Buprenorphine is protective against the depressive effects of norbuprenorphine on ventilation
- INSERM U705, CNRS UMR 7157, Universite Paris VII, Hopital Fernand Widal, Paris (France) and Reanimation Medicale et Toxicologique, Hopital Lariboisiere, 2 Rue Ambroise Pare, 75010 Paris (France)
- INSERM U705, CNRS UMR 7157, Universite Paris VII, Hopital Fernand Widal, Paris (France)
- INSERM U705, CNRS UMR 7157, Universite Paris VII, Hopital Fernand Widal, Paris (France) and Departments of Emergency Medicine and Medicine - Occupational and Environmental Health, George Washington University, Washington, DC 22052 (United States)
High dose buprenorphine is used as substitution treatment in heroin addiction. However, deaths have been reported in addicts using buprenorphine. The role of norbuprenorphine, an N-dealkyl metabolite of buprenorphine, was hypothesized to explain these fatal cases. We determined the median intravenous lethal dose (LD{sub 5}) of norbuprenorphine in male Sprague-Dawley rats. The effects of a single intravenous dose of 3 or 9 mg/kg norbuprenorphine alone on arterial blood gases were studied. Finally, the effect of pre- and post-administrations of buprenorphine on norbuprenorphine-induced changes on arterial blood gases were analyzed. Norbuprenorphine's LD{sub 5} was 10 mg kg{sup -1}. Norbuprenorphine 3 mg kg{sup -1} produces the rapid onset of sustained respiratory depression, as demonstrated at 20 min by a maximal significant increase in PaCO{sub 2} (8.4 {+-} 0.9 versus 5.7 {+-} 0.1 kPa), decrease in arterial pH (7.25 {+-} 0.06 versus 7.44 {+-} 0.01), and hypoxia (8.3 {+-} 0.6 versus 11.1 {+-} 0.2 kPa). Buprenorphine not only protected against the effects of 3 mg kg{sup -1} norbuprenorphine in a dose-dependent manner but also reversed the effects when given afterward. Binding experiments suggest a role for mu- and to a lesser extent for delta-opioid receptors in buprenorphine protective effect against norbuprenorphine-induced respiratory depression. In conclusion, our data clearly show that norbuprenorphine alone causes important deleterious effects on ventilation in rats. However, buprenorphine protective effect calls into question the role for norbuprenorphine in respiratory toxicity associated with buprenorphine use.
- OSTI ID:
- 20783472
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 212, Issue 3; Other Information: DOI: 10.1016/j.taap.2005.08.002; PII: S0041-008X(05)00509-0; Copyright (c) 2005 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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