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 fluorimetry. 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.