Archives of Academic Emergency Medicine. 2019; 7 (1): e9 OR I G I N A L RE S E A RC H Oral Piracetam vs Betahistine in Outpatient Management of Peripheral Vertigo; a Randomized Clinical Trial Ali Arhami Dolatabadi1, Seyedeh Roghieh Larimi1, Arash Safaie2∗ 1. Emergency Department, Imam Hossein Hospital, Medical School, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Emergency Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. Received: October 2018; Accepted: December 2018; Published online: 23 January 2019 Abstract: Introduction: Although vertigo is a common complaint in patients presenting to the emergency department (ED), its ideal treatment is still under debate. This study was conducted to compare oral betahistine and oral piracetam in management of outpatients with peripheral vertigo. Methods: This was a randomized clinical trial performed on patients who were presented to the EDs of 4 teaching hospitals, with complaint of true ver- tigo. Patients were randomly allocated to either betahistine or piracetam group and their 7-day outcomes were compared. Results: 100 cases with the mean age of 54.72 ± 14.09 years were randomly allocated to either group (62.0% female). The two groups were similar regarding age, sex, and intensity of symptom at the time of present- ing to the ED. Twelve (24%) patients in piracetam group and 6 (12%) patients in betahistine group experienced adverse events (odds ratio: 2.32, CI 95%: 0.79-6.76; p = 0.125). There were 3 (6%) patients in each group that ex- perienced a recurrence of their symptoms and 2 (4%) patients in each group saw another physician for vertigo. Conclusion: Oral piracetam is a potentially proper treatment for management of peripheral vertigo and there are few adverse effects associated with it. Keywords: Vertigo; piracetam; betahistine; emergency medicine; treatment outcome Cite this article as: Arhami Dolatabadi A, Larimi S R, Safaie A. Oral Piracetam vs Betahistine in Outpatient Management of Peripheral Vertigo; a Randomized Clinical Trial. Arch Acad Emerg Med. 2019; 7(1): e9. 1. Introduction Vertigo is an illusion of movement when there is no motion (1, 2). It is a common complaint in patients presenting to the emergency department (ED) and categorized as periph- eral or central vertigo (1-3). Although ideally the underlying cause of vertigo should be treated, peripheral vertigo is usu- ally treated symptomatically. Different drugs from various pharmacologic categories are used to treat peripheral ver- tigo, including antiemetics, anticholinergics, antihistamines, and calcium channel blockers. Despite the availability of var- ious options for symptomatic treatment of vertigo, a drug of choice has not been defined yet. There are sometimes paradoxical data on the effectiveness of each drug for symp- tomatic treatment of vertigo (1, 4). Betahistine is one of the common medications, which is currently used to treat pe- ripheral vertigo. Piracetam is a cyclic derivative of neuro- ∗Corresponding Author: Arash Safaie; Sina Hospital, Imam Khomeini Av- enue, Tehran, Iran. Tel: +989111366966 Fax: +982163121413 Email: a- safaie@sina.tums.ac.ir transmitter gamma-aminobutyric acid, which might be ef- fective in treatment of vertigo (5-10). By using the combination of betahistine and piracetam in management of peripheral vestibular vertigo Oleg and col- leagues concluded that this combination may be more ef- fective than piracetam alone in this regard (11). Intravenous piracetam was as effective as intravenous dimenhydrinate in relieving symptom of vertigo patients in Dugan et al. study (12). However, the evidence regarding effectiveness of oral piracetam after acute manifestation of peripheral vertigo is sparse. Therefore, this study aimed to compare oral betahis- tine and oral piracetam in outpatient management of periph- eral vertigo. 2. Methods 2.1. Study design and setting This randomized clinical trial was conducted on patients who presented to the emergency departments of Imam Hos- sein, Shohadaye Tajrish, Loghman Hakim and Sina Hospi- tals, Tehran, Iran, throughout 2016, complaining from true vertigo. All of these hospitals are teaching hospitals. Eth- 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. Arhami Dolatabadi et al. 2 ical approval was obtained from Shahid Beheshti medical University ethics committee (IR.SBMU.SM.REC.1394.25) and the study was registered on Iranian registry of clinical trials with code number: IRCT2016011921063N3. Informed con- sent was obtained from each patient prior to his or her en- rollment in the study. 2.2. Participants Patients with acute vertigo who were discharged from the emergency department were included. Exclusion criteria were age below 18 years, prior history of sensitivity to be- tahistine or piracetam, consumption of drugs which can possibly improve vertigo (antihistamines, benzodiazepines or anticholinergics), history of peptic ulcer disease or pheochromocytoma, patients who did not give consent to participate in the study, patients with central vertigo and pa- tients who were lost to follow-up. 2.3. Intervention Patients were enrolled using convenience sampling method and were randomly assigned to either piracetam or be- tahistine group. Upon discharge, piracetam group pa- tients received 800 mg piracetam tablets (Darou Pakhsh Pharma Chem Co., Tehran, Iran) every 8 hours for 7 days and betahistine group patients received 8 mg be- tahistine tablets (Betaserc ®, Abbott Healthcare SAS, Chatillon-sur-Chalaronne, France) every 8 hours for 7 days. Simple randomization was done using a ran- dom numbers table, which was generated using Stattrek website “http://stattrek.com/statistics/random-number- generator.aspx”. 2.4. Outcomes The primary outcome was vertigo intensity control 7 days af- ter discharge from ED. The secondary outcomes were nausea and fatigue intensities control 7 days after discharge from ED, drug compliance, and adverse events. 2.5. Data gathering Data were acquired using face to face interview with patients at the times of presenting to ED and discharge from ED and using telephone interview 7 days after discharge. Patients’ vertigo, nausea, and fatigue intensities were investigated us- ing 10-point numeric rating scale (NRS). We asked patients about their compliance (taking piracetam or betahistine) us- ing 5-point Likert scale and the occurrence of any compli- cation while taking medications. Patients were asked about the recurrence of their vertigo symptoms, visiting another physician for vertigo or requiring hospitalization because of vertigo during the 7-day period after discharge from ED. An emergency physician and a 3r d year emergency medicine resident were responsible for patients’ allocation and data flowchart 1: CONSORT flow diagram of the studied patients. gathering. The prescribing physicians and the patients were not blinded. However, both the physician who interviewed the patients 7 days after their discharge and the statistical ana- lyst were blinded to the prescribed drug. 2.6. Statistical Analysis We analyzed data using SPSS software version 21 and inten- tion to treat analysis method. Categorical data were analyzed using chi-square or Fisher’s exact tests. Quantitative data were analyzed using t-test, Mann-Whitney or Kruskal-Wallis tests. The sample size of 48 patients in each group was calculated. Failure to control symptoms was defined as score ≥ 3 7 days after taking medicines. P < 0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics One hundred twenty-two patients were assessed for eligibil- ity, out of which 18 cases were excluded for various reasons (flowchart 1). There were 4 (3.8%) cases of loss to follow up. Finally, 100 cases with the mean age of 54.72 ± 14.09 (18-90) years were randomly allocated to each group (62.0% female). Baseline characteristics of the studied patients are compared in table 1. The two groups were similar regarding age, sex, and intensity of symptom at the time of presenting to the emergency department and discharge. 3.2. Outcome There were no statistically significant differences between two groups regarding intensity of vertigo, nausea and fa- tigue 7 days after discharge from ED. Twelve (24%) patients in piracetam group and 6 (12%) patients in betahistine group experienced adverse events (odds ratio: 2.32, CI 95%: 0.79- 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): e9 Table 1: Baseline characteristics of the studied patients Variables Groups P Piracetam n=50 Betahistine n=50 Age 56.36 ± 12.92 53.08 ± 15.13 0.245 Sex Male 21 (42.0) 17 (34.0) 0.268 Female 29 (58.0) 33 (66.0) Intensity of symptom (on presentation) Vertigo 8.36 ± 1.98 8.44 ± 1.63 0.844 Nausea 8.24 ± 2.50 7.52 ± 2.87 0.136 Fatigue 4.98 ± 3.18 5.16 ± 2.92 0.723 Intensity of symptom (on discharge) Vertigo 1.82 ± 1.08 1.58 ± 0.73 0.397 Nausea 1.22 ± 0.55 1.26 ± 0.44 0.455 Fatigue 1.42 ± 1.07 1.22 ± 0.55 0.415 Data are presented as mean ± standard deviation or frequency (%). Table 2: Comparing the outcomes between the two groups 7 days after discharge from emergency department Outcome Groups P Piracetam n=50 Betahistine n=50 Vertigo Intensity 1.78 ± 1.38 1.84 ± 1.20 0.648 Success 48 (96.0) 48 (96.0) 0.691 Failure* 2 (4.0) 2 (4.0) Nausea Intensity 1.12 ± 0.52 1.10 ± 0.21 0.987 Success 49 (98.0) 50 (100.0) 0.500 Failure* 1 (2.0) 0 (0) Fatigue Intensity 1.28 ± 0.67 1.36 ± 1.41 0.437 Success 49 (98.0) 48 (96.0) 0.500 Failure* 1 (2.0) 2 (4.0) secondary outcomes Drug compliance 4.52 ± 0.58 4.58 ± 0.50 0.713 Adverse events 12 (24.0) 6 (12.0) 0.125 *: score ≥ 3 seven days after discharge. Data are presented as mean ± standard deviation or frequency (%). 6.76; p = 0.125). There were 3 (6%) patients in each group who experienced a recurrence of their symptoms and 2 (4%) patients in each group saw another physician for vertigo. The symptoms of one patient in the piracetam group were so se- vere that required hospitalization on the 7t h day after dis- charge from ED. There was not any significant difference be- tween groups regarding failure to control symptoms. 4. Discussion Based on the findings, there was not any significant differ- ence between oral betahistine and oral piracetam regarding recurrence, relieving vertigo, nausea, and fatigue symptoms 7 days after discharge from ED. Adverse events in the two groups were comparable as well. Despite being a common presentation in both ED and general settings, the ideal treat- ment for vertigo is still under debate (1, 4). Betahistine dihy- drochloride is a drug with structural similarity to histamine (13, 14). Betahistine is a strong H3 receptor antagonist and a weak H1 receptor agonist, which is relatively inactive at H2 receptor (13-15). Betahistine increases cochlear blood flow via H3 receptor antagonism (16). It also increases histamine turnover in central and vestibular nervous systems and de- creases vestibular sensory input through the same mecha- nism. Betahistine has excitatory effects on cortical and sub- cortical neuronal activity by H1 receptor agonist (13-15). Be- tahistine has been used for treating vertigo for years and its effectiveness was shown in many studies (7, 13-15, 17-22). In a Cochrane review conducted by Murdin, 16 studies compar- ing betahistine and placebo in different vertigo types were included. Pooled data showed that betahistine was better than placebo in reducing vertigo symptoms and the propor- tion of patients reporting an overall reduction of their ver- tigo symptoms was higher in the betahistine group (risk ra- 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. Arhami Dolatabadi et al. 4 tio (RR)= 1.30, 95% confidence interval (CI)= 1.05 to 1.60). However, statistical heterogeneity of data was high. The most common adverse effects were gastrointestinal symp- toms and headache, which were statistically similar in both groups (16% in betahistine group and 15% in placebo group and RR= 1.03, 95% CI= 0.76 to 1.40). Authors concluded that low quality evidence suggests that betahistine may have a positive effect on reduction of vertigo symptoms and there is a low risk of adverse events associated with betahistine (13). It has been shown that piracetam might be effective on both chronic and acute vertigo (6-10, 23). Although the exact mechanism by which piracetam affects vertigo is not determined yet, it seems to be due to an increase in vestibu- lar compensation by exerting effects on neurotransmission and microcirculation; which result from its effects on cell membrane fluidity (8, 10, 24, 25). There are previous stud- ies, which have evaluated the effectiveness of piracetam in various vertigo settings. Ozdemir and Dogan compared in- travenous piracetam with intravenous dimenhydrinate in the acute setting in two separate studies. Both studies showed that intravenous piracetam and intravenous dimenhydrinate have similar effectiveness in improving acute vertigo (6, 9). In a study by Akdogan, oral piracetam and placebo were com- pared in chronic vertigo lasting more than 3 months. Pirac- etam was more effective than placebo in treating all of the symptoms (5). In a sub-analysis of data from OSVaLD study, which was conducted by Melnikov, it was shown that pirac- etam and betahistine combination therapy is more effective than treatment with betahistine alone in patients with pe- ripheral vestibular vertigo(7). Rosenhal evaluated the effec- tiveness of betahistine in comparison with placebo for treat- ing chronic vertigo in a multicenter, randomized clinical trial. Piracetam was more effective than placebo in decreasing fre- quency of vertigo episodes, interval malaise, and imbalance (10). In a study by Ince Gunal, Patients with autosomal dom- inant cerebellar ataxia were given intravenous piracetam. It was shown that piracetam causes improvement in posture and gait disturbances of these patients (23). It seems that oral piracetam is an alternative choice for treatment of periph- eral vertigo and should be considered for in- and out-patient management of peripheral vertigo. 5. Limitation The patients and allocating physician were not blinded to the prescribed drugs. There was no placebo group in the study. We cannot rule out the probability of spontaneous recovery of vertigo, nausea and fatigue symptoms of the patients in the seven-day period after the initial presentation to ED. Because of the small sample size and differences in the settings of pre- vious studies, it is hard to reach a definite conclusion about the role of piracetam in vertigo treatment. It seems that there is a need for larger, multicenter studies and meta-analyses for a strong conclusion. 6. Conclusion Based on the findings, there was not any significant differ- ence between oral betahistine and oral piracetam regarding recurrence, relieving vertigo, nausea, and fatigue symptoms, as well as adverse events 7 days after discharge from ED. 7. Appendix 7.1. Acknowledgements The authors wish to thank all Emergency Department staff of Imam Hossein, Shohadaye Tajrish, Loghman Hakim and Sina Hospitals for their contribution. This article is extracted from the residency thesis of Seyedeh Roghieh Larimi. 7.2. Author contribution Ali Arhami Dolatabadi: idea development, and supervising the team. Seyedeh Roghieh Larimi: patient allocation, initial interview, and writing the manuscript. Arash Safaie: follow up interview with the patients, statistical analysis, and writing the manuscript. Authors’ ORCIDs Ali Arhami Dolatabadi: 0000-0001-9492-9520 Arash Safaie: 0000-0002-1127-6681 7.3. Funding/Support None. 7.4. Conflict of interest None. References 1. Omron R. Peripheral Vertigo. 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