What Is the Best Analgesic Option for Patients Presenting with Renal Colic to the Emergency Department? Protocol for a Systematic Review and Meta-Analysis

Home , Aceclofenac, Aminophenazone, Ampyrone, Azapropazone, Benoxaprofen, Clonixin

BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from

Non-steroidal anti-inflammatory drugs (NSAIDS) versus opioids (update) and NSAIDS versus paracetamol in the management of acute renal colic-Protocol for a systematic review and meta-analysis

For peer review only Journal: BMJ Open

Manuscript ID bmjopen-2016-015002

Article Type: Protocol

Date Submitted by the Author: 01-Nov-2016

Complete List of Authors: Pathan, Sameer; Hamad Medical Corp, Emergency Department; Monash University School of Public Health and Preventive Medicine, Mitra, Biswadev; Monash University, Romero, Lorena ; The Ian Potter Library, Ground Floor, AMREP Building, The Alfred Cameron, Peter; Monash University, Department of Epidemiology and Preventive Medicine

Primary Subject Emergency medicine Heading:

Secondary Subject Heading: Evidence based practice, Medical management, Urology http://bmjopen.bmj.com/

Renal colic, Urolithiasis < UROLOGY, NSAIDS, Paracetamol, Opioids, Keywords: Analgesia

on September 25, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Non-steroidal anti-inflammatory drugs (NSAIDS) versus opioids (update) and NSAIDS 4 5 versus paracetamol in the management of acute renal colic-Protocol for a systematic 6 7 review and meta-analysis 8 9 10 Authors’ names and degrees 11 12 1. Dr. Sameer A. Pathan 1,2,3 MBBS, CABEM, MRCEM 13 2,3,4 14 2. A/Prof. Biswadev Mitra MBBS, MHSM, PhD, FACEM 15 For peer5 review only 16 3. Ms. Lorena Romero BA, MBIT 17 2,3,4 18 4. Prof. Peter A. Cameron MBBS, MD, FACEM 19 20 21 Affiliations 22 23 1 Emergency Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar 24 2 25 Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia. 26 3 National Trauma Research Institute, The Alfred Hospital, Melbourne, Australia. 27 4 28 Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia. 29 5 Alfred Health, The Ian Potter Library, Melbourne, Australia. 30 31 32

33 Corresponding author http://bmjopen.bmj.com/ 34 Dr. Sameer A. Pathan 35 36 P.O.BOX. 50107, Mesaieed Post Office, Qatar. 37 38 Email: [email protected] 39 40 Telephone: 00974 6685 7650

41 on September 25, 2021 by guest. Protected copyright. 42 43 Word count: Abstract- 300, Manuscript – 2224 44 45 46 47 Registration: This systematic review is registered on the PROSPERO international 48 49 prospective register of systematic reviews (PROSPERO 2016:CRD42016047559). 50 51 Amendments: Any change(s) in the protocol will be updated in the PROSPERO registry. 52 The amendments will be accompanied by the information regarding time, date, 53 54 description of changes, and rationally behind the changes made. 55 56 Support: This systematic review is non-funded. 57 58 59 60 1

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 ABSTRACT 4 5 Introduction 6 7 Patients with renal colic, present to the emergency department in excruciating pain. 8 9 There is uncertainty and wide variability among the choice of initial analgesic to be used 10 11 in renal colic. The aim of this review is to assess the efficacy and safety of NSAIDS, 12 13 opioids, and paracetamol use in renal colic pain management. 14 15 Methods andFor analysis peer review only 16 17 This is the protocol for a systematic review, comparing efficacy of NSAIDS, opioids, and 18 19 paracetamol in renal colic studied under randomized controlled trial design. We will 20 conduct a comprehensive literature search for both peer-reviewed and grey literature 21 22 published until 1st October 2016. Using a predefined search strategy MEDLINE, Embase, 23 24 Cochrane Central Register of Controlled Trials will be searched. Additional searches will 25 26 include WHO International Clinical Trials Registry Platform, abstract list of relevant 27 28 major conferences and the reference lists of relevant publications. Two authors will 29 30 independently screen and identify the studies to be included. The RCT comparing 31 32 NSAIDS versus opioids or paracetamol will be included in the review, if the age of

33 http://bmjopen.bmj.com/ 34 participants in the study was >16 years, and they presented with moderate to severe 35 renal colic. Any disagreement between the screening authors will be resolved through 36 37 discussion and reaching to consensus, if not, a third reviewer will arbitrate. Quantitative 38 39 data from homogenous studies will be pooled in the meta-analysis using RevMan 5.3 40

41 software. The findings of this review will be presented according to guidelines in the on September 25, 2021 by guest. Protected copyright. 42 43 Cochrane Handbook of Systematic Reviews of Interventions and PRISMA statement. 44 45 Ethics and dissemination 46 47 Formal ethics approval is not required for a systematic review. We plan to publish the 48 49 result of this review in a peer-review journal. We believe that the results of this review 50 51 will provide robust evidence in deciding superiority among commonly used analgesics, 52 and help to improve guidance for protocolised analgesia in renal colic. 53 54 55 56 57 58 59 60 2

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 INTRODUCTION 4 5 6 Kidney stones are very common in the “stone belt” region, which extends over America 7 8 (Southeast), Africa (North), Middle East, Asia (Southeast), and Australia (Northeast). 1 9 10 Globally, the lifetime prevalence of stone disease is 10-15%, and it counts for millions of 11 12 patient visits to the emergency departments (ED) or the outpatient clinics. 1 2 The acute 13 14 painful presentation is commonly known as renal colic, and movement of stone in the 15 For peer review only 16 urinary tract produce this excruciating pain. The National Health Service (NHS) England, 17 18 statistics for year 2012-13, estimated the cost for renal colic was nearly £20 million, 19 3 20 where median patient stay in the hospital was 1 day. In the management of renal colic, 21 one of the priorities in the ED is to provide quick, safe and effective analgesia to the 22 23 patients. 24 25 26 27 The most commonly prescribed analgesics in renal colic are non-steroidal anti- 28 4 5 29 inflammatory drugs (NSAIDS), opioids and paracetamol. The important factors in the 30 31 selection of first-line analgesic in ED are efficacy, safety, the ease and rapid 32

33 administration, and the logistics involved around it. Effective ongoing analgesia can be http://bmjopen.bmj.com/ 34 35 practically challenging to deliver in an ED with a diverse population, and a high volume 36 of patients being managed concurrently.6 The previously published meta-analysis 37 38 comparing NSAIDS with opioids suggested NSAIDS to be better than opioids in terms of 39 40 requiring lesser rescue analgesia and having fewer side effect. However, it did not

41 on September 25, 2021 by guest. Protected copyright. 42 establish superior efficacy of either drug group.5 7 The use of intravenous opioids, as the 43 44 first-line analgesic in renal colic, continues to be a common practice in many developed 45 46 countries. However, the logistical delay involved in intravenous administrations, dose- 47 48 dependent side-effects, need for titrating dosage, and overly bureaucratic restrictions 49 50 are some of the challenges associated with the IV opioid use as the first-line analgesic in 51 8 9 10 52 the busy ED. Routine use of NSAIDS has been limited because of the fear of 53 gastrointestinal (GI) and renal complications. In addition, there has been undue 54 55 emphasis placed on the possibility of abscess and muscle necrosis secondary to 56 57 intramuscular injection, given the extremely low level of documented cases. 58 59 60 3

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 5 The obvious limitations of previous studies and systematic reviews may partly explain 6 7 the continued clinical orthodoxy of intravenous opioid use as the first analgesic in many 8 9 settings. Firstly, this review was conducted and published in 2004 and the studies 10 11 included were published between 1982-1999. 5 In the last 15 years, newer, well 12 13 powered, pragmatic, clinical trials have been published with clinically relevant outcomes 14 15 in renal colicFor management. peer Secondly, reviewmost studies in the reviewonly only included patients 16 17 who had confirmed renal calculi on subsequent testing. This may limit the applicability 18 19 of evidence in routine clinical practice where patients are treated with a clinical picture 20 of renal colic well before any imaging can be performed. Thirdly, significant 21 22 heterogeneity between the studies included, did not allow pooled analysis to conclude 23 24 the superiority of a drug based on efficacy. 4 5 A pooled analysis of NSAIDS other than 25 26 Ketorolac in the review showed pain reduction of 4.6mm (on VAS 0-100) only, which is 27 11 28 minimal compared to the newer trial results. Fourthly, as 12 of the 20 included trials 29 30 used pethidine as their opioid arm, which is not a commonly used opioid in current 31 5 32 practice. Lastly, studies available to include at the time of review lacked consistent

33 http://bmjopen.bmj.com/ 34 reporting of serious adverse events such as renal failure and GI bleeding limiting 35 comparability. 36 37 38 39 There is ongoing controversy regarding the superiority of any of the commonly used 40

41 analgesics in terms of efficacy, optimum dosing and route of administration. Therefore, on September 25, 2021 by guest. Protected copyright. 42 43 we aim to examine the efficacy and safety of NSAIDS, opioids, and paracetamol use in 44 45 renal colic pain management. 46 47 48 49 METHODS AND DESIGN 50 51 52 Types of participants 53 The systematic review will only include studies involving adult patients (age >16 years), 54 55 with a clinical diagnosis of acute renal colic (pain less than 12 hours), and moderate to 56 57 severe pain severity. If a study reports data on both adult and pediatric population, we 58 59 60 4

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 will only include the data if the mean age of patients is over 18. The data from mixed 4 5 population studies will be highlighted when reporting final results. 6 7 8 9 Type of studies 10 11 Only randomized controlled trials (RCT) comparing NSAIDS versus opioids or NSAIDS 12 13 versus paracetamol, will be included in the review. There will be no language restriction 14 15 to conduct primaryFor search. peer If the language review used to write the only article is other than English, 16 17 we will use Google translator to translate the text. 18 19 20 Types of interventions 21 22 The studies will be reviewed if interventions include: 23 24 NSAIDS versus opioids in any dose, by any route in any setting, used for pain relief in 25 26 acute renal colic episode will be eligible. 27 28 NSAIDS versus paracetamol (acetaminophen) in any dose, by any route in any 29 30 setting, used for pain relief in acute renal colic episode will be eligible. 31 32 NSAIDS included will be salicylates, propionic acid derivatives, acetic acid derivatives,

33 http://bmjopen.bmj.com/ 34 enolic acid derivatives, fenamates, selective COX-2 inhibitors, and sulfonamides. 35 36 37 Types of outcome measures 38 39 Studies with at least one of the following outcomes will be included. 40

41 • Outcome measures using a validated pain scale on September 25, 2021 by guest. Protected copyright. 42 43 • Difference in pain score at 30 minutes 44 45 • Difference in the proportion of patients with pain relief at 30 minutes 46 47 • Time to pain relief 48 49 • Need for rescue analgesia 50 51 • Pain recurrence 52 53 • Major adverse event (e.g. GI bleeding and renal complications, complications at the 54 55 IM injection site) 56 57 58 59 60 5

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 5 Information sources 6 7 The search will not be restricted by language or date of publication to avoid publication 8 9 or retrieval biases. We will search the following databases and sources for relevant 10 11 studies: 12 13 Cochrane Central Register of Controlled Trials (CENTRAL) 14 15 CochraneFor Renal Group peer Specialised Registerreview for randomized only controlled trials 16 17 Ovid MEDLINE(R) 1946 to Present with Daily Update 18 19 Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations 20 Ovid MEDLINE (R) Epub Ahead of Print 21 22 Embase Classic+ Embase 1947 to 2016 September 23 24 WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) 25 26 Reference lists of nephrology, urology and emergency medicine textbooks, 27 28 previously published review articles, and relevant trials. 29 30 Abstract list of the major nephrology, urology and emergency medicine conferences. 31 32 Correspondence documents seeking information about unpublished or incomplete

33 http://bmjopen.bmj.com/ 34 trials from the investigators known to be involved in previous trials. 35 The initial search strategy was developed in the Ovid MEDLINE database, using subject 36 37 heading and using free-text words. The relevant sub-classes of NSAIDS and commercial 38 39 names for the commonly used drugs were searched through Google and used in the 40

41 free-text search. We also compared the search strategies used for the previous two on September 25, 2021 by guest. Protected copyright. 42 43 Cochrane reviews4 5, and modified our strategy if any important terms were found 44 45 missing. Drugs such as Phenylbutazone, Aminophenazone (or aminopyrine), Ampyrone, 46 47 were excluded as these drugs have risk of agranulocytocis, and they are no longer used 48 49 as routine analgesics. 50 51 52 Search strategy 53 54 We will perform the first search on MEDLINE, Embase, and Cochrane CENTRAL via Ovid. 55 56 The detailed search strategy is attached as Appendix-A. The second search will be 57 58 59 60 6

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 performed for ongoing clinical trials on WHO international clinical trial registry platform. 4 5 Finally, a manual search will be conducted in relevant key journals, conference 6 7 abstracts, textbook chapters, and the bibliography of included articles. Outcome of 8 9 each database search will be individually imported into Endnote X7 (Thomson Reuters) 10 11 reference manager. After this, using Endnote, the references will be combined and 12 13 duplications will be removed. The record of total search results retrieved and screened 14 15 will be kept andFor reported peer using PRISMA review guidelines. only 16 17 18 19 Selection process 20 Two authors will independently screen the titles and abstracts of de-duplicated results 21 22 to identify potentially eligible studies. These studies then will be further reviewed 23 24 independently, going through the full text, to confirm the inclusion criteria. Any 25 26 disagreement will be resolved through discussion or by consulting a third review author. 27 28 Agreement on independent inclusion of titles, abstract or full text will be quantified 29 30 using K statistics. Reasons for excluding potentially eligible studies will be recorded and 31 32 reported as supplementary to the main review.

33 http://bmjopen.bmj.com/ 34 35 Data collection process 36 37 Two authors will independently extract the data using Cochrane Collaboration Review 38 39 Manager statistical software (RevMan 5.3) (http://ims.cochrane.org/RevMan) and a pre- 40

41 piloted Microsoft excel sheet. Before starting the review calibration exercises will be on September 25, 2021 by guest. Protected copyright. 42 43 conducted among the reviewers to ensure consistency. Discrepancies between the data 44 45 extraction will be resolved by discussion and reaching a consensus. If needed a third 46 47 reviewer will be contacted to reach a decision. 48 49 50 51 Data items 52 Data will be collected on the following data points. 53 54 1. Research information: the first author, the site where study was conducted, year 55 56 of publication, research design (randomization and concealed allocation) and the 57 58 59 60 7

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 sample size. 4 5 2. Characteristics of the study subjects: Age, sex, numbers in each group, inclusion 6 7 and exclusion of criteria of individual study, pain scores at the time of randomization, 8 9 diagnostic confirmation of renal colic. 10 11 3. Information on intervention and comparison arms: number of groups, 12 13 intervention and comparator(s) (drug, dose, and route), and the information about 14 15 blinding (treatingFor person, peer assessor, and review patient). Also information only about exclusion after 16 17 randomization will also be recorded (intention to treat). 18 19 20 Outcomes and prioritization 21 22 Definition used for the primary outcome, measuring tool used, change in pain scores, 23 24 need for rescue analgesia and at what time, side effects and follow up (GI bleed or renal 25 26 impairment). Notes important but not classified in the above category will be entered as 27 28 a free text. 29 30 31 32 Quality assessment of studies

33 http://bmjopen.bmj.com/ 34 To assess the risk of bias, study data will be extracted using the Cochrane Collaboration 35 tool for assessing the risk of bias (Table 8.5.a in the Cochrane Handbook for Systematic 36 37 Reviews of Interventions). This includes information gathering on method of 38 39 randomization, allocation concealment, blinding of participants and investigators, 40

41 blinding of the assessor, incomplete outcome data, and other bias if any. Each domain on September 25, 2021 by guest. Protected copyright. 42 43 will be rated as having low, unclear or high risk of bias. 44 45 46 47 Missing data 48 49 We will try to contact corresponding authors to request missing data if contacts are 50 51 available. If this is not achieved, we will try to impute the missing information based on 52 the information available in the manuscript or the protocol of the study. For continuous 53 54 measures, missing standard deviation (SD) will be imputed from available information 55 56 such as standard error (SE), confidence interval (CI), or p-values. For a dichotomous 57 58 59 60 8

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 outcome, proportion or percentages will be used to calculate the number of 4 5 events/people assessed for that outcome. The results will be interpreted considering 6 7 the impact of missing data. 8 9 10 11 ANALYSIS 12 13 14 15 Data synthesisFor peer review only 16 17 For dichotomous outcomes, such as more than or equal to 50% reduction in pain, need 18 19 for rescue analgesia, recurrence of pain, or adverse events, a risk ratio (RR) with 95% 20 confidence intervals (95% CI) will be reported. The studies where continuous scale of 21 22 measure were used to assess the primary effect, such as patient rated pain, difference 23 24 in mean pain score, time to pain relief, a mean difference (MD) will be reported. If 25 26 different measure scales were used, a standardized mean difference will be used to 27 28 express the results. For the adverse effects we will calculate the risk difference (RD) with 29 30 95% CI. Skewed data and non-quantitative data will be presented descriptively. 31 32

33 http://bmjopen.bmj.com/ 34 Quantitative data will be pooled in the meta-analysis using RevMan 5.3 software. Fixed 35 effect model or random effect model will be used appropriately based on the 36 37 heterogeneity observed among the studies included in the pooled analysis. Statistical 38 39 heterogeneity in each model will be assessed using the χ² test of heterogeneity and 40 2 41 quantified using the Higgins’ I statistics. If the heterogeneity is insignificant the Mantel- on September 25, 2021 by guest. Protected copyright. 42 43 Haenszel method will be used for the fixed effect model. We will use the random effects 44 45 model if significant statistical heterogeneity (I2 >=50% or P <0.1) is present. 46 47 48 49 Subgroup analysis 50 51 We intend to perform the primary analysis based on the treatment groups such as 52 53 NSAIDS vs opioids and NSAIDS vs paracetamol. We will also perform subgroup analysis 54 55 based on the types of opioids or NSAIDS used, routes of administration, and based on 56 57 the quality of the study. If heterogeneity is substantial, we will not perform a meta- 58 59 60 9

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 analysis; a narrative, qualitative summary will be done and the information will be 4 5 presented using text and tables. 6 7 8 9 Meta-bias(es) 10 11 To assess reporting bias amongst the included studies, where possible, we will 12 13 determine if there was any deviation from the published protocol or information 14 st 15 registered priorFor to conduct peer of the study. review If a study was published only after July 1 2005, we 16 17 will screen the Clinical Trial Register at the International Clinical Trials Registry Platform 18 19 of the World Health Organisation (http://apps.who.int/ trialssearch). To assess the 20 possibility of publication bias, we also plan to use a Funnel plot if 10 or more studies are 21 22 available for the meta-analysis. 23 24 25 26 Assessing cumulative evidence 27 28 We will assess the quality of body of evidence for each outcome according to Grading 29 30 of Recommendations Assessment, Development and Evaluation (GRADE) working group 31 32 methodology.

33 http://bmjopen.bmj.com/ 34 35 DISCUSSION 36 37 Renal colic is a common cause of ED presentations and the excruciating pain demands 38 39 effective analgesia to be administered in the shortest possible time. To minimize the 40

41 delay in rapid administration of effective and safe analgesia, an evidence-based protocol on September 25, 2021 by guest. Protected copyright. 42 43 is needed. Previous reviews were inconclusive in establishing superior efficacy to 44 45 support first-line analgesia. It is important to use the first-line agent that is most 46 47 effective, has the best safety profile, and is quick and easy to administer with a single 48 49 rather than titrated first dose. Given that there have been significant publications since 50 51 the last review on this topic, we believe that it is likely that improved guidance for 52 protocolised first-line analgesia for renal colic can be given. 53 54 55 56 Contributions: SAP is the guarantor. SAP, BM and PAC drafted protocol for the 57 58 59 60 10

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 systematic review. SAP and LR developed the search strategy. All authors contributed to 4 5 the development of the selection criteria, the risk of bias assessment strategy and data 6 7 extraction criteria. All authors read, provided feedback and approved the final 8 9 manuscript. 10 11 Competing interest: We have read and understood BMJ policy on declaration of 12 13 interests and declare that we have no competing interests. 14 15 For peer review only 16 17 REFERENCES 18 19 20 1. Fisang C, Anding R, Muller SC, et al. Urolithiasis--an interdisciplinary diagnostic, 21 therapeutic and secondary preventive challenge. Deutsches Arzteblatt 22 international 2015;112(6):83-91. doi: 10.3238/arztebl.2015.0083 [published 23 Online First: 2015/02/28] 24 2. Ghani KR, Roghmann F, Sammon JD, et al. Emergency department visits in the 25 26 United States for upper urinary tract stones: trends in hospitalization and 27 charges. The Journal of urology 2014;191(1):90-6. doi: 28 10.1016/j.juro.2013.07.098 [published Online First: 2013/08/13] 29 3. Pickard R, Starr K, MacLennan G, et al. Use of drug therapy in the management of 30 symptomatic ureteric stones in hospitalised adults: a multicentre, placebo- 31 32 controlled, randomised controlled trial and cost-effectiveness analysis of a

33 calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the http://bmjopen.bmj.com/ 34 SUSPEND trial). Health technology assessment (Winchester, England) 35 2015;19(63):vii-viii, 1-171. doi: 10.3310/hta19630 [published Online First: 36 2015/08/06] 37 38 4. Afshar K, Jafari S, Marks AJ, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) 39 and non-opioids for acute renal colic. The Cochrane database of systematic 40 reviews 2015;6:Cd006027. doi: 10.1002/14651858.CD006027.pub2

41 [published Online First: 2015/06/30] on September 25, 2021 by guest. Protected copyright. 42 5. Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus 43 44 opioids for acute renal colic. The Cochrane database of systematic reviews 45 2005(2):Cd004137. doi: 10.1002/14651858.CD004137.pub3 [published 46 Online First: 2005/04/23] 47 6. Pines JM, Hollander JE. Emergency department crowding is associated with poor 48 49 care for patients with severe pain. Annals of emergency medicine 50 2008;51(1):1-5. doi: 10.1016/j.annemergmed.2007.07.008 [published Online 51 First: 2007/10/05] 52 7. Labrecque M, Dostaler LP, Rousselle R, et al. Efficacy of nonsteroidal anti- 53 inflammatory drugs in the treatment of acute renal colic. A meta-analysis. 54 55 Archives of internal medicine 1994;154(12):1381-7. [published Online First: 56 1994/06/27] 57 58 59 60 11

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 8. Manjiani D, Paul DB, Kunnumpurath S, et al. Availability and Utilization of Opioids 4 5 for Pain Management: Global Issues. The Ochsner Journal 2014;14(2):208-15. 6 9. Berterame S, Erthal J, Thomas J, et al. Use of and barriers to access to opioid 7 analgesics: a worldwide, regional, and national study. Lancet (London, 8 England) 2016;387(10028):1644-56. doi: 10.1016/s0140-6736(16)00161-6 9 10 [published Online First: 2016/02/08] 11 10. Pathan SA, Mitra B, Cameron PA. Titrated doses are optimal for opioids in pain 12 trials - Authors' reply. Lancet (London, England) 2016;388(10048):961-2. 13 doi: 10.1016/s0140-6736(16)31494-5 [published Online First: 2016/09/07] 14 11. Pathan SA, Mitra B, Straney LD, et al. Delivering safe and effective analgesia for 15 For peer review only 16 management of renal colic in the emergency department: a double-blind, 17 multigroup, randomised controlled trial. Lancet 2016;387(10032):1999- 18 2007. doi: http://dx.doi.org/10.1016/S0140-6736(16)00652-8 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 12

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 5 Appendix A 6 7 8 Ovid MEDLINE(R) 1946 to Present with Daily Update+ In-Process & Other Non- 9 10 Indexed Citations (2016 Month, Date) 11 12 # Search Statement Annotation 13 exp Urinary Bladder Calculi/ or exp Urinary Calculi/ or 14 exp Kidney Calculi/ or exp Ureteral Calculi/ or exp 15 1 Urolithiasis/For or exp peer Nephrolithiasis/ review or exp Renal Colic/ only 16 17 or exp Ureteral Diseases/ or exp Ureteral Obstruction/ or 18 exp Kidney Diseases/ 19 ((Urin* or renal or kidney or ureter* or bladder) adj3 20 2 (stone* or calcul* or colic* or lith* or obstruct* or 21 occlusi*)).mp. 22 23 3 ((Kidney or ureter*) adj2 diseas*).mp. 24 4 (Urolith* or nephrolith*).mp. 25 5 or/1-4 26 Population- Renal colic 27 exp Anti-Inflammatory Agents, Non-Steroidal/ or exp 28 6 Cyclooxygenase Inhibitors/ or exp Cyclooxygenase 2 29 Inhibitors/ 30 ((Nonsteroidal adj2 antiinflammatory) or (Non-steroidal 31 adj2 antiinflammatory) or (Nonsteroidal adj2 anti- 32 7 33 inflammatory) or (Non-steroidal adj2 anti- http://bmjopen.bmj.com/ 34 inflammatory)).mp. 35 exp diclofenac/ or exp ketorolac/ or exp apazone/ or exp 36 37 aspirin/ or exp ibuprofen/ or exp ketoprofen/ or exp Salicylates/ or exp etodolac/ or exp naproxen/ or exp 38 8 39 indomethacin/ or exp piroxicam/ or exp celecoxib/ or exp 40 fenoprofen/ or exp sulindac/ or exp tolmetin/ or exp 41 mesalazine/ or exp aminosalicylic acid/ on September 25, 2021 by guest. Protected copyright. 42 43 9 NSAID*.mp. 44 (Diclofenac or adiflam or agile or diclonac or dicol or 45 10 diclonat* or feloran or voltarol or Voltaren or Cataflam or 46 Voltaren-XR or Zipsor).mp. 47 (Aceclofenac or Hifenac or Cincofen or Nacsiv or 48 11 49 Acenac).mp. 50 (Ketorolac or toradol or torolac or kealc or kenalfin or 12 51 ketlac).mp. 52 53 13 (Apazon* or Azapropazon* or cinnopropazon*).mp. 54 (Aspirin* or acetylsal* or dispril or easprin* or 14 55 salicylic*).mp. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 (Ibuprofen or brufen or nuprin or rufen or salprofen or dolgit or salprofen or advil* or motrin or nurofen or 5 15 6 actiprofen or addaprin or aktren or anadin or bugesic or 7 ibuprox).mp. 8 (ketoprofen or orudis or oruvail or ketoflam or oruvail or 9 10 16 fastum or ketonal or ketodol or knavon or actron or 11 ketoprofeno).mp. 12 (Dexketoprofen or keral or enantyum or ketesgel or 17 13 dolmen).mp. 14 (Naproxen or naprosyn or naprosin or proxen or synflex 15 18 For peer review only 16 or Aleve or Anaprox or Apronax or Naprelan).mp. 17 (etodolac or ramodar or ultradol or etova or dualgan or 18 19 etodin or etopan or flancox or proxym or etodine or 19 20 dolarit).mp. 21 (Indomethacin* or indocid or indocin or indomet or 20 22 indometacin or metindol or osmosin).mp. 23 (Piroxicam or feldene or dolocare or dolonex or 24 21 25 ketolin).mp. 26 22 (Meloxicam or mobic or vivlodex).mp. 27 23 (Tenoxicam or mobiflex).mp. 28 29 24 (celecoxib or celebrex or celebra).mp. 30 25 (rofecoxib or vioxx or ceoxx or ceeoxx).mp. 31 26 (valdecoxib or bextra).mp. 32

(Nimesulid* or aulin or mesulid or nimalox or sulid* or http://bmjopen.bmj.com/ 33 27 34 sintalgin or nimsid* or nise or nimulid).mp. 35 28 (Meclofenamic or meclofenamat* or meclomen).mp. 36 37 29 (fenoprofen or fenopron).mp. 38 (oxaprozin or oxaprozinum or daypro or dayrun or 30 39 duraprox).mp. 40 31 (sulindac or cinoril or imbaral).mp. 41 on September 25, 2021 by guest. Protected copyright. 42 32 (tolmetin or tolectin).mp. 43 (flurbiprofen* or sulindac* or mesalazin* or sulfasalazin* 44 or flufenamic* or tolmetin* or fenoprofen* or diflunisal* 45 46 or niflumic* or ketorolac or trometamol* or parecoxib* or teriflunomid* or benoxaprofen* or suprofen* or fenbufen* 47 33 48 or mebron* or mepirizole* or mepyrizole* or 49 methopyrimazole* or Epirizolum* or Polihexanid* or 50 51 Dalex* or Miton* or epirizol* or clonixin* or tolemetin* or 52 nabumeton*).mp. 53 34 or/6-33 NSAIDS 54 exp Analgesics, opioid/ or exp alkaloids, opiate/ or exp 55 35 56 narcotics/ 57 36 opioid*.mp. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 exp hydrocodone/ or exp dextropropoxyphene/ or exp fentanyl/ or exp meperidine/ or exp methadone/ or exp 5 37 6 Morphine/ or exp Morphine Derivatives/ or exp 7 oxymorphone/ or exp pentazocine/ or exp tramadol/ 8 38 exp alfentanil/ or alfentanil*.mp. 9 10 39 exp codeine/ or codein*.mp. 11 (hydrocodon* or vicodin* or norco or lortab or 40 12 zohydro).mp. 13 14 41 exp oxycodone/ or oxycodon*.mp. 15 (dextropropoxyphen* or darvon or darvocet or digesic or 42 For peer review only 16 capadex).mp. 17 43 exp dihydromorphine/ or dihydromorphin*.mp. 18 (fentanyl or actiq or duragesic or fentora or sublimaz* or 19 44 20 fenta).mp. 21 45 (meperidin* or demerol or pethidin*).mp. 22 (methadon* or dolophin* or methadose or amidon* or 23 46 24 symoron or physephton* or heptadon).mp. 25 (morphin* or oramorph or morphia or duramorph or 26 47 27 contin or mscontin or sevredol or zomorphzomo).mp. 28 48 (oxymorphon* or numorphan or opana or morphon).mp. 29 (pentazocin* or fortal or sosegon or talwin or fortwin or 49 30 talacen).mp. 31 32 50 (tramadol or ultram).mp. 33 51 or/35-50 Opioids http://bmjopen.bmj.com/ 34 52 exp Acetaminophen/ 35 36 (abenol* or acamol* or acenol* or acephen* or acet 37 suppositories* or acetalgin* or acetamino phenol* or 38 acetaminophen* or acetaminophene* or 39 acetaminophenol* or acetamol* or acetomenophen* or 40 acetylaminophenol* or adorem* or afebrin* or algiafin* or 41 on September 25, 2021 by guest. Protected copyright. 42 algotropyl* or alphagesic* or alvedon* or amadil* or 43 anacin 3* or anaflon* or analgiser* or apamide* or apirex* 44 or arthralgen* or benuron* or biogesic* or calapol* or 45 53 calodol* or dafalgan* or depyretin* or dirox* or dolex* or 46 47 dolofen* or dolomol* or calpol* or eneril* or meforagesic* 48 or dolorol* or metagesic* or napamol* or naprex* or 49 pacemol* or pacimol* or duorol* or pamol* or panadol* or 50 panamax* or panodil* or paracet* or paracetamole* or 51 parageniol* or paragin* or paralen* or paralief* or 52 53 paramax* or paramidol* or paximol* or paratabs* or 54 perfalgan* or pyrigesic* or setamol* or tylenol* or tylex* 55 or valadol* or winadol* or zydinol).mp. 56 54 or/52-53 Paracetamol 57 58 55 5 and 34 and 51 NSAIDS Vs Opioids 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 56 5 and 34 and 54 NSAIDS Vs Paracetamol 5 57 randomized controlled trial.pt. 6 58 controlled clinical trial.pt. 7 (random$ or placebo$ or single blind$ or double blind$ or 8 59 9 triple blind$).ti,ab. 10 60 (retraction of publication or retracted publication).pt. 11 61 or/57-60 12 RCTs 13 62 (animals not humans).sh. 14 ((comment or editorial or meta-analysis or practice- 15 63 guidelineFor or review peer or letter or journalreview correspondence) only 16 17 not "randomized controlled trial").pt. 18 (random sampl$ or random digit$ or random effect$ or 19 64 random survey or random regression).ti,ab. not 20 "randomized controlled trial".pt. 21 non-human subject or 22 65 or/62-64 23 non RCTs 24 66 61 not 65 Human subject RCTs 25 NSAIDS Vs Opioids 26 67 55 and 66 27 +Human subject RCTs 28 NSAIDS Vs 29 68 56 and 66 Paracetamol+Human 30 subject RCTs 31 32 NSAIDS (Opioids or 33 69 67 or 68 paracetamol) in human http://bmjopen.bmj.com/ 34 subject RCTs 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 Embase Classic+Embase 1947 to 2016 Month, Date 43 44 # Search Statement Annotation 45 exp kidney pain/ or exp kidney colic/ or exp bladder stone/ or 46 47 1 exp ureter stone/ or exp urolithiasis/ or exp nephrolithiasis/ 48 or exp ureter obstruction/ 49 2 ((Urin* or renal or kidney or ureter* or bladder) adj3 (stone* 50 or calcul* or colic* or lith* or obstruct* or occlusi*)).mp. 51 52 3 ((Kidney or ureter*) adj2 diseas*).mp. 53 4 (Urolith* or nephrolith*).mp. 54 Population- Renal 55 5 56 or/1-4 colic 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 exp nonsteroid antiinflammatory agent/ or exp 5 cyclooxygenase 2 inhibitor/ or exp indometacin/ or exp 6 piroxicam/ or exp acetylsalicylic acid/ or exp celecoxib/ or 7 exp diclofenac/ or exp ibuprofen/ or exp naproxen/ or exp 8 6 azapropazone/ or exp acetylsalicylic acid/ or exp ketoprofen/ 9 10 or exp salicylic acid/ or exp ketorolac/ or exp ketoprofen/ or 11 exp salicylic acid derivative/ or exp etodolac/ or exp 12 fenoprofen/ or exp sulindac/ or exp tolmetin/ or exp 13 mesalazine/ or exp aminosalicylic acid/ 14 15 ((NonsteroidalFor adj2 peer antiinflammatory) review or (Non-steroidal only adj2 16 7 antiinflammatory) or (Nonsteroidal adj2 anti-inflammatory) 17 or (Non-steroidal adj2 anti-inflammatory)).mp. 18 8 NSAID*.mp. 19 20 (Diclofenac or adiflam or agile or diclonac or dicol or diclonat* 21 9 or feloran or voltarol or Voltaren or Cataflam or Voltaren-XR 22 or Zipsor).mp. 23 10 (Aceclofenac or Hifenac or Cincofen or Nacsiv or Acenac).mp. 24 (Ketorolac or toradol or torolac or kealc or kenalfin or 25 11 26 ketlac).mp. 27 12 (Apazon* or Azapropazon* or cinnopropazon*).mp. 28 29 13 (Aspirin* or acetylsal or dispril or easprin* or salicylic*).mp. 30 (Ibuprofen or brufen or nuprin or rufen or salprofen or dolgit 31 14 or salprofen or advil* or motrin or nurofen or actiprofen or 32

33 addaprin or aktren or anadin or bugesic or ibuprox).mp. http://bmjopen.bmj.com/ 34 (ketoprofen or orudis or oruvail or ketoflam or oruvail or 35 15 fastum or ketonal or ketodol or knavon or actron or 36 ketoprofeno).mp. 37 (Dexketoprofen or keral or enantyum or ketesgel or 38 16 39 dolmen).mp. 40 (Naproxen or naprosyn or naprosin or proxen or synflex or 17 41 Aleve or Anaprox or Apronax or Naprelan).mp. on September 25, 2021 by guest. Protected copyright. 42 (etodolac or ramodar or ultradol or etova or dualgan or etodin 43 18 44 or etopan or flancox or proxym or etodine or dolarit).mp. 45 (Indomethacin* or indocid or indocin or indomet or 46 19 47 indometacin or metindol or osmosin).mp. 48 20 (Piroxicam or feldene or dolocare or dolonex or ketolin).mp. 49 21 (Meloxicam or mobic or vivlodex).mp. 50 51 22 (Tenoxicam or mobiflex).mp. 52 23 (celecoxib or celebrex or celebra).mp. 53 24 (rofecoxib or vioxx or ceoxx or ceeoxx).mp. 54 55 25 (valdecoxib or bextra).mp. 56 (Nimesulid* or aulin or mesulid or nimalox or sulid* or 26 57 sintalgin or nimsid* or nise or nimulid).mp. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 21 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 27 (Meclofenamic or meclofenamat* or meclomen).mp. 5 28 (fenoprofen or fenopron).mp. 6 (oxaprozin or oxaprozinum or daypro or dayrun or 29 7 duraprox).mp. 8 9 30 (sulindac or cinoril or imbaral).mp. 10 31 (tolmetin or tolectin).mp. 11 (flurbiprofen* or sulindac* or mesalazin* or sulfasalazin* or 12 13 flufenamic* or tolmetin* or fenoprofen* or diflunisal* or 14 niflumic* or ketorolac or trometamol* or parecoxib* or 15 32 teriflunomid*For or benoxaprofen* peer orreview suprofen* or fenbufen* only or 16 mebron* or mepirizole* or mepyrizole* or methopyrimazole* 17 or Epirizolum* or Polihexanid* or Dalex* or Miton* or 18 19 epirizol* or clonixin* or tolemetin* or nabumeton*).mp. 20 33 or/6-32 NSAIDS 21 exp opiate/ or exp narcotic analgesic agent/ or exp opiate 34 22 agonist/ 23 24 exp hydrocodone/ or exp dextropropoxyphene/ or exp 25 35 fentanyl/ or exp pethidine/ or exp methadone/ or exp 26 oxymorphone/ or exp pentazocine/ or exp tramadol/ 27 28 36 opioid*.mp. 29 37 exp alfentanil/ or alfentanil*.mp. 30 38 exp codeine/ or codein*.mp. 31 32 39 (hydrocodon* or vicodin* or norco or lortab or zohydro).mp. 33 40 exp oxycodone/ or oxycodon*.mp. http://bmjopen.bmj.com/ 34 (dextropropoxyphen* or darvon or darvocet or digesic or 35 41 36 capadex).mp. 37 42 exp dihydromorphine/ or dihydromorphin*.mp. 38 (fentanyl or actiq or duragesic or fentora or sublimaz* or 43 39 fenta).mp. 40

41 44 (meperidin* or demerol or pethidin*).mp. on September 25, 2021 by guest. Protected copyright. 42 (methadon* or dolophin* or methadose or amidon* or 45 43 symoron or physephton* or heptadon).mp. 44 45 46 exp morphine/ or exp morphine derivative/ 46 (morphin* or oramorph or morphia or duramorph or contin or 47 47 mscontin or sevredol or zomorphzomo).mp. 48 49 48 (oxymorphon* or numorphan or opana or morphon).mp. 50 (pentazocin* or fortal or sosegon or talwin or fortwin or 49 51 talacen).mp. 52 53 50 (tramadol or ultram).mp. 54 51 or/34-50 Opioids 55 52 exp paracetamol/ 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 (abenol* or acamol* or acenol* or acephen* or acet 5 suppositories* or acetalgin* or acetamino phenol* or 6 acetaminophen* or acetaminophene* or acetaminophenol* or 7 acetamol* or acetomenophen* or acetylaminophenol* or 8 adorem* or afebrin* or algiafin* or algotropyl* or alphagesic* 9 10 or alvedon* or amadil* or anacin 3* or anaflon* or analgiser* 11 or apamide* or apirex* or arthralgen* or benuron* or 12 biogesic* or calapol* or calodol* or dafalgan* or depyretin* or 53 13 dirox* or dolex* or dolofen* or dolomol* or calpol* or eneril* 14 or meforagesic* or dolorol* or metagesic* or napamol* or 15 For peer review only 16 naprex* or pacemol* or pacimol* or duorol* or pamol* or 17 panadol* or panamax* or panodil* or paracet* or 18 paracetamole* or parageniol* or paragin* or paralen* or 19 paralief* or paramax* or paramidol* or paximol* or paratabs* 20 or perfalgan* or pyrigesic* or setamol* or tylenol* or tylex* or 21 22 valadol* or winadol* or zydinol).mp. 23 54 or/52-53 Paracetamol 24 55 5 and 33 and 51 NSAIDS Vs Opioids 25 NSAIDS Vs 26 56 27 5 and 33 and 54 Paracetamol 28 (random$ or placebo$ or single blind$ or double blind$ or 57 29 triple blind$).ti,ab. 30 31 58 RETRACTED ARTICLE/ 32 59 or/57-58 RCTs 33 60 (animal$ not human$).sh,hw. http://bmjopen.bmj.com/ 34 35 61 (book or conference paper or editorial or letter or review).pt. 36 not exp randomized controlled trial/ 37 (random sampl$ or random digit$ or random effect$ or 38 62 random survey or random regression).ti,ab. not exp 39 40 randomized controlled trial/

non-human subject on September 25, 2021 by guest. Protected copyright. 41 63 42 or/60-62 or non RCTs 43 64 59 not 63 Human subject RCTs 44 45 NSAIDS Vs Opioids 46 65 +Human subject 47 55 and 64 RCTs 48 NSAIDS Vs 49 Paracetamol 50 66 51 +Human subject 52 56 and 64 RCTs 53 54 NSAIDS (Opioids or 55 67 paracetamol) in 56 65 or 66 human subject RCTs 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from Page 20 of 21

1 1 6 1 4 3 1 1 1 10 4-5 6 6 and (Page (Page No.#) Appendix-A grey grey

Checklist item Checklist item BMJ Open http://bmjopen.bmj.com/ mail address mail address authors; of all protocol address provide physical mailing of corresponding - on September 25, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only Describe allintended informationDescribe (suchsources electronic as contact databases, with study trialregisters authors, or other literature sources)literature dates with planned coverageof If the If protocol anrepresents amendment a completedpreviously of or published protocol, as identify list and changes; such otherwise, state otherwise, planstate for documentingimportant protocol amendments Provide Provide affiliation, name, institutional e author author Present draft of search draftPresent search strategy of for leastto used at be electronic one database, including limits,thatsuchplanned couldit be repeated Specify characteristicsstudy Specify the as (such PICO,study design,timeframe) setting, report and characteristics as(such years language,considered, publication tostatus) be criteria eligibilityas used forfor the review Provide an Provide explicit statement the of question(s) review the will referenceaddress with to interventions,participants, and comparators, (PICO) outcomes

7 7 6 6 the rationale Describe for the context review in the of is what knownalready 9 9 5c roles Describe funder(s), of sponsor(s), and/or institution(s), in any, developing if the protocol tem tem No I

Role of Role of sponsor funderor Sponsor 5b Provide reviewfor the name funderand/or sponsor Sources 5a financial Indicate sources of supportother or reviewfor the Contributions 3b contributions Describe authors protocol and identify of the reviewthe guarantor of Contact 3a Update 1b the for If protocol is an update a systematic previous of review, as identify such Identification 1a reportthe as Identify a a protocol systematicof review Search Search strategy 10 Information Information sources Eligibility criteriaEligibility 8 METHODS Objectives Rationale Rationale INTRODUCTION Support: Amendments 4 Authors: Registration 2 registered, If provide the (suchnamethe registry of PROSPERO) as and registrationnumber Title: ADMINISTRATIVE INFORMATION PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to to items recommended checklist: 2015 Protocols) Meta-Analysis review for and Systematic Items (PreferredReporting PRISMA-P reviewprotocol* a systematic in address Section topic and 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from

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BMJ Open http://bmjopen.bmj.com/ ati ati A,Petticrew M, P, Shekelle Stewart L, PRISMA-P Preferred Group. reportingitems for systematic andreview ad in conjunctionad with Explanationthe PRISMA-P and Elaboration when(cite available) for important on September 25, 2021 by guest. Protected copyright. l outcomes for which data will sought,including be prioritization of main and additional outcomes, with For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only Describe Describe planned method of extracting from data (suchreports piloting forms,as done independently, in any duplicate), Describe anticipated Describe methods assessing for risk of bias of studies, individual including whether this will done the atbe outcome level,or study both; howstate or this information will synthesis be in used data If data aredata If appropriate for synthesis,quantitative describe planned summary measures, methods handling and data of methods of combining from data any studies, including planned exploration of consistency (such as I List and defineList al rationale State the the State that process for will used selectingbe (suchstudies independent reviewers)as two eachthrough phase of (that is, screening, is, (that eligibility and inclusion in meta-analysis) List and defineList all variables for which will data sought asbe (such items, PICO funding sources),any pre-planned data assumptions and simplifications processes for processes confirmingobtaining and from data investigators 14 14 13 13 17 17 Describe how strengththe body evidencethe of of assessed be will (such as GRADE) 11c 11c 11a 11a the mechanism(s) Describe that will records be to used manage and throughoutdata reviewthe 15c 15c any Describe proposed additional asanalyses (such subgroupsensitivity or analyses, meta-regression) 11b 15d quantitative synthesis If is not appropriate, typethe describe summary of planned 15b

Data Data Selection collection Data process process management It is It stronglyrecommended checklist this that be re

clarification theclarification items. on to Amendments a review protocol should be tracked copyrightand dated. The for (includingPRISMA-P checklist) byheld the is Group PRISMA-P and is distributedunder a Creative Commons Attribution Licence 4.0. Shamseer From: L, Moher D, Clarke M, Ghersi Liber D, * Confidence inConfidence evidence cumulative Meta-bias(es) 16 any Specify assessmentplanned of meta-bias(es) as (such publication biasacross studies, selective reporting within studies) 10 Data Data synthesis 15a criteria under Describe data which study be will quantitatively synthesised Risk Risk in of bias studiesindividual Outcomes and Outcomes prioritization Data itemsData 12 Study records:Study meta-analysis protocols(PRISMA-P) elaboration2015: explanation. andBMJ. Jan 2015 2;349(jan02 1):g7647. Page 21 of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from

Analgesic options for management of acute renal colic- Protocol for a systematic review and meta-analysis.

ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2016-015002.R1

Article Type: Protocol

Date Submitted by the Author: 08-Feb-2017

Primary Subject Emergency medicine Heading:

Secondary Subject Heading: Evidence based practice, Medical management, Urology, Research methods

Renal colic, Urolithiasis < UROLOGY, NSAIDS, Paracetamol, Opioids, Keywords: http://bmjopen.bmj.com/ Analgesia

on September 25, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Analgesic options for management of acute renal colic- Protocol for a systematic 4 5 review and meta-analysis 6 7 8 Authors’ names and degrees 9 10 1. Dr. Sameer A. Pathan 1,2,3 MBBS, CABEM, MRCEM 11 12 2. A/Prof. Biswadev Mitra 2,3,4 MBBS, MHSM, PhD, FACEM 13 5 14 3. Ms. Lorena Romero BA, MBIT 15 For peer2,3,4 review only 16 4. Prof. Peter A. Cameron MBBS, MD, FACEM 17 18 19 20 Affiliations 21 1 Emergency Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar 22 2 23 Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia. 24 3 National Trauma Research Institute, The Alfred Hospital, Melbourne, Australia. 25 26 4 Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia. 27 5 Alfred Health, The Ian Potter Library, Melbourne, Australia. 28 29 30 31 Corresponding author 32

33 Dr. Sameer A. Pathan http://bmjopen.bmj.com/ 34 P.O.BOX. 50107, Mesaieed Post Office, Qatar. 35 36 Email: [email protected] 37 38 Telephone: 00974 6685 7650 39 40

41 Word count: Abstract- 303, Manuscript – 2301 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 Registration: This systematic review is registered on the PROSPERO international 46 47 prospective register of systematic reviews (PROSPERO 2016:CRD42016047559). 48 49 Amendments: Any change(s) in the protocol will be updated in the PROSPERO registry. 50 51 The amendments will be accompanied by the information regarding time, date, 52 description of changes, and rationally behind the changes made. 53 54 Support: This systematic review is non-funded. 55 56 57 58 59 60 1

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 ABSTRACT 4 5 6 7 Introduction 8 9 Patients with renal colic, present to the emergency department in excruciating pain. 10 11 There is variability in practice regarding the choice of initial analgesic to be used in renal 12 13 colic. The aim of this article is to outline the protocol for review of the efficacy and 14 15 safety of NSAIDS,For opioids, peer and paracetamol review use in renal colic only pain management. 16 17 18 19 Methods and analysis 20 This is the protocol for a systematic review, comparing efficacy of NSAIDS, opioids, and 21 22 paracetamol in renal colic studied under randomized controlled trial design. We will 23 24 conduct a comprehensive literature search for both peer-reviewed and grey literature 25 26 published until 1st October 2016. Using a predefined search strategy MEDLINE, Embase, 27 28 Cochrane Central Register of Controlled Trials will be searched. Additional searches will 29 30 include WHO International Clinical Trials Registry Platform, abstract list of relevant 31 32 major conferences and the reference lists of relevant publications. Two authors will

33 http://bmjopen.bmj.com/ 34 independently screen and identify the studies to be included. The RCT comparing 35 NSAIDS versus opioids or paracetamol will be included in the review, if the age of 36 37 participants in the study was >16 years, and they presented with moderate to severe 38 39 renal colic. Any disagreement between the screening authors will be resolved through 40

41 discussion and reaching consensus, if not, a third reviewer will arbitrate. Quantitative on September 25, 2021 by guest. Protected copyright. 42 43 data from homogenous studies will be pooled in the meta-analysis using RevMan 5.3 44 45 software. The findings of this review will be presented according to guidelines in the 46 47 Cochrane Handbook of Systematic Reviews of Interventions and PRISMA statement. 48 49 50 51 Ethics and dissemination 52 Formal ethics approval is not required, as primary data will not be collected. We plan to 53 54 publish the result of this review in a peer-reviewed journal. 55 56 57 58 59 60 2

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Strengths and limitations of this study 4 5 6 • Systematic review and meta-analysis of randomised controlled trials 7 8 • We plan to follow the Preferred Reporting Items for Systematic review and 9 10 Meta-Analysis Protocols (PRISMA-P), Grading of Recommendations Assessment, 11 12 Development and Evaluation (GRADE) framework and COCHRANE tools for 13 14 assessing the risk of bias. 15 For peer review only 16 • We anticipate difficulty in pooling data due to heterogeneity among the 17 18 published research. 19 20 • It will provide robust evidence in deciding superiority among commonly used 21 22 analgesics, and help to improve guidance for protocolised analgesia in renal 23 24 colic. 25 26 INTRODUCTION 27 28 29 Kidney stones are common in the “stone belt” region, which extends over America 30 31 (Southeast), Africa (North), Middle East, Asia (Southeast), and Australia (Northeast). 1 32 33 Globally, the lifetime prevalence of stone disease is 10-15%, and accounts for millions of http://bmjopen.bmj.com/ 34 35 patient visits to emergency departments (ED) or the outpatient clinics. 1 2 The acute 36 37 painful presentation is commonly known as renal colic, and movement of stone in the 38 39 urinary tract produces this excruciating pain. The National Health Service (NHS), 40 England statistics for year 2012-13, estimated the cost for renal colic was nearly £20 41 on September 25, 2021 by guest. Protected copyright. 42 3 43 million, where median patient stay in the hospital was 1 day. In the management of 44 renal colic, one of the priorities in the ED is to provide quick, safe and effective 45 46 analgesia. 47 48 49 50 The most commonly prescribed analgesics in renal colic are non-steroidal anti- 51 4 5 52 inflammatory drugs (NSAIDS), opioids and paracetamol. The important factors in the 53 54 selection of first-line analgesia in the ED are efficacy, safety, the ease of rapid 55 56 administration and logistics involved. Effective ongoing analgesia can be practically 57 58 challenging to deliver in an ED with a diverse population, and a high volume of patients 59 60 3

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 being managed concurrently.6 A previously published meta-analysis comparing NSAIDS 4 5 with opioids suggested NSAIDS were better than opioids in terms of requiring less 6 7 rescue analgesia and having fewer side effect. However, it did not establish superior 8 9 efficacy of either drug group.5 7 The use of intravenous opioids, as the first-line analgesic 10 11 in renal colic, continues to be a common practice in many developed countries.8-11 12 13 However, the logistical delay involved in intravenous administrations, dose-dependent 14 15 side-effects,For need for titratingpeer dosage, review and overly bureaucratic only restrictions are some of 16 17 the challenges associated with the IV opioid use as the first-line analgesic in the busy ED. 18 12 13 14 19 Routine use of NSAIDS has been limited because of the fear of gastrointestinal 20 (GI) and renal complications. In addition, there has been undue emphasis placed on the 21 22 possibility of abscess and muscle necrosis secondary to intramuscular injection, given 23 24 the extremely low level of documented cases. 25 26 27 28 The obvious limitations of previous studies and systematic reviews may partly explain 29 30 the continued clinical orthodoxy of intravenous opioid use as the first analgesic in many 31 32 settings. Firstly, this review was conducted and published in 2004 and the studies

33 5 http://bmjopen.bmj.com/ 34 included were published between 1982-1999. In the last 15 years, newer, well 35 powered, pragmatic, clinical trials have been published with clinically relevant outcomes 36 37 in renal colic management. Secondly, most studies in the review only included patients 38 39 who had confirmed renal calculi on subsequent testing. This may limit the applicability 40

41 of evidence in routine clinical practice where patients are treated with a clinical picture on September 25, 2021 by guest. Protected copyright. 42 43 of renal colic well before any imaging can be performed. Thirdly, significant 44 45 heterogeneity between the studies included, did not allow pooled analysis to test the 46 4 5 47 superiority of a drug based on efficacy. A pooled analysis of NSAIDS other than 48 49 Ketorolac in the review showed pain reduction of 4.6mm (on VAS 0-100) only, which is 50 14 51 minimal compared to the newer trial results. Fourthly, 12 of the 20 included trials used 52 pethidine as their opioid arm, which is not a commonly used opioid in current practice. 5 53 54 Lastly, studies available to include at the time of review lacked consistent reporting of 55 56 serious adverse events such as renal failure and GI bleeding limiting comparability. 57 58 59 60 4

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 5 There is ongoing controversy regarding the superiority of any of the commonly used 6 7 analgesics in terms of efficacy, optimum dosing and route of administration. Therefore, 8 9 we aim to examine the efficacy and safety of NSAIDS, opioids, and paracetamol use in 10 11 renal colic pain management. 12 13 14 15 METHODS ANDFor DESIGN peer review only 16 17 18 Types of participants 19 20 The systematic review will only include studies involving adult patients (age >16 years), 21 with a clinical diagnosis of acute renal colic (pain less than 12 hours), and moderate to 22 23 severe pain severity. If a study reports data on both adult and pediatric populations, we 24 25 will only include the data if the mean age of patients is over 18. The data from mixed 26 27 population studies will be highlighted when reporting final results. 28 29 30 31 Type of studies 32

33 Only randomized controlled trials (RCT) comparing NSAIDS versus opioids or NSAIDS http://bmjopen.bmj.com/ 34 35 versus paracetamol, will be included in the review. There will be no language restriction 36 to conduct primary search. If the language used to write the article is other than English, 37 38 we will use a professional translator to translate the text in English. 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 Types of interventions 43 44 The studies will be reviewed if interventions include: 45 46 NSAIDS versus opioids in any dose, by any route in any setting, used for pain relief in 47 48 acute renal colic episode will be eligible. 49 50 NSAIDS versus paracetamol (acetaminophen) in any dose, by any route in any 51 52 setting, used for pain relief in acute renal colic episode will be eligible. 53 NSAIDS included will be salicylates, propionic acid derivatives, acetic acid derivatives, 54 55 enolic acid derivatives, fenamates, selective COX-2 inhibitors, and sulfonamides. 56 57 58 59 60 5

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Types of outcome measures 4 5 Studies with at least one of the following outcomes will be included. 6 7 • Outcome measures using a validated pain scale 8 9 • Difference in pain score at 30 minutes 10 11 • Difference in the proportion of patients with pain relief at 30 minutes 12 13 • Time to pain relief 14 15 • Need forFor rescue analgesia peer review only 16 17 • Pain recurrence 18 19 • Major adverse event (e.g. GI bleeding and renal complications, complications at the 20 21 IM injection site) 22 23 24 25 26 Information sources 27 28 The search will not be restricted by language or date of publication to avoid publication 29 30 or retrieval biases. We will search the following databases and sources for relevant 31 32 studies: 33 http://bmjopen.bmj.com/ 34 Cochrane Central Register of Controlled Trials (CENTRAL) 35 36 Cochrane Renal Group Specialised Register for randomized controlled trials 37 38 Ovid MEDLINE(R) 1946 to Present with Daily Update 39 40 Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations

41 Ovid MEDLINE (R) Epub Ahead of Print on September 25, 2021 by guest. Protected copyright. 42 43 Embase Classic+ Embase 1947 to 2016 September 44 45 WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) 46 47 Reference lists of nephrology, urology and emergency medicine textbooks, 48 49 previously published review articles, and relevant trials. 50 51 Abstract list of the major nephrology, urology and emergency medicine conferences. 52 53 Correspondence documents seeking information about unpublished or incomplete 54 55 trials from the investigators known to be involved in previous trials. 56 57 The initial search strategy was developed in the Ovid MEDLINE database, using subject 58 59 60 6

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 heading and using free-text words. The relevant sub-classes of NSAIDS and commercial 4 5 names for the commonly used drugs were searched through Google and used in the 6 7 free-text search. We also compared the search strategies used for the previous two 8 9 Cochrane reviews4 5, and modified our strategy if any important terms were found 10 11 missing. Drugs such as Phenylbutazone, Aminophenazone (or aminopyrine), Ampyrone, 12 13 were excluded as these drugs have a risk of agranulocytocis, and are no longer used as 14 15 routine analgesics.For peer review only 16 17 18 19 Search strategy 20 We will perform the first search on MEDLINE, Embase, and Cochrane CENTRAL via Ovid. 21 22 The detailed search strategy is attached as Appendix-A. The second search will be 23 24 performed for ongoing clinical trials on WHO international clinical trial registry platform. 25 26 Finally, a manual search will be conducted in relevant key journals, conference 27 28 abstracts, textbook chapters, and the bibliography of included articles. Outcome of 29 30 each database search will be individually imported into Endnote X7 (Thomson Reuters) 31 32 reference manager. After this, using Endnote, the references will be combined and

33 http://bmjopen.bmj.com/ 34 duplications will be removed. The record of total search results retrieved and screened 35 will be kept and reported using PRISMA guidelines. 36 37 38 39 Selection process 40

41 Two authors will independently screen the titles and abstracts of de-duplicated results on September 25, 2021 by guest. Protected copyright. 42 43 to identify potentially eligible studies. These studies then will be further reviewed 44 45 independently, going through the full text, to confirm the inclusion criteria. Any 46 47 disagreement will be resolved through discussion or by consulting a third review author. 48 49 Agreement on independent inclusion of titles, abstract or full text will be quantified 50 51 using K statistics. Reasons for excluding potentially eligible studies will be recorded and 52 reported as supplementary to the main review. 53 54 55 56 Data collection process 57 58 59 60 7

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Two authors will independently extract the data using Cochrane Collaboration Review 4 5 Manager statistical software (RevMan 5.3) (http://ims.cochrane.org/RevMan) and a pre- 6 7 piloted Microsoft excel sheet. Before starting the review calibration exercises will be 8 9 conducted among the reviewers to ensure consistency. Discrepancies between the data 10 11 extraction will be resolved by discussion and reaching a consensus. If needed a third 12 13 reviewer will be contacted to reach a decision. 14 15 For peer review only 16 17 Data items 18 19 Data will be collected on the following data points. 20 1. Research information: the first author, the site where study was conducted, year 21 22 of publication, research design (randomization and concealed allocation) and the 23 24 sample size. 25 26 2. Characteristics of the study subjects: Age, sex, numbers in each group, inclusion 27 28 and exclusion of criteria of individual study, pain scores at the time of randomization, 29 30 diagnostic confirmation of renal colic. 31 32 3. Information on intervention and comparison arms: number of groups,

33 http://bmjopen.bmj.com/ 34 intervention and comparator(s) (drug, dose, and route), and the information about 35 blinding (treating person, assessor, and patient). Also information about exclusion after 36 37 randomization will also be recorded (intention to treat). 38 39 40

41 Outcomes and prioritization on September 25, 2021 by guest. Protected copyright. 42 43 To compare outcomes, identification of the definition used for the primary outcome, 44 45 measuring tool used, change in pain scores, need for rescue analgesia and at what time, 46 47 side effects and follow up (GI bleed or renal impairment), will be assessed. Notes 48 49 important but not classified in the above category will be entered as a free text. 50 51 52 Quality assessment of studies 53 54 To assess the risk of bias, study data will be extracted using the Cochrane Collaboration 55 56 tool for assessing the risk of bias (Table 8.5.a in the Cochrane Handbook for Systematic 57 58 59 60 8

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Reviews of Interventions). This includes information gathering on method of 4 5 randomization, allocation concealment, blinding of participants and investigators, 6 7 blinding of the assessor, incomplete outcome data, and other bias if any. Each domain 8 9 will be rated as having low, unclear or high risk of bias. 10 11 12 13 Missing data 14 15 We will try Forto contact peercorresponding review authors to request onlymissing data if contacts are 16 17 available. If this is not achieved, we will try to impute the missing information based on 18 19 the information available in the manuscript or the protocol of the study. For continuous 20 measures, missing standard deviation (SD) will be imputed from available information 21 22 such as standard error (SE), confidence interval (CI), or p-values. For a dichotomous 23 24 outcome, proportion or percentages will be used to calculate the number of 25 26 events/people assessed for that outcome. The results will be interpreted considering 27 28 the impact of missing data. 29 30 31 32 ANALYSIS

33 http://bmjopen.bmj.com/ 34 35 Data synthesis 36 37 For dichotomous outcomes, such as more than or equal to 50% reduction in pain, need 38 39 for rescue analgesia, recurrence of pain, or adverse events, a risk ratio (RR) with 95% 40

41 confidence intervals (95% CI) will be reported. The studies where continuous scale of on September 25, 2021 by guest. Protected copyright. 42 43 measure were used to assess the primary effect, such as patient rated pain, difference 44 45 in mean pain score, time to pain relief, a mean difference (MD) will be reported. If 46 47 different measurement scales were used, a standardized mean difference will be used 48 49 to express the results. For the adverse effects we will calculate the risk difference (RD) 50 51 with 95% CI. Skewed data and non-quantitative data will be presented descriptively. 52 53 54 Quantitative data will be pooled in the meta-analysis using RevMan 5.3 software. Fixed 55 56 effect models or random effect models will be used appropriately based on the 57 58 59 60 9

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 heterogeneity observed among the studies included in the pooled analysis. Statistical 4 5 heterogeneity in each model will be assessed using the χ² test of heterogeneity and 6 7 quantified using the Higgins’ I2 statistics. If the heterogeneity is insignificant the Mantel- 8 9 Haenszel method will be used for the fixed effect model. We will use the random effects 10 11 model if significant statistical heterogeneity (I2 >=50% or P <0.1) is present. 12 13 14 15 Subgroup analysisFor peer review only 16 17 We intend to perform the primary analysis based on the treatment groups such as 18 19 NSAIDS vs opioids and NSAIDS vs paracetamol. We will also perform subgroup analysis 20 21 based on the types of opioids or NSAIDS used, routes of administration, and based on 22 23 the quality of the study. If heterogeneity is substantial, we will not perform a meta- 24 25 analysis; a narrative, qualitative summary will be done and the information will be 26 presented using text and tables. 27 28 29 30 Meta-bias(es) 31 32 To assess reporting bias amongst the included studies, where possible, we will 33 http://bmjopen.bmj.com/ 34 determine if there was any deviation from the published protocol or information 35 st 36 registered prior to conduct of the study. If a study was published after July 1 2005, we 37 38 will screen the Clinical Trial Register at the International Clinical Trials Registry Platform 39 40 of the World Health Organisation (http://apps.who.int/ trialssearch). To assess the

41 on September 25, 2021 by guest. Protected copyright. 42 possibility of publication bias, we also plan to use a Funnel plot if 10 or more studies are 43 available for the meta-analysis. 44 45 46 47 Assessing cumulative evidence 48 49 We will assess the quality of body of evidence for each outcome according to Grading 50 51 of Recommendations Assessment, Development and Evaluation (GRADE) working group 52 53 methodology. 54 55 56 57 DISCUSSION 58 59 60 10

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Renal colic is a common cause of ED presentations and the excruciating pain demands 4 5 effective analgesia to be administered in the shortest possible time. To minimize the 6 7 delay in rapid administration of effective and safe analgesia, an evidence-based protocol 8 9 is needed. Previous reviews were inconclusive in establishing superior efficacy to 10 11 support first-line analgesia. It is important to use the first-line agent that is most 12 13 effective, has the best safety profile, and is quick and easy to administer with a single 14 15 rather than titratedFor first peer dose. Given thatreview there have been onlysignificant publications since 16 17 the last review on this topic, we believe that it is likely that improved guidance for 18 19 protocolised first-line analgesia for renal colic can be given. 20 21 22 Ethics and dissemination 23 24 Formal ethics approval is not required, as primary data will not be collected. We plan to 25 26 publish the result of this review in a peer-reviewed journal. We believe that the results 27 28 of this review will provide robust evidence in deciding superiority among commonly 29 30 used analgesics, and help to improve guidance for protocolised analgesia in renal colic. 31 32

33 http://bmjopen.bmj.com/ 34 Contributions: SAP is the guarantor. SAP, BM and PAC drafted the protocol for the 35 systematic review. SAP and LR developed the search strategy. All authors contributed to 36 37 the development of the selection criteria, the risk of bias assessment strategy and data 38 39 extraction criteria. All authors read, provided feedback and approved the final 40

41 manuscript. on September 25, 2021 by guest. Protected copyright. 42 43 Competing interest: We have read and understood BMJ policy on declaration of 44 45 interests and declare that we have no competing interests. 46 47 48 49 REFERENCES 50 51 52 1. Fisang C, Anding R, Muller SC, et al. Urolithiasis--an interdisciplinary diagnostic, 53 therapeutic and secondary preventive challenge. Deutsches Arzteblatt 54 international 2015;112(6):83-91. doi: 10.3238/arztebl.2015.0083 [published 55 Online First: 2015/02/28] 56 2. Ghani KR, Roghmann F, Sammon JD, et al. Emergency department visits in the 57 58 United States for upper urinary tract stones: trends in hospitalization and 59 60 11

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 charges. The Journal of urology 2014;191(1):90-6. doi: 4 5 10.1016/j.juro.2013.07.098 [published Online First: 2013/08/13] 6 3. Pickard R, Starr K, MacLennan G, et al. Use of drug therapy in the management of 7 symptomatic ureteric stones in hospitalised adults: a multicentre, placebo- 8 controlled, randomised controlled trial and cost-effectiveness analysis of a 9 10 calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the 11 SUSPEND trial). Health technology assessment (Winchester, England) 12 2015;19(63):vii-viii, 1-171. doi: 10.3310/hta19630 [published Online First: 13 2015/08/06] 14 4. Afshar K, Jafari S, Marks AJ, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) 15 For peer review only 16 and non-opioids for acute renal colic. The Cochrane database of systematic 17 reviews 2015;6:Cd006027. doi: 10.1002/14651858.CD006027.pub2 18 [published Online First: 2015/06/30] 19 5. Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus 20 opioids for acute renal colic. The Cochrane database of systematic reviews 21 22 2005(2):Cd004137. doi: 10.1002/14651858.CD004137.pub3 [published 23 Online First: 2005/04/23] 24 6. Pines JM, Hollander JE. Emergency department crowding is associated with poor 25 care for patients with severe pain. Annals of emergency medicine 26 2008;51(1):1-5. doi: 10.1016/j.annemergmed.2007.07.008 [published Online 27 28 First: 2007/10/05] 29 7. Labrecque M, Dostaler LP, Rousselle R, et al. Efficacy of nonsteroidal anti- 30 inflammatory drugs in the treatment of acute renal colic. A meta-analysis. 31 Archives of internal medicine 1994;154(12):1381-7. [published Online First: 32 1994/06/27] 33 http://bmjopen.bmj.com/ 34 8. Dave C, Shetty S, Faraj K. Nephrolithiasis Treatment & Management: WebMD; 35 2016 [updated Dec 03, 2016. Available from: 36 http://emedicine.medscape.com/article/437096-treatment - d7 accessed 37 Feb 05, 2017. 38 9. Ketabchi AA, Ebad-Zadeh MR, Parvaresh S, et al. Opium Dependency in Recurrent 39 40 Painful Renal Lithiasis Colic. Addiction & Health 2012;4(1-2):73-8.

41 10. Worster A. Renal colic. In: Thomas SH, ed. Emergency Department Analgesia: An on September 25, 2021 by guest. Protected copyright. 42 Evidence-Based Guide. New York: Cambridge University Press 2008:359-62. 43 11. Bounes V, Valle B, Concina F, et al. Treatment of Acute Renal Colic in US and 44 French EDs: Simulated Cases and Real Cases in Acute Pain Management. The 45 46 American journal of emergency medicine 2016;34(10):1955-58. doi: 47 10.1016/j.ajem.2016.06.107 [published Online First: 2016/07/20] 48 12. Manjiani D, Paul DB, Kunnumpurath S, et al. Availability and Utilization of 49 Opioids for Pain Management: Global Issues. The Ochsner Journal 50 51 2014;14(2):208-15. 52 13. Berterame S, Erthal J, Thomas J, et al. Use of and barriers to access to opioid 53 analgesics: a worldwide, regional, and national study. Lancet (London, 54 England) 2016;387(10028):1644-56. doi: 10.1016/s0140-6736(16)00161-6 55 [published Online First: 2016/02/08] 56 57 58 59 60 12

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 14. Pathan SA, Mitra B, Cameron PA. Titrated doses are optimal for opioids in pain 4 5 trials - Authors' reply. Lancet (London, England) 2016;388(10048):961-2. 6 doi: 10.1016/s0140-6736(16)31494-5 [published Online First: 2016/09/07] 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Appendix A 4 5 6 7 Ovid MEDLINE(R) 1946 to Present with Daily Update+ In-Process & Other Non- 8 Indexed Citations (2016 Month, Date) 9 10 # Search Statement Annotation 11 12 exp Urinary Bladder Calculi/ or exp Urinary Calculi/ or 13 exp Kidney Calculi/ or exp Ureteral Calculi/ or exp 14 1 Urolithiasis/ or exp Nephrolithiasis/ or exp Renal Colic/ 15 or exp Ureteral Diseases/ or exp Ureteral Obstruction/ or For peer review only 16 17 exp Kidney Diseases/ 18 ((Urin* or renal or kidney or ureter* or bladder) adj3 19 2 (stone* or calcul* or colic* or lith* or obstruct* or 20 occlusi*)).mp. 21 22 3 ((Kidney or ureter*) adj2 diseas*).mp. 23 4 (Urolith* or nephrolith*).mp. 24 5 or/1-4 Population- Renal colic 25 26 exp Anti-Inflammatory Agents, Non-Steroidal/ or exp 27 6 Cyclooxygenase Inhibitors/ or exp Cyclooxygenase 2 28 Inhibitors/ 29 ((Nonsteroidal adj2 antiinflammatory) or (Non-steroidal 30 adj2 antiinflammatory) or (Nonsteroidal adj2 anti- 31 7 32 inflammatory) or (Non-steroidal adj2 anti-

33 inflammatory)).mp. http://bmjopen.bmj.com/ 34 exp diclofenac/ or exp ketorolac/ or exp apazone/ or exp 35 aspirin/ or exp ibuprofen/ or exp ketoprofen/ or exp 36 Salicylates/ or exp etodolac/ or exp naproxen/ or exp 37 8 38 indomethacin/ or exp piroxicam/ or exp celecoxib/ or exp 39 fenoprofen/ or exp sulindac/ or exp tolmetin/ or exp 40 mesalazine/ or exp aminosalicylic acid/ 41 9 NSAID*.mp. on September 25, 2021 by guest. Protected copyright. 42 43 (Diclofenac or adiflam or agile or diclonac or dicol or 44 10 diclonat* or feloran or voltarol or Voltaren or Cataflam or 45 Voltaren-XR or Zipsor).mp. 46 (Aceclofenac or Hifenac or Cincofen or Nacsiv or 47 11 48 Acenac).mp. (Ketorolac or toradol or torolac or kealc or kenalfin or 49 12 50 ketlac).mp. 51 13 (Apazon* or Azapropazon* or cinnopropazon*).mp. 52 (Aspirin* or acetylsal* or dispril or easprin* or 53 14 54 salicylic*).mp. 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 (Ibuprofen or brufen or nuprin or rufen or salprofen or dolgit or salprofen or advil* or motrin or nurofen or 5 15 6 actiprofen or addaprin or aktren or anadin or bugesic or 7 ibuprox).mp. 8 (ketoprofen or orudis or oruvail or ketoflam or oruvail or 9 10 16 fastum or ketonal or ketodol or knavon or actron or 11 ketoprofeno).mp. 12 (Dexketoprofen or keral or enantyum or ketesgel or 17 13 dolmen).mp. 14 (Naproxen or naprosyn or naprosin or proxen or synflex 15 18 For peer review only 16 or Aleve or Anaprox or Apronax or Naprelan).mp. 17 (etodolac or ramodar or ultradol or etova or dualgan or 18 19 etodin or etopan or flancox or proxym or etodine or 19 20 dolarit).mp. 21 (Indomethacin* or indocid or indocin or indomet or 20 22 indometacin or metindol or osmosin).mp. 23 (Piroxicam or feldene or dolocare or dolonex or 24 21 25 ketolin).mp. 26 22 (Meloxicam or mobic or vivlodex).mp. 27 23 (Tenoxicam or mobiflex).mp. 28 29 24 (celecoxib or celebrex or celebra).mp. 30 25 (rofecoxib or vioxx or ceoxx or ceeoxx).mp. 31 26 (valdecoxib or bextra).mp. 32

(Nimesulid* or aulin or mesulid or nimalox or sulid* or http://bmjopen.bmj.com/ 33 27 34 sintalgin or nimsid* or nise or nimulid).mp. 35 28 (Meclofenamic or meclofenamat* or meclomen).mp. 36 37 29 (fenoprofen or fenopron).mp. 38 (oxaprozin or oxaprozinum or daypro or dayrun or 30 39 duraprox).mp. 40 31 (sulindac or cinoril or imbaral).mp. 41 on September 25, 2021 by guest. Protected copyright. 42 32 (tolmetin or tolectin).mp. 43 (flurbiprofen* or sulindac* or mesalazin* or sulfasalazin* 44 or flufenamic* or tolmetin* or fenoprofen* or diflunisal* 45 46 or niflumic* or ketorolac or trometamol* or parecoxib* or teriflunomid* or benoxaprofen* or suprofen* or fenbufen* 47 33 48 or mebron* or mepirizole* or mepyrizole* or 49 methopyrimazole* or Epirizolum* or Polihexanid* or 50 Dalex* or Miton* or epirizol* or clonixin* or tolemetin* or 51 52 nabumeton*).mp. 53 34 or/6-33 NSAIDS 54 exp Analgesics, opioid/ or exp alkaloids, opiate/ or exp 55 35 56 narcotics/ 57 36 opioid*.mp. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 exp hydrocodone/ or exp dextropropoxyphene/ or exp fentanyl/ or exp meperidine/ or exp methadone/ or exp 5 37 6 Morphine/ or exp Morphine Derivatives/ or exp 7 oxymorphone/ or exp pentazocine/ or exp tramadol/ 8 38 exp alfentanil/ or alfentanil*.mp. 9 10 39 exp codeine/ or codein*.mp. 11 (hydrocodon* or vicodin* or norco or lortab or 40 12 zohydro).mp. 13 14 41 exp oxycodone/ or oxycodon*.mp. 15 (dextropropoxyphen* or darvon or darvocet or digesic or 42 For peer review only 16 capadex).mp. 17 43 exp dihydromorphine/ or dihydromorphin*.mp. 18 (fentanyl or actiq or duragesic or fentora or sublimaz* or 19 44 20 fenta).mp. 21 45 (meperidin* or demerol or pethidin*).mp. 22 (methadon* or dolophin* or methadose or amidon* or 23 46 24 symoron or physephton* or heptadon).mp. 25 (morphin* or oramorph or morphia or duramorph or 26 47 27 contin or mscontin or sevredol or zomorphzomo).mp. 28 48 (oxymorphon* or numorphan or opana or morphon).mp. 29 (pentazocin* or fortal or sosegon or talwin or fortwin or 49 30 talacen).mp. 31 32 50 (tramadol or ultram).mp. 33 51 or/35-50 Opioids http://bmjopen.bmj.com/ 34 52 exp Acetaminophen/ 35 36 (abenol* or acamol* or acenol* or acephen* or acet 37 suppositories* or acetalgin* or acetamino phenol* or 38 acetaminophen* or acetaminophene* or 39 acetaminophenol* or acetamol* or acetomenophen* or 40 acetylaminophenol* or adorem* or afebrin* or algiafin* or 41 on September 25, 2021 by guest. Protected copyright. 42 algotropyl* or alphagesic* or alvedon* or amadil* or 43 anacin 3* or anaflon* or analgiser* or apamide* or apirex* 44 or arthralgen* or benuron* or biogesic* or calapol* or 45 53 calodol* or dafalgan* or depyretin* or dirox* or dolex* or 46 47 dolofen* or dolomol* or calpol* or eneril* or meforagesic* 48 or dolorol* or metagesic* or napamol* or naprex* or 49 pacemol* or pacimol* or duorol* or pamol* or panadol* or 50 panamax* or panodil* or paracet* or paracetamole* or 51 parageniol* or paragin* or paralen* or paralief* or 52 53 paramax* or paramidol* or paximol* or paratabs* or 54 perfalgan* or pyrigesic* or setamol* or tylenol* or tylex* 55 or valadol* or winadol* or zydinol).mp. 56 54 or/52-53 Paracetamol 57 58 55 5 and 34 and 51 NSAIDS Vs Opioids 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 56 5 and 34 and 54 NSAIDS Vs Paracetamol 5 57 randomized controlled trial.pt. 6 58 controlled clinical trial.pt. 7 (random$ or placebo$ or single blind$ or double blind$ or 8 59 9 triple blind$).ti,ab. 10 60 (retraction of publication or retracted publication).pt. 11 61 or/57-60 RCTs 12 13 62 (animals not humans).sh. 14 ((comment or editorial or meta-analysis or practice- 15 63 guideline or review or letter or journal correspondence) For peer review only 16 17 not "randomized controlled trial").pt. 18 (random sampl$ or random digit$ or random effect$ or 19 64 random survey or random regression).ti,ab. not 20 "randomized controlled trial".pt. 21 22 65 or/62-64 non-human subject or 23 non RCTs 24 66 61 not 65 Human subject RCTs 25 NSAIDS Vs Opioids 26 67 55 and 66 27 +Human subject RCTs 28 NSAIDS Vs 29 68 56 and 66 Paracetamol+Human 30 subject RCTs 31 32 NSAIDS (Opioids or 33 69 67 or 68 paracetamol) in human http://bmjopen.bmj.com/ 34 subject RCTs 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 Embase Classic+Embase 1947 to 2016 Month, Date 43 44 # Search Statement Annotation 45 exp kidney pain/ or exp kidney colic/ or exp bladder stone/ or 46 47 1 exp ureter stone/ or exp urolithiasis/ or exp nephrolithiasis/ 48 or exp ureter obstruction/ 49 2 ((Urin* or renal or kidney or ureter* or bladder) adj3 (stone* 50 or calcul* or colic* or lith* or obstruct* or occlusi*)).mp. 51 52 3 ((Kidney or ureter*) adj2 diseas*).mp. 53 4 (Urolith* or nephrolith*).mp. 54 Population- Renal 55 5 56 or/1-4 colic 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 exp nonsteroid antiinflammatory agent/ or exp 5 cyclooxygenase 2 inhibitor/ or exp indometacin/ or exp 6 piroxicam/ or exp acetylsalicylic acid/ or exp celecoxib/ or 7 exp diclofenac/ or exp ibuprofen/ or exp naproxen/ or exp 8 6 azapropazone/ or exp acetylsalicylic acid/ or exp ketoprofen/ 9 10 or exp salicylic acid/ or exp ketorolac/ or exp ketoprofen/ or 11 exp salicylic acid derivative/ or exp etodolac/ or exp 12 fenoprofen/ or exp sulindac/ or exp tolmetin/ or exp 13 mesalazine/ or exp aminosalicylic acid/ 14 15 ((Nonsteroidal adj2 antiinflammatory) or (NonFor peer review-steroidal adj2 only 16 7 antiinflammatory) or (Nonsteroidal adj2 anti-inflammatory) 17 or (Non-steroidal adj2 anti-inflammatory)).mp. 18 8 NSAID*.mp. 19 20 (Diclofenac or adiflam or agile or diclonac or dicol or diclonat* 21 9 or feloran or voltarol or Voltaren or Cataflam or Voltaren-XR 22 or Zipsor).mp. 23 10 (Aceclofenac or Hifenac or Cincofen or Nacsiv or Acenac).mp. 24 (Ketorolac or toradol or torolac or kealc or kenalfin or 25 11 26 ketlac).mp. 27 12 (Apazon* or Azapropazon* or cinnopropazon*).mp. 28 29 13 (Aspirin* or acetylsal or dispril or easprin* or salicylic*).mp. 30 (Ibuprofen or brufen or nuprin or rufen or salprofen or dolgit 31 14 or salprofen or advil* or motrin or nurofen or actiprofen or 32

33 addaprin or aktren or anadin or bugesic or ibuprox).mp. http://bmjopen.bmj.com/ 34 (ketoprofen or orudis or oruvail or ketoflam or oruvail or 35 15 fastum or ketonal or ketodol or knavon or actron or 36 ketoprofeno).mp. 37 (Dexketoprofen or keral or enantyum or ketesgel or 38 16 39 dolmen).mp. 40 17 (Naproxen or naprosyn or naprosin or proxen or synflex or 41 Aleve or Anaprox or Apronax or Naprelan).mp. on September 25, 2021 by guest. Protected copyright. 42 (etodolac or ramodar or ultradol or etova or dualgan or etodin 43 18 44 or etopan or flancox or proxym or etodine or dolarit).mp. 45 (Indomethacin* or indocid or indocin or indomet or 46 19 47 indometacin or metindol or osmosin).mp. 48 20 (Piroxicam or feldene or dolocare or dolonex or ketolin).mp. 49 21 (Meloxicam or mobic or vivlodex).mp. 50 51 22 (Tenoxicam or mobiflex).mp. 52 23 (celecoxib or celebrex or celebra).mp. 53 24 (rofecoxib or vioxx or ceoxx or ceeoxx).mp. 54 55 25 (valdecoxib or bextra).mp. 56 (Nimesulid* or aulin or mesulid or nimalox or sulid* or 26 57 sintalgin or nimsid* or nise or nimulid).mp. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 27 (Meclofenamic or meclofenamat* or meclomen).mp. 5 28 (fenoprofen or fenopron).mp. 6 (oxaprozin or oxaprozinum or daypro or dayrun or 29 7 duraprox).mp. 8 9 30 (sulindac or cinoril or imbaral).mp. 10 31 (tolmetin or tolectin).mp. 11 (flurbiprofen* or sulindac* or mesalazin* or sulfasalazin* or 12 13 flufenamic* or tolmetin* or fenoprofen* or diflunisal* or 14 niflumic* or ketorolac or trometamol* or parecoxib* or 15 32 teriflunomid* or benoxaprofen* or suprofenFor peer review* or fenbufen* or only 16 mebron* or mepirizole* or mepyrizole* or methopyrimazole* 17 or Epirizolum* or Polihexanid* or Dalex* or Miton* or 18 19 epirizol* or clonixin* or tolemetin* or nabumeton*).mp. 20 33 or/6-32 NSAIDS 21 exp opiate/ or exp narcotic analgesic agent/ or exp opiate 34 22 agonist/ 23 24 exp hydrocodone/ or exp dextropropoxyphene/ or exp 25 35 fentanyl/ or exp pethidine/ or exp methadone/ or exp 26 oxymorphone/ or exp pentazocine/ or exp tramadol/ 27 28 36 opioid*.mp. 29 37 exp alfentanil/ or alfentanil*.mp. 30 38 exp codeine/ or codein*.mp. 31 32 39 (hydrocodon* or vicodin* or norco or lortab or zohydro).mp. 33 40 exp oxycodone/ or oxycodon*.mp. http://bmjopen.bmj.com/ 34 (dextropropoxyphen* or darvon or darvocet or digesic or 35 41 36 capadex).mp. 37 42 exp dihydromorphine/ or dihydromorphin*.mp. 38 (fentanyl or actiq or duragesic or fentora or sublimaz* or 43 39 fenta).mp. 40

41 44 (meperidin* or demerol or pethidin*).mp. on September 25, 2021 by guest. Protected copyright. 42 45 (methadon* or dolophin* or methadose or amidon* or 43 symoron or physephton* or heptadon).mp. 44 45 46 exp morphine/ or exp morphine derivative/ 46 47 (morphin* or oramorph or morphia or duramorph or contin or 47 mscontin or sevredol or zomorphzomo).mp. 48 49 48 (oxymorphon* or numorphan or opana or morphon).mp. 50 (pentazocin* or fortal or sosegon or talwin or fortwin or 49 51 talacen).mp. 52 53 50 (tramadol or ultram).mp. 54 51 or/34-50 Opioids 55 52 exp paracetamol/ 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 (abenol* or acamol* or acenol* or acephen* or acet 5 suppositories* or acetalgin* or acetamino phenol* or 6 acetaminophen* or acetaminophene* or acetaminophenol* or 7 acetamol* or acetomenophen* or acetylaminophenol* or 8 adorem* or afebrin* or algiafin* or algotropyl* or alphagesic* 9 10 or alvedon* or amadil* or anacin 3* or anaflon* or analgiser* 11 or apamide* or apirex* or arthralgen* or benuron* or 12 biogesic* or calapol* or calodol* or dafalgan* or depyretin* or 53 13 dirox* or dolex* or dolofen* or dolomol* or calpol* or eneril* 14 or meforagesic* or dolorol* or metagesic* or napamol* or 15 For peer review only 16 naprex* or pacemol* or pacimol* or duorol* or pamol* or 17 panadol* or panamax* or panodil* or paracet* or 18 paracetamole* or parageniol* or paragin* or paralen* or 19 paralief* or paramax* or paramidol* or paximol* or paratabs* 20 or perfalgan* or pyrigesic* or setamol* or tylenol* or tylex* or 21 22 valadol* or winadol* or zydinol).mp. 23 54 or/52-53 Paracetamol 24 55 5 and 33 and 51 NSAIDS Vs Opioids 25 NSAIDS Vs 26 56 27 5 and 33 and 54 Paracetamol 28 (random$ or placebo$ or single blind$ or double blind$ or 57 29 triple blind$).ti,ab. 30 31 58 RETRACTED ARTICLE/ 32 59 or/57-58 RCTs 33 60 (animal$ not human$).sh,hw. http://bmjopen.bmj.com/ 34 35 61 (book or conference paper or editorial or letter or review).pt. 36 not exp randomized controlled trial/ 37 (random sampl$ or random digit$ or random effect$ or 38 62 random survey or random regression).ti,ab. not exp 39 40 randomized controlled trial/

1 1 6 1 4 3 1 1 1 10 4-5 6 6 and (Page (Page No.#) Appendix-A grey grey

Role of Role of sponsor funderor Sponsor 5b Provide reviewfor the name funderand/or sponsor Sources 5a financial Indicate sources of supportother or reviewfor the Contributions 3b contributions Describe authors protocol and identify of the reviewthe guarantor of Contact 3a Update 1b the for If protocol is an update a systematic previous of review, as identify such Identification 1a reportthe as Identify a a protocol systematicof review Search Search strategy 10 Information Information sources Eligibility criteriaEligibility 8 METHODS Objectives Rationale Rationale INTRODUCTION Support: Amendments 4 Authors: Registration 2 registered, If provide the (suchnamethe registry of PROSPERO) as and registrationnumber Title: ADMINISTRATIVE INFORMATION PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist: recommended items to to items recommended checklist: 2015 Protocols) Meta-Analysis review for and Systematic Items (PreferredReporting PRISMA-P reviewprotocol* a systematic in address Section topic and Page 21 of 22 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from Page 22 of

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clarification theclarification items. on to Amendments a review protocol should be tracked copyrightand dated. The for (includingPRISMA-P checklist) byheld the is Group PRISMA-P and is distributedunder a Creative Commons Attribution Licence 4.0. Shamseer From: L, Moher D, Clarke M, Ghersi Liber D, * Confidence inConfidence evidence cumulative Meta-bias(es) 16 any Specify assessmentplanned of meta-bias(es) as (such publication biasacross studies, selective reporting within studies) 10 Data Data synthesis 15a criteria under Describe data which study be will quantitatively synthesised Risk Risk in of bias studiesindividual Outcomes and Outcomes prioritization Data itemsData 12 Study records:Study meta-analysis protocols(PRISMA-P) elaboration2015: explanation. andBMJ. Jan 2015 2;349(jan02 1):g7647. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from

What is the best analgesic option for patients presenting with renal colic to the Emergency department? Protocol for a systematic review and meta-analysis.

For peer review only Journal: BMJ Open

Manuscript ID bmjopen-2016-015002.R2

Article Type: Protocol

Date Submitted by the Author: 06-Mar-2017

Primary Subject Emergency medicine Heading:

Secondary Subject Heading: Evidence based practice, Medical management, Urology, Research methods http://bmjopen.bmj.com/ Renal colic, Urolithiasis < UROLOGY, NSAIDS, Paracetamol, Opioids, Keywords: Analgesia

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 What is the best analgesic option for patients presenting with renal colic to the 4 5 Emergency department? Protocol for a systematic review and meta-analysis. 6 7 8 Authors’ names and degrees 9 10 1. Dr. Sameer A. Pathan 1,2,3 MBBS, CABEM, MRCEM 11 12 2. A/Prof. Biswadev Mitra 2,3,4 MBBS, MHSM, PhD, FACEM 13 5 14 3. Ms. Lorena Romero BA, MBIT 15 For peer2,3,4 review only 16 4. Prof. Peter A. Cameron MBBS, MD, FACEM 17 18 19 20 Affiliations 21 1 Emergency Department, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar 22 2 23 Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia. 24 3 National Trauma Research Institute, The Alfred Hospital, Melbourne, Australia. 25 26 4 Emergency & Trauma Centre, The Alfred Hospital, Melbourne, Australia. 27 5 Alfred Health, The Ian Potter Library, Melbourne, Australia. 28 29 1. [email protected] 30 31 2. [email protected] 32 3. [email protected] 33 http://bmjopen.bmj.com/ 34 4. [email protected] 35 36 37 Corresponding author 38 39 Dr. Sameer A. Pathan 40

41 P.O.BOX. 50107, Mesaieed Post Office, Qatar. on September 25, 2021 by guest. Protected copyright. 42 43 Email: [email protected] 44 Telephone: 00974 6685 7650 45 46 Word count: Abstract- 276, Manuscript – 2458 47 48 Registration: This systematic review is registered on the PROSPERO international 49 50 prospective register of systematic reviews (PROSPERO 2016:CRD42016047559). 51 52 Amendments: Any change(s) in the protocol will be updated in the PROSPERO registry. 53 54 The amendments will be accompanied by the information regarding time, date, 55 56 description of changes, and rationally behind the changes made. 57 Support: This systematic review is non-funded. 58 59 60 1

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 ABSTRACT 4 5 Introduction 6 7 Patients with renal colic, present to the emergency department in excruciating pain. 8 9 There is variability in practice regarding the choice of initial analgesic to be used in renal 10 11 colic. The aim of this article is to outline the protocol for review of the efficacy and 12 13 safety of NSAIDS, opioids, and paracetamol use in renal colic pain management. 14 15 Methods andFor analysis peer review only 16 17 This is the protocol for a systematic review, comparing efficacy of NSAIDS, opioids, and 18 19 paracetamol in renal colic studied under randomized controlled trial design. We will 20 conduct a comprehensive literature search for both peer-reviewed and grey literature 21 22 published until 1st October 2016. Using a predefined search strategy MEDLINE, Embase, 23 24 Cochrane Central Register of Controlled Trials will be searched. Additional searches will 25 26 include WHO International Clinical Trials Registry Platform, abstract list of relevant 27 28 major conferences and the reference lists of relevant publications. Two authors will 29 30 independently screen and identify the studies to be included. The RCT comparing 31 32 NSAIDS versus opioids or paracetamol will be included in the review, if the age of

33 http://bmjopen.bmj.com/ 34 participants in the study was >16 years, and they presented with moderate to severe 35 renal colic. Any disagreement between the screening authors will be resolved through 36 37 discussion and reaching consensus, if not, a third reviewer will arbitrate. Quantitative 38 39 data from homogenous studies will be pooled in the meta-analysis using RevMan 5.3 40

41 software. The findings of this review will be presented according to guidelines in the on September 25, 2021 by guest. Protected copyright. 42 43 Cochrane Handbook of Systematic Reviews of Interventions and PRISMA statement. 44 45 Ethics and dissemination 46 47 Formal ethics approval is not required, as primary data will not be collected. We plan to 48 49 publish the result of this review in a peer-reviewed journal. 50 51 52 53 54 55 56 57 58 59 60 2

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 being managed concurrently.6 A previously published meta-analysis comparing NSAIDS 4 5 with opioids suggested NSAIDS were better than opioids in terms of requiring less 6 7 rescue analgesia and having fewer side effect. However, it did not establish superior 8 9 efficacy of either drug group.5 7 Although the European Association of Urology guidelines 10 11 on urolithiasis recommends NSAIDs as the first choice, the use of intravenous opioids as 12 13 the first-line analgesic in renal colic, continues to be a common practice in many 14 8-12 15 developed For countries. peer However, review the logistical delay only involved in intravenous 16 17 administrations, dose-dependent side-effects, need for titrating dosage, and overly 18 19 bureaucratic restrictions are some of the challenges associated with the IV opioid use as 20 the first-line analgesic in the busy ED. 13 14 15 Routine use of NSAIDS has been limited 21 22 because of the fear of gastrointestinal (GI) and renal complications. In addition, there 23 24 has been undue emphasis placed on the possibility of abscess and muscle necrosis 25 26 secondary to intramuscular injection, given the extremely low level of documented 27 28 cases. 29 30 31 32 The obvious limitations of previous studies and systematic reviews may partly explain

33 http://bmjopen.bmj.com/ 34 the continued clinical orthodoxy of intravenous opioid use as the first analgesic in many 35 settings. Firstly, this review was conducted and published in 2004 and the studies 36 37 included were published between 1982-1999. 5 In the last 15 years, newer, well 38 39 powered, pragmatic, clinical trials have been published with clinically relevant outcomes 40

41 in renal colic management. Secondly, most studies in the review only included patients on September 25, 2021 by guest. Protected copyright. 42 43 who had confirmed renal calculi on subsequent testing. This may limit the applicability 44 45 of evidence in routine clinical practice where patients are treated with a clinical picture 46 47 of renal colic well before any imaging can be performed. Thirdly, significant 48 49 heterogeneity between the studies included, did not allow pooled analysis to test the 50 4 5 51 superiority of a drug based on efficacy. A pooled analysis of NSAIDS other than 52 Ketorolac in the review showed pain reduction of 4.6mm (on VAS 0-100) only, which is 53 54 minimal compared to the newer trial results.15 Fourthly, 12 of the 20 included trials used 55 56 pethidine as their opioid arm, which is not a commonly used opioid in current practice. 5 57 58 59 60 4

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Lastly, studies available to include at the time of review lacked consistent reporting of 4 5 serious adverse events such as renal failure and GI bleeding limiting comparability. 6 7 8 9 There is ongoing controversy regarding the superiority of any of the commonly used 10 11 analgesics in terms of efficacy, optimum dosing and route of administration. Therefore, 12 13 we aim to examine the efficacy and safety of NSAIDS, opioids, and paracetamol use in 14 15 renal colic painFor management. peer review only 16 17 18 19 METHODS AND DESIGN 20 21 Types of participants 22 23 The systematic review will only include studies involving adult patients (age >16 years), 24 25 with a clinical diagnosis of acute renal colic (pain less than 12 hours), and moderate to 26 27 severe pain severity. If a study reports data on both adult and pediatric populations, we 28 29 will only include the data if the mean age of patients is over 18. The data from mixed 30 31 population studies will be highlighted when reporting final results. 32

33 http://bmjopen.bmj.com/ 34 35 Type of studies 36 Only randomized controlled trials (RCT) comparing NSAIDS versus opioids or NSAIDS 37 38 versus paracetamol, will be included in the review. There will be no language restriction 39 40 to conduct primary search. If the language used to write the article is other than English,

41 on September 25, 2021 by guest. Protected copyright. 42 we will use a professional translator to translate the text in English. 43 44 45 46 Types of interventions 47 48 The studies will be reviewed if interventions include: 49 50 NSAIDS versus opioids in any dose, by any route in any setting, used for pain relief in 51 52 acute renal colic episode will be eligible. 53 NSAIDS versus paracetamol (acetaminophen) in any dose, by any route in any 54 55 setting, used for pain relief in acute renal colic episode will be eligible. 56 57 NSAIDS included will be salicylates, propionic acid derivatives, acetic acid derivatives, 58 59 60 5

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 enolic acid derivatives, fenamates, selective COX-2 inhibitors, and sulfonamides. 4 5 6 7 Types of outcome measures 8 9 Studies with at least one of the following outcomes will be included. 10 11 • Outcome measures using a validated pain scale 12 13 • Difference in pain score at 30 minutes 14 15 • DifferenceFor in the proportion peer of patients review with pain relief onlyat 30 minutes 16 17 • Time to pain relief 18 19 • Need for rescue analgesia 20 21 • Pain recurrence 22 23 • Major adverse event (e.g. GI bleeding and renal complications, complications at the 24 25 IM injection site) 26 27 28 29 30 Information sources 31 32 The search will not be restricted by language or date of publication to avoid publication 33 http://bmjopen.bmj.com/ 34 or retrieval biases. We will search the following databases and sources for relevant 35 36 studies: 37 38 Cochrane Central Register of Controlled Trials (CENTRAL) 39 40 Cochrane Renal Group Specialised Register for randomized controlled trials

41 Ovid MEDLINE(R) 1946 to Present with Daily Update on September 25, 2021 by guest. Protected copyright. 42 43 Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations 44 45 Ovid MEDLINE (R) Epub Ahead of Print 46 47 Embase Classic+ Embase 1947 to 2016 September 48 49 WHO International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/) 50 51 Reference lists of nephrology, urology and emergency medicine textbooks, 52 53 previously published review articles, and relevant trials. 54 55 Abstract list of the major nephrology, urology and emergency medicine conferences. 56 57 Correspondence documents seeking information about unpublished or incomplete 58 59 60 6

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 trials from the investigators known to be involved in previous trials. 4 5 The initial search strategy was developed in the Ovid MEDLINE database, using subject 6 7 heading and using free-text words. The relevant sub-classes of NSAIDS and commercial 8 9 names for the commonly used drugs were searched through Google and used in the 10 11 free-text search. We also compared the search strategies used for the previous two 12 4 5 13 Cochrane reviews , and modified our strategy if any important terms were found 14 15 missing. DrugsFor such as Phenylbutazone,peer review Aminophenazone (oronly aminopyrine), Ampyrone, 16 17 were excluded as these drugs have a risk of agranulocytocis, and are no longer used as 18 19 routine analgesics. 20 21 22 Search strategy 23 24 We will perform the first search on MEDLINE, Embase, and Cochrane CENTRAL via Ovid. 25 26 The detailed search strategy is attached as Appendix-A. The second search will be 27 28 performed for ongoing clinical trials on WHO international clinical trial registry platform. 29 30 Finally, a manual search will be conducted in relevant key journals, conference 31 32 abstracts, textbook chapters, and the bibliography of included articles. Outcome of

33 http://bmjopen.bmj.com/ 34 each database search will be individually imported into Endnote X7 (Thomson Reuters) 35 reference manager. After this, using Endnote, the references will be combined and 36 37 duplications will be removed. The record of total search results retrieved and screened 38 39 will be kept and reported using PRISMA guidelines. 40

41 on September 25, 2021 by guest. Protected copyright. 42 43 Selection process 44 45 Two authors will independently screen the titles and abstracts of de-duplicated results 46 47 to identify potentially eligible studies. These studies then will be further reviewed 48 49 independently, going through the full text, to confirm the inclusion criteria. Any 50 51 disagreement will be resolved through discussion or by consulting a third review author. 52 Agreement on independent inclusion of titles, abstract or full text will be quantified 53 54 using K statistics. Reasons for excluding potentially eligible studies will be recorded and 55 56 reported as supplementary to the main review. 57 58 59 60 7

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 5 Data collection process 6 7 Two authors will independently extract the data using Cochrane Collaboration Review 8 9 Manager statistical software (RevMan 5.3) (http://ims.cochrane.org/RevMan) and a pre- 10 11 piloted Microsoft excel sheet. Before starting the review calibration exercises will be 12 13 conducted among the reviewers to ensure consistency. Discrepancies between the data 14 15 extraction willFor be resolved peer by discussion review and reaching a consensus.only If needed a third 16 17 reviewer will be contacted to reach a decision. 18 19 20 Data items 21 22 Data will be collected on the following data points. 23 24 1. Research information: the first author, the site where study was conducted, year 25 26 of publication, research design (randomization and concealed allocation) and the 27 28 sample size. 29 30 2. Characteristics of the study subjects: Age, sex, numbers in each group, inclusion 31 32 and exclusion of criteria of individual study, pain scores at the time of randomization,

33 http://bmjopen.bmj.com/ 34 diagnostic confirmation of renal colic. 35 3. Information on intervention and comparison arms: number of groups, 36 37 intervention and comparator(s) (drug, dose, and route), and the information about 38 39 blinding (treating person, assessor, and patient). Also information about exclusion after 40

41 randomization will also be recorded (intention to treat). on September 25, 2021 by guest. Protected copyright. 42 43 44 45 Outcomes and prioritization 46 47 To compare outcomes, identification of the definition used for the primary outcome, 48 49 measuring tool used, change in pain scores, need for rescue analgesia and at what time, 50 51 side effects and follow up (GI bleed or renal impairment), will be assessed. Notes 52 important but not classified in the above category will be entered as a free text. 53 54 55 56 Quality assessment of studies 57 58 59 60 8

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 To assess the risk of bias, study data will be extracted using the Cochrane Collaboration 4 5 tool for assessing the risk of bias (Table 8.5.a in the Cochrane Handbook for Systematic 6 7 Reviews of Interventions). This includes information gathering on method of 8 9 randomization, allocation concealment, blinding of participants and investigators, 10 11 blinding of the assessor, incomplete outcome data, and other bias if any. Each domain 12 13 will be rated as having low, unclear or high risk of bias. 14 15 For peer review only 16 17 Missing data 18 19 We will try to contact corresponding authors to request missing data if contacts are 20 available. If this is not achieved, we will try to impute the missing information based on 21 22 the information available in the manuscript or the protocol of the study. For continuous 23 24 measures, missing standard deviation (SD) will be imputed from available information 25 26 such as standard error (SE), confidence interval (CI), or p-values. For a dichotomous 27 28 outcome, proportion or percentages will be used to calculate the number of 29 30 events/people assessed for that outcome. The results will be interpreted considering 31 32 the impact of missing data.

33 http://bmjopen.bmj.com/ 34 35 ANALYSIS 36 37 38 39 Data synthesis 40

41 For dichotomous outcomes, such as more than or equal to 50% reduction in pain, need on September 25, 2021 by guest. Protected copyright. 42 43 for rescue analgesia, recurrence of pain, or adverse events, a risk ratio (RR) with 95% 44 45 confidence intervals (95% CI) will be reported. The studies where continuous scale of 46 47 measure were used to assess the primary effect, such as patient rated pain, difference 48 49 in mean pain score, time to pain relief, a mean difference (MD) will be reported. If 50 51 different measurement scales were used, a standardized mean difference will be used 52 to express the results. For the adverse effects we will calculate the risk difference (RD) 53 54 with 95% CI. Skewed data and non-quantitative data will be presented descriptively. 55 56 57 58 59 60 9

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 Quantitative data will be pooled in the meta-analysis using RevMan 5.3 software. Fixed 4 5 effect models or random effect models will be used appropriately based on the 6 7 heterogeneity observed among the studies included in the pooled analysis. Statistical 8 9 heterogeneity in each model will be assessed using the χ² test of heterogeneity and 10 11 quantified using the Higgins’ I2 statistics. If the heterogeneity is insignificant the Mantel- 12 13 Haenszel method will be used for the fixed effect model. We will use the random effects 14 15 model if significantFor statistical peer heterogeneity review (I2 >=50% or P only<0.1) is present. 16 17 18 19 Subgroup analysis 20 21 We intend to perform the primary analysis based on the treatment groups such as 22 23 NSAIDS vs opioids and NSAIDS vs paracetamol. We will also perform subgroup analysis 24 25 based on the types of opioids or NSAIDS used, routes of administration, and based on 26 the quality of the study. If heterogeneity is substantial, we will not perform a meta- 27 28 analysis; a narrative, qualitative summary will be done and the information will be 29 30 presented using text and tables. 31 32 33 http://bmjopen.bmj.com/ 34 Meta-bias(es) 35 36 To assess reporting bias amongst the included studies, where possible, we will 37 38 determine if there was any deviation from the published protocol or information 39 st 40 registered prior to conduct of the study. If a study was published after July 1 2005, we

41 on September 25, 2021 by guest. Protected copyright. 42 will screen the Clinical Trial Register at the International Clinical Trials Registry Platform 43 of the World Health Organisation (http://apps.who.int/ trialssearch). To assess the 44 45 possibility of publication bias, we also plan to use a Funnel plot if 10 or more studies are 46 47 available for the meta-analysis. 48 49 50 51 Assessing cumulative evidence 52 53 We will assess the quality of body of evidence for each outcome according to Grading 54 55 of Recommendations Assessment, Development and Evaluation (GRADE) working group 56 57 methodology. 58 59 60 10

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 5 DISCUSSION 6 7 Renal colic is a common cause of ED presentations and the excruciating pain demands 8 9 effective analgesia to be administered in the shortest possible time. To minimize the 10 11 delay in rapid administration of effective and safe analgesia, an evidence-based protocol 12 13 is needed. Previous reviews were inconclusive in establishing superior efficacy to 14 15 support first-lineFor analgesia. peer It is important review to use the first-lineonly agent that is most 16 17 effective, has the best safety profile, and is quick and easy to administer with a single 18 19 rather than titrated first dose. Given that there have been significant publications since 20 the last review on this topic, we believe that it is likely that improved guidance for 21 22 protocolised first-line analgesia for renal colic can be given. 23 24 25 26 Ethics and dissemination 27 28 Formal ethics approval is not required, as primary data will not be collected. We plan to 29 30 publish the result of this review in a peer-reviewed journal. We believe that the results 31 32 of this review will provide robust evidence in deciding superiority among commonly

33 http://bmjopen.bmj.com/ 34 used analgesics, and help to improve guidance for protocolised analgesia in renal colic. 35 36 37 Contributions: SAP is the guarantor. SAP, BM and PAC drafted the protocol for the 38 39 systematic review. SAP and LR developed the search strategy. All authors contributed to 40

41 the development of the selection criteria, the risk of bias assessment strategy and data on September 25, 2021 by guest. Protected copyright. 42 43 extraction criteria. All authors read, provided feedback and approved the final 44 45 manuscript. 46 47 Competing interest: We have read and understood BMJ policy on declaration of 48 49 interests and declare that we have no competing interests. 50 51 52 REFERENCES 53 54 55 1. Fisang C, Anding R, Muller SC, et al. Urolithiasis--an interdisciplinary diagnostic, 56 57 therapeutic and secondary preventive challenge. Deutsches Arzteblatt 58 59 60 11

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 international 2015;112(6):83-91. doi: 10.3238/arztebl.2015.0083 [published 4 5 Online First: 2015/02/28] 6 2. Ghani KR, Roghmann F, Sammon JD, et al. Emergency department visits in the 7 United States for upper urinary tract stones: trends in hospitalization and 8 charges. The Journal of urology 2014;191(1):90-6. doi: 9 10 10.1016/j.juro.2013.07.098 [published Online First: 2013/08/13] 11 3. Pickard R, Starr K, MacLennan G, et al. Use of drug therapy in the management of 12 symptomatic ureteric stones in hospitalised adults: a multicentre, placebo- 13 controlled, randomised controlled trial and cost-effectiveness analysis of a 14 calcium channel blocker (nifedipine) and an alpha-blocker (tamsulosin) (the 15 For peer review only 16 SUSPEND trial). Health technology assessment (Winchester, England) 17 2015;19(63):vii-viii, 1-171. doi: 10.3310/hta19630 [published Online First: 18 2015/08/06] 19 4. Afshar K, Jafari S, Marks AJ, et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) 20 and non-opioids for acute renal colic. The Cochrane database of systematic 21 22 reviews 2015;6:Cd006027. doi: 10.1002/14651858.CD006027.pub2 23 [published Online First: 2015/06/30] 24 5. Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus 25 opioids for acute renal colic. The Cochrane database of systematic reviews 26 2005(2):Cd004137. doi: 10.1002/14651858.CD004137.pub3 [published 27 28 Online First: 2005/04/23] 29 6. Pines JM, Hollander JE. Emergency department crowding is associated with poor 30 care for patients with severe pain. Annals of emergency medicine 31 2008;51(1):1-5. doi: 10.1016/j.annemergmed.2007.07.008 [published Online 32 First: 2007/10/05] 33 http://bmjopen.bmj.com/ 34 7. Labrecque M, Dostaler LP, Rousselle R, et al. Efficacy of nonsteroidal anti- 35 inflammatory drugs in the treatment of acute renal colic. A meta-analysis. 36 Archives of internal medicine 1994;154(12):1381-7. [published Online First: 37 1994/06/27] 38 8. Dave C, Shetty S, Faraj K. Nephrolithiasis Treatment & Management: WebMD; 39 40 2016 [updated Dec 03, 2016. Available from:

41 http://emedicine.medscape.com/article/437096-treatment - d7 accessed on September 25, 2021 by guest. Protected copyright. 42 Feb 05, 2017. 43 9. Ketabchi AA, Ebad-Zadeh MR, Parvaresh S, et al. Opium Dependency in Recurrent 44 Painful Renal Lithiasis Colic. Addiction & Health 2012;4(1-2):73-8. 45 46 10. Worster A. Renal colic. In: Thomas SH, ed. Emergency Department Analgesia: An 47 Evidence-Based Guide. New York: Cambridge University Press 2008:359-62. 48 11. Bounes V, Valle B, Concina F, et al. Treatment of Acute Renal Colic in US and 49 French EDs: Simulated Cases and Real Cases in Acute Pain Management. The 50 51 American journal of emergency medicine 2016;34(10):1955-58. doi: 52 10.1016/j.ajem.2016.06.107 [published Online First: 2016/07/20] 53 12. Turk C, Petrik A, Sarica K, et al. EAU Guidelines on Diagnosis and Conservative 54 Management of Urolithiasis. European urology 2016;69(3):468-74. doi: 55 10.1016/j.eururo.2015.07.040 [published Online First: 2015/09/01] 56 57 58 59 60 12

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 13. Manjiani D, Paul DB, Kunnumpurath S, et al. Availability and Utilization of 4 5 Opioids for Pain Management: Global Issues. The Ochsner Journal 6 2014;14(2):208-15. 7 14. Berterame S, Erthal J, Thomas J, et al. Use of and barriers to access to opioid 8 analgesics: a worldwide, regional, and national study. Lancet (London, 9 10 England) 2016;387(10028):1644-56. doi: 10.1016/s0140-6736(16)00161-6 11 [published Online First: 2016/02/08] 12 15. Pathan SA, Mitra B, Cameron PA. Titrated doses are optimal for opioids in pain 13 trials - Authors' reply. Lancet (London, England) 2016;388(10048):961-2. 14 doi: 10.1016/s0140-6736(16)31494-5 [published Online First: 2016/09/07] 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32

33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13

(Nimesulid* or aulin or mesulid or nimalox or sulid* or http://bmjopen.bmj.com/ 33 27 34 sintalgin or nimsid* or nise or nimulid).mp. 35 28 (Meclofenamic or meclofenamat* or meclomen).mp. 36 37 29 (fenoprofen or fenopron).mp. 38 (oxaprozin or oxaprozinum or daypro or dayrun or 30 39 duraprox).mp. 40 31 (sulindac or cinoril or imbaral).mp. 41 on September 25, 2021 by guest. Protected copyright. 42 32 (tolmetin or tolectin).mp. 43 (flurbiprofen* or sulindac* or mesalazin* or sulfasalazin* 44 or flufenamic* or tolmetin* or fenoprofen* or diflunisal* 45 46 or niflumic* or ketorolac or trometamol* or parecoxib* or teriflunomid* or benoxaprofen* or suprofen* or fenbufen* 47 33 48 or mebron* or mepirizole* or mepyrizole* or 49 methopyrimazole* or Epirizolum* or Polihexanid* or 50 Dalex* or Miton* or epirizol* or clonixin* or tolemetin* or 51 52 nabumeton*).mp. 53 34 or/6-33 NSAIDS 54 exp Analgesics, opioid/ or exp alkaloids, opiate/ or exp 55 35 56 narcotics/ 57 36 opioid*.mp. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 exp hydrocodone/ or exp dextropropoxyphene/ or exp fentanyl/ or exp meperidine/ or exp methadone/ or exp 5 37 6 Morphine/ or exp Morphine Derivatives/ or exp 7 oxymorphone/ or exp pentazocine/ or exp tramadol/ 8 38 exp alfentanil/ or alfentanil*.mp. 9 10 39 exp codeine/ or codein*.mp. 11 (hydrocodon* or vicodin* or norco or lortab or 40 12 zohydro).mp. 13 14 41 exp oxycodone/ or oxycodon*.mp. 15 (dextropropoxyphen* or darvon or darvocet or digesic or 42 For peer review only 16 capadex).mp. 17 43 exp dihydromorphine/ or dihydromorphin*.mp. 18 (fentanyl or actiq or duragesic or fentora or sublimaz* or 19 44 20 fenta).mp. 21 45 (meperidin* or demerol or pethidin*).mp. 22 (methadon* or dolophin* or methadose or amidon* or 23 46 24 symoron or physephton* or heptadon).mp. 25 (morphin* or oramorph or morphia or duramorph or 26 47 27 contin or mscontin or sevredol or zomorphzomo).mp. 28 48 (oxymorphon* or numorphan or opana or morphon).mp. 29 (pentazocin* or fortal or sosegon or talwin or fortwin or 49 30 talacen).mp. 31 32 50 (tramadol or ultram).mp. 33 51 or/35-50 Opioids http://bmjopen.bmj.com/ 34 52 exp Acetaminophen/ 35 36 (abenol* or acamol* or acenol* or acephen* or acet 37 suppositories* or acetalgin* or acetamino phenol* or 38 acetaminophen* or acetaminophene* or 39 acetaminophenol* or acetamol* or acetomenophen* or 40 acetylaminophenol* or adorem* or afebrin* or algiafin* or 41 on September 25, 2021 by guest. Protected copyright. 42 algotropyl* or alphagesic* or alvedon* or amadil* or 43 anacin 3* or anaflon* or analgiser* or apamide* or apirex* 44 or arthralgen* or benuron* or biogesic* or calapol* or 45 53 calodol* or dafalgan* or depyretin* or dirox* or dolex* or 46 47 dolofen* or dolomol* or calpol* or eneril* or meforagesic* 48 or dolorol* or metagesic* or napamol* or naprex* or 49 pacemol* or pacimol* or duorol* or pamol* or panadol* or 50 panamax* or panodil* or paracet* or paracetamole* or 51 parageniol* or paragin* or paralen* or paralief* or 52 53 paramax* or paramidol* or paximol* or paratabs* or 54 perfalgan* or pyrigesic* or setamol* or tylenol* or tylex* 55 or valadol* or winadol* or zydinol).mp. 56 54 or/52-53 Paracetamol 57 58 55 5 and 34 and 51 NSAIDS Vs Opioids 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 56 5 and 34 and 54 NSAIDS Vs Paracetamol 5 57 randomized controlled trial.pt. 6 58 controlled clinical trial.pt. 7 (random$ or placebo$ or single blind$ or double blind$ or 8 59 9 triple blind$).ti,ab. 10 60 (retraction of publication or retracted publication).pt. 11 61 or/57-60 RCTs 12 13 62 (animals not humans).sh. 14 ((comment or editorial or meta-analysis or practice- 15 63 guideline or review or letter or journal correspondence) For peer review only 16 17 not "randomized controlled trial").pt. 18 (random sampl$ or random digit$ or random effect$ or 19 64 random survey or random regression).ti,ab. not 20 "randomized controlled trial".pt. 21 22 65 or/62-64 non-human subject or 23 non RCTs 24 66 61 not 65 Human subject RCTs 25 NSAIDS Vs Opioids 26 67 55 and 66 27 +Human subject RCTs 28 NSAIDS Vs 29 68 56 and 66 Paracetamol+Human 30 subject RCTs 31 32 NSAIDS (Opioids or 33 69 67 or 68 paracetamol) in human http://bmjopen.bmj.com/ 34 subject RCTs 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 Embase Classic+Embase 1947 to 2016 Month, Date 43 44 # Search Statement Annotation 45 exp kidney pain/ or exp kidney colic/ or exp bladder stone/ or 46 47 1 exp ureter stone/ or exp urolithiasis/ or exp nephrolithiasis/ 48 or exp ureter obstruction/ 49 2 ((Urin* or renal or kidney or ureter* or bladder) adj3 (stone* 50 or calcul* or colic* or lith* or obstruct* or occlusi*)).mp. 51 52 3 ((Kidney or ureter*) adj2 diseas*).mp. 53 4 (Urolith* or nephrolith*).mp. 54 Population- Renal 55 5 56 or/1-4 colic 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 22 BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 exp nonsteroid antiinflammatory agent/ or exp 5 cyclooxygenase 2 inhibitor/ or exp indometacin/ or exp 6 piroxicam/ or exp acetylsalicylic acid/ or exp celecoxib/ or 7 exp diclofenac/ or exp ibuprofen/ or exp naproxen/ or exp 8 6 azapropazone/ or exp acetylsalicylic acid/ or exp ketoprofen/ 9 10 or exp salicylic acid/ or exp ketorolac/ or exp ketoprofen/ or 11 exp salicylic acid derivative/ or exp etodolac/ or exp 12 fenoprofen/ or exp sulindac/ or exp tolmetin/ or exp 13 mesalazine/ or exp aminosalicylic acid/ 14 15 ((Nonsteroidal adj2 antiinflammatory) or (NonFor peer review-steroidal adj2 only 16 7 antiinflammatory) or (Nonsteroidal adj2 anti-inflammatory) 17 or (Non-steroidal adj2 anti-inflammatory)).mp. 18 8 NSAID*.mp. 19 20 (Diclofenac or adiflam or agile or diclonac or dicol or diclonat* 21 9 or feloran or voltarol or Voltaren or Cataflam or Voltaren-XR 22 or Zipsor).mp. 23 10 (Aceclofenac or Hifenac or Cincofen or Nacsiv or Acenac).mp. 24 (Ketorolac or toradol or torolac or kealc or kenalfin or 25 11 26 ketlac).mp. 27 12 (Apazon* or Azapropazon* or cinnopropazon*).mp. 28 29 13 (Aspirin* or acetylsal or dispril or easprin* or salicylic*).mp. 30 (Ibuprofen or brufen or nuprin or rufen or salprofen or dolgit 31 14 or salprofen or advil* or motrin or nurofen or actiprofen or 32

33 addaprin or aktren or anadin or bugesic or ibuprox).mp. http://bmjopen.bmj.com/ 34 (ketoprofen or orudis or oruvail or ketoflam or oruvail or 35 15 fastum or ketonal or ketodol or knavon or actron or 36 ketoprofeno).mp. 37 (Dexketoprofen or keral or enantyum or ketesgel or 38 16 39 dolmen).mp. 40 17 (Naproxen or naprosyn or naprosin or proxen or synflex or 41 Aleve or Anaprox or Apronax or Naprelan).mp. on September 25, 2021 by guest. Protected copyright. 42 (etodolac or ramodar or ultradol or etova or dualgan or etodin 43 18 44 or etopan or flancox or proxym or etodine or dolarit).mp. 45 (Indomethacin* or indocid or indocin or indomet or 46 19 47 indometacin or metindol or osmosin).mp. 48 20 (Piroxicam or feldene or dolocare or dolonex or ketolin).mp. 49 21 (Meloxicam or mobic or vivlodex).mp. 50 51 22 (Tenoxicam or mobiflex).mp. 52 23 (celecoxib or celebrex or celebra).mp. 53 24 (rofecoxib or vioxx or ceoxx or ceeoxx).mp. 54 55 25 (valdecoxib or bextra).mp. 56 (Nimesulid* or aulin or mesulid or nimalox or sulid* or 26 57 sintalgin or nimsid* or nise or nimulid).mp. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 22 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2016-015002 on 4 May 2017. Downloaded from 1 2 3 4 27 (Meclofenamic or meclofenamat* or meclomen).mp. 5 28 (fenoprofen or fenopron).mp. 6 (oxaprozin or oxaprozinum or daypro or dayrun or 29 7 duraprox).mp. 8 9 30 (sulindac or cinoril or imbaral).mp. 10 31 (tolmetin or tolectin).mp. 11 (flurbiprofen* or sulindac* or mesalazin* or sulfasalazin* or 12 13 flufenamic* or tolmetin* or fenoprofen* or diflunisal* or 14 niflumic* or ketorolac or trometamol* or parecoxib* or 15 32 teriflunomid* or benoxaprofen* or suprofenFor peer review* or fenbufen* or only 16 mebron* or mepirizole* or mepyrizole* or methopyrimazole* 17 or Epirizolum* or Polihexanid* or Dalex* or Miton* or 18 19 epirizol* or clonixin* or tolemetin* or nabumeton*).mp. 20 33 or/6-32 NSAIDS 21 exp opiate/ or exp narcotic analgesic agent/ or exp opiate 34 22 agonist/ 23 24 exp hydrocodone/ or exp dextropropoxyphene/ or exp 25 35 fentanyl/ or exp pethidine/ or exp methadone/ or exp 26 oxymorphone/ or exp pentazocine/ or exp tramadol/ 27 28 36 opioid*.mp. 29 37 exp alfentanil/ or alfentanil*.mp. 30 38 exp codeine/ or codein*.mp. 31 32 39 (hydrocodon* or vicodin* or norco or lortab or zohydro).mp. 33 40 exp oxycodone/ or oxycodon*.mp. http://bmjopen.bmj.com/ 34 (dextropropoxyphen* or darvon or darvocet or digesic or 35 41 36 capadex).mp. 37 42 exp dihydromorphine/ or dihydromorphin*.mp. 38 (fentanyl or actiq or duragesic or fentora or sublimaz* or 43 39 fenta).mp. 40

1 1 6 1 4 3 1 1 1 10 4-5 6 6 and (Page (Page No.#) Appendix-A grey grey

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