Emergency (****); * (*): *-* This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2014 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 77 Emergency (2014); 2 (2): 77-80 ORIGINAL RESEARCH Comparison of Intravenous Ketamine with Morphine in Pain Relief of Long Bones Fractures: a Double Blind Randomized Clinical Trial Saeed Majidinejad, Mehrdad Esmailian, Mehrdad Emadi* Department of Emergency Medicine, Isfahan University of Medical Sciences, Isfahan, Iran Abstract Introduction: The selective medication for pain control in many clinical situations is morphine but its complica- tions prevent its widespread use. Ketamine has been introduced as an alternative for morphine in some studies. However, the efficacy of its solitary use has not yet been evaluated. Therefore, the present study was undertaken to evaluate the effect of ketamine alone in relieving pain in trauma patients referring to an emergency unit. Methods: In this double-blind clinical trial, patients with long bone fractures were randomly divided into two groups of treatment with intravenous (IV) morphine at a dose of 0.1 mg/kg and treatment with IV ketamine at a dose of 0.5 mg/kg. Pain severity of the patients was recorded before and 10 minutes after injection based on nu- meric rating scale. The means in the two groups were compared using independent t-test. Then the Kaplan-Meier curve and log rank analysis were used to evaluate the success of treatment. Results: 126 patients were included in this study. The mean ages of the patients in the morphine and ketamine groups were 33.6±14.3 and 35.1±13.5 years, respectively (P=0.54). After therapeutic intervention, the pain severity significantly decreased in ketamine (2.7±1.8; P<0.0001) and morphine (2.4±1.5; P<0.0001) groups, with a similar effect of both medications on alle- viating pain (P=0.28). The success rate of the treatment at 10-minute interval in groups receiving ketamine and morphine were 59 (93.65%) and 61 (96.8%) patients, respectively (P=0.62). Conclusion: The results of the pre- sent study showed that administration of ketamine at a low dose (0.5 mg/kg) results in a significant decrease in the severity of acute pain in patients with fractures of long bones. This palliative effect is very similar to that of morphine. Key words: Bone fracture; pain management; analgesia; ketamine; morphine Cite this article as: Majidinejad S, Esmailian M, Emadi M. Comparison of intravenous ketamine with morphine in pain relief of long bones fractures: a double-blind randomized clinical trial. Emergency. 2014;2(2):77-80. Introduction:1 ractures have a high incidence rate in traffic acci- dents and are one of the three most important complications during accidents (1). Each year millions of people all over the world suffer from bone fractures, the complications of which threaten the pa- tients’ health for several years (2, 3). One of the most important measures in the management of such pa- tients in the emergency unit is fixation and pain control. Opioids are one of the main and most effective medica- tions to relieve pain (4, 5) by suppression of pain center in the CNS through stimulation of µ and δ receptors. However, complications such as dependence, tolerance, suppression of respiratory center and activation of vomiting center are some of their problems (6). Other medications are NSAIDs, which prevent synthesis of *Corresponding Author: Mehrdad Emadi; Department of emergency medicine, Al-Zahra Hospital, Soffeh Blvd, Isfahan, Iran. Tel: +989133275409; Fax:+983116685555 Email: emadimehrdad66@yahoo.com Received: 13 March 2014; Accepted: 16 May 2014 prostaglandin E2 by inhibiting cycloxygenase. Nonethe- less, this group of medications has gastrointestinal complications and even some of them exhibit renal and hepatic toxicity (7). Paracetamol, Aminophylline, Tra- madol, Nefopam etc are some other drugs that have been evaluated in different studies for pain relief. Apart from these medications, ketamine is another medica- tion, which has been introduced. It is one of the medica- tions, which is used for general anesthesia and sedation. Ketamine is an antagonist of N-methyl-D-aspartate (NMDA) (8, 9) and is used in IV, intramuscular, enteric, subcutaneous, intra-nasal, rectal and epidural forms. However, at higher doses it can have complications such as hallucination, dysphoria, nightmares, an in- crease in intracranial pressure, hypertension, tachycar- dia, tremors and clonic-tonic seizures (10, 11). Several studies have shown that ketamine is effective in pain relief; however, in the majority of studies available, ket- amine has been used in conjunction with other analge- sics and no study is available in which use of this medi- cation alone has been comprehensively evaluated for F This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2014 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Majidinejad et al 78 pain relief. On the other hand, studies available have not evaluated the use of this medication in trauma pa- tients in emergency units. Therefore, the present study was designed to evaluate the effect of ketamine alone on pain relief in trauma patients referring to an emer- gency unit of a third-level hospital. Methods: Study design and setting The present double-blind clinical trial was carried out in 2012-2013 in Al-Zahra and Ayatollah Kashani Educa- tional Centers in Isfahan, Iran. The subjects consisted of patients with fractures of long bones, referring to the emergency unit. The patients were included in the study consecutively. The protocol of the study was ap- proved by the Ethics Committee of Isfahan University of Medical Sciences. The Helsinki Research Protocol was observed during the whole study period. The study was registered in Iranian registry of clinical trial (IRCT number: IRCT2015042812072N3). Subject The inclusion criteria consisted of an age range of 18-55 years, fractures of long bones and consent to participate in the study. Exclusion criteria consisted of drug abuse, trauma to the head, symptoms and signs of increased intracranial pressure, a decrease in consciousness level, respiratory problems, a history of asthma, contraindica- tions for ketamine (i.e. a history of cardiac problems, especially congestive heart failure, ischemic cardiac conditions, hypertension and patients with cerebrovas- cular attack) and morphine (i.e. asthma, respiratory problems, hemodynamic instability). In addition, in case of any allergic reaction to any of the medications used, the patient was excluded from the study. The sample size was estimated at 63 subjects in each group based on numeric rating scale (NRS) at 95% confidence inter- val, a study power of 80%, a standard deviation of 1.6 for pain severity and a minimum difference significance of 2 between the two groups (12). Intervention First the patients’ demographic and clinical data were recorded, which consisted of background diseases, drugs taken, drug abuse, drug allergies, the last meal eaten, location of fracture and severity of pain. Then the eligible patients were randomly divided into two groups: the group receiving IV morphine at a dose of 0.1 mg/kg and the group receiving IV ketamine at a dose of 0.5 mg/kg. To make sure of the double-blind protocol of the study, preparation of the solutions, injections and registration of the results were carried out by three different physicians who had no contact or relationship with each other. The data on the injection of medica- tions were available only to the chief researcher and the medical care personnel were granted access to such data only when drug complications arose. In such a case, the patient in question was excluded from the study. The severity of pain was registered before injec- tion and 10 minutes after injection based on NRS (13). In cases in which pain did not subside after 10 minutes (a decrease in pain severity equal to or less than 3), the patient received half the initial dose again. Finally, drug side effects in patients were evaluated and recorded. Statistical analysis Data were entered into SPSS 11.5 and were analyzed after being transferred to STATA 11.0 software. The severity of pain before administration of medications and 10 minutes after initiation of treatment, was re- ported as means ± standard deviations and analyzed using independent t-test. Then Kaplan-Meier curves and log rank analysis were used to evaluate the success of treatment, which was defined as a decrease of 3 scores in pain severity. Statistical significance was set at P<0.05 in all the analyses. Results: 126 patients were included in the study and randomly divided into two equal groups of morphine and keta- mine. The mean ages of the patients in the morphine and ketamine groups were 53.6±14.3 and 35.1±13.5 years, respectively (P=0.54). Forty-five (71.4%) and 51 (80.95%) patients were male in the ketamine and mor- phine groups, respectively (P=0.21). Table1 shows the site of fractures. The mean pain severity scores at ad- mission in the ketamine and morphine groups were 8.8±0.8 and 8.95±0.8, respectively (P=0.32). After ther- apeutic intervention, the severity of pain decreed signif- icantly in the ketamine (2.7±1.8; P<0.001) and mor- phine groups (2.4±1.5; P<0.001), with no significant differences between the two groups (P=0.28), indicat- ing that both medications are equally effective in allevi- ating pain (Figure 1). Kaplan-Meier curve showed that five minutes after initiation of injection, ketamine and morphine resulted in a successful decrease in pain se- verity in 33 (52.4%) and 38 (60.3%) patients, respec- tively. This rate increased to 59 (93.65%) and 61 (96.8%) patients, respectively, after 10 minutes. Log rank test did not show any significant difference in suc- cess rates between the two groups (P=0.62) (Figure 2). None of the patients receiving morphine exhibited any complications; however, during the intervention, six patients (9.5%) receiving ketamine developed emer- Table1: Demographic variables (%) of patients  Variable Ketamine Morphine p Gender Male 45 (71.4) 51 (81.0) 0.2 Female 18 (28.6) 12 (19.0) Site of fracture Upper extremities 23(37.1) 30 (48.4) 0.2 Lower extremities 39 (62.9) 32 (51.6) Baseline pain score 8.8±0.8 8.95±0.8 0.32 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2014 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com 79 Emergency (2014); 2 (2): 77-80 gence phenomenon (P=0.28). and four patients (6.3%) in this group required a rescue dose due to the short period of the drug effect (P=0.12). Discussion: The results of the present study showed that admin- istration of a low dose of ketamine (0.5 mg/kg) results in a significant decrease in pain severity of long bone fractures. This analgesic effect is very similar to that of morphine. The incidence of drug complications was higher in the ketamine group compared to the mor- phine group (P=0.028), with emergence phenomenon in four subjects. Although the incidence of this compli- cation was higher in the ketamine group, other studies have emphasized that since ketamine is one of the saf- est and most appropriate medications for sedation in emergency wards, such a complication should not pre- clude its use because this complication is resolved spontaneously without any therapeutic intervention (14). The majority of studies available have evaluated the efficacy of combination treatment with morphine/ ket- amine in decreasing pain due to fractures. Galinski et al showed that use of low doses of ketamine decreases the need for morphine up to 26% and its efficacy when ad- ministered alone is similar to that of morphine in alle- viating pain (5). Weinbroum et al evaluated the simul- taneous administration of morphine/ketamine com- pared with morphine alone in decreasing pain severity after surgery and showed that simultaneous admin- istration of morphine and ketamine results in a signifi- cant decrease in pain severity perception by patients (15). A systematic review, too, showed that use of ket- amine as a supplementary medication results in a de- crease in the need for morphine, preventing unfavora- ble complications (16). McCarty et al, too, reported that ketamine is an appro- priate, rapid and safe sedative agent, which facilitates reduction of fractures in children in the emergency unit. However, they claim that ketamine should only be ad- ministered in locations, such as emergency units, where precise monitoring of patients is possible and an expe- rienced physician is available in the center for the man- agement of airways (17). Snijdelaar et al reported that the combination of ketamine/morphine significantly decreases the need for morphine and has better analge- sic effects (18). Jennings et al reported similar findings but emphasized that more minor complications are seen with a combination of morphine/ketamine (12). One of the most important limitations of the present study was a short follow-up period of patients. In the present study, all the patients were evaluated for only 10 minutes, which precluded evaluation of the effect of ketamine at longer periods. Therefore, it is suggested that in future studies the efficacy of the medication be evaluated at longer follow-up periods. Another short- coming of the present study was the absence of a place- bo group. Due to ethical considerations, it was not pos- sible to follow the patients without any medicinal inter- vention and use only placebo. It was shown in the pre- sent study that IV administration of ketamine results in pain relief in bone fracture patients. However, the effect of this medication on the recurrence of pain is still un- known. Therefore, it is possible that further administra- tion of the medication will prevent recurrence of pain. In addition, the efficacy of other routes for administra- tion of the medication, such as intramuscular, intra- nasal and local use, should be evaluated in future stud- ies. In addition, use of different administration regi- mens, such the continuous use or infusion, should be evaluated in future studies. Conclusion: The results of the present study showed that admin- Figure 1: Means (SD) of pain severity in patients receiv- ing ketamine and morphine before and after interven- tion. * indicates significant difference from the period before intervention at P<0.001. NRS: numeric rating scale.  0 .0 0 0 .2 5 0 .5 0 0 .7 5 1 .0 0 63 63 25 8 2 2Morphine 63 63 30 11 4 4Ketamine Number of failure 0 10 151 2 3 4 5 6 7 8 9 11 12 13 14 Time (minute) Ketamine Morphine Kaplan-Meier failure estimates Figure 2: The treatment success rate in the morphine and ketamine groups at different time intervals.  This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Copyright © 2014 Shahid Beheshti University of Medical Sciences. All rights reserved. Downloaded from: www.jemerg.com Majidinejad et al 80 istration of a low dose of ketamine (0.5 mg/kg) results in a significant decrease in the severity of acute pain in patients with fractures of long bones. This analgesic effect is very similar to that of morphine. Acknowledgments: The authors appreciate the insightful cooperation of Medical Sciences and the staffs of the Emergency De- partment of Al-Zahra Hospital, Isfahan, Iran. 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. Cameron M. World Report on Road Traffic Injury Prevention. Inj Prev. 2004;10(4):255-6. 2. Griffin XL, Smith N, Parsons N, Costa ML. Ultrasound and shockwave therapy for acute fractures in adults. Cochrane Database Syst Rev. 2012;2:CD008579. PubMed PMID: 22336847. 3. Woolf AD, Erwin J, March L. 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