[Mechanisms of opioid-induced overdose: experimental approach to clinical concerns].
The widely used term "overdose" denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO(2). However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO(2)). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO(2). This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO(2,) even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.
Baud
F-J
FJ
Inserm U705-UMR7157, laboratoire de toxicologie, faculté de pharmacie, universités Denis-Diderot et René-Descartes, France. frederic.baud@lrb.aphp.fr
D000701:Analgesics, Opioid / Q000506:poisoning*; D000818:Animals; D002047:Buprenorphine / Q000506:poisoning; D004347:Drug Interactions; D062787:Drug Overdose / Q000453:epidemiology / Q000503:physiopathology*; D005602:France / Q000453:epidemiology; D006801:Humans; D008691:Methadone / Q000506:poisoning; D009292:Narcotic Antagonists / Q000506:poisoning; D009294:Narcotics / Q000506:poisoning; D009293:Opioid-Related Disorders / Q000473:pathology / Q000503:physiopathology; D012137:Respiratory System / Q000187:drug effects / Q000503:physiopathology
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009294:Narcotics; D002047:Buprenorphine; D008691:Methadone