Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers

Background: Cebranopadol is a novel strong analgesic that coactivates the nociceptin/orphanin FQ receptor and classical opioid receptors. There are indications that activation of the nociceptin/orphanin FQ receptor is related to ceiling in respiratory depression. In this phase 1 clinical trial, we performed a pharmacokinetic-pharmacodynamic study to quantify cebranopadol's respiratory effects. Methods: Twelve healthy male volunteers received 600 mu g oral cebranopadol as a single dose. The following main endpoints were obtained at regular time intervals for 10 to 11 h after drug intake: ventilation at an elevated clamped end-tidal pressure of carbon dioxide, pain threshold and tolerance to a transcutaneous electrical stimulus train, and plasma cebranopadol concentrations. The data were analyzed using sigmoid Emax (respiration) and power (antinociception) models. Results: Cebranopadol displayed typical opioid-like effects including miosis, analgesia, and respiratory depression. The bloodeffect- site equilibration half-life for respiratory depression and analgesia was 1.2 +/- 0.4 h (median +/- standard error of the estimate) and 8.1 +/- 2.5 h, respectively. The effect-site concentration causing 50% respiratory depression was 62 +/- 4 pg/ml; the effect-site concentration causing 25% increase in currents to obtain pain threshold and tolerance was 97 +/- 29 pg/ml. The model estimate for minimum ventilation was greater than zero at 4.9 +/- 0.7 l/min (95% CI, 3.5 to 6.6 l/min). Conclusions: At the dose tested, cebranopadol produced respiratory depression with an estimate for minimum ventilation greater than 0 l/min. This is a major advantage over full mu-opioid receptor agonists that will produce apnea at high concentrations. Further clinical studies are needed to assess whether such behavior persists at higher doses.