The dramatic rise in overdose deaths linked to synthetic opioids (e.g., fentanyl, carfentanil) may require more potent, longerduration opiate antagonists than naloxone. Both the high affinity of nalmefene at m opiate receptors and its long half-life led us to examine the feasibility of developing an intranasal (IN) formulation as a rescue medication that could be especially useful in treating synthetic opioid overdose. In this study, the pharmacokinetic properties of IN nalmefene were compared with an intramuscular (i.m.) injection in a cohort of healthy volunteers. Nalmefene was absorbed slowly following IN administration, with a median time to reach C max (T max) of 2 hours. Addition of the absorption enhancer dodecyl maltoside (Intravail, Neurelis, Inc., Encinitas, CA) reduced T max to 0.25 hour and increased C max by ∼2.2-fold. The pharmacokinetic properties of IN nalmefene (3 mg) formulated with dodecyl maltoside has characteristics consistent with an effective rescue medication: its onset of action is comparable to an i.m. injection of nalmefene (1.5 mg) previously approved to treat opioid overdose. Furthermore, the C max following IN administration was ∼3-fold higher than following i.m. dosing, comparable to previously reported plasma concentrations of nalmefene observed 5 minutes following a 1-mg i.v. dose. The high affinity, very rapid onset, and long half-life (.7 hours) of IN nalmefene present distinct advantages as a rescue medication, particularly against longer-lived synthetic opioids.