Archives of Academic Emergency Medicine. 2019; 7 (1): e28 BR I E F RE P O RT Seizure Prevalence and Its Related Factors in Tramadol In- toxication; a Brief Report Asrin Babahajian1, Payam Khomand2, Farhad Manoochehri3, Roozbeh Fakhimi3, Behrooz Ahsan2, Mohiadin Amjadian4, Vahid Yousefinejad1∗ 1. Liver and Digestive Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. 2. Department of Neurology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. 3. School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. 4. Basic Science Department, Kurdistan University of Medical Sciences, Sanandaj, Iran. Received: March 2019; Accepted: April 2019; Published online: 7 May 2019 Abstract: Introduction: Seizure is known to be a serious complication of tramadol consumption even in its therapeu- tic doses. The aim of this study was to determine the prevalence of seizure and its related factors in tramadol intoxicated patients referred to emergency department (ED). Methods: In this cross-sectional study, all indi- viduals, admitted to ED following tramadol intoxication were divided into two groups based on the presence or absence of seizures. Demographic data as well as clinical, electroencephalogram and imaging findings were compared between the two groups using SPSS software version 22. Results: 167 patients with the median age of 23 (13-45) years were studied (85% male). Seizure was seen in 97 (58.0%) cases. Risk of seizure had increased 3.7 times in patients with a history of seizure (OR: 3.71 Cl 95%: 1.17 - 11.76). Tramadol dose was significantly higher in patients who had seizure more than once (Median: 2800 IQR: 1800-4000), compared to those who had one seizure episode (Median: 850 IQR: 1800-400) (p <0.0001). Conclusion: Based on the findings of this study, history of seizure increased the risk of seizure in patients taking tramadol, and the increase in dose correlated with a significant increase in seizure frequency. Keywords: Tramadol; seizure; toxicity; emergency service, hospital; risk factor Cite this article as: Babahajian A, Khomand P, Manoochehri F, Fakhimi R, Ahsan B, Amjadian M, Yousefinejad V. Seizure Prevalence and Its Related Factors in Tramadol Intoxication; a Brief Report. Arch acad Emerg Med. 2019; 7(1): e28. 1. Introduction Tramadol is a synthetic opioid drug with central effects, which is administered to relieve mild to severe pain. Tra- madol is an analogue of 4-phenylpiperidine codeine. It ex- erts its therapeutic effects by influencing opioid receptors (µ), noradrenergic system, serotonergic system and GABAer- gic system, and also by inhibiting reuptake of norepinephrine in the central nervous system (1). Tramadol completely crosses the brain blood barrier. Its maximum plasma con- centration is seen 90 minutes after oral administration. Its half-life is 5 to 6 hours. Its excretion is more renal and its ther- apeutic concentration in the blood is about 100-300 ng/ml (2). Tramadol can be given orally, subcutaneously, intra- ∗Corresponding Author: Vahid Yousefinejad; Liver and Digestive Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. Tel: +98-87- 33247855 Email: hooman56y@yahoo.com venously or suppository, but it has maximal absorption in oral administration. Therapeutic dose is 50 mg in oral, 50- 100mg in injection and 100mg in anal administration. Also, the maximum daily dose should not exceed 400mg (3). Intox- ication with tramadol may cause neurological complications such as seizure, respiratory arrest (apnea), and coma. The tramadol-induced seizure is often non-dose dependent and self-limited with generalized tonic-clonic feature (2). The neurotoxicity of tramadol occurs predominantly within the first 24 hours after ingestion and 84.6% of seizures occur in the first 6 hours after ingestion (4). The risk of seizure in- creases with concomitant use of tramadol with serotonin re- uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and monoamine oxidase MAO Inhibitors (5). Some studies have shown that tramadol could cause seizures in people with a history of epilepsy and in healthy people even at recommended doses, but most cases were observed among young people. Opiate dependency, drug abuse and This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Babahajian et al. 2 their complications were common in all age groups of both males and females in Iran (6, 7). In recent years in Iran, exces- sive intake and intoxication with tramadol has been one of the most common causes of admissions in emergency wards (4, 8-10). An increase in seizure frequencies because of tra- madol intoxication was also reported. It was reported that 15 to 35% of patients with tramadol intoxication experienced seizures (10, 11). Because of the increase in the number of tramadol users in recent years and, consequently, the in- crease of seizure associated with it, the prevalence of seizure and its related factors were evaluated in tramadol intoxicated patients in this study. 2. Methods 2.1. Study design and setting This cross-sectional study was done in the emergency de- partment of Tohid Hospital, Sanandaj, Iran, from March 2016 to August 2018. Tramadol intoxicated patients were divided into two groups based on the presence or absence of seizures, then demographic data as well as clinical, electroencephalo- gram and imaging findings were compared between the two groups. The protocol of the study was approved by the Ethics Committee of Kurdistan University of Medical Sciences (NO- MUK1394/318). All participants gave written informed con- sent to participate in the study and the principles of confi- dentiality of data were respected by the researchers accord- ing to the Helsinki Declaration. 2.2. Participants The study population consisted of all patients who had signs or symptoms of poisoning due to the use of tramadol (oral or injectable). Seizures with metabolic causes such as hypocal- cemia or hypoglycemia were excluded from the study. Pa- tients were selected and entered via consecutive sampling method. 2.3. Data collection Demographic data, clinical findings, dosage and duration of tramadol intake, history of seizure, time interval between taking tramadol and manifestation of seizure, type of seizure, concomitant use of other drugs, as well as the frequency of seizures were collected using a researcher-made question- naire by two general physicians. Then, the patients were di- vided into two groups based on the presence or absence of seizure. Computed tomography (CT) scan was done for all patients at the time of admission. 2.4. Statistical analysis Minimum sample size required for the present study con- sidering 95% confidence interval, 8% error, and 46.2% the prevalence of seizure following tramadol use (4), was calcu- lated to be 150 cases. The results of the study were analyzed using SPSS V.22 software. Qualitative data were reported as frequency and percentages, and quantitative data were re- ported as median and interquartile range (IQR) due to abnor- mal distribution of data. Based on the incidence of seizure, patients were divided into two groups of with seizure and without seizure, then demographic characteristics and fac- tors affecting seizure were compared in the two groups. To assess the relationship between quantitative and qualitative variables with seizure, Mann-Whitney U and Chi-square tests were used. Then, in order to determine the independent fac- tors affecting seizure, variables with a p value <0.1 in the uni- variate analysis were entered into a multivariate logistic re- gression model and the data were reported as odds ratio (OR) with 95% confidence interval (CI). Spearman test was used to assess the correlation between tramadol intake dose and frequency of seizures. P<0.05 was considered as significance level. 3. Results: 167 patients with the median age of 23 (13-45) years were studied (85% male). All patients took oral tramadol and the median dose of tramadol was 1200 mg (100 to 12,000 mg). Seizure occurred in 97 (58.0%) patients. The frequency of seizure was one time in 80.4% and the type of seizure was a tonic-clonic type in 93.8% of cases. The median time inter- val between tramadol intake and seizure was 2 (1-12) hours. There was not any significant relationship between seizure occurrence and age (p = 0.39) and gender (p = 0.28). The in- cidence of seizure was significantly higher in patients with a history of seizure (p = 0.03). Comparison of other risk factors between the two groups did not show any significant differ- ence (Table 1). In addition, the tramadol dose was significantly higher in pa- tients who had seizures more than once (Median: 2800 IQR: 1800-4000), compared to those who had seizures only once (Median: 850 IQR: 1800-400) (r = 0.41; p <0.0001). The results of multivariate regression analysis showed that the history of seizure increased the risk of seizure in these patients by about four times (OR = 3.71; 95% CI: 1.17 to 11.76; p = 0.03) (Table 2). 4. Discussion The findings of this study showed that 58.1% of patients with tramadol intoxication experienced seizures. The incidence of seizure was significantly higher in those with a history of seizure, and the dose of tramadol was significantly higher in patients who had experienced seizure more than once. Tra- madol intoxication rate showed a significant increase in Iran like any other part of the world (12, 13), and in some studies in Iran, the incidence of seizure was reported to be high in This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2019; 7 (1): e28 Table 1: Baseline characteristics of patients based of presence or absence of seizure Variables Seizure P Without (n=97) With (n=70) Age (year) Median (percentile) 23.0 ( 21.0 -29.0 ) 22.0 ( 19.0 – 30.0 ) 0.39 Gender Female 12 (12.4) 13 (18.6) 0.28 Male 85 (87.6) 57 (81.4) Tramadol intake (mg) Median (percentile) 1000 (500 – 2000) 1600 (800 -2850) 0.06 Time to hospital admission (hour) Median (percentile) 3.5 (2.0 – 5.0) 3.0 (2.0 -7.0) 0.35 History of seizure Yes 17 (17.7) 4 (5.7) 0.03 No 79 (82.3) 66 (94.3) Concomitant use of opioids Yes 5 (5.2) 9 (12.9) 0.09 No 92 (94.8) 61 (87.1) Concomitant use of other drugs Yes 6 (6.2) 4 (5.7) 0.09 No 91 (93.8) 66 (94.3) Episodes of seizure Single seizure 78 (80.4) - NA Multiple seizures 19 (19.6) - Data are presented as median (percentile 25-75) or frequency (%). NA: not applicable. Table 2: Independent risk factors of seizure following tramadol intoxication Variables Odds ratio 95% CI P History of seizure 3.71 1.17 – 11.76 0.03 Concomitant use of opioids 0.35 0.11 – 1.13 0.08 patients with tramadol intoxication. Although excessive in- take of tramadol was not life threatening, seizures sometimes increased mortality in these individuals (14-16). Talaie et al., reported the incidence of seizure to be 46.2% (4). In another study, 48% of the 144 patients with tramadol intoxication ex- perienced seizures (17). The precise mechanism of tramadol’s effect on seizure in- duction has not yet been determined. Research showed that at high doses, tramadol had inhibitory effects on gamma aminobutyric acid (GABA) receptors (18, 19), and in ani- mal models, inhibition of GABA receptors increased seizure severity (20). In addition, seizure was known to be a ma- jor side effect of tramadol which might occur with the use of both therapeutic and toxic doses (4, 21-26). Also, the di- rect effect of tramadol on seizure has not been fully proven. In the present study, the median dose of tramadol was 1,000 mg (ranging from 100 to 1200 mg) in patients with seizure, which showed that none of the seizures was induced by the therapeutic doses, but when compared with the doses used in patients without seizure, there was no significant differ- ence (P=0.06). This data showed that incidence of seizure in the patients was not dose-dependent. However, with an in- crease in the dose, the frequency of seizures increased. The dose of tramadol intake in patients who had more than one seizure was three times more than those with only one seizure, which showed a moderate correlation between drug dose and frequency of seizures. In the study by Shadnia et al., in patients who had seizures more than once, tramadol intake dose was significantly higher compared to those who had seizure only once, which is consistent with the results of this study (24). However, in our study the correlation be- tween the intake dose and the frequency of seizure was poor. Considering that in both studies the tramadol dose assess- ment was done based on asking the patient or his relatives, confirmation of the relationship between the dose and the frequency of seizure requires more detailed studies. Also, the results of this study showed that the risk of seizure had increased in patients with a history of seizure. Based on this finding, it is recommended to take history of seizure in patients who might need tramadol administration, especially for long-term use. The limitation of this study was that the dose of the drug taken by each patient was determined based on his/her self-declaration, which is not very accurate and re- liable. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem A. Babahajian et al. 4 5. Conclusion Based on the findings of this study, a history of seizure in- creased the risk of seizure in patients taking tramadol, and an increase in the dose correlated with a significant increase in seizure frequency. It is recommended to take an accurate history of seizure in patients who might need tramadol ad- ministration, especially for long-term use. 6. Appendix 6.1. Acknowledgements This study was supported by Vice Chancellor for research, Kurdistan University of Medical Sciences (Grant number: 1394/318). 6.2. Author contribution Vahid Yousefinejad, Payam Khomand, and Behrouz Ahsan designed the study. Farhad Manoochehri and Rouzbeh Fakhimi participated in acquisition of data. Asrin Babaha- jian analyzed the data. Payam Khomand and Behrouz Ahsan participated in management of data. Vahid Yousefinejad, Mohiadin Amjadian and Asrin Babahajian wrote the first draft and others revised the manuscript critically. 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Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results: Discussion Conclusion Appendix References