Emergency (****); * (*): *-* This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 137 Emergency (2015); 3 (4): 137-140 ORIGINAL RESEARCH Comparing the Antiemetic Effects of Ondansetron and Metoclopramide in Patients with Minor Head Trauma Majid Zamani, Behnam Namdar*, Reza Azizkhani, Omid Ahmadi, Mehrdad Esmailian Department of Emergency Medicine, Al-Zahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran. *Corresponding Author: Behnam Namdar; Department of Emergency Medicine, Al-Zahra Hospital, Soffeh Blvd, Isfahan, Iran. Tel: +989132587956; Fax: +983117923445; Email: behnamnamdar@ymail.com Received: December 2014; Accepted: January 2015 Abstract Introduction: Nausea and vomiting are the most common complications after minor head trauma that increases the risk of intracranial pressure rising. Therefore, the present study was aimed to compare the antiemetic effects of metoclopramide and ondansetron in the treatment of post-traumatic nausea and vomiting. Methods: The study was a controlled, randomized, double blind clinical trial, which was conducted in the first 6 months of 2014 in emergency department Al-Zahra and Kashani Hospitals in Isfahan, Iran. The patients with minor head trauma as- sociated with nausea and vomiting were randomly divided into 2 groups: treatment with metoclopramide (10mg/2ml, slow injection) and treatment with ondansetron (4mg/2ml, slow injection). The comparison between the 2 groups was done regarding antiemetic efficacy and side effects using SPSS 21 statistical software. Results: 120 patients with minor head trauma were distributed and studied into two groups of 60 patients (mean age 35.6±14.1 years; 50.0% male). Administration of both ondansetron and metoclopramide significantly reduced the severity of nausea (P<0.001). Changes in the severity of nausea in both groups before and after the treatment re- vealed that nausea had been decreased significantly in both groups (P < 0.001). The incidence of fatigue (p=0.44), headache (p=0.58) and dystonia (p=0.06) had no significant difference in the two groups but the incidence of drowsiness and anxiety in the metoclopramide group was significantly higher (P < 0.001). Conclusion: The present study indicated that the treatment effectiveness of ondansetron and metoclopramide are similar. However, inci- dence of drowsiness and anxiety in the metoclopramide was considerably higher. Since these complications can have adverse effects on the treatment of patients with brain injury, it is suggested that it may be better to use ondansetron in these patients. Key words: Head injuries, closed; nausea; vomiting; multiple trauma Cite this article as: Zamani M, Namdar B, Azizkhani R, Ahmadi O, Esmailian M. comparing the antiemetic effects of ondansetron and metoclopramide in patients with minor head trauma. Emergency. 2015;3(4):137-40. Introduction: n general, brain injury can occur due to sudden and severe head strike to a hard object, which can be mild, moderate or severe (1). The main causes of head injury include traffic accidents, falling from heights, physical violence, accidents at work, inside home acci- dents and during exercise incidents. However, the most important cause of head trauma in Iranian population is traffic accident (2). Among the warning signs of head trauma are nausea, vomiting, dizziness, headache, blurred vision, and loss of balance, difficulty in sleeping, memory problems, tinnitus and fatigue (3). Nausea and vomiting are the most common complications after mi- nor head trauma that in addition to severe harassment of patients increases the risk of aspiration and intracra- nial pressure rising. Ondansetron and metoclopramide are two available antiemetic agents in the emergency de- partment. Ondansetron is a serotonin 5-HT3 receptor antagonist, which connects to the peripheral and central receptors of serotonin (1). This drug is mostly used in nausea and vomiting after chemotherapy and surgery (2). It does not have any effect on dopamine receptors thus; it does not have extra pyramidal effect (3). Its max- imum effect is in intravenous administration right after the injection. This drug has a half-life of 2-7 hours and is metabolized in the liver where it changes into Glucu- ronide and sulfate which is inactive. Its most common side effects include headaches, fatigue, diarrhea, consti- pation, dizziness and anxiety. The recommended dose for the treatment of nausea and vomiting is 4-8 milli- grams (4, 5). Metoclopramide as an old antiemetic is mostly used in high doses, before chemotherapy and for I This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Zamani et al 138 nausea and vomiting caused by various reasons (6-8). This drug blocks the dopamine receptors on the periph- eral and central dopamine receptors and increases the movement of the upper gastrointestinal tract without in- creasing secretion (9, 10). Its intravenous absorption takes about 3 minutes and the peak of its effect is about 15 minute. This drug is metabolized in the liver and its half-life is approximately 4-5 hours (11). Its most com- mon side effects include dystonia < 10%, fatigue, drows- iness, and flushing. Based on the above-mentioned rea- sons, the present study was aimed to compare the antie- metic effects of metoclopramide and ondansetron in the treatment of post head trauma nausea and vomiting. Methods: Study design and setting The study was a controlled, randomized, double blind clinical trial, which was conducted in the first 6 months of 2014 in Al-Zahra and Kashani Hospitals in Isfahan, Iran. The present study was supervised and accepted by the ethics committee of Isfahan University of Medical Sciences. All the participants have consciously signed a written consent before entering the study. The study was registered in Iranian registry of clinical trial (IRCT num- ber: IRCT2015043012072N6). Participants The studied population included patients with minor head trauma associated with nausea and vomiting who were referred to the emergency department . Minor head trauma has been considered as GCS 14-15. The patients older than 15 years old, with minor head trauma, nausea and vomiting, and a triage level of 3 or higher based on emergency severity score were included. The exclusion criteria were considered as follow: hemodynamic insta- bility; pregnancy/lactation; any neurologic deficit; rest- less leg syndrome; alcohol usage; consumption of any an- tiemetic drugs during the 8 hours prior to admission; pre- vious administration of intravenous fluids; motion/ver- tigo related nausea and vomiting; chemotherapy or radio- therapy; inability to complete and understand study ex- planations or outcome measures; finally allergy or previ- ous adverse reactions to metoclopramide or ondansetron; and lack of data regarding demographic data and the se- verity of nausea and vomiting based on the visual analog scale (VAS). The qualified patients then entered the study using convenience sampling. Permuted-block randomiza- tion was done with a bock size of 6. Intervention The patients were randomly divided into 2 groups: treat- ment with metoclopramide (10mg/2ml, slow injection) and treatment with ondansetron (4mg/2ml, slow injec- tion). Preparing the drugs was done by an independent pharmacologist in a sterilized manner. For the study to be double –blind, the drugs were packed in nameless sy- ringes, and in numbered, dark packs and only the main researcher knew about the drug content. The drugs were kept in a fridge in the emergency department. The pa- tients and the other researchers were blind to the drug content and the treatment group. Drug information and treatment group of the patients would only be revealed if the patients showed extrapyramidal side effects of the drugs, which did not happen in this study. Drug admin- istration and patient assessment was done by emer- gency medicine residents. 20 minutes post drug admin- istration, nausea level was measured again. If the sever- ity of nausea had not decreased at least by 20 mm com- pared to the rate before the treatment intervention, a rescue dose (4mg ondansetron) would be prescribed for the patient. Measurements Nausea severity was measured using self-rated visual analogue scale (VAS) before and 20 minutes after the in- tervention. VAS was a standard 100 mm (mm) method on which the left side indicated no nausea and the right side was an indicator of the worst nausea possible. Using this scale for assessing nausea severity was accepted in previous studies. According to these studies the mini- mum difference in nausea severity counted as clinically significant, was set at 20 mm. Nausea severity was di- vided into 3 levels: severe nausea (VAS > 70 mm), mod- erate nausea (50 mm < VAS <70 mm) and mild nausea (VAS < 50 mm). Outcomes The primary outcome was defined as mean nausea se- verity according to VAS in the twentieth minute post drug administration. Secondary outcomes included needing a rescue dose and side effects of the drugs. Statistical analysis Population sample size for each group was determined based on comparing mean nausea severity between the 2 treatment groups. Based on previous studies (12), mean and standard deviation of nausea severity reduc- tion before and after ondansetron administration was 40 mm and 24 mm respectively. Based on this, by consider- ing α = 0.05 and 90% power (β = 0.1), the sample size of 43 patients in each group was sufficient. Finally, 60 pa- tients were included in each group. The data were ana- lyzed using SPSS 21.0. Nausea severity was expressed as mean and standard deviation. To compare the 2 groups, t-test was used and for comparing the effects of the drug before and after administration, paired t-test was used. The drug side effect was also expressed as frequency and percentage. The comparison between the 2 groups was done using the chi square, the Fisher exact, or Mann- Whitney U test. In all the analyses, p < 0.05 was defined as the level of significance. Results: Finally, 120 patients with minor head trauma were dis- tributed and studied into two groups of 60 patients (mean age 35.6 ± 14.1 years; 50.0% male). Mean age of metoclopramide and ondansetron treated groups were This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 139 Emergency (2015); 3 (4): 137-140 36.1 ± 14.0 and 35.0 ± 14.2 years, respectively (p = 0.69). The sex distribution in ondansetron (45.0% male) and metoclopramide groups (55.0% male) had no significant difference. Administration of both ondansetron and metoclopramide significantly reduced the severity of nausea (P < 0.001). The average score of nausea severity before the injection of ondansetron and metoclopramide in the groups were 89.3±12.5 and 85.3 ± 14.9, respectively (p = 0.11). After intervention, nausea in the two groups were 32.3 ± 14.8 and 36. 5 ± 17.8, respectively (p = 0.17) (Figure 1). Be- fore intervention 51 patients (85.0%) of the on- dansetron group and 47 patients (78.3%) of the meto- clopramide group had severe nausea (VAS > 70 mm) (p = 0.35). After intervention only 2 patients (3.3%) of the ondansetron treated and 5 patients (8.3%) of the meto- clopramide treated group had severe nausea (p = 0.16). However, changes in the severity of nausea in both groups before and after the treatment revealed that nau- sea had been decreased significantly in both groups (P < 0.001) (Figure 2). The incidence of fatigue (p = 0.44), headache (p=0.58) and dystonia (p = 0.06) had no signif- icant difference in the two groups but the incidence of drowsiness and anxiety in the metoclopramide group was significantly higher (P < 0.001) (Table 1). 2 (1.7%) patients needed the rescue dose which were in the meto- clopramide treated group (p = 0.50). Discussion: The present study showed that the antiemetic effect of ondansetron and metoclopramide in patients with mi- nor head trauma is the same. The frequency of severe nausea in the ondansetron group reduced from 85% to 3.3% while in the metoclopramide group, reduced from 78.3% to 8.3%. The incidence of drowsiness and anxiety were significantly lower in the ondansetron treated pa- tients. The antiemetic effects of ondansetron and metoclo- pramide have been compared in various studies, the re- sults of which are in line with the current study. For in- stance, a study by Pitts et al. reveals that the effective- ness of ondansetron and metoclopramide compared to the placebo, show no significant difference in decreasing nausea and vomiting in the patients admitted to the emergency department (13). Also Egerton-Warburton et al. expressed in their study that the antiemetic effects of ondansetron and metoclopramide were no different compared to the placebo (14). In addition, Barrett et al. and Al-Ansari et al. have reported similar results (12, 15). In the present study, mean pain relief was 48.8 mm in the metoclopramide group and 57.0 mm in the on- dansetron ones which was significantly different from the results of the mentioned studies. In this regard, Eger- ton-Warburton et al. showed that administering 4mg on- dansetron and 20mg metoclopramide resulted in a 27 mm and 28 mm decrease in nausea severity, respectively (2). These levels in the Barrett et al. study was 40 mm for ondansetron and 32 mm for metoclopramide (15). Con- cerning the drugs’ side effects, Patanwala et al. propose in their review study that due to safety, ondansetron is a better choice for the first line of treatment for decreasing nausea and vomiting in the patients admitted to the emergency department (16). The present study also showed that compared to metoclopramide, ondansetron administration, showed less side effects. In addition, in a study by Egerton-Warburton et al. 6 patients showed side effects in the group treated with metoclopramide, Table 1: Distribution of clinical signs in the two groups Variable Metoclopramide N (%) Ondansetron N (%) P Age (Mean ± SD) 36.1 ± 14.0 35.0 ± 14.2 0.69 Gender Male 27 (45.0) 33 (55.0) 0.27 Female 33 (55.0) 27 (45.0) Headache Yes 30 (50.0) 33 (55.0) 0.58 No 30 (50.0) 27 (45.0) Drowsiness Yes 26 (43.3) 8 (13.3) <0.001 No 34 (56.7) 52 (86.7) Fatigue Yes 23 (38.3) 19 (31.7) 0.44 No 37 (61.7) 41 (68.3) Anxiety Yes 37 (61.7) 11 (18.3) <0.001 No 23 (38.3) 49 (81.7) Dystonia Yes 5 (8.3) 0 (0.0) 0.057 No 55 (91.7) 60 (100.0) This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2015 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Zamani et al 140 whereas only 2 showed side effects in the group treated with ondansetron (14). A shortcoming in the present study was the lack of a placebo group. If such a group was studied, an assessment of the placebo effect would have been possible. In addition, since convenience sampling was used, selection bias is possible. Conclusion: The present study indicated that the treatment effective- ness of ondansetron and metoclopramide are similar. However, incidence of drowsiness and anxiety in the metoclopramide was considerably higher. Since these complications can have adverse effects on the treatment of patients with brain injury, it is suggested that it may be better to use ondansetron in these patients. Findings. Acknowledgments: The authors appreciate the insightful cooperation of staffs of the Emergency Department. Conflict of interest: None Funding support: None Authors’ contributions: All authors passed four criteria for authorship contribu- tion based on recommendations of the International Committee of Medical Journal Editors. References: 1. Cooke CE, Mehra IV. Oral ondansetron for preventing nausea and vomiting. Am J Hosp Pharm. 1994;51(6):762-71. 2. Carlisle JB, Stevenson CA. Drugs for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2006 (3):Cd004125. 3. Naumann CR, Zelig C, Napolitano PG, Ko CW. Nausea, vomiting, and heartburn in pregnancy: a prospective look at risk, treatment, and outcome. J Matern Fetal Neonatal Med. 2012;25(8):1488-93. 4. Keller K, Beule J, Dippold W. Cyclic vomiting syndrome in adults. Wien Med Wochenschr. 2013;163(21-22):514-6. 5. Hejazi RA, McCallum RW. Cyclic vomiting syndrome: treatment options. Exp Brain Res. 2014;232(8):2549-52. 6. Yadav Deepak R, Ayyappan T, Shanmugam S, Sundaramoorthy K, Vetrichelvan T. Development and in-vitro evaluation of buccoadhesive Metoclopramide hydrochloride tablet formulations. Development. 2011;3(1):516-25. 7. Olver I, Clark-Snow RA, Ballatori E, Espersen BT, Bria E, Jordan K. Guidelines for the control of nausea and vomiting with chemotherapy of low or minimal emetic potential. Support Care Cancer. 2011;19(1):33-6. 8. Snow V, Weiss K, Wall EM, Mottur-Pilson C. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137(10):840-9. 9. Yi HS, Kim HS, Seo MR. Trial of Oral Metoclopramide on Diurnal Bruxism of Brain Injury. Ann Rehabil Med. 2013;37(6):871-4. 10. Faridaalaee G, Rahmani SH, Mehryar H, et al. Comparison of Intravenous Metoclopramide and Acetaminophen in Primary Headaches: a Randomized Controlled Trial. Emergency. 2015;3(2):67-71. 11. Livezey MR, Briggs ED, Bolles AK, Nagy LD, Fujiwara R, Furge LL. Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6. Xenobiotica. 2013;44(4):309-19. 12. Al-Ansari K, Alomary S, Abdulateef H, Alshawagfa M, Kamal K. Metoclopramide versus ondansetron for the treatment of vomiting in children with acute gastroenteritis. J Pediatr Gastroenterol Nutr. 2011;53(2):156-60. 13. Pitts SR. Neither ondansetron nor metoclopramide reduced nausea and vomiting in the emergency department. Ann Intern Med. 2014;161(12):JC3. 14. Egerton-Warburton D, Meek R, Mee MJ, Braitberg G. Antiemetic Use for Nausea and Vomiting in Adult Emergency Department Patients: Randomized Controlled Trial Comparing Ondansetron, Metoclopramide, and Placebo. Ann Emerg Med. 2014;64:526-32. 15. Barrett TW, DiPersio DM, Jenkins CA, et al. A randomized, placebo-controlled trial of ondansetron, metoclopramide, and promethazine in adults. Am J Emerg Med. 2011;29(3):247-55. 16. Patanwala AE, Amini R, Hays DP, Rosen P. Antiemetic Therapy for Nausea and Vomiting in the Emergency Department. J Emerg Med. 2010;39(3):330-6. Figure 1: Mean changes of nausea severity before and after intervention in the 2 groups Figure 2: Frequency of nausea before and after treatment in both groups 0 20 40 60 80 100 120 Before intervention After intervention M e a n n a u s e a s e v e r it y Time Ondansetron Metoclopramide 0 9 51 23 35 2 0 43 47 17 38 5 0 10 20 30 40 50 60 Mild Moderate Severe Mild Moderate Severe Before intervention After intervention N u m b e r o f p a ti e n ts Ondansetron Metoclopramide Introduction: Methods: Study design and setting Participants Intervention Measurements Outcomes Statistical analysis Results: Discussion: Conclusion: Acknowledgments: Conflict of interest: Funding support: Authors’ contributions: References: