title: Effects of various combinations of benzodiazepines with buprenorphine on arterial blood gases in rats.
abstract: Fatalities have been attributed to combinations of high-dose buprenorphine with benzodiazepines. In rats, high-dose buprenorphine combined with midazolam was shown to induce sustained respiratory acidosis, while buprenorphine alone did not. However, the effects of buprenorphine combined with pharmacological doses of benzodiazepines remain unknown. Our objective was to compare the acute effects of four selected benzodiazepines used intravenously at equi-efficacious doses in rats, alone and in combination with buprenorphine on sedation, respiratory rate and arterial blood gases. Buprenorphine (30 mg/kg) did not significantly modify sedation level or respiratory rate, but induced mild and transient effects on pH and PaCO(2) (P < 0.05). Similarly, despite having no effects on respiratory rate, nordiazepam (10 mg/kg), bromazepam (1 mg/kg) and oxazepam (12 mg/kg) mildly and transiently altered pH and PaCO(2) (P < 0.05), whereas clonazepam (5 mg/kg) did not. Buprenorphine combined with each benzodiazepine induced no significant effects on respiratory rate or blood gases, in comparison with buprenorphine alone. However, combinations of oxazepam or nordiazepam with buprenorphine significantly deepened sedation. While both combinations reduced respiratory rate, buprenorphine + 30 mg/kg clonazepam significantly increased PaCO(2) and buprenorphine + 30 mg/kg nordiazepam decreased PaO(2). In conclusion, not all benzodiazepines induce significant respiratory depression at therapeutic doses. We were unable to demonstrate significant effects on rat ventilatory parameters of buprenorphine combined with equi-efficacious pharmacological doses of benzodiazepines in comparison with buprenorphine alone. Our results may suggest that effects of these combinations are rather mild. Respiratory failure may, however, result from the association of buprenorphine with elevated doses of benzodiazepines.
authors.affiliation: INSERM U705, CNRS UMR 7157, Paris-Diderot and Paris-Descartes University, Paris, France. pirnaystephane@yahoo.com
authors.forename: Stéphane O
authors.initials: SO
authors.lastname: Pirnay
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Borron
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Claire
authors.initials: C
authors.lastname: Monier
authors.forename: Ivan
authors.initials: I
authors.lastname: Ricordel
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
mesh_terms: D000818:Animals; D001158:Arteries; D001569:Benzodiazepines / Q000008:administration & dosage / Q000633:toxicity*; D001784:Blood Gas Analysis; D002047:Buprenorphine / Q000008:administration & dosage / Q000633:toxicity*; D002245:Carbon Dioxide / Q000097:blood*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D008297:Male; D009294:Narcotics / Q000008:administration & dosage / Q000633:toxicity*; D010100:Oxygen / Q000097:blood*; D010313:Partial Pressure; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects
chemical_list: D009294:Narcotics; D011619:Psychotropic Drugs; D001569:Benzodiazepines; D002245:Carbon Dioxide; D002047:Buprenorphine; D010100:Oxygen