Synthetic opioids have disrupted conventional wisdom for treating opioid overdose

Abstract

More than 90 % of opioid overdose deaths in North America are now caused by synthetic opioids, and while they are not as prevalent in the European illicit drug market, there are indications that they may become so in the near future. Multiple publications have argued that neither higher doses of naloxone nor more potent opioid receptor antagonists are needed to reverse a synthetic opioid overdose. However, the unique physicochemical properties of synthetic opioids result in a very rapid onset of respiratory depression compared to opium-based molecules, reducing the margin of opportunity to reverse an overdose. While intravenous administration rapidly delivers the high naloxone concentrations needed to reverse a synthetic opioid overdose, this option is often unavailable to first responders. A translational mechanistic model of opioid overdose developed by the FDA’s Division of Applied Regulatory Science provides an unbiased approach to evaluate the effectiveness of overdose reversal strategies. Reports using this model demonstrated the naloxone tools (2 mg intramuscular and 4 mg intranasal) used by many first responders can result in an unacceptable loss of life following a synthetic opioid (fentanyl, carfentanil) overdose. Moreover, sequential (2.5 minutes between doses) administration of up to four doses of intranasal naloxone was no more effective at reducing the incidence of cardiac arrest (a surrogate endpoint for lethality) than a single dose, suggesting that attempts at titration may not provide the rapid absorption required to reverse a synthetic opioid overdose. This model was also used to compare the effectiveness of intranasal naloxone to intranasal nalmefene, a recently FDA-approved opioid receptor antagonist with a more rapid absorption and a higher affinity at mu-opioid receptors compared to intranasal naloxone. Intranasal nalmefene resulted in large and clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone. Furthermore, simultaneous administration of four doses of intranasal naloxone was needed to reduce the incidence of cardiac arrest to levels approaching those produced by a single dose of intranasal nalmefene. These data are consistent with evidence that synthetics have indeed disrupted conventional wisdom in the treatment of opioid overdose.

1. Introduction

The ready availability of illegally manufactured synthetic opioids (“synthetics”) like fentanyl is the primary driver of opioid overdose deaths in the United States. Nearly 77,000 fatal opioid overdoses were reported in the 12-month period ending January 2024, with almost 92 % (70,486) linked to synthetics (Ahmad et al., 2024). In 2023, the Drug Enforcement Administration (DEA) seized more than 80 million fentanyl-laced counterfeit pills and nearly 12,000 pounds of fentanyl powder, equivalent to more than 381 million lethal doses (United States Drug Enforcement Administration, 2024). In North America, synthetics have largely replaced heroin in the illicit drug supply. The production of synthetics is neither restricted by geography nor impacted by the intricate supply chain issues which affect the availability of heroin. Thus, opium poppies must be cultivated, harvested and processed, and the availability of opium-based products like heroin are impacted by factors ranging from weather to geopolitical unrest. For example, Afghanistan had been the major source of opium until the Taliban banned cultivation of opium poppies in 2022, resulting in a 95 % drop in production (European Monitoring Centre for Drugs and Drug Addiction, 2024). A continued ban on poppy cultivation will have a knock-on effect, reducing the heroin supply to the rest of the world. A variable heroin supply together with the low cost of producing high-potency synthetics (Skolnick, 2018) could result in a similar shift in the illicit drug supply for the rest of the world. Synthetics ranging from fentanyl and fentanyl analogs to benzimidazoles, a chemically distinct class of high potency opioids, have already been identified in the illicit drug supply in at least 16 European Member States, Norway and Turkey (Pardal et al., 2024, European Monitoring Centre for Drugs and Drug Addiction, 2024).

Naloxone has been used for the treatment of opioid overdose for over sixty years and is listed as a World Health Organization essential medicine (Saari et al., 2024). Naloxone is likely to remain the standard of care in health care settings where intravenous (IV) dosing can be titrated to restore respiration and adequate ventilatory support is provided. As a competitive mu-opioid receptor antagonist, with sufficient dosing, naloxone can reverse the respiratory depression produced by any opioid, including fentanyl and other potent synthetics (van Lemmen et al., 2023). Several recent publications (Hill et al., 2022, Infante et al., 2024, Stolbach et al., 2023) have concluded that naloxone remains fit for purpose to treat an overdose in an era dominated by synthetics despite distinct physicochemical properties which make them inherently more deadly than opium-based molecules such as heroin (Skolnick, 2022). Infante, et al. discuss the use of IV and intramuscular (IM) injections to “carefully titrate the reversal rather than overwhelm the receptors”. Intravenous administration is often not an option for first responders (e.g., police, fire and rescue personnel, friends and family of the overdose victim) in a community setting, who instead rely on intranasal (IN) and IM naloxone products. Within this treatment framework, neither this statement, nor referencing a publication (Hill et al., 2022) indicating there was “…no difference in the median dose of [IV] naloxone required for successful reversal…” either fully or accurately captures the challenges of treating a synthetic opioid overdose. Thus, the authors do not cite the primary reference, a retrospective chart review (Carpenter et al., 2020) which reached this conclusion by standardizing naloxone doses administered by different routes (e.g., IV, IM, IN) as naloxone “IV equivalents” based on bioavailability. For example, 100 % bioavailability is assumed between IM and IV dosing (Carpenter et al., 2020). This assumption is technically correct (McDonald et al., 2018, Saari et al., 2024), and gives equal weight to a 0.4 mg dose of IM and IV naloxone based on plasma exposure (AUC_0-inf). However, this method of estimating naloxone dosing (also employed by other investigators concluding the average doses of naloxone have not increased over time (e.g. Rock et al., 2024), does not consider the differences in early naloxone exposure (i.e., within minutes after dosing) across routes of administration (McDonald et al., 2018, Saari et al., 2024) which is critical for a successful rescue following a synthetic opioid overdose (Mann et al., 2022, Strauss et al., 2024, van Lemmen et al., 2023).

In contrast to the data described by Infante, et al. and others (Hill et al., 2022, Rock et al., 2024), there is a compelling body of evidence which suggests higher doses of naloxone are  required to reverse a synthetic opioid overdose. This evidence includes multiple emergency department reports describing patients with a confirmed fentanyl overdose requiring large IV doses of naloxone (0.4–12 mg) followed by a prolonged infusion in a subset of these individuals (Schumann et al., 2008, Sutter et al., 2017, Shastri et al., 2024), a meta-analysis of emergency services studies including three with longitudinal results reporting a significant increase in mean naloxone doses over time (Abdelal et al., 2022), and the results of a quantitative systems pharmacology model based on fentanyl blood levels measured in overdose victims (Moss et al., 2020). The latter study concludes that doses of naloxone used by many first responders (i.e., 4 mg IN or 2 mg IM) “…may be inadequate for rapid reversal of toxicity due to fentanyl exposure” and concludes that higher doses of naloxone are likely to improve patient outcomes. The Health Advisory Network, a component of the Centers for Disease Control, issued a health advisory consistent with this body of evidence, stating: “…. multiple doses of naloxone may be needed for a single overdose event because of the potency of illicitly manufactured fentanyl and fentanyl analogs, and that multiple doses may be needed over time due to prolonged effects of opioids in some cases” (Centers for Disease Control and Prevention, 2020).

2. The need for speed in reversing a synthetic opioid overdose

The need for rapid reversal of a synthetic opioid overdose is supported by both preclinical and clinical studies which demonstrate that synthetics like fentanyl lead to a faster onset of respiratory depression compared to opium-based alkaloids such as heroin and morphine. These highly lipophilic molecules rapidly partition into the central nervous system, a desirable characteristic for an analgesic/anesthetic but which results in a reduced window of opportunity for rescue following an overdose. In clinical studies, respiratory depression reaches a maximum within 2–5 min after IV fentanyl administration (Suzuki and El-Haddad, 2017). Consistent with this rapid onset of action, in a review of 125 overdose deaths abstracted from medical examiner charts (which included autopsy and toxicology findings, bystander descriptions, and EMS logs), Somerville et al. (2017) documented that fentanyl produced an overdose within seconds to minutes after drug use in 36 % of decedents, whilst 90 % lacked a pulse when emergency medical services arrived. The speed of a fentanyl overdose was deduced from evidence available on scene such as “….needles inserted in decedents’ bodies, syringes found in hand, tourniquets still in place, and bystander reports of rapid unconsciousness after drug use.” This is consistent with reports (Green and Gilbert, 2016) that IV fentanyl can cause life threatening respiratory depression within two minutes; by contrast, Darke and Duflou (2016) reported a 20–30-minute potential window for intervention following a heroin overdose. Multiple factors, including the quantity and type of opioid(s) taken, co-ingestion of other substances, and a patient’s history of opioid use complicate interpretation of overdose data (Skolnick, 2022) including accurate estimates of the time to onset of life-threatening respiratory depression. However, nonclinical studies in rodents examining temporal changes in opioid-induced respiratory depression in the absence of these confounds have clearly demonstrated that synthetics produce a more rapid onset of respiratory depression than opium-based alkaloids. For example, using a sensor implanted in the nucleus accumbens, Kiyatkin (2019) demonstrated the latency of fentanyl to reduce oxygen concentration was twice as fast as oxycodone and morphine. Moreover, the time to produce maximum reductions in brain oxygen concentrations was shortest for fentanyl (62–80 seconds depending on dose), approximately 2–3-fold longer for oxycodone, and up to 20 minutes for morphine, respectively. Hill et al. (2020) used plethysmography to study the rates at which opioids depress minute ventilation. Following equipotent IV doses of fentanyl, heroin, and morphine (which reduced minute ventilation to 50 % of baseline), the rate of onset for fentanyl was approximately 3- and 9 -fold faster than heroin and morphine, respectively. Hill et al. (2020) also noted that whilst all three opioids reduced respiratory rate, only fentanyl produced an immediate and significant reduction in tidal volume, driving its ability to rapidly reduce minute ventilation.

3. Key insights from a translational model of opioid overdose: it’s not just the naloxone dose that matters (speed is paramount)

Mann, et al. (2022) recently described a model-based approach to predict the effectiveness of IM naloxone to reverse respiratory depression and cardiac arrest following overdose scenarios based on real-world data from ~ 500 fatal cases of fentanyl overdose. This translational mechanistic model represents an unbiased, alternative approach to evaluate the effectiveness of overdose reversal strategies which eliminates the challenges inherent in analysis and interpretation of case studies and chart reviews, including variability in reporting outcomes (e.g., reversal of respiratory depression versus reversal of stupor), study design, and study quality.

The intravenous fentanyl doses (1.63 and 2.97 mg) used in this model were based on the mean and one standard deviation above the mean of blood fentanyl concentrations obtained in this sample of fatal overdoses. For context, the Drug Enforcement Administration considers 2 mg a potentially lethal dose of fentanyl (United States Drug Enforcement Administration, 2024). In the absence of intervention, Mann et al. (2022) reported an incidence of cardiac arrest in approximately 52 % of 2000 simulated overdoses in individuals with a history of chronic opioid use following the 1.63 mg IV dose of fentanyl. Rescue with the standard IM naloxone dose (2 mg/2 mL) under the conditions described in the model reduced the incidence of cardiac arrest to approximately 30 % (that is, a “rescue rate” of 42 %), yet an identical dose of naloxone delivered in a lower volume (2 mg/0.4 mL) resulted in a substantially lower incidence (approximately 16 %) of cardiac arrest (that is, a rescue rate of 69 %). While no longer commercially available, the increased effectiveness of the 2 mg/0.4 mL naloxone injection is explained by the more rapid absorption of naloxone delivered in a lower volume despite both identical dosing and exposure (i.e., AUC) (Mann et al., 2022). A substantially lower incidence of cardiac arrest was also reported following rescue with the low-volume naloxone injection (approximately 34 % compared to approximately 54 % using the 2 mg/2 mL injection) in simulations with the higher (2.97 mg) IV fentanyl dose that resulted in an incidence of cardiac arrest of approximately 78 % in the absence of intervention (Mann et al., 2022). The low-volume naloxone injection also proved substantially more effective in reducing the incidence of cardiac arrest in simulations using the more potent synthetic opioid, carfentanil (Mann et al., 2022), reinforcing the importance of rapidly delivering high plasma concentrations of naloxone to effectively reverse a synthetic opioid overdose.

The Mann model (Mann et al., 2022) was then expanded using data from a randomized clinical trial in healthy volunteers comparing naloxone plasma concentrations across different IN naloxone (4 mg) repeat dosing strategies to estimate their effectiveness in reversing a fentanyl or carfentanil overdose (Strauss et al., 2024). These data demonstrate that following administration of the 2.97 mg fentanyl dose (with an incidence of cardiac arrest of approximately 78 % absent intervention), the incidence of cardiac arrest was reduced to 46 % following one dose of naloxone, and remained at 46 % when up to four doses were administered at 2.5-minute intervals (i.e. 4 mg IN naloxone dose administered at 0, 2.5, 5, and 7.5 minutes) (Strauss et al., 2024). Similar data demonstrated no additional benefit of sequential dosing with IN naloxone across the other dosing scenarios originally described in the Mann model (i.e., the 1.63 mg IV dose of fentanyl and two IV doses (0.012 and 0.022 mg of carfentanil), Therefore, these findings indicate that any delay in reaching critical plasma naloxone concentrations by either sequential IN dosing or attempting to titrate IM dosing could be fatal in the face of a potentially lethal dose of a synthetic opioid (Strauss et al., 2024).

4. Nalmefene is not merely an alternative to naloxone: implementing the Mann model for a head-to-head comparison in reversing opioid-induced respiratory depression and survival outcomes

Despite pharmacokinetic data demonstrating a more rapid absorption of IN nalmefene (2.7 mg) (Crystal et al., 2024) compared to IN naloxone (4 mg) (Krieter et al., 2016), a higher affinity at mu-opioid receptors (Cassel et al., 2005, Toll et al., 1998) and the FDA approval of injectable nalmefene for the treatment of opioid overdose, in their Commentary, Infante et al. (2024) raise a concern about a lack of evidence supporting the use of IN nalmefene for overdose, such as a comparative study to determine non-inferiority to IN naloxone. While such studies are about to commence (RENDOR Project - ACMT), prior to the approval of IN nalmefene, ethical considerations precluded a comparative field study. However, multiple studies in healthy volunteers have shown that hypercapnia-induced increases in minute ventilation, which is a physiological component of the ventilatory response to hypercapnia, is both reduced by opioids (including synthetics such as fentanyl) (Gelberg et al., 2012, Glass et al., 1999) and reversed by parenteral administration of opioid receptor antagonists (Dahan et al., 2010, Glass et al., 1994, Konieczko et al., 1988). Using this clinical model of opioid-induced respiratory depression, IN nalmefene (2.7 mg, equivalent to 3 mg of nalmefene hydrochloride) produced a reversal of remifentanil-induced reductions in minute ventilation that was almost twice as great as that produced by IN naloxone (4 mg) 5 minutes after administration (5.75 vs 3.01 L/min; p< 0.0009), demonstrating both non-inferiority and superiority compared to naloxone at the primary endpoint (Ellison et al., 2024). If speed of onset is critical to effective reversal of a synthetic opioid overdose, then the more rapid reversal of remifentanil-induced respiratory depression by nalmefene reported in the Ellison et al., (2024) study should be reflected in the Mann model. To test this hypothesis, Laffont et al. (2024) recently expanded the Mann model to compare the relative effectiveness of IN naloxone and IN nalmefene. The simulations in Fig. 1 illustrate the endpoint, the incidence of cardiac arrest, following the 2.97 mg IV dose of fentanyl described earlier in this Commentary. In the absence of intervention, the incidence of cardiac arrest was 77.9 % which was reduced by approximately 30 % (i.e., down to 54.2 %) following a 2 mg/2 mL dose of IM naloxone. A single 4 mg dose of IN naloxone reduced the incidence of cardiac arrest by approximately 40 % (i.e., down to 47.1 %) (Fig. 1). By contrast, a single dose of IN nalmefene reduced the incidence of cardiac arrest by approximately 85 % (i.e., down to 11.6 %). Large and clinically meaningful differences in the incidence of cardiac arrest were also observed across the other three overdose scenarios described in the Mann model (2022) following a single dose of IN nalmefene compared to a single dose of IN naloxone (Laffont et al., 2024).

Fig. 1.

Predicted incidence of cardiac arrest following an intravenous dose (2.97 mg) of fentanyl: reversal by naloxone and nalmefene. Symbols represent the percentage (and 95 % confidence interval) of simulated subjects experiencing cardiac arrest after randomly sampling 400 out of 2000 virtual subjects 2500 times. The simulations were conducted using data from individuals with a history of chronic opioid use as described by Mann et al. (2022). Legend: filled circle, None (no intervention); square, IM NX 2 mg (2 mg intramuscular naloxone); triangles, IN NX (4 mg intranasal naloxone); circle, IN NLM 2.7 (2.7 mg intranasal nalmefene). Simultaneous administration of two, three or four doses of IN naloxone was simulated by administering a dose equal to 8 mg (2 ×4 mg), 12 mg (3 ×4 mg), or 16 mg (4×4 mg), respectively. The data was generated using the translational model of overdose described by Mann et al. (2022). Using this model, Strauss et al. (2024) reported a median simulated incidence of cardiac arrest of 46 % (compared to 47.1 % illustrated here) following a single 4 mg dose of IN naloxone using an independent set of pharmacokinetic data. The data are from Laffont et al. (2024).

Because Strauss et al. (2024) demonstrated that sequential administration of up to four doses of IN naloxone did not improve outcomes compared to a single dose, Laffont et al. (2024) interrogated the Mann model to examine the effect of simultaneous administration of multiple IN doses of naloxone. Two, three and four doses (total doses of 8, 12, and 16 mg of naloxone) produced dose-related reductions in the incidence of cardiac arrest (Fig. 1). Following four simultaneous doses of naloxone (i.e., 16 mg) the incidence of cardiac arrest was reduced to values (approximately 17 %) approaching the incidence following a single dose of nalmefene. A similar trend was obtained across the other overdose scenarios described in the Mann model, with four doses of IN naloxone needed to reduce the incidence of cardiac arrest to values approaching but not as low as following one dose of IN nalmefene (Laffont et al., 2024).

The Mann model can be interrogated to assess multiple physiological outcomes following an opioid overdose (Mann et al., 2022), and it accurately predicted (Laffont et al., 2024) the reversal of remifentanil-induced respiratory depression reported by Ellison et al. (2024) by both nalmefene and naloxone, reinforcing the robustness of the data obtained using this model. Nonetheless, cardiac arrest is used as an endpoint in this model (Mann et al., 2022, Strauss et al., 2024, Laffont et al., 2024) because in the absence of intervention (i.e., administration of an opioid receptor antagonist and/or ventilatory support) the cardiovascular complications produced by sustained respiratory depression will ultimately prove fatal (van Lemmen et al., 2023, Knopf, 2024). The differences in effectiveness between IN naloxone and IN nalmefene evinced using this translational model of opioid overdose reflect both preclinical and clinical findings, including a higher affinity of nalmefene at mu-opioid receptors (Toll et al., 1998; Cassel et al., 2005), a higher exposure of nalmefene within minutes after dosing (Krieter et al., 2016, Crystal et al., 2024, Ellison et al., 2024), and the more rapid onset of nalmefene in a clinical model of remifentanil-induced respiratory depression (Ellison et al., 2024).

5. Concluding remarks

The upward trajectory of opioid overdose deaths has continued for more than two decades. The root cause can be traced to a societal failure to destigmatize opioid use disorder and move beyond the current rudimentary approaches to treatment and rehabilitation of individuals with opioid use disorder. Widespread deployment of more effective reversal agents represents only one component of a strategy outlined by NIH Leadership to address the opioid crisis (Volkow and Collins, 2017).

There are four lines of evidence which support the need for more effective reversal agents. First and perhaps most obvious is that opioid overdose deaths remain at unacceptably high levels (Ahmad et al., 2024) despite an increased public awareness of the dangers posed by synthetic opioids (United States Drug Enforcement Administration, 2024), naloxone saturation strategies (Irvine et al., 2022), and State Opioid Response grants (FY’23 funding was more than $1.4 billion-which enable states to purchase and distribute reversal agents). While these efforts have undoubtedly increased the availability and use of naloxone, 2022 data from the CDC’s State Unintentional Drug Overdose Reporting System (SUDORS) (Centers for Disease Control and Prevention, 2024) reported in a national survey of thirty jurisdictions, that an average of 21.8 % of decedents had received naloxone. Multiple jurisdictions (e.g., VT, ME, MA, MN, and UT), perhaps by dint of more effective distribution networks, reported between 31 % and 39.4 % of decedents had been administered naloxone. Second, the low cost and ready availability of synthetics has resulted in their use as adulterants for other illicit drugs, most notably, stimulants like cocaine and methamphetamine (Cano et al., 2023). In a 2022 survey of more than 400 suspected overdoses in San Francisco, 42.7 % of respondents with data on intended use reported no intentional opioid use; most of these individuals (>72 %) intended to use stimulants (Bazazi et al., 2024). Third, synthetics in the form of counterfeit pills are now very much part of the illicit drug supply (Cano et al., 2023, United States Drug Enforcement Administration, 2024). As a result, there has been an increasing number of fatal overdoses involving opioid naïve individuals, including adolescents (Friedman and Hadland, 2024) and even children younger than 6 years of age (Temple and Hendrickson, 2024), who are now exposed to potentially lethal doses of synthetics. Moreover, individuals who have not developed tolerance to the respiratory depressant effects of opioids are more likely to experience a fatal overdose and require higher doses of an opioid receptor antagonist to restore respiration compared to people who use opioids and have developed some degree of tolerance (Mann et al., 2022, Strauss et al., 2024, Laffont et al., 2024). While the data illustrated in Fig. 1 simulates outcomes in individuals with a history of chronic opioid use (Mann et al., 2022, Laffont et al., 2024), the large differences in effectiveness between a single dose of IN nalmefene and naloxone across all four overdose scenarios were also manifested in simulations in opioid naïve individuals (Laffont et al., 2024). Fourth, Watson et al. (1998) reported that 20–45 % of overdose victims initially rescued with (IV) naloxone experience a renarcotization event. A rescue agent with a longer half-life reduces the potential for renarcotization, which may be especially important in the era of synthetics. For example, fentanyl has a long terminal elimination as well as a secondary peaking phenomenon which can be manifested as “fentanyl rebound” (Bird et al., 2023). Moreover, the clinical pharmacology, including the pharmacokinetic profiles of most illicit synthetics are unknown, adding another layer of complexity to the management of a synthetic opioid overdose. Nonetheless, patients initially treated with a longer duration agent may require less intensive monitoring for a renarcotization event in both the ambulance and emergency department. This may also result in fewer complications (e.g., aspiration) than patients with an impaired level of consciousness as well as reduce the potential for administering additional doses and/or an infusion of naloxone. Patients refusing further treatment following a rescue may also benefit from a longer duration opioid antagonist if the individual subsequently misuses opioids upon discharge.

Administration of either higher naloxone doses or a more potent, rapid acting reversal agent such as nalmefene has been met with resistance due to the assumption this will inevitably lead to sustained and severe withdrawal in people who use opioids. Much of the discussion around precipitated withdrawal centers on studies of individuals who were reluctant to carry naloxone based on withdrawal symptoms suffered during a previous rescue (Hill et al., 2022, Infante et al., 2024). While this is a valid concern, survey data collected between October and December 2021 from over 1150 patients entering treatment for an opioid use disorder found that most respondents either expressed no preference (48.4 %) or preferred a higher-dose formulation (35.9 %) if they personally experienced an overdose (Strickland et al., 2022). The majority of these individuals (59.9 %) reported that two or more doses of Narcan® (i.e., 8 mg or more of naloxone nasal spray) were required to reverse their most recent overdose. It is also noteworthy that the respondents who preferred higher-dose naloxone formulations had greater odds (adjusted odds ratio, 2.11 [95 % CI=1.29, 3.44; p=.003) of having experienced a suspected fentanyl exposure (Strickland et al., 2022). Nonetheless, the risk to benefit ratio of administering higher doses of naloxone or faster acting, more potent antagonists like nalmefene will continue to be an area of debate and discussion despite medical consensus that the risk of under-dosing with naloxone outweighs the potential risk of precipitating opioid withdrawal, which can be medically managed (Boyer, 2012, Lombardi et al., 2016, Harris et al., 2020, Mann et al., 2022). Although the majority of opioid overdoses are nonfatal (Skolnick, 2022), given the prevalence of synthetics in the illicit drug supply, every overdose is potentially lethal in the absence of appropriate intervention. While IV administration of naloxone is a highly effective means of reversing an opioid overdose (Strauss et al., 2024), this approach is generally impractical in a community setting. Based on the evidence summarized in this Commentary, initiating treatment with a low IM (e.g., 0.4 mg) or IN (e.g., 3–4 mg) dose of naloxone in an environment dominated by synthetic opioids with the expectation that there will be an opportunity to ‘titrate up’ could inappropriately delay reversal of respiratory depression, resulting in the potential for either enduring brain damage (Winstanley et al., 2021, Todaro et al., 2024) or death (Ahmad et al., 2024).

CRediT authorship contribution statement

Jordan Paavola: Writing – review & editing, Writing – original draft, Validation. Phil Skolnick: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Data curation, Conceptualization. Christian Heidbreder: Writing – review & editing, Writing – original draft, Validation, Supervision, Resources, Methodology, Data curation, Conceptualization.

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christian Heidbreder is a full-time employee of Indivior Plc. Jordan Paavola reports a relationship with Indivior PLC that includes: employment. Phil Skolnick reports financial support was provided by Indivior Inc. Phil Skolnick reports a relationship with Indivior Inc that includes: consulting or advisory, employment, and travel reimbursement. Phil Skolnick has patent pending to Indivior Inc. The authors declare that they have no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.