Archives of Academic Emergency Medicine. 2020; 8(1):e27 REV I EW ART I C L E Intravenous Amide Anesthetics to Treat Pain Associated with Renal Colic in the Emergency Department: a System- atic Review Andrew C. Miller1,2∗, Colton Faza1, Alberto A. Castro Bigalli3, Abbas M. Khan2, Kerry A. Sewell4, Alexandra King5, Amir Vahedian-Azimi6, Shahriar Zehtabchi7 1. Department of Emergency Medicine, Vidant Medical Center, East Carolina University Brody School of Medicine, Greenville, NC, USA. 2. The Morzak Collaborative, Greenville, NC, USA. 3. East Carolina University Brody School of Medicine, Greenville, NC, USA. 4. William E. Laupus Health Sciences Library, East Carolina University, Greenville, NC, USA. 5. Emergency Medicine and Toxicology Department, Vidant Medical Center, Greenville, NC, USA. 6. Trauma Research Center, Nursing Faculty, Baqiyatallah University of Medical Sciences, Tehran, Iran 7. Department of Emergency Medicine, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, USA. Received: January 2020; Accepted: February 2020; Published online: 18 March 2020 Abstract: Introduction: Renal colic affects 12% of the U.S. population, accounting for nearly 1% of emergency department (ED) visits. Current recommendations advocate narcotic-limiting multimodal analgesia regimens. The objec- tive of this review is to determine if in patients with renal colic (Population), intravenous (IV ) amide anesthetics (Intervention) result in better pain control, lower requirements for rescue analgesia, or less adverse medication effects (outcome) compared to placebo, non-steroidal anti-inflammatory drugs (NSAIDs), or opiates (Compar- isons). Methods: Scholarly databases and relevant bibliographies were searched using a pre-designed system- atic review protocol and registered with PROSPERO. Inclusion criteria were: (1) randomized clinical trial (RCT), (2) age ≥ 18 years, (3) confirmed or presumed renal colic, (4) amide anesthetic administered IV. Eligible compar- ison groups included: placebo, conventional therapy, acetaminophen, NSAID, or opiate. The primary outcome was pain intensity at baseline, 30, 60, and 120 minutes. Trial quality was graded, and risk-of-bias was assessed. Results: Of the 3930 identified references, 4 RCTs (479 participants) were included. One trial (n=240) reported improved analgesia with IV lidocaine (LidoIV ) plus metoclopramide, compared to morphine. All other trials reported unchanged or less analgesia compared to placebo, ketorolac, or fentanyl. Very severe heterogeneity (I2= 88%) precluded pooling data. Conclusion: Current evidence precludes drawing a firm conclusion on the efficacy or superiority of LidoIV over traditional therapies for ED patients with renal colic. Evidence suggests Li- doIV may be an effective non-opiate analgesic alliterative; however, it’s efficacy may not exceed that of NSAIDs or opiates. Further study is needed to validate the potential improved efficacy of LidoIV plus metoclopramide. Keywords: Renal Colic; Kidney Calculi; Lidocaine; Analgesia; Emergency Service, Hospital Cite this article as: C. Miller A, Faza C, A. Castro Bigalli A, M. Khan A, A. Sewell K, King A, Vahedian-Azimi A, Zehtabchi Sh. Intravenous Amide Anesthetics to Treat Pain Associated with Renal Colic in the Emergency Department: a Systematic Review. Arch Acad Emerg Mede. 2020; 8(1): e27. ∗Corresponding Author: Dr. Andrew C. Miller; Department of Emergency Medicine East Carolina University, Brody School of Medicine, 600 Moye Blvd, mailstop 625, Greenville, NC 27834, Phone: +1 (252) 744-5726, Fax: +1 (252) 744-5014, E-Mail: Taqwa1@gmail.com, E-Mail: MillerAndr17@ecu.edu. 1. Introduction Pain is the most common reason for emergency department (ED) visits in the United States (U.S.) (1), and its management requires mastery of multimodal approaches to achieve safe and effective analgesia. Nephrolithiasis and renal colic affect approximately 12% of the U.S. population (up to 5% in China) (2) and accounts for nearly 1% of ED visits and hospital ad- 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 A. C. Miller et al. 2 missions in the U.S. (2–5). For patients with prior stones, 10-year recurrence rates approach 50% (3,6). The pain of re- nal colic origin is multifactorial and is related to obstruction of urinary flow with subsequent increase in prostaglandin- mediate ureteral spasm (6,7). As most renal calculi pass spontaneously, acute manage- ment should focus on rapid analgesia, diagnosis confirma- tion, and recognition of complications requiring immediate intervention (7). Approximately 85% of ED patients with renal colic are treated with analgesics (3). Whether used alone or in combination, NSAIDs and opioids constitute the primary therapeutic medications in ED management of re- nal colic (8). Each drug class possesses potentially unfavor- able side effects and contraindications. Disadvantages to NSAIDs include lack of titratability, nausea, epigastric pain, and contraindications including renal insufficiency, peptic ulcer disease, the elderly (age >70 years), and concomitant use of anticoagulation or antiplatelet agents (9). Opioid ad- ministration in turn may lead to nausea, vomiting, pruri- tus, lethargy, bradycardia, hypotension, or respiratory de- pression, and may be relatively contraindicated for patients with a history of opioid abuse or dependence. Despite ef- ficacy and possibly favorable side-effect profile of NSAIDS over opiates (6), 43% of patients are treated with an opiate, and 70% are prescribed an opiate on discharge (3). Moreover, ED opioid administration and prescription has been linked to an increased risk of recurrent opioid use (10). Current practice is moving towards recent U.S. Food and Drug Ad- ministration (FDA) goals that emphasize analgesia through multimodal regimens that decrease opiate use (11). Insuffi- cient data regarding the efficacy of alternative regimens and their side-effect profiles have hampered efforts to move away from opiate heavy regimens (12). There is a need for identi- fication and validation of safe and effective analgesia tech- niques for renal colic, which limit narcotic consumption and prescription, and provide treatment alternatives for patients who are unable to tolerate or have serious contraindications to NSAIDs or opiates (12). Intravenous local anesthetic use has emerged as an opiate- sparing alternative in treatment of renal colic. Local anes- thetics halt impulse initiation and transmission processes in neuronal axons, and may be categorized into two major chemical classes: amino esters and amino amides (6). Amide local anesthetics are widely used for topical and local anes- thesia, and as systemic antiarrhythmics (1). Lidocaine, an amino amide, has been described to have analgesic, anti- hyperalgesic, anti-inflammatory, and anti-bacterial proper- ties (1,13,14). The analgesic effect from systemic adminis- tration affects both the peripheral and central nervous sys- tem (15). Lidocaine decreases excitability and conduction of unmyelinated C fibers, and intravenous lidocaine (Li- doIV ) suppresses post-synaptic reflexes in the spinal dor- sal horn (15). Its mechanisms include reversible inhibi- tion of voltage-gated open and inactivated sodium channels and G-protein-coupled receptors (3,13,15,16). Central anti- nociceptive effects are mediated through actions on mus- carinic and nicotinic receptors, which in turn increase in- traspinal acetylcholine release to reinforce the inhibitory de- scending pain pathway (15). Anti-hyperalgesic effects are mediated through the N-methyl-D-aspartate (NMDA) recep- tor (14,15). LidoIV has a desirable pharmacokinetic profile, with a rapid onset and long duration-of-action (half-life 60-120 min), but the analgesic effects may last longer (1,17). Approximately, 90% of lidocaine is metabolized in the liver by dealkylation to lower potency active metabolites monoethylglycinexylidide (MEGX) and glycinexylidide (GX) (13,15), while ≤10% is ex- creted unchanged in the urine (15). LidoIV application for ED patients with renal colic has been reported to improve pain intensity, time to pain relief, and nausea in randomized clinical studies (8,18–21), non- randomized clinical studies (22), and case series (17,23–25), and may be considered as a viable non-opioid addition or an alternative to traditional treatment modalities. We inves- tigated the evidence on using intravenous amide anesthet- ics for analgesia and opioid sparing effects in patients with acute renal colic. The objective of this project is to address the following research question: In patients with renal colic (Population) do intravenous amide anesthetics such as li- docaine (Intervention) improve pain intensity, need for res- cue analgesia, opiate consumption, or adverse events (Out- comes) compared to placebo, NSAIDs, or opiates (Compar- isons)? 2. Methods This systematic review followed the steps outlined in Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (26). A systematic protocol was developed a priori and registered with PROSPERO (# CRD42019130355). The primary outcome was pain intensity at baseline and 15, 30, 60, and 120 minutes post-treatment. The secondary outcomes were: (1) need for rescue analgesia at 30 or 60 minutes, (2) time to pain free, (3) treatment failure, and (4) adverse events. A librarian-performed systematic search strategy was conducted (Supplemental Digital Content 1) in Cochrane CENTRAL, CINAHL, Embase, Latin American and Caribbean Health Sciences Literature (LILACS), Medline, Scopus, and Web of Science (WoS). Additional investigator- performed structured searches were conducted in: China National Knowledge Infrastructure (CHKD-CNKI), infor- mation/Chinese Scientific Journals database (CSJD-VIP), Directory of Open Access Journals (DOAJ), IEEE-Xplorer, 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):e27 Magiran, Scientific Information Database (SID), TUBITAK ULAKBIM, Russian Science Citation Index (RSCI), Korean Journal Database (KCI), and Scientific Electronic Library Online (SciELO). Relevant bibliographies were searched. Searches were not limited by date, language, or publica- tion status. Clinical trial registries were searched to limit publication bias, including: ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and the Australian New Zealand Clinical Trials Registry (ANZCTR). Abstracts of the conference pro- ceedings of the relevant disciplines (emergency medicine, urology, nephrology, pain management) were searched (past 5 years). When the presented data were incomplete, the authors were contacted to obtain the missing information. These trials were only included if the authors responded to correspondence affirmatively with the requested informa- tion. Inclusion criteria were: (1) randomized controlled human clinical trial, (2) patients aged ≥ 18 years, (3) presumed or confirmed renal colic, (4) amino amide anesthetic admin- istered intravenously (eg. LidoIV ) compared to placebo or another analgesic. Data of pain intensity that measured as either a 10 cm visual analogue scale (VAS) or 10-point numeric rating scale (NRS) were summarized. Significant improvement in pain intensity was defined as improvement in ≥ 3 cm or points on VAS or NRS, respectively. Rescue anal- gesia was defined as any analgesia medication administered following the study drug. Exclusion criteria were: (1) non-randomized study design, (2) studies enrolling patients aged < 18 years, (3) drug ad- ministration by routes other than intravenous, (4) studies published only in abstract form (or unpublished) for which the authors did not respond to correspondence by providing the requested information. Reference management and application of inclu- sion/exclusion criteria was performed using Covidence (Covidence, Melbourne, Australia). Four authors reviewed the titles and abstracts to determine inclusion eligibility. Four authors extracted study data. Any disagreements were resolved by consensus. Four authors independently assessed the risk-of-bias (RoB) using two validated tools: (1) Grading of Recommendations, Assessment, Development and Eval- uations (GRADE) (27), and RoB 2.0: "Revised tool for Risk of Bias in randomized trials" (28). The authors considered methods of randomization and allocation, blinding (of treat- ment administrator, participants, and outcome assessors), selective outcome reporting (e.g. failure to report adverse events), incomplete outcome data, and sample size calcu- lation. Each trial was graded as high, low or unclear risk of bias (RoB) for each criterion. Publication bias was assessed using both the Egger (29) and Begg-Mazumdar methods (30). Heterogeneity was evaluated using I2 statistic. The confidence interval for I2 was constructed using the iterative non-central chi-square distribution method of Hedges and Piggott (31). The threshold value for severe heterogenity was specified to be I2 ≥50%, and very serious heterogenity was specified as I2 >75%. Data pooling and meta-analysis was planned if I2 <50%. 3. Results The complete search was performed on December 19, 2018. The search strategy identified 3930 references, of which 4 RCTs (479 participants) met the inclusion criteria (8,18–20). Two ongoing studies were identified in clinical trial registries (32,33). See Figure 1 for the PRISMA flow diagram. The in- cluded studies are summarized in Table 1. One study took place in a high-income economy (USA) (8). Three were in a middle-income economy (Iran) (18–20). No studies were identified in low-income economies. Two published ab- stracts were excluded. The first was an RCT published only in abstract form for which the authors did not respond to corre- spondence (21). The second duplicated information avail- able in a published manuscript (22). The primary reason for exclusion of full-text manuscripts was non-randomized study design. Two unpublished ongoing trials were identi- fied (32,33). No additional studies were identified through bibliographic and conference abstracts analyses that were not previously identified through other search methods. The GRADE assessments are presented in Table 2. RoB assess- ment indicated that how each study ranked regarding the risk of selection bias, performance bias, detection bias, reporting bias, and "other" bias (8,18–20). Two studies were similarly at low risk for attrition bias (8,18), whereas 2 had unclear risk of attrition bias (19,20). Lastly, 3 studies had low risk of bias due to sample size (8,19,20), whereas one had unclear RoB (18). Additionally, all of the included studies were double-blind (8,18–20). Although all 4 studies had a control arm, but only one had a placebo arm (lidocaine + morphine vs. placebo + morphine) (18). One study reported no patient attrition (8), whereas one reported 19% attrition (18), and two did not re- port attrition data (19,20). Furthermore, each included study reported their intended primary outcomes. Moreover, one study reported adverse events (AE) (20), 2 reported no AEs (8,18), and one did not report on AEs (19). All but one study reported the method of sample size calculation (18). All included studies gave adequate information regarding di- agnostic criteria, namely that patients were diagnosed with presumed or confirmed renal colic (8,18–20). Heterogeneity was noted in the methods and timing of pain intensity as- sessments. Three studies utilized a 10 cm VAS scale (18–20), and 1 utilized a 10-point NRS (8). Pain intensity was assessed at 15 minutes in 3 studies (8,19,20), at 30 minutes in 4 stud- ies (8,18–20), at 60 minutes in 3 studies (8,18,20), and at 120 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 A. C. Miller et al. 4 Table 1: List of included studies Author [ Year]; (Reference #) Setting, design (N) Intervention Comparison Demographics: Lidocaine (L) vs. no lidocaine (NL) Primary End- points Secondary End- points Firouzian [2016]; (18) Iran, single cen- ter, RCT, double- blind (89) Lidocaine 1.5 mg/kg IV plus morphine 0.1 mg/kg infusion over 2-4 minutes. Morphine 0.1 mg/kg plus N.S. bolus infusion over 2-4 minutes. Age, years: (L) 37.91±10.76, (NL) 37.95±12.6 Sex, male: (L) 77%, (NL) 83% Pain intensity measured by VAS (0-10) at baseline, 5, 10, 30, 60, and 120 minutes. (1) Time to pain free (2) Nausea in- tensity (3) Time to nausea free Motamed [2017]; (19) Iran, single cen- ter, RCT, double- blind (90) Lidocaine 1.5 mg/kg IV infusion over 2 minutes. Fentanyl 1.5 mcg/kg IV in- fusion over 2 minutes. Age, years: (L) 39.08±6.64, (NL) 34.08±8.87 Sex, male: (L) 86.7%, (NL) 93.3% Pain intensity measured by VAS (0-10) at baseline, 5, 10, 15, and 30 minutes. Rescue medi- cation at 15- & 30-minutes post- administration. Motov [2019]; (8) USA, single cen- ter, RCT, double- blind (150) Lidocaine 1.5 mg/kg IV infusion over 10 minutes. (1) Ketorolac 30 mg IV push with 10 min N.S. infu- sion. (2) Ketoro- lac 30 mg IV push plus Lidocaine 1.5 mg/kg IV infusion over 10 minutes. Age, years: (L only) 39.34±10.95 (Combination) 42.92±10.36 (NL) 42.34±10.47 Sex, male: (L only) 54%, (Combina- tion) 56%, (NL) 56% Pain intensity measured by numerical rating scale (0-10) at baseline, 5, 10, 30, and 60 minutes. (1) Adverse effects (2) Use of diag- nostic imaging Soleimanpour [2012]; (20) Iran, single cen- ter, RCT, double- blind, (150) Lidocaine 1.5 mg/kg IV slow push from 10 cc syringe. Morphine 0.1 mg/kg IV slow push from 10 cc syringe. Age, years: (L) 37.71±11.08, (NL) 35.23±12.37 Sex, male: (L) 28%, (NL) 72% Pain intensity measured by VAS (0-10) at baseline, 5, 10, 15, and 30 minutes. (1) Pain resolu- tion measured as VAS < 3/10 for 30 minutes. (2) Res- cue medication at 30 minutes. (3) Adverse effects Abbreviations: ED means emergency department; IV means intravenous; N.S. means normal saline; RCT means randomized controlled trial; VAS means visual analogue scale. Table 2: GRADE quality of evidence ratings Certainty assessment Variable No of stud- ies Study de- sign Risk of bias Inconsis- tency Indirectness Imprecision Other con- siderations Certainty Pain inten- sity 4 RCT Not serious Serious Not serious Not serious None ⊕⊕⊕©MODERATE Rescue medication 1 RCT Not serious Not Serious Not Serious Not Serious Publication bias strongly suspected ⊕⊕⊕©MODERATE Time to pain free 1 RCT Not serious Not Serious Not Serious Not Serious Publication bias strongly suspected ⊕⊕⊕©MODERATE Treatment failure 1 RCT Not serious Not Serious Not Serious Not Serious Publication bias strongly suspected ⊕⊕⊕© MODERATE RCT means randomized controlled trial. minutes in 2 studies (8,18). Only one study assessed time to pain-free (18), one assessed treatment failure (19), and one assessed the need for rescue analgesia (at 30 and 60 minutes) (8). All four included trials gave adequate statistical descriptions; including appropriate use of statistical tests (8,18–20). No significant baseline differences were noted between groups (8,18–20). With the exception of one trial that reported bet- ter pain control with lidocaine (compared to IV morphine) at 10, 15, and 30 minutes post-administration (20), all other trials reported similar (or worse) pain intensity compared to placebo (18), ketorolac (8), or fentanyl (Figure 3) (19). 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):e27 Figure 1: PRISMA Flow Diagram. Since not all trials reported immediate (10 minutes post- administration) or longer pain relief (60 or 120 minutes post- administration), it was not possible to draw a conclusion about the immediate or long-term analgesia effects of LidoIV. A forest plot depicting pain score comparisons between regi- mens with and without lidocaine is provided in Figure 2. Neither the Egger (z = 1.31, p-value = 0.1892) nor Begg- Mazumdar method (z = -0.89, P-Value = 0.6273) identified evidence of publication bias (Figure 3). The planned meta- analysis was not performed due to very severe heterogeneity (I2 >75%). 4. Discussion This project aimed to clarify the clinical efficacy of Li- doIV for decreasing the pain intensity and analgesic require- ments associated with acute renal colic. Although substan- tial improvement was not noted over comparators, overall, some observations warrant further discussion. Of note, the methodology of the Soleimanpour et al. study that did report improvement over morphine differed from the other studies in a few important ways, namely: (1) coadministration with metoclopramide and (2) conservative IV fluid strategy (20). Metoclopramide is a procaine amide structural analogue that may exert both antiemetic and analgesic effects. Pro- posed mechanisms include calcium channel-, opiate-, and prolactin-mediated mechanisms. The latter contributes to the analgesic action of the endogenous opioid system as evidenced by its reversibility by naloxone. Addition- ally, metoclopramide is a dopamine antagonist, increasing acetylcholine levels at neuro-effector junctions and post- ganglionic nerve terminals by inhibiting the action of acetyl- cholinesterase. Metoclopramide has been described to have antispasmodic effects on ureteral smooth muscle (34). Stud- ies have described its analgesic efficacy in acute renal colic to exceed those of the isosorbide dinitrate (35), morphatropin (36), tenoxicam (37), and xintonding (38); however, findings were not significant for metoclopramide plus dipyrone vs. ketorolac alone (39), or metoclopramide plus pethidine vs. morphine alone (40). It has been described that combining lidocaine with metoclopramide may increase analgesia over lidocaine alone (41). It remains unclear whether an analge- sia augmenting synergistic relationship exists between meto- clopramide and the amide anesthetics. The second way in which the study by Soleimanpour et al. differed from the others was fluid management strategy. In many regions, it is commonplace to treat patients with acute renal colic with forced IV fluids; however, this remains controversial. Large volumes of IV fluids are often administered to produce a di- uresis that mechanically "flushes out" the stone. However, the benefit of this approach has not consistently borne out in clinical practice (42,43). The Soleimanpour et al. protocol did not administer forced IV fluids (20), whereas the other in- cluded studies did not specify the IV fluid management strat- 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 A. C. Miller et al. 6 Figure 2: Forrest plot of pain scores in lidocaine-containing versus no lidocaine regimens. egy (8,18,19). The influence of varied hydration strategies on the outcomes of these studies remains unclear. In some situations, LidoIV doses may need to be modified. With commonly recommended doses, lidocain’s therapeu- tic index remains very high and plasma concentrations stay largely below the cardiotoxic and neurotoxic threshold lev- els (15). For renal colic, the recommended dose of LidoIV is 1.5 mg/kg (maximum 200 mg/dose) administered over 20- 30 minutes (17,23,25). For patients being admitted, repeat dosing or an infusion may be used to maintain a steady- state plasma concentration: 1.5 mg/kg IV bolus, then 50 µg/kg/min (3.0 mg/kg) IV infusion for one hour, then 25 µg/kg/min (1.5 mg/kg) IV infusion for the second hour (h), then 12 µg/kg/min (0.7 mg/kg) IV infusion for the next 22 h, and finally 10 µg/kg/min (0.6 mg/kg) IV infusion from 24 to 48 h (15). Without a loading dose, it takes >60 min for Li- doIV to achieve a therapeutic steady-state plasma concen- tration (15). Although continuous lidocaine infusion might theoretically lead to toxicity over time, blood concentrations reported in clinical studies have remained below toxic levels ( 5 µg/ml), except for cardiac surgery trials in which higher doses were used for longer durations (15). As hepatic blood flow appears to be a limiting factor for lido- caine metabolism (13), the reduction in hepatic blood flow in patients with congestive heart failure may prolong the elimi- nation half-life (T1/2) (44). No dose adjustment is necessary in patients with moderate liver cirrhosis; however, the dose should be decreased by 50% in patients with severe cirrhosis (Child score C) (45). Additionally, first- and second-degree heart blocks could be exacerbated and progress to a higher degree block with lidocaine administration, and both cardio- vascular instability and concomitant use of alpha-agonists or beta-blockers are relative contraindications (46). More- over, lidocaine clearance is linearly altered with kidney im- pairment, thus the elimination T1/2 of lidocaine and GX (but not MEGX) is doubled in case of severe renal insufficiency (47). Volume of distribution is also an important factor when con- sidering LidoIV dose and metabolism. Elderly patients have an increase in apparent volume of distribution, and conse- quently a significantly longer elimination T1/2 compared to younger patients (2.7 vs. 1.6 h) (48). For elderly patients, 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 7 Archives of Academic Emergency Medicine. 2020; 8(1):e27 Figure 3: Funnell plot and publication bias assessment. the initial loading dose should be the same, but any continu- ous infusion rate should be decreased by approximately 35% (15). The increased volume of distribution similarly accounts for the prolonged clearance seen in obese patients compared to non-obese patients (48). For obese patients, the bolus or loading dose should be calculated based on the patient’s to- tal body weight, but the continuous infusion rate should be based on the ideal body weight (15). Lastly, lidocaine crosses the placenta and the blood–brain barriers via simple passive diffusion, and is excreted in breast milk (15). Thus, the clear- ance rate should be taken into consideration for breastfeed- ing mothers to avoid toxicity in the breast-fed infant (15). 5. Limitations Since the data from some studies was unavailable, some risk of publication and selective reporting bias exists. Ad- ditionally, all included studies were conducted in Asia and North America. It is possible that genetic differences in drug metabolism or response may account for some of the ob- served variation in response. We identified no other system- atic reviews or meta-analyses on this topic for comparison. 6. Conclusion While we cannot draw a firm conclusion on the efficacy or superiority of intravenous lidocaine over traditional therapy for the treatment of renal colic in the emergency department, the available evidence indicates that the analgesic effects of intravenous lidocaine may not exceed that of NSAIDS or opi- ates. Although evidence exists to suggest the efficacy of in- travenous lidocaine as an alternative treatment modality for acute renal colic, additional study is needed to clarify its role as compared to other traditional treatment modalities. 7. Declaration 7.1. Acknowledgements We thank Dr. Seyed M. Hosseininejad from Mazandaran University of Medical Sciences (Sari, Iran) (18), Dr. Hassan Soleimanpour from Tabriz University of Medical Sciences (Tabriz, Iran) (20), and Dr. Mohammadreza Maleki Verki from Ahvaz Jundishapur University of Medical Sciences (Ah- vaz, Iran) (19) for supplying unpublished summary data from their respective studies (18). We also thank Mr. Jefferson Drapkin from Maimonides Medical Center in Brooklyn, NY, USA for responding to inquiries for data clarification (8). The authors attest to the originality of this previously unpub- lished work, that all listed authors contributed meet Interna- tional Committee of Medical Journal Editors (ICMJE) criteria for authorship, and that all persons meeting ICMJE author- ship criteria are credited. 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 A. C. Miller et al. 8 7.2. Authors Contributions Concept generation and project supervision was performed by ACM. Literature searches were performed by ACM and KAS. Studies were screened for inclusion by ACM, CF, AACB and AMK. Data was abstracted by ACM, CF, AACB and AMK. Unpublished data was acquired from corresponding authors by ACM, AVA and SZ. Risk-of-bias analysis and evidence grading was performed by ACM, CF, AACB and AMK. Statis- tics and figure generation was performed by ACM, AVA and SZ. Manuscript preparation was performed by ACM, CF, AACB, AMK, AVA and SZ. Manuscript revision was performed by ACM and SZ. Authors ORCIDs Andrew C. Miller: 0000-0001-8474-5090 Colton Faza: 0000-0002-0287-2801 Alberto A. Castro Bigali: 0000-0002-1813-3333 Abbas M. Khan: 0000-0001-6295-3788 Kerry Sewell: 0000-0002-0405-3789 Alexandra R. King: 0000-0002-6123-2943 Amir Vahedian-Azimi: 0000-0002-1678-7608 Shahriar Zehtabchi: 0000-0002-6427-986X 7.3. Funding Support No funding was received for this work. 7.4. Conflict of Interest The authors have no conflicts of interest to disclose. There were no sources of funding or support for this project. 7.5. Differences between protocol and review Due to significant methodological heterogeneity between studies, the planned meta-analysis was not performed. 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Supplemental Digital Content 1; Literature search strategy MEDLINE via PubMed ("Renal Colic"[Mesh] OR "Kidney Calculi"[Mesh] OR "Colic"[Mesh] OR "Nephrolithiasis"[Mesh:NoExp] OR "Urinary Calculi"[Mesh] OR ((Renal[tiab] OR kidney[tiab] OR ureteral[tiab] OR ureteric[tiab] OR urinary[tiab]) AND (Colic[tiab] OR colics[tiab] OR pain[tiab] OR stone[tiab] OR stones[tiab] OR calculus[tiab] OR calculi[tiab])) OR urolithi- asis[tiab] OR Nephrolithiasis[tiab] OR "tract stone"[tiab] OR "tract stones"[tiab] OR "acute pain"[tiab] OR "abdominal pain"[tiab] OR "abdominal cramps"[tiab] OR "abdominal cramping"[tiab]) AND (Lidocaine[Mesh] OR Lignocaine[tiab] OR Xylocaine[tiab] OR lidocaine[tiab] OR lignocain[tiab] OR xylocain[tiab] OR xyloneural[tiab] OR octocaine[tiab] OR xylocitin[tiab]) AND (randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug ther- apy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]) NOT ((animals [mh] NOT humans [mh])) OR Articaine OR (mepivacaine AND intravenous AND renal) OR (rrilocaine AND intravenous AND renal) OR (ropivacaine AND intravenous AND renal) OR (Cinchocaine AND intra- venous) OR (etidocaine AND intravenous) Embase: (’kidney colic’/exp OR ’colic’/exp OR ’urolithiasis’/exp OR ’ureter obstruction’/exp OR ((Renal:ab,ti OR kidney:ab,ti OR ureteral:ab,ti OR ureteric:ab,ti OR urinary:ab,ti) AND (Colic:ab,ti OR colics:ab,ti OR pain:ab,ti OR stone:ab,ti OR stones:ab,ti OR calculus:ab,ti OR calculi:ab,ti)) OR Nephrolithiasis:ab,ti OR urolithiasis:ab,ti OR "tract stone":ab,ti OR "tract stones":ab,ti OR "acute pain":ab,ti OR "abdominal pain":ab,ti OR "abdominal cramps":ab,ti OR "abdominal cramping":ab,ti) AND (’lidocaine’/exp OR Lignocaine:ab,ti OR Xylocaine:ab,ti OR lidocaine:ab,ti OR lignocain:ab,ti OR xylocain:ab,ti OR xyloneural:ab,ti OR octocaine:ab,ti OR xylocitin:ab,ti) AND (’crossover procedure’:de OR ’double-blind procedure’:de OR ’randomized controlled trial’:de OR ’single-blind pro- cedure’:de OR (random* OR factorial* OR crossover* OR cross NEXT/1 over* OR placebo* OR doubl* NEAR/1 blind* OR singl* NEAR/1 blind* OR assign* OR allocat* OR volun- teer*):de,ab,ti) CINAHL (MH "Colic" OR MH "Kidney Calculi+" OR MH "Ureteral Calculi" OR MH "Urolithiasis" OR MH "Ureteral Obstruc- tion" OR MH "Ureterolithiasis" OR TI (((Renal OR kidney OR ureteral OR ureteric OR urinary) AND (Colic OR colics OR pain OR stone OR stones OR calculus OR calculi)) OR Nephrolithiasis OR "tract stone" OR "tract stones" OR "acute pain") OR AB (((Renal OR kidney OR ureteral OR ureteric OR urinary) AND (Colic OR colics OR pain OR stone OR stones OR calculus OR calculi)) OR urolithiasis OR Nephrolithiasis OR "tract stone" OR "tract stones" OR "acute pain" OR "abdominal pain" OR "abdominal cramps" OR "abdominal cramping")) AND (MH "Lidocaine" OR TX (Lidocaine OR Lignocaine OR Xylo- caine OR lignocain OR xylocain OR xyloneural OR octocaine OR xylocitin)) AND (MH "Randomized Controlled Trials" OR MH "Clinical Tri- als" OR MH "Double-Blind Studies" OR MH "Triple-Blind Studies" OR MH "Therapeutic Trials" OR MH "Drug Ther- apy+" OR TX (randomized OR placebo OR randomly OR trial OR groups)) CENTRAL (Lidocaine or Lignocaine or Xylocaine or lignocain or xylo- cain or xyloneural or octocaine or xylocitin).mp. AND ((Renal or kidney or ureteral or ureteric or urinary) and (Colic or colics or pain or stone or stones or calculus or calculi)).mp. OR (urolithiasis or Nephrolithiasis or "tract stone" or "tract stones" or "acute pain" or "abdominal pain" or "abdominal cramps" or "abdominal cramping").mp. China National Knowledge Infrastructure (CHKD-CNKI) (lidocaine AND renal) OR (Ropivacaine AND Renal) OR Bupivicaine OR Articaine OR Mepivacaine OR Prilocaine OR Cinchocaine OR Etidocaine Directory of Open Access Journals (DOAJ) (Lidocaine AND renal AND colic) OR (ropivacaine AND (intravenous OR renal)) OR bupivacaine OR articaine OR mepivacaine OR prilocaine OR cinchocaine OR etidocaine 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 11 Archives of Academic Emergency Medicine. 2020; 8(1):e27 information/Chinese Scientific Journals database (CSJD- VIP) ((Bupivicaine OR Articaine OR Ropivacaine) AND (renal OR colic OR stone OR lithiasis)) OR (lidocaine OR articaine OR mepivacaine OR prilocaine OR cinchocaine OR etidocaine) IEEE-Xplorer Renal colic OR (lidocaine AND renal) OR bupivacaine OR articaine OR mepivacaine OR prilocaine OR ropivacaine OR cinchocaine OR etidocaine Korean Journal Database (KCI) Renal colic OR (Lidocaine AND renal) OR ((bupivacaine OR ropivacaine) AND intravenous) OR articaine OR mepiva- caine OR prilocaine OR cinchocaine OR etidocaine LILACS (tw:(((Renal or kidney or ureteral or ureteric or urinary) and (Colic or colics or pain or stone or stones or calculus or calculi)).mp. OR (urolithiasis or Nephrolithiasis or "tract stone" or "tract stones" or "acute pain" or "abdominal pain" or "abdominal cramps" or "abdominal cramping"))) AND (tw:(Lidocaine or Lignocaine or Xylocaine or lignocain or xylocain or xyloneural or octocaine or xylocitin)) OR (Articaine AND intravenous) OR (Mepivacaine AND in- travenous AND (renal OR stone or lithiasis or colic)) OR (prilocaine AND intravenous AND renal) OR (ropivacaine AND intravenous AND renal) OR (cinchocaine AND intra- venous) OR (etidocaine AND intravenous) Magiran Renal colic OR (lidocaine AND renal) OR bupivacaine OR articaine OR mepivacaine OR prilocaine OR ropivacaine OR cinchocaine OR etidocaine Russian Science Citation Index (RSCI) Renal colic OR (lidocaine AND renal) OR bupivacaine OR articaine OR mepivacaine OR prilocaine OR ropivacaine OR cinchocaine OR etidocaine Scientific Electronic Library Online (SciELO) Renal colic OR (lidocaine AND renal) OR bupivacaine OR articaine OR mepivacaine OR prilocaine OR ropivacaine OR cinchocaine OR etidocaine Scientific Information Database (SID) Renal colic OR (lidocaine AND renal) OR bupivacaine OR articaine OR mepivacaine OR prilocaine OR ropivacaine OR cinchocaine OR etidocaine TUBITAK ULAKBIM Renal colic OR (Lidocaine AND renal) OR ((prilocaine OR ropivacaine) AND intravenous) OR articaine OR mepiva- caine OR bupivacaine OR cinchocaine OR etidocaine Web of Science TS=(((Renal OR kidney OR ureteral OR ureteric OR urinary) AND (Colic OR colics OR pain OR stone OR stones OR calcu- lus OR calculi)) OR urolithiasis OR Nephrolithiasis OR tract stone OR tract stones OR acute pain OR abdominal pain OR abdominal cramps OR abdominal cramping) AND TS=(Lidocaine or Lignocaine or Xylocaine or lignocain or xylocain or xyloneural or octocaine or xylocitin) AND TS= clinical trial* OR TS=research design OR TS=comparative stud* OR TS=evaluation stud* OR TS=controlled trial* OR TS=follow-up stud* OR TS=prospective stud* OR TS=random* OR TS=placebo* OR TS=(single blind*) OR TS=(double 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: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Declaration References