Alternative Medical Interventions Versus Conventional Treatment of Renal Colic: An Updated Systematic Review and Network Meta-Analysis Ghazal Seghatoleslami1, Mohammad Sadegh Sanie Jahromi2, Roohie Farzaneh3, Sara Rahsepar1, Mehrdad Malekshoar4, Majid Vatankhah4, Reza Akhavan3, Bita Abbasi5, Hossein Akhavan6, Samaneh Abiri7, Lohrasb Taheri8, Navid Kalani9, Mahdi Foroughian3, Arman Hakemi10* Purpose: To systematically review the recent alternative medical interventions on renal colic pain and compare their efficiency with conventional treatments. Materials and Methods: This was a systematic review and network meta-analysis (NMA) study, based on the PRISMA guidelines on online databases of PubMed, Scopus, and web of science. We quarried these databases with relevant keywords for clinical trial studies that aimed at reducing renal colic pain in patients refereeing to the ED from after January 2011 to February 2022. Randomized clinical trials that used the Visual Analogue Scale (VAS) for assessment of renal colic pain before and after medical interventions in adult patients were included in this study. NMA was conducted based on the continuous values of the mean difference of the pain after 30 and 60 minutes of the medication administration. Results: Twenty-four studies that were meeting the inclusion criteria were included in our review with 2724 adult participants who were mostly male. Study arms included conventional medications (NSAID, Opioid, paraceta- mol), ketamine, MgSo4, desmopressin, and lidocaine. Based on the qualitative synthesis, ten studies (41.7%) did not find significant differences between conventional and alternative treatments. Also, there is no agreement on some more recent medications like using ketamine or desmopressin while MgSO4 and lidocaine use are supported by most studies. NMA revealed that desmopressin is significantly having worse pain reduction properties. NMA did not show any difference between ketamine, lidocaine, and MgSo4, versus the conventional treatment. Conclusion: To conclude, lidocaine and MgSo4 might be good alternative treatments for renal colic when con- ventional treatments are contraindicated or pain is not responding to those. Ketamine might be indicated in pa- tient-based circumstances. Desmopressin may be agreeably avoided in further research or clinics. Keywords: urolithiasis; emergency department; renal colic INTRODUCTION Renal colic is a severe pain caused by transient kidney stones through the urinary tract and uri- nary system that 12% in males and 6% in women can experience in a lifetime(1) and is a common reason for emergency room visits worldwide(2). Management of renal colic pain is mainly a conservative approach that focused on treating the symptoms like pain and nau- sea and vomiting(3). In case of pain, renal colic pain is 1Department of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 2Anesthesiology, Critical care and pain management research center, Jahrom University of Medical Sciences, Jahrom, Iran. 3Department of Emergency Medicine, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 4Department of Anesthesiology, Anesthesiology & Critical Care and Pain Management Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. 5Department of Radiology, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 6Department of Pediatric, Faculty of Medicine, Mashhad University of Medical sciences, Mashhad, Iran. 7Department of Emergency Medicine, Jahrom University of Medical sciences, Jahrom, Iran. 8Department of Surgery, Jahrom University of Medical sciences, Jahrom, Iran. 9Research center for social Determinants of Health, Jahrom University of Medical Sciences, Jahrom, Iran. 10Department of Emergency Medicine, Mashhad University of Medical sciences, Mashhad, Iran. Correspondence: Department of Emergency Medicine, Mashhad University of Medical sciences, Mashhad, Iran. Email: hakemia971@mums.ac.ir. Received February 2022 & Accepted August 2022 caused by a rise in prostaglandin production, which causes arterial vasodilation, vascular permeability, and ureteric edema and contractions. Renal colic is charac- terized by referral and migratory pain, which is peculiar to renal colic due to the stone's gradual transit down the ureter(4). Several major systematic reviews and me- ta-analyses studies have supported various medications to help achieve a longer duration of pain relief, a lower requirement for further analgesia, and fewer adverse ef- fects(5). Systematic review studies have compared many Urology Journal/Vol 19 No. 6/ November-December 2022/ pp. 412-419. [DOI: 10.22037/uj.v19i.7204] REVIEW Review 413 Alternative Medications of Renal Colic- Seghatoleslami et al. Table 1. Characteristics of included studies ID Country Setting Design intervention IV age Sex end clinical conclusion Jaded therapy (male) points response score Motov et al., USA multicenter prospective, a- IV lidocaine 2019 (12) interventional, (1.5 mg/k), n = 50 100 ml IV a- 39.34 a-54% 60 min Pain NA no 5 blinded b- ketorolac 30 mg, normal b- 42.34 b- 56% relief rate; difference n = 50 c- a+b, n = 50 saline c- 43.92 b- 56% Adverse event c- 56% Soleimanpour et al., Iran single-center prospective randomized a- 0.1 mg/kg Morphine NA a- 35.23 ± 12.37 a-75% VAS till 30 NA b was better 3 2012 (13) double-blind clinical trial IV slowly, n = 120 b- 37.71 ± 11.08 b- 71% min values b- IV lidocaine (1.5 mg/k), n = 120 Sadrabad et al., Iran single-center double-blind randomized a- 0.1 mg/kg IV morphine a- 10 cc a- 34.65(8.47) a- 27 (67.5) 10, 20 min 3 scores no difference 4 2021 (14) clinical trial sulfate (maximum of distilled b-34.97 (9.71) b- 30 (75) VAS reduction 5 mgs), n=40 water + 20- of VAS b- 50 mg/kg (maximum minute infusion of 2 grams) MgSo4, N=40 100 cc normal saline. B- 100 cc normal saline for 20 minutes Kumar et al., India single-center nonblind randomized a- desmopressin 40 None NA in detail, NA in second NA all patients 3 2011 (15) clinical trial gm IN, n=24 matched groups detail, analagesic; in group a b- diclofenac 75 mg matcched VAS at 10, received secondary IM, n=24 groups 30 min and 1 h analagesic; c- both, n=24 2 in group b, and 3 in group c Ghafouri et al., Iran single-center nonblind randomized a- 40 mcg of IN NA matched a- 99 (82.5) second 30 mm no difference 5 2020 (16) clinical trial desmopressin spray, b- 88 (73.3) analgesic decrease n=120 b- IV paracetamol (Morphine (15 mg/kg), n=120 use after 15 min); VAS at 0, 15, 30 min and 1 h Drapkin et al., USA single-center randomized, a- IV lidocaine None NA NA VAS at 0, NA c is better - 2018 (17) double-blind (1.5 mg/k),n = 50 15, 30 min b- ketorolac 30 mg, n = 50 and 1 h c- a+b, n = 50 Forouzan et al., Iran single-center randomized, a- intravenous ketamine None matched NA VAS at 30, NA no difference - 2019 (18) placebo-controlled, (0.3 mg/kg) 45, and 60 min double-blinded b- intravenous morphine & adverse event (0.1 mg/kg) total 135 participants Sotoodehnia et al., Iran single-center randomized a- intravenous ketamine NA matched a- 71% VAS till 120 NA no difference 4 2019 (19) double-blind (0.6 mg/kg), n=62 b- 81.2% min & adverse b- intravenous ketorolac event 30 mg, n=64 Grill et al., 2019 (20) USA single-center randomized non blind a- ketorolac 30 mg, n=26 Ketamine in a- 37.25 a- 75.0% 120 min 11- NA b was better 4 b- intravenous ketamine 50 cc NS b- 41.69 b- 30.8% point VAS, (0.3 mg/kg) plus ketorolac, n=8 results of MD were multiplied by 1.1 Pouraghaei et al., Iran single-center randomized double blind a- 1 mg/kg intranasal (IN) None a- 39.39±3.7 matched VAS at NA no difference 5 2021 (21) ketamine, n=95 b- 41.27±5.2 20, 40 and b- - intravenous morphine 60 minutes (0.1 mg/kg) , n=89 Metry et al., Egypt single-center prospective, open-label, a- IV pethidine 50 mg, None a- 39.8±11.3 a- n=40 VAS till NA b was better 4 2021(22) randomized, double- b- lornoxicam 8 mg+ b- 37.8±12.8 b- n=38 30 min blindedn=60 0.15 mg.kg−1 ketamine, n=60 Dolatabadi et al., Iran single-center double-blind randomized a- 40 µg of intranasal None. a- 31.0 ± 6.5 a- 13 (65) VAS at 10, 3 cm b is better. 4 2017 (23) clinical trial, desmopressin spray, n=20 b- 34.1 ± 7.1 b- 16 (80) 30, and 60 change Avoid a b- 30 mg of IV ketorolac, n=20 min Ahmed et al., Egypt multi center randomized, a- IV magnesium sulfate 100ml a- 31.96±8.29 a- 60.4% VAS at 15, NA a was better 3 2019 (24) double-blind, double- 50%, n=48 intravenous b- 31.94±8.08 b- 56.3% 30, 45, and dummy comparative b- ketorolac 30 mg IV, normal saline 60 minutes n=48 Verki et al. 2019 (25) Iran multicenter randomized, double-blind, a- 50 mg/kg magnesium 100ml a- 39.43±12.089 matched VAS till 30 NA no difference 4 sulfate 50% +, ketorolac intravenous b- 37.19±10.032 min 30 mg IV, n=44 normal saline b- ketorolac 30 mg IV, n= 43 Motamed and Verki, Iran single center Randomized Clinical a- fentanyl (1.5 µg/kg), IV infusion a- 39.08 ± 6.64 a- 39 (86.7) VAS at 30 NA no difference 4 2017 (26) Trial, double blind n=45 during 2 b- 34.08 ± 9.49 b- 42 (93.3) min; rescue b- lidocaine (1.5 mg/kg), minutes n=45 Jokar et al., 2017(27) Iran single center randomized double-blind a- 0.1 mg/Kg of IV a- 100 ml IV a- 35.16±8.97 a- 29 (58%) 30 and 60 NA b was better 4 morphine sulfate, 30 mg normal b- 33.64±8.61 b- 30 (60%) min VAS; of IV ketorolac, and 100 saline morphine ml IV normal saline, n=50 b- 100 ml dose b- 15 mg/Kg of IV normal saline magnesium sulfate 50% , within 15 minutes n=50 Shirazi et al., Iran single center prospective, single blind a- tramadol 50 mg IM ly, None a- 39.1±8.9 a- 23 30 min NA a was best 4 2015 (28) randomized clinical n=40 b- 38.8±7.6 (57.5%) VAS; b- desmopressin 40 µg c- 36.7±9.2 b- 25 (62.5%) Complete intranasally, n=40 c- 22 (55%) relief ; Rescue c- indomethacin 100mg rectally , n=40 types of medications and some review studies have only focused on a special medication(6). A review of 36 RCTs, published in 2016, showed that many available medical choices among the medications belonging to the NSAIDs, opioids, and paracetamol are having com- parable efficiency in relieving acute renal colic pain; while the adverse events might be different(7). One more systematic review study on 183 studies till 2020 revealed that as a common choice, opioid medications were linked to lower or equivalent efficacy to NSAIDs for several acute pain situations, but also a higher risk of short-term side effects(8). Multiple drugs are proven to be effective for renal colic pain in individuals ac- cused of carrying kidney stones; nevertheless, much research on novel treatment options or novel combina- tions of previous medications is being released that are not reviewed in recent years. As mentioned, the pain induced by urolithiasis is one of the most annoying pain experiences that an individual can sense and is respon- sible for a high rate of emergency department (ED) visits worldwide. Multiple conventional medications (Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids) are known to be efficient for renal colic pain in patients suspected of kidney stones, but yet some pa- tients might still not respond to conventional methods that necessitate alternative methods. So, we aimed at conducting an updated systematic review study of the alternative methods from 2011 to 2022. MATERIALS AND METHODS This was a systematic review study on renal colic pain treatment in the emergency department that was con- ducted based on the PRISMA guidelines. Study questions were structured based on a PICO mod- el. (P)opulation of interest was acute renal colic pa- tients. Suspected or definitive cases were considered for the study. Based on the ICD-10 definitions [2022 ICD-10-CM Diagnosis Code N23], renal colic was de- fined as “A condition characterized by intermittent and severe flank pain due to kidney stone (renal calculus) moving through the ureter or other urinary channel ob- struction is the most common cause of acute discomfort in the lower back extending to the groin, scrotum, or labia. Nausea, vomiting, fever, restlessness, dull dis- comfort, frequent urine, and hematuria are all common symptoms.” (I)ntervention was pain relief interventions (medical or non-medical). Based on the preliminary search of the literature, high-quality pooled studies were available comparing NSAIDs, Opioids, Paracetamol, and Desm- opressin. Network Meta-analysis was available on dif- ferent routes of NSAIDs and paracetamol administra- tion(9). There was a lack of pooled data in comparison of newer interventions with previously interventions that have stood the test of time. So, we aimed at categoriz- ing interventions into 4 categories of (i) Conventional monotherapy [including monotherapy with NSAIDs, Vol 19 No 6 November-December 2022 414 ID Country Setting Design intervention IV age Sex end clinical conclusion Jaded therapy (male) points response score Majidi and Iran single center double a- IV 2cc of 50% normal a- 39.1 ± 13.2 a- 27 (60.0) 180 min 3 no difference 4 Derakhshani, blind Mg sulfate, n=45 saline b- 35.6 ± 10.8 b- 32 (71.1) VAS scores 2020(29) randomized b- IV morphine 100 ml reduction (0.1 mg/kg dose), n=45 injected of VAS during 15 minutes Shirvani et al., Iran single center single blind a- 0.1 mg/kg IM NA matched matched 30 min VAS NA no difference 4 2015 (30) randomized, 60 µg of clinical trial morphine + sublingual desmopressin b- morphine + placebo total 81 cases Firouzian et al., Iran single center double-blind, a- morphine (0.1 mg/kg) NA a- 37.91 ± 10.76 a- 36 VAS till 120 NA a was better 4 2016 (31) randomized + lidocaine (1.5 mg/kg), b- 37.95 ± 12.6 b- 35 min for both controlled n= 47 pain and naussea trial b- morphine (0.1 mg/kg) + normal saline 0.9% [ placebo], n=42 Farnia et al., Iran single center prospective, a- A 0.1 mg/kg diluted NA a-34.75 ± 11.71 a- 17 30 min VAS NA a was better 5 2017 (32) randomized, IV morphine + IN b- 39.25 ± 10.75 (85.0%) double-blind placebo, n=20 b- 12 b- 1 mg/kg IN ketamine (60.0%) + IV placebo. n=20 Abbasi et al., Iran single center double a- Morphine 0.1 NA matched matched 120 min NA b was better 4 2018 (33) blind mg/kg IV and placebo, n=53 VAS randomized b- morphine 0.1 mg/kg IV and clinical trial ketamine 0.15 mg/kg IV, n=53 Jalili et al., 2019(34) Iran single center prospective, a- indomethacin NA a- 34.67 ± 10.03 a- 70.15% 60 minVAS NA a was better 4 double- suppository (100 mg) + b- 34.31 ± 10.73 b- 69.35% blinded, , desmopressin intranasal randomized spray (4 puffs with 10 placebo- microgram per puff), n=62 controlled b- indomethacin suppository clinical trial (100 mg) + palcebo intranasal spray , n=62 Mozafari et al., Iran single center double-blind a- 1 mg/kg of intranasal NA matched matched 30 min NA b was better 4 2020 (35) clinical trial drops of ketamine + IV palcebo, n=65 VAS; b- 50 µg/(kg/bw) IV fentanyl + Rescue intranasal palcebo, n=65 medication; NA, not addresed. Alternative Medications of Renal Colic- Seghatoleslami et al. Opioids, and Paracetamol] or combined with each oth- er; (ii) Alternative treatments; (iii) combination of the conventional and alternative methods. Nonpharmaco- logical methods were not included in the study. (C)omparisons were tried to be conducted between these three types of interventions being compared pair- wise and versus the conventional treatment. The route of the medication administration was waived to observe the prerequisites of NMA. (O)utccome of interest was the analgesic effects of in- terventions and the need for rescue treatment. Based on the preliminary review, some studies of filed are not reporting rescue treatment rates that we only considered 30- and 60-min pain. Search strategy Searches were performed from 1 January 2011 to 2022 in online databases of Scopus, PubMed, and Web of science. Two independent researchers ran the search Review 415 Figure 1. PRISMA flowchart Figure 2. Network plot of included studies. (a) 30 min pairwise analysis network. (b) 60 min pairwise analysis network. Each node representing a single intervention and connecting lines between nodes showing where one or more trials have compared the two therapies head-to-head. Alternative Medications of Renal Colic- Seghatoleslami et al. strategy of the combination of the MeSH keywords. The detailed search strategy was “ (Renal colic OR Uro- lithiasis OR Acute Nephrolithiasis OR Nephrolithiasis OR renal colic pain OR Urolithiasis pain OR ureteric colic) AND (randomized controlled trials OR Trial OR randomized trial OR Blinded trial OR RCT) AND (Pain OR VAS OR Visual Analogue Scale OR analgesia OR analgesic) AND emergency department” . Searches were conducted by two independent researchers. The reference list of the selected articles for full-text review was also hand-quarried for relevant studies. Study selection, data extraction, and quality assessment Studies were limited to randomized clinical trials, in the English language, published after January 2011. The study setting was also limited to the Emergency department. Pre-print studies and gray literature did not include in the study. Any studies on subjects with trauma to the flank or any other concurrent significant trauma were not included. The age of study subjects had to be higher than 16 years old and lower than 65 years; subjects did not have any previous renal failure. Any disagreement between independent researchers was judged by a third researcher. Inclusion criteria were also containing a non-conventional treatment arm of the study in RCT. The quality of studies was assessed by Jadad Score to prevent any bias(10). A checklist containing study id, country, Setting, design, minimum vas for inclusion, intervention, amount of iv therapy, age, sex, endpoints, conclusion, and clinical response definition was provid- ed along with the amount of the mean difference be- tween the 30 and 60 min VAS pain score. Network meta-analysis We used MetaInsight based on the “netmeta” R pack- age to perform the meta-analysis(11). Mean differences were calculated based on the baseline VAS pain score and 30 and 60 min scores. Lower values (more nega- tive) of mean difference were considered desirable out- comes. The random effects model was used to pool the mean differences in each arm of intervention. Network plots were used as a graphic illustration of the network of evidence to indicate pairwise interventions, as well as if there is a linked network of evidence, which is a prerequisite for NMA. A Forest plot was used to show the pooled effect estimate. Consistencies were checked for each comparison by “netmeta”, where a P value of lower than 0.05 shows inconsistency and not achieving the perquisites of the NMA. RESULTS Following the literature review, our primary search came into 1654 records. After removing duplicated cas- es and selecting studies for abstract review based on the title, 89 potentially relevant studies were included for full-text review. Seven studies were not retrieved due to having retrospective design, two were case reports, 3 studies were review studies and 7 studies had not used VAS for scoring the pain. The remaining excluded stud- ies were out of date. Finally, 24 studies that were meet- ing the inclusion criteria were selected among those studies. Continuous data was not extractable from 7 studies and one was due to a lack of reporting bassline pain, so 16 studies were entered the NMA (Figure 1). In this systematic review, we included 24 studies with 2724 adult participants. There were 18 studies conduct- ed in Iran, 3 in the USA, one in India, and 2 in Egypt (Table 1). IV therapy volume was also recorded. Stud- ies with IV infusion medications were using the maxi- mum volume of 500 ml of normal saline. In most stud- ies, the male participants were more than female ones. Study timelines of pain reassessment after administra- tion of the medication was ranging from a minimum of 30 minutes to 120 minutes. Some studies had also evaluated the need for rescue medication if the main intervention was not able to relieve the pain. Most stud- ies had used continuous amounts of the pain based on the VAS scores for statistical decisions; while some had defined clinical response. Fifty percent pain reduction or 3 scores (30 mm) reduction in pain was considered for most studies. Qualitative synthesis Ten studies (41.7%) did not find significant differences between conventional and alternative treatments. Des- mopressin was showing fewer analgesic effects than conventional. Only one study mentioned its combina- tion with NSAID to be more effective than NSAID; while MgSO4 and lidocaine use are supported by most studies. NMA results In our NMA analysis, 1759 participants were included in 30 min VAS mean difference analyses and 1038 in 60 min analysis. The number of the pairwise compari- Figure 3. Forrest plot of NMA in 30 min (a) and 60 min (b) pain reduction mean differences. Alternative Medications of Renal Colic- Seghatoleslami et al. Vol 19 No 6 November-December 2022 416 sons is shown in Figure 2, a for 30 min pain scores, and figure 2,b for 60 min. There were a total number of 8 interventions [Dessmopressin, Lidocaine, Ketamine, MgSo4, and combinations of lidocaine, ketamine, and desmopressin with conventional medicine] in 30 min NMA and 7 in 60 min. 16 studies included the 30 min analysis and 9 in 60 min analysis. As shown in Figure 2. We did not achieve the perquisites of head-to-head comparison in most comparisons and only desmopres- sin and lidocaine-based studies had such performances. Consistency results are shown in supplementary tables 1&2. While there was a satisfactory number of studies that we compared different interventions individually with conventional medicines. The forest plot of the results of the studies based on the study arms is presented in Figure 3. Using the random-effects model, arms are compared versus conventional treatment. Mean differences of VAS after 30 min were not significantly higher or low- er than conventional treatment in any of the evaluat- ed arms (P > 0.05) except for the desmopressin that showed significantly lower pain decrease than conven- tional treatment (MD=1.67, 95%CI: 0.23-3.11). Mean differences of VAS after 60 min were not significantly higher or lower than conventional treatment in any of the evaluated arms (P > 0.05). Individual study’s mean differences are shown in supplementary Figures 1&2. DISCUSSION Our network meta-analysis was carried out to determine the most effective medications that can be used as an alternative treatment for renal colic pain. While many previous meta-analyses and systematic reviews are conducted in the field, those are comparing different methods of the conventional medication prescription as well as different types of the NSAIDs or opioids and their different routes of administration. Leng et al. com- pared the efficacy of these conventional medications (NSAIDs versus Opioids) and found no significant differences based on the meta-analysis(36). Another sys- tematic review suggests that some particular NSAIDs might act better for acute renal colic pain reliving(37). Systematic review and meta-analysis by Pathan et al. also showed the same results of the equivalent efficacy of NSAIDs, Opioids, and paracetamol(7). While in some circumstances, due to pre-existing med- ical conditions, administration of conventional medi- cations might get contraindicated, as well as in kidney disease and liver failure patients. So, there is a need for alternative treatments as well as for patients whose pain does not relieve by conventional medications. Our re- view showed that there are multiple pharmacological choices as the alternative. We included Desmopressin, Lidocaine, Ketamine, MgSo4, and combinations of li- docaine, ketamine, and desmopressin with conventional medicine as the alternative treatment; while other po- tential interventions exist that we did not include due to not achieving saturation of the number of required studies for the meta-analysis as well as the Aminophyl- line and Hyoscine(38,39). Our review showed that there were no significant dif- ferences between conventional and alternative therapies in twelve trials (41.7%). Furthermore, there is no con- sensus on the use of certain more modern drugs, such as ketamine or desmopressin. but MgSO4 and lidocaine are supported by the majority of research. Desmopres- sin has many inferior pain-relieving abilities, according to NMA. Ketamine, lidocaine, and MgSo4 had no su- perior effect compared to the standard therapy based on our NMA. In the case of desmopressin, we suggest that this med- ication might not have a good pain-reducing capacity and should be avoided in further research and clinical management as better choices are available. In the study of Jalili et al., pain relief with NSAIDs (e.g. in- domethacin) in renal colic did not improve appreciably when administered in conjunction with intranasal des- mopressin (34). Kumar et al. imply that desmopressin is not efficient analgesia in renal colic, since it only has a minor analgesic effect after 30 minutes. More effective and fast-acting analgesics in the form of NSAIDs or opioids are more appropriate than desmopressin alone because of the agonizing character of renal colic(15). In one more study, Desmopressin has been found to be less effective than ketorolac(23). But, the addition of sub- lingual desmopressin to morphine had no benefit(30). On the other hand. Ghafouri et al. findings revealed that both IV paracetamol and intranasal desmopressin were effective in the ED for the treatment of renal colic pain, while desmopressin had a faster beginning of the action, while finally had no difference(16). Our study showed that MgSO4 and lidocaine use are supported by most studies. In Motamed and Verki's study, the mean pain severity did not change substan- tially between IV fentanyl and IV lidocaine at various intervals after injection, but, the treatment failure rate in the IV lidocaine group was considerably greater 15 minutes after administration(26). Lidocaine may be pre- scribed as an effective, safe, and economical adjuvant to morphine for shortening the time it takes to get pain and nausea relief. Our search was limited to English language papers that might make biased as some important studies might not get included in the review. Also, there are some major limitations in combining all studies of NSAIDs, Opi- oids, and paracetamol into one category; while pooled evidence in literature is showing no significant differ- ence between these medications. We also merged all routes of the administration of medication as there were not enough studies to individually analyze routes of medication administration. CONCLUSIONS Our review showed that there were no significant dif- ferences between conventional and alternative therapies in twelve trials (41.7%). Furthermore, there is no con- sensus on the use of certain more modern drugs, such as ketamine or desmopressin. but MgSO4 and lidocaine are supported by the majority of research. Desmopres- sin has many inferior pain-relieving abilities, according to NMA. Ketamine, lidocaine, and MgSo4 had no su- perior effect compared to the standard therapy based on our NMA. Because several studies support the use of various drugs to treat renal colic pain, physicians can choose medications based on their patient's condition and response to therapy. CONFLICT ON INTEREST None declared by the authors. Review 417 Alternative Medications of Renal Colic- Seghatoleslami et al. SUMMARY lidocaine and MgSo4 can be used for kidney pain of not responding to ordinary medications. Ketamine might be useful in some circumstances. Desmopressin is better to be avoided REFERENCES 1. Bultitude M, Rees J. Management of renal colic. Bmj. 2012 Aug 29;345. 2. Kominsky HD, Rose J, Lehman A, Palettas M, Posid T, Caterino JM, Knudsen BE, Sourial MW. Trends in acute pain management for renal colic in the emergency department at a tertiary care academic medical center. J of Endourol. 2020 Nov 1;34:1195-202. 3. Alanazi NF, Alanazi MA, Alanazi BA, Alsaleh AK, Alomayri MI, Alanazi AT, Badaood AM, Wazzan HR, Alhadhari YA, Nasser G, Aldawsari FS. Renal Colic Disease: Overview, Management, and Prevention. J of Biochem Tech. 2020;11: 85-8. 4. Thia I, Saluja M. An update on management of renal colic. Aust J Gen Pract. 2021;50:445- 9. 5. Gandhi A, Hashemzehi T, Batura D. The management of acute renal colic. Br J Hosp Med. 2019;80:C2-6. 6. e Silva LO, Scherber K, Cabrera D, Motov S, Erwin PJ, West CP, Murad MH, Bellolio MF. Safety and efficacy of intravenous lidocaine for pain management in the emergency department: a systematic review. Ann Emerg Med. 2018; 72:135-44. 7. Pathan SA, Mitra B, Cameron PA. A systematic review and meta-analysis comparing the efficacy of nonsteroidal anti- inflammatory drugs, opioids, and paracetamol in the treatment of acute renal colic. Eur Urol. 2018; 73:583-95. 8. Chou R, Wagner J, Ahmed AY, Blazina I, Brodt E, Buckley DI, Cheney TP, Choo E, Dana T, Gordon D, Khandelwal S. Treatments for acute pain: a systematic review. Agency for Healthcare Research and Quality (US), Rockville (MD); 2020. 9. Gu HY, Luo J, Wu JY, Yao QS, Niu YM, Zhang C. Increasing nonsteroidal anti-inflammatory drugs and reducing opioids or paracetamol in the management of acute renal colic: based on three-stage study design of network meta- analysis of randomized controlled trials. Front in Pharmacol. 2019;10:96. 10. Halpern SH, Douglas MJ. Appendix: Jadad scale for reporting randomized controlled trials. Evidence-based Obstetric Anesthesia. Oxford, UK: Blackwell Publishing Ltd. 2005:237-8. 11. Owen RK, Bradbury N, Xin Y, Cooper N, Sutton A. MetaInsight: an interactive web‐ based tool for analyzing, interrogating, and visualizing network meta‐analyses using R‐shiny and netmeta. Res Synth Methods. 2019;10:569-81. 12. Motov S, Fassassi C, Drapkin J, Butt M, Hossain R, Likourezos A, Monfort R, Brady J, Rothberger N, Mann SS, Flom P. Comparison of intravenous lidocaine/ ketorolac combination to either analgesic alone for suspected renal colic pain in the ED. Am J Emerg Med. 2020; 38:165-72. 13. Soleimanpour H, Hassanzadeh K, Vaezi H, EJ Golzari S, Esfanjani RM, Soleimanpour M. Effectiveness of intravenous lidocaine versus intravenous morphine for patients with renal colic in the emergency department. BMC Urol. 2012;12:1-5. 14. Sadrabad AZ, Abarghouei SA, Rad RF, Salimi Y. Intravenous magnesium sulfate vs. morphine sulfate in relieving renal colic: A randomized clinical trial. Am J Emerg Med. 2021;46:188-92. 15. Kumar S, Behera NC, Sarkar D, Prasad S, Mandal AK, Singh SK. A comparative assessment of the clinical efficacy of intranasal desmopressin spray and diclofenac in the treatment of renal colic. Urol Res. 2011; 39:397-400. 16. Ghafouri HB, Abazarian N, Yasinzadeh M, Modirian E. Intravenous paracetamol vs intranasal desmopressin for renal colic in the emergency department: A randomized clinical trial. Pain Med. 2020;21:3437-42. 17. Drapkin J, Motov S, Likourezos A, Monfort R, Butt M, Hossain R, Gulati V, Brady J, Mann S, Rothberger N, Marshall J. 1 a randomized trial comparing the combination of intravenous lidocaine and ketorolac to either analgesics alone for emergency department patients with acute renal colic. Ann Emerg Med. 2018 1;72:S1. 18. Forouzan A, Masoumi K, Motamed H, Esfahani S, Delirrooyfard A. Comparison of the analgesic effect of intravenous ketamine versus intravenous morphine in reducing pain of renal colic patients: double-blind clinical trial study. Rev Recent Clin Trials. 2019 ;14:280-5. 19. Sotoodehnia M, Farmahini-Farahani M, Safaie A, Rasooli F, Baratloo A. Low-dose intravenous ketamine versus intravenous ketorolac in pain control in patients with acute renal colic in an emergency setting: a double- blind randomized clinical trial. Korean J Pain. 2019;32:97. 20. Grill J, Bryant C, Dunikoski L, Carrasco Z, Wisniewski SJ, Price K. Sub-Dissociative Ketamine Use in the Emergency Department for Treatment of Suspected Acute Nephrolithiasis: The SKANS Study. Spartan Med Res J. 2019;3. 21. Pouraghaei M, Moharamzadeh P, Paknezhad SP, Rajabpour ZV, Soleimanpour H. Intranasal ketamine versus intravenous morphine for pain management in patients with renal colic: a double-blind, randomized, controlled trial. World J of Urol. 2021;39:1263-7. 22. Metry AA, Fahmy NG, Nakhla GM, Wahba RM, Ragaei MZ, Abdelmalek FA. Lornoxicam with low-dose ketamine versus pethidine to control pain of acute renal colic. Pain Res and treat. 2019:3976027. 23. Dolatabadi AA, Memary E, Kariman H, Gigloo Vol 19 No 4 July-August 2022 252 Alternative Medications of Renal Colic- Seghatoleslami et al. Vol 19 No 6 November-December 2022 418 KN, Baratloo A. Intranasal desmopressin compared with intravenous ketorolac for pain management of patients with renal colic referring to the emergency department: a randomized clinical trial. Anesthesiology and pain medicine. Anesth Pain Med . 2017; 7:e43595. 24. AHMED EA, ZAYNAB M, EL SOOD IA. Evaluating Effectiveness of Intravenous Magnesium Sulfate As a Treatment in Acute Renal Colic Patients Attending Suez Canal University Hospital Emergency Department. The Med J of Cairo Uni. 2019 ;87:4021-5. 25. Verki MM, Porozan S, Motamed H, Fahimi MA, Aryan A. Comparison the analgesic effect of magnesium sulphate and Ketorolac in the treatment of renal colic patients: Double- blind clinical trial study. Am J Emerg Med. 2019;37:1033-6. 26. Motamed H, Verki MM. Intravenous lidocaine compared to fentanyl in renal colic pain management; A randomized clinical trial. Emerg (Tehran). 2017; 5:e82. 27. Jokar A, Cyrus A, Babaei M, Taheri M, Almasi- Hashiani A, Behzadinia E, Yazdanbakhsh A. The effect of magnesium sulfate on renal colic pain relief; a randomized clinical trial. Emerg (Tehran). 2017; 5. 28. Shirazi M, Salehipour M, Afrasiabi MA, Aminsharifi A. Analgesic effects and safety of desmopressin, tramadol and indomethacin in patients with acute renal colic; a randomized clinical trial. Bult of Emerg & Trauma. 2015;3:41. 29. Majidi A, Derakhshani F. Intravenous magnesium sulfate for pain management in patients with acute renal colic; a randomized clinical trial. Arch Acad Emerg Med . 2019;8:e5. eCollection 2020. 30. Shirvani MK, Mahboub MD, Ghazi M, Delijani A. A comparison of the effects of morphine and sublingual desmopressin combination therapy with morphine alone in treatment of renal colic: a controlled clinical trial. Urol J. 2015;12:2001-4. 31. Firouzian A, Alipour A, Dezfouli HR, Kiasari AZ, Baradari AG, Zeydi AE, Ahidashti HA, Montazami M, Hosseininejad SM, Kochuei FY. Does lidocaine as an adjuvant to morphine improve pain relief in patients presenting to the ED with acute renal colic? A double-blind, randomized controlled trial. Am J Emerg Med. 2016;34:443-8. 32. Farnia MR, Jalali A, Vahidi E, Momeni M, Seyedhosseini J, Saeedi M. Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic. Am J Emerg Med. 2017;35:434-7. 33. Abbasi S, Bidi N, Mahshidfar B, Hafezimoghadam P, Rezai M, Mofidi M, Farsi D. Can low-dose of ketamine reduce the need for morphine in renal colic? A double-blind randomized clinical trial. Am J Emerg Med. 2018;36:376-9. 34. Jalili M, Shirani F, Entezari P, Hedayatshodeh M, Baigi V, Mirfazaelian H. Desmopressin/ indomethacin combination efficacy and safety in renal colic pain management: a randomized placebo controlled trial. Am J Emerg Med. 2019;37:1009-12. 35. Mozafari J, Verki MM, Motamed H, Sabouhi A, Tirandaz F. Comparing intranasal ketamine with intravenous fentanyl in reducing pain in patients with renal colic: A double-blind randomized clinical trial. Am J Emerg Med. 2020;38:549-53. 36. Leng XY, Liu CN, Wang SC, Peng HD, Wang DG, Pan HF. Comparison of the Efficacy of Nonsteroidal Anti-Inflammatory Drugs and Opioids in the Treatment of Acute Renal Colic: A Systematic Review and Meta-Analysis. Front in pharmacol. 2021;12:728908. 37. García-Perdomo HA, Echeverría-García F, López H, Fernández N, Manzano-Núñez R. Pharmacologic interventions to treat renal colic pain in acute stone episodes: systematic review and meta-analysis. Progrès en Urologie. 2017;27:654-65. 38. Akbari H, Foroughian M, Abiri S, Kalani N, Rayatdoost E, Safaei M, Zarei MJ. Comparing the Analgesic Effect of Aminophylline and Hyoscine with Morphine on Renal Colic: a Randomized Clinical Trial. Front in Emerg Med. 2020;4:e85. 39. Foroughian M, Abiri S, Akbari H, Shayesteh Bilandi V, Habibzadeh SR, Alsana F, Taghipour N, Kalani N, Rayat Dost E. Effectiveness of intravenous lidocaine versus intravenous morphine in reducing acute extremity trauma-induced pain: A triple- blind randomized clinical trial. Koomesh. 2020;22:411-8. Review 419 Alternative Medications of Renal Colic- Seghatoleslami et al.