Reversal of Opioid‐Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone

Abstract

An open‐label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil‐induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT 04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight‐fitting mask for an initial period of 46 min prior to a series of mask “holidays” introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time‐dependent reversal of remifentanil‐induced reductions in MV measured 2.5–20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P < .0009); the point estimate favors nalmefene, demonstrating non‐inferiority and superiority. In this model of opioid‐induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose.

Comparison of intranasal naloxone and intranasal nalmefene in a translational model assessing the impact of synthetic opioid overdose on respiratory depression and cardiac arrest

“…Overall, the difference in the apparent effectiveness between IN nalmefene and IN naloxone is consistent with preclinical and clinical evidence including: a higher affinity of nalmefene at mopioid receptors (24,44), higher plasma concentrations of nalmefene delivered at the critical early time points (e.g., 5 min) after dosing (10,22,23), and a more rapid onset of action as demonstrated in a clinical model of opioid-induced respiratory depression (23). The model may be further used to assess the effects of other synthetic opioids, including novel synthetic opioids (NSOs) such as the benzimidazoles (e.g., etonitazene and isotonitazene).…”

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“…Overall, the difference in the apparent effectiveness between IN nalmefene and IN naloxone is consistent with preclinical and clinical evidence including: a higher affinity of nalmefene at mopioid receptors (24,44), higher plasma concentrations of nalmefene delivered at the critical early time points (e.g., 5 min) after dosing (10,22,23), and a more rapid onset of action as demonstrated in a clinical model of opioid-induced respiratory depression (23). The model may be further used to assess the effects of other synthetic opioids, including novel synthetic opioids (NSOs) such as the benzimidazoles (e.g., etonitazene and isotonitazene).…”

“…Nonetheless, Mann et al were able to successfully predict the respiratory effects of fentanyl, remifentanil and alfentanil in clinical laboratory studies (18). With respect to the model expansion with IN naloxone and IN nalmefene data, robust pharmacokinetic models were developed from pharmacokinetic data collected in three studies (22,23). Since the Mann model did not include binding parameters for nalmefene, those were derived from published data (24) using a scaling approach.…”

“…Additionally, the model predicted a slower absorption of IN nalmefene in the pharmacodynamic study, with a 35% decrease in first-order absorption rate compared to the two other pharmacokinetic studies also conducted in healthy volunteers. This decrease was attributed to the drying effect of breathing a hypercapnic mixture on the nasal mucosa, which blunted the effects of the nasal absorption enhancer, dodecyl maltoside (23). To reflect the use of IN nalmefene in a rescue setting, absorption parameters estimated in the absence of a mask delivering a hypercapnic gas mixture were used for opioid overdose simulations.…”

“…Once the translational model was expanded with parameters for IN nalmefene and IN naloxone, the predictive validity of the model was assessed by simulation of the pharmacodynamic study which compared the efficacy of IN nalmefene and IN naloxone in reversing remifentanil-induced respiratory depression (23). Here, simulations accounted for the slower absorption of IN nalmefene resulting from experimental study conditions as described above.…”