Reversal of Fentanyl‐Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene Administered by Auto‐Injector Versus Intranasal Naloxone

Abstract

As illegally made fentanyl and congeners continue to drive overdose deaths in the US, experts have called for stronger and longer‐lasting antagonists. A randomized, 4‐period, 2‐treatment crossover replicate‐design study in healthy moderately‐experienced opioid users (n = 24) evaluated the reversal of opioid‐induced respiratory depression (OIRD) by intramuscular (IM) nalmefene 1.5 mg administered by auto‐injector delivering a formulation developed for faster onset, compared to intranasal (IN) naloxone 4 mg. Fentanyl infusions were administered to induce a 50% reduction in minute ventilation (MV). Reversal of OIRD, pharmacokinetics, and safety were investigated under steady‐state fentanyl agonism. For the primary endpoint, nalmefene demonstrated superiority at 5 min with an MV increase of 4.59 L/min, more than twice the 1.99 L/min increase for naloxone (P < .0001). Nalmefene superiority was also demonstrated at 10, 15, 20, and 30 min, while non‐inferiority was demonstrated at 2.5 and 90 min. The time‐course of mean antagonist concentrations correlated with increases in mean MV, peaking at approximately 5‐10 min following nalmefene compared to 20‐30 min following naloxone. Decreases in transcutaneous CO₂ (TCO₂) followed a similar time‐course with a slight delay. At each threshold of percent reversal (25%‐100%), nalmefene consistently showed a faster time to onset than naloxone. Both antagonist treatments were tolerated with no serious adverse events. This study shows that nalmefene 1.5 mg IM administered by auto‐injector achieved a faster onset, higher magnitude, and longer duration of reversal of OIRD compared to naloxone 4 mg IN and represents another option for the treatment of opioid overdose.

Introduction

Over the past decade, the increase in illicit synthetic opioid abuse has been associated with increased overdose fatalities. ¹ The early to mid‐2010s saw an unprecedented rise in opioid overdose deaths, due in large part to the increasing prevalence of fentanyl and fentanyl congeners (i.e., synthetic opioids) as adulterants in illicit drug supplies, including heroin and methamphetamine, and in counterfeit pills. ² , ³ , ⁴ Deaths attributed to the fentanyl analog carfentanil as an adulterant in illicit drug products were first reported in 2016. ⁵ Recently, the CDC has reported an increase in overdose deaths involving carfentanil, most commonly mixed with illegally made fentanyl (IMF). ⁶ Nitazenes, often found mixed with other illicit drugs, represent another emerging high‐potency opioid threat contributing to opioid overdoses and fatalities. ⁷ More recently, provisional data for the 12 months ending October 2024 show that approximately 90% of opioid overdose deaths were from synthetic opioids (primarily fentanyl). ⁸ , ⁹

Fentanyl is a powerful opioid, approximately 50 to 100 times more potent than morphine, that was developed in the 1960s as an analgesic and anesthetic agent. ¹⁰ Compared to morphine, fentanyl has approximately two to three times greater affinity for the μ‐opioid receptor (MOR) and 1000 times greater lipophilicity. ¹¹ , ¹² Because of the ease with which fentanyl traverses membranes to reach the sites of toxic action in the central nervous system (CNS), it has a very rapid onset of action and readily redistributes to fatty tissues. Whereas the duration of analgesic action of fentanyl is 60 to 120 min, its elimination half‐life is up to 7 h. Its persistent respiratory‐depressant effects have been attributed to its long elimination half‐life and slow re‐distribution from fatty tissues back into plasma. ⁶ The high MOR affinity and high lipophilicity of fentanyl and other synthetic opioids complicate the reversal of opioid overdoses.

Naloxone is a MOR antagonist and is currently the standard of care for the reversal of opioid overdose. In the US, naloxone is approved by the Food and Drug Administration (FDA) in various injectable and intranasal (IN) products. ¹³ , ¹⁴ The longer half‐life and greater potency of synthetic opioids may require repeated dosing with naloxone to reverse opioid overdose symptoms due to its shorter half‐life. ³ , ⁸ , ¹⁵ Consequently, the FDA, along with the National Institutes of Health and the President's Commission on Combatting Drug Addiction and the Opioid Crisis, called for the development of more potent and longer‐acting opioid antagonists. ¹⁶ , ¹⁷

Nalmefene is a MOR antagonist that was initially approved in 1995 as an intravenous (IV), intramuscular (IM), or subcutaneous (SC) injectable (Revex^®) for the reversal of opioid overdose or postoperative anesthesia. Although it was withdrawn from the market by the manufacturer in 2008 for reasons other than safety or effectiveness, ¹⁸ nalmefene has received renewed interest based on its potential to provide stronger and longer‐acting antagonism as compared to naloxone in the treatment of opioid overdose. The terminal elimination half‐life of nalmefene ranges from 7 to 11 h and is longer than that of naloxone, which is reported to range from 1.25 to 2.5 h. ¹⁹ , ²⁰ , ²¹ In vitro, nalmefene also has approximately 4.9‐5.4 times greater affinity for human MOR than naloxone. ¹⁶ , ²²

In February 2022, the US FDA approved a generic injectable formulation of nalmefene (2 mg/2 mL vial) indicated for the “complete or partial reversal of opioid drug effects, including respiratory depression, induced by either natural or synthetic opioids.” ²³ , ²⁴ This approval was followed in May 2023 with approval of a 2.7 mg intranasal formulation of nalmefene (Opvee^®) for the emergency treatment of known or suspected opioid overdose in community or health care settings. ²⁵ More recently, in August 2024, the FDA approved Zurnai™, the first and only auto‐injector that delivers IM or SC 1.5 mg of nalmefene for the emergency treatment of known or suspected opioid overdose in adults and children 12 years and older. ²⁶ The nalmefene auto‐injector contains a formulation that includes magnesium chloride and is intended to achieve more rapid absorption of nalmefene during the critical early moments in the reversal of opioid overdose in the community or health‐care settings. As part of the development of this nalmefene auto‐injector product, a pharmacodynamic study comparing the onset of action to an approved naloxone product was conducted. This study was requested by the FDA. Product approval required that the onset and magnitude of reversal of fentanyl‐induced respiratory depression by nalmefene be comparable to or better than that provided by standard‐of‐care intranasal naloxone. The clinical model of opioid‐induced respiratory depression (OIRD) used in this study was developed and refined over the course of several prior studies, including one that has been published to date. ²⁷ Here, we present data analyzed using non‐inferiority and superiority statistical testing, demonstrating the onset of action at critical early timepoints, as well as the effectiveness and duration of action of nalmefene 1.5 mg IM by auto‐injector compared to standard‐of‐care treatment with IN naloxone 4 mg under steady‐state fentanyl agonism.

Methods

Study Overview

The clinical study protocol and informed consent form were reviewed and approved by Advarra institutional review board in Columbia, MD (protocol reference number NAL1004). All subjects provided informed consent prior to enrolling in the study. The study was conducted at Ohio Clinical Trials, Columbus, OH, and was conducted in accordance with the US Code of Federal Regulations, the International Council for Harmonization (ICH) Guidelines for Good Clinical Practice, the Belmont Report, and the Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was registered (www.clinicaltrials.gov) as NCT 06719986.

This study was a single‐center, randomized, 2‐treatment, 4‐period crossover replicate study designed to evaluate the pharmacodynamic effects of nalmefene 1.5 mg IM given via an auto‐injector compared to naloxone 4 mg IN in the reversal of fentanyl‐induced respiratory depression. The primary objective was to characterize the change in minute ventilation (MV) from the OIRD nadir for nalmefene 1.5 mg IM given via an auto‐injector compared to naloxone 4 mg IN.

Subjects

To be included in the study, male and female subjects were required to meet age (18 to 55 years), weight (50 to 100 kg), and body mass index (18 to 30 kg/m²) restrictions. Subjects were required to be healthy and free of significant abnormal findings as determined by medical history, physical examination, clinical laboratory values, vital signs, and electrocardiography (ECGs). While potential subjects dependent on opioids were excluded, eligible subjects were required to have moderate (≥10 times within the previous year and ≥3 times within the previous 12 weeks) experience with using opioids for nontherapeutic purposes. The potential subjects were also required to have taken an opioid dose equivalent to at least 30 mg oxycodone immediate release at least once within the previous year. Potential subjects who were pregnant, significantly ill within the previous 30 days, or had any condition that would interfere with drug absorption, distribution, metabolism, or excretion were not eligible for the study. In addition, subjects were not eligible if they had: a history of increased intracranial pressure, brain tumor, seizures, or head trauma with sequelae; any pulmonary condition within the previous 2 years that required hospitalization; a history of obstructive sleep apnea; SpO₂ < 95%; currently smoked ≥ half a pack of cigarettes per day; or had a resting heart rate <45 or >100 bpm at screening. Potential subjects were also excluded if they self‐reported a history of substance use disorder in the previous 2 years or any participation in a drug rehabilitation program (other than for smoking cessation). In addition, if subjects had current substance use disorder within the last 12 months (except for caffeine), as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) or if they had an Objective Opioid Withdrawal Scale score of ≥3 on the screening naloxone challenge test, they were excluded from the study. Subjects were required to abstain from the following during the study: products such as tea, coffee, and cocoa (which may contain xanthines, such as caffeine, theobromine, and theophylline), poppy seeds (beginning 1 week prior to study start), alcohol (beginning 48 hours before the first dose of study drug), recreational drugs, and tobacco/nicotine in order to minimize the potential for drug interactions. They were also required to abstain from strenuous exercise during the study. All food and beverages were supplied by the study unit in accordance with the study protocol requirements.

Study Design

The study consisted of a screening visit, a qualification phase (for subjects who had not previously qualified in a similar OIRD study at the same site), a treatment phase, and a follow‐up phone call. Subjects were continuously confined to the study unit for the entire treatment phase (including all four treatment periods).

During the qualification phase, treatment sessions began with an intravenous (IV) infusion of normal saline for 30 to 45 min at a rate of 6 mL/h. The saline infusion was followed by an IV infusion of fentanyl at a rate of 5 µg/min for up to 120 min. The fentanyl infusion was stopped after OIRD, defined as a sustained decrease in MV of ≈50% for 5 min, was achieved or the maximum duration (120 min) was reached. Thus, the overall duration of the fentanyl infusion was individualized on the basis of each subject's response. Successful qualification required that participants achieve a decrease from baseline in MV of approximately 50% for approximately 5 min without excessive variability (“excessive” being defined subjectively as variability that rendered the evaluation of the 50% decrease in MV as questionable) and with no safety or tolerability concerns. Subjects received supplemental oxygen by mask at a rate of 2 L/min for enhanced safety during the qualification sessions.

The 4‐period treatment phase included administrations of two opioid antagonists, each on two separate occasions: (A) nalmefene 1.5 mg IM administered by auto‐injector (Zurnai^TM, Purdue Pharma L.P.), and (B) naloxone 4 mg IN (Narcan^®; Emergent BioSolutions Inc.). The washout time between periods was approximately 72 h. The nalmefene auto‐injector comprises a prefilled syringe with a staked 5/8‐inch needle housed within a single‐dose, disposable, spring powered auto‐injector, that contains 1.5 mg nalmefene. Treatments were administered according to a replicate randomization schedule (ABAB or BABA). The randomization was generated in blocks of 2, with each sequence occurring once in each block.

Within each period, prior to each experimental session, subjects fasted overnight. They were not permitted to consume liquids beginning 2 h before the start of the experimental session through 1 h after the end of fentanyl administration. Subjects remained upright for 4 h after the end of the last infusion.

Each experimental session began with an IV infusion of 0.9% saline at a rate of 6 mL/h for 30 to 45 min to establish baseline measurements, followed immediately by the start of the first fentanyl infusion. Fentanyl was administered as a sequence of three successive IV infusions that were designed to maintain approximately constant fentanyl concentrations after OIRD was achieved during the first fentanyl infusion (Figure 1). Thus, the rates of the second and third fentanyl infusions were successively reduced to maintain a concentration approximately equal to the concentration present when OIRD was achieved at the end of the first infusion.

Figure 1.

Schematic of the opioid‐induced respiratory depression treatment phase. Each treatment period began with an IV infusion of 0.9% saline solution, followed 30 to 45 min later by fentanyl infusion #1: Rate = 5.0 µg/min and is stopped when minute ventilation (MV) has decreased by ≈50% for ≈5 min or when 2 h have elapsed (opioid‐induced nadir). Fentanyl infusion #2 and #3: Both infusion rates are always lower than the rate of infusion #1 and are based on the duration of infusion #1. The rates are selected to maintain the fentanyl concentration approximately constant at the value attained at the end of infusion #1. MV and other continuous monitoring began 30 min before the start of the saline infusion and continued until 1 h after the end of the infusions. MV, minute ventilation (L/min); OIRD, opioid induced respiratory depression.

The rates of the second and third fentanyl infusions were determined from a 3‐compartment pharmacokinetic model for fentanyl exposure based on the duration of the first fentanyl infusion. This model was developed from concentration data obtained following intravenous bolus administration of fentanyl in a previous study (data on file). Using this model, fentanyl concentration profiles were simulated for constant‐rate IV infusion across the full range of possible durations for the first infusion (i.e., 5 through 120 min). The total duration of the fentanyl infusions was determined by each subject's response (i.e., time to reach ≈50% MV for 5 min). The maximum total duration of the three‐infusion sequence in each period was 230 min. Regardless of the duration, all subjects were monitored with the full set of equipment and administered supplemental oxygen for an additional hour after the end of the fentanyl infusions.

The first fentanyl infusion was administered at a fixed rate of 5 µg/min for no longer than 120 min. Once OIRD was achieved, the infusion rate was reduced to a rate determined by the empirical pharmacokinetic model. This lower rate of infusion represented the second fentanyl infusion. Ten minutes after initiating the second fentanyl infusion, the subject received either nalmefene 1.5 mg IM by auto‐injector placed directly on the skin and administered into the anterolateral thigh or naloxone 4 mg IN. The duration of the second infusion was 20 min. The next rate change (third fentanyl infusion, scheduled for 90 min) was then initiated (Figure 1), with the rate based on the duration of the first infusion as calculated by the pharmacokinetic model.

During the entire experimental session, subjects received continuous supplemental oxygen (2 L/min) via a simple mask. A noninvasive ExSpiron ventilation monitor (model 1Xi; Respiratory Motion Inc., Waltham, MA) was used to monitor MV continuously. ²⁸ , ²⁹ Real‐time continuous monitoring of oxygen saturation (SpO₂) and transcutaneous CO₂ (TCO₂) was conducted with a Sentec Digital Monitoring System (Sentec AG, Therwil, Switzerland). Continuous TCO₂ monitoring was performed at predose (baseline) and throughout the fentanyl infusions, antagonist dosing, and for 1 after the end of the infusion of fentanyl with a transdermal sensor placed at multiple anatomical sites, primarily on the subject's cheek.

The experimental setting and activities were standardized for all subjects across all treatment periods in a fashion designed to provide a relaxing environment with minimal visual and auditory stimulation during the procedures. Subjects were seated in a padded chair with an optional ottoman, wore eye masks in a dimly lit room, and wore noise‐cancelling headphones in addition to ear plugs. They were separated from one another by dividers in a large open room, and all conversations and other noise were kept at a minimum.

Pharmacodynamics

The pharmacodynamic assessments were MV, calculated as the product of tidal volume and respiratory rate measured continuously by the ExSpiron monitor. In addition, TCO₂ was continuously monitored as a lagging measure of respiratory status in OIRD.

The MV baseline was defined as the median value of MV during the 10 min before the start of fentanyl infusion. Nadir was defined as the median value obtained between 10 and 5 min prior to the administration of the antagonist. The median MV was determined during a 1‐min window around each time point. Thus, the median MV for the timepoint of 5 min was the median of the values that were obtained between 4.5 and 5.5 min.

The primary outcome measure was the change in MV from opioid‐induced nadir observed at 5 min after opioid antagonist administration. The secondary endpoints were change in MV from opioid induced nadir at 2.5, 10, 15, 20, 30, and 90 min after administration of antagonist, maximum of reversal in MV, and time to maximum of reversal in MV at 0‐90 min from administration of antagonist.

Assessment of TCO₂ was an exploratory outcome measure supplemental to MV. As was done for MV, the baseline was defined as the median value of the TCO₂ data collected during the 10 min before the start of fentanyl infusion. Nadir was defined as the median value obtained between 10 and 5 min prior to the administration of the antagonist. TCO₂ raw data was used to calculate median TCO₂ data.

A second exploratory outcome measure assessing MV was time to onset (TTO) of reversal following antagonist administration. For this outcome, a 30‐mi window, beginning with administration of the antagonist, was selected to ensure that the initial onset was fully captured. The TTO was defined as the time from administration of antagonist to thresholds (X%) of baseline reversal, where baseline was defined as the median value of MV during the 10 min before the start of fentanyl.

Thresholds (X%) of reversal were defined as X% of baseline reversal and calculated as

$$\begin{array}{ccc}& & \mathrm{X}\%\mathrm{of}\mathrm{baseline}\mathrm{reversal}=\mathrm{X}\%*\left(\mathrm{Baseline}-\mathrm{nadir}\right)\hfill \\ & & +\mathrm{nadir}\hfill \end{array}$$

for X values of 25%, 33%, 50%, 67%, 75%, 90%, and 100%.

If X% reversal was not achieved within 30 min in a session, then TTO for that reversal threshold was imputed to 30 min.

Pharmacokinetics

Blood samples were collected at 2.5, 5, 10, 15, 20, and 30 min and at 1, 2, 4, 8, 12, and 24 h after antagonist administration. The blood samples were collected in K₂EDTA‐coated Vacutainer^® tubes and centrifuged at 3000 rpm at 4°C for 15 min. The plasma samples were stored at −20°C. The concentrations of fentanyl, nalmefene, and naloxone in plasma were determined by validated high‐performance liquid chromatography methods in tandem with mass spectrometry (LC‐MS/MS). Plasma concentrations of nalmefene and naloxone were used to calculate the area under the plasma concentration‐time curve (AUC)_{0‐2.5 min}, AUC_{0‐5 min}, AUC_{0‐10 min}, AUC_{0‐15 min}, AUC_{0‐20 min}, AUC_0‐t (where t was the time of the last measurable plasma concentration), AUC_inf (AUC extrapolated to infinity), C_max (peak plasma concentration), T_lag (time to first measurable plasma concentration), T_max (time to peak plasma concentration), and T_½ (terminal half‐life). Pharmacokinetic metrics were not calculated for fentanyl.

Safety

Safety assessments included recording adverse events (AEs) coded to Medical Dictionary for Regulatory Activities (MedDRA) terms. Treatment‐emergent adverse events (TEAEs) were those AEs that emerged or re‐emerged during treatment, or that worsened in intensity during treatment compared to the pre‐treatment period. Any AE that occurred within 7 days after a subject's last dose of study drug was considered a TEAE. The TEAEs were assessed for severity, seriousness, and causality. Additional safety assessments included laboratory safety tests (biochemistry, hematology, and urinalysis), vital signs (systolic and diastolic blood pressure, pulse rate, breathing rate, body temperature, and oxygen saturation), physical examination, and ECGs.

Statistical Analyses

Estimation of Sample Size

In a non‐inferiority test on MV at 5 min from a 4‐period, 2‐treatment replicate crossover design, a total sample size of 20 subjects would achieve >90% power at a 2.5% significance level (1‐sided) when the true difference between the means is 0.8 L/min, the non‐inferiority margin is −0.5 L/min, and the within‐subject standard deviation is 1.2 L/min. In a superiority test on MV at 5 min from a 4‐period, 2‐treatment replicate crossover design, a total sample size of 20 subjects would achieve 83% power at a 2.5% significance level (1‐sided) when the true difference between the means is 0.8 L/min and the within‐subject standard deviation is 1.2 L/min. The study planned to randomize up to 22 subjects to complete approximately 20. This sample size is adequate for conducting sequential testing, first to assess non‐inferiority and then to evaluate superiority.

Statistical programming and analyses were performed with SAS^® software (v. 9.4; SAS Institute, Cary, NC), and pharmacokinetic analyses were performed with Phoenix WinNonlin version 8.0 (Certara, Princeton, NJ).

The primary objectives were to demonstrate non‐inferiority and superiority at the primary endpoint (5 min post administration) of IM nalmefene compared to IN naloxone to reverse the change in MV from opioid‐induced nadir (i.e., OIRD).

Hypothesis #1: For non‐inferiority testing, the null hypothesis was that nalmefene treatment (µT) was inferior to the reference (naloxone) treatment (μR). The alternative hypothesis was that nalmefene treatment was not inferior to naloxone treatment.

$$\mathrm{H}0:\mu \mathrm{T}-\mu \mathrm{R}\le -0.5\mathrm{versus}\mathrm{H}1:\mu \mathrm{T}-\mu \mathrm{R}>-0.5.$$

Hypothesis #2: For superiority testing, the null hypothesis was that nalmefene (µT) was not superior to the reference treatment (naloxone) (μR). The alternative hypothesis was that nalmefene was superior to naloxone.

$$\mathrm{H}0:\mu \mathrm{T}-\mu \mathrm{R}\le 0.0\mathrm{versus}\mathrm{H}1:\mu \mathrm{T}-\mu \mathrm{R}>0.0$$

Statistical analysis was performed for hypothesis #1 first. If non‐inferiority was met, then the analysis proceeded to hypothesis #2. In this gatekeeping framework, the hierarchical testing sequence ensures that multiplicity is controlled at the overall alpha level (one‐sided alpha = 0.025). Least square means were based on a general linear model (GLM) with change in MV from nadir at each timepoint as outcome, subject, treatment, treatment sequence, and period as factors.

In this study, non‐inferiority would be established if the lower bound of the 95% confidence interval (CI) for nalmefene was greater than the pre‐specified margin (−0.5 L/min), and superiority would be established if greater than 0 L/min.

Results

Disposition of Subjects

The subjects randomized in the study included 13 who qualified as part of this study and 11 who had previously been qualified in related studies. Of the 24 subjects randomized, 22 subjects completed the study, and 2 subjects discontinued due to treatment‐emergent adverse events.

Subject Characteristics

Subject characteristics are summarized in Table 1. The median age was 41 years (range 24 to 52) and 91.7% of subjects were male. The majority of subjects were Black or African American (45.8%) and White (41.7%). The remaining 12.5% were of mixed race.

Table 1.

Subject Characteristics

Characteristics	Treatment Phase (N = 24)
Age (years)
Mean (SD)	39.1 (7.60)
Median (range)	39.5 (24 to 52)
Age group (years), n (%)
18 to 34	8 (33.3)
35 to 49	13 (54.2)
50 to 54	3 (12.5)
Male, n (%)	22 (91.7)
Ethnicity, n (%)
Hispanic or Latino	5 (20.8)
Not Hispanic or Latino	19 (79.2)
Race
Black or African American	11 (45.8)
White	10 (41.7)
Mixed Race	3 (12.5)
Weight (kg)
Mean (SD)	81.1 (10.4)
Median (range)	82.0 (63.5 to 100.4)
Body mass index (kg/m2)
Mean (SD)	26.4 (2.5)
Median (range)	26.3 (22.3 to 30.4)

SD, standard deviation.

Reversal of Fentanyl‐Induced Respiratory Depression by Opioid Antagonists

The mean MV profile over time shows that baseline and nadir were similar for nalmefene and for naloxone (Figure 2). The MV profiles for both treatments showed a brief positive spike beginning shortly before the administration of the antagonist (i.e., before time 0) that was followed by a decline over the next 5 min. It is likely that the spike represents stimulation of the subject by activities just prior to dosing and by the dosing at time 0, and the subsequent brief decline represents waning of that stimulation. Mean MV was maintained at a higher level over time after administration of nalmefene relative to naloxone administration (Figure 2). Mean MV after naloxone administration remained noticeably below the baseline level until approximately 20 min after administration. In contrast, the mean MV after nalmefene administration quickly reached and exceeded baseline values. After 30 min, the mean MV for both treatments stabilized near the baseline level.

Figure 2.

Time‐course of reversal of fentanyl‐induced respiratory depression following nalmefene 1.5 mg IM by auto‐injector and naloxone 4 mg IN. MV, minute ventilation (L/min).

Primary Endpoint Analysis

Changes in MV from nadir for nalmefene and naloxone are shown in Figure 3. The greatest treatment difference was at 5 min after administration (i.e., primary endpoint), when the change in MV from nadir was estimated to be 2.60 L/min greater for nalmefene (LS mean: 4.59 L/min) than for naloxone (LS mean: 1.99 L/min), with an associated 95% confidence interval of (1.83, 3.38), representing a statistically significant finding of not only non‐inferiority (P < .0001) but also superiority (P < .0001) (Figure 4, Table 2). These results were confirmed following a sensitivity analysis that excluded reversal session data for which the change in MV at 5 min was more than 1.5 interquartile range (IQR) below the first quartile (Q1) or more than 1.5 IQR above the third quartile (Q3). In this analysis, the LS mean difference between naloxone and nalmefene was 2.33 L/min (95% CI: [1.63, 3.04]), also achieving both non‐inferiority (P < .001) and superiority (P < .001) over naloxone.

Figure 3.

The change from nadir over time. Data are presented as mean change in MV from nadir at select time‐points after administration of the antagonist. Nadir was defined as the median of MV between 10 and 5 min prior to the administration of the opioid antagonist. Data represent the mean of 45 treatments in 23 subjects for nalmefene and 47 treatments in 24 subjects for naloxone. CI, confidence interval; LSM, least‐squares mean; MV, minute ventilation (L/min).

Figure 4.

Non‐inferiority and superiority at a pre‐specified primary endpoint (5 min post administration) using naloxone as the reference treatment and nalmefene as the test treatment. The analysis was conducted according to Food and Drug Administration (FDA) guidance on non‐inferiority trials (FDA, 2016; https://www.fda.gov/media/78504/download). The non‐inferiority test was performed first. If non‐inferiority was achieved, superiority was tested sequentially: Hypothesis #1 (Non‐inferiority test): H0: µT ‐ μR ≤ −0.5 versus H1: µT ‐ μR > −0.5; Hypothesis #2 (Superiority test): H0: µT ‐ μR ≤ 0 versus H1: µT ‐ μR > 0. Non‐inferiority would be established if the lower bound of the 95% CI for nalmefene was greater than the pre‐specified margin (−0.5 L/min), and superiority would be established if greater than 0 L/min. CI: confidence interval; LS mean: Least‐squares mean; Nadir, median of MV between −10 and −5 min before the start of the Antagonist.

Table 2.

Inferential Analysis of Change in MV from Nadir at Specified Timepoints

Parameter MV (L/min)	Statistic	Nalmefene 1.5 mg IM Auto‐injector (n = 23)	Naloxone 4 mg IN (n = 24)	Difference of Nalmefene and Naloxone
Nadir	LS mean (SE) [1]	4.36 (0.147)	4.34 (0.137)	0.02 (0.198)
	95% CI	4.06, 4.65	4.07, 4.61	−0.38, 0.41
	P‐value (non‐inferiority test)			0.9361
	P‐value (superiority test)			0.9361
2.5 min	LS mean (SE) [1]	2.12 (0.238)	1.69 (0.220)	0.43 (0.319)
	95% CI	1.64, 2.59	1.25, 2.13	−0.21, 1.07
	P‐value (non‐inferiority test)			0.0050
	P‐value (superiority test)		f‐0.5	0.1818
5 min	LS mean (SE) [1]	4.59 (0.289)	1.99 (0.268)	2.60 (0.388)
	95% CI	4.01, 5.17	1.45, 2.52	1.83, 3.38
	P‐value (non‐inferiority test)			<0.0001
	P‐value (superiority test)			<0.0001
10 min	LS mean (SE) [1]	4.09 (0.182)	2.56 (0.169)	1.53 (0.245)
	95% CI	3.72, 4.45	2.22, 2.89	1.04, 2.02
	P‐value (non‐inferiority test)			<0.0001
	P‐value (superiority test)			<0.0001
15 min	LS mean (SE) [1]	4.22 (0.249)	2.76 (0.231)	1.46 (0.334)
	95% CI	3.72, 4.71	2.30, 3.22	0.79, 2.13
	P‐value (non‐inferiority test)			<0.0001
	P‐value (superiority test)			<0.0001
20 min	LS mean (SE) [1]	4.08 (0.278)	3.06 (0.258)	1.02 (0.374)
	95% CI	3.52, 4.64	2.55, 3.58	0.27, 1.77
	P‐value (non‐inferiority test)			0.0001
	P‐value (superiority test)			0.0086
30 min	LS mean (SE) [1]	3.59 (0.226)	2.92 (0.210)	0.68 (0.304)
	95% CI	3.14, 4.05	2.50, 3.34	0.07, 1.29
	P‐value (non‐inferiority test)			0.0003
	P‐value (superiority test)			0.0291
90 min	LS mean (SE) [1]	2.81 (0.184)	2.57 (0.171)	0.24 (0.247)
	95% CI	2.44, 3.17	2.23, 2.91	−0.26, 0.73
	P‐value (non‐inferiority test)			0.0041
	P‐value (superiority test)			0.3363

The non‐inferiority test was performed first. If non‐inferiority was achieved, superiority was tested sequentially:

LS mean, least square mean; SE: standard error; Nadir, median of MV between−10 and −5 min before the start of the antagonist.

Hypotheses #1 (Non‐inferiority test): H0: µT ‐ μR ≤ −0.5 versus H1: µT ‐ μR > −0.5;

Hypotheses #2 (Superiority test): H0: µT ‐ μR ≤ 0 versus H1: µT ‐ μR > 0.

[1] LS means were based on GLM with change in MV from nadir at each timepoint as outcome, subject, treatment, treatment sequence, and period as factors.

Secondary and Exploratory Endpoints

The change in MV from nadir at 2.5, 10, 15, 20, and 30 min after administration of antagonist exhibited trends similar to those observed for the 5‐min timepoint (Figure 3). The average change in MV resulting from nalmefene administration was always greater than that from naloxone. The inferential analysis (Figure 4, Table 2) obtained similar results, as the estimated mean difference between treatments was consistently greater than zero. Nalmefene was demonstrated to be statistically non‐inferior to naloxone at all timepoints (lower bound of 95% CI greater than −0.5 L/min) and was statistically superior (lower bound of 95% CI greater than zero) at all measured timepoints except 2.5 and 90 min (Figure 4). Additionally, over the 0 to 5 min interval, the mean (SD) maximal reversal of MV obtained with nalmefene was 9.22 (2.48) L/min, and the mean (SD) time to maximal reversal was 3.52 (1.53) min (Table S1). The mean (SD) maximal reversal of MV obtained with naloxone was 7.68 (1.54) L/min which occurred at a mean (SD) time of 1.89 (1.39) min after administration (Table S1).

Overall, the mean treatment profiles for TCO₂ (Figure S1) showed a similar trend to the profiles for MV (Figure 2). Notably, the onset of effect as measured by TCO₂ was slightly slower than that of MV, as was expected for this lagging indicator of OIRD. After nalmefene administration, mean TCO₂ concentrations stabilized within less than 10 min to levels slightly below baseline. After naloxone administration, TCO₂ concentrations did not stabilize until approximately 20 min and remained slightly higher than the baseline. Both nalmefene and naloxone showed a gradual increase in TCO₂ concentrations after stabilizing (Figure S1).

The TTO of reversal of OIRD for nalmefene and naloxone, as measured by change in MV from nadir to baseline, is summarized for 25%, 33%, 50%, 67%, 75%, 90%, and 100% thresholds of baseline reversal (Table S2). If a subject did not achieve a specified level of reversal (threshold failure) in a session, a TTO value of 30 min was imputed for that reversal threshold. Following naloxone administration, reversal threshold failures occurred during five sessions beginning at thresholds of 50% (1), 67% (2), and 100% (2). There were no reversal threshold failures following nalmefene administration.

At each of the reversal thresholds, nalmefene showed faster mean TTO than naloxone. For example, the mean (SD) time to 50% reversal was 1.66 (1.47) min for nalmefene compared to 4.68 (6.63) min for naloxone (Table S2).

Pharmacokinetics of IM Nalmefene and IN Naloxone

The sequential infusions of fentanyl produced consistently similar plasma concentrations over the infusion period (Figure 5a). Fentanyl plasma concentrations did not appear to be affected by the administration of the opioid antagonists.

Figure 5.

(a) Time‐course of mean (SD) plasma fentanyl concentrations (ng/mL) across the treatment periods. Data represent the mean of 45 treatments in 23 subjects for nalmefene and 47 treatments in 24 subjects for naloxone. SD, standard deviation. (b) Time‐course of mean (SE) plasma concentrations (ng/mL) of nalmefene 1.5 mg IM by auto‐injector and naloxone 4 mg IN from 0‐30 min. Data represent the mean of 45 treatments in 23 subjects for nalmefene and 47 treatments in 24 subjects for naloxone. SE, standard error. (c) Time‐course of mean (SE) plasma concentrations (ng/mL) of nalmefene 1.5 mg IM by auto‐injector and naloxone 4 mg IN from 0‐24 h. Data represent the mean of 45 treatments in 23 subjects for nalmefene and 47 treatments in 24 subjects for naloxone. SE, standard error.

Mean plasma concentrations of nalmefene rose rapidly after IM administration and reached a peak within 5 min (Figure 5b). Nalmefene showed an extended duration of relatively higher exposures compared to IN naloxone (Figure 5c). Mean plasma concentrations of naloxone rose more slowly than those of nalmefene and reached a peak at 30 min (Figure 5b). The pharmacokinetic plots appear to correlate well with the pharmacodynamic graphs (i.e., change in MV from nadir), with nalmefene showing earlier onset and more robust reversal of fentanyl‐induced respiratory depression (Figures 3, and 5b,c).

The pharmacokinetic parameters for nalmefene and naloxone are summarized in Table 3. The overall mean AUC_inf was 25.74 ng·h/mL for the nalmefene auto‐injector and 13.49 ng·h/mL for naloxone. The mean C_max was 8.36 ng/mL for nalmefene and 5.60 ng/mL for naloxone. The median time to peak plasma concentration (T_max) following antagonist administration was 12.5 min for nalmefene, compared to 40 min for naloxone. The median time to first measurable plasma concentration (T_lag) after antagonist administration was 2.5 min for both nalmefene and naloxone. The T_½ of nalmefene was 7.98 h, compared to only 1.64 h for naloxone.

Table 3.

Plasma Pharmacokinetic Parameters for the Opioid Antagonists

	AUC0‐2.5 (ng•h/mL)	AUC0‐5 (ng•h/mL)	AUC0‐10 (ng•h/mL)	AUC0‐15 (ng•h/mL)	AUC0‐20 (ng•h/mL)	AUCt (ng•h/mL)	AUCinf (ng•h/mL)	Cmax (ng/mL)	Tmax (h)	Tlag (h)	T½ (h)
Nalmefene 1.5 mg IM Auto‐injector (N = 23)
Mean (SD)	0.044 (0.039)	0.223 (0.136)	0.758 (0.381)	1.27 (0.524)	1.75 (0.613)	23.16 (3.61)	25.74 (4.65)	8.36 (3.71)	0.221 (0.192)	0.053 (0.019)	7.98 (2.17)
Median (min‐max)	0.043 (0‐0.136)	0.190 (0.046‐0.504)	0.665 (0.265‐1.66)	1.17 (0.558‐2.47)	1.63 (0.896‐3.10)	24.07 (16.31‐29.33)	26.71 (17.64‐33.24)	6.86 (4.83‐19.30)	0.208 (0.062‐1.02)	0.042 (0.042‐0.122)	7.18 (5.55‐13.0)
CV%	89.07	60.97	50.35	41.18	35.10	15.58	18.07	44.41	87.00	36.27	27.15
GMCV	0.016	0.181	0.673	1.18	1.65	22.88	25.33	7.73	0.179	0.050	7.73
GMCV%	7224.58 a	77.99	53.47	41.55	35.12	16.35	18.77	40.37	68.43	30.25	25.03
Naloxone 4 mg IN (N = 24)
Mean (SD)	0.026 (0.037)	0.100 (0.115)	0.331 (0.272)	0.630 (0.433)	0.982 (0.611)	13.4 (2.79)	13.49 (2.87)	5.60 (2.31)	0.596 (0.264)	0.046 (0.010)	1.64 (0.503)
Median (minimum–maximum)	0.014 (0.001‐0.137)	0.062 (0.013‐0.435)	0.236 (0.067‐1.09)	0.569 (0.158‐1.77)	0.91 (0.283‐2.44)	12.76 (9.82‐19.67)	12.78 (9.982‐19.89)	5.28 (2.715‐12.80)	0.667 (0.167‐1.00)	0.042 (0.042‐0.083)	1.50 (1.18‐3.53)
CV%	143.24	115.23	82.16	68.66	62.19	20.68	21.27	41.20	44.29	22.07	30.73
GM	0.012	0.060	0.243	0.505	0.819	13.22	13.22	5.21	0.53	0.046	1.58
GMCV%	203.13	137.98	96.46	77.96	68.66	20.24	20.81	39.84	57.25	18.43	24.63

AUC, area under the plasma concentration‐time curve; C_max, peak plasma concentration; GM, geometric mean, GMCV, geometric mean coefficient of variation; IM, intramuscular; IN, intranasal; t, time of the last measurable plasma concentration; T_lag, time to first measurable plasma concentration; T_max, time to peak plasma concentration; T_½, apparent terminal phase half‐life.

^a The high GMCV% for AUC0‐2.5 (h × ng/mL) is attributable to subjects that have exceptionally low AUC0‐2.5 values (less than 0.000001) shown as 0 in the table.

Safety

A total of 22 of the 24 (91.7%) randomized subjects reported at least one TEAE (Table 4). Nine (9) of 24 subjects (37.5%) reported TEAEs after administration of fentanyl only, 21 of 23 (91.3%) subjects reported TEAEs after administration of fentanyl and nalmefene (1.5 mg IM), and 18 of 24 (75.0%) subjects reported TEAEs after administration of fentanyl and naloxone (4 mg IN). There were no SAEs, and most subjects reported TEAEs that were either mild or moderate. A total of two subjects receiving either naloxone or nalmefene discontinued the study due to an AE. One of these subjects receiving naloxone experienced severe hypotension and moderate sinus bradycardia and 1 subject withdrew from the study because of the AEs experienced with nalmefene (feeling hot, discomfort, dry mouth, allodynia, nausea, abdominal pain, early satiety, and headache).

Table 4.

Treatment Emergent Adverse Events by System Organ Class and Preferred Term Occurring in ≥5% of All Subjects

System Organ Class Preferred Term	Fentanyl (N = 24) n (%)	Fentanyl + Nalmefene (N = 23) n (%)	Fentanyl + Naloxone (N = 24) n (%)	All Subjects (N = 24) n (%)
Any TEAE	9 (37.5)	21 (91.3)	18 (75.0)	22 (91.7)
Cardiac disorders	1 (4.2)	4 (17.4)	1 (4.2)	5 (20.8)
Palpitations	1 (4.2)	4 (17.4)	0	4 (16.7)
Ear and labyrinth disorders	0	6 (26.1)	1 (4.2)	7 (29.2)
Tinnitus	0	4 (17.4)	0	4 (16.7)
Ear discomfort	0	3 (13.0)	0	3 (12.5)
Gastrointestinal disorders	3 (12.5)	9 (39.1)	8 (33.3)	15 (62.5)
Nausea	3 (12.5)	6 (26.1)	5 (20.8)	10 (41.7)
Dyspepsia	0	2 (8.7)	2 (8.3)	4 (16.7)
Vomiting	0	3 (13.0)	1 (4.2)	4 (16.7)
Dry mouth	0	1 (4.3)	1 (4.2)	2 (8.3)
General disorders and administration site conditions	4 (16.7)	16 (69.6)	5 (20.8)	18 (75.0)
Feeling hot	2 (8.3)	11 (47.8)	4 (16.7)	13 (54.2)
Chills	0	6 (26.1)	0	6 (25.0)
Feeling abnormal	1 (4.2)	3 (13.0)	0	3 (12.5)
Feeling cold	0	2 (8.7)	1 (4.2)	3 (12.5)
Injection site pain	0	2 (8.7)	0	2 (8.3)
Nervous system disorders	1 (4.2)	14 (60.9)	12 (50.0)	16 (66.7)
Headache	0	5 (21.7)	5 (20.8)	8 (33.3)
Dysgeusia	0	1 (4.3)	7 (29.2)	7 (29.2)
Allodynia	0	5 (21.7)	2 (8.3)	6 (25.0)
Dizziness	1 (4.2)	4 (17.4)	1 (4.2)	5 (20.8)
Burning sensation	0	3 (13.0)	0	3 (12.5)
Muscle contractions involuntary	0	1 (4.3)	1 (4.2)	2 (8.3)
Paresthesia	0	1 (4.3)	1 (4.2)	2 (8.3)
Psychiatric disorders	0	6 (26.1)	3 (12.5)	7 (29.2)
Irritability	0	3 (13.0)	1 (4.2)	4 (16.7)
Agitation	0	2 (8.7)	0	2 (8.3)
Anxiety	0	2 (8.7)	1 (4.2)	2 (8.3)
Insomnia	0	1 (4.3)	1 (4.2)	2 (8.3)
Restlessness	0	1 (4.3)	1 (4.2)	2 (8.3)
Respiratory, thoracic and mediastinal disorders	1 (4.2)	0	1 (4.2)	2 (8.3)
Dyspnoea	1 (4.2)	0	1 (4.2)	2 (8.3)
Skin and subcutaneous tissue disorders	4 (16.7)	2 (8.7)	4 (16.7)	9 (37.5)
Hyperhidrosis	2 (8.3)	1 (4.3)	3 (12.5)	5 (20.8)
Pruritus	2 (8.3)	0	0	2 (8.3)
Skin lesion	0	1 (4.3)	1 (4.2)	2 (8.3)
Vascular disorders	1 (4.2)	4 (17.4)	3 (12.5)	6 (25.0)
Hot flush	1 (4.2)	3 (13.0)	1 (4.2)	4 (16.7)

TEAE, treatment emergent adverse event.

For two subjects, the third fentanyl infusion during the experimental session was stopped early. One subject's infusion was stopped due to an AE of headache after receiving naloxone, and the other due to an AE of emesis after receiving nalmefene. Both subjects continued study participation and otherwise completed all procedures.

TEAEs by System Organ Class and Preferred Term are shown in Table 4. The most frequently reported TEAEs by subjects included feeling hot (13/24 [54.2%]), nausea (10/24 [41.7%]), headache (8/24 [33.3%]), dysgeusia (7/24 [29.2%]), allodynia (6/24 [25.0%]) and chills (6/24 [25.0%]). Overall, 87.0% (20/23) of subjects reported a TEAE after administration of fentanyl and nalmefene compared to 70.8% (17/24) after fentanyl and naloxone. All TEAEs had an outcome of “recovered/resolved” by the end of the study. No abnormal ECG or physical examination findings were considered to be adverse events. No device deficiencies were noted for any nalmefene auto‐injectors.

Discussion

This clinical study, requested by FDA, generated the pivotal pharmacodynamic data required for the approval of the first auto‐injector to deliver nalmefene IM or SC for use by healthcare professionals as well as by anyone in the community (e.g., family members, friends, bystanders) for opioid overdose reversal in the pre‐hospital setting. ²⁶ Specifically, FDA approval required that this study establish that the onset and magnitude of reversal of fentanyl‐induced respiratory depression by nalmefene was comparable to or better than that provided by the standard‐of‐care IN naloxone.

The results of the present investigation show that the method of fentanyl infusion used in this study produces consistent and stable plasma concentrations of fentanyl over time, and that fentanyl‐induced respiratory depression can be reliably used to assess the effect of opioid antagonists on minute ventilation. In this study, nalmefene 1.5 mg IM administered via auto‐injector met the primary endpoint of reversal of fentanyl‐induced respiratory depression at 5 min. Non‐inferiority was demonstrated with the increase from nadir in MV at 5 min favoring nalmefene 1.5 mg IM auto‐injector (2.6 L/min; P < .0001) compared to naloxone 4 mg IN. In accordance with FDA guidance for non‐inferiority trials, ³⁰ the lower bound of the 95% confidence interval of this difference (1.83 L/min) demonstrated both non‐inferiority and superiority in favor of nalmefene. In addition, superiority was consistently demonstrated for nalmefene at the 10‐, 15‐, 20‐, and 30‐minute timepoints, while non‐inferiority was demonstrated at all timepoints including 2.5 and 90 min. Nalmefene was tolerated with no serious TEAEs.

The pharmacokinetic profiles of the two antagonist treatments in this study were consistent with their respective pharmacodynamic profiles, with plasma concentrations showing a similar trend over time as the degree of reversal of respiratory depression. The prolonged duration of action of nalmefene compared to naloxone is consistent with findings from a previous study in which respiratory depression was induced in healthy volunteers by morphine (10 mg/70 kg IM), who were challenged 1 hour later with nalmefene (0.4 mg/70 kg IV) or naloxone (0.4 mg and 1.6 mg/70 kg IV. ³¹ At 1.5 to 6 h after antagonist administration, MV was significantly greater with nalmefene than with either dose of naloxone. ³¹ An additional pharmacokinetic finding from the current study is that nalmefene demonstrated less variable exposures over the first 20 min after IM administration (Table 3, partial AUCs from 0 to 5 through 20 mins [GMCV%]) compared to naloxone following IN administration. This reduction in variability for IM nalmefene by auto‐injector was observed during the critical early period following antagonist administration.

The treatment mean profiles of TCO₂ showed similar trends as for MV, but with a slightly slower onset, as expected for this lagging indicator of reversal of OIRD (Figure S1). Mean TCO₂ stabilized to levels below baseline within 10 min after nalmefene administration, while mean TCO₂ after naloxone stabilized above baseline at 20 to 30 min following administration.

In this study, all nalmefene auto‐injector doses were administered with the device held at approximately a 90° angle to the administration site located directly on the skin of the anterolateral thigh. Consistent with other approved auto‐injectors, ³² the nalmefene auto‐injector houses a staked 5/8‐inch‐long needle that delivers a dose IM, or in some cases SC. While IM administration is the intended route, the actual delivery may be SC depending on factors such as the subject's body composition, the angle of the device during administration, and the thickness of any clothing layer present.

A prior study, using this fentanyl model of OIRD, showed that IM nalmefene or IM naloxone produced faster reversal of depressed MV than did IN naloxone, and that IM nalmefene had a longer duration of reversal, with MV maintained at a higher level than with naloxone. ²⁷ In the earlier study some subjects experienced increases in MV in the minutes just prior to antagonist administration, likely due to stimulation. In the present study, subject stimulation prior to antagonist administration was minimized, thus reducing the transient increases in MV just prior to antagonist dosing. The results of this study provide further evidence that OIRD in a controlled clinical setting can be used to quantitatively evaluate the reversal of respiratory depression by MOR antagonists.

Fentanyl and its congeners are adulterants that are found in illicit drugs with increasing frequency. These drugs are especially challenging because their pharmacokinetic and pharmacodynamic properties make reversal with standard dosing regimens of naloxone more complicated. ³ , ⁶ , ³³ For example, after initial reversal of opioid overdose symptoms, the longer half‐life and greater potency of synthetic opioids may require repeated dosing with naloxone. ³ , ⁸ , ¹⁵ In vitro, nalmefene has greater affinity for the MOR, ²⁴ and in vivo, in healthy subjects who had received ¹¹C‐carfentanyl, it was shown to have a longer occupancy at the MOR than naloxone. In addition, it has a half‐life of approximately 9 to 11 h, ²⁴ which is longer than that of naloxone. Thus, given the long terminal half‐lives of some synthetic opioids, including fentanyl (up to ≈7 h), ³⁴ , ³⁵ , ³⁶ sufentanil (≈6 h) ³⁵ and carfentanil (≈6 h), ³⁷ nalmefene has the potential to reduce the reoccurrence of respiratory depression. ³⁸ Conversely, it may be possible that individuals who have received nalmefene could try to override the antagonist effect by taking additional doses of opioids, thus increasing the risk of overdose. ²⁴ , ³⁹ This is also a risk following reversal with naloxone. Nevertheless, recent real‐world data are lacking and further research is needed.

In life‐threatening overdose situations in the community setting, there are many unknowns including the identity, route(s) of administration, combination, and dose of the opioid(s) used, and the timing of last use. Thus, the ability of an opioid antagonist to reverse respiratory depression quickly is critically important to patient survival in real‐world settings. The results of this study demonstrate that the nalmefene auto‐injector has a faster onset and greater magnitude of reversal of fentanyl induced respiratory depression compared to IN naloxone. These results reflect the pharmacologic differences between the two antagonists and the increased rate of early absorption achieved by the nalmefene auto‐injector formulation. While a controlled model of OIRD was used in the present study, we anticipate that the differences observed will be reflected in real‐world performance of the two opioid antagonist treatments.

Furthermore, the ability of nalmefene to maintain its effect may provide a benefit in community settings, especially in rural or other settings where a delay in the provision of emergency care is more likely, and where a single initial dose that will work in the majority of cases is desired.

It is a public health benefit to have a variety of opioid overdose treatments available for use, including in the community setting. For public health benefits from these treatments to be maximized, it is critically important to improve public access to opioid overdose reversal treatments through measures such as OTC availability, pharmacy standing orders, and ensuring affordability.

While the nalmefene auto‐injector represents an additional option for the treatment of opioid overdose, caution should be used in patients who are known to be opioid‐dependent because nalmefene may carry a risk of prolonged precipitated withdrawal. Precipitated withdrawal can occur with naloxone or nalmefene. In a study of real‐world opioid overdose reversal published in 1999, the frequency and intensity of withdrawal reactions following reversal of overdose with nalmefene and naloxone were similar. ⁴⁰ In some instances, the risk of precipitated withdrawal is low. For example in cases of accidental overdoses or poisonings that occur in non‐dependent opioid users, such as a child accidently ingesting an opioid, or in settings where subjects are unlikely to be regular users of opioids (e.g., schools, college campuses). Future real‐world data are needed to more fully understand the benefits and risks of opioid antagonist treatments.

Auto‐injectors are commonly used in the community setting by lay persons for emergency situations (e.g., epinephrine for anaphylaxis); they require minimal or no experience or skill to reliably deliver medications even through clothing, if needed, and no specific positioning of the patient. ⁴¹ , ⁴² In contrast, preparation for proper intranasal administration requires substantial interaction with the patient, including laying the person on their back, tilting the person's head back while providing support under the neck with your hand, inserting the tip of the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person's nose. ⁴³ , ⁴⁴ For these reasons, auto‐injectors may have a role or even be preferred in emergency overdose situations in the community, especially where the person administering the reversal agent may be a bystander or someone unfamiliar with the patient, and who wants to avoid contact with the patient's face or nostrils.

Limitations of the present study include that the reversal sessions were not of sufficient duration to reliably document the full time‐course of reversal effects. Therefore, limited information can be gleaned on the duration of each treatment. Variability in continuous MV measurements using the ExSpiron device reflects both intrinsic variability in MV as well as variability caused by motion artifact from subject movement. The impact of this variability was reduced by using a 1‐minute smoothing window during data analysis. This study was conducted in an experimental setting, where fentanyl was infused over an extended period and titrated to maintain consistent plasma concentrations, and may not reflect real‐world outcomes. Further studies are needed to substantiate the real‐world clinical implications of these data.

Conclusions

In this study, nalmefene 1.5 mg IM administered by auto‐injector, delivering a formulation developed for faster onset, reversed fentanyl‐induced respiratory depression with a shorter time to onset and a greater magnitude of reversal than were achieved with standard‐of‐care naloxone 4 mg IN. These findings for the reversal of fentanyl‐induced respiratory depression in this controlled experimental setting formed the basis for the FDA approval of the nalmefene 1.5 mg IM autoinjector and demonstrate that it is a useful addition to the pharmacologic armamentarium used in the treatment of opioid overdose.

Conflicts of Interest

Alessandra Cipriano, Manjunath Shet, and Stephen C. Harris are employees of Imbrium Therapeutics L.P., a subsidiary of Purdue Pharma L.P., the study sponsor. Ellie He was an employee of Imbrium Therapeutics L.P. at the time of the study. Glen Apseloff received no direct compensation for work related to the development of this manuscript. Glen Apseloff was directly compensated by Purdue Pharma L.P. for his involvement as the principal investigator for this study.

Funding

This work was funded by Purdue Pharma L.P.

Supporting information

Supporting Information

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.