• Br J Anaesth · Mar 2022

    Randomized Controlled Trial

    Mechanisms of respiratory depression induced by the combination of buprenorphine and diazepam in rats.

    • Dominique Vodovar, Lucie Chevillard, Fabien Caillé, Patricia Risède, Géraldine Pottier, Sylvain Auvity, Bruno Mégarbane, and Nicolas Tournier.
    • Inserm UMRS-1144, Paris, France; Université de Paris, Paris, France; Université Paris-Saclay - CEA - CNRS - Inserm - BioMaps, Orsay, France; Paris Poison Center, Assistance Publique - Hôpitaux de Paris, Paris, France; Department of Medical and Toxicological Critical Care, Assistance Publique - Hôpitaux de Paris, Paris, France.
    • Br J Anaesth. 2022 Mar 1; 128 (3): 584595584-595.

    BackgroundThe safety profile of buprenorphine has encouraged its widespread use. However, fatalities have been attributed to benzodiazepine/buprenorphine combinations, by poorly understood mechanisms of toxicity. Mechanistic hypotheses include (i) benzodiazepine-mediated increase in brain buprenorphine (pharmacokinetic hypothesis); (ii) benzodiazepine-mediated potentiation of buprenorphine interaction with opioid receptors (receptor hypothesis); and (iii) combined effects of buprenorphine and benzodiazepine on respiratory parameters (pharmacodynamic hypothesis).MethodsWe studied the neuro-respiratory effects of buprenorphine (30 mg kg-1, i.p.), diazepam (20 mg kg-1, s.c.), and diazepam/buprenorphine combination in rats using arterial blood gas analysis, plethysmography, and diaphragm electromyography. Pretreatments with various opioid and gamma-aminobutyric acid receptor antagonists were tested. Diazepam impact on brain 11C-buprenorphine kinetics and binding to opioid receptors was studied using positron emission tomography imaging.ResultsIn contrast to diazepam and buprenorphine alone, diazepam/buprenorphine induced early-onset sedation (P<0.05) and respiratory depression (P<0.001). Diazepam did not alter 11C-buprenorphine brain kinetics or binding to opioid receptors. Diazepam/buprenorphine-induced effects on inspiratory time were additive, driven by buprenorphine (P<0.0001) and were blocked by naloxonazine (P<0.01). Diazepam/buprenorphine-induced effects on expiratory time were non-additive (P<0.001), different from buprenorphine-induced effects (P<0.05) and were blocked by flumazenil (P<0.01). Diazepam/buprenorphine-induced effects on tidal volume were non-additive (P<0.01), different from diazepam- (P<0.05) and buprenorphine-induced effects (P<0.0001) and were blocked by naloxonazine (P<0.05) and flumazenil (P<0.05). Compared with buprenorphine, diazepam/buprenorphine decreased diaphragm contraction amplitude (P<0.01).ConclusionsPharmacodynamic parameters and antagonist pretreatments indicate that diazepam/buprenorphine-induced respiratory depression results from a pharmacodynamic interaction between both drugs on ventilatory parameters.Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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