BMJ  2004;329:1317 (4 December), doi:10.1136/bmj.38273.626655.63 (published 23 November 2004)

Primary care

Non-steroidal anti-inflammatory drugs, including cyclo-oxygenase-2 inhibitors, in osteoarthritic knee pain: meta-analysis of randomised placebo controlled trials

¹ Department of Public Health and Primary Health Care, University of Bergen, 5018 Bergen, Norway, ² Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, 7489 Trondheim, Norway

Abstract

Objective To estimate the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 inhibitors (coxibs), in patients with osteoarthritis of the knee.

Design Systematic review and meta-analysis of randomised placebo controlled trials.

Studies reviewed 23 trials including 10 845 patients, median age of 62.5 years. 7807 patients received adequate doses of NSAIDs and 3038 received placebo. The mean weighted baseline pain score was 64.2 mm on 100 mm visual analogue scale (VAS), and average duration of symptoms was 8.2 years.

Main outcome measure Change in overall intensity of pain.

Results Methodological quality of trials was acceptable, but 13 trials excluded patients before randomisation if they did not respond to NSAIDs. One trial provided long term data for pain that showed no significant effect of NSAIDs compared with placebo at one to four years. The pooled difference for pain on visual analogue scale in all included trials was 10.1 mm (95% confidence interval 7.4 to 12.8) or 15.6% better than placebo after 2-13 weeks. The results were heterogeneous, and the effect size for pain reduction was 0.32 (0.24 to 0.39) in a random effects model. In 10 trials that did not exclude non-responders to NSAID treatment the results were homogeneous, with an effect size for pain reduction of 0.23 (0.15 to 0.31).

Conclusion NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support long term use of NSAIDs for this condition. As serious adverse effects are associated with oral NSAIDs, only limited use can be recommended.

Introduction

Osteoarthritis of the knee is the most common type of osteoarthritis,¹ the prevalence of which is rising in parallel with the increasing age of the population.² The condition is associated with pain and inflammation of the joint capsule, impaired muscular stability, reduced range of motion, and functional disability. Treatment guidelines for knee osteoarthritis recommend pharmacological intervention, initially with paracetamol and subsequently with a non-steroidal anti-inflammatory drug (NSAID).³ In a recent UK survey, 15% of patients with osteoarthritis used paracetamol, whereas 50% reported regular use of NSAIDs. Of the latter, 32% were using traditional NSAIDs and 18% were using cyclo-oxygenase-2 inhibitors (coxibs).⁴ This widespread use is one explanation for the interest in tolerability and efficacy issues regarding these drugs.^{3 5 6} The recent introduction of coxibs seemed to promise a reduction in serious adverse events related to NSAIDs,^{6 7} but this remains controversial.^8-11

Guidelines state that both pharmacological and non-pharmacologial interventions are needed for optimal treatment of knee osteoarthritis.¹² The various potentially effective pharmacological interventions at the clinicians' disposal¹² highlight the need for information regarding treatment efficacy.

We carried out a meta-analysis of published randomised placebo controlled trials to estimate the analgesic efficacy of NSAIDs, including coxibs, in patients with knee osteoarthritis.

Methods

Protocol specification
We identified relevant randomised placebo controlled trials from Medline, Embase, and the Cochrane central register of controlled trials, and evaluated their methodological quality according to predefined criteria.¹³ We calculated their pooled effect as the mean difference in change between NSAID groups and placebo groups in mm on a visual analogue scale and as a unitless effect size. Effect size measures the magnitude of a treatment effect independent of sample size.¹⁴ There is no current operational definition for what constitutes a sufficiently large effect size for a therapeutic intervention to be considered as useful, but a value of 0.2 is usually considered small, 0.5 moderate, and 0.8 large.¹⁵

Inclusion criteria
Trials had to study patients whose knee osteoarthritis had been verified by clinical examination according to the American College of Rheumatology criteria and by x ray. The symptoms had to have been present for more than three months. All trials had to be randomised, blinded, placebo controlled, and of parallel design. Pain intensity had to be scored on the subscale of pain on the osteoarthritis index of Western Ontario and McMaster Universities (WOMAC)¹⁶ or on a 100 mm visual analogue scale for one or the mean score of two or more pain dimensions. Functional disability had to be measured on the WOMAC subscale for function.

The intervention groups had to have received matched placebo drug or adequate NSAID dose (see bmj.com).

Results

Included studies
We evaluated 268 randomised controlled trials and identified 23 trials that satisfied the inclusion criteria.^w1-w23 Of these, 16 were sponsored by the pharmaceutical industry,^{w1 w4-10 w12 w13 w16 w17 w18 w20 w21 w23} while three others did not state sponsorship but gave an address of a pharmaceutical company as the workplace of most of the authors.^{w1 w3 w11} The final sample included 10 845 patients, of whom 7767 received NSAIDs and 3078 received placebo (table).

View this table: [in this window] [in a new window]   Characteristics of trials of NSAIDs for pain relief in patients with knee osteoarthritis

 

Patients and possible selection bias
The included patients had a median age of 62.5 years, and three trials had an upper age limit of 75 years.^{w2 w10 w22} There were more women (67.9%) than men, and the median duration of symptoms was 8.2 years. Most trials excluded individuals with concomitant health disorders by a median of 14 exclusion criteria. All trials had a minimum limit for pain intensity or disease activity for inclusion, and they all used a pretreatment washout period of 3-14 days for previous pharmacotherapy. Thirteen trials used an additional criterion by requiring a predefined minimum flare of symptoms when NSAID treatment was discontinued in the pretreatment wash out period.^{w1 w2 w4 w6 w7 w9 w12 w13 w16 w17 w20 w21 w23} Five of these trials reported the proportion of regular NSAIDs users, ranging from 66% to 100% (median 90.5%).^{w2 w7 w9 w12 w13}

Trial quality
The methodological quality was adequate or good (table). All trials were randomised and double blinded, but adequate randomisation procedure, concealed allocation to groups, and blinding procedure were described satisfactorily in only eight studies.^{w1 w4 w6-9 w21-w23} All trials described dropouts and withdrawals well, but one trial did not perform intention to treat analyses.^w22

Effect size for reduction in functional disability and pain
We excluded from analysis six intervention groups (n = 867) in five trials because patients did not receive an adequate NSAID dose.^{w1 w2 w7 w8 w23} As most trials with multiple time points showed rather stable results from 2-13 weeks, we pooled data. Eleven trials with 7433 patients provided separate scores for reduction in functional disability,^{w1 w2 w4 w6 w8 w9 w11 w12 w18 w21 w23} and their combined effect size was 0.29 (95% confidence interval 0.18 to 0.40) in a random effects model. One trial reported long term effects on pain but found no significant difference between tiaprofenic acid and placebo at one, two, three, and four years after start of treatment.w15 For short term effects (2-13 weeks) the pooled effect size of all included trials was 10.1 mm on visual analogue scale (7.4 to 12.8) or 15.6% better than placebo, and the effect size was 0.32 (0.24 to 0.39) in a random effects model (figure).

View larger version (51K): [in this window] [in a new window]   Effect size (pain) for all trials on NSAID use in knee osteoarthritis

 

For the subgroup of 10 trials (n = 4565) that did not require patients to have a minimum flare of symptoms after treatment with NSAIDs was stopped before the trial, trial results were homogeneous both for function and pain.^{w3 w5 w8 w10 w11 w14 w15 w18 w19 w23} For pain reduction, we used a fixed effect model to calculate a pooled effect size of 0.23 (0.16 to 0.31) or 5.9 mm on visual analogue scale (3.8 to 7.9).

Discussion

NSAIDs can reduce short term pain in osteoarthritis of the knee slightly better than placebo, but the current analysis does not support the long term use of these drugs. Several NSAIDs, of which rofecoxib is the most recent example, have been withdrawn because of adverse effects.¹⁷ We initially included rofecoxib in our investigation, but did not include it in the final subgroup analysis. As use of oral NSAIDs may incur serious adverse effects, they can only be recommended for limited use in osteoarthritis of the knee. Although NSAIDs have been used for nearly three decades, most trials included in this review were from the past decade. This is mainly due to the inclusion in older studies of patients with multiple joint osteoarthritis and the lack of separate data for osteoarthritis of the knee.

Strengths and weaknesses of analysis
The strengths of the present study include the acceptable methodological quality of the separate trials on which the analysis is based, as well as the considerable number of trials and patients included. We also translated categorical WOMAC data and P values, t test results, standard error of mean values, and before and after values to mean differences in change between groups to avoid bias. For instance, we excluded all groups with less than adequate NSAID doses from the efficacy calculations.

One possible limitation of our study is that we included nine trials in which outcomes were recorded with fewer than the five pain dimensions covered by the WOMAC pain subscale.^{w3 w5 w9-w11 w13-w15 w22} We thought that this, as well as the different time points in the individual studies (2, 3, 4, 6, 12, and 13 weeks) for registering outcome measures, could explain the heterogeneity that was found in the trial results, but heterogeneity persisted after we performed relevant subgroup analyses. Heterogeneity was not apparent, however, when we performed a subgroup analysis of trials that did not exclude non-responders to NSAIDs. The validity of requiring a certain increase in symptoms after discontinuation of NSAIDs before inclusion in an NSAID trial seems dubious. Indeed, our results show that this procedure significantly inflates effect sizes in favour of the trial drug. In a clinical setting, it may nevertheless be useful to have information about the magnitude of effect to be expected in patients who are known responders to NSAIDs. In comparisons of various treatments, however, the selective exclusion of people who do not respond to NSAIDs among patients given this type of therapy will introduce bias in favour of NSAID efficacy and may hence be inappropriate.

Another possible source of selection bias in patients is that the average age of the participants was low (62.5 years) for people with osteoarthritis of the knee, reflecting the exclusion of patients above 75 years of age in some trials.^{w2 w10 w22} Data on efficacy and tolerability as a function of age were reported in only one comparatively small trial.^w22

Benefits of NSAIDs
NSAIDs significantly reduce pain in acute conditions.^{18 19} In chronic conditions, however, patients have reported that pain has to be reduced by about 30% to be considered meaningful.²⁰ For knee osteoarthritis in particular, an effect size of 0.4 or 17-22% change from baseline has been calculated from empirical data and suggested as the minimal clinically important change.²¹ Other authors have found that the least perceptible change in pain from osteoarthritis of the knee is 9.7 mm measured by the WOMAC subscale for pain.²² In accordance with this, the effect size of 0.32 or 10.1 mm on visual analogue scale for pain reduction and the effect size of 0.29 for disability reduction may be considered too small to be clinically significant. This may in turn explain non-compliance with prescribed drug therapy in 29% of patients and the use of non-conventional drug therapy by one in four patients with osteoarthritis.⁴

The widespread and long term use of NSAIDs among elderly people with osteoarthritis is associated with considerable side effects. NSAIDs cause serious gastrointestinal complications such as bleeding or perforation in one in 50-100 patient years, and this risk increases with age, concurrent use of other medications, and probably also duration of treatment.⁵ Substantial epidemiological and experimental data show that NSAIDs may increase blood pressure,²³ and NSAID use has been linked to the development and acceleration of congestive heart failure.²⁴ Elderly patients also have an increased risk for development of associated renal failure.²⁵ In addition, NSAID users are at risk of interactions, including pharmacodynamic interactions with antihypertensive drugs²³ and pharmacokinetic interactions with compounds eliminated by renal excretion, such as lithium.²⁶ These important caveats were not considered in the short term studies of NSAIDs that we included. Thus, it may be reasonable to assume that the benefits of NSAIDs may be less and the harmful effects more common in an unselected population of patients with knee osteoarthritis compared with the patients in these studies.

What is already known on this topic Current guidelines recommend the use of oral non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of osteoarthritis of the knee Oral NSAIDs are used regularly by half of all patients with painful osteoarthritis What this study adds The advantage of oral NSAIDs over placebo for short term pain relief is small and probably clinically insignificant Evidence of long term effects from oral NSAIDs is still lacking

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This is the abridged version of an article that was posted on bmj.com on 23 November 2004: http://bmj.com/cgi/doi/10.1136/bmj.38273.626655.63

The references for the studies included in the meta-analysis (w1-w23) can be found on bmj.com

Contributors: See bmj.com

Funding: None.

Competing interests: None declared.

Ethical approval: Not required.

References

1. Andrianakos A, Trontzas P, Christoyannis F, Dantis P, Voudouris C, Georgountzos A, et al. Prevalence of rheumatic diseases in Greece: a cross-sectional population based epidemiological study. The ESORDIG study. J Rheumatol 2003;30: 1589-601.[ISI][Medline]
2. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, et al. Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med 2000;133: 635-46.[Abstract/Free Full Text]
3. Wegman A, van der Windt D, van Tulder M, Stalman W, de Vries T. Nonsteroidal anti-inflammatory drugs or acetaminophen for osteoarthritis of the hip or knee? A systematic review of evidence and guidelines. J Rheumatol 2004;31: 344-54.[ISI][Medline]
4. OA Nation survey. http://oanation.arthritiscare.org.uk/fileadmin/oanation/downloads/OA_Nation_report.pdf (accessed 10 Sept 2004).
5. Tramer MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000;85: 169-82.[CrossRef][ISI][Medline]
6. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 2002;325: 619.[Abstract/Free Full Text]
7. Zabinski RA, Burke TA, Johnson J, Lavoie F, Fitzsimon C, Tretiak R, et al. An economic model for determining the costs and consequences of using various treatment alternatives for the management of arthritis in Canada. Pharmacoeconomics 2001;19(suppl 1): 49-58.
8. Juni P, Rutjes AW, Dieppe PA. Are selective COX 2 inhibitors superior to traditional non-steroidal anti-inflammatory drugs? BMJ 2002;324: 1287-8.[Free Full Text]
9. Cerezo J, Hristov RL, Sansuan AJ, Rodriguez JJV. Outcome trials of COX-2 selective inhibitors: global safety evaluation does not promise benefits. Eur J Clin Pharmacol 2003;59: 169-75.[ISI][Medline]
10. Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ 2002;167: 1131-7.[Abstract/Free Full Text]
11. Sturkenboom MC, Romano F, Simon G, Correa-Leite ML, Villa M, Nicolosi A, et al. The iatrogenic costs of NSAID therapy: a population study. Arthritis Rheum 2002;47: 132-40.[CrossRef][ISI][Medline]
12. 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.[Abstract/Free Full Text]
13. Jadad AR, McQuay HJ. Meta-analyses to evaluate analgesic interventions: a systematic qualitative review of their methodology. J Clin Epidemiol 1996;49: 235-43.[CrossRef][ISI][Medline]
14. Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989;27:suppl: S178-89.[ISI][Medline]
15. Cohen J. Statistical power analysis for behavioural sciences. New York: Academic Press, 1977.
16. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of hip or knee. J Rheumatol 1988;15: 1833-40.[ISI][Medline]
17. Dieppe PA, Ebrahim S, Martin RM, Juni P. Lessons from the withdrawal of rofecoxib. BMJ 2004;329: 867-8.[Free Full Text]
18. Oxford league table of analgesics in acute pain. www.jr2.ox.ac.uk/bandolier/booth/painpag/Acutrev/Analgesics/Leagtab.html (accessed 10 Sept 2004).
19. Barden J, Edwards JE, McQuay HJ, Moore RA. Single dose oral celecoxib for postoperative pain. Cochrane Database Syst Rev 2003;(2): CD004233.
20. Rowbotham MC. What is a `clinically meaningful' reduction in pain? Pain 2001;94: 131-2.[CrossRef][ISI][Medline]
21. Angst F, Aeschlimann A, Michel BA, Stucki G. Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. J Rheumatol 2002;29: 131-8.[ISI][Medline]
22. Ehrich EW, Davies GM, Watson DJ, Bolognese JA, Seidenberg BC, Bellamy N. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol 2000;27: 2635-41.[ISI][Medline]
23. Johnson AG. NSAIDs and increased blood pressure. What is the clinical significance? Drug Saf 1997;17: 277-89.[ISI][Medline]
24. Bleumink GS, Feenstra J, Sturkenboom MC, Stricker BH. Nonsteroidal anti-inflammatory drugs and heart failure. Drugs 2003;63: 525-34.[CrossRef][ISI][Medline]
25. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999;106(5B): 13-24S.
26. Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry 2003;64: 1328-34.[ISI][Medline]

(Accepted 14 September 2004)

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