Plasma M1 and M5 metabolites were mildly increased, contributing additionally to tramadol-related respiratory depression. 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. 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). Median lethal-doses of tramadol and diazepam/tramadol combination did not significantly differ, although time-to-death was longer with combination (P = 0.04). Plasma, platelet and brain monoamines were measured using liquid-chromatography coupled to fluorimetry. Concentrations of tramadol and its metabolites were measured using liquid-chromatography-high-resolution-mass-spectrometry. Sedation, seizures, electroencephalography and plethysmography parameters were studied. Median lethal-doses were determined using Dixon–Bruce's up-and-down method. Our objectives were to investigate tramadol-related neurotoxicity, consequences of diazepam/tramadol combination, and mechanisms of drug-drug interactions in rats.

Tramadol may induce respiratory depression, seizures and serotonin syndrome, possibly worsened when in combination to benzodiazepines.

Poisoning with opioid analgesics including tramadol represents a challenge.

Antidote diazepam overdose