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Controlling diabetes by diet alone: closing the gaps in GP care

Following their recent analysis of aspirin in OA, Bandolier editors Dr Andrew Moore and Professor Henry McQuay move on to address the controversial role of NSAIDs

Topical NSAIDs are a hot topic at the moment. Reasons include concerns over prescribing coxibs, lack of gastric or lower bowel protection with NSAID use and prescribing advisers making use of topical NSAIDs as a marker of bad prescribing, despite them being safe and effective.

There have been a number of systematic reviews, slightly conflicting, but limited by short duration studies.

Now we have the studies in OA that were lacking before and there are calls for the prescribing guidelines to be rewritten.

In 2004 we have seen an upsurge of publications, with three recent systematic reviews and several new randomised trials.

The main unknown is in chronic conditions, where larger, longer trials have been needed to give confidence in longer-term efficacy of topical NSAIDs.

In particular, direct comparison of the same NSAID in topical and oral formats has been missing. We now have three large randomised trials (outlined in the box below) against placebo and oral NSAID that increase our confidence substantially.

Application site reactions occurred almost uniquely in patients using active topical diclofenac. Dry skin (27 per cent), rash (12 per cent), and pruritus (6 per cent) were most common.

Gastrointestinal adverse events occurred in both groups, but with oral diclofenac they occurred significantly more often for dyspepsia, abdominal pain and diarrhoea. These gastrointestinal adverse events were also more likely to be severe with oral than topical diclofenac.

Overall, the number needed to harm (NNH) for severe dyspepsia, abdominal pain or diarrhoea for oral compared with topical diclofenac for 12 weeks was 11 (95 per cent CI 8 to 19).

Asthma, dyspnoea and dizziness occurred infrequently, but more commonly with oral diclofenac, while pharyngitis was infrequent and more common with topical diclofenac.

Important milestones

These three studies are important milestones in providing better evidence that topical NSAID is better than placebo, and augment shorter studies showing that topical and oral NSAIDs have equivalent efficacy.

There is substantially more evidence that topical NSAIDs do less harm than oral NSAIDs. The studies were performed impeccably and were large. They were properly randomised and blinded, and used outcomes recommended by the latest trial guidelines in osteoarthritis. They paid proper attention to adverse events. If there is a problem, it may be a question of formulation.

And it is the adverse effects that are so important. Concentrating on them gives us a better insight into what happens with oral diclofenac, a frequently used NSAID.

With doubts about the efficacy of paracetamol in osteoarthritis and concerns about cardiovascular effects of oral coxibs that remain to be fully elucidated, guidelines on treatment will have to be revisited. The growing evidence of efficacy and safety with topical NSAIDs should become part of that process.

Three large randomised trials comparing topical NSAID against placebo or oral control

1. Placebo control, four weeks1

This trial was properly randomised (independent computer-generated allocation), with concealed allocation, and identical controls to maintain blinding. The 248 patients had primary osteoarthritis in at least one knee verified radiologically within the previous six months, at least moderate pain, and aged 18 to 80.

Three topical treatments were tested: topical diclofenac in dimethylsulphoxide (DMSO), DMSO without diclofenac (vehicle), and a placebo without either diclofenac and with a low concentration of DMSO. A monitored amount of solution was applied to the knee being treated in a standard way, without rubbing, four times daily.

Results

After four weeks WOMAC scores for pain, physical functioning, stiffness and pain on walking all fell significantly more with topical diclofenac than vehicle or placebo (figure 1). Patient global assessment was significantly better with topical diclofenac than vehicle or placebo.

Dry skin (36 per cent) and rash (11 per cent) were more frequent with topical diclofenac than vehicle or placebo. There was no difference in gastrointestinal or other adverse events.

2. Placebo control, 12 weeks2

The basic design features of this trial were as for the four-week study, with efficacy measured after 12 weeks. A monitored amount of solution containing diclofenac or vehicle placebo control identical but without diclofenac was applied to the knee being treated in a standard way without rubbing, four times daily.

Results

Randomisation involved 326 patients and after 12 weeks WOMAC scores for pain, physical functioning, stiffness and pain on walking all fell significantly more with topical diclofenac than vehicle placebo control (figure 2). Patient global assessment was significantly better with topical diclofenac than vehicle placebo control.

Local adverse reactions of dry skin and rash occurred more frequently with topical diclofenac than with vehicle control (37 per cent vs 25 per cent and 11 per cent vs 5 per cent respectively). Gastrointestinal adverse events were rare and occurred no more frequently with topical diclofenac than with placebo.

3. Oral control, 12 weeks3

The basic design features of the third study were similar to the placebo-controlled trials, except that here the design was double-dummy, with oral diclofenac 150mg daily or oral placebo and

topical diclofenac or topical placebo arranged so that topical and oral diclofenac were directly compared.

Topical or oral diclofenac were used three times daily for 12 weeks, and only one knee, that with the highest pain score at baseline, was used for efficacy measurement.

Results

The 622 patients randomised had an average age of 64 and 58 per cent were women; 61 per cent completed the 12 weeks. Of those withdrawing, adverse events contributed 20 per cent with topical and 25 per cent with oral diclofenac.

WOMAC scores for pain, physical functioning, stiffness, pain on walking, patient global assessment, and number of responders were similar with topical and oral diclofenac

(figure 3) using an intention to treat analysis, or a per protocol analysis. A responder was defined as a patient with a 50 per cent or greater improvement in pain or function that was 20mm or more on a 100mm VAS, or 20 per cent or greater improvement in at least two of pain, function, or patient global assessment that was 10mm or more on a 100mm VAS.

References

1 AA Bookman et al. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomised controlled study. Canadian Medical Association Journal 2004 171: 333-338

2 SH Roth, JZ Shainhouse. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee. Archives of Internal Medicine 2004 164: 2017-2023

3 PS Tugwell et al. Equivalence study of a topical diclofenac solution (PENNSAID) compared with oral diclofenac

in the symptomatic treatment of osteoarthritis of the knee: a randomised controlled study. Journal of Rheumatology 2004 31: 2002-2012

Useful website

www.jr2.ox.ac.uk/bandolier/Extraforbando/Topextra3.pdf

Andrew Moore

is honorary professor

of health sciences at University College Swansea and editor-in-chief of Bandolier

Henry McQuay

is professor of pain

relief at the Oxford Pain Relief Unit and co-editor of Bandolier

Bandolier(www.ebandolier.com) is an independent monthly journal on evidence-based health care. Subscription costs £36 for 12 issues and subscribers receive the print journal three months before articles are available on the website. A subscription form is available on the website or from: maura.moore@pru.ox.ac.uk

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