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• Paracetamol and the placebo effect in osteoarthritis trials. The missing link
  henning zeidler, MD
  Published on: 13 April 2016

• Published on: 13 April 2016

  Paracetamol and the placebo effect in osteoarthritis trials. The missing link

  • henning zeidler, MD, professor emeritus

  Dear Editor,

  Zhang and colleagues reported in a recent metaanalysis of randomised trials that placebo is very effective in the treatment of osteoarthritis (OA), especially for pain, stiffness and self-reported function.[1] In addition Zhang et al. concluded:” Important determinants of the magnitude of effect appear to be the baseline severity, the expected strength of the treatment, the route of delivery and the sample...

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  Dear Editor,

  Zhang and colleagues reported in a recent metaanalysis of randomised trials that placebo is very effective in the treatment of osteoarthritis (OA), especially for pain, stiffness and self-reported function.[1] In addition Zhang et al. concluded:” Important determinants of the magnitude of effect appear to be the baseline severity, the expected strength of the treatment, the route of delivery and the sample size”.[1] But neither Zhang et al. nor Bijlsma and Welsing in the accompanying editorial discussed the impact of acetaminophen (paracetamol) on the placebo effect. [1, 2]

  Current guidelines emphasize paracetamol as the first-line therapy, when pharmacological agents are needed, [3, 4] and paracetamol (500 mg up to 4000 mg) is used as rescue medication in nearly all OA trials. In a recent trial on retention on treatment with lumiracoxib and celecoxib, in which a maximum dose of 2 g paracetamol was permitted, rescue medication was used by 79.5% to 81.3% of the patients. [5] Individuals with greater baseline level of OA pain or use of a limited form of treatment would be more likely to utilize rescue therapy. This was the case in the Glucosamine/chondroitinArthritis Intervention Trial (GAIT), which allowed up to 4000 mg of paracetamol daily as rescue analgesia. Patients with moderate-to-severe pain used 1.9 ± 1.9 to 2.5 ± 2.2 tablets (500 mg) per day at the end of follow-up compared to 1.4 ± 1.6 to 1.7 ± 1.8 tablets in patients with mild pain. [6] A meta-analysis of randomised controlled trials reported that paracetamol is effective in relieving pain due to OA when used in a fixed dose between 2000 mg and 4000 mg and that paracetamol has a higher response rate than placebo. [7] The effect size (ES) of 0.21 is small but statistically significant. A most recent Cochrane systemic review concluded that paracetamol is superior to placebo in OA with an improvement from baseline of 5%, an absolute change of 4 points on a 0 to 100 pain scale and a number needed to treat (NNT) ranging from 4 to 16. [8]

  Altogether, paracetamol may be the missing link to explain at least partially the high placebo rate in pain and OA trials not seen in other medical conditions. [9] Indeed, Zhang et al. reported in their metaanalysis that only 15 trials analysed did not allow rescue medications.
  The effect size (ES) was 0.71 without rescue medication compared to 0.51 in all trials (n=193) and 0.03 in trials with untreated controls (n=14), which suggest to me that rescue medication can mask the efficacy of the active treatment. But rescue medication use is not assessed sequentially along with other variables in OA trials and mostly limited or no data are available from published trials on the starting dose, final dose, dose over time of paracetamol rescue medication and the percentage of patients who used rescue medication during the study. However, without comprehensive data on active use of rescue medication from all or most of the studies in OA, final conclusions in regard to the determinants of placebo effect are fairly speculative.

  References

  1. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67:1716-23.

  2. Bijlsma JW, Welsing PM. The art of medicine in treating osteoarthritis:I will please. Ann Rheum Dis 2008;67:1653-55.

  3. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines: recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis Rheum 2000;43:1905-1915.

  4. Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, et al. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis 2003;62:1145-55.

  5. Fleischmann R, Tannenbaum H, Patel NP, Notter M, Sallstig P, Reginster JY. Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: a randomised controlled trial in patients with osteoarthritis. BMC Musculoskelet Disord 2008;9:32.

  6. Clegg DO, Reda DJ, Harris CL, Klein MA, O'Dell JR, Hooper MM, et al. Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis. N Engl J Med 2006;354:795-808.

  7. 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;63:901-7.

  8. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;1:CD004257.

  9. Hrobjartsson A, Gotzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 2001;344:1594–602.

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  Conflict of Interest:
  None declared.

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