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• NSAIDs, including coxibs, probably do more harm than good, and paracetamol is ineffective for hip OA
  Jan M. Bjordal
  Published on: 13 April 2016

• Published on: 13 April 2016

  NSAIDs, including coxibs, probably do more harm than good, and paracetamol is ineffective for hip OA

  • Jan M. Bjordal, Postdoctoral Research Fellow
  • Other Contributors:
    • Anne Elisabeth Ljunggren, Atle Klovning and Lars Slørdal

  Dear Editor,

  New EULAR treatment guidelines in hip osteoarthritis were recently reviewed [1]. The recommendations are allegedly based on top level scientific (grade 1a) data, and advocate the use of paracetamol (US: acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase 2 inhibitors (coxibs), in osteoarthritis of the hip. We interpret the underlying data differently...

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  Dear Editor,

  New EULAR treatment guidelines in hip osteoarthritis were recently reviewed [1]. The recommendations are allegedly based on top level scientific (grade 1a) data, and advocate the use of paracetamol (US: acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase 2 inhibitors (coxibs), in osteoarthritis of the hip. We interpret the underlying data differently:

  The review [1] states that due to a lack of studies evaluating paracetamol in hip osteoarthritis alone, recommendations rely on studies that also include osteoarthritic conditions in other joints. A review of 4 placebo-controlled trials demonstrated an effect size (ES) of 0.21 (0.02- 0.41)[2]. Two small (n=50 and n=60) trials could not be pooled for lack of data. Thus, ES calculations are from 2 trials, where the smallest reported no significant effect, leaving us with a final sample of 387 patients. The EULAR review does not mention that a recent large (n=779) knee osteoarthritis trial reported a non-significant effect of paracetamol corresponding to a miniscule 0.8 mm on a visual analogue pain scale (VAS)[3]. Together, available data clearly demonstrate a lack of effect of paracetamol in large joint osteoarthritis.

  Concomitant with the withdrawal of rofecoxib (Vioxx), and an increasing awareness that other coxibs may also induce serious cardiovascular toxicity, EULAR recommend the use of coxibs as second line treatment after paracetamol for patients at risk for gastrointestinal adverse effects1. However, no references to randomised controlled trials (RCTs) or systematic reviews on efficacy are given. To our knowledge only two RCTs evaluate the use of coxibs in hip osteoarthritis alone. A Pfizer- funded trial with valdecoxib [4] found a difference over placebo of only 1.6 from a baseline value of 10.8 on the WOMAC subscale of pain, which corresponds to a modest 7.9 mm on VAS. Similar results were found for celecoxib in another Pfizer-funded trial [5]. These results are well below the threshold of 15 mm on VAS which defines minimal clinically important differences [6]. On the other hand, pivotal questions regarding the safety of coxibs remain unresolved. In our view, this calls for caution and suggests that the use of these drugs should be suspended until comprehensive safety data for all coxibs are available.

  The EULAR review states that NSAIDs are effective, but that adverse effects may counter their benefit1. This conclusion is based on one systematic Cochrane review [7] which allegedly included 14 placebo- controlled trials. The ES for pain relief was 0.69 (95% CI 0.12-1.26). However, the cited Cochrane review does not include a single study published after 1994. It is not based on 14 placebo-controlled trials, but on 14 placebo-controlled comparisons. The number of included placebo- controlled trials was 3-three-(with 9, 146, and 104 patients, respectively) of 2-8 weeks duration. The given ES of 0.69 was calculated from the results of a single 8-week trial (n=146)(8), which reported a mean difference over placebo corresponding to 10 mm on VAS. To our knowledge, no further hip-specific RCTs with NSAIDs have been published except the two coxib trials mentioned above, where groups of patients treated with naproxen were included. The efficacy for naproxen in these trials was not significantly different from that of the coxibs. A recent analysis of 23 trials on the efficacy of NSAIDs (including coxibs) in knee osteoarthritis demonstrated a small effect of therapy on pain corresponding to 10.1 mm on VAS [9], which is too modest to be of any clinical significance in the average patient. No long term trials (>13 weeks) have demonstrated beneficial effects of NSAIDs over placebo in hip or knee osteoarthritis. Although all NSAIDs may induce serious adverse effects, relevant safety issues cannot be addressed from short term studies. In our view, it is highly likely that long term use of NSAIDs, including coxibs, do more harm than good in patients with osteoarthritis of the hip.

  We support the EULAR guidelines initiative as a positive contribution for evidence based care of patients with arthritis. However, we believe that some of the recommendations are erroneous and misleading. In general, lack of hard data to estimate treatment effects is a common problem. However, in ostearthritis there is a plethora of data. In our view, the available information unequivocally demonstrates that standard pharmacological interventions with paracetamol and NSAIDs, including coxibs, cannot be recommended for the osteoarthritic patient.

  References

  (1). Zhang W, Doherty M, Arden N, et al. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2004: 2004.028886.

  (2). Zhang W, Jones A, Doherty M. Does paracetamol (acetaminophen) reduce the pain of osteoarthritis? A meta-analysis of randomised controlled trials. Ann Rheum Dis 2004.

  (3). Miceli-Richard C, Le Bars M, Schmidely N, Dougados M. Paracetamol in osteoarthritis of the knee. Ann Rheum Dis 2004;63:923-930.

  (4). Makarowski W, Zhao WW, Bevirt T, Recker DP. Efficacy and safety of the COX-2 specific inhibitor valdecoxib in the management of osteoarthritis of the hip: a randomized, double-blind, placebo-controlled comparison with naproxen. Osteoarthritis Cartilage 2002;10:290-6.

  (5). Kivitz AJ, Moskowitz RW, Woods E, et al. Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip. J Int Med Res 2001;29:467-79.

  (6). Tubach F, Ravaud P, Baron G, et al. Evaluation of clinically relevant changes in patient- reported outcomes in knee and hip osteoarthritis: the Minimal Clinically Important Improvement. Ann Rheum Dis 2004.

  (7). Non-aspirin, non-steroidal anti-inflammatory drugs (NSAIDS) for osteoarthritis of the knee [15 p) (16 ref 12 bib) (Update Software, online or CD-ROM, updated quarterly program]: The Cochrane Library (Oxford), 2001.

  (8). Nguyen M, Dougados M, Berdah L, Amor B. Diacerhein in the treatment of osteoarthritis of the hip. Arthritis Rheum 1994;37:529-36.

  (9). Bjordal JM, Ljunggren AE, Klovning A, Slordal L. Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials. BMJ 2004;329:1317-.

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  Conflict of Interest:
  None declared.

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