In reply to Dr. Chhabra, Dr. Mégarbane, and colleagues

We would like to thank Dr. Chhabra and colleagues for their letter “Tramadol, Naloxone, and Seizures “[1], and we appreciate the added data they shared from a Regional Poison Center regarding the incidence of seizure activity after tramadol overdose. We would also like to thank Dr. M egarbane and his colleagues for their letter “Understanding the risk of seizure in tramadol overdose: still a long way to go” [2] in response to our study “Seizures in tramadol overdoses reported in the ToxIC registry: predisposing factors and the role of naloxone” [3]. We agree with Dr. M egarbane that the increased rate of seizures we reported in Asian patients may not be due to the increased serotonin reuptake inhibition caused from the relatively higher percentage of slow CYP2D6 metabolizers. As described in both articles presented by Dr. M egarbane, there is evidence of GABA inhibition by tramadol. There may also be an undescribed mechanism where tramadol induces seizure activity in humans. However, both referenced articles utilized rat models and may not be representative of how tramadol acts in humans. Additionally, the referenced studies presented conflicting results regarding whether serotonin had a protective effect, or no effect, on the development of seizure activity after tramadol administration. Tramadol does result in serotonin reuptake inhibition and has also been shown to cause an increased amount of synaptic serotonin by mechanisms independent of reuptake [4]. Additionally, tramadol is associated with serotonin syndrome, most frequently in combination with other serotonergic agents, but also by itself [5]. Indeed, we found approximately 11% of patients exposed to tramadol were diagnosed with serotonin syndrome after exposure [3]. Regardless of the mechanism by which seizures are induced, or the effect of tramadol on serotonin release and reuptake, it appears that patients likely to have a slow CYP2D6 pathway, such as Asian patients, are at increased risk for seizures. Therefore, we believe that great care should be used when prescribing tramadol to patients who are known to be slow metabolizers or in populations that are at an elevated risk for slow metabolism. Dr. M egarbane also commented that naloxone administration is controversial and recommended administration of benzodiazepines for “CNS toxicity”. These two agents should not be used interchangeably. We agree that benzodiazepines should be first line treatment for agitation and seizure activity in the setting of a toxicological illness and do not recommend the use of naloxone in an agitated or seizing patient. However, if a patient presents with central nervous system (CNS) and respiratory depression, it is intuitive that the treating physician would not administer a benzodiazepine, but instead would treat the toxidrome and give a trial of naloxone to reverse respiratory depression. The question then presents whether this could cause harm after a tramadol overdose. To date, no human studies have demonstrated an increased risk of seizures from the administration of naloxone following tramadol overdose [3,6]. This may be due to the metabolism of the parent compound tramadol and the relatively increased amounts of the metabolite o-desmethyltramadol, thus favoring the opioid toxidrome, and making seizure activity unlikely due to depletion of the parent compound.