Stronger, longer, better opioid antagonists? Nalmefene is NOT a naloxone replacement

Infante, Alexander F.; Elmes, Abigail T.; Gimbar, Renee Petzel; Messmer, Sarah E.; Neeb, Christine; Jarrett, Jennie B.

doi:10.1016/j.drugpo.2024.104323

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…Consistent with this evidence, the State Unintentional Drug Overdose Reporting System (SUDORS) database indicates that some form of naloxone had been administered in more than 20% of opioid-related overdose deaths in 2022; in some jurisdictions, more than 35% of decedents had received naloxone ( 32 ). Nonetheless, there is resistance to using either higher doses of naloxone or more potent and rapid onset agents like nalmefene ( 33 – 35 ). Much of this resistance is driven by the potential for more severe withdrawal in patients with a pre-existing opioid use disorder and justified by reports that “standard doses of naloxone” needed to reverse an overdose have not risen significantly ( 36 – 38 ) despite the demonstrable rise in synthetic opioids in the illicit drug supply ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

“…As such, they should not limit the use of more effective reversal strategies, especially when the odds of a synthetic opioid overdose are high ( 18 , 48 , 49 ). On the other hand, there are concerns that precipitated withdrawal could pose acute risks to the patient and medical personnel and could trigger further opioid use to counter the effects of the opioid antagonist ( 33 , 35 , 41 , 50 , 51 ). Additionally, the knowledge and avoidance of precipitated withdrawal could reduce both use and acceptance of the reversal agent among patients with an opioid use disorder ( 33 , 35 , 41 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, there are concerns that precipitated withdrawal could pose acute risks to the patient and medical personnel and could trigger further opioid use to counter the effects of the opioid antagonist ( 33 , 35 , 41 , 50 , 51 ). Additionally, the knowledge and avoidance of precipitated withdrawal could reduce both use and acceptance of the reversal agent among patients with an opioid use disorder ( 33 , 35 , 41 , 50 ). Nonetheless, a recent study ( 52 ) of 1152 patients entering treatment for opioid use disorder across 49 addiction treatment facilities reported that most respondents had either no preference (48.4%) or preferred a higher dose (35.9%) reversal agent if they were to experience another overdose.…”

Section: Discussionmentioning

confidence: 99%

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

Laffont,

Purohit,

Delcamp

et al. 2024

Front. Psychiatry

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IntroductionUsing a validated translational model that quantitatively predicts opioid-induced respiratory depression and cardiac arrest, we compared cardiac arrest events caused by synthetic opioids (fentanyl, carfentanil) following rescue by intranasal (IN) administration of the μ-opioid receptor antagonists naloxone and nalmefene.MethodsThis translational model was originally developed by Mann et al. (Clin Pharmacol Ther 2022) to evaluate the effectiveness of intramuscular (IM) naloxone. We initially implemented this model using published codes, reproducing the effects reported by Mann et al. on the incidence of cardiac arrest events following intravenous doses of fentanyl and carfentanil as well as the reduction in cardiac arrest events following a standard 2 mg IM dose of naloxone. We then expanded the model in terms of pharmacokinetic and µ-opioid receptor binding parameters to simulate effects of 4 mg naloxone hydrochloride IN and 3 mg nalmefene hydrochloride IN, both FDA-approved for the treatment of opioid overdose. Model simulations were conducted to quantify the percentage of cardiac arrest in 2000 virtual patients in both the presence and absence of IN antagonist treatment.ResultsFollowing simulated overdoses with both fentanyl and carfentanil in chronic opioid users, IN nalmefene produced a substantially greater reduction in the incidence of cardiac arrest compared to IN naloxone. For example, following a dose of fentanyl (1.63 mg) producing cardiac arrest in 52.1% (95% confidence interval, 47.3-56.8) of simulated patients, IN nalmefene reduced this rate to 2.2% (1.0-3.8) compared to 19.2% (15.5-23.3) for IN naloxone. Nalmefene also produced large and clinically meaningful reductions in the incidence of cardiac arrests in opioid naïve subjects. Across dosing scenarios, simultaneous administration of four doses of IN naloxone were needed to reduce the percentage of cardiac arrest events to levels that approached those produced by a single dose of IN nalmefene.ConclusionSimulations using this validated translational model of opioid overdose demonstrate that a single dose of IN nalmefene produces clinically meaningful reductions in the incidence of cardiac arrest compared to IN naloxone following a synthetic opioid overdose. These findings are especially impactful in an era when >90% of all opioid overdose deaths are linked to synthetic opioids such as fentanyl.

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