Introduction

The opioid epidemic in the USA began in the late 1990s and has recently entered the third decade of increasing opioid overdose deaths. On October 16, 2017, the US federal government declared the opioid epidemic a public health emergency (Hargan 2017). Estimates suggest that the opioid crisis has cost the US economy more than $1 trillion from 2001 to 2017 when considering costs related to productivity, health and child care, family assistance, criminal justice, and education (Altarum 2018; Rhyan 2017). Opioid overdose was responsible for less than 10,000 deaths in 1999 but increased to nearly 50,000 by 2019 (National Institute on Drug Abuse 2021) and opioids accounted for the majority (69.5%) of total drug overdose deaths in 2018 (Hedegaard et al. 2020). Although there was a slight decline in opioid overdose deaths in 2018, in 2019, opioid overdose deaths increased again (from 46,802 in 2018 to 49,860 in 2019) (Hedegaard et al. 2020; National Institute on Drug Abuse 2021). These numbers spiked even further during the COVID-19 pandemic, reaching new all-time highs; data indicate that the 12-month period leading up to April 2021 had more than 100,000 drug overdose deaths and over 74,000 opioid overdose deaths (Ahmad et al. 2021; O’Donnell et al. 2021). It is likely, were it not for the availability of naloxone, that the number of opioid overdose deaths would be higher, but it is difficult to quantify the number of lives saved by naloxone because of the lack of a unified data system.

The opioid epidemic has exhibited three distinct waves due to (1) prescription opioids, (2) heroin, and (3) fentanyl and fentanyl analogs (F/FAs). Opioid overdose deaths due to prescription opioids climbed steadily from the start of the opioid epidemic in the late 1990s to 2011, marking the first wave of the opioid epidemic (Paulozzi et al. 2011). Opioid prescription volume increased between 1992 and 2011 but has decreased substantially (43%) since 2011 (Aitken and Kleinrock 2019). Still, prescription opioid overdose deaths have remained high; 17,029 people died from a prescription opioid overdose in 2017 and these numbers declined to 14,139 in 2019 (National Institute on Drug Abuse 2021). Overdose deaths involving heroin rose during the second wave; 3036 deaths were attributed to heroin in 2010 and this number increased to a peak of 15,469 deaths in 2016 (National Institute on Drug Abuse 2021; Rudd et al. 2014). Since 2016, there has been a slight decrease in overdose deaths involving heroin (14,029 heroin-involved deaths were reported in 2019) (National Institute on Drug Abuse 2021). The third wave marks perhaps the most rapid increase in opioid overdose deaths. Opioid overdose deaths due to high potency opioids such as F/FAs have spiked more than tenfold since 2013; there were 3105 overdose deaths in 2013 and 31,335 deaths just 5 years later (Hedegaard et al. 2020). Concerns have been raised that intranasal naloxone commonly distributed in communities (i.e., Narcan®) may be insufficient for the treatment of F/FA overdose (France et al. 2021; Kim et al. 2019; Lynn and Galinkin 2018); these concerns arise from (1) case studies and retrospective analyses, (2) pharmacokinetics, and (3) pharmacodynamics. The present narrative literature review discusses the utility of naloxone and the current advances and new technologies that may provide additional treatment options for opioid overdose symptoms. This review also closely assesses the methodological details of the observational reports to evaluate their value for informing the efficacy of naloxone against F/FA overdose. The focus of this review is primarily on case studies, controlled clinical trials, and epidemiological evidence; please see France et al. (2021) for a thorough review of the relevant preclinical literature.

Naloxone

History and pharmacology

In the 1950s, the opioid receptor antagonists nalorphine and levallorphan were used to reverse opioid-induced respiratory depression; however, when administered alone, these drugs could also cause respiratory depression (Foldes et al. 1969; Thomas and Tenney 1955). Naloxone hydrochloride was developed in the 1960s and was the first opioid receptor antagonist capable of reducing opioid-induced respiratory depression without producing opioid receptor agonist effects. The FDA approved naloxone in 1971 (U.S. Food and Drug Administration, NDA 016,636), and it is now the most widely used opioid overdose reversal agent. Naloxone was almost exclusively administered in the hospital setting by trained clinical professionals until 1996 when the Chicago Recovery Alliance program became the first opioid overdose prevention program to distribute naloxone to the community (Any Positive Change 2021).

Naloxone is a semisynthetic, lipophilic, competitive, non-selective opioid receptor antagonist that reverses and blocks opioid-induced effects (e.g., analgesia, respiratory depression). Naloxone can be administered via various routes, the time to maximum plasma concentration (tmax) of naloxone is about 2–3 min when administered IV, 10–20 min when administered IM, and 15–30 min when administered IN (Adapt Pharma Operations Limited 2019; McDonald et al. 2018; Ryan and Dunne 2018; Tylleskar et al. 2017). Naloxone has an elimination half-life (t1/2) of 1–2 h when administered IN or IM (Adapt Pharma Operations Limited 2019; Tylleskar et al. 2017), while IV fentanyl has an elimination half-life of 4.4–9.7 h (Ahonen et al. 2000; Bentley et al. 1982). The short half-life of naloxone relative to many opioid receptor agonists may lead to the recurrence of respiratory depression during an overdose event and require that multiple doses of naloxone be administered (Carpenter et al. 2020; Fareed et al. 2015; Kitch and Portela 2016; Lyttle et al. 2012; Raja et al. 2017; Rogers et al. 2016; Wilde et al. 2020; Zuckerman et al. 2014) (see Table 2).

While naloxone is generally considered safe and effective, one of the most common risks regarding naloxone administration is precipitation of abrupt onset opioid withdrawal in those who are physically dependent on opioids (Evans et al. 1973; Loimer et al. 1992; Wikler et al. 1953). Higher naloxone doses are associated with a higher incidence of opioid withdrawal symptoms (Purssell et al. 2021), which may have implications for the utility/acceptability of higher dose formulations. More rarely, cardiovascular effects can also be seen in people who inject high doses of opioids or use stimulants (Cuss et al. 1984; Hunter 2005; Lameijer et al. 2014; Merigian 1993; Osterwalder 1996).

One concern about the efficacy of naloxone to treat a real-life overdose event is that multiple intoxicating substances, in addition to opioids, may also be present and may contribute to the overdose event (e.g., stimulants, benzodiazepines, alcohol, etc.). The complex pharmacology of polysubstance overdose can pose serious challenges for overdose treatment. Only one non-opioid overdose reversal agent is available for commonly misused psychoactive drugs; flumazenil is approved for the reversal of benzodiazepine overdose. However, flumazenil should only be administered in a hospital setting because it can cause potentially serious side effects (e.g., seizures) and can worsen overdose involving both stimulants or antidepressants and benzodiazepines (Burr et al. 1989; Penninga et al. 2016). In a real-life situation, drugs contributing to a polysubstance-related overdose are typically unknown and the risks of naloxone administration are outweighed by the risk of death from respiratory depression due to opioid overdose.

Currently, the FDA has approved labeling for generic naloxone in the clinical setting which states that initial doses of 0.4 to 2 mg of IM naloxone are appropriate and that naloxone administration can be repeated to a maximum dose of 10 mg (Adapt Pharma Operations Limited 2016). Other products have been developed for use by medical and non-medical personnel. Narcan®, developed by Adapt Pharma (acquired by Emergent BioSolutions in 2018), was approved by the FDA in 2015 and is available as a 4 mg/0.1 mL IN spray (Adapt Pharma Operations Limited 2019; Center for Drug Evaluation and Research 2015). Evzio® was manufactured and distributed by Kaléo Inc.; it was originally FDA-approved as a 0.4 mg/0.4 mL IM/SC autoinjector but received approval at a higher dose of 2 mg/0.4 mL in 2016 (Center for Drug Evaluation and Research 2016; Kaleo Inc. 2014; Kalei Inc. 2016). However, this product was removed from the market in 2020 (U.S. Food and Drug Administration 2021c). More recently, the FDA granted approval of Teva Pharmaceutical’s generic naloxone 4 mg/0.1 mL IN spray in 2019 (U.S. Food & Drug Administration 2019), which became available in December 2021 despite ongoing litigation with Adapt Pharma. Within that same month, Sandoz launched a generic naloxone 4 mg/0.1 mL IN spray with approval by Emergent BioSolutions (PRNewswire 2021). Unfortunately, the entry of these generic formulations onto the market does not provide the hoped-for increase in access that would accompany substantive financial discounts. Teva Pharmaceutical’s generic product is 5% less than the Narcan® wholesale price and Sandoz’s product is 6.5% less than Narcan® (Dunleavy 2022). Additionally, at this point, it is not clear that these new generic products will offer a public health discount that is currently available for Narcan®, which reduces the price by ~ 40% (Dunleavy 2022).

The NIH has previously called for higher dose naloxone products due to the rise in opioid overdose deaths (Volkow and Collins 2017). In 2021, the FDA approved two higher dose naloxone products: KLOXXADO™ (Hikma Pharmaceuticals) received FDA approval in April 2021 and became available on the market in August 2021. This product delivers 8 mg IN naloxone, double the highest dose available in the previous products (Hikma Specialty USA Inc. 2021; U.S. Food and Drug Administration 2021a). Some have voiced concerns that an 8 mg IN naloxone spray may be too high and potentially harmful (Hill et al. 2022). ZIMHI™ (Adamis Pharmaceuticals), a product that delivers 5 mg IM or SC naloxone, also received FDA approval in October 2021 and is expected to be available on the market in early 2022 (Global Newswire 2021; U.S.  Food and Drug Administration 2021b).

Efficacy against fentanyl and fentanyl analogs

The efficacy of naloxone to reverse opioid-induced respiratory depression has been well-known for over 50 years. Some clinical studies have demonstrated naloxone reversal of respiratory depression induced by morphine, morphine-6-glucuronide (Olofsen et al. 2010), and buprenorphine (van Dorp et al. 2006). A double-blind study of patients in the emergency department for suspected opioid overdose reported that naloxone was a safe and efficacious treatment (Kaplan et al. 1999). Another randomized trial of 172 patients with suspected opioid overdose found that 72.3 and 77.5% of patients responded within 10 min of pre-hospital IN and IM naloxone administration, respectively (Kerr et al. 2009). One study reported that roughly 66% of patients who received naloxone before arriving at the hospital had a Glasgow Coma Score greater than 14 (indicating the patient is fully awake and alert) and that these patients were less likely to require additional medical intervention (Fidacaro et al. 2019).

It is important to understand the efficacy of naloxone as a reversal agent for F/FA overdose given the recent rise in illicit F/FA overdose deaths. We were unable to find any rigorously controlled prospective clinical studies directly examining the dose–response of naloxone for the treatment of illicit F/FA overdose in humans. The FDA has not recommended a minimal naloxone dose for administration by a layperson but has advised that products developed for bystander use should achieve a minimum exposure that is similar to 0.4 mg IM naloxone with a similarly rapid onset (Adapt Pharma Operations Limited 2016).

Morphine, fentanyl, and naloxone share some pharmacokinetic characteristics, but a notable exception is their lipophilicity. The lipophilicity of naloxone (logP = 2.09) is greater than morphine (logP = 0.89–1.07), but lower than fentanyl (logP = 4.28) (National Library of Medicine 2021a; National Library of Medicine 2021b; National Library of Medicine 2021c). The high lipophilicity of fentanyl results in rapid distribution; the distribution half-life of fentanyl has been reported at 1.36–2.5 min after IV administration and ~ 6.5 min after IN administration (Bentley et al. 1982; Foster et al. 2008). Rapid distribution of F/FAs and movement across the blood–brain barrier may contribute to the rapidity of F/FA overdose. In an emergency overdose situation, the window of time that naloxone administration will effectively reverse F/FA overdose may be very narrow compared to other opioids. In one report 75% of people interviewed (n = 64) in Massachusetts who witnessed, received, or administered naloxone due to a fentanyl overdose reported that overdose symptoms occurred within “seconds to minutes” (Somerville et al. 2017). This study also reported that records of those who died from fentanyl overdose indicated that 90% of overdose decedents were pulseless when EMS arrived and 36% of these overdose cases occurred within “seconds to minutes” after drug use (Somerville et al. 2017). Another study found that healthy patients undergoing a surgical procedure experienced changes in their respiratory pattern and heart rate 15–30 s after receiving 0.25–0.8 mg fentanyl IV (Grell et al. 1970). This narrow window of time in which an overdose needs to be identified and treated with naloxone is a significant concern that differs from other commonly misused opioids (e.g., heroin).

Another concern with F/FAs centers around non-morphine-like effects that occur at relatively low doses, specifically the rapid onset of diaphragm and muscle wall rigidity and vocal cord closure, a clinical effect termed “wooden chest syndrome.” One clinical study of fentanyl as a supplement to N2O-O2 in 584 patients requiring anesthesia reported that a fentanyl dose of 0.25 mg consistently produced chest wall rigidity within 60–90 s, and this effect persisted for 8–15 min (Grell et al. 1970). Other studies have reported fentanyl-induced chest wall rigidity in patients scheduled for open-heart surgery, with no concurrent administration of N2O. In these studies, 90–100% of patients administered fentanyl (19–50 μg/kg) experienced chest wall rigidity (Comstock et al. 1981; Hill et al. 1981; Kentor et al. 1980). Two studies have also reported that F/FA-induced muscle rigidity occurred in the vocal cords, resulting in vocal cord closure (Bennett et al. 1997; Scamman 1983). Preclinical studies have suggested that naloxone is incapable of treating F/FA-induced muscle rigidity (Miner et al. 2021) and that F/FA-induced muscle rigidity may be at least in part due to activity at noradrenergic receptors in addition to μ-opioid receptors (Lui et al. 1993, 1989, 1990, 1995; Weinger et al. 1988). Patients who receive fentanyl anesthesia also typically receive paralytics with mechanical ventilation for akinesia which conveniently prevents wooden chest syndrome and paralytics are listed as a treatment for fentanyl-induced muscle rigidity in the highlights of prescribing information for fentanyl citrate injection (Akorn Inc. 2019). A number of published reports outline concerns about the ability to treat non-opioid receptor-mediated F/FA-induced muscle rigidity during an overdose event (Pergolizzi et al. 2021; Torralva and Janowsky 2019; Volkow 2021). However, the prevalence of wooden chest syndrome and vocal cord closure in people who are experiencing an overdose, the role it plays in F/FA overdose, and naloxone efficacy against wooden chest syndrome are largely unmeasured at this point.

Studies in patients administered fentanyl anesthesia during surgery have reported that naloxone reversed respiratory depression (Takahashi et al. 2004; Tigerstedt 1977). While these data are intriguing, it is difficult to generalize these results to illicit fentanyl overdose scenarios, which can vary widely with respect to the dose administered and specific fentanyl analog. Some retrospective chart reviews, community outbreaks, and surveys have suggested that the incidence of multiple doses of naloxone per overdose event is increasing, while others suggest no change in naloxone dose administration (Table 1). A CDC report interviewed 64 people in Massachusetts who witnessed, received, or administered naloxone due to a fentanyl overdose and found that 83% of respondents reported more than two doses of naloxone were required (Somerville et al. 2017). Available naloxone kits at that time contained 2 mg/2 ml, IN; therefore, if functioning optimally, two doses of naloxone at that time would be equivalent to one dose of the currently used product, Narcan® (4 mg naloxone); however, it is unknown if the jerry-rigged naloxone atomizer used for IN administration during this time was optimized for full delivery. A prospective analysis of 89 patients admitted to the emergency department from July 2016 to July 2017 due to unintentional opioid overdose reported that the average pre-hospital naloxone dose administered was 5.8 ± 5.0 mg (range: 0–26 mg; median: 4 mg). Additionally, only two patients received naloxone in the emergency department after being treated pre-hospital; however, it is important to note that this study excluded people who were incapable of completing the survey (possibly due to opioid overdose signs and symptoms, e.g., sedation) and that the overdoses captured in this study cannot be attributed to F/FAs as urine toxicology was performed on only 7% of patients (Marco et al. 2018). Several case studies of F/FA overdose have been reported in the literature, but it is difficult to draw conclusions from these reports due to numerous caveats, including inconsistent patient treatment and outcomes (see Table 2).

Table 1 Community fentanyl outbreaks, retrospective reports, and surveys
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Table 2 Case studies on naloxone effects against highly potent opioid receptor agonist overdose
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In contrast, in a retrospective study of emergency department records from a fentanyl outbreak (confirmed via medical examiner findings) in Chicago, IL, from April 2005 to December 2006, the average pre-hospital dose of naloxone was 1.53 mg (range: 0.4–4 mg, 81% via IV route and 11% SL), whereas naloxone administration in the emergency department was an average of 3.36 mg (range: 0.4–12 mg). Again, a direct fentanyl-naloxone relationship cannot be established in this study because no blood or urine screens were tested for fentanyl (Schumann et al. 2008). When records of 957 EMS-transported patients suspected of “uncomplicated” (i.e., without comorbid acute medical conditions) fentanyl overdose were retrospectively analyzed, 47.1% had received naloxone from a bystander and 57.2% of patients received naloxone from EMS, with the average naloxone dose administered by EMS being 0.4 mg, parenteral. Additionally, 18.2% of patients received naloxone from both a bystander and EMS. However, no analyses were performed to confirm if F/FAs were involved in the overdose episodes (Scheuermeyer et al. 2018). Finally, one recent retrospective emergency department chart review reported that there was no significant difference in the amount of IV naloxone required to reverse overdose symptoms in 121 patients who had urine drug screens test positive for fentanyl, other opioids, or both fentanyl and other opioids (Carpenter et al. 2020).

Collectively, these various reports from emergency departments and emergency medical services do not support the contention that naloxone is incapable of reversing a F/FA overdose. Interpretation of these reports is limited by a lack of data reported regarding total or incremental naloxone doses, routes of administration, and qualitative or quantitative serum and urine toxicology reports; inclusion of decedents in analysis; and exclusion of patients with severe opioid overdose symptoms (i.e., unable to complete a survey due to overdose symptoms). The doses of naloxone administered in these studies, if reported, are often reported as averages or ranges, which can be misleading if one patient required a substantially higher dose of naloxone than others. When toxicology reports are included, they are often qualitative (i.e., positive/negative within a specified cutoff), which provides little information about the actual concentration of the opioid agonist and its contribution to the overdose event. Additionally, EMS and ED opioid reversal protocols may be locally standardized, which could drive dosing practices, but these are rarely available alongside empirical data. Even when these protocols are reported, the opioid(s) responsible for an overdose may be novel or unknown, omitted from reports, or detected in combination with other drugs. These issues make drawing conclusions about naloxone’s ability to reverse F/FA overdose nearly impossible from the extant literature. More research is needed to fully understand the relationship between F/FAs and overdose reversal by naloxone. Overall, there is an absence of quality data supporting the conclusion that currently available naloxone products are ineffective at treating illicit F/FA overdose.

Recent advances in overdose treatments and technologies

Nalmefene

Nalmefene is a μ-opioid receptor antagonist capable of reversing opioid overdose signs and symptoms, including respiratory depression. Revex®, an injectable nalmefene product, was approved by the FDA in 1995 for the reversal of opioid overdose signs and symptoms but was removed from the market by Baxter Healthcare Corporation in 2008 due to “business reasons,” not safety or efficacy concerns (Abram 2017). A meta-analysis of eight randomized controlled trials comparing nalmefene (10–100 mg/day for 1–52 weeks) to placebo or active control in patients with substance use or impulse control disorders reported no evidence that nalmefene was associated with increased risk of serious adverse events, suggesting nalmefene is safe (Johansen et al. 2017). However, those taking nalmefene were 3.22 times more likely to withdraw from the study due to unwanted side effects/adverse events, these side effects are outweighed when nalmefene is administered acutely during an emergency overdose event.

Nalmefene has a considerably longer half-life (8–11 h) than naloxone (1–2 h), which may be beneficial against many opioid receptor agonists that also have a longer half-life (Dixon et al. 1987; Gal and Difazio 1986; Glass et al. 1994; Konieczko et al. 1988). Two randomized double-blind studies of six healthy men each reported that nalmefene (2 mg IV or 50 mg oral) pretreatment prevented subjective and respiratory effects for up to 8 h and 48 h, respectively, when challenged with 2 μg/kg of fentanyl (a dose commonly used during surgical procedures and for postoperative pain) (Gal and Difazio 1986; Gal et al. 1986; Prescriber’s Digital Reference 2021). One study directly compared naloxone and nalmefene (1, 2, 4, or 8 μg/kg of either drug) reversal of fentanyl (IV infusion to obtain 1.5 ng/mL plasma concentration) and reported both antagonists were equipotent at reversing opioid-induced respiratory depression (Glass et al. 1994). This study also reported that nalmefene clearance was approximately 2.5-fold slower and the elimination half-life nearly two times longer than naloxone (Glass et al. 1994).

Unfortunately, nalmefene has a slow absorption rate when given intranasally; a study in healthy adults reported that IN nalmefene had a Tmax of 2 h (Krieter et al. 2019). As such, the FDA granted fast-track designation of injectable nalmefene to Purdue Pharma L.P. in 2019 (Purdue Pharma 2019), but no IN products have been approved. Opiant Pharmaceutical is currently developing and testing an IN nalmefene formulation, OPNT003. A recent study by the sponsor reported that dodecyl maltodise, an absorption enhancement agent used in other approved pharmacotherapies (e.g., Tosymra®), significantly improves the bioavailability of IN nalmefene (Krieter et al. 2019). The formulation of dodecyl maltoside + nalmefene had a Tmax of 15 min, while nalmefene alone had a Tmax of 2 h. Additionally, the combination of dodecyl maltodise and nalmefene produced maximum plasma concentrations more than double that of nalmefene alone, and at 15 min post-administration the plasma concentration of nalmefene was nearly 12-fold greater in those who received dodecyl maltodise + nalmefene (Krieter et al. 2019).

Taken together, these data suggest that nalmefene is safe and well-tolerated. In contrast to naloxone, the long half-life of nalmefene is similar to or greater than that of many opioid receptor agonists. Although nalmefene alone has poor IN bioavailability, new data suggest a combination formula with dodecyl maltoside may obviate this issue and show promise for a novel opioid overdose reversal agent.

Respiratory stimulants

There is some interest in utilizing non-opioid respiratory stimulants to treat respiratory depression caused by opioid overdose. While this work is largely still in the preclinical stage (for a thorough review of the preclinical literature see Imam et al. 2020), a few clinical reports have examined respiratory stimulants (potassium channel blockers, N-methyl-D-aspartate receptor antagonists, ampakines, and analeptics), albeit with little-to-no evidence of utility during a real-life overdose event. 4-Aminopyridine, a potassium channel blocker, was the first reported to reverse respiratory depression caused by IV fentanyl (Sia and Zandstra 1981). However, 4-aminopyridine can have considerable side effects, including dysesthesias and dizziness (Blight and Henney 2009; Hayes et al. 2003). An analysis of clinical studies examining 4-aminopyridine reported that paranesthesia and dizziness occurred in roughly 34% of people (Jensen et al. 2014). Other side effects reported in this meta-analysis included, among others, nausea and vomiting, anxiety, difficulty walking, abdominal pain, hyperkalemia, and seizures; these side effects could limit the potential utility of 4-aminopyridine during an illicit opioid overdose event. More recently, studies reported that IV GAL021 (Galleon Pharmaceuticals Corp.), a calcium-activated potassium channel blocker was able to reverse alfentanil-induced respiratory depression, with few adverse events (Roozekrans et al. 2015, 2014). However, GAL021 may not be ideal during an opioid overdose event due to its short half-life and a decrease/ceiling in its efficacy to treat opioid-induced respiratory depression (Roozekrans et al. 2015). Taken together, these studies do not provide strong support for the use of potassium channel blockers for the treatment of opioid overdose. Ampakines have also been investigated as opioid overdose reversal agents; RespireRx Pharmaceuticals Inc. pursued the development of ampakines after one double-blind, placebo-controlled, crossover study in 16 men reported that pretreatment with the ampakine CX717 partially prevented alfentanil-induced respiratory depression (Oertel et al. 2010). In a phase 2a clinical trial a similar ampakine, CX1739, antagonized respiratory depression induced by a remifentanil infusion but did not prevent respiratory depression when a bolus of remifentanil was administered (RespireRX Pharmaceuticals Inc. 2016), suggesting that CX1793 would not be a preferred treatment for opioid overdose. A single double-blind, placebo-controlled study reported that doxapram caused small reductions in alfentanil-induced respiratory depression (Roozekrans et al. 2017). Finally, the N-methyl-D-aspartate receptor antagonist esketamine improved remifentanil-induced respiratory depression in one double-blind, placebo-controlled study (Jonkman et al. 2018). However, esketamine may not be ideal as an overdose treatment due to its documented psychomimetic effects (Jonkman et al. 2018). While these developments with respiratory stimulants to treat opioid overdose are intriguing, overall clinical evidence in support of respiratory stimulants as an opioid overdose treatment is lacking. Many of the stimulants examined thus far have substantial side effects that limit their ability to be used in the field. Additionally, studies have only used IV administration of respiratory stimulants, a route that is unlikely to be used by bystanders to an overdose event. Finally, it is unclear if respiratory stimulants will interact with other substances that may contribute to the overdose event (e.g., cocaine, benzodiazepines, alcohol, etc.) or have sufficient activity to reverse the effects of supratherapeutic opioid doses typically seen in overdose.

Buprenorphine

Buprenorphine is a μ-opioid receptor partial agonist that is currently approved by the FDA for the treatment of opioid use disorder and as an analgesic. There are three reports of bystanders using buprenorphine to reverse opioid overdoses when naloxone was not readily available. One report indicated that a bystander used an IV dose of a transmucosal formulation (8 mg buprenorphine/2 mg naloxone) to reverse a heroin overdose, but the overdose reversal may be attributed to naloxone in this case (Yokell et al. 2012). However, in another case report, a bystander reported that he successfully used sublingual buprenorphine/naloxone on a person experiencing a heroin overdose (Welsh et al. 2008). Naloxone has poor bioavailability when administered sublingually or orally, due to a large first-pass effect, suggesting that buprenorphine was the primary reversal agent in this case (Smith et al. 2012). Finally, a man was administered buprenorphine in the emergency department for an overdose involving several substances (150 mg methadone syrup, 200 mg fluoxetine, and 20 mg clonazepam) (Zamani and Hassanian-Moghaddam 2017). Although the patient responded to buprenorphine, the development of apnea led medical providers to switch to naloxone for the remainder of the treatment. In addition to these case reports, a phase 2 open-label controlled clinical trial compared buprenorphine and naloxone treatment of methadone overdose (Zamani et al. 2020). This study reported that several patients required high doses and prolonged infusions of naloxone to reverse methadone-induced sedation, resulting in high rates of side effects (e.g., withdrawal) attributed to naloxone. Additionally, patients who received buprenorphine had more “complete responses” with less recurrence of respiratory depression than patients who received naloxone. There are several concerns with this study though, as described by Mégarbane et al. (2020), including the mild opioid poisoning (i.e., Glasgow Coma Scores of 13–15 and respiratory rate of 10–16 breaths/min) of these patients and the high doses of naloxone. It is also important to consider that buprenorphine may be less effective at reducing high efficacy μ-opioid agonist effects in people who have developed tolerance and/or physical dependence on opioids. While the available data support naloxone efficacy over buprenorphine in overdose reversal, the observation that buprenorphine (a low efficacy agonist) can reduce the effects of high efficacy μ-opioid agonists, at some doses, is well documented and, in some circumstances or locations, buprenorphine may be available when naloxone is not. That said, we are not aware of any development efforts that are currently underway to utilize buprenorphine as an overdose treatment due to the potential diversion of buprenorphine (e.g., see review by Lofwall and Walsh 2014) and the superiority of naloxone over buprenorphine.

Wearable naloxone delivery device

Many barriers may prevent bystander naloxone administration during an opioid overdose. One major concern with F/FAs is the short time frame in which an overdose event occurs (thereby limiting the window for naloxone administration). A recent multi-city study reported that nearly half of people who use opioids reported that they usually used drugs while alone (Park et al. 2019). To combat fatal opioid overdose occurring while alone (with a narrow treatment window as seen with F/FAs), researchers from Purdue University recently designed an “automatic antidote delivery device (A2D2),” a wearable device that, in theory, would identify respiratory depression via ECG and magnetically activate a naloxone containing subcutaneous implant to release the opioid receptor antagonist (Dhowan et al. 2019). A preliminary proof-of-concept study of this device reported that the A2D2 product is capable of releasing 1.9 mg of powdered acetaminophen in one min when manually activated. To our knowledge, this prototype device has not been tested with naloxone or activated by an ECG signal of respiratory depression. Additionally, the study also found drug leakage after 1000 h, suggesting that the product may need to be replaced frequently. This device is a creative approach to addressing an issue many people who use opioids may experience. In a survey of 97 people who use opioids, 76% reported that they would be willing to wear a device that automatically administers a reversal agent when an overdose is detected (Kanter et al. 2021). However, the implementation of a wearable device has barriers including potential market price, patient interest, and insurance coverage, and extensive preclinical and clinical testing is still needed before this product will be able to reach the market. NIDA is currently funding research on several wearable devices, including biosensors that notify emergency personnel and are paired with either a wearable or implantable automatic naloxone delivery device. Another currently funded study is developing a wrist monitor and smartphone application to automatically administer IM naloxone. These devices are in early development, and no results have been published.

Summary and conclusions

Naloxone is the most widely used opioid overdose reversal agent. The FDA has approved initial doses of 0.4 to 2 mg of IM naloxone in the clinical setting and repeated administration to a maximum dose of 10 mg is appropriate (Adapt Pharma Operations Limited 2016). Intranasal products that are currently available to the public include Narcan® (4 mg IN spray), KLOXXADO® (8 mg IN spray), and generic naloxone (4 mg IN spray), and ZIMHI™ (5 mg IM or SC) is expected to be available in early 2022. Clinical studies have demonstrated that naloxone is a safe and efficacious treatment for opioid overdose reversal. However, several concerns have been raised in the literature regarding the ability of naloxone to reverse F/FA overdose (France et al. 2021; Kim et al. 2019; Lynn and Galinkin 2018). Retrospective analyses and case studies have given rise to some of these concerns, but many of these studies lack toxicological confirmation of F/FA use and do not provide naloxone dose or administration route. Additionally, some studies include people who have expired while others exclude people who are unable to answer questions. These studies have numerous limitations (see Tables 1 and 2) and overall provide limited evidence that naloxone is ineffective at treating F/FA overdose. Another concern with F/FA overdose is non-opioid receptor-mediated effects, such as wooden chest syndrome. However, the rate at which wooden chest syndrome occurs in people who use drugs and are experiencing an overdose, as well as the role of wooden chest syndrome in overdose is largely unknown. The major concern regarding naloxone treatment of F/FA overdose is based on the pharmacokinetics of fentanyl which result in a narrow window of time during which naloxone can be administered for reversal of overdose. These studies provide a complex picture of the extant evidence regarding naloxone’s efficacy against F/FAs but also reflect substantial success in naloxone reversal of F/FA overdoses. Prospective studies of overdose reversal that collect accurate dosing information in the field are extremely challenging to conduct and are largely absent from the literature.

Recent advances in opioid overdose treatments have attempted to address several of these concerns. The use of an absorption enhancer may shorten the Tmax and increase the bioavailability of IN nalmefene and is currently under development (Krieter et al. 2019). The benefit of nalmefene (compared to naloxone) is its long duration of action, which may prevent the re-occurrence of respiratory depression that can occur with long-acting opioid receptor agonists, such as fentanyl. However, patient acceptance of a long-acting opioid receptor antagonist is a concern. Other alternatives to naloxone that are in the early stages of development include respiratory stimulants. However, the potential for side effects and unknown interactions with other illicit substances that could be contributing to the overdose event are major concerns with respiratory stimulants. A few case reports and one pilot study have also indicated that buprenorphine can be used as a treatment for opioid overdose.

Nalmefene, buprenorphine, and respiratory stimulants all are incapable of addressing perhaps the most prominent issue with treating F/FA overdose: the narrow treatment window. There is recent interest in the development of a wearable naloxone delivery device that could theoretically overcome the narrow treatment window with F/FA overdose. Only one wearable device product has undergone a proof-of-concept study, but this device still requires extensive development before reaching the market and will need to overcome several factors, such as patient interest, cost, and insurance coverage.