What is the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat

Context: Since the banning of dextropropoxyphene from the market, overdoses, and fatalities attributed to tramadol, a WHO step-2 opioid analgesic, have increased markedly. Tramadol overdose results not only in central nervous system (CNS) depression attributed to its opioid properties but also in seizures, possibly related to non-opioidergic pathways, thus questioning the efficiency of naloxone to reverse tramadol-induced CNS toxicity. Objective: To investigate the most efficient antidote to reverse tramadol-induced seizures and respiratory depression in overdose. Materials and methods: Sprague-Dawley rats overdosed with 75 mg/kg intraperitoneal (IP) tramadol were randomized into four groups to receive solvent (control group), diazepam (1.77 mg/kg IP), naloxone (2 mg/kg intravenous bolus followed by 4 mg/kg/h infusion), and diazepam/naloxone combination. Sedation depth, temperature, number of seizures, and intensity, whole-body plethysmography parameters and electroencephalography activity were measured. Results: Naloxone reversed tramadol-induced respiratory depression (p < .05) but significantly increased seizures (p < .01) and prolonged their occurrence time. Diazepam abolished seizures but significantly deepened rat sedation (p < .05) without improving ventilation. Diazepam/naloxone combination completely abolished seizures, significantly improved rat ventilation by reducing inspiratory time (p < .05) but did not worsen sedation. None of these treatments significantly modified rat temperature. Conclusions: Diazepam/naloxone combination is the most efficient antidote to reverse tramadol-induced CNS toxicity in the rat.