Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat

Abstract

Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)A receptors in vivo in the brain using positron emission tomography (PET) imaging and 11C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of 11C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABAA receptors. Management of tramadol-poisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway.

Recent Advances in Conductive Polymers-Based Electrochemical Sensors for Biomedical and Environmental Applications

“…Similarly, tramadol (TRA) is a weak opioid analgesic utilized for the management of mild to moderately severe pain [ 131 ]. However, excessive use of TRA has been frequently associated with adverse effects such as vomiting, depression, tachycardia, convulsions, morbidity, and mortality [ 132 ]. Diouf developed an electrochemical sensor based on a molecularly imprinted conductive polymers (MICP) for the quantitative and non-invasive detection of TRA [ 133 ].…”

An Update on Psychoactive Substances: Pharmacology and Toxicology Issues

“…The six published articles highlight different aspects of the pharmacology and toxicology of several psychotropics; most of them are represented by opiates/opioids, e.g., tramadol [ 4 , 5 ], tapentadol [ 4 ], and fentanyl [ 6 ], but other categories here mentioned are selective serotonin reuptake inhibitor (SSRI) antidepressants [ 7 ], new psychoactive substances (NPSs) known as cathinones [ 8 ], and the hallucinogen drug psilocybin [ 9 ].…”

“…The second study [ 5 ] investigated the mechanisms of tramadol-attributed seizures in rats, which have been hypothesized to involve both serotoninergic and non-serotoninergic, e.g., γ-aminobutyric acid-(GABA)ergic, histaminergic, dopaminergic, and opiatergic pathways. According to the results of the study, tramadol seizures were only prevented by diazepam, a positive allosteric modulator of GABAA receptor, suggesting that tramadol-induced seizures result from tramadol’s interaction with the GABAA receptor, involving a non-competitive mechanism at the benzodiazepine-binding site and that a strategy primarily relying on benzodiazepines may be appropriate in the management of tramadol-induced seizures.…”