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

Clin Toxicol (Phila). 2018 Aug;56(8):737-743. doi: 10.1080/15563650.2017.1401080. Epub 2017 Nov 17.


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.

Keywords: Tramadol; diazepam; intoxication; naloxone; seizure.

MeSH terms

  • Analgesics, Opioid / poisoning*
  • Animals
  • Antidotes / therapeutic use*
  • Drug Overdose / drug therapy*
  • Naloxone / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Insufficiency / chemically induced*
  • Seizures / chemically induced*
  • Tramadol / poisoning*


  • Analgesics, Opioid
  • Antidotes
  • Naloxone
  • Tramadol