Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and μ-opioid receptor deficient mice

Background: Morphine-6-glucuronide (M6G) is a metabolite of morphine with potent analgesic properties. The influence of M6G on respiratory and antinociceptive responses was investigated in mice lacking the micro -opioid receptor (MOR) and compared with morphine.Methods: Experiments were performed in mice lacking exon 2 of the MOR (n=18) and their wild type (WT) littermates (n=20). The influence of M6G and morphine on respiration was measured using whole body plethysmography during three elevations of inspired carbon dioxide. Antinociception was assessed using tail flick and hotplate tests.Results: In WT but not null mutant mice, a dose-dependent depression of the slope of the ventilatory carbon dioxide response was observed after M6G and morphine. Similarly, both opioids were devoid of antinociceptive effects in null mutant mice, but showed potent dose-dependent analgesia in WT animals. Potency differences between M6G and morphine in WT mice were of the same order of magnitude for analgesia and respiration.Conclusions: The data indicate that the desired (antinociceptive) and undesired (respiratory depression) effects of M6G and morphine are linked to the same gene product; that is the MOR. Other opioid- and non-opioid-receptor systems may play a minor role in the actions of M6Gs and morphine. The clinical implications of our findings are that any agent acting at the MOR will invariably cause (potent) analgesia in combination with (variable) respiratory depression

Modeling the Non-Steady State Respiratory Effects of Remifentanil in Awake and Propofol-sedated Healthy Volunteers

Background: Few studies address the dynamic effect of opioids on respiration. Models with intact feedback control of carbon dioxide on ventilation (non-steady-state models) that correctly incorporate the complex interaction among drug concentration, end-tidal partial pressure of carbon dioxide concentration, and ventilation yield reliable descriptions and predictions of the behavior of opioids. The authors measured the effect of remifentanil on respiration and developed a model of remifentanil-induced respiratory depression. Methods: Ten male healthy volunteers received remifentanil infusions with different infusion speeds (target concentrations: 4-9 ng/ml; at infusion rates: 0.17-9 ng . ml(-1) . min(-1)) while awake and at the background of low-dose propofol. The data were analyzed with a nonlinear model consisting of two additive linear parts, one describing the depressant effect of remifentanil and the other describing the stimulatory effect of carbon dioxide on ventilation. Results: The model adequately described the data including the occurrence of apnea. Most important model parameters were as follows: C-50 for respiratory depression 1.6 +/- 0.03 ng/ml, gain of the respiratory controller (G) 0.42 - 0.1 l.min(-1) . Torr(-1), and remifentanil blood effect site equilibration half-life (t1/2k(e0)) 0.53 +/- 0.2 min. Propofol caused a 20-50% reduction of C50 and G but had no effect on t1/2k(e0). Apnea occurred during propofol infusion only. A simulation study revealed an increase in apnea duration at infusion speeds of 2.5-0.5 ng.ml(-1).min(-1) followed by a reduction. At an infusion speed of <= 0.31 ng.ml(-1).min(-1), no apnea was seen. Conclusions: The effect of varying remifentanil infusions with and without a background of low-dose propofol on ventilation and end-tidal partial pressure of carbon dioxide concentration was described successfully using a non-steady-state model of the ventilatory control system. The model allows meaningful simulations and predictions.Perioperative Medicine: Efficacy, Safety and Outcom

Naloxone Reversal of Morphine- and Morphine-6-Glucuronide-induced Respiratory Depression in Healthy Volunteers A Mechanism-based Pharmacokinetic-Pharmacodynamic Modeling Study

Background: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist -antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers. Methods: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 = g naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 = g naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal PCO2. A mechanismbased pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data. Results: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (k(off) M6G = 0.0327 +/- 0.00455 min(-1) versus morphine 0.138 +/- 0.0148 min(-1); values are typical +/- SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration. Conclusions: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.Perioperative Medicine: Efficacy, Safety and Outcom