Mechanisms of respiratory depression induced by the combination of buprenorphine and diazepam in rats. (March 2022)

• Record Type: Journal Article
• Authors: Vodovar, Dominique; Chevillard, Lucie; Caillé, Fabien; Risède, Patricia; Pottier, Géraldine; Auvity, Sylvain; Mégarbane, Bruno; Tournier, Nicolas
• Is Part Of: British journal of anaesthesia. Volume 128:Number 3(2022)
• Page Start: 584
• Page End: 595
• Publication Date: 2022-03
• Subjects: benzodiazepine -- buprenorphine -- diazepam -- PET imaging -- rat -- pharmacodynamic interaction -- respiratory depression; Anesthesiology -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1016/j.bja.2021.10.029
• Languages: English
• ISSNs: 0007-0912

Abstract

Abstract: Background: The 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). Methods: We 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 11 C-buprenorphine kinetics and binding to opioid receptors was studied using positron emission tomography imaging. Results: In 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 11 C-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). Conclusions: Pharmacodynamic parameters and antagonist pretreatments indicate that diazepam/buprenorphine-induced respiratory depression results from a pharmacodynamic interaction between both drugs on ventilatory parameters.