NEXT Distro has, since 2017, provided OEND via an online training and registration portal and mailed naloxone, effectively advancing a telehealth model for OEND.^98,99 While NEXT Distro has, to date, provided more than 20,000 mail ordered naloxone kits across the United States, this is only the beginning of what could be achieved with more extensive federal or state support for the telehealth model. Publicizing the availability of naloxone across the rural United States is, in itself, a considerable task that would require participation from local healthcare providers, law enforcement, EMS, and treatment providers if it were to be fully realized.

Lowering barriers to pharmacy access.

Naloxone access laws have improved access to naloxone in pharmacies resulting in significant increases in naloxone uptake in the years following the implementation of standing orders.^52,100–102 Some indications suggest, however, that access laws are effective in lowering rates of fatal overdose only when they include a provision allowing pharmacists to dispense directly and under their own authority.¹⁰³ Need for a physician’s prescription can involve stigmatizing experiences of being designated high-risk and involves an additional hurdle for those not well-connected to healthcare services.⁷¹ Even where pharmacists are granted authority to dispense and express favorable attitudes about naloxone, many continue not to dispense it to clients receiving high-dose opioid analgesics and/or opioid-contraindicated substances like benzodiazepines.^100,104 Indeed, one study found that mandating the co-prescribing of naloxone quickly expanded access to naloxone for people in more places,¹⁰⁵ a finding which holds considerable implications for larger saturation efforts. Especially in light of the pain management and psychological co-morbidities so common among PWUO we highlighted, providing naloxone at no-cost and no charge along with other medications to people who may be at risk due to pain or psychological challenges can greatly expand naloxone in communities.

Co-prescription recommendations would likely benefit from specific co-prescription recommendations for patients with: OUD who are prescribed opioids, those on long-term MOUD, co-prescribed opioid and benzodiazepines, previous overdose, patients with alcohol use disorder, and other medical comorbidities that impact respiration. Establishing protocols for co-prescribing of medications when patients present other health concerns can help extend the reach of pharmacy-based naloxone distribution. Relatedly, given the well-established use of lay prescribers in many OEND programs across the United States and the technical simplicity of administering the more popular intranasal naloxone formulations on the market, a redesignation of naloxone as an over-the-counter drug, requiring no prescription process at all, could be implemented alongside other measures to increase access. To this end, the FDA held hearings on naloxone and recently developed and evaluated a model drug facts label for over-the-counter naloxone sales to assess consumer comprehension of safety and effectiveness and found the model label acceptable for over-the-counter sales.¹⁰⁶

Ambulance settings.

The COVID-19 pandemic and its resulting disruptions to traditional treatment and harm reduction services^107–109 have highlighted the vital role that hospitals and ambulance settings can play in filling some of the gaps in naloxone saturation efforts. One critical area in which emergency medical personnel have begun to do so is in the area of “leave-behind” naloxone, a term which refers to naloxone reversal kits left, most often, with bystanders at the scene of recent opioid-involved overdose, either by law enforcement or EMS.³⁵ As Scharf et al have found, naloxone leave-behind programs can augment existing community-based naloxone distribution efforts and can assure that in resource-limited areas, naloxone is provided to those at highest risk for overdose.³⁵ Training EMS, for example, in more supportive and effective approaches to working with overdose survivors may also have the additional benefit of destigmatizing the experience for more survivors, potentially making them more receptive to treatment and other harm reduction services available to them post-overdose.¹¹⁰

Hospital settings.

While THN emerged in the context of community-based approaches and settings (eg, syringe service programs), hospitals and health systems have great potential as critical settings for delivering OEND to laypersons, patients and their social networks.^111,112 In light of the ratio of fatal to nonfatal OD discussed earlier, OD survivors engaged in emergency departments or other health care “touchpoints”¹¹³ are excellent candidates for OEND and other OD prevention interventions.¹¹³ For these initiatives to be effective, however, some health-care providers may require training interventions of their own, designed to reduce negative and stigmatizing views of PWUO, OD survivors, and substance use disorders in general.^78,79 To address attitudinal barriers among providers, programs are emerging to help reduce stigma toward PWUO among medical students^114–116 and nurses in training,¹¹⁷ and a promising program delivering OEND curricula for medical students and grounded in harm reduction has recently been developed.¹¹⁸

Naloxone co-prescribing and medications for opioid use disorder.

Patients receiving both an opioid analgesic or medication for opioid use disorder (MOUD; ie, buprenorphine, methadone, or naltrexone) have historically only rarely been provided with concurrent prescriptions for naloxone. Although rates of co-prescription have been increasing for those receiving prescription opioid painkillers or painkillers and benzodiazepines, less than 1% of Medicare Part D beneficiaries using licit opioids in 2017 also received naloxone within the week following their opioid prescription.¹¹⁹ These low rates persist despite clear CDC guidelines in support of co-prescription,¹²⁰ widespread support for the practice among physicians,¹²¹ no evidence of increased overdose rates,¹²² and negligible associated legal liability.¹²³ Considerably less is currently known about national rates of co-prescription of naloxone with MOUD. State opioid treatment authorities interviewed about the topic presented differing levels of support and opposition but have historically lacked the authority to mandate co-prescription and note that some treatment conglomerates have already adopted the practice.¹²⁴ Given the gradual process of transitioning from illicit opioid use into MOUD for many, the value of applying the Universal Precautions model¹²² from opioid analgesic prescribing to MOUD seems obvious. While access to co-prescribed naloxone for those receiving MOUD is often dependent on the treatment ideology of the largely private companies providing treatment, federal agencies including the CDC now endorse naloxone co-prescription.¹²⁵

Prison and post-release programs.

Incarceration and being justice involved in the United States both represent heightened risk environments for PWUO and can limit naloxone uptake and use. People who leave prison or jail are at greater risk for overdose and face additional challenges when in the community that may reduce the likelihood that they would use or possess naloxone. An estimated 25% of incarcerated individuals struggle with OUD.^126,127 The lack of evidence-based treatments, an unstable drug supply, and limited access to sterile injection equipment confront many within prisons and jails, although the greatest risk of overdose mortality appears to confront those recently released.¹²⁸ Due to diminished opioid tolerance and the numerous psychosocial challenges faced post-incarceration, recent releases have among the highest overdose rates of any subpopulation of PWUO in the United States. Those with incarceration histories are, overall, more than 4 times more likely to die from an overdose, and in the first 2 weeks post-incarceration overdose is roughly 12 times the rate of the general population.^129,130 Additionally, due to the stigma associated with drug use and its link to naloxone, justice involved persons may be less likely to carry the medication or even associate with others who do, for fear of being labeled a drug user and violating the guidelines set forth by a parole or probation officer.

New York, Pennsylvania and Rhode Island are among the states that have implemented successful OEND interventions into their corrections systems that have shown promise in reducing overdose during and after incarceration.^131,132 Video interventions exist to educate people approaching release about the risks and challenges related to opioid use “on the outside,”^133, and in 2015 the National Commission on Correctional Health Care declared their support of increased access to and use of naloxone in correctional facilities.¹³⁴

Homelessness and shelters.

People experiencing homelessness and living in shelters are also at greatly elevated risks for overdose,¹³⁵ and historically shelters have been ill-prepared to address overdose emergencies effectively due to the lack of harm reduction interventions, including naloxone.¹³⁶ Recent work in emergency shelters and among people experiencing homelessness have proposed potent models grounded in harm reduction^97,136 especially OEND delivered by “peers”—in this context, people with personal histories of substance use and homelessness.¹³⁷ A recent study found that use of MOUD and naloxone among homeless and unstably housed veterans was very low, indicating opportunities for program-specific interventions.¹³⁸ Given the strong evidence for the efficacy of current approaches to targeted outreach among people recently released from prison and those experiencing homelessness, the current need is simply for expansion of existing models across more states and agencies in the United States.

Emergency access naloxone in public and commercial locations.

One of the limitations created by the current prescription and/or training requirement for OEND across the United States is that naloxone cannot be made publicly available at high-traffic, or high-risk locations. Numerous simple, visual instruction guides to naloxone administration exist already, making provision of reversal kits in well-marked containers in public parks, playgrounds, and bars, as well as other locations frequented by PWUO, an important step toward expanding the potential value of a single naloxone kit. Ours and others’ research has shown how restaurants and bar employees, for example, typically encounter drug use, overdoses, and syringes in their businesses and are a population of potential responders that should be equipped with the skills to respond to an overdose.^139,140 Similarly, public places like restaurants and bars should all have naloxone available to employees and patrons in bathrooms.¹⁴¹ Indeed, local overdose hotspots such as parks, restaurants, homeless encampments, and fast-food restaurant bathrooms— could easily be provided with emergency-access naloxone within weather-proof enclosures, akin to the presentation of automated external defibrillators in public settings across the United States.¹⁴²

BEYOND SATURATION

As we suggest in earlier sections, the challenges do not end with the achievement of saturation, and in the final paragraphs here we map out some of the domains in which we perceive opportunity to work toward a greater potential utility for every kit dispensed such that every overdose that occurs might have even a marginally higher likelihood of being met with a timely administration of naloxone.

Supporting PWUO protective networks.

Naloxone expansion in partnership with PWUO and their social networks has proven especially fruitful in fighting overdose mortality. Social networks involving PWUO − especially if a network member is connected to a harm reduction agency or other location to obtain naloxone—can greatly extend the reach of naloxone distribution while providing other forms of support.^143,144 While traditional twelve-step and other abstinence-based treatment approaches stress the importance for those in recovery of severing social ties with PWUO, social isolation from other PWUO remains one of the biggest risk factors for overdose mortality. As such, PWUO who carry naloxone, use together, and adopt norms related to taking turns and monitoring each other after drug administration—particularly when using a new or untested supply—are much less likely to experience overdose mortality. For socially disconnected PWUO, the absence of existing networks creates an opportunity for social service agencies, including syringe exchange programs, to help support networking while suggesting best-practices for PWUO. Recent innovations include phone and social media technologies to link individuals so that, even in the absence of co-present monitoring, “buddy systems” can connect otherwise socially isolated PWUO to lay first-responders in possession of naloxone. One such platform, Neverusealone.com, for instance, was utilized over 2,000 times as of the time of this publication, resulting in 12 “saves” where EMS was contacted and intervened in the overdose.¹⁴⁵

Safe consumption.

In many ways, the informal institution of the “shooting gallery” during earlier eras of opioid use in the United States were highly harm reducing. They provided a location where even a single naloxone kit could be used to protect against overdose mortality for a large group of PWUO. Attempts to formalize supervised drug consumption with the formation of “safe consumption facilities” (SCFs; also known as: safe consumption rooms, overdose prevention sites, and safe injection facilities) have largely failed in the United States to date, despite their existence in Europe, Canada, and Australia and widespread support from public health officials and drug researchers. Supervised consumption facilities predominantly face opposition NIMBY politics, rising real estate values in metropolitan areas, and the federal ‘Crack House Statute’ which makes property owners liable for SCF operation.^146–149 By providing a safe indoor environment for the use of illegal substances, most commonly heroin and primarily consumed via injection, SCFs have been demonstrated to effectively remove the risk of OD fatalities (by having staff oversee opioid use and responding immediately in the event of an overdose with oxygen and naloxone), while also minimizing improper disposal of syringes and HIV/HCV transmission among PWUO. A recent evaluation of an unsanctioned SCF found that with 10,514 injections there were only 33 opioid-involved overdoses over 5 years, all of which were reversed by a staff person with naloxone, and no deaths.¹⁵⁰ To date, however, the US Department of Justice remains in opposition to SCFs, and, even in Philadelphia where a federal judge deemed a proposed SCF to be likely to “reduce drug use, not facilitate it” and granted a reprieve to continue development, myriad forms of local pushback have prevented its opening as of early 2021.¹⁵¹

Deputizing dealers.

As Caulkins and Reuter have pointed out, there are many kinds of drug dealing in the United States, and much of it is small-scale and represents relatively little harm compared with larger-scale, violent drug organizations and cartels,¹⁵² especially if law enforcement embraces a “hands off approach” toward smaller “free-lance” dealers and refrains from targeted enforcement, which often make drug markets more volatile.¹⁵³ Despite this, the current trend is toward an escalation of criminal justice pressure, including prosecution of opioid dealers for murder and/or manslaughter after the overdose deaths of their clients,^154,155 even when the “dealing” is effectively the sharing of small quantities of opioids among friends.¹⁵⁶ This practice creates serious legal risks for PWUO who witness an overdose and cannot trust that Good Samaritan Laws will protect them against prosecution after calling 911,¹⁵⁴ while also potentially making dealers less likely to engage with harm reduction outreach due to legitimate fears of detection. This creates a powerful barrier to recruiting dealers as lay prescribers of naloxone. Despite these barriers, research with people who sell drugs has shown their life saving capacity as harm reduction agents, especially when trust and communication has been established between users and dealers.¹⁵⁷ Providing multiple naloxone kits to well-networked secondary distributors, like dealers, allows for stronger informal and grassroots education and naloxone distribution and is supported by recent research indicating that people who sell drugs are highly responsive to interventions, like drug checking, that help ensure the safety of their customers.¹⁵⁸

Self- and auto-administration of naloxone.

Supportive social networks of PWUO and contexts for group use clearly represent the most cost-efficient and direct form of increasing the odds of any given naloxone kit being put to use in the reversal of an overdose. However, for those who PWUO are truly socially isolated, face mobility issues, and/or live in the countless regions in the United States that have no harm reduction infrastructure, relatively inexpensive pulse oximeters and auto-injecting formations of naloxone can potentially be combined to create a watch-like apparatus that would detect the diminished blood oxygen saturation resulting from an opioid-involved overdose and administer naloxone automatically.

Self-administration of naloxone has for obvious reasons (namely the inability of anyone taking a potentially fatal dose of opioids to respond in time to save their own life) remained essentially a nonissue,¹⁵⁹ but in certain limited contexts the topic might deserve additional consideration. The loss of life due to opioid-involved traffic accident is rarely discussed or addressed in policy¹⁶⁰ but recent research suggests roughly a doubling of driving accident hazard for people using prescription opioids.¹⁶¹ For people using opioids of any type who suddenly find themselves in need of driving or operating heavy machinery, a small dose of naloxone—sufficient to precipitate only partial withdrawal—has the potential to render the individual more alert and less likely to be involved in an accident. Promoting this form of use among people managing chronic pain with physician-prescribed opioids, for example, could potentially help minimize non-overdose opioid-related mortality while also helping to further normalize naloxone as a drug with multiple forms of utility even outside of the context of substance “abuse.”

Lowering cost of naloxone.

Whether through innovative telehealth distribution networks such as NEXT Distro,⁹⁹ health care or criminal justice settings, co-prescription, or community-based channels, harm reduction agencies have, and continue to, shoulder the logistical and financial burden of getting naloxone into the hands of PWUO, their friends and family members.⁶ Considering estimates that the vast majority of naloxone use is by PWUO themselves¹⁶² and that the community-based organizations that serve them have historically given out the bulk of THN naloxone,³¹ ensuring that community-based harm reduction programs have adequate supplies of naloxone is especially salient. The two main forms of naloxone for community use are injectable intramuscular and intranasal, both of which are recommended for lay and community use by the FDA.¹⁶³ While the price for intranasal naloxone has come down recently, and kits of intramuscular naloxone are likely acceptable to many PWUO, given the presence of fentanyl in the drug supply and that many people are uncomfortable with syringes, ensuring affordable if not no-cost access to both formulations should remain a public health priority.¹⁶⁴

Addressing stigma.

Finally, any discussion of the rather slow process of naloxone expansion and barriers confronted over the past 25 years must address the ongoing stigma directed act people who use drugs. Earlier, we discussed the historical roots of this stigma and its lasting pervasiveness in settings such as hospitals. We have also discussed the indirect role this stigma has played in limiting the provision of naloxone to PWUO as well as to incarcerated persons upon release from jail, including the role of stigma in shaping our reliance on criminal justice frameworks to tackle the overdose crisis in the first place. Here we state simply: there is no magic bullet that will eradicate stigma, but the more we can ensure universal access to naloxone and reframe the way society views PWUO, the more readily naloxone can become normalized as a medicine for every cabinet or backpack.

CONCLUSIONS

As OEND/THN continues to expand to new populations in new settings, and the stigmatizing discourses about PWUO are replaced with discourses of their agency and empowerment, naloxone possession will become more normalized and routine. Adding support to this cultural reframing is perhaps the best thing we can do to help saturate communities with naloxone, as PWUO come to be recognized increasingly as intrinsically part of the social “self” in need of care and compassion, and not the “other” to be ostracized or eliminated. This may ultimately help us, as a society, reconfigure our highly stigmatized and codified conceptions of addiction and begin to address many of the social and structural inequities underpinning them that effectively render drug use problematic for so many.

Practically, our review provides several takeaways that can be acted upon with varying degrees of ease. It is important to understand the ideological struggles that activists faced when establishing OENDs (and syringe exchange programs) that was in part related to the stigmatized status of PWUO in the U.S. context. The expanding image of PWUO to include people from all walks of life has pushed us toward a more benign, compassionate and therapeutic approach to the overdose crisis, rather than one that relies solely on the criminal justice system and many other supply-reduction interventions that may have had the opposite effect of increasing harms rather than reducing them. Efforts to ensure over-the-counter and low- or no-cost naloxone are ongoing and stand alongside medication-assisted treatments as efficacious, readily-actionable, and cost-efficient population-level interventions available for combatting opioid-related overdose in the United States. Even as communities face overdose fatigue,¹⁶⁵ naloxone saturation remains as important as ever, and collective efforts are needed to expand the reach of naloxone distribution and help foster a climate where people in any geographical location and from any sociocultural, racial, or ethnic background can both access and carry the medication without fear of police repercussion and judgment by others.¹⁶⁶

Abbreviations:

CDC

Centers for Disease Control and Prevention

DEA

Drug Enforcement Agency

EMS

Emergency Medical Services

FDA

Food and Drug Administration

MOUD

Medications for Opioid Use Disorder

NIMBY

Not in My Back Yard

OD

Overdose

OEND

Overdose Education and Naloxone Distribution

OUD

Opioid Use Disorder

PO

Prescription Opioids

PWID

People Who Inject Drugs

PWUD

People Who Use Drugs

PWUO

People Who Use Opioids

SCF

Safe Consumption Facilities

SEP

Syringe Exchange Program

SSP

Syringe Service Program

THN

Take Home Naloxone

US

United States

VA

Veterans Administration