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Does flare trial design affect the effect size of non-steroidal anti-inflammatory drugs in symptomatic osteoarthritis? A systematic review and meta-analysis
  1. Toby O Smith1,
  2. Kun Zou2,
  3. Natasya Abdullah3,
  4. Xi Chen3,
  5. Sarah R Kingsbury4,
  6. Michael Doherty3,
  7. Weiya Zhang5,
  8. Philip G Conaghan4
  1. 1Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK
  2. 2Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, Sichuan, China
  3. 3Division of Rheumatology, Orthopaedics and Dermatology, University of Nottingham, Nottingham, UK
  4. 4Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds & NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
  5. 5Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK
  1. Correspondence to Professor Philip G Conaghan, NIHR Leeds Musculoskeletal Biomedical Research Unit, Section of Musculoskeletal Disease, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK; p.conaghan{at}


Objectives It is thought that the clinical trial benefits of oral non-steroidal anti-inflammatory drugs (NSAIDs) may relate to flare designs. The aim of this study was to examine the difference in NSAID (including cyclooxygenase-2 (COX-2) inhibitors) response in osteoarthritis (OA) trials based on different designs.

Methods Systematic review was undertaken of the databases MEDLINE, EMBASE, AMED, CINAHL and the Cochrane library till February 2015. Randomised controlled trials assessing pain, function and/or stiffness following commencement of NSAIDs in flare and non-flare designs were eligible. Trials were assessed using the Cochrane Risk of Bias tool. Meta-analyses were conducted to assess the effect sizes (ES) of NSAIDs for OA with flare versus non-flare trial designs.

Results Fifty-seven studies including 33 263 participants assessing 26 NSAIDs were included. Twenty-two (39%) were flare design, 24 (42%) were non-flare designs, 11 (19%) were possible flare designs. On meta-analysis, there was no statistically significant difference in ES of NSAIDs versus placebo between flare and non-flare trial designs for absolute pain and function or stiffness at immediate-term (1 week), short-term (2–4 week) or longer-term (12–13 week) follow-up periods (p>0.05). However there was a lower ES for mean change in pain in flare and possible flare trials compared with non-flare trials at short-term follow-up (0.36 vs 0.69; p=0.05).

Conclusions Contrary to previous understanding, flare trial designs do not result in an increased treatment effect for NSAIDs in people with OA compared with non-flare design. Whether flare design influences other outcomes such as joint effusion remains unknown.

  • NSAIDs
  • Osteoarthritis
  • Health services research

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  • Handling editor Tore K Kvien

  • Twitter Follow Toby Smith at @tobyosmith

  • Contributors PGC and WZ conceptualised the study. PGC, WZ and TOS contributed to the design of the study. TOS, KZ and WZ conducted the analysis. All authors contributed to data collection, interpretation of research findings and manuscript writing.

  • Funding KZ was supported by the International Scholarship for Research Excellence from the University of Nottingham. XC was funded by the Nottingham Arthritis Research UK Pain Centre.

  • Competing interests PGC and SRK are part-funded through the National Institute for Health Research (NIHR) though the Leeds Musculoskeletal Biomedical Research Unit. WZ had grants from Nottingham-China Scholarship, during the conduct of the study; MD reports personal fees from ad hoc advisory boards for osteoarthritis and gout for AstraZeneca, Menarini, Nordic Biosciences, Pfizer, outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We are happy to share our data after approval from our institution (University of Nottingham).

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