Emergency. 2018; 6 (1): e43 OR I G I N A L RE S E A RC H Intravenous Haloperidol versus Midazolam in Manage- ment of Conversion Disorder; a Randomized Clinical Trial Mohammadali Jafari1, Amir Aliheidari Biuki1∗, Majid Hajimaghsoudi2, Mehdi Bagherabadi1, Ehsan Zarepur3 1. Emergency Medicine department, Shahid Sadoughi Hospital, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 2. Emergency Medicine Department, Shahid Sadoughi Hospital, Trauma Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. 3. Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. Received: April 2018; Accepted: July 2018; Published online: 14 July 2018 Abstract: Introduction: Conversion disorder is a condition in which the patient shows psychological stress in physical ways. This study aimed to compare the effects of haloperidol versus midazolam in patients with conversion disorder. Methods: This double-blind randomized clinical trial was conducted on patients with conversion dis- order who had presented to the emergency department, throughout 2015. Patients were randomly divided into two groups and were either treated with 2.5 mg of intravenous (IV ) haloperidol or 2.5 mg of IV midazolam. Re- covery rate, time to recovery, and side effects of both drugs 1 hour, 24 hours, and 1 week after treatment were compared using SPSS19. Results: 140 patients were divided into two groups of 70. There were no significant differences between the groups regarding the baseline characteristics. 12 (17.1%) patients who were treated with IV haloperidol experienced drug side effects within 1 hour and 12 (17.1%) within 24 hours, while only 3 (4.3%) patients in IV midazolam experienced side-effects within 1 hour after drug administration (p = 0.026). The symptoms of the disease subsided in 45 (success rate: 64.3%) patients in midazolam and in 64 (success rate: 91.5%) participants in haloperidol group (P<0.001). Mean recovery time was 31.24 ± 7.03 minutes in IV mida- zolam and 30.53 ± 7.11 minutes in IV haloperidol group (p = 0.592). Absolute risk reduction (ARR) of treating patients with haloperidol compared to midazolam is about 27%. Conclusion: The response of patients to treat- ment with haloperidol is clearly better than midazolam. Although more transient and minor side-effects were observed in the group treated with haloperidol compared to midazolam group, serious side-effects were rare for both treatments. Keywords: Conversion disorder; hysteria; Haloperidol; Midazolam; side effects; intravenous © Copyright (2018) Shahid Beheshti University of Medical Sciences Cite this article as: Jafari M, Aliheidari Biuki A, Hajimaghsoudi M, Bagherabadi M, Zarepur E. Intravenous Haloperidol versus Midazolam in Management of Conversion Disorder; a Randomized Clinical Trial. Emergency. 2018; 6(1): e43. 1. Introduction A large number of patients with physical manifesta- tions of underlying psychological disorders present to the emergency department annually (1). Conver- sion disorder (CD) or hysteria is a diagnostic category de- fined in some psychiatric classification systems under the main branch of somatoform disorders. This disorder is more prominent in women, early adulthood, and uneducated pa- ∗Corresponding Author: Amir Aliheidari Biuki; Emergency Medicine depart- ment, Shahid Sadoughi Hospital, Ibn Sina St., Riazi Sq., PO Box 8915887857, Yazd, Iran. Tel/Fax: 0098 353 8224000 E-mail: amir6381@gmail.com tients. The symptoms may be established unconsciously and involuntarily (2). This illness is more frequent in histri- onic personalities. Clinical signs of the disease include a wide range of different organs being involved: Movement disorders including paralysis, ataxia, and aphonia, sensory disorders including blindness, anosmia and Stocking-Glove paresthesia, and consciousness disorders including coma and pseudo-seizure (3-6). Based on studies in non-emergent cases, the best management for long-term treatment is be- havioral therapy accompanied by treating other underling psychological impairments (4-6). However, the management of patient’s signs and symptoms in the emergency depart- ment is quite necessary because it helps the patients 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: www.jemerg.com M. Jafari et al. 2 their families to overcome one of the most stressful situa- tions they have ever been faced with. So, administration of the required drugs is essential to alleviate the symptoms as soon as possible. Since years ago, administration of haloperi- dol and some types of benzodiazepines like Lorazepam and Diazepam as well as Lithium and Sodium valproate was a common practice in management of psychiatric emergen- cies, particularly in conversion disorders, and their efficacies have been approved so far (7, 8). Considering the high frequency of patients with psycholog- ical or neurological problems, especially conversion disor- ders, admitted to emergency departments and the urgent need to reduce the severity of symptoms in order to tranquil- ize tremulous patients and their relatives, and since haloperi- dol has more side-effects than midazolam, which has a rapid effect and is available in most cases (2, 6, 7), we de- cided to evaluate and compare the effects of intravenous (IV ) haloperidol and midazolam in patients with conversion dis- orders presenting to emergency departments. 2. Methods: 2.1. Study Design and setting This double-blind parallel randomized clinical trial was con- ducted on 140 patients with conversion disorder (based on DSM-IV, Diagnostic and Statistical Manual of Mental Dis- orders, 4th Edition) who had presented to emergency de- partment of Shahid Sadoughi Hospital, Yazd, central Iran, in 2015. The protocol of this research project was approved by the Ethics Committee of Shahid Sadoughi University of Medical Sciences and registered on Iranian Registry of Clini- cal Trial (Trial registration number: IRCT 2015100712050N2). We did not perform any additional invasive procedures and patient’s written consent was taken. The purpose of the study was explained to the patients. A written consent form was obtained from all patients and patients’ information re- mained confidential. Patients were informed of the probable drug side-effects and recommended to come back in case of the mentioned complications happening. Ethical issues re- lated to human studies (according to the Helsinki Statement) were considered. 2.2. Participants All patients aged 18 to 60 years who met the following in- clusion criteria were enrolled in the study: any alteration or impairment in daily performances, an experience of recent emotional stress, a symptom or deficit that could not be ex- plained by another medical or mental disorder, and a symp- tom or deficit that was not restricted to pain or sexual disor- ders. The exclusion criteria were as follows: patients with ab- normal vital signs, pregnant or lactating women, addicted patients, patients with known hepatic or renal failure, se- vere cardio-pulmonary impairment, cases of parkinsonism, a history of recent seizure or patients who were taking anti- epileptic agents, long Q-T syndrome, having allergies to neu- roleptics or benzodiazepines, a history of psychiatric disor- ders, and patients who did not sign the informed written con- sent. 2.3. Procedures After patients’ admission to the emergency department, conversion disorder diagnosis was made by an emergency medicine specialist, based on DSM-IV, Diagnostic and Sta- tistical Manual of Mental Disorders, 4th Edition. After evalu- ating eligibility criteria, history taking and physical examina- tion were done by an emergency medicine resident and the data were recorded. The participating patients were randomly assigned to the two groups based on the table of random numbers by an in- dependent physician blind to the study (random sequence number generation was done by a computer). 2.5 mg of IV haloperidol (HALODIC, 5 mg/1mL, Exir Pharma- ceutical Co.) was administered to the patients in group A and 2.5 mg of IV midazolam (Midazolam Aburaihan, 5 mg/1ml, Aburaihan Pharmaceutical Co.) was prescribed for patients in group B (based on reliable guidelines). The drugs were administered to the patients by a trained nurse, and the as- sessor was blind. After drug administration, all patients re- mained under direct supervision of an emergency medicine resident with concurrent cardiac monitoring (heart rate, O2 saturation, diastolic blood pressure, systolic blood pressure). The patients were followed up through the next 24 h and 1 week after treatment. The outcomes were recorded. All pa- tients and emergency staff including physicians, nurses, and researchers were blind to the therapeutic groups. 2.4. Data Gathering A questionnaire was completed for all the patients including demographic data, marital status, level of education, recent emotional stress, taking medications, underlying physical ill- ness, movement disorders, sensory disorders, consciousness disorders, recovery rate, time of recovery, and side-effects in both groups. A trained emergency medicine resident was re- sponsible for data gathering. 2.5. Outcome Recovery rate (acute symptoms subsiding), time to recov- ery, and side-effects of haloperidol (extrapyramidal and an- ticholinergic side-effects, and hypotension) and midazolam (decreased respiratory rate, apnea, drowsiness, nausea, vom- iting) at 1 hour, 24 hours, and 1 week after treatment were considered as main study outcomes and compared between the groups. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 3 Emergency. 2018; 6 (1): e43 Figure 1: Follow-up of candidates for receiving intravenous haloperidol or midazolam (according to consort statement). 2.6. Statistical analysis The participants were selected via convenience sampling method. The sample size was determined to be at least 52 patients in each group and it was achieved by 95% confi- dence coefficient (α=0.05) and power of 80% (β=0.2); how- ever, 70 subjects were included in each group. The data were analyzed by an experienced statistics consultant. All the col- lected data were imported to SPSS19 (IBM, SPSS statics for windows, Armonk, IBM Corp.) and analyzed using statisti- cal tests. Mean and standard deviation (SD) for quantitative variables and frequencies (percentages) for qualitative vari- ables were calculated. To compare the quantitative variables between two groups, independent Student’s t-test (or Mann- Whitney test) was used and categorical variables were com- pared between the two groups using the Chi-square test. P < 0.05 was considered as statistically significant. 3. Results 3.1. Baseline characteristics 140 patients with conversion disorder manifestations were enrolled (Figure 1). Patients were randomly divided into two groups of 70: group A who were treated with haloperidol, and group B who received midazolam. The mean age of patients in midazolam and haloperidol groups was 29.67± 7.50 and 29.54 ± 7.22 years, respectively (p = 0.918). Table 1 compares the baseline characteristics of studied patients between the groups. There were no significant differences between the groups regarding the means of educational level (p = 0.988), marital status (p = 1.00) and sex (p = 0.365). 3.2. Outcomes 12 (17.1%) patients who were treated with IV haloperidol experienced drug side-effects within 1 hour and 12 (17.1%) within 24 hours, while only 3 (4.3%) patients in IV midazolam This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com M. Jafari et al. 4 Table 1: Comparing baseline characteristics of patients with conversion disorder treated with IV midazolam (n = 70) and IV haloperidol (n = 70) Variable Midazolam Haloperidol P Age (year) Mean ± SD 29.67 ± 7.50 29.54 ±7.22 0.918 Sex Male 29 (41.4) 26 (37.1) 0.365 Female 41 (58.6) 44 (62.9) Marital status Single 23 (32.9) 24 (43.3) 1.000 Married 47 (67.1) 46 (65.7) Level of education Uneducated 4 (5.7) 4 (5.7) Junior school 30 (42.9) 28 (40.0) 0.998 High school 23 (32.9) 24 (43.3) Bachelor and higher 13 (18.6) 14 (20.0) Recent emotional stress Yes - - - No 70 (100.0) 70 (100.0) Taking medications Yes - - - No 70 (100.0) 70 (100.0) Underlying physical illness Yes - - - No 70 (100.0) 70 (100.0) Movement disorders No 44 (62.9) 43 (61.4) Paralysis 16 (22.9) 15 (21.4) 0.893 Aphonic 10 (14.3) 12 (17.1) Sensory disorders No 54 (77.1) 53 (75.7) 1.000 Stocking-glove 16 (22.9) 17 (24.3) Consciousness disorders No 42 (60) 44 (62.9) Coma 13 (18.6) 14 (20) 0.812 Seizure 15 (21.4) 12 (17.1) Vital signs Heart Rate 79.59 ± 4.14 79.60 ± 3.99 0.983 O2 Saturation 95.39 ±1.19 95.41 ± 1.25 0.891 DBP 76.43 ± 7.80 76.57 ± 7.64 0.913 SBP 117.86 ± 8.14 118.43 ± 8.45 0.684 Data were presented as mean ± standard deviation or frequency (%). DBP: Diastolic blood pressure, SBP: Systolic blood pressure. experienced side-effects within 1 hour after drug administra- tion (p = 0.026). The symptoms of the disease subsided in 45 (success rate: 64.3%) patients in midazolam and 64 (success rate: 91.5%) patients in haloperidol group (P<0.001). Mean recovery time was 31.24 ± 7.03 minutes in IV midazolam and 30.53 ± 7.11 minutes in IV haloperidol group (p = 0.592). Ab- solute risk reduction (ARR) of treating patients with haloperi- dol compared to midazolam is about 27%. 4. Discussion The results of this clinical trial showed that the success rate of IV haloperidol in managing conversion disorder is signif- icantly higher than midazolam (91.5% versus 64.3%). How- ever, patients who were treated with IV haloperidol expe- rienced more transient and minor side-effects 1 hour, 24 hours, and 1 week after treatment. Serious side-effects for both treatments were rare. In a study conducted by Esmailian et al. (2015) the efficacy and safety of haloperidol and midazolam have been evalu- ated in management of 48 patients with manifestations of conversion disorder, who were admitted to the emergency department. The efficacy of both drugs in alleviating the symptoms of the disease was reported to be the same (9). In another study conducted by Nobay et al. (2003), the effects of 3 medications including midazolam, haloperidol, and Lo- razepam were evaluated in patients with behavioral disor- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com 5 Emergency. 2018; 6 (1): e43 ders. The results showed that the efficacy of all 3 drugs was the same (10). The effects of haloperidol plus promethazine vs midazolam were investigated in sedation of agitated pa- tients presenting to the psychiatric emergency room in an- other study. Their study showed that both treatments were effective (11). The difference between the results of this study and previous studies almost all of which indicate that mida- zolam is more effective on psychological stresses, may be at- tributed to the design and the drugs used. In addition, our study was held in the emergency department of a large teach- ing hospital in South and South East of Iran with a high fre- quency of new patient admission. This means that the re- searchers of the study were often under excessive pressure and that they may have been at the risk of over-assessment (12). Despite the complications of haloperidol, it is currently still the drug of choice in emergency situations (13). In the mid-1980s, several studies looked at the effect of haloperidol in treatment of devastating diseases (10, 14). In this study, we observed that haloperidol is effective in 91.5% of cases. However, midazolam was only effective in 64.3% of patients. In another study, similar results have been reported in 81 patients. In addition, further research is re- quired to discover drugs with faster and better effect to use in combination with other drugs (15). The present study investigated the clinical effects of mida- zolam and haloperidol in patients with conversion disorder at 1 h, 24 h and one week after administration. In the two intervals of 1 and 24 h after initiation of treatment, the side- effects of haloperidol were significantly higher than midazo- lam. Contrary to the results of the present study, Huf et al. (2003) reported that side-effects of haloperidol plus promet- hazine are not significantly more than midazolam in patients with conversion disorder (11). In another study, Powney et al. (2012) reported the results of 32 previous studies that mea- sured the effects of haloperidol compared to other therapies. According to the study, two clinical trials have reported that patients in the haloperidol group had experienced one or more adverse events compared to the placebo group (n=395, RR=1.64, CI 1.2323-2.20) (16). According to the results of the present trial as well as previ- ous studies, it is clear that the probable side-effects of both drugs are mostly seen within the first few minutes after ad- ministration. In the study by Huf et al. (2003), it is re- ported that both cases of severe side-effects occurred in the first 20 min after injection of haloperidol and midazolam and they have been associated with other factors. So, preparing for probable side-effects in the first few minutes after injec- tion as well as considering the patient’s clinical records such as a history of epilepsy or drug consumption are necessary (11). It suggested that future studies investigate the sedation speed, type and severity of side-effects, and optimal dose of haloperidol and midazolam, and the effect of combination therapy with haloperidol and midazolam in patients with conversion disorder. In addition, to assess the possible in- fluence of stressful situations in emergency department, do- ing further studies in other wards of the hospital with calmer conditions is recommended. 5. Limitation Sedation speed and severity of side-effects were not investi- gated in this single-center study. The main limitation of the present study was that we did not consider a group treated by combination therapy with haloperidol and midazolam. 6. Conclusion Based on the results, the response of patients to treatment with haloperidol is clearly better than midazolam. Although transient and minor side-effects in the group treated with haloperidol were more than midazolam, serious side-effects were rare for both treatments. 7. Appendix 7.1. Acknowledgements We would like to thank the patients for their cooperation and their families for assistance. Also, we would like to thank the staff of Shahid Sadoughi Hospital, Yazd, Iran. We also thank the hospital staff and authorities for their support. 7.2. Author’s contribution All the authors meet the standard criteria of authorship based on the recommendations of the international committee of medical journal editors. 7.3. Funding/Support This study enjoyed the support of the staff of Shahid Sadoughi Teaching Hospital affiliated to Shahid Sadoughi University of Medical Sciences. We used the equipment and facilities of this hospital. Dr. Aliheidari provided the financial support. 7.4. Conflict of interest All authors declare that they have no conflicts of interest. References 1. American Psychiatric Association. Diagnostic and Statis- tical Manual of Mental Disorders, Fifth Edition. Washing- ton, DC: American Psychiatric Association. 2013. 2. 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Ochsner J. 2013;13(2):214-23. 16. Powney MJ, Adams CE, Jones H. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev. 2012;11:CD009377. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: www.jemerg.com Introduction Methods: Results Discussion Limitation Conclusion Appendix References