Comment on: Can Intranasal Nalmefene Reduce the Number of Opioid Overdose Deaths?

With an emphasis on the disappointing limited impact of naloxone in reducing opioid overdose deaths, Sellers and Romach¹ raise a number of compelling arguments. Their view is supported by data from the Centers for Disease Control and Prevention: According to the State Unintentional Drug Overdose Reporting System database, naloxone had been administered in more than 20% of opioid-related overdose deaths nationally, with some jurisdictions reporting that more than 35% of decedents had received naloxone.² Thus, the estimated death toll from opioid overdoses exceeded 85,000 for the 12-month period ending July 2023³ despite the availability of multiple naloxone products and naloxone saturation strategies.⁴ More than 90% of these fatalities were attributed to high-potency synthetic opioids (synthetics) such as fentanyl.³

In addition to the points raised by Sellers and Romach,¹ these data raise another fundamental issue: Is the availability of standard naloxone tools (ie, doses of 4 mg intranasal and 2 mg/2 mL intramuscular) available in a community setting sufficient to effectively reverse a synthetic opioid overdose?

There is now compelling evidence^5-8 that rapid delivery of higher doses of naloxone are needed to reverse an overdose involving synthetics compared to morphinan-based molecules such as morphine and heroin. Synthetics have a more rapid onset of action than morphinans,^{5, 6} which reduces the window of opportunity to successfully reverse an overdose. Both the shorter time to maximum concentration (t_max; 0.25 hours) and higher maximum concentration (C_max; 12.2 ng/mL)⁹ of intranasal nalmefene (2.7 mg), when taken together with a higher affinity at μ-opioid receptors,⁶ are consistent with a more rapid onset of action compared to intranasal naloxone (t_max 0.5 hours and C_max 5.3 ng/mL, respectively).⁶ However, in an overdose involving synthetics, antagonist exposure during the crucial first few minutes after dosing is far more significant⁷: In this regard, plasma nalmefene concentrations 5 minutes after administration⁹ are approximately 3-fold higher than following intranasal naloxone.⁶ A more rapid onset of action is also supported by comparative efficacy data in a clinical model of opioid-induced respiratory depression.¹⁰ In this study, intranasal nalmefene led to a reversal of remifentanil-induced reductions in minute ventilation that was almost twice as high as the reversal produced by intranasal naloxone (5.75 vs 3.01 L/min; P less than .0009) at 5 minutes after administration, the primary end point).

The dose of naloxone required to reverse an overdose is symptom driven and, by this criterion, empirical. Multiple factors, ranging from the type and quantity of opioid and the presence of other drugs (eg, alcohol, benzodiazepines) to the victim's general health, challenge accurate analysis of the quantities of naloxone required to reverse an overdose.⁶ Nonetheless, multiple clinical reports indicate higher doses of naloxone are required to reverse an overdose involving synthetics, with some authors recommending parenteral administration of 12-15 mg.⁶ Furthermore, in a well-controlled preclinical study that eliminates the many variables attending an overdose, Kelly et al⁵ have demonstrated that a 10-fold higher dose of naloxone is required to reverse fentanyl- compared to morphine-induced respiratory depression. In a quantitative translational approach, Mann et al⁷ recently developed and validated a model to evaluate the effectiveness of intramuscular naloxone in reversing the hypoxia-induced cardiac arrest produced by fentanyl and carfentanil. In the absence of intervention, an intravenous bolus of 1.63 mg fentanyl resulted in cardiac arrest in approximately 52% of 2000 virtual patients in this model. An intramuscular dose of naloxone (2 mg/2 mL) favored by many first responders reduced the incidence of cardiac arrest to 30% in model simulations of 2000 patients, a rescue rate of approximately 42%. We have implemented and expanded this model to compare the effectiveness of intranasal nalmefene to intranasal naloxone (4 mg), generally viewed as the “gold standard” in a community setting. Nalmefene resulted in clinically meaningful reductions in the incidence of cardiac arrest compared to intranasal naloxone at fentanyl and carfentanil doses that resulted in a 50%-90% incidence of cardiac arrest in the absence of antagonist treatment (manuscript in preparation).

Many of the important issues raised by Sellers and Romach¹ reflect a broader societal failure to effectively destigmatize and treat opioid use disorder. Effective deployment of reversal agents is only one facet of a strategy to mitigate the societal impact of opioid misuse. Nonetheless, based on the available data, adoption of nalmefene nasal spray in a community use setting, where establishing an intravenous line is not practical and respiratory support is often absent, will have a significant impact on reducing overdose deaths in the synthetic opioid era.

The author is an employee of Indivior Inc. and is named as a coinventor on four patent applications which describe formulations, compositions, and methods for the prevention and treatment of opioid overdose.