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Understanding the risk of seizure in tramadol overdose: still a long way to go

Dear Editor, We read with interest the report by Murray et al. [1] who investigated the risk factors associated with seizure in single tramadol overdose. Due to their frequency, tramadol-induced seizures represent a major health concern. We would like to congratulate the authors on their attempt to solve this exciting issue and comment on their findings. Asian patients were shown significantly more likely to seize. This enhanced risk was attributed to the increased risk from serotoninergic toxicity due to the expected prolonged half-life of the ingested parent compound in relation to possible cytochrome 2D6 gene polymorphisms in the Asian population resulting in slower drug metabolism. Surprisingly, seizures have been commonly included in the serotoninergic syndrome and attributed to post-synaptic serotonin receptor overstimulation, mainly the 1A and 2A receptor subtypes, by increasing synaptic serotonin concentration. However, recent animal data strongly questioned the serotoninergic origin of tramadol-induced seizure. Seizures were shown to persist in the tramadol-overdosed rat despite pretreatment with cyproheptadine, a serotonin receptor antagonist [2] but were completely abolished [3] or remained unchanged [2] following pretreatment with the 5-hydroxytryptophane/benserazide combination that increases brain serotonin concentration. Interestingly, these findings contrasted with the preventive effects of cyproheptadine on seizures in a model of citalopram-overdosed rats [4], suggesting that attribution of seizures to the serotoninergic syndrome should only be considered according to the involved drug. These experimental data clearly explain why Murray and coworkers did not find significant association between the diagnosis of serotonin syndrome and seizures despite the strict clinical evaluation of their patients at the bedside by trained toxicologists. Patients presenting with opioid toxidrome had significantly reduced risk [1]. This observation should be understood in the light of the time-course of tramadol overdose and the progressive shift from initial high risk of seizure to further main risk of opioid toxicity that accompanies tramadol metabolism to O-desmethyltramadol, as evidenced in our rat model [2]. The reason why abuse/misuse of tramadol was significantly associated with increased risk of seizures [1] is not clear. It was attributed by the authors to possibly more chronic ingestion although they also stated that chronicity of ingestion did not significantly differ between patients who seized and those who did not. Similarly to other psychotropic drugs, repeated tramadol exposure is likely associated with the development of tolerance to its central nervous system (CNS) effects rather than to sensitization. In the absence of measurement of plasma tramadol concentrations in the seizing tramadol-abuser, distinguishing between withdrawal syndrome that may result in seizure and acute poisoning is challenging. Finally, naloxone administration in the tramadol-poisoned patient remains controversial. No significant association between naloxone administration and seizure onset was found [1] while previous experimental and clinical works supported both enhanced and decreased risks [5]. In agreement with Murray and coworkers, we strongly believe that their report lacked adequate power to determine risk. Due to the currently most accepted hypothesis of tramadol-induced inhibitory effects on gamma-aminobutyric acid receptors at elevated concentrations to explain seizures in overdose, benzodiazepines should be considered as first-line treatment. Here, the consequences on seizure of the co-administration of a benzodiazepine and naloxone were not analyzed, while our experimental data [5] greatly encourage administering the diazepam/naloxone combination rather than naloxone alone as first-line antidote to reverse tramadol-related CNS toxicity.