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Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomised controlled trials
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     1 Academic Rheumatology, University of Nottingham, City Hospital, Nottingham NG5 1PB, 2 Rheumatology Unit, City Hospital

    Correspondence to: W Zhang weiya.zhang@nottingham.ac.uk

    Abstract

    Osteoarthritis is the most common form of arthritis and the major cause of disability in elderly people.1 2 It represents a major disease burden for patients, health services, and society.3 Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to relieve pain in musculoskeletal tissues, but their use comes at the cost of toxicity, with a 2-4% annual incidence of serious gastrointestinal ulcer and complications—four times higher than in non-users.4-9 NSAIDs have been applied topically for decades. This route possibly reduces gastrointestinal adverse reactions by maximising local delivery and minimising systemic toxicity.10 Some experimental evidence supports this, but at large joints such as the knee, bloodborne delivery may be the predominant mechanism for deep tissues.11 Pain associated with osteoarthritis may be periarticular in origin rather than intracapsular, and topical application may act through effects on peripheral and central sensitisation.12 Irrespective of the mechanism, topical NSAIDs are popular with health professionals and with patients as over the counter medicines. Several randomised controlled trials of short duration (less than four weeks) have been undertaken in both periarticular lesions and osteoarthritis.13-26 A systematic review in 1998 confirmed that topical NSAIDs were superior to placebo over two weeks in the treatment of chronic pain, including pain due to osteoarthritis and tendinitis.27 We did a meta-analysis to determine the benefit of NSAIDs in treating osteoarthritis beyond two weeks.

    Methods

    We identified 133 citations, of which 77 remained after omission of duplicate articles. Overall, there were 18 potentially relevant randomised controlled trials (16 in English and two in German). Five were further excluded because either the participants did not exclusively have osteoarthritis or the comparison was between topical NSAIDs and oral NSAIDs compared with oral NSAIDs. Our inclusion criteria were met by 13 trials, representing 1983 patients (fig 1 and table 1). All trials, except for one with unknown sponsorship, were sponsored or partially sponsored with study drugs and placebo by pharmaceutical companies.18 All were stated as randomised controlled trials, but there were no details on method of randomisation. The withdrawal rate was 1% to 23%. A funnel plot showed noticeable asymmetry in the 11 placebo controlled trials (fig 2).

    Fig 1 Selection of randomised controlled trials

    Table 1 Characteristics of randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs (NSAIDs) with placebo or oral NSAIDs in patients with osteoarthritis

    Fig 2 Funnel plot of randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs with placebo (asymmetry P=0.04)

    Efficacy

    Reduction in pain

    Topical NSAIDs were superior to placebo in the first two weeks of treatment but not the following two weeks (fig 3 and table 2). Topical NSAIDs were less effective than oral NSAIDs numerically at any week and statistically in the first week (see table 2).

    Fig 3 Effect sizes (95% confidence intervals) in pain relief between topical non-steroidal anti-inflammatory drugs and placebo

    Table 2 Pooled effect sizes for pain relief and improvements in function and stiffness in randomised controlled trials comparing topical non-steroidal anti-inflammatory drugs (NSAIDs) with placebo or oral NSAIDs

    Improvements in function and stiffness

    The effect size for improvement in function also showed superiority of topical NSAIDs over placebo in the first two weeks but not in weeks 3 and 4 (see table 2). A statistically significant effect size for improvement in stiffness was seen at one week but not at two weeks.

    Clinical response rate

    The clinical response rate ratio was statistically significant in the first but not fourth week (table 3). No difference was found between topical NSAIDs and oral NSAIDs.

    Table 3 Clinical response rate ratio and numbers needed to treat with 95% confidence intervals

    Adverse events

    Topical NSAIDs had no more side effects than placebo. Compared with oral NSAIDs, fewer patients taking topical NSAIDs had any adverse events, withdrawals due to side effects, and gastrointestinal side effects, but significantly more patients had local side effects such as rash, itch, and burning(table 4).

    Table 4 Pooled rate ratio (95% confidence intervals) of side effects

    Sensitivity analysis

    Sensitivity analyses showed that although baseline pain score influenced the statistical inference only, the type of topical NSAID produced significantly different effect sizes. Other factors did not affect the results (table 5).

    Table 5 Sensitivity analysis of effect size (95% confidence interval) for reduction in pain between topical non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, according to quality of studies, site of osteoarthritis, and pain scores at baseline

    Discussion

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