title: Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers.
abstract: 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.
  
  
  
  Twelve healthy male volunteers received 600 μg 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.
  
  
  
  Cebranopadol displayed typical opioid-like effects including miosis, analgesia, and respiratory depression. The blood-effect-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).
  
  
  
  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 μ-opioid receptor agonists that will produce apnea at high concentrations. Further clinical studies are needed to assess whether such behavior persists at higher doses.
authors.affiliation: From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (A.D., M.B., E.S., E.O.); Centre for Human Drug Research, Leiden, The Netherlands (J.H., G.J.G., L.A.); and Grünenthal GmbH, Aachen, Germany (M.N., J.B.).
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.forename: Merel
authors.initials: M
authors.lastname: Boom
authors.forename: Elise
authors.initials: E
authors.lastname: Sarton
authors.forename: Justin
authors.initials: J
authors.lastname: Hay
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Groeneveld
authors.forename: Meike
authors.initials: M
authors.lastname: Neukirchen
authors.forename: John
authors.initials: J
authors.lastname: Bothmer
authors.forename: Leon
authors.initials: L
authors.lastname: Aarts
authors.forename: Erik
authors.initials: E
authors.lastname: Olofsen
mesh_terms: D000293:Adolescent; D000328:Adult; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D017288:Pain Threshold / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists*; D012016:Reference Values; D012119:Respiration / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D055815:Young Adult; D000094942:Nociceptin Receptor
chemical_list: C000589289:6'-fluoro-4',9'-dihydro-N,N-dimethyl-4-phenylspiro(cyclohexane-1,1'(3'H)-pyrano(3,4-b)indol)-4-amine; D007211:Indoles; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human