Topical non-steroidal anti-inflammatory drugs in osteoarthritis

Best used for short periods during flares in the disease

MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD

Cyrus Cooper

professor of rheumatology (cc@mrc.soton.ac.uk)

Kelsey M Jordan

clinical research fellow

Worldwide, osteoarthritis is the most common disease of synovial joints and also a major cause of locomotor pain and disability.⁽¹⁾ It is characterised pathologically by focal loss of articular cartilage as well as marginal and central formation of new bone. Sites typically affected include the interphalangeal joints of the hand, knee, and hip. Worldwide, symptomatic osteoarthritis, particularly of the knee and hip, has been estimated by the World Health Organization to be the fourth most important cause of disability among women and the eighth most important among men.⁽²⁾

Osteoarthritis is a disorder whose time has come. Epidemiological and clinical research has suggested a range of preventive and therapeutic strategies over the past three decades. Preventive approaches are focused on modifying risk factors in the general population. These risk factors are broadly characterised as those that influence a generalised predisposition to the condition (obesity, genetic factors, reproductive variables in women, cigarette smoking, and the associations with diabetes, hypertension, and hyperuricaemia) and those that result in abnormal biomechanical loading at specific sites (joint injury, joint shape, occupational and recreational physical activity, and reduced muscle strength and proprioception).⁽³⁾ Among these, the influences of obesity, knee injury, and occupational physical activity have been observed most consistently. Altering the distribution of adiposity in the population, such that people with a body mass index above 25 kg/m² move into the normal part of the distribution, could prevent 40% of osteoarthritis of the knee and 26% of osteoarthritis of the hip.⁽⁴⁾

Even after adjusting for the effects of obesity, the elimination of excessive occupational loading of the knee and hip, and reduction in the frequency of knee injuries in the workplace, might be associated with a further 30% reduction in the burden of osteoarthritis of the knee.⁽⁵⁾ Although randomised controlled trials showing the effectiveness of such strategies require completion, studies are under way and hold promise as a means of reducing the burden of osteoarthritis of the lower limb in future generations.

Much energy has also been spent on developing non-surgical interventions to alleviate the pain and disability in patients with osteoarthritis, once the disease has become established. Non-pharmacological therapeutic options include education programmes and social support; a host of physical treatments (aerobic exercises, muscle strengthening exercises, and patella strapping); the provision of aids and appliances through occupational therapists; and advice on weight loss.⁽⁶⁾ Pharmacological modalities that have a place in the management of patients with osteoarthritis include simple analgesics such as paracetamol; non-steroidal anti-inflammatory drugs and cyclo-oxygenase-2 inhibitors; and intra-articular therapy with glucocorticoids and derivatives of hyaluronic acid. Research has also begun to address treatments that modify joint structure and thereby stabilise or reverse morphological changes. Proposals for such putative “chondro-protective” agents include glucosamine and chondroitin sulfate, other glycosaminoglycan derivatives found in mammalian articular cartilage, diacerhein, and tetracycline. The ability of some of these agents, in particular glucosamine sulfate, to modify the course of osteoarthritis has been investigated in a limited number of clinical trials. Evidence of effect is generally based on assessment of the rate of radiographic progression of osteoarthritis, a notoriously difficult outcome to assess. As alternative imaging techniques (for example, magnetic resonance imaging) become more widely available and novel intermediary outcome measures (such as biochemical measures of cartilage and synovial turnover) are developed, they are increasingly likely to be used in trials of such agents. The problem remains, however, that the heterogeneity of osteoarthritis; the chronicity of the condition; the discordance between anatomical, functional, and symptomatic manifestations; and these unresolved difficulties of intermediary assessment make the conduct of these trials difficult.

Guidelines for the management of osteoarthritis have been assembled in the United Kingdom,⁽⁷⁾ Europe,⁽²⁾ and the United States.⁽⁸⁾ These generally agree on the joint approach to the disorder between primary and secondary care; and the importance of basing symptomatic management around simple analgesic agents as compared with non-steroidal anti-inflammatory drugs or COX-2 inhibitors. Although use of COX-2 inhibitors markedly reduces the risk of serious gastrointestinal events among patients with osteoarthritis, non-steroidal anti-inflammatory drugs remain in widespread use for the management of pain arising in musculoskeletal tissues, and with both classes of agent, adherence remains a problem. The topical application of non-steroidal anti-inflammatory drugs provides an attractive means of reducing adverse events by maximising local delivery while minimising systemic toxicity.⁽⁹⁾ Although the way in which topical non-steroidal anti-inflammatory drugs induce pain relief remains uncertain, it is likely to rest on both bloodborne delivery and local alleviation of symptoms arising from periarticular, rather than intracapsular, structures. The place of topical non-steroidal anti-inflammatory drugs within guidelines for the management of osteoarthritis has not been well defined. A systematic review of seven years ago included the results of 13 placebo controlled trials in which patients were being treated for a variety of conditions, including osteoarthritis.⁽⁹⁾ Topical non-steroidal anti-inflammatory drugs were found to be superior to placebo in reducing pain, such that 65% of treated patients showed a halving of their pain score compared with only 30% treated with placebo. In addition, a systematic review of topical capsaicin (an agent with depletes both afferent and epidermal nerve fibres of the neuropeptide, substance P) in the treatment of chronic pain reported the agent to have moderate efficacy at best, with a relatively high frequency (30%) of local cutaneous reactions.⁽¹⁰⁾

Given the widespread use of topical NSAID treatment, a review of the situation is timely. In this issue, Lin et al report a further meta-analysis exploring the use of these agents in the treatment of osteoarthritis.⁽¹¹⁾ This well conducted study found that topical non-steroidal anti-inflammatory drugs were superior to placebo in reducing pain and improving function over a fortnight, but that these effects were lost after four weeks had elapsed. The authors conclude that little evidence exists to support the long term use of topical non-steroidal anti-inflammatory drugs in osteoarthritis and suggest that current recommendations be revised. Most of the randomised controlled trials included in the review were of short duration (two weeks or less) and not a single study extended beyond one month. Marked heterogeneity became obvious in the results of the meta-analysis, with the strong likelihood that publication bias would, if anything, have acted to over estimate the benefits of topical non-steroidal anti-inflammatory drugs. Finally, the study found that the type of non-steroidal anti-inflammatory drug influenced the effect size observed (studies used salicylic acid, eltenac, diclofenac, and ibuprofen).

Clearly, these data will have an impact on the enthusiasm with which practitioners and patients resort to the use of topical non-steroidal anti-inflammatory drug therapy in osteoarthritis. On the one hand, the clear evidence of effectiveness in pain relief over a two week period supports their inclusion as part of any multidisciplinary armamentarium. However, the waning of effectiveness over four weeks implies that topical therapy is best used for short periods during flares in the disease. The comparability between topical and systemic use of non-steroidal anti-inflammatory drugs remains a difficult issue. The current review could only address this with limited statistical power, and further information will be gleaned from a trial comparing topical and oral ibuprofen supported by the NHS Health Technology Assessment.⁽¹¹⁾ Without results of comparative trials of different topical agents, one cannot convincingly argue that one topical non-steroidal anti-inflammatory drug is definitely more effective than another. Finally, and perhaps most importantly, the review shows the dearth of information available on a widely used treatment for one of our commonest causes of musculoskeletal disability. Carefully designed randomised controlled trials of interventions in osteoarthritis, which use appropriate end points and are conducted over sufficiently long duration to assess protracted effectiveness, are required so that we can delineate appropriate therapeutic strategies for a disorder whose frequency is bound to increase with the demographic changes in our population.

Competing interests: None declared.

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