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Toxicological Sciences 65, 107-114 (2002)
Copyright © 2002 by the Society of Toxicology

SAFETY EVALUATION

Buprenorphine and Midazolam Act in Combination to Depress Respiration in Rats

Papa N. Gueye*,1, Stephen W. Borron*,{dagger},{ddagger}, Patricia Risède*, Claire Monier*, Françoise Buneaux§, Marcel Debray and Frédéric J. Baud*

* INSERM U26 et Université Paris VII, Hôpital Fernand Widal, 200, rue du Faubourg Saint-Denis, 75475 Paris Cedex 10, France {dagger} Department of Emergency Medicine, George Washington University, Washington, DC 20037 {ddagger} International Toxicology Consultants, LLC, 2000 L Street NW, Suite 200, Washington, DC 20036–4924 § Laboratoire de Biochimie-Toxicologie, Hôpital Fernand Widal, 75475 Paris, France and Laboratoire de Biomathématiques, Université Paris V, UFR Pharmacie, 75006 Paris, France

High dose buprenorphine is used as substitution treatment in human heroin addiction. Deaths have been reported in addicts using buprenorphine, frequently in association with benzodiazepines. In the current study, we observed the effects of buprenorphine and midazolam alone and in combination on arterial blood gases. Four groups of 10 male Sprague-Dawley rats received a parenteral injection of aqueous solvent, buprenorphine (30 mg/kg, iv), midazolam (160 mg/kg, ip), or buprenorphine (30 mg/kg, iv) plus midazolam (160 mg/kg, ip). Serial blood gases were obtained over 3 hours. There was a mild but significant effect of buprenorphine alone in comparison with the aqueous solvent on PaCO2 at 60 min (6.24 vs. 5.65 kPa, p< 0.01). There was also a mild but significant effect of midazolam alone in comparison with aqueous solvent on arterial pH at 90 min (7.33 vs. 7.41,p< 0.001) and PaCO2at 60 min (6.52 vs. 5.65 kPa,p< 0.01). The combination of midazolam and buprenorphine produces a rapid, profound, and prolonged respiratory depression, as demonstrated by an increase in PaCO2at 7.65 ± 0.12 kPa at 20 min and a decrease in arterial pH at 7.25 ± 0.02 at 20min, with appearance of delayed hypoxia with a decrease in PaO2at 8.74 ± 0.20 kPa at 120 min. These data show that high doses of midazolam and buprenorphine alone have limited effects on arterial blood gases in rats while midazolam and buprenorphine appear to act in an additive or synergistic fashion to depress ventilation in rats.

Key Words: buprenorphine; midazolam; acute toxicity; respiratory depression; safety; rats; LD50; arterial blood gas; opioids; heroin substitution; drug abuse.


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