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 70 Emergency (2015); 3 (2): 70-74 ORIGINAL RESEARCH Comparison of Intravenous Metoclopramide and Acetaminophen in Primary Headaches: a Randomized Controlled Trial Gholamreza Faridaalaee1, Seyed Hesam Rahmani1, Hamidreza Mehryar1, Shahab Bina Shishavan*1, Seyedeh Zahra Merghati2, Mohammad Amin Valizade Hasanloei3, Bahman Naghipour4, Farzad Rahmani5 1. Department of Emergency Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, IR Iran. 2. Department of Internal Surgery, School of Nursing and Midwifery, International branch of Urmia University of Medical Sciences, Urmia, IR Iran. 3. Department of Anesthesiology, Urmia University of Medical Sciences, Urmia, IR Iran. 4. Department of Anesthesiology, Tabriz University of Medical Sciences, Tabriz, IR Iran. 5. Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. *Corresponding Author: Bina Shishavan Shahab, Department of Emergency Medicine, Imam Khomeini Hospital, Ershad Avenue, Urmia, Iran. Tel: +989141889486; Fax: +984433457286; Email: shahabbina@gmail.com Received: September 2014; Accepted: November 2014 Abstract Introduction: Headache is the most common neurologic symptom among referees to the emergency department (ED), while the best treatment has not yet been found. Therefore, in the present study pain relief effects of meto- clopramide and acetaminophen were compared in patients suffered acute primary headache. Methods: This study was a double-blind randomized clinical trial performed in Imam Khomeini Hospital, Urmia, Iran, through July to October 2014. All adult patients, with acute primary (migraine, tension type and cluster) headache referred to the ED were included in this study. Pain severity was measured with 10 centimeters numeric rating scales. The patients were randomized into two groups of intravenous (IV) metoclopramide (10 milligrams) and acetaminophen (1 gram). Pain score, success rate, and drug complications were compared between the 2 groups at 0, 15, 30, 60, and 120 minutes after injection. Results: 100 patients were equally categorized into two groups (mean age of 32 ± 13.2 years; 51.2% male). Initial pain score in metoclopramide and acetaminophen groups were 9.1 and 9.4, respectively (p = 0.46). IV metoclopramide did not have any analgesic effect at 15 minutes, but had good effect at 30 minutes. While, the analgesic effect of acetaminophen initiated after 15 minutes. After 2 hours, both drugs had good thera- peutic effect on primary headaches (p < 0.001). Conclusion: The present study demonstrated that efficacy of meto- clopramide for pain relief in primary headaches is lower than acetaminophen. In this regard, success rate of acet- aminophen was 42.0% versus 0% for metoclopramide within 15 minutes. The efficacy of acetaminophen continued until 60 minutes. Key words: Metoclopramide; acetaminophen; headache; migraine; acute pain Cite this article as: 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):70-4. Introduction: Headache is one of the most common neurologic symptoms among patients admitted to the emer- gency department (ED), as 3 million patients are annually visited only in the EDs of United States (1, 2). The disease is categorized into primary (such as mi- graine, tension type, and cluster) and secondary (such as those following intracerebral hemorrhage, trauma, tu- mor, etc.) groups. Primary is the most frequent type seen in EDs and 90% of them include migraine, tension, or even a combination of them (3, 4). Approximately, 12% of general population suffer from migraine and acute ex- acerbations cause severe and disabling disorders (5-7). Several agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, antiemetics, antipsychotics, etc. have been used for treatment (8). Recently, the use of do- pamine antagonists, such as metoclopramide (alone or in combination with other drugs), and serotonin ago- nists, like sumatriptan, for this purpose has increased (9, 10). Administration of metoclopramide relieves the in- tensity of headaches; however, its efficacy varies among studies. For example, while, Tec et al. declared an ac- P 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 71 Emergency (2015); 3 (2): 70-74 ceptable therapeutic effect for metoclopramide in pri- mary headaches, Coppola et al. deemed its efficacy to be equal to placebo (4, 11, 12). Given the above results, evaluation of metoclopramide’s efficacy in management of primary headaches requires more studies to derive a concrete and clear conclusion. Therefore, the present study aimed to compare analgesic effects of intravenous (IV) metoclopramide and acetaminophen for acute pri- mary headaches. Methods: Study design and setting This study was a double-blind randomized clinical trial performed in Imam Khomeini Hospital, Urmia, Iran, through July to October 2014. The effect of IV metoclo- pramide (10 milligrams) and acetaminophen (1 gram) in treatment of acute headaches was compared. For ethical reasons, there was no placebo arm. The study protocol was confirmed by Ethical Committee of Urmia University of Medical Sciences and informed consent was obtained from patients. This protocol was registered in Iranian Registry of Clinical Trials with IRCT Number: IRCT2014081817812N3. Subjects Patients with acute primary headache and pain severity over 4 based on numeric rating scale (NRS), who were referred to the ED and did not have any systematic dis- ease, were included. Exclusion criteria were having al- lergy to metoclopramide and acetaminophen, hepatic failure, secondary headache, pregnancy, breast-feeding, renal insufficiency, arbitrary treatment, and the case of recurrent headache. Migraine, tension type, and cluster headaches were diagnosed based on International Head- ache Society’s International Classification of Headache Disorders (ICHD) criteria (13). Intervention The patients were randomized into two groups of meto- clopramide (intervention group) with dosage of 10 mil- ligrams, IV, in 2 minutes and acetaminophen group (con- trol group) with dosage of 1 gram, slow IV, in 10 minutes. Randomization was performed by block randomization (size of 5 for blocks), using an online random number generator (RNG). Solutions were prepared by an inde- pendent pharmacist and kept in a sealed envelope. Drugs were injected by a physician blinded to the studied groups. Response to treatment and the side effects were assessed within 15, 30, 60, and 120 minutes after receiv- ing medications and then compared with the baseline. The ED staff were blinded to composition of solutions and studied groups. The data of the prescribed solution were only available for the staff when drug complica- tions and other adverse effects appeared in patients and the patient was excluded from the study. Rescue dose was prescribed, if the pain continued after 30 minutes from first drug administration. The disclosure of the data about the prescribed medicine(s) was not required dur- ing the study period. Measurements 11-scale standard numeric rating scale (NRS) was used to assess the pain score of patients (14). Patients were given a score number between 0 and 10, 0 representing no pain and 10 demonstrating the worst conceivable pain. Pain severity was assessed in the baseline (admin- istration time) and then reassessed 15, 30, 60, and 120 minutes after medication. This follow up was performed because 120 minutes is a more standard endpoint for outpatient migraine trials (15). Nausea, vomiting, ver- tigo, and lethargy were recorded as adverse effects based on self-reports and clinical manifestations. Thera- peutic success rate was defined as decreasing pain score to at least 3. Statistical analysis The minimum required sample size for the present study considering the clinically significant change of 2 scores in pain severity, standard deviation of 2.7 and 1.2 centi- meters for effects of metoclopramide and acetamino- phen in decreasing headache, power of 90% (β=0.1) and the error rate of 5% (α=0.05) was estimated to be 33 subjects (16, 17). Data were analyzed using SPSS 21. Quantitative varia- bles were reported as mean and standard deviation and qualitative ones as frequency and percentage. Chi- square and Fisher exact tests were also used for compar- ison of basic characteristics of the two groups. Because data was not normally distributed, the comparison be- tween pain severity changes in patients was performed using Wilcoxon-rank test. The success rate was reported as frequency and percentage as well as comparison of time changes between two therapies performed by non- parametric test for trend, which is an extension model of the Wilcoxon rank-sum test. Since some basic features between two therapeutic groups had significant differ- ence, general linear model was done to find if success rate had significant difference after moderating these factors. P < 0.05 was considered as a significant level. Results: 100 patients were equally categorized into two groups of IV acetaminophen and metoclopramide (mean age of 32 ± 13.2 years; 51.2% male). Table 1 shows demographic data of patients. As can be seen, age distribution of the two groups was significantly different (p < 0.001). Most mi- graine sufferers received IV acetaminophen, while patients with tension headache mostly took metoclopramide (Table 1, p < 0.001). The pain severity at administration time had no difference between the groups (p = 0.46). However, the mean pain severity at 15 minutes after taking acetamino- phen was significantly less than metoclopramide group (7.0 ± 1.4 versus 9.0 ± 1.3, p < 0.001). This pattern was seen within 30 minutes (4.5 ± 2.0 versus 6.6 ± 1.5; p < 0.001), 60 minutes (3.1 ± 2.1 versus 5.4 ± 1.6; p < 0.001), and even 120 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 Faridaalaee et al 72 minutes (3.6 ± 2.0 versus 1.5 ± 1.2; p < 0.001) after injection (Table 2). 21 (42%) patients in acetaminophen group had signifi- cant pain relief, while none of subjects in metoclo- pramide group had such effectiveness in 15 minutes af- ter medication. The 30-minute success rate for aceta- minophen and metoclopramide groups were 100% and 74%, respectively. 100% therapeutic success rate in IV acetaminophen remained until 120 minutes (Table 2, p = 0.001). No side effect was seen among patients. Only 3 (6%) patients of metoclopramide group needed the res- cue dose. After adjustment of analysis for basic charac- teristics, the rate of therapeutic success for IV aceta- minophen at 15 minutes (OR=1.43; 95% Cl=1.2-1.7; p < 0.001), 30 minutes (OR=1.38; 95%Cl=1.17-1.64; p < 0.001), and 60 minutes (OR=1.10; 95% Cl=1.01-1.26; p = 0.04) was more than metoclopramide (Table 3). Discussion: Based on the present study and similar to other major studies, metoclopramide had a pain relief effect on pri- mary headaches, but in contrast to other researches, here metoclopramide had inferior effect to acetamino- phen. It can be justified under racial differences. Several studies have been performed regarding therapeutic ef- fects of metoclopramide on the primary headaches with Table 1: Comparison of demographic data between two studied groups Variable Acetaminophen Metoclopramide p1 Age (year) <18 7 (43.8) 9 (56.2) <0.001 18-40 43 (67.2) 21 (32.8) 41-60 0 (0.0) 18 (100.0) 61-75 0 (0.0) 2 (100.0) Gender Male 22 (51.2) 21 (48.8) Female 28 (49.1) 29 (50.9) 0.84 Marital status Single 15 (53.6) 13 (46.4) 0.66 Married 35 (48.6) 37 (51.4) Type of headache Migraine 35 (67.3) 17 (32.7) Tension type 8 (23.5) 26 (76.5) <0.001 Cluster 7 (50.0) 7 (50.0) 1, Based on Chi-Squared test; 2, based on Fisher exact test. Table 2: comparison of pain score and successes rate in medical interventions between studied groups Time (minute) Acetaminophen Metoclopramide p1 Mean ± SD Success rate (%) Mean ± SD Success rate (%) Baseline 9.4 ± 0.7 ---- 9.1 ± 1.3 ---- 0.46 15 7.0 ± 1.4 21 (42.0) 9.0 ± 1.3 0 (0.0) <0.001 30 4.5 ± 2.0 50 (100.0) 6.6 ± 1.5 34 (74.0) <0.001 60 3.1 ± 2.1 50 (100.0) 5.4 ± 1.6 47 (94.0) <0.001 120 1.5 ± 1.2 50 (100.0) 3.6 ± 2.0 50 (100.0) <0.001 1, Based on Kruskal-Wallis equality of populations rank test; SD: Standard deviation. Table 3: results of multivariate analysis for comparison of success rate between two groups Time (minute) Odds ratio 95% CI p1 15 1.43 1.21-1.73 <0.001 30 1.38 1.17-1.64 <0.001 60 1.10 1.01-1.26 0.04 1, Based on general linear model adjusted for age and type of headache; CI: Confidence interval. 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 73 Emergency (2015); 3 (2): 70-74 different results. While some of them showed good effi- cacy of metoclopramide for primary headaches, others concluded no efficacy. Salazar-Zúñiga and Garfias-Arvizu compared metoclopramide and sumatriptan in migraine sufferers and demonstrated that metoclopramide is more effective (18). Tec et al. showed that metoclo- pramide has therapeutic effects on headache, alone (4). Coppola et al. compared prochlorperazine, metoclo- pramide, and placebo; they showed that prochlorpera- zine has therapeutic effects on headache, but metoclo- pramide is more effective than placebo (9). In contrast, Cameron et al. compared prochlorperazine and metoclo- pramide, and demonstrated that prochlorperazine and metoclopramide are both effective on acute migraine headaches (19). Colman et al. concluded that metoclo- pramide is effective on the migraine especially in combi- nation with other agents (20). Friedman et al. stated that a combination of metoclopramide and diphenhydramine are more effective than ketorolac for headaches (21). In another study, Friedman et al. compared 10 milligrams of IV prochlorperazine and combination of 20 milligrams metoclopramide and 25 milligrams diphenhydramine for acute migraine headaches. They showed pro- chlorperazine and combination of metoclopramide and diphenhydramine have the same effect for acute mi- graine headaches (22). In another study, Friedman et al. displayed 10 metoclopramide are more efficient than 30 milligrams ketorolac or 1000 milligrams valproate so- dium (23). Weinman et al. performed a systemic review to find an effective drug for tension type of headaches and reviewed 8 studies. Their results were as below: metamizole, chlorpromazine, and metoclopramide are more effective than placebo for acute pain. The combina- tion of metoclopramide with diphenhydramine has su- periority to ketorolac. mepivacaine, meperidine with promethazine, and sumatriptan are not more effective than placebo (24). The results of this study had some similarities and dissimilarities with other studies. Vari- ances in regimens and doses of medications can result in different efficacy of medications, so that use of one standard regimen may lead to results that are more co- herent. Extrapyramidal reactions are one of the most im- portant side effects of metoclopramide, which have been reported in nearly 10% of cases. For example, Coppola et al. demonstrated 2.5% of patients displayed dystonia or akathisia in initial minutes of drug administration (12). Also Friedman et al. stated that akathisia developed in 9.3% of patients (25). However, no side effect was found in the present study. There were several limitations in this study. The first limitation was the short follow-up period. Although, during 2 hours follow up no side effect was observed, the longer period such as 1or 2 days and even 1week follow up might have provided a better op- portunity to evaluate long-term side effects and head- ache recurrence. Another limitation was single-blinded design of the trial. We were unable to do the study in a double-blinded way, because the routes of administra- tion for drugs were different. Moreover, the lack of a pla- cebo group or standard arm due to ethical consideration was also considered as another limitation. Conclusion: The present study demonstrated that efficacy of meto- clopramide in pain relief of headaches is lower than ac- etaminophen. In this regard, success rate of acetamino- phen in pain relief was 42.0%, while it was 0% for meto- clopramide within 15 minutes. The efficacy of aceta- minophen continued until 60 minutes. Acknowledgments: All authors would like to say thanks to all staff of Imam Khomeini Hospital and the research center of Urmia Uni- versity of Medical Sciences. Conflict of interest: None Funding support: This study was granted by the research center of Urmia University of Medical Sciences, grant number: 1872143-25 Authors’ contributions: All authors passed four criteria for authorship contribu- tion based on recommendations of the International Committee of Medical Journal Editors. References: 1. Taylor FR. Diagnosis and classification of headache. Prim Care. 2004;31(2):243-59. 2. McCaig LF, Nawar EW. National hospital ambulatory medical care survey: 2004 emergency department summary: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics; 2006. p. 372. 3. Friedman BW, Hochberg ML, Esses D, et al. 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