Recurrent Seizures in Tramadol Intoxication: Implications for Therapy Based on 100 Patients Shahin Shadnia 1 , Jeffrey Brent 2 , Khatereh Mousavi-Fatemi 3 , Peyman Hafezi 3 and Kambiz Soltaninejad 4 1 Department of Clinical Toxicology, Loghman Hakim Hospital Poison Center, Faculty of Medicine, Toxicological Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, 2 Toxicology Associates, School of Medicine, University of Colorado, Denver, CO, USA, 3 Emergency Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran and 4 Department of Forensic Toxicology, Legal Medicine Research Center, Legal Medicine Organization of Iran, Tehran, Iran (Received 19 December 2011; Accepted 13 February 2012) Abstract: Tramadol is an atypical opioid analgesic used in the treatment of mild to moderate pain. Despite being a GABA A ago- nist, seizures are a prominent complication with its therapeutic use, abuse or overdose. For patients who have had a tramadol- induced seizure, the likelihood of recurrent seizures and the need for emergent anticonvulsant prophylaxis is unknown. However, treatment of patients with anticonvulsants prophylactically may cause adverse effects and increased morbidity in tramadol poison- ing. We studied the outcome and frequency of recurrent seizures in tramadol-intoxicated patients in an attempt to determine the need for prophylactic anticonvulsant therapy. This was a retrospective cohort study of tramadol-intoxicated patients who had at least one seizure. Patients’ age, sex, cause(s) of intoxication, route of poisoning, dose or number of capsules or tablets taken, vital signs, other signs or symptoms, numbers of seizures, length of stay, co-ingestions and past medical history were ascertained. Exactly 100 patients met the inclusion criteria. Eighty-two per cent were men, and 50% were between 21 and 30 years old. By our standard clinical protocol, none were treated with seizure prophylaxis after their first seizure. Only 7% had recurrent seizures and all patients recovered without sequelae. Because of the low risk of multiple seizures in tramadol poisoning and the lack of morbidity in patients who do seize, it appears to be unnecessary to administer prophylactic anticonvulsant therapy in patients with tramadol poisoning, even if they have an initial seizure. Tramadol is a centrally acting synthetic opioid-like analgesic, commonly prescribed for mild to moderate pain, which was introduced in Germany in 1977 [1, 2]. It has been approved for use in the United States since 1995 and in Iran since 2003 [2, 3]. Unlike most other opioids, tramadol has a low affinity for μ opioid receptors, inhibits the reuptake of both norepi- nephrine and serotonin, and has agonist effects at the GABA A receptor [2, 4]. Some of tramadol’s effects derive from its ago- nist properties at j opioid receptors [4]. Its analgesic effect is only partially blocked by naloxone, and further blocked by the a 2 antagonist yohimbine [2, 5, 6]. Standard therapeutic doses of tramadol are 50 mg orally, 50 –100 mg parenterally and 100 mg rectally. Its maximum rec- ommended dose is 400 mg/day [2, 6]. Seizures are a major complication of tramadol use. These may occur with therapeu- tic or toxic doses [2–4, 7–11]. In a previous study, 35% of 114 tramadol intoxicated cases had seizures and naloxone administration appeared to increase this risk [7]. Although tramadol-related seizures may usually be controlled with ben- zodiazepines, several reports suggest that benzodiazepines, even at therapeutic doses, may increase the morbidity and pos- sible lethality of tramadol overdoses [12, 13]. In most instances, tramadol overdose is non-life-threatening. However, if accompanied by seizures, it has rarely been asso- ciated with reports of increased morbidity and mortality [7, 14]. However, the likelihood of multiple seizures and thus the possible need for prophylaxis, following tramadol overdose, is unknown. The purpose of this study, therefore, was to assess the inci- dence of recurrence of seizures in tramadol-poisoned patients after a first seizure and to assess the need for prophylactic anticonvulsant administration in these patients. Methods We assessed all tramadol-intoxicated patients who had at least one seizure and who were admitted to Loghman Hakim Hospital Poison Center, Tehran, Iran, from 1 March 2008 to 30 June 2008. We excluded all patients with a history of epilepsy, head trauma, cerebro- vascular accident, hypoxia, hypoglycaemia, hypo- and hypernatraemia, hypocalcaemia and toxicity from other drugs or chemical substances that potentially can lead to seizures. Exactly 100 patients fulfilled the above criteria. Patients’ age, sex, marital status, cause(s) of intoxication, route of poisoning, dose and number of tablets or capsules taken, vital signs, numbers of seizures before and during hospitalization, treatments, other signs and symptoms and length of hospitalization were extracted from their medical records. All patients were treated with standard supportive care. Specific interventions, such as gastrointestinal decontamination, were provided at the discretion of the treating physician. Witnessed seizures were treated with 5 mg of intravenous midazolam. No prophylactic anticon- vulsant therapy was provided as per the standard clinical approach to these patients at our centre. GraphPad-Prism 5 software (GraphPad Software, Inc., CA, USA) was used for the statistical analysis. We used the standard Student’s t-test with a taken as <0.05 for statistical analyses of continuous Author for correspondence: Kambiz Soltaninejad, Department of Forensic Toxicology, Legal Medicine Research Center, Legal Medi- cine Organization of Iran, Behesht Street, Tehran 1114795113, Iran (fax + 9821 55613731, e-mail kamsoltaninejad@yahoo.com). © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society Basic & Clinical Pharmacology & Toxicology, 2012, 111, 133–136 Doi: 10.1111/j.1742-7843.2012.00874.x