Archives of Academic Emergency Medicine. 2020; 8(1): e68 REV I EW ART I C L E Comparison of Ketamine and Tramadol in Management of Acute Pain; a Systematic Review Bahman Naghipour1, Mahboub Pouraghaei2, Ali Tabatabaey3, Allahveirdy Arjmand4, Gholamreza Faridaalaee5,2∗ 1. Department of Anesthesiology and Critical Care, Tabriz University of Medical Sciences, Tabriz, Iran. 2. Emergency Medicine Research Team, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. 3. Department of Emergency Medicine, Amiralmomenin Hospital, Islamic Azad University-Tehran Medical Branch, Tehran, Iran. 4. Department of Anesthesiology, Maragheh University of Medical Sciences, Maragheh, Iran. 5. Department of Emergency Medicine, Maragheh University of Medical Sciences, Maragheh, Iran. Received: June 2020; Accepted: July 2020; Published online: 23 August 2020 Abstract: Introduction: Management of pain is an important part of care in the emergency department (ED). Tramadol and Ketamine have both been introduced as alternatives to opioids in the ED and post-operative setting. In this study, we conducted a systematic review of available literature to compare the analgesic efficacy, and side effect profile of these two medications in management of severe acute pain. Methods: This is a systematic review based on the PRISMA protocol. In this study, peer-reviewed papers published by March 3, 2020, which compared analgesic effects of tramadol and ketamine in management of acute pain were included. Results: The initial search of online databases identified 2826 non-duplicate records. Finally, three papers available in full text were analyzed for study quality. The results show that ketamine has consistently been shown to be superior to tramadol for pain control and causes fewer significant side effects. Conclusion: Results of this review show that low-dose ketamine is more effective than tramadol in pain control, while causing fewer side effects. Keywords: Ketamine; Tramadol; pain management; emergency treatment; acute pain Cite this article as: Naghipour B, Pouraghaei M, Tabatabaey A, Arjmand A, Faridaalaee Gh. Comparison of Ketamine and Tramadol in Man- agement of Acute Pain; a Systematic Review. Arch Acad Emerg Med. 2020; 8(1): e68. 1. Introduction Pain is one of the most common patient complaints in the emergency department (ED), and management of pain is an important part of care in the ED (1). Multicenter studies have reported that up to 78% of patients admitted to ED complain of acute pain (1). Pain control has been considered a human right (2) and in 2011, analgesics were administered in 97 mil- lion ED visits (3). Many medications are used as analgesics for acute pain; examples include opioids, non-steroidal anti- inflammatory drugs, acetaminophen, ketamine, and dulox- etine (4-8). Educational campaigns in the 1990s focused on systematic assessment and treatment of pain (9). A perfect ∗Corresponding Author: Gholamreza Faridaalaee; Department of Emer- gency Medicine, Maragheh University Road, Maragheh University of Medical Sciences, Maragheh, Iran. Email: faridaalaee@tbzmed.ac.ir, grf.aalae@yahoo.com, Tel: +98-4137276363 analgesic is one with quick onset, no side effects, and an ex- tended effect. Since, such a medication has yet to be discov- ered strategies such as "analgesic pyramid", "balanced anal- gesia" and "Channels-Enzymes-Receptors Targeted Analge- sia" have emerged (10). In the analgesic pyramid, medication is chosen based on severity of pain. Yet, for severe pain, treat- ment options are limited and opioids are the most common analgesic used (9), despite their unfavorable adverse effect profile, including respiratory depression, dependence, and risk of overdose. In Canada, one in every 550 people who are started on opioids die (11), and death from an opioid over- dose is an important cause of death in the 18 to 35 age group (11, 12). Therefore, clinicians are looking at safer alternatives for the management of severe pain in the postoperative and ED settings. Tramadol is considered an atypical opioid with multiple ef- fects on various receptors (13, 14). It has shown efficacy in reducing different types of pain and is less likely to cause de- pendence than opioids. Its adverse effect profile is different 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 B. Naghipour et al. 2 from opioids and is less likely to cause respiratory depres- sion but more likely to induce seizures (7, 13, 15-17). In re- cent years, ketamine has gained popularity as a sedative and analgesic in the ED. Ketamine is a phencyclidine derivative, which is a dissociative sedative and an amnestic in addition to having analgesic properties (6). It has also been found to have fast acting antidepressant effects (18). It can easily be administered through oral, intranasal, rectal, intramuscular, or intravenous routes. It has rapid onset and a wide window of effects without the risk of respiratory depression, which makes it an attractive choice for management of acute pain. Yet fear of other side effects, such as increased intracranial pressure, increased cardiovascular load, and emergence re- actions, has limited its use (19-22). Ketamine and tramadol both have advantages and disadvantages, so in this study we decided to systematically review available literature to com- pare the analgesic efficacy, and side effect profile of these two medications in management of severe pain. 2. Methods 2.1. Study design This is a systematic review based on the PRISMA protocol (23). The study PICO is: Population of patients with severe acute pain in the ED or postoperative setting, Intervention is Ketamine, intravenously, compared with tramadol, and the Outcome is control of acute pain. Secondary outcome is the prevalence of side effects. 2.2. Eligibility criteria In this study, peer-reviewed papers published by March 3, 2020, which compared analgesic effects of tramadol and ke- tamine for in management of acute pain were included. In- travenous administration of ketamine and tramadol was an inclusion criteria and other routes of administration, such as nasal or epidural routes, were excluded from the study. For papers that were only available as abstracts, multiple attempts were made to contact the authors using available means (emails, social media, researchgate, etc.). Unfortu- nately, we were not able to secure full text versions for ab- stracts presented in seminars. 2.3. Search Strategy Relevant search items and keywords for the study question were selected from MeSH and Emtree terms after consult- ing an Emergency Medicine specialist and an Anesthesiol- ogist. A literature search was conducted via electronic re- sources including Medline, Web of Science, Embase, and Central Cochrane Library up to the March 3, 2020. References of found papers were also searched for relevant studies. The search strategy in Medline followed the pattern described in table 1. 2.4. Study selection, data collection, and out- come measurement Initially, all the studies found, which evaluated effects of ke- tamine and tramadol in management of acute pain, were in- cluded. Abstracts of all papers were reviewed by two mem- bers of the research team and papers were further screened based on inclusion and exclusion criteria described above. Relevant papers were then reviewed in full text and those meeting the criteria were included in the study. Their find- ings were then summarized and evaluated using standard- ized checklists and study quality was assessed by two mem- bers of the research team, independently. Any discrepancy between the reviews was resolved either through discussion or a verdict by a third researcher. In this systematic review, the primary outcome was analgesic efficacy of tramadol and ketamine, described through decrease in pain score or ne- cessity of a second analgesic. Secondary outcome was preva- lence of adverse effects among patients receiving tramadol and ketamine. 2.5. Statistical analysis Descriptive analysis was performed on data. All included studies were summarized and categorized based on prede- fined variables. 3. Results 3.1. Study selection and study characteristics The initial search of online databases identified 2826 non- duplicate records. After screening of abstracts, 2813 studies were eliminated. Thirteen papers were assessed in full text. Five were found to be ineligible for the study. Four stud- ies were presentation abstracts and attempts were made to contact authors in order to obtain them in full text without success (24-27). Two of the presentations consisted of sim- ilar findings (26, 27). One paper was only available in ab- stract form and the author did not respond to researchers (28). Therefore, only three papers, available in full text, were analyzed for study quality (29-31). Due to the paucity of eligi- ble studies, the authors decided to include findings from the presentation abstracts with relevant findings in this system- atic review. Figure 1 summarizes the selection process. Spec- ifications and characteristics of included studies are reported in table 2. Overall, 257 patients were evaluated for analgesic effects of ketamine and tramadol in acute pain. 3.2. Quality control of study and risk of bias The quality of included studies was evaluated, and results are summarized in Table 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 3 Archives of Academic Emergency Medicine. 2020; 8(1): e68 Table 1: Medline search strategy Database Search terms MEDLINE (PubMed) 1) Ketamine OR Ketalar OR Ketaset OR Ketanest OR Calipsol OR Kalipsol OR Calypsol OR Ketamine Hydrochloride OR Esketamine 2) Tramadol OR Tramundin OR Biodalgic OR Jutadol OR MTW-Tramadol OR MTW Tramadol OR MTWTramadol OR Nobligan OR Prontofort OR Zytram OR Takadol OR Theradol OR Tiral OR Tramadol Lindo OR Topalgic OR Tradol OR Tradol-Puren OR Tradol Puren OR TradolPuren OR Tradonal OR Tralgiol OR Trama AbZ OR Trama KD OR Trama-Dorsch OR Trama Dorsch OR TramaDorsch OR Biokanol OR Tramabeta OR Tramadin OR Tramadol-ratiopharm OR Tramadolratiopharm OR Tramadol Ratiopharm OR Tramadoc OR Tramadol PB OR Tramadol acis OR Tramadol AL OR Tramadol Basics OR Tramadol Bayvit OR Tramadol Bexal OR Tramadol 1A OR Ranitidin 1A Pharma OR Trama 1A Pharma OR Tramadol Cinfa OR Tramadol Edigen OR Tramadol Hydrochloride OR Trasedal OR Ultram OR Tramadol Heumann OR Xymel 50 OR Zamudol OR Zumalgic OR Zydol OR Tramadol Kern OR Tramadol Lichtenstein OR Tramadol Mabo OR Tramadol Normon OR Tramadol Stada OR Tramadol-Dolgit OR Tramadol Dolgit OR TramadolDolgit OR Tramadol-Hameln OR Tramadol Hameln OR TramadolHameln OR Tramadolor OR Tramadura OR Tramagetic OR Tramagit OR Tramake OR Tramal OR Tramex OR Adolonta OR Contramal OR Amadol OR Tramadol Asta Medica 3) 1 &2 Table 2: Characteristics of included studies Author Ketamine group Tramadol group N Age Male Dose N Age Male Dose Khajavi 2016 40 46.93 29 0.5 mg/kg 40 42.17 25 0.7 mg/kg Burimsittichai 2016 70 47 14 0.5 mg/kg 67 44 12 1.5 mg/kg Yu C 2005 20 44.67 14 0.5 mg/kg 20 47.33 9 0.3 mg/kg Kilinc Y 2018 16 7-21 10 Ketamine (0.25 mg/ kg/ dose) 31 6-21 16 tramadol (0.1-0.4 mg /kg/ h) Zghidi 2011 20 adult - 0.2mg/kg, +2µ/kg/min 20 adult - 100 mg + 0.5 mg/kg and 0.1mg/kg/h Table 3: Risk of bias assessment of included studies based on NHLBI tools Variable Khajavi Burimsittichai Yu C Publication in peer-reviewed journal © © © Sample size calculation © © ? Description of group and intervention © © § Description of control group © © § Exclusion criteria © © © Randomization © © © Blinding © © ? Ethical approval ? © © Informed consent © © ? Specified main outcome © © © Specified secondary outcome © © © Description of statistical analysis © © © Statement of conflict of interest § © § High risk of bias: §, low risk of bias: © 3.3. Analgesic effect Systematic review of results shows that analgesic effects of low-dose ketamine (0.25-0.5 mg/kg) are significantly larger/stronger than tramadol (0.3-1.5 mg/kg). Khajavi et al. looked at 80 patients with acute pain following renal surgery in a double blind randomized controlled study (29). One group received intravenous paracetamol plus ke- tamine and the other received intravenous paracetamol plus tramadol. They found that patients who received ketamine had significantly lower pain scores compared to those who received tramadol. In the study by Burimsittichai et al. 207 patients with pain secondary to foley catheters in the post- operative setting were randomly allocated to a group in a double blind randomized clinical trial (RCT) to receive ei- ther ketamine 0.5mg/kg or tramadol 1.5mg/kg, or placebo (30). Analgesic effects were compared 6 and 24 hours after 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 B. Naghipour et al. 4 Figure 1: PRISMA diagram of systematic review. laparoscopic surgery. The authors reached the conclusion that use of either medication significantly reduces pain, com- pared to placebo, but did not compare these groups to one another. Although the group receiving ketamine appeared to have lower pain scores, the statistical significance of this observation was not discussed by the authors. Yu C. and colleagues studied patients suffering from postoperative hy- peralgesia and also found that those receiving intravenous ketamine had significantly better pain control compared to those receiving tramadol (31). Kilinc and colleagues in their study looked at patients with sickle cell anemia, aged 6 years and over, suffering from acute pain episodes (25). One group received ketamine and the other received tramadol. Results showed that ketamine was more effective that tramadol in controlling pain. Alp re- ported using either ketamine 0.5mg/kg or tramadol 1mg/kg for pain control in 100 women undergoing uterine dilatation and curettage in Turkey (24). In the results presented at the 35th Annual European Society of regional Anaesthesia and Pain Therapy, they reported significantly better pain control in the group receiving ketamine. At the 30th Annual Euro- pean Society of regional Anaesthesia, a study from Tunisia, 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. 2020; 8(1): e68 presented by Zghidi, reported the findings of comparison of ketamine and tramadol in controlling post laparotomy pain in 40 patients and revealed that ketamine was a more effec- tive analgesic (26). These results are similar to another study by Djaziri, presented at 32nd Annual European Society of re- gional Anaesthesia and Pain Therapy (27). 3.4. Need for rescue analgesic Khajavi et al. used morphine as their rescue analgesic and showed that those receiving ketamine had significantly lower rescue morphine injections during the first 6 hours (0.47 ± 0.94 mg versus 2.50 ± 1.35 mg, P = 0.001) (29). Burimsittichai and colleagues, on the other hand, did not see any signif- icant difference between the groups regarding rescue mor- phine therapy (30). 3.5. Side effect profile Evaluation of included studies shows that ketamine has a safer side effect profile compared to tramadol. In the study by Khajavi and colleagues, patients’ agitation was measured, using the Ramsey Scale Score, 10 and 20 min- utes after the injection of analgesics (29). The group receiv- ing ketamine had significantly lower agitation compared to the group receiving tramadol. Also, the prevalence of side ef- fects was significantly lower in the ketamine group (20% for ketamine and 53% for tramadol). Patients receiving tramadol experienced higher rates of nausea, vomiting, and hallucina- tions but the difference between the two groups was not sta- tistically significant. In the study by Burimsittichai et al. rates of nausea and vomiting were higher in the ketamine group, but the difference was not found to be significant compared to the either the tramadol group or the placebo group (30). The groups were found to have comparable rates of other side effects. In the study by Yu C. the two groups were not sig- nificantly different regarding incidence of side effects (31). In a study by Elkassem, effects of ketamine and tramadol were compared in patients undergoing cruciate ligament recon- struction surgery and it was found that tramadol had higher rates of side effects compared to ketamine (28). In the study by Alp, ketamine was reported to have higher rates of side ef- fects, which included increased heart rate and blood pressure (24). 4. Discussion This systematic review aimed to explore existing literature to compare the analgesic effects of ketamine and tramadol in treating acute pain and compare their side effect profiles. Results of this review show that low-dose ketamine is more effective than tramadol in pain control, while causing fewer side effects. Three full text papers were included in this study alongside four studies only reported as abstract presenta- tions in scientific gatherings. The authors concluded that these results demonstrate that use of ketamine for acute pain control is advisable. Several systematic reviews have looked at analgesic effects of ketamine in the past. In 2018 Karlow et al. looked at liter- ature comparing low-dose ketamine to morphine for treat- ment of acute pain in the ED (32). This review included three studies and reached the conclusion that low-dose ketamine is equally effective as morphine in pain control, while hav- ing fewer significant side effects. They suggested using ke- tamine instead of morphine for treatment of severe pain in the ED (32). Ghate and colleagues also looked at the ef- fects of low-dose ketamine (0.15-0.3mg/kg) for pain control in the ED (33). They included 6 RCTs and two observa- tional studies. The authors concluded that ketamine is as effective as morphine in controlling pain and patients re- ported similar satisfaction rates. Side effects reported for us- ing ketamine included dysphoria, hallucinations, agitation, and confusion (33). A systematic review by Lee and col- leagues in 2016 included 6 studies and looked at the effec- tiveness of ketamine in patients with moderate to severe pain in the ED (34). They concluded that ketamine had com- parable effects with morphine but it was found to be infe- rior to fentanyl in two studies. One of the included stud- ies had found that ketamine was not superior to placebo at 0.15mg/kg and only showed analgesic effects at 0.3 mg/kg. The authors found that ketamine caused more neurologic (dizziness, headache, light-headedness, nystagmus, visual disturbance, drowsiness, numbness, or increased skeletal tone) and psychological (hallucination, dysphoria or confu- sion, agitation, disorientation, or mood change) side effects compared to morphine but had fewer cardiac side effects (major: hypoxia and hypotension; minor: tachycardia and hypertension) (34). Other studies have also looked at ketamine in different set- tings. Yousefifard et al. recently looked at the effects of ke- tamine in the prehospital setting and found that ketamine is less effective than morphine and fentanyl, but it also has fewer side effects (35). Others have looked at ketamine in the perioperative setting. Wang et al. looked at 20 clinical trials in cesarian sections (36), while Riddell et al. looked at ortho- pedic surgeries (37), and Garcia-Henares JF. et al. looked at general surgery patients (38). All of these reviews found that ketamine is effective in reducing postoperative pain and de- creasing the need for opioids without causing an increase in significant side effects. Our results show that ketamine has consistently been shown to be superior to tramadol in pain control, also causing fewer significant side effects. Therefore, we suggest the use of ke- tamine instead of tramadol as an opioid-spearing analgesic in treatment of acute pain. 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 B. Naghipour et al. 6 5. Limitation We only found three articles that compared the analgesic ef- fects of Ketamine and tramadol, so we did not perform a meta-analysis. Risk of bias for all three articles is shown in table 3. All three articles have low risk of bias regarding main and secondary outcomes. 6. 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Effects of ketamine on postoperative pain af- ter remifentanil-based anesthesia for major and minor surgery in adults: a systematic review and meta-analysis. Frontiers in pharmacology. 2018;9:921. 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 Limitation Conclusion Declarations References