Antagonism of morphine-induced respiratory depression with nalmefene

The duration of respiratory depression induced by morphine 10 mg/70 kg was studied following the administration of one of two opioid antagonists. Respiratory measurements included: (i) the ventilatory response to carbon dioxide, described in two ways--the minute ventilation at an end-tidal carbon dioxide partial pressure of 8 kPa (VE8) and the log slope of the ventilatory response to carbon dioxide; (ii) resting end-tidal carbon dioxide partial pressure; (iii) rate of ventilation. One hour after administration of morphine, one of the following was given i.v.: nalmefene 0.4 mg/70 kg; naloxone 0.4 mg/70 kg (low dose); naloxone 1.6 mg/70 kg (high dose); or saline placebo. The depression of VE8 by morphine was antagonized by all three treatments for the 1.5 h after the injection. However, for the 1.5-6 h after antagonist, VE8 following naloxone became depressed, whereas VE8 after nalmefene remained significantly increased compared with other treatments. Nalmefene restored the slope of the ventilatory response to baseline for 6 h and differed significantly from low but not high dose naloxone. Resting end-tidal carbon dioxide measurements demonstrated that nalmefene activity exceeded that of low but not high dose naloxone over the 1.5-4.5 h period. Rate of ventilation was not different between treatments.