Archives of Academic Emergency Medicine. 2022; 10(1): e19 OR I G I N A L RE S E A RC H Propofol + Granisetron vs. Propofol + Metoclopramide in Symptom Management of Acute Migraine Headache; a Double-Blind Randomized Clinical Trial Samaneh Abiri1, Mehdi Chegin1, Reza Soleimani2, Naser Hatami2, Navid Kalani3, Esmail Rayatdoost1∗ 1. Department of Emergency Medicine, Research Center for Noncommunicable Diseases, Jahrom University of Medical Sciences, Jahrom, Iran. 2. Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran. 3. Research Center for Social Determinants of Health, Jahrom University of Medical Sciences, Jahrom, Iran. Received: January 2022; Accepted: February 2022; Published online: 5 March 2022 Abstract: Introduction: Acute headache is one of the most common reasons for emergency department (ED) visits. This study aimed to compare the combination of propofol and granisetron with propofol and metoclopramide in symptom management of acute migraine headache. Methods: In this double-blind randomized clinical trial, 60 adult patients with acute migraine headache who referred to ED were randomly divided into two groups of propofol + metoclopramide and propofol + granisetron. Pain and nausea/vomiting severity as well as blood pressure were compared between groups 30, 45, and 60 minutes after treatment. Results: The two groups had similar situation regarding mean age (p = 0.606), sex distribution (p = 0.793), baseline severity of pain (p = 0.642), frequency of nausea/vomiting (p = 0.488), and vital signs (p > 0.05). The severity of pain was similar in the two groups 30 (p = 0.731), 45 (p = 0.460), and 60 (p = 0.712) minutes after treatment. The number of patients with resistant nausea and vomiting 60 minutes after treatment was significantly higher in metoclopramide group (30.0% versus 10.0%; p = 0.033). Diastolic pressure 60 minutes after treatment (81.43 ±8.94 vs. 74.97 ± 4.8; p = 0.001) and heart rate 30 minutes after treatment (68.87 ±6.52 vs. 73.57± 7.62; p = 0.013) had statistically sig- nificant differences between the groups. Conclusion: The combination of propofol and granisetron was supe- rior to propofol and metoclopramide in case of controlling nausea and vomiting of cases with acute migraine headache; meanwhile, no differences were observed in case of pain relief and hemodynamic status between the two groups. Keywords: Propofol; granisetron; metoclopramide; migraine disorders Cite this article as: Abiri S, Chegin M, Soleimani R, Hatami N, Kalani N, Rayatdoost E. Propofol + Granisetron vs. Propofol + Metoclopramide in Symptom Management of Acute Migraine Headache; a Double-Blind Randomized Clinical Trial. Arch Acad Emerg Med. 2022; 10(1): e19. https://doi.org/10.22037/aaem.v10i1.1561. 1. Introduction Headache is one of the most common types of pain that make many patients go to pain clinics or emergency departments (ED). In the United States, 90% of the population experi- enced a headache, 50% of the population suffered from one type of headache, and 25% experienced recurrent and debil- itating attacks (1). According to a study done in the United ∗Corresponding Author: Esmail Rayatdoost; Department of Emergency Medicine, Jahrom University of Medical Sciences, Jahrom, Iran. Email: e.rayat.dost@gmail.com/ Tel: 00989177396014, ORCID: http://orcid.org/0000- 0002-9430-7913. States, headaches cost the US economy more than $50 billion a year, resulting in decreased work and educational efficiency as well as a significant increase in medical expenditures for the US health system. Migraine is the most frequent form of headache, and it can cause incapacity, as well as a loss of financial resources and a reduction in the efficiency of work and education. At least once a year, 15-20 percent of women and 6-10 per- cent of men suffer from migraines. It has been revealed that the age ranges of 25-55 years have the highest occur- rence (2). Migraine disorders, including classic migraine, are caused by spasms of cerebral arteries, and migraine pain is caused by subsequent dilation of extra cranial arteries (3). 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 S. Abiri et al. 2 Migraine headaches often present as one-sided, throbbing pains and are accompanied by nausea and vomiting, sensi- tivity to light, and fatigue (4-6). Current prophylactic treat- ments usually include dopamine receptor antagonists such as prochlorperazine or metoclopramide, which are often combined with diphenhydramine. Studies have shown that these drugs are safer and more effective than nonsteroidal anti-inflammatory drugs and sumatriptan (7-10). Metoclo- pramide stops the effects of dopamine on the central ner- vous system and other organs. Its effects on the medulla ob- longata (CTZ) region suggest that it is a beneficial antiemetic for nausea and vomiting, while it may be an 5-HT3 receptor antagonist. It should also be noted that granisetron is a po- tent selective 5-HT3 antagonist that is primarily used to treat nausea due to chemotherapy. Side effects include headache, diarrhea, constipation, anxiety, and insomnia (12). Another recommended treatment for acute migraine is an anesthetic agent called propofol. The mechanism of action of propofol is through its agonist activity on the gamma-Aminobutyric acid (GABA) aminobutyric acid (GABAA) beta 1 subunit, which leads to hyperpolarization and inhibition of neuronal stimulation (13). This study aimed to compare the use of propofol + granisetron with propofol + metoclopramide in symptom management of patients who referred to the emer- gency department (ED) with migraine headache. 2. Methods 2.1. Study design and setting The present study is a double-blind randomized clinical trial that was performed during a one-year period from June 2018 to June 2019 on patients with acute migraine headache who referred to ED of Peymaniyeh Hospital, Jahrom, Iran. Be- fore the patients were included in this study, the research process was explained and informed consent was obtained from them. Throughout the study, researchers adhered to the principles of Helsinki Declaration and confidentiality of patient information. All costs of the project were covered by the researchers and no additional costs were incurred by the patients. This study has been approved by the ethics committee of Jahrom University of Medical Sciences under the ethical code IR.JUMS.REC.1397.060 and has been regis- tered in the Iranian registry of clinical trials under the num- ber IRCT20201003048903N2. (Http: //www.irct .ir). 2.2. Participants Adult patients (18 years old or older) without history of head trauma in recent months, no abnormal neurological find- ings, and no hearing or verbal impairment with the criteria of migraine headache based on International Headache So- ciety’s definition (2 to 8 headache episodes per month in the previous 3 months, with or without aura) were included. Pa- tients with moderate to severe pain (Visual Analogue Scale (VAS) > 3) were included. Patients who had taken other med- ication for pain relief before presenting to the ED, those with history of allergy to the studied drugs, pregnant cases, cases with unstable hemodynamic or loss of consciousness, and fi- nally cases not agreeing to enter the study were excluded (14). 2.3. Intervention Patients were randomly divided into 2 groups: 1) propofol and granisetron and 2) propofol and metoclopramide, using simple random sampling method by tossing coins. The per- son performing the work steps, the person collecting the in- formation, and the patient were unaware of the type of drug used. All patients were under close clinical, electrocardiographic, pulse oximetry, and non-invasive blood pressure monitoring during the procedure. Patients in group one received intra- venous (IV ) bolus dose of 2 mg granisetron (Caspian Tamin Pharmaceutical Co., Iran) over 3 minutes plus 10 mg propo- fol 1% (Aram Pharmaceutical Co.,Ltd , Iran) over 3 minutes (every 5 to 10 minutes up to a maximum dose of 80 mg) through cephalic, basilic, or any available superficial veins of the hands; patients in group two received 10 mg meto- clopramide (Caspian Tamin Pharmaceutical Co., Iran) over 3 minutes plus 10 mg propofol 1% over 3 minutes (every 5 to 10 minutes up to a maximum dose of 80 mg). Propofol injec- tions continued until the headache resolved. 2.4. Outcomes Pain and nausea/vomiting management were considered as the primary measured outcomes of the study. Hemodynamic changes (blood pressure and heart rate) were considered as the secondary outcomes. Pain and nausea/vomiting severity were measured before the injection of the drugs and at intervals of 30, 45 and 60 min- utes after the injection. Nurses were blinded to type of treat- ment as medications were provided in syringes in packets and also patients did not know the exact medication type. We planned pethidine administration as the rescue treatment in cases of resistant pain. 2.5. Data collection The checklist designed by the researcher included demo- graphic information (age, sex), history of headache, severity of pain, nausea and vomiting score, and vital signs (systolic and diastolic blood pressure, heart rate). The severity of pain was assessed using a visual acuity pain score, in which zero indicates no pain and ten indicates unimaginable pain. Also, the score of nausea and vomiting (0 = without nausea and vomiting, 1 = mild nausea without the need for treat- ment or curable nausea, 2 = nausea that can be relieved with 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. 2022; 10(1): e19 Table 1: Comparing the baseline characteristics between the two groups Variable Granisetron Metoclopramide P* Age (year) Less than 30 3 (10.0) 1 (3.3) 30-50 14 (46.6) 16 (53.3) 0.606 More than 50 13 (43.3) 13 (43.3) Sex Male 17 (56.6) 18 (60.0) 0.793 Female 13 (43.3) 12 (40.0) Blood pressure (mmHg) Systolic 142.7±17 139.2 ±15.5 0.108 Diastolic 73.97 ± 4.8 75.43± 8.9 0.432 Heart rate (beats/minutes) Mean ± SD 69.87±6.52 70.87±6.52 0.371 Pain severity (VAS) Mean ± SD 5.5 ±2.29 5.2 ±2.4 0.642 Nausea/vomiting severity before treatment No nausea/vomiting 4 (13.3) 6 (20.0) 0.488 Treatable 26 (86.7) 24 (80.0) Data are presented as mean ± standard deviation (SD) or frequency (%). VAS: visual analog scale. Table 2: Comparing the outcomes between the two studied groups 30, 45, and 60 minutes after injections Variables Granisetron Metoclopramide P 30 minutes 3.87 ±2.06 4.1 ±2.2 0.731 45 minutes 3.3 ± 1.56 3.6 ±1.6 0.460 60 minutes 3.6 ±1.61 3.9 ±1.8 0.712 Systolic blood pressure (mmHg) 30 minutes 146.4 ±18.3 147.1 ±18.6 0.222 45 minutes 140. 4 ±15.2 140.1 ±14.9 0.344 60 minutes 145.8 ±18.5 147.1 ±18.6 0.113 Diastolic blood pressure (mmHg) 30 minutes 75.96 ± 4.79 77.43 ±8.94 0.433 45 minutes 76.97 ±4.8 78.43 ±8.94 0.188 60 minutes 74.97 ± 4.8 81.43 ±8.94 0.001 Heart rate (beat/minute) 30 minutes 68.87 ±6.52 73.57± 7.62 0.013 45 minutes 69.87±6.52 71.87±6.52 0.146 60 minutes 73.57±7.62 72.57±7.62 0.704 Nausea/vomiting 60 minutes after injection Mild 13 (43.3) 3 (10.0) Curable 7 (23.3) 9 (30.0) 0.033 Treatable 3 (10.0) 3 (10.0) Resistant 3 (10.0) 9 (30.0) Data are presented as mean ± standard deviation or frequency (%). VAS: visual analog scale. anti-nausea medication or treatable nausea, 3= interactable nausea and vomiting) was used for measuring the severity at baseline and 60 minutes after the treatment. 2.6. Data analysis Data analysis was performed using SPSS software version 21 and intention to treat analysis. Data were reported using mean ± standard deviation or frequency (percentage). Re- peated measurement Anova, chi-square, and independent t were used for comparisons. P <0.05 was considered as level of significance. Also, we calculated number needed to treat (NNT) and absolute risk reduction (ARR)(15). 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 S. Abiri et al. 4 Figure 1: The CONSORT flow chart of the randomized trial. 3. Results 3.1. Baseline characteristics 60 cases with acute migraine headache were randomly di- vided into two 30-case groups. Table 1 compares the baseline characteristics between groups. The two groups were simi- lar regarding mean age (47.43±15.25 in granisetron and 48.80 ±13.38 years in metoclopramide group; p = 0.606), sex distri- bution (p = 0.793), history of headache (p = 0.606), baseline severity of pain (p = 0.642), and vital signs (p > 0.05). Regard- ing nausea and vomiting, 4 patients in granisetron group and 6 patients in metoclopramide had no nausea and vomiting; while other patients needed treatment for nausea and vom- iting based on our scoring (p=0.488). 3.2. Outcomes Table 2 compares the outcomes between the two studied groups at different times after injections. The severity of pain was similar in the two groups at 30 (p = 0.731), 45 (p = 0.460), and 60 (p = 0.712) minutes after treat- ment. The number of patients with resistant nausea and vomiting 60 minutes after treatment was significantly higher in metoclopramide group (30.0% versus 10.0%; p = 0.033). Although there was a statistically significant difference be- tween the groups regarding diastolic pressure 60 minutes af- ter treatment (81.43 ±8.94 vs. 74.97 ± 4.8; p = 0.001) and heart 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 5 Archives of Academic Emergency Medicine. 2022; 10(1): e19 rate 30 minutes after treatment (68.87 ±6.52 vs. 73.57± 7.62; p = 0.013), these differences were not clinically important. The pain was relieved in all cases and no case needed res- cue treatment in the two groups. In granisetron group, in- tractable or resistant vomiting rate in 60 minutes was less than metoclopramide group (10% vs. 30%) with NNT of 5 (ARR=0.2). 4. Discussion The results of this study showed that the combination of propofol and granisetron has a similar effect to propofol and metoclopramide regarding pain management and a superior effect regarding controlling nausea/vomiting after 60 min- utes in patients presenting to ED following acute migraine headache. The two combinations had similar effects on vi- tal signs. The effects of metoclopramide and granisetron on migraine headaches and nausea in migraine sufferers were examined by Amiri et al. The level of pain was recorded using the VRS scale at intervals of 1 to 4 hours in this study, and the pa- tients’ nausea and vomiting condition was also assessed. The findings of Amiri et al.’s study were similar to ours in that the incidence of nausea and vomiting in the granisetron group was considerably lower than in the metoclopramide group at all time intervals after taking the medicine. Similar to our study, there was no significant difference in the incidence of headache between the two study groups (16). Medications used to treat migraines fall into two groups: sup- pressive or preventive. There are many options for treating acute migraine. In the present study, we focused on the com- bination of metoclopramide and granisetron with propo- fol for the treatment of headache, nausea, and vomiting in an acute migraine attack. Metoclopramide is an antiemetic agent that blocks dopamine and serotonin receptors in the CNS chemoreceptor hub receptor. Granisetron is a selec- tive 5-HT3 antagonist that binds to receptors in the periph- eral and central nervous systems with primary effects on the Golgi apparatus (17). Leyasin et al. concluded that granisetron and metoclo- pramide gel have similar effects in the management of post- operative nausea and vomiting in obstetric and gynecolog- ical surgeries and that granisetron has no superiority over metoclopramide in prevention of nausea and vomiting. In contrast, we found granisetron to be better than metoclo- pramide in treating migraine pain (18). Bojan Bagi and colleagues compared the effect of dex- amethasone in combination with metoclopramide and granisetron on postoperative nausea and vomiting. The re- sults of their study showed that the incidence of nausea and vomiting in the group receiving the combination of dexamethasone with metoclopramide was not significantly different from the group receiving granisetron. In fact, in this study, the effects of dexamethasone in combination with metoclopramide and granisetron in controlling nau- sea and vomiting after surgery were very similar and this study showed that the effectiveness of dexamethasone in combination with metoclopramide is not low compared with granisetron. This study was in line with the positive effects of granisetron and metoclopramide in controlling and reducing nausea and vomiting (19). Akerman et al. studied the effect of metoclopramide. It inhibits the excitability of vascular neu- rons, which is highly predictive of the anti-migraine action of this drug (20). Another study evaluated the antiemetic ef- fects of ondansetron and granisetron in preventing postop- erative nausea and vomiting in a patient undergoing laparo- scopic surgery. This study showed that the incidence of se- vere nausea and vomiting was 7% among patients receiving intravenous granisetron, followed by 20% in the ondansetron group and 50% in the placebo group (22). The results of this study are in line with our study regarding the effect of granisetron. In our study, the number of patients with severe nausea and vomiting resistant to treatment in the granisetron group was significantly lower than the number these patients in the metoclopramide group. We have shown that the effect of granisetron on nausea and headache is relatively higher than that of metoclopramide. In line with the results of our study, in a randomized double-blind study on 100 female pa- tients, the effect of granisetron and ondansetron in prevent- ing nausea and vomiting was evaluated in patients undergo- ing elective laparoscopic cholecystectomy. There was a sig- nificant difference between the two groups and the incidence of nausea and vomiting in the granisetron receiving group was significantly lower than the incidence of nausea and vomiting in the group receiving ondansetron (23). Gauchan et al. Evaluated the antiemetic effect of ondansetron and granisetron in patients undergoing laparoscopic cholecys- tectomy during the first 24 hours after anesthesia. They showed that granisetron was able to effectively reduce the in- cidence of nausea and vomiting compared to ondansetron in the first 24 hours (24). In line with the results of the present study, in another study by Savant et al., the effects of on- dansetron and granisetron on preventing nausea and vomit- ing in the patients undergoing oral and maxillofacial surgery were investigated. The results of this study showed that the incidence of nausea and vomiting in the granisetron group was significantly lower than ondansetron. Patients receiving granisetron showed a higher rate of a headache compared to the ondansetron group (25). In contrast, in our study the incidence of headache after drug injection was not signifi- cantly different from that of metoclopramide. In one study, Mohammed and colleagues examined the effects of meto- clopramide and ondansetron on the control of postopera- tive nausea and vomiting. The results of their study showed 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 S. Abiri et al. 6 that metoclopramide was more effective than ondansetron in controlling nausea and vomiting after surgery (26). This was also confirmed in Malekshoar et al.’s study(27). 5. Strength and Limitations The strength of this study was using the combination of these medications so that a statistically and clinically significant decrease in pain score was recorded in both groups. We did not record the number of propofol doses for each group to be able to compare the groups in this regard, this might have biased the conclusion. Another limitation of this study was the low number of patients, which might be a possible reason for the absence of difference in pain reduction properties of medications. Also, we did not assess the other patient char- acteristics as well as any painkiller being consumed before referral and time from initiation of symptom to presentation to ED. 6. Conclusion The results of this study showed that the effect of propo- fol and granisetron combination was similar to propofol and metoclopramide combination regarding pain manage- ment; but it had a superior effect regarding controlling nau- sea/vomiting after 60 minutes in patients presenting to ED following acute migraine headache. Both combinations had similar effects on vital signs. 7. Declarations 7.1. 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Comparing the effect of metoclopramide and promet- hazine on preventing nausea and vomiting after laparo- scopic cholecystectomy: A double-blind clinical trial. Koomesh journal. 2021;23(2):203-10. 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 Introduction Methods Results Discussion Strength and Limitations Conclusion Declarations References