Non‐steroidal anti‐inflammatory drugs (NSAIDs) for chronic non‐cancer pain in children and adolescents

Christopher Eccleston; Tess E Cooper; Emma Fisher; Brian Anderson; Nick MR Wilkinson

doi:10.1002/14651858.CD012537.pub2

Fármacos antiinflamatorios no esteroideos (AINE) para el dolor crónico no relacionado con el cáncer en niños y adolescentes

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References

References to studies included in this review

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excluded studies
additional references

Bhettay E, Thomson AJG. Double‐blind study of ketoprofen and indomethacin in juvenile chronic arthritis. South African Medical Journal 1978;54(7):276‐8.

Google Scholar

Brewer EJ, Giannini EH, Baum J. Aspirin and fenoprofen (Nalfon) in the treatment of juvenile rheumatoid arthritis results of the double blind‐trial. A segment II study. Journal of Rheumatology 1982;9(1):123‐8.

Google Scholar

Foeldvari I, Szer IS, Zemel LS, Lovell DJ, Giannini EH, Robbins JL, et al. A prospective study comparing celecoxib with naproxen in children with juvenile rheumatoid arthritis. Journal of Rheumatology 2009;36(1):174‐82.

Giannini EH, Brewer EJ, Miller M L, Gibbas D, Passo MH, Hoyeraal HM. Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis. Journal of Pediatrics 1990;117(4):645‐52.

Moran H, Ansell BM, Hanna B. Naproxen in juvenile chronic polyarthritis. European Journal of Rheumatology and Inflammation 1979;2(1):79‐83.

Reiff A, Lovell DJ, Van Adelsberg J, Kiss MHB, Goodman S, Zavaler MF, et al. Evaluation of the comparative efficacy and tolerability of rofecoxib and naproxen in children and adolescents with juvenile rheumatoid arthritis: a 12‐week randomized controlled clinical trial with a 52‐week open‐label extension. Journal of Rheumatology 2006;33(5):985‐95.

Google Scholar

Ruperto N, Nikishina I, Pachanov ED, Shachbazian Y, Prieur AM, Mouy R, et al. A randomized, double‐blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis. Arthritis & Rheumatism 2005;52(2):563‐72.

References to studies excluded from this review

Jump to:

included studies
additional references

Coutinho A, Bonello J, da Carvalho PC. A double‐blind comparative study of the analgesic effects of fenbufen, codeine, aspirin, propoxyphene and placebo. Current Therapeutic Research, Clinical and Experimental 1976;19(1):58‐65.

Google Scholar

Girschick HJ, Seyberth HW, Huppertz HI. Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs. Bone 1999;25(5):603‐7.

Jenkins DG, Ebbutt AF, Evans CD. Tofranil in the treatment of low back pain. Journal of International Medical Research 1976;4(2 Suppl):28‐40.

Google Scholar

Johnsen V, Brun JG, Fjeld E, Hansen K, Sydnes OA, Ugstad MB. Morning stiffness and nighttime pain in ankylosing spondylitis. A comparison between enteric‐coated and plain naproxen tablets. European Journal of Rheumatology and Inflammation 1992;12(2):37‐42.

Google Scholar

Natour J, Puertas EB, Radu AS, Freire M, Bonfigliolo R, Schincaroil NRB, et al. Loxoprofen in the treatment of low back pain ‐ clinical efficacy and safety in comparison to diclofenac. Revista Brasileira de Medicina 2002;59(3):161‐70.

Google Scholar

Reicher E, Reipert D, Kowalczewska J. Results of the treatment of juvenile rheumatoid arthritis with indomethacine. Polskie Archiwum Medycyny Wewnętrznej 1969;42(1):105‐12.

Google Scholar

Sadowska‐Wroblewska M, Garwolinska H, Filipovicz‐Sosnowska A. Azapropazone versus indomethacin in a double blind test with patients with ankylosing spondylitis [Azapropazon versus indometacin im doppelblindversuch bei patienten mit spondylitis ankylosans]. Zeitschrift fur Rheumatologie 1980;39:11‐2.

Google Scholar

Additional references

Jump to:

included studies
excluded studies

American Medical Association. Pediatric pain management. https://www.ama‐assn.org/ (accessed 25 January 2016).

Cochrane Pain, Palliative and Supportive Care Group. PaPaS author and referee guidance. papas.cochrane.org/papas‐documents (accessed 16 July 2016).

Blanca‐López N, Cornejo‐García JA, Plaza‐Serón MC, Doña I, Torres‐Jaén MJ, Canto G, et al. Hypersensitivity to nonsteroidal anti‐inflammatory drugs in children and adolescents: cross‐intolerance reactions. Journal of Investigational Allergology & Clinical Immunology 2015;25(4):259‐69.

Google Scholar

Joint Formulary Committee. British National Formulary. London (UK): BMJ Group and Pharmaceutical Press, 2016.

Caes L, Boemer KE, Chambers CT, Campbell‐Yeo M, Stinson J, Birnie KA, et al. A comprehensive categorical and bibliometric analysis of published research articles on pediatric pain from 1975 to 2010. Pain 2016;157(2):302‐13. [DOI: 10.1097/j.pain.0000000000000403]

Calvo M, Dawes JM, Bennett DL. The role of the immune system in the generation of neuropathic pain. Lancet Neurology 2012;11(7):629‐42. [DOI: 10.1016/S1474‐4422(12)70134‐5]

Cooper TE, Fisher E, Gray A, Krane E, Sethna NF, van Tilburg M, et al. Opioids for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD012538.pub2]

Google Scholar

Cooper TE, Heathcote L, Clinch J, Gold J, Howard R, Lord S, et al. Antidepressants for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012535.pub2]

Google Scholar

Cooper TE, Heathcote L, Anderson B, Gregoire MC, Ljungman G, Eccleston C. Non‐steroidal anti‐inflammatory drugs (NSAIDs) for cancer‐related pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD012563.pub2]

Google Scholar

Cooper TE, Fisher E, Anderson B, Wilkinson N, Williams G, Eccleston C. Paracetamol (acetaminophen) for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012539.pub2]

Google Scholar

Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence of trial sample size on treatment effect estimates: meta‐epidemiological study. BMJ 2013;346:f2304. [DOI: 10.1136/bmj.f2304]

Dechartres A, Altman DG, Trinquart L, Boutron I, Ravaud P. Association between analytic strategy and estimates of treatment outcomes in meta‐analyses. JAMA 2014;312:623‐30. [DOI: 10.1001/jama.2014.8166]

Dworkin RH, Turk DC, Wyrwich KW, Beaton D, Cleeland CS, Farrar JT, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. Journal of Pain 2008;9(2):105‐21. [DOI: 10.1016/j.jpain.2007.09.005]

Eccleston C, Malleson PM. Management of chronic pain in children and adolescents (editorial). BMJ 2003;326:1408‐9.

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck‐Ytter Y, Alonso‐Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924‐6. [DOI: 10.1136/bmj.39489.470347.AD]

Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction ‐ GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64:383‐94. [DOI: 10.1016/j.jclinepi.2010.04.026]

Guyatt G, Oxman AD, Sultan S, Brozek J, Glasziou P, Alonso‐Coelle P, et al. Making an overall rating of the confidence in effect estimates for a single outcome and for all outcomes. Journal of Clinical Epidemiology 2013;66(2):151‐7. [DOI: 10.1016/j.jclinepi.2012.01.006]

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables ‐ binary outcomes. Journal of Clinical Epidemiology 2013;66(2):158‐72. [DOI: 10.1016/j.jclinepi.2012.01.012]

Hasnie FS, Breuer J, Parker S, Wallace V, Blackbeard J, Lever I, et al. Further characterization of a rat model of varicella zoster virus‐associated pain: relationship between mechanical hypersensitivity and anxiety‐related behavior, and the influence of analgesic drugs. Neuroscience 2007;144(4):1495‐508. [DOI: 10.1016/j.neuroscience.2006.11.029]

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org. The Cochrane Collaboration.

Hoffman DL, Sadosky A, Dukes EM, Alvir J. How do changes in pain severity levels correspond to changes in health status and function in patients with painful diabetic peripheral neuropathy?. Pain 2010;149(2):194‐201. [DOI: 10.1016/j.pain.2009.09.017]

Kawakami M, Matsumoto T, Hashizume H, Kuribayashi K, Tamaki T. Epidural injection of cyclooxygenase‐2 inhibitor attenuates pain‐related behavior following application of nucleus pulposus to the nerve root in the rat. Journal of Orthopaedic Research 2002;20(2):376‐81. [DOI: 10.1016/S0736‐0266(01)00114‐0]

L'Abbé KA, Detsky AS, O'Rourke K. Meta‐analysis in clinical research. Annals of Internal Medicine 1987;107:224‐33.

Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen. JAMA 1995;273(12):929‐33.

Lesko SM, Mitchell AA. Renal function after short‐term ibuprofen use in infants and children. Pediatrics 1997;100(6):954‐7.

Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics 1999;104(4):e39.

McQuay H, Moore R. An Evidence‐based Resource for Pain Relief. Oxford (UK): Oxford University Press, 1998.

Misurac JM, Knoderer CA, Leiser JD, Nailsecu C, Wilson AC, Andreoli SP. Nonsteroidal anti‐inflammatory drugs are an important cause of acute kidney injury in children. Journal of Pediatrics 2013;6:1153‐9 e.1. [DOI: 10.1016/j.jpeds.2012.11.069]

Moher D, Liberati A, Tetzlaff J, Altman DG, the PRISMA Group. Preferred reporting items for systematic reviews and meta‐analyses: the PRISMA statement. PLoS Medicine 2009;6(7):e1000097.

Moore RA, Barden J, Derry S, McQuay HJ. Managing potential publication bias. In: McQuay HJ, Kalso E, Moore RA editor(s). Systematic Reviews in Pain Research: Methodology Refined. Seattle (WA): IASP Press, 2008:15‐24. [ISBN: 978‐0‐931092‐69‐5]

Google Scholar

Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 3. [DOI: 10.1002/14651858.CD007076.pub2]

Moore RA, Eccleston C, Derry S, Wiffen P, Bell RF, Straube S, et al. "Evidence" in chronic pain ‐ establishing best practice in the reporting of systematic reviews. Pain 2010;150(3):386‐9. [DOI: 10.1016/j.pain.2010.05.011]

Moore RA, Straube S, Paine J, Phillips CJ, Derry S, McQuay HJ. Fibromyalgia: moderate and substantial pain intensity reduction predicts improvement in other outcomes and substantial quality of life gain. Pain 2010;149(2):360‐4.

Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder analysis for pain relief and numbers needed to treat in a meta‐analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice. Annals of the Rheumatic Diseases 2010;69(2):374‐9. [DOI: 10.1136/ard.2009.107805]

Moore RA, Smugar SS, Wang H, Peloso PM, Gammaitoni A. Numbers‐needed‐to‐treat analyses ‐ do timing, dropouts, and outcome matter? Pooled analysis of two randomized, placebo‐controlled chronic low back pain trials. Pain 2010;151(3):592‐7. [DOI: 10.1016/j.pain.2010.07.2013]

Moore RA, Derry S, McQuay HJ, Straube S, Aldington D, Wiffen P, et al. ACTINPAIN writing group of the IASP Special Interest Group (SIG) on Systematic Reviews in Pain Relief. Clinical effectiveness: an approach to clinical trial design more relevant to clinical practice, acknowledging the importance of individual differences. Pain 2010;149:173‐6. [PUBMED: 19748185]

Moore RA, Straube S, Paine J, Derry S, McQuay HJ. Minimum efficacy criteria for comparisons between treatments using individual patient meta‐analysis of acute pain trials: examples of etoricoxib, paracetamol, ibuprofen, and ibuprofen/paracetamol combinations after third molar extraction. Pain 2011;152(5):982‐9. [DOI: 10.1016/j.pain.2010.11.030]

Moore RA, Mhuircheartaigh RJ, Derry S, McQuay HJ. Mean analgesic consumption is inappropriate for testing analgesic efficacy in post‐operative pain: analysis and alternative suggestion. European Journal of Anaesthesiology 2011;28(6):427‐32. [DOI: 10.1097/EJA.0b013e328343c569]

Moore RA, Straube S, Eccleston C, Derry S, Aldington D, Wiffen P, et al. Estimate at your peril: imputation methods for patient withdrawal can bias efficacy outcomes in chronic pain trials using responder analyses. Pain 2012;153(2):265‐8. [DOI: 10.1016/j.pain.2011.10.004]

Moore RA, Straube S, Aldington D. Pain measures and cut‐offs ‐ 'no worse than mild pain' as a simple, universal outcome. Anaesthesia 2013;68(4):400‐12. [DOI: 10.1111/anae.12148]

Moore A, Derry S, Eccleston C, Kalso E. Expect analgesic failure; pursue analgesic success. BMJ 2013;346:f2690. [DOI: 10.1136/bmj.f2690]

Moore RA, Derry S, Taylor RS, Straube S, Phillips CJ. The costs and consequences of adequately managed chronic non‐cancer pain and chronic neuropathic pain. Pain Practice 2014;14(1):79‐94.

Google Scholar

Moore RA, Cai N, Skljarevski V, Tölle TR. Duloxetine use in chronic painful conditions ‐ individual patient data responder analysis. European Journal of Pain 2014;18(1):67‐75. [DOI: 10.1002/j.1532‐2149.2013.00341.x]

National Institute of Health and Care Excellence (NICE). Guidance ‐ sickle cell acute painful episode. https://www.nice.org.uk/guidance/cg143/evidence/full‐guideline‐pdf‐186634333 (accessed 7 September 2015).

Nüesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG, et al. Small study effects in meta‐analyses of osteoarthritis trials: meta‐epidemiological study. BMJ 2010;341:c3515. [DOI: 10.1136/bmj.c3515]

O'Brien EM, Staud RM, Hassinger AD, McCulloch RC, Craggs JG, Atchinson JW, et al. Patient‐centered perspective on treatment outcomes in chronic pain. Pain Medicine 2010;11(1):6‐15. [DOI: 10.1111/j.1526‐4637.2009.00685.x]

McGrath PJ, Walco GA, Turk DC, Dworking RH, Brown MT, Davidson K, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT. Journal of Pain 2008;9(9):771‐83.

Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Ripamonti C, Bandieri E. Pain therapy. Critical Reviews in Oncology/Hematology 2008;70:145‐59. [DOI: 10.1016/j.critrevonc.2008.12.005]

Google Scholar

Stinson JN, Kavanagh T, Yamada J, Gill N, Stevens B. Systematic review of the psychometric properties, interpretability and feasibility of self‐report pain intensity measures for use in clinical trials in children and adolescents. Pain 2006;125(1‐2):143‐57. [DOI: 10.1016/j.pain.2006.05.006]

Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrolment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. British Journal of Clinical Pharmacology 2008;66(2):266‐75. [DOI: 10.1111/j.1365‐2125.2008.03200.x]

Straube S, Derry S, Moore RA, Paine J, McQuay HJ. Pregabalin in fibromyalgia ‐ responder analysis from individual patient data. BMC Musculoskeletal Disorders 2010;11:150. [DOI: 10.1186/1471‐2474‐11‐150]

Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurology 2008;8:29. [DOI: 10.1186/1471‐2377‐8‐29]

Thorlund K, Imberger G, Walsh M, Chu R, Gluud C, Wetterslev J, et al. The number of patients and events required to limit the risk of overestimation of intervention effects in meta‐analysis ‐ a simulation study. PLoS ONE 2011;6(10):e25491. [DOI: 10.1371/journal.pone.0025491]

United Nations. World population prospects 2015 ‐ population indicators. esa.un.org/unpd/wpp/Download/Standard/Population/ (accessed 29 February 2016).

Vo T, Rice ASC, Dworkin RH. Non‐steroidal anti‐inflammatory drugs for neuropathic pain: How do we explain continued widespread use?. Pain 2009;143(3):169‐71. [DOI: 10.1016/j.pain.2009.03.013]

von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioural) measures of pain for children and adolescents aged 3 to 18 years. Pain 2007;127(1‐2):140‐50. [DOI: 10.1016/j.pain.2006.08.014]

Google Scholar

World Health Organization. WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses. Geneva: WHO Press, World Health Organization, 2012. [ISBN 978 92 4 154812 0]

Wiffen P, Cooper T, Anderson AK, Gray A, Gregoire MC, Ljungman G, et al. Opioids for cancer‐related pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 7. [DOI: 10.1002/14651858.CD012564.pub2]

Google Scholar

Wiffen PJ, Cooper TE, Heathcote L, Clinch J, Howard R, Krane E, et al. Antiepileptic drugs for chronic non‐cancer pain in children and adolescents. Cochrane Database of Systematic Reviews 2017, Issue 8. [DOI: 10.1002/14651858.CD012536.pub2]

Google Scholar

World Bank. Data ‐ population ages 0‐14 (% of total). data.worldbank.org/indicator/SP.POP.0014.TO.ZS (accessed 29 February 2016).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

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excluded studies

Bhettay 1978

Methods	Allocation: randomised Blinding: double‐blind Controlled: placebo Centre: multicentre Arm: 2 arms, cross‐over design
Participants	Inclusion criteria: children with juvenile chronic arthritis Exclusion criteria: known history of contraindications to study drugs; receiving gold, d‐penicillamine, or corticosteroids; in a state of remission Baseline characteristics N = 30 Age: mean not reported, range 2 to 16 years Gender: male (unstated); female (unstated) Number randomised: intervention (15); control (15) Number completed: intervention (15); control (15) Setting and location: South Africa
Interventions	Intervention group (N = 15): indomethacin (2 weeks), cross‐over ketoprofen (2 weeks) Control group (N = 15): ketoprofen (2 weeks), cross‐over indomethacin (2 weeks) Participants < 20 kg: ketoprofen 25 mg capsule twice daily; participants > 20 kg: ketoprofen capsules x 2 = 50 mg twice daily Participants < 20 kg: indomethacin 25 mg capsule twice daily; participants > 20 kg: indomethacin capsules x 2 = 50 mg twice daily Study duration: 5 weeks
Outcomes	Primary outcomes Severity of pain: morning stiffness; interference with function; general feeling of well‐being; symptoms interpreted by the participant that were due to treatment; preference of either drug Articular index 0 to 4: passive movement of a joint; knee score; combined finger‐joint circumference Grip strength Temporomandibular joint Patient Impression of Change (5‐point scale) Fever, rash, splenomegaly, or lymphadenopathy Investigator's impression of change Secondary outcomes Side effects Amount of rescue analgesia
Notes	Sources of funding: Maybaker (SA) (Pty) Ltd provided drug supplies.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: Randomised drug administration, not participants
Allocation concealment (selection bias)	Unclear risk	Comment: Insufficient information
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: Insufficient information
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All participants were accounted for. Lost to follow‐up and withdrawals explained.
Selective reporting (reporting bias)	Unclear risk	Comment: Means and standard deviations not reported, nor blood sedimentation rate, haemoglobin level, platelet and white cell count.
Size	High risk	Comment: Total participants = 30 (< 50 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

Brewer 1982

Methods	Allocation: randomised Blinding: double‐blind Controlled: active comparator Centre: multicentre Arm: 2 arms, parallel groups
Participants	Inclusion criteria: children with juvenile rheumatoid arthritis Exclusion criteria: unstated Baseline characteristics N = 99 Age: range unstated; mean age 8.5 years Gender: male (23); female (76) Number randomised: fenoprofen (49); aspirin (50) Number completed: fenoprofen (47); aspirin (40) Setting and location: multicentre, location unstated
Interventions	Intervention group (N = 49): aspirin 1500 mg/m²/day increased to 3000 mg/m²/day, maximum 5450 mg/day Control group (N = 50): fenoprofen 900 mg/m²/day increased to 1800 mg/m²/day, maximum 3200 mg/day Study duration: 12 weeks
Outcomes	Primary outcomes Unstated Secondary outcomes Adverse reactions
Notes	Sources of funding: unstated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "99 patients were randomized into the study" Comment: No information regarding method of randomisation
Allocation concealment (selection bias)	Unclear risk	Quote: Insufficient information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "capsules containing either fenoprofen or ASA were white opaque size #2 for the 0.5 to 0.75m² groups, and white opaque size #1 for the 0.76m² and over groups. Therefore it was impossible to determine which drug the subjects were receiving by observing capsule size, colour, or administration regimen"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: All participants were accounted for. Lost to follow‐up and withdrawals explained. However, authors do not report whether there were significant differences between completers and non‐completers.
Selective reporting (reporting bias)	Unclear risk	Quote: "all investigators used an identical protocol and case report forms" Comment: No outcomes were not set out in the methods. Unable to locate protocol.
Size	High risk	Comment: Total participants = 99 (< 50 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

Foeldvari 2009

Methods	Allocation: randomised Blinding: double‐blind Controlled: active comparator Centre: multicentre Arm: 2 arms, parallel groups
Participants	Inclusion criteria: children ≥ 9 kg, with pauciarticular of polyarticular course JRA, with or without systemic onset, according to ACR criteria; > 1 swollen joint with limited motion; parent global assessment ≥ 10 mm (100‐millimetre VAS) Exclusion criteria: active systemic manifestations; oral corticosteroid doses ≤ 0.2 mg/kg/day or 10 mg prednisone or methotrexate < 1 mg/kg/week Baseline characteristics N = 242 Age: 2 to 16 years Gender: male (71); female (171) Number randomised: intervention A (77); intervention B (82); control (83) Number completed: intervention A (67); intervention B (71); control (74) Setting and location: 17 centres worldwide
Interventions	Intervention group (N = 77): celecoxib 50 mg/5 mL oral suspension (target dose approximately 3 mg/kg twice daily) Intervention group (N = 82): celecoxib 100 mg/5 mL oral suspension (target dose approximately 6 mg/kg twice daily) Control group (N = 83): naproxen 125 mg/5 mL oral suspension (target dose approximately 7.5 mg/kg twice daily) Study duration: 12 weeks
Outcomes	Primary outcomes Time‐weighted average proportion of patients achieving ACR Pediatric 30 (at least 30% improvement in any 3 of 6 variables) Investigators' global assessment of disease activity (100‐millimetre VAS) Parent/patient's global assessment of overall well‐being (100‐millimetre VAS) Measure of physical functional ability (CHAQ: 0‐to‐3‐point scale) Number of joints with active arthritis Number of joints with limited range of motion Measure of inflammation (ESR) Secondary outcomes Change from baseline at each visit for the individual Juvenile Rheumatoid Arthritis score set measures Parent's assessment of child's arthritis pain (100‐millimetre VAS) as reported on the CHAQ Health‐related quality of life (Pediatric Quality of Life Inventory)
Notes	Sources of funding: editorial support funded by Pfizer
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "children were randomly assigned to 1 of 3 treatment groups in a 1:1:1 ratio ... randomized according to the allocation number provided by an interactive voice response system"
Allocation concealment (selection bias)	Unclear risk	Comment: Insufficient information
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: Insufficient information
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: All participants were accounted for. Lost to follow‐up and withdrawals explained. However, authors do not report whether there were significant differences between completers and non‐completers.
Selective reporting (reporting bias)	High risk	Comment: Secondary outcome data not reported (e.g. Pediatric Quality of Life Inventory)
Size	Unclear risk	Comment: Total participants = 242 (between 50 and 200 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

Giannini 1990

Methods
Participants
Interventions	Intervention group (N = 45): ibuprofen suspension (concentration 100 mg/5 mL) + placebo aspirin Control group (N = 47): aspirin 200 mg tablet (participant weight 10 to 30 kg) or 300 mg capsules (participant weight > 30 kg) + placebo ibuprofen Week 2: physician's option to increase dose to 40 mg/kg/day ibuprofen or 80 mg/kg/day aspirin, provided no significant side effects Study duration: 12 weeks
Outcomes
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients were randomly assigned, in random blocks of four within each centre, to receive ibuprofen or aspirin"
Allocation concealment (selection bias)	Unclear risk	Quote: "patients were assigned numbers sequentially, on the basis of body weight, from blocks of numbers allotted to each site" Quote: "Before initiation of this trial, each centre was given a list of consecutive numbers from Boots Pharamceuticals. Patients were assigned numbers in the sequence in which they entered the study" Quote: "Patients received one of the two active medications plus a dummy of the alternative agent"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Quote: "Patients received one of the two active medications plus a dummy of the alternative agent" Comment: The study personnel would have known what they were giving the participants (as one was a liquid and the other was a tablet).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Comment: All participants were accounted for. Lost to follow‐up and withdrawals explained. However, authors do not report whether there were significant differences between completers and non‐completers.
Selective reporting (reporting bias)	Low risk	Comment: All planned outcomes from the methods were reported in the results.
Size	High risk	Comment: Total participants = 92 (< 50 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

Moran 1979

Methods	Allocation: randomised Blinding: double‐blind Controlled: active comparator Centre: single Arm: 2 arms, cross‐over design; 4 weeks, followed by cross‐over and a further 4 weeks
Participants	Inclusion criteria: children suffering from seronegative juvenile polyarthritis; disease sufficiently active to be considered in need of an anti‐inflammatory analgesic agent Exclusion criteria: unstated Baseline characteristics N = 23 Age: 5 to 16 years; median 11 to 12 years Gender: male (unstated); female (unstated) Number randomised: intervention (23); control (23) Number completed: intervention (22); control (20) Setting and location: unstated
Interventions	Intervention group (N = 23): naproxen 10 mg/kg/24 hrs given as a suspension in 2 divided doses Control group (N = 23): aspirin soluble 80 mg/kg/day, divided into 4 doses Study duration: 2 x 4 weeks
Outcomes	Primary outcomes Functional grading Joint involvement Grip strength Walking time over 20 m Functional test Comparison with last visit to physician Laboratory tests (haemoglobin, full blood count, platelets, ESR, liver function tests, urea, urine analysis, stools for occult blood) Secondary outcomes Side effects
Notes	Sources of funding: unstated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "random allocation for either ... drug"
Allocation concealment (selection bias)	Unclear risk	Comment: Insufficient information
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "placebo suspension and tablets were given to make the study double‐blind"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "placebo suspension and tablets were given to make the study double‐blind"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All participants were accounted for. Lost to follow‐up and withdrawals explained.
Selective reporting (reporting bias)	Low risk	Comment: All planned outcomes from the methods were reported in the results.
Size	High risk	Comment: Total participants = 23 (< 50 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

Reiff 2006

Methods	Allocation: randomised Blinding: double‐blind, double‐dummy Controlled: active comparator Centre: multicentre Arm: 2 arms, parallel groups
Participants	Inclusion criteria: children with pauci‐ (oligo) or polyarticular course JRA for ≥ 3 months meeting the ACR criteria for juvenile rheumatoid arthritis. Must have patient assessment of overall well‐being (0‐to‐100 VAS) of > 90 with at least 1 swollen joint. Exclusion criteria: active systemic JRA symptoms within 3 months of randomisation or if they were not within the 5th to 95th percentile of weight for height; hypersensitivity to aspirin and/or an NSAID; unstable antirheumatic medication regimens; requiring alkylating agents, anticonvulsants, warfarin, or rifampicin; female patients who had reached menarche were required to be in a non‐gravid state as determined by measurement of serum beta‐human chorionic gonadotropin. Baseline characteristics N = 310 Age: 2 to 17 years; mean 9.9 years Gender: male (83); female (227) Number randomised: intervention A (109); intervention B (100); control (101) Number completed: intervention A (99); intervention B (95); control (91) Setting and location: 41 clinical centres in Australia, Europe, Asia, Central America, South America, USA
Interventions	Intervention group (N = 209): (children) low‐dose rofecoxib 0.3 mg/kg/day maximum 12.5 mg/day, or high‐dose rofecoxib 0.6 mg/kg/day maximum 25 mg/day; (adolescents) rofecoxib 12.5 or 25 mg daily Control group (N = 101): (children) naproxen 15 mg/kg/day 5 mg oral suspension; (adolescents) 15 mg/kg/day maximum 1000 mg/day Study duration: 12 weeks (+ 52‐week open‐label extension)
Outcomes	Primary outcomes Time‐weighted average proportion of patients achieving ACR Pediatric 30 (at least 30% improvement in any 3 of 6 variables Investigators' global assessment of disease activity (100‐millimetre VAS) Parent/patient's global assessment of overall well‐being (100‐millimetre VAS) Measure of physical functional ability (CHAQ: 0‐to‐3‐point scale) Number of joints with active arthritis Number of joints with limited range of motion Measure of inflammation (ESR) Secondary outcomes Proportion of patients showing improvement from baseline using (b) above Safety assessments ‐ adverse events Serious adverse events
Notes	Sources of funding: unstated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "randomisation to treatment groups in equal proportions was performed using a computer‐generated allocation schedule. Treatment assignment was stratified based on joint involvement (pauci‐ or polyarticular course) and age group (2‐11 years or 12‐17 years)."
Allocation concealment (selection bias)	Low risk	Quote: "randomisation to treatment groups in equal proportions was performed using a computer‐generated allocation schedule. Treatment assignment was stratified based on joint involvement (pauci‐ or polyarticular course) and age group (2‐11 years or 12‐17 years)."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "to maintain blinding to treatment assignment during the base study, each patient received 2 coded test products ‐ active or identical‐appearing placebo"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All participants were accounted for. Lost to follow‐up and withdrawals explained.
Selective reporting (reporting bias)	Low risk	Comment: All planned outcomes from the methods section were reported in the results.
Size	Unclear risk	Comment: Total participants = 310 (between 50 and 200 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

Ruperto 2005

Methods	Allocation: randomised Blinding: double‐blind, double‐dummy Controlled: active comparator Centre: multicentre Arm: 3 arms, parallel groups
Participants	Inclusion criteria: diagnosis of JIA (Durban criteria); NSAID therapy is required; have at least 2 joints with active arthritis plus abnormal results in at least 2 of any of the 5 remaining JIA core set criteria Exclusion criteria: current systemic manifestations; abnormal laboratory results unrelated to JIA; pregnancy, breastfeeding; bleeding disorders; peptic ulcer in past 6 months; hypersensitivity to NSAIDs; other rheumatic conditions; other medications related to rheumatic conditions; taking other NSAIDs Baseline characteristics N = 225 Age: 2 to 16 years Gender: male (148); female (67) Number randomised: meloxicam low (73); meloxicam high (74); naproxen (78) Number completed: meloxicam low (58); meloxicam high (63); naproxen (61) Setting and location: 34 paediatric rheumatology tertiary care units in Austria, Belgium, France, Germany, Italy, Russia, and the UK
Interventions	Intervention group 1 (N = 73): meloxicam 0.125 mg/kg, 1 dose per day Intervention group 2 (N = 74): meloxicam 0.25 mg/kg, 1 dose per day Control group (N = 78): naproxen 5 mg/kg, twice per day Placebo 'naproxen' tablets for the meloxicam groups and placebo 'meloxicam' tablets for the naproxen group Study duration: 48 weeks
Outcomes	Primary outcomes At least 30% improvement from baseline (ACR Pediatric 30 criteria) At least 50% improvement from baseline (ACR Pediatric 30 criteria) At least 70% improvement from baseline (ACR Pediatric 30 criteria) Secondary outcomes Number of joints with active arthritis (JIA score set) Number of joints with limited range of motion (0 to 67) Physician's global evaluation of disease activity (double‐anchored 100‐millimetre VAS) Parent's global assessment of the child's overall well‐being (double‐anchored 100‐millimetre VAS) Disability index (CHAQ) Western ESR Parent's evaluation of the child's pain (double‐anchored 100‐millimetre VAS) Parent's evaluation of the child's arthritis (double‐anchored 100‐millimetre VAS) Child's assessment of discomfort by facial affective scale (1 to 9 points)
Notes	Sources of funding: grant from Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany, to the Paediatric Rheumatology International Trials Organisation
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "patients were allocated to 1 of the 3 treatment groups in a 1:1:1 randomization scheme" Comment: Randomisation method not described.
Allocation concealment (selection bias)	Unclear risk	Comment: No description of allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "to keep the trial blinded, children in the meloxicam group also received naproxen placebo suspension and vice versa, in a double‐dummy design"
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: Insufficient information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All participants were accounted for. Loss to follow‐up and withdrawals explained. However, authors do not report whether there were significant differences between completers and non‐completers.
Selective reporting (reporting bias)	Low risk	Comment: All planned outcomes from the methods were reported in the results.
Size	Unclear risk	Comment: Total participants = 225 (between 50 and 200 per treatment arm)
Other bias	Low risk	Comment: No other potential sources of bias found.

ACR: American College of Rheumatology; CHAQ: Child Health Assessment Questionnaire; ESR: erythrocyte sedimentation rate;JIA: juvenile idiopathic arthritis; JRA: juvenile rheumatoid arthritis; VAS: visual analogue scale.

Characteristics of excluded studies [ordered by study ID]

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included studies

Study	Reason for exclusion
Coutinho 1976	Population: adults
Girschick 1999	Allocation: not a randomised controlled trial
Jenkins 1976	Population: adults
Johnsen 1992	Population: adults
Natour 2002	Population: adults
Reicher 1969	Allocation: not a randomised controlled trial
Sadowska‐Wroblewska 1980	Population: adults

Data and analyses

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Comparison 1. Meloxicam versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐reported pain relief of 30% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.1 Comparison 1 Meloxicam versus naproxen, Outcome 1 Participant‐reported pain relief of 30% or greater.
1.1 Meloxicam 0.125mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Meloxicam 0.25mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Participant‐reported pain relief of 50% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 1.2 Comparison 1 Meloxicam versus naproxen, Outcome 2 Participant‐reported pain relief of 50% or greater.
2.1 Meloxicam 0.125mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Meloxicam 0.25mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

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Comparison 2. Celecoxib versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐reported pain relief of 30% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 2.1 Comparison 2 Celecoxib versus naproxen, Outcome 1 Participant‐reported pain relief of 30% or greater.
1.1 Celecoxib 3mg/kg vs naproxen 7.5mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Celecoxib 6mg/kg vs naproxen 7.5mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

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Comparison 3. Rofecoxib versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐reported pain relief of 30% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
Open in figure viewer Analysis 3.1 Comparison 3 Rofecoxib versus naproxen, Outcome 1 Participant‐reported pain relief of 30% or greater.
1.1 Rofecoxib 0.3 to 12.5mg/kg vs naproxen 15mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Rofecoxib 12.5 to 25mg/kg vs naproxen 15mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 3

Forest plot of comparison: 1 Meloxicam versus naproxen, outcome: 1.1 Participant‐reported pain relief of 30% or greater.

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Figure 4

Forest plot of comparison: 2 Celecoxib versus naproxen, outcome: 2.1 Participant‐reported pain relief of 30% or greater.

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Figure 5

Forest plot of comparison: 3 Rofecoxib versus naproxen, outcome: 3.1 Participant‐reported pain relief of 30% or greater.

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Figure 6

Forest plot of comparison: 1 Meloxicam versus naproxen, outcome: 1.2 Participant‐reported pain relief of 50% or greater.

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Analysis 1.1

Comparison 1 Meloxicam versus naproxen, Outcome 1 Participant‐reported pain relief of 30% or greater.

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Analysis 1.2

Comparison 1 Meloxicam versus naproxen, Outcome 2 Participant‐reported pain relief of 50% or greater.

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Analysis 2.1

Comparison 2 Celecoxib versus naproxen, Outcome 1 Participant‐reported pain relief of 30% or greater.

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Analysis 3.1

Comparison 3 Rofecoxib versus naproxen, Outcome 1 Participant‐reported pain relief of 30% or greater.

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Summary of findings for the main comparison. Meloxicam compared with naproxen for chronic non‐cancer pain

Meloxicam compared with naproxen for chronic non‐cancer pain
Patient or population: children and adolescents with chronic non‐cancer pain Settings: multicentre paediatric rheumatology tertiary care units (international) Intervention: meloxicam Comparison: naproxen
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Naproxen	Meloxicam	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Participant‐reported pain relief of 30% or greater	50/78	89/147	N/A	225 participants (1 study)	⊕⊕⊝⊝ low^a
Participant‐reported pain relief of 50% or greater	39/78	70/147	N/A	225 participants (1 study)	⊕⊕⊝⊝ low^a
Patient Global Impression of Change much or very much improved	No data	No data	N/A	N/A		No evidence to support or refute^c
Any adverse event	10/78	18/147	N/A	225 participants (1 study)	⊕⊝⊝⊝ very low^b
Serious adverse event	10/78	11/147	N/A	225 participants (1 study)	⊕⊝⊝⊝ very low^b
Withdrawals due to adverse events	10/78	10/147	N/A	225 participants (1 study)	⊕⊝⊝⊝ very low^b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; N/A: not applicable
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once for serious study limitations (risk of bias), and once for imprecision. ^bDowngraded three levels due to too few data and number of events are too small to be meaningful. ^cNo data available for this outcome, and therefore no GRADE rating has been applied and there is no evidence to support or refute.

Summary of findings for the main comparison. Meloxicam compared with naproxen for chronic non‐cancer pain

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Summary of findings 2. Celecoxib compared with naproxen for chronic non‐cancer pain

Celecoxib compared with naproxen for chronic non‐cancer pain
Patient or population: children and adolescents with chronic non‐cancer pain Settings: 17 paediatric centres worldwide Intervention: celecoxib Comparison: naproxen
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Naproxen	Celecoxib	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Participant‐reported pain relief of 30% or greater	56/83	119/159	N/A	242 participants (1 study)	⊕⊕⊝⊝ low^a
Participant‐reported pain relief of 50% or greater	No data	No data	N/A	N/A	‐	No evidence to support or refute^c
Patient Global Impression of Change much or very much improved	No data	No data	N/A	N/A	‐	No evidence to support or refute^c
Any adverse event	No data	No data	N/A	N/A	‐	No evidence to support or refute^c
Serious adverse event	0/83	5/159	N/A	242 participants (1 study)	⊕⊝⊝⊝ very low^b
Withdrawals due to adverse events	3/83	10/159	N/A	242 participants (1 study)	⊕⊝⊝⊝ very low^b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; N/A: not applicable
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once for serious study limitations (risk of bias), and once for imprecision. ^bDowngraded three levels due to too few data and number of events are too small to be meaningful. ^cNo data available for this outcome, and therefore no GRADE rating has been applied and there is no evidence to support or refute.

Summary of findings 2. Celecoxib compared with naproxen for chronic non‐cancer pain

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Summary of findings 3. Rofecoxib compared with naproxen for chronic non‐cancer pain

Rofecoxib compared with naproxen for chronic non‐cancer pain
Patient or population: children and adolescents with chronic non‐cancer pain Settings: 41 clinical centres in Australia, Europe, Asia, Central America, South America, USA Intervention: rofecoxib Comparison: naproxen
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Naproxen	Rofecoxib	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Participant‐reported pain relief of 30% or greater	48/87	94/187	N/A	274 participants (1 study)	⊕⊕⊝⊝ low^a
Participant‐reported pain relief of 50% or greater	No data	No data	N/A	N/A	‐	No evidence to support or refute^c
Patient Global Impression of Change much or very much improved	No data	No data	N/A	N/A	‐	No evidence to support or refute^c
Any adverse event	28/101	43/209	N/A	274 participants (1 study)	⊕⊝⊝⊝ very low^b
Serious adverse event	0/101	0/209	N/A	310 participants (1 study)	⊕⊝⊝⊝ very low^b
Withdrawals due to adverse events	3/101	3/209	N/A	310 participants (1 study)	⊕⊝⊝⊝ very low^b
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; N/A: not applicable
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of effect, but there is a possibility that it is substantially different. Low quality: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low quality: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded once for serious study limitations (risk of bias), and once for imprecision. ^bDowngraded three levels due to too few data and number of events were too small to be meaningful. ^cNo data available for this outcome, and therefore no GRADE rating has been applied and there is no evidence to support or refute.

Summary of findings 3. Rofecoxib compared with naproxen for chronic non‐cancer pain

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Comparison 1. Meloxicam versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐reported pain relief of 30% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Meloxicam 0.125mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Meloxicam 0.25mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Participant‐reported pain relief of 50% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Meloxicam 0.125mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Meloxicam 0.25mg/kg vs naproxen 10mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Meloxicam versus naproxen

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Comparison 2. Celecoxib versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐reported pain relief of 30% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Celecoxib 3mg/kg vs naproxen 7.5mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Celecoxib 6mg/kg vs naproxen 7.5mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Celecoxib versus naproxen

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Comparison 3. Rofecoxib versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Participant‐reported pain relief of 30% or greater Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Rofecoxib 0.3 to 12.5mg/kg vs naproxen 15mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Rofecoxib 12.5 to 25mg/kg vs naproxen 15mg/kg	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Rofecoxib versus naproxen

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References

References to studies included in this review

Bhettay 1978 {published data only}

Brewer 1982 {published data only}

Foeldvari 2009 {published data only}

Giannini 1990 {published data only}

Moran 1979 {published data only}

Reiff 2006 {published data only}

Ruperto 2005 {published data only}

References to studies excluded from this review

Coutinho 1976 {published data only}

Girschick 1999 {published data only}

Jenkins 1976 {published data only}

Johnsen 1992 {published data only}

Natour 2002 {published data only}

Reicher 1969 {published data only}

Sadowska‐Wroblewska 1980 {published data only}

Additional references

AMA 2013

AUREF 2012

Blanca‐Lopez 2015

BNF 2016

Caes 2016

Calvo 2012

Cooper 2017a

Cooper 2017b

Cooper 2017c

Cooper 2017d

Dechartres 2013

Dechartres 2014

Dworkin 2008

Eccleston 2003

Guyatt 2008

Guyatt 2011

Guyatt 2013a

Guyatt 2013b

Hasnie 2007

Higgins 2011

Hoffman 2010

Kawakami 2002

L'Abbé 1987

Lesko 1995

Lesko 1997

Lesko 1999

McQuay 1998

Misurac 2013

Moher 2009

Moore 2008

Moore 2009

Moore 2010a

Moore 2010b

Moore 2010c

Moore 2010d

Moore 2010e

Moore 2011a

Moore 2011b

Moore 2012

Moore 2013a

Moore 2013b

Moore 2014a

Moore 2014b

NICE 2015

Nüesch 2010

O'Brien 2010

PedIMMPACT 2008

RevMan 2014 [Computer program]

Ripamonti 2008

Stinson 2006

Straube 2008

Straube 2010

Sultan 2008

Thorlund 2011

United Nations 2015

Vo 2009

von Baeyer 2007

WHO 2012

Wiffen 2017a

Wiffen 2017b