The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomized placebo-controlled trial

Rheumatology (Oxford). 2000 Oct;39(10):1095-101. doi: 10.1093/rheumatology/39.10.1095.


Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat osteoarthritis (OA), though their long-term efficacy is uncertain. We report a comparison of the symptomatic responses to therapy with tiaprofenic acid, indomethacin and placebo over 5 yr.

Methods: A parallel-group, randomized, single-blind trial of patients with knee OA recruited 812 patients from 20 centres; 307 patients received tiaprofenic acid (300 mg b.d.), 202 indomethacin (25 mg t.d.s.) and 303 matching placebo for up to 5 yr. At the end of the parallel-group study, patients receiving tiaprofenic acid or placebo entered a 4-week blinded cross-over study of tiaprofenic acid or placebo, both given for 2 weeks. Assessments were at baseline, 4 weeks, then at 6-month intervals for up to 5 yr in the parallel group study and at 2-week intervals in the cross-over study. They comprised pain scores, duration of morning stiffness, patients' global assessments, paracetamol consumption, adverse reactions, withdrawals and functional outcomes.

Results: There were significant falls in overall pain scores in patients receiving NSAIDs compared with placebo at 4 weeks in the parallel-group phase. Thereafter there were no advantages favouring active therapy. In the cross-over phase, pain scores were significantly lower in patients receiving tiaprofenic acid than placebo. Patients who had been receiving long-term tiaprofenic acid showed significant rises in their pain scores when receiving placebo therapy and vice versa. Adverse events were reported by 61% of patients receiving tiaprofenic acid, 63% on indomethacin and 51% on placebo. Potentially severe side-effects were rare; for example, there were only three cases of gastrointestinal bleeding on NSAIDs. The pattern of withdrawal was similar in patients taking NSAIDs and placebo in the parallel-group study; at 48 weeks 53% of the patients remained on tiaprofenic acid, 50% on indomethacin and 54% on placebo.

Conclusions: NSAIDs significantly reduce overall pain over 4 weeks. This short-term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was changed to placebo. Our results do not show long-term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Inflammatory Agents, Non-Steroidal / adverse effects
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
  • Cross-Over Studies
  • Double-Blind Method
  • Female
  • Humans
  • Indomethacin / therapeutic use*
  • Knee Joint / drug effects*
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Osteoarthritis / drug therapy*
  • Osteoarthritis / physiopathology
  • Placebos
  • Propionates / therapeutic use*
  • Time Factors
  • Treatment Outcome
  • Walking


  • Anti-Inflammatory Agents, Non-Steroidal
  • Placebos
  • Propionates
  • tiaprofenic acid
  • Indomethacin