Does flare trial design affect the effect size of non-steroidal anti-inflammatory drugs in symptomatic osteoarthritis? A systematic review and meta-analysis

Toby O. Smith, Kun Zuo, Natasya Abdullah, Xi Chen, Sarah R. Kingsbury, Michael Doherty, Weiya Zhang, Philip G. Conaghan

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11 Citations (Scopus)
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Objectives: It is thought that the clinical trial benefits of oral non-steroid anti-inflammatory drugs (NSAIDs) may relate to flare designs. The aim of this study was to examine the difference in NSAID (including 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 to 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 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 effect size of NSAIDs versus placebo between flare and non-flare trial designs for absolute pain and function or stiffness at immediate (1 week), short (2 to 4 week) or longer (12 to 13 week) follow-up periods (p>0.05). However there was a lower effect size for mean change in pain in flare and possible flare trials compared to non-flare trials at short-term follow-up (0.36 versus 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 to non-flare design. Whether flare design influences other outcomes such as joint effusion remains unknown.  
Original languageEnglish
Pages (from-to)1971-1978
Number of pages8
JournalAnnals of the Rheumatic Diseases
Issue number11
Early online date16 Feb 2016
Publication statusPublished - 1 Nov 2016


  • Randomised controlled trial
  • NSAIDs
  • Osteoarthritis
  • Effect size
  • Methodology

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