Antagonism of Morphine-Induced Respiratory Depression With Nalmefene

Abstract

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.

The effect of age on the pharmacokinetics of the opioid antagonist nalmefene

“…At doses in the range of 0.1-1 mg kg−1, of distribution of approximately 8 l kg−1, a total body clearance that approaches 1100 ml min−1 and a terminal it has effectively reversed post-operative opioid respiratory depression without ablating the analgesic response elimination half-life of approximately 10 h in healthy middle age volunteers [6 ]. The longer elimination to subsequently administered opioids [1,2]. When administered at higher doses (0.5-1.6 mg), nalmefene half-life contributes to the observation that nalmefene has a longer duration of action than naloxone, and is has been shown to be effective in the reversal of respiratory depression in patients who presented to the more effective in reversing opioid-induced respiratory depression and sedation [ 2,4].…”

“…The longer elimination to subsequently administered opioids [1,2]. When administered at higher doses (0.5-1.6 mg), nalmefene half-life contributes to the observation that nalmefene has a longer duration of action than naloxone, and is has been shown to be effective in the reversal of respiratory depression in patients who presented to the more effective in reversing opioid-induced respiratory depression and sedation [ 2,4]. emergency room with opioid overdose [ 3].…”

“…However, its relatively short elimination half-life of filtration rate and hepatic metabolism [7 ]. Furthermore, alterations in body fat content as well as intra-and 1-1.5 h has limited its clinical usefulness, and recurrence of respiratory depression has been reported [2,4 ]. extracellular body water have been reported in elderly adults [8,9 ].…”

Effects of liver disease on the disposition of the opioid antagonist nalmefene*

“…They fasted overnight and continued to fast for 4 hours after the intravenous bolus administration of 2.0 mg nalmefene over 30 seconds. Blood samples were collected into heparinized tubes before nalmefene administration and at 5,10,15,30, and 45 minutes and at 1,2,3,4,5,6,8,10,12,14,18,24,36, and 48 hours after administration. An additional blood sample was collected 1 hour after dosing for the determination of nalmefene protein binding.…”

Fatal overdoses involving hydromorphone and morphine among inpatients: a case series

“…This is particularly important because opioid toxicity can almost always be reversed with naloxone in a care setting if detected promptly. 19 The ability to intervene effectively is dependent upon recognition of the signs and symptoms of overdose, as well as the proper and knowledgeable use of naloxone relative to the opioid dosage form administered. This is illustrated in case 5, in which a single dose of naloxone was given to a patient who had received a long-acting opioid.…”