Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat. (3rd August 2018)

• Record Type: Journal Article
• Authors: Lagard, Camille; Malissin, Isabelle; Indja, Wassila; Risède, Patricia; Chevillard, Lucie; Mégarbane, Bruno
• Is Part Of: Clinical toxicology. Volume 56:Number 8(2018)
• Page Start: 737
• Page End: 743
• Publication Date: 2018-08-03
• Subjects: Tramadol -- intoxication -- naloxone -- diazepam -- seizure; Toxicology -- Periodicals; Toxicological emergencies -- Periodicals; 615.9
• DOI: 10.1080/15563650.2017.1401080
• Languages: English
• ISSNs: 1556-3650

Abstract

Abstract: 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.