Paracetamol still persona grata or game over in Rheumatology? Comment on article by Machado et al.
Paracetamol, a grade I analgesic is recommended as the first line therapy in osteoarthritis (1-3). Despite reports of its limited efficacy in this disease (4,5), rheumatologists continue to urge general practitioners on the importance of prescribing paracetamol in first intention, this, in compliance with present guidelines (6). Discussions on the efficacy and safety of paracetamol have resurfaced in the year 2015 (7,8).
A systematic review with meta-analysis by Machado et al. showed that in the short term, paracetamol is not effective in reducing pain intensity, disability and the improvement of the quality of life of patients with low back pain. For knee and hip osteoarthritis, though paracetamol provides a significant reduction of pain intensity and disability in the short term, this efficacy is not clinically apparent (7). Machado et al. also raised some issues as concerns the safety of paracetamol. Indeed, patients taking paracetamol (3 000 mg to 3 900 mg) are more likely to have abnormal results of liver function tests in the short term. However, the relevance of these liver abnormalities remains unclear (7) thereby warranting a long-term evaluation of the consequences of this disturbance of liver function tests so as to provide answers to this question. The long term safety of paracetamol has been questioned in several reports (1,4,8), particularly in a recent systematic review conducted by Roberts et al (8). Despite methodological limitations, this review enhances the blaze by showing that paracetamol is associated with cardiovascular, gastrointestinal, and renal adverse events. Moreover, paracetamol might increase mortality (8). Association with non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen has also been shown to increase the risk of mild gastrointestinal bleeding (9).
Therefore, the apparent unfavorable benefit to risk ratio of paracetamol raises a key issue: should we change our paradigm for the management of osteoarthritis and recommend as first line therapy grade II analgesics and/or NSAIDs? (10,11).
So far we have been blinded by a double game on paracetamol: its double name (acetaminophen and paracetamol) and its double AA+ (good efficacy and good tolerance). Today it seems to make room to a double CC– status (poor efficacy and poor safety). Notwithstanding, the benefit to risk ratio of any drug should also be evaluated owing to its duration in the armamentarium of prescription. Indeed, acetaminophen when prescribed at high dose on the long term, might be risky for the cardiovascular system but also for the gastrointestinal tract (9). However, we lack data on the safety profile of paracetamol when given on a short period of time. We should therefore think on this question and know what is most effective and safe in a disease such as osteoarthritis which has a limited available therapeutic arsenal. Consequently, excluding paracetamol as first line analgesic in such a situation may open the door for grade II analgesics and/or NSAIDs which have severe associated side effects, especially in osteoarthritis patients who often have multiple comorbidities (9-11).
The answer might be that in a disease like osteoarthritis it is time to consider not only the effect size of one drug but the additional effect of several non-pharmacological and pharmacological therapies among which paracetamol. Meanwhile, the approach would be to use the lowest dose of paracetamol for the shortest duration.
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 2005;64:669-81.
2. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465-74.
3. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage 2014;22:363-88.
4. 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.
5. Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;1:CD004257.
6. Chevalier X, Marre JP, de Butler J, Hercek A. Questionnaire survey of management and prescription of general practitioners in knee osteoarthritis: a comparison with 2000 EULAR recommendations. Clin Exp Rheumatol 2004;22:205-12.
7. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled trials. BMJ 2015;350:h1225.
8. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis 2015 Mar 2. pii: annrheumdis-2014-206914. doi: 10.1136/annrheumdis-2014-206914.
9. Doherty M, Hawkey C, Goulder M, et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis 2011;70:1534-41.
10. Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis. Cochrane Database Syst Rev 2006;3:CD005522.
11. Scarpignato C, Lanas A, Blandizzi C, et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis - an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med 2015;13:55. doi: 10.1186/s12916-015-0285-8.
Competing interests: No competing interests