Paracetamol, Ibuprofen, Or a Combination of Both Drugs Against Knee Pain: an Excellent New Randomised Clinical Trial Answers
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Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2011-200242 on 30 July 2011. Downloaded from relief, but was not superior to ibuprofen Paracetamol, ibuprofen, or a alone (table 1). At the second study end point (week 13), signifi cantly more par- ticipants taking one or two combination combination of both drugs against tablets rated their treatment as excellent/ good compared with paracetamol alone; knee pain: an excellent new ibuprofen alone was better than parac- etamol and not statistically inferior to the high-dose combination. randomised clinical trial answers Adverse events were comparable between all groups, but numerically old questions and suggests new higher in the groups receiving combina- tion tablets. Interestingly, the incidence therapeutic recommendations of dyspepsia or diarrhoea was not lower in the paracetamol only group (as would 1 2 have been expected by common wis- Kay Brune, Burkhard Hinz dom). On the other hand, it is not surpris- ing to fi nd that the ibuprofen only group At fi rst glance, the title of the article pub- 3. one fi xed-dose combination tablet had no signs of liver toxicity in contrast lished by Doherty et al1 (see page 1534) (ibuprofen 200 mg/paracetamol to all three paracetamol groups. After does not promise much. Who would be 500 mg (low-dose) three times a 13 weeks a fall in haemoglobin (>1 g/ interested in reading an investigation day); dl) occurred more frequently in patients taking a combination than in those on comparing two old well-known analge- 4. two fi xed-dose combination monotherapy with paracetamol or ibu- sics with each other or combinations of tablets (ibuprofen 400 mg/parac- profen. The blood loss in the high-dose both? At a second glance, however, this etamol 1000 mg (high-dose) three combination group was signifi cantly cautious and excellent long-term study times a day). reveals many new and important fi ndings higher than in all the other groups and In their four cohorts which included which should be the basis for reconsider- reached clinically relevant proportions. almost 900 participants the authors ation of the treatment of musculoskeletal The authors conclude that the analge- found that, at the fi rst study end point conditions with over-the-counter (OTC) sic regimen of an ibuprofen/paracetamol (day 10), the high-dose combination was analgesics. It may turn out that many of combination confers modest short-term superior to paracetamol alone for pain our widely-held beliefs and assumptions benefi ts for knee pain/osteoarthrosis and are wrong and that the recommendation for our patients needs to be changed. Table: Effects of paracetamol (P) and ibuprofen (I) alone or in combination (P + I) in long term therapy Doherty et al investigate whether the of OA of the knee combination of ibuprofen and parac- http://ard.bmj.com/ 1 etamol is better than the active compo- Effects P 3 x 1g/d I 3x 0.4g/d P (3 x 0.5g) + P (3 x 1g) + Comments I (3 x 0.2g/d) I (3 x 0.4g/d) nents alone. To answer this question the authors compared the effi cacy and safety Pain reduction 10.1 13.3 12.8 15.0 **3 vs P P is inferior to I or (mm reduction from P + I of paracetamol and ibuprofen as well baseline, day 10)2 as that of two combinations of these Patients’ global 38.1 54.6 *vs P 53.9 61.4 **vs P combinations are not drugs in community-derived patients assessment superior to I on September 25, 2021 by guest. Protected copyright. aged >40 years with chronic knee pain. (% rating good or In a randomised, double-blind, four-arm excellent) parallel-group active controlled trial, the AEs, any drug 27.5 21.0 p<? 28.8 30.8 P alone or in combination related4,5 causes more AEs than I short-term (day 10) and long-term (week Dyspepsia (day 10)4 5 . 0 6 . 3 1 1 . 7 6 . 3 P alone or in combination 13) benefi ts and side effects of four differ- Diarrhoea (day 10)4 4 . 5 1 . 8 1 . 8 6 . 7 causes as many dyspepsia ent therapeutic regimens were analysed: or diarrhea as I 1. ibuprofen (400 mg three times a ALAT3,4,5 3 . 1 0 . 0 1 . 0 3 . 4 P alone or in combination causes impairment of liver day); γ GT (> 2x normal limit)4 6 . 7 0 . 5 3 . 5 3 . 4 function 2. paracetamol (1000 mg three times Hb ↓ (> 1 g from 7 . 3 1 1 . 3 1 0 . 8 1 7 . 5 P and I cause blood loss; a day); baseline, day 10)4,5 p<0.01** P + I (high dose) enhance blood loss 1Department of Experimental and Clinical > 1 g at study 20.3 19.6 24.1 38.4 Blood loss due to Pharmacology and Toxicology, Friedrich-Alexander- endpoint4,5 p<0.01** P + I reaches clinically relevant proportions with University Erlangen-Nuremberg, Erlangen, Germany time 2Institute of Toxicology and Pharmacology, University > 2 g at study 0 . 9 0 . 9 1 . 8 6 . 9 p < ? The effect of P + I appears of Rostock, Rostock, Germany endpoint4,5 more than additive (p<?) Correspondence to: Dr Kay Brune, Department 1 If not stated otherwise: at day 10 of Experimental and Clinical Pharmacology and 2 As measured with a 10 cm VAS Toxicology, Friedrich-Alexander-University Erlangen- 3 * p<0.05; ** p<0.01 Nuremberg, Fahrstrasse 17, 91052 Erlangen, Germany; 4 results as % of cohort [email protected] 5 Alanine transferase (alanine transaminase; % of patients showing > 2x normal limit) Ann Rheum Dis September 2011 Vol 70 No 9 1521 01_annrheumdis-2011-200242.indd Sec1:1521 7/27/2011 5:01:54 PM Editorial Ann Rheum Dis: first published as 10.1136/annrheumdis-2011-200242 on 30 July 2011. Downloaded from that patients taking paracetamol (3 g/day) and γ-glutamyltransferase) were seen that either claim—higher effi cacy and/ may have similar degrees of blood loss to in all groups receiving paracetamol. or less toxicity—can be substantiated— those taking ibuprofen (1200 mg/day). In Paracetamol administration accompa- rather, the contrary is true. addition, patients on the high-dose com- nies (causes?) and enhances blood loss. bination appear to have a higher blood Acknowledgment KB is Doerenkamp-Professor, Remarkably, the blood loss increases supported by the Hertie Foundation. loss than those on ibuprofen alone. with time and the dose of paracetamol, Competing interests None. However, there is more to be consid- with or without ibuprofen. ered. The important results are sum- The fi nding that patients on the high- Contributors KB developed the concept of this marised in table 1. editorial and compiled the table. BH wrote parts of the dose combination lost more blood than article and added to the literature. Concerning pain relief, the data clearly those on ibuprofen alone is in agreement show that (1) paracetamol 1000 mg three Provenance and peer review Commissioned; with a previously published retrospec- externally peer reviewed. times a day does not provide satisfactory tive cohort study of older patients who Accepted 7 July 2011 pain relief in the majority of patients; reported an increased risk of gastroin- (2) neither the high- nor the low-dose testinal bleeding with a combination of Ann Rheum Dis 2011;70:1521–1522. doi:10.1136/annrheumdis-2011-200242 combination of ibuprofen with paraceta- a traditional NSAID and paracetamol mol is superior to ibuprofen alone; and compared with either agent alone.6 The (3) ibuprofen alone or combined with authors explained this fi nding by the REFERENCES paracetamol is superior to paracetamol 1. Michael Doherty, Chris Hawkey, Michael Goulder, additional COX-1 inhibition by paraceta- et al. A randomised controlled trial of ibuprofen, alone. mol, which is plausible in view of data paracetamol or a combination tablet of ibuprofen/ The results described here should be showing that paracetamol augments the paracetamol in community-derived people with u s e d a s a n a r g u m e n t t o a v o i d t h e c o m b i n a - inhibitory action of diclofenac on platelet knee pain. Ann Rheum Dis 2011;70:1534–41. 2. Boutaud O, Aronoff DM, Richardson JH, tion of different cyclo-oxygenase (COX) aggregation.7 inhibitors. Interestingly, several studies et al. Determinants of the cellular specifi city of In conclusion, it is very gratifying to acetaminophen as an inhibitor of prostaglandin published during the past few years have see that this study which investigates the H(2) synthases. Proc Natl Acad Sci USA shown that paracetamol is an inhibitor therapeutic value of combining two non- 2002;99:7130–5. 2–4 of peripheral COX enzymes. In one of aspirin COX inhibitors is published at all. 3. Hinz B, Cheremina O, Brune K. Acetaminophen these studies preferential COX-2 inhibi- (paracetamol) is a selective cyclooxygenase-2 We doubt that another study of compara- inhibitor in man. FASEB J 2008;22:383–90. tion was reported in volunteers receiving ble size, cost and quality will be performed 4. Lee YS, Kim H, Brahim JS, et al. Acetaminophen 3 1000 mg paracetamol. However, this in the near future, certainly not supported selectively suppresses peripheral prostaglandin effect was short-lived and did not result in by a drug company. The results indicate E2 release and increases COX-2 gene expression in a clinical model of acute infl ammation. Pain the prolonged 80% inhibition of COX-2 that we should reconsider using a com- that is necessary for pain relief,5 thus 2007;129:279–86.