Emergency. 2016; 4 (4): 202-206 OR I G I N A L RE S E A RC H Intravenous Morphine vs Intravenous Ketofol for Treating Renal Colic; a Randomized Controlled Trial Gholamreza Faridaalaee1, Neda Mohammadi 2∗, Seyedeh Zahra Merghati 3, Fatemeh Keyghobadi Khajeh 4, Bahman Naghipour 5, Mahboob Pouraghaei 6, Sajjad Ahmadi 1 1. Emergency MedicineDepartment, Maragheh University of Medical Sciences, Maragheh, Iran. 2. Emergency MedicineDepartment, Urmia University of Medical Sciences, Urmia, Iran. 3. International branch of Urmia University of Medical Sciences, Urmia, Iran. 4. Department of Community Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. 5. AnesthesiologyDepartment, Tabriz University of Medical Sciences, Tabriz, Iran. 6. Department of Emergency Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Received: 2 December 2015; Accepted: 1 January 2016 Abstract: Introduction: The main purpose of emergency department (ED) managementfor renal colic is prompt pain relief. The present study aimed to compare the analgesic effects of intravenus (IV ) ketofol with morphine in management of ketorolac persistent renal colic. Methods: This study is a single blind randomized, clinical trial, on patients who were presented to ED with renal colic, whose pain was resistant to 30 mg IV ketorolac. The patients were randomly assigned to either IV morphine (0.1 mg/kg) or IV ketofol (0.75 mg/kg propofol and 0.75 mg/kg) and the measures of treatment efficacy were compared between the groups after 5 and 10 minutes. Results: 90 patients with mean age of 38.01±9.78 years were randomly divided into 2 groups of 45 (66.7% male). Treatment failure rate was significantly lower in ketofol group after 5 (20% vs 62.2%, p < 0.001) and 10 minutes (11.1% vs 44.4%, p < 0.001). ARR and NNT for ketofol after 5 miutes were 42.22% (95% CI: 23.86 - 60.59) and 3 (95% CI: 1.7 - 4.2), respectively. After 10 minutes, these measures reached 33.33 (95% CI:16.16 - 50.51) and 4 (95% CI: 2.0 - 6.2), respectively. NNH and ARI for hallucination or agitation were 12 (95% CI: 5.8 - 174.2) and 8.89% (0.57 - 17.20), respectively. Conclusion: The results of the present study, showed the significant superiority of ketofol (NNT at 5 minute = 3 and NNT at 10 minute = 4) in ketorolac resistant renal colic pain management. However, its NNH of 12, could limit its routine application in ED for this purpose. Keywords: Renal colic; pain; morphine; propofol; ketamine © Copyright (2016) Shahid Beheshti University of Medical Sciences Cite this article as: Faridaalaee Gh, Mohammadi N, Merghati SZ, Keyghobadi Khajeh F, Naghipour B, Pouraghaei M, Ahmadi S. Intravenous Morphine vs Intravenous Ketofol for Treating Renal Colic; a Randomized Controlled Trial. Emergency. 2016; 4 (4): 202-206. 1. Introduction R enal colic usually presents as a severe and intermittent flank pain that can radiate to the genitalia, abdomen and groin (1, 2). It is a common cause for emergency department (ED) visits and affects 3-5% of the general popu- lation (3). Its incidence is higher in men and increases with age (4). The main purpose of ED managament is prompt pain ∗Corresponding Author: Neda Mohammadi; Department of Emergency Medicine, Imam Khomeini Hospital, Ershad Avenue, Urmia, Iran; Tel: +989122347140, fax: +984433457286; Email: neda.mohammadi@gmail.com. relief. Both non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are usually used in this regard (1). In a met- analysis, NSAIDs were found to be as effective as analgesic agents in treatment of acute renal colic (5). NSAIDs are cheap and easily available but may cause complications such as renal failure and gastrointestinal bleeding (6). Opioids are highly potent drugs as well, but havethe risk of dependency and respiratory depression and cause more adverse side ef- fects compared to NSAIDs (7). In addition, the painwon’t be relieved inup to 42% of renal colic patients treated with morphineand 33% of those treated with ketorolac (8). Alter- native choices such as ketofol (a combination of ketamine and propofol) are available for this population (9). Ketamine 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 neda.mohammadi@gmail.com 203 Emergency. 2016; 4 (4): 203-206 is a phencyclidine derivative drug with analgesic, amnes- tic and sedative effects without respiratory side effects (10, 11). In addition, ketamine has antidepressive and smooth muscle relaxant effects that can facilitate stone passage (12). Propofol is an alkylphenol derivative drug withsedative effect (13). In ketofol, ketamine and propofol have a synergistic ef- fect with fewer side effects compared to both ketamine and propofol alone (9). Based on the above-mentioned points, the present study was aimed to compare the analgesic effects of ketofol withmorphine sulphate in management of ketoro- lac resistant renal colics. 2. Methods 2.1. Study setting and design This study is a randomized, controlled, single blind, paral- lel, clinical trial, which was performed in the ED of Imam Khomeini Hospital, Urmia, Iran between 23 July 2014 and 18 March 2015. The Ethics Committee of Urmia University Of Medical Sciences approved the study on 20 May 2014 (ap- proval number is umsu. rec. 1393.66). Written informed consent was obtained from all participants. The study was registered at Iranian registry of clinical trial (IRCT number: IRCT2014052417812N1). 2.2. Participants This study was conducted on patients whowere presented to ED with chief complaint of flank pain and highly suspect- edrenal colic. All patients, whose pain severity was greater than 7 and did not respond to 30 mg intravenous (IV ) ketoro- lac, were includedusing convenience sampling. The exclu- sion criteria were possible allergy to NSAIDs, opioids, propo- fol, egg, and ketamine; addiction to opioid; renal failure; gas- trointestinal bleeding and recent use of analgesics. Renal colic was defined as acute severe flank pain that radiated to ipsilateral groin. The intensity of pain was measured on a 100 millimeter (10 numerical) visual analogue scale (VAS). 10 was considered the worst possible pain and 0 was considered painless. 2.3. Intervention Patients were randomly divided into two groups using per- mutated blocks of 4. Each block contained a pre-specified number of treatment assignments in a random order. Alloca- tion was planned before starting the study by one of the au- thors. Participants and data analysts were blinded to treat- ment allocation. We could not blind the researcher as a re- sult of rapid sedative effects of ketofol. All renal colic pa- tients received 30 mg IV ketorolac, and pain intensity was measured before and 10 minutes after injection. If patients pain score had not decreased by at least 3 scores after 10min- utes, the second step was begun and the patient was enrolled in the study. In group 1, (control group) patients were given 0.1 mg/kg IV morphine sulfate and in group 2 (intervention group) patients were given IV ketofol (combination of 0.75 mg/kg propofol and 0.75 mg/kg ketamine) (14). The ketoro- lac, morphine, ketamine, and propofol (PROVIVE) used, were made by Alborz darou company of Iran, Darou pakhsh com- pany of Iran, Hameln company of Germany and Claris com- pany of India, respectively. 2.4. Outcome Based on previous studies, 13mm reduction on VAS is clin- ically significant; but in patients with severe pain, a greater change on VAS is considered pain reduction (15-17). Thus,a treatment leading to at least 3 scores reduction in pain inten- sity was considered effective. If pain score had not dropped by at least 30 mm after 10 minutes, pain management was considered unsuccessful. The patients were under continu- ousmonitoring of blood pressure, O2 saturation, and respira- tory and heart rates. Respiratory depression, hallucination, agitation, nausea, vomiting, and emergence phenomenon were considered as secondary outcomes (complication). 2.5. Statistical analaysis Considering 80% power, 95% confidence interval (CI), 1.7 variance of pain severity, and 0.8 minimum significant differ- ence, sample size of 45 patients in each group was calculated to be enough. Data were analyzed using SPSS 19. Quanti- tative variables difference were assessed by Mann Whitney U test, and qualitative and numerical variables difference were assessed by Chi-square and Fishers exact tests. Num- ber needed to treat (NNT), relative risk reduction (RRR), and absulute risk reduction (ARR), as well asnumber needed to harm (NNH) and absulute risk increase (ARI)were used as measures of treatment efficacy. P< 0.05 was considered sta- tistically significant. 3. Results 90 patients with mean age of 38.01 ± 9.78 years (22-78) were randomly divided into 2 groups of 45(66.7% male). Table 1 summarizes demographic data of the participants. Initial pain score was 9.0 ± 1.2 in morphine and 9.2 ± 1.1 in keto- fol groups (P = 0.469). Table 2 compares the characteris- tics of pain management and complications betweenthe 2 groups.Treatment failure rate was significantly lower in keto- fol group after 5 (20% vs 62.2%, p <0.001) and 10 minutes (11.1% vs 44.4%, p < 0.001). ARR and NNT for ketofol after 5 miutes were 42.22% (95% CI: 23.86 - 60.59) and 3 (95% CI: 1.7 - 4.2), respectively. After 10 minutes, these measures reached 33.33 (95% CI:16.16 - 50.51) and 4 (95% CI: 2.0 - 6.2), respec- tively. NNH and ARI for hallucination or agitation were 12 (95% CI: 5.8 - 174.2) and 8.89% (0.57 - 17.20), respectively. 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 Gh. Faridaalaee et al. 204 Table 1: Demoghraphic characteristics of the studied patients Variables Morphine sulfate Ketofol P-Value Sex; n (%) Male 31 (68.9) 29 (64.4) 0.823 Female 14 (31.1) 16 (35.6) Age mean ± SD (year) 39.29 ± 12.40 36.73 ± 6.05 0.217 Weight mean ± SD (Kg) 70.73 ± 13.28 75.82 ± 10.83 0.049 Stone size mean ± SD (mm) 6.38 ± 1.85 6.04 ± 1.76 0.383 SD: standard deviation. Table 2: Comparision of treatment effects and cmplications between morphine and ketofol groups Variables Morphine sulfate Ketofol P-Value Pain Intensity mean± SD On admission 9.00 ± 1.22 9.18 ± 1.09 0.469 5 minutes after administration 6.76 ± 3.13 3.24 ± 2.83 < 0.001 10 minutes after administration 4.96 ± 3.83 2.40 ± 2.77 <0.001 Failure rate; n (%) 5 minutes after administration 28 (62.2) 9 (20) < 0.001 10 minutes after administration 20 (44.4) 5 (11.1) < 0.001 Complication; n (%) Hallucination, agitation 0 (0) 4 (8.9) < 0.058 Nausea, vomiting 2 (4.4) 0 (0) < 0.041 Stone size mean ± SD (mm) 6.38 ± 1.85 6.04 ± 1.76 0.383 SD: standard deviation. 4. Discussion The results of the present study, showed the significant supe- riority of ketofol (NNT at 5 minute = 3 and NNT at 10 minute = 4) in rapid pain management of patients presented to ED complaining from renal colic and resistant to ketorolac. NNT of 3 means that about one in every 3 patients treated with ketofol will benefit from the treatment after 5 minutes. How- ever, its NNH was 12, which means that about one in every 12 patientstreated with ketofol will be affected with hallu- cination andagitation. This relatively high NNH could limit routine application of ketofol in this regard. We didn’t find any studiesthatverified using ketofol for treating acute pain of urolithiasisup to the time of writing this article. Thus, this study is the first to verify the effect of ketofol, and compare IV ketofol with IV morphine for treating acute renal colic. Re- garding the opioid agents for treating acute renal colic, the result of our study is similar to those previously published (1, 18-23). Holdgate and Pollock, performed a systematic re- view on efficacy of NSAIDs and opioids. They reported that patients who received opioids, neededa rescue dose of anal- gesicsmore frequently (1). Safdar et al. investigated the effect of ketorolac and morphine for treating renal colic. They re- portedthat 30% of the patients who received a combination of ketorolac and morphine needed a rescue dose (8). Ma- soumi et al. compared IV acetaminophen with morphine for treating renal colic and concluded that acetaminophen is more effective than morphine (24). In contrast, azizkhani et al. reported that morphine is more effective than ac- etaminophen for this purpose (25). However, both groups reported that morphine had more side effects (24, 25). In ad- dition, Soleimanpour et al. compared IV lidocaine and mor- phie, and showed that lidocaine is siginificantly more effec- tive in relieving pain in renal colic patients (26). Yet, Bektas et al. revealed that paracetamol and morphine are equally effective for this purpose (27). Researchers have been trying to verify an alternative drug for treating acute renal colic in emergency settings (28). Ketofol has been used in anesthesi- ology and has recently begun to spread into ED (29). Nejati et al. compared ketamine/propofol and midazolam/fentanyl in the ED and found that ketamine/propofol is safe and ef- fective for sedation and analgesia (14). Willman et al. eval- uated the effectiveness of ketofol for orthopedic procedural sedation in ED. They concluded that ketofol is an effective drug with minimal and transient side effects (9). The present study illustrated that efficacy of ketofol in renal colic pain re- lief is more than morphine. However, further study is needed before we suggestroutine use of ketofol, in this regard. 4.1. Limitations Due to sedative effect of ketofol, we could only blind the pa- tients and not the researchers, thus this study issingle blind. 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 205 Emergency. 2016; 4 (4): 205-206 Conveniences amplingand short duration of follow-up are also among the most important limitations of the present trial. 5. Conclusion The results of the present study, showed the significant supe- riority of ketofol (NNT at 5 minute = 3 and NNT at 10 minute = 4) in ketorolac resistant renal colic pain management. How- ever, it’s NNH of 12, could limit its routine application in ED for this purpose. 6. Appendix 6.1. Acknowlegdment All authors would like to thank all the staff of Imam Khomeini Hospital of Urmia and the research center of Urmia Univer- sity of Medical Sciences. 6.2. Author contribution All authors passed four criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors. 6.3. Conflict of interests None 6.4. Funding None References 1. Holdgate A, Pollock T. 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