Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone

Abstract

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

Keywords: fentanyl; nalmefene; naloxone; opioid antagonist; opioid overdose; pharmacodynamics; pharmacokinetics; respiratory depression reversal.

Figure 1

Time course of mean minute volume by treatment, pooled across experimental sessions, from 0 to 30 min after opioid antagonist administration. CI, confidence interval; IM, intramuscular; IN, intranasal; MV, minute volume. The dashed line represents the mean MV (7.87 L/min) prior to fentanyl administration (mean pre‐fentanyl baseline MV). Mean fentanyl infusion rate during antagonist administration was 5.0 µg/min for infusion #1, 4.2 µg/min for infusion #2, and 3.2 µg/min for infusion #3.

Figure 2

Mean absolute and percentage change in minute volume from opioid‐induced nadir. (a) Absolute change and (b) percentage change. CI, confidence interval; IM, intramuscular; IN, intranasal; MV, minute volume. Dashed lines represent the mean MV prior to fentanyl administration (mean pre‐fentanyl baseline MV): 3.43 L/min in (a) and 84.3 L/min in (b).

Figure 3

Differences in least‐square mean change in MV from nadir at specified time points. (a) IM nalmefene versus IN naloxone and (b) IM nalmefene versus IM naloxone. IM, intramuscular; IN, intranasal; LS, least‐square; MV, minute volume. Error bars represent 95% confidence intervals.

Figure 4

Time course of plasma fentanyl, naloxone, and nalmefene concentrations. (a) Mean plasma fentanyl concentrations from 0 to 30 min after opioid antagonist administration. Mean plasma naloxone concentrations from 0 to 30 min (b) and 0 to 8 h (c) after opioid antagonist administration. Mean plasma nalmefene concentrations from 0 to 30 min (d) and 0 to 8 h (e) after opioid antagonist administration. IM, intramuscular; IN, intranasal; IV, intravenous; SE, standard error.