A historic issue of the Annals: three papers examine paracetamol in osteoarthritis.

A lthough current European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines both support paracetamol (acetaminophen) as the first line oral analgesic for patients with knee osteoarthritis (OA), until now there has been a paucity of clinical trial data to confirm the efficacy of paracetamol in large joint OA. This issue of the Annals is unique in containing one meta-analysis and two large placebo controlled studies that examine evidence for the efficacy of paracetamol in OA. Never in the 127 years of paracetamol’s existence have so much trial data on OA been reported. Because of the marked placebo effect in pain trials comparison with a placebo is clearly important to determine the true efficacy of any analgesic. Therefore it is surprising that despite the widespread use and support of paracetamol in OA until now there have been only four placebo controlled trials of this drug in OA. The first two studies reported in 1983 and in 1995 both demonstrated the superiority of paracetamol over placebo for pain relief in large joint OA using parallel group designs. However, the first study contained only 25 patients with knee OA followed up for just 6 weeks. The second study was larger (60 patients) but was of just 1 week’s duration and contained a mixed population with knee or hip OA. A third parallel group study was reported in 2003. This compared paracetamol, diclofenac, and placebo over a 12 week period in 82 patients with knee OA but was the first negative study for paracetamol, showing no difference between paracetamol and placebo using Western Ontario McMaster Osteoarthritis Index (WOMAC) assessments. Most recently, Pincus et al carried out a crossover study comparing paracetamol, celecoxib, and placebo taken for 6 week periods (PACES-a). The authors found that paracetamol was effective for pain but was no better than placebo for total WOMAC scores. In the light of these heterogeneous data, Zhang et al undertook a metaanalysis to aggregate the evidence that was available up until July 2003. The analysis, published in this issue, shows that paracetamol gives pain relief in OA that is better than placebo (effect size 0.21, 95% confidence interval (CI) 0.02 to 0.41). This estimate was based only on the two studies 7 that provided pain intensity at both baseline and end point. Nevertheless, the finding is in accord with other evidence from pain studies and with clinical experience. Two large randomised placebo controlled studies of paracetamol in large joint OA are now reported in this issue. They use different designs and interestingly find contrasting results, one being negative and one positive for paracetamol, so each will be discussed separately.