COMPARISON OF POTENCY AND DURATION OF ACTION OF NALMEFENE AND NALOXONE

Nalmefene, a pure opiate antagonist structurally similar to naloxone, possesses a longer duration of action than naloxone at the same dose. However, the relative potency of these two antagonists is not known. This study was, therefore, designed to establish their potency ratio and duration of action at equipotent doses. Sixteen healthy, adult volunteers were allocated to one of four groups of four subjects each. A continuous fentanyl infusion was started to obtain a target plasma concentration of 1.5 ng/mL. The extent of respiratory depression was evaluated at 20 min (first depression) by recording end-tidal CO2 (E(T)CO(2)), respiratory rate (RR), arterial oxygen saturation (Spo(2)), arterial blood gases, and ventilatory response to a hypercapnic challenge. Consecutive groups then received 1, 2, 4, and 8 pg/kg of naloxone and nalmefene, in a double-blind, cross-over fashion, on separate occasions. Fentanyl infusion was continued and E(T)CO(2), Spo(2), and RR were recorded every 5 min until the values obtained at the first depression were reestablished (second depression). Multiple blood samples for plasma levels of the test drug and fentanyl were taken. Ventilatory function was assessed at baseline, first depression, 5 min after test drug administration, and at second depression. The ventilatory variables were compared using analysis of variance (ANOVA). There was a significant improvement in the slope and intercept of the CO2 response curve produced by the increasing doses (P < 0.05). There was no difference in recovery of these variables between the two drugs at the same dose, implying that the doses were equipotent. The mean plasma concentrations of nalmefene and naloxone at which ventilatory depression recurred were 0.3 +/- 0.08 ng/mL and 0.28 +/- 0.05 ng/mL, respectively (P > 0.05). The duration of action of nalmefene was longer than naloxone over the dose range studied (P < 0.01). The initial volume of distribution (V-1) for naloxone was 0.29-L/kg and its steady-state volume of distribution (Vd(ss)) was 2.64 L/kg. These values were similar to those for nalmefene (V-1 = 0.26 L/kg, Vd(ss) = 2.28 L/kg). The clearance of naloxone (0.049 L/min) was more rapid than that of nalmefene (0.019 L/min) and thus, the elimination half-life of naloxone (54.5 min) was significantly shorter than that of nalmefene (108 min) (P < 0.05). We conclude that nalmefene is equipotent to naloxone, both in terms of dose (mg/mg) and plasma concentration; however, due to its slower clearance, its duration of effect is prolonged compared to that of naloxone.