Mechanisms of tramadol-related neurotoxicity in the rat: Does diazepam/tramadol combination play a worsening role in overdose?

被引:37
作者
Lagard, Camille [1 ,2 ,3 ]
Chevillard, Lucie [1 ,2 ,3 ]
Malissin, Isabelle [4 ]
Risede, Patricia [1 ,2 ,3 ]
Callebert, Jacques [1 ,2 ,3 ,5 ]
Labat, Laurence [1 ,2 ,3 ,6 ]
Launay, Jean-Marie [5 ,7 ]
Laplanche, Jean-Louis [1 ,2 ,3 ,5 ]
Megarbane, Bruno [1 ,2 ,3 ,4 ]
机构
[1] INSERM, U1144, Paris, France
[2] Paris Descartes Univ, UMR S 1144, Paris, France
[3] Paris Diderot Univ, UMR S 1144, Paris, France
[4] Lariboisiere Hosp, AP HP, Dept Med & Toxicol Crit Care, Paris, France
[5] Lariboisiere Hosp, AP HP, Lab Biochem & Mol Biol, Paris, France
[6] Cochin Hosp, AP HP, Toxicol Lab, Paris, France
[7] INSERM, U942, Paris, France
关键词
Diazepam; Poisoning; Respiratory depression; Seizure; Serotonin; Tramadol; SEROTONIN-SYNDROME; SEIZURE ACTIVITY; ANTICONVULSANT; DIAZEPAM; ABUSE; PHARMACOLOGY; METABOLITE; PARAMETERS; MORPHINE; RELEASE;
D O I
10.1016/j.taap.2016.09.013
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Poisoning with opioid analgesics including tramadol represents a challenge. Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines. Our objectives were to investigate tramadol-related neurotoxicity, consequences of diazepam/tramadol combination, and mechanisms of drug-drug interactions in rats. Median lethal-doses were determined using Dixon Bruce's up-and-down method. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Concentrations of tramadol and its metabolites were measured using liquid-chromatography high-resolution-mass-spectrometry. Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetty. Median lethal-doses of tramadol and diazepam/tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Tramadol induced dose-dependent sedation (P < 0.05), early-onset seizures (P < 0.001) and increase in inspiratory (P < 0.01) and expiratory times (P < 0.05). The diazepam/tramadol combination abolished seizures but significantly enhanced sedation (P < 0.01) and respiratory depression (P < 0.05) by reducing tidal volume (P < 0.05) in addition to tramadol-related increase in respiratory times, suggesting a pharmacodynamic mechanism of interaction. Plasma M1 and M5 metabolites were mildly increased, contributing additionally to tramadol-related respiratory depression. Tramadol-induced early-onset increase in brain concentrations of serotonin and norepinephrine was not significantly altered by the diazepam/tramadol combination. Interestingly neither pretreatment with cyproheptadine (a serotonin-receptor antagonist) nor a benserazide/5-hydroxytryptophane combination (enhancing brain serotonin) reduced tramadol-induced seizures. Our study shows that diazepam/tramadol combination does not worsen tramadol-induced fatality risk but alters its toxicity pattern with enhanced respiratory depression but abolished seizures. Drug-drug interaction is mainly pharmacodynamic but increased plasma M1 and M5 metabolites may also contribute to enhancing respiratory depression. Tramadol-induced seizures are independent of brain serotonin. (C) 2016 Elsevier Inc. All rights reserved.
引用
收藏
页码:108 / 119
页数:12
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