Topical NSAIDs for OA: Update

Bandolier 110 had an updated look at topical NSAIDs. 2004 has seen an upsurge of publications, with three recent systematic reviews and several new randomised trials. The current state of knowledge has been summed up on the new Bandolier Internet section on topical analgesics, but briefly for topical NSAIDs it comes down to the following:

• Topical NSAIDs can penetrate skin and underlying tissues, with ketoprofen and diclofenac amongst the most likely to be effective based on laboratory experiments.
• Topical NSAIDs are found in high concentration in the knee joint (particularly meniscus and cartilage).
• Topical NSAIDs produce much lower plasma concentrations than oral NSAIDs, typically 5% of oral concentrations or less.
• In strains and sprains over seven days, topical ketoprofen is probably better than other topical NSAIDs, and topical indomethacin is not significantly better than placebo.
• In chronic musculoskeletal pains, topical NSAIDs are better than placebo at two weeks, but confidence is limited by the short duration of 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 [1-3] against placebo and oral NSAID that increase our confidence substantially.

Placebo control, 4 weeks [1]
This trial was properly randomised (independent computer-generated allocation), with concealed allocation, and identical controls to maintain blinding. 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 years. There were sensible exclusion criteria such as use of oral NSAIDs. Assessments were made at baseline and after four weeks, and the trial outcomes accorded with those of the latest advice on trials in arthritis.

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
There were 248 patients in the three groups, and the groups were well matched at baseline, being about 60% women with an average age of about 62 years. Almost 90% completed the four weeks of treatment. The main reasons for withdrawal were lack of effect in vehicle and placebo groups (8/80 and 10/84 respectively), and adverse events with topical diclofenac (5/84) and vehicle
(3/80).

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.

Figure 1: Results of four-week comparison of topical diclofenac with vehicle and placebo

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

Placebo control, 12 weeks [2]
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 treatment and placebo groups were well matched at baseline, being about 68% women with a mean age of 64 years. With placebo and topical diclofenac the main reason for withdrawal was lack of efficacy (42/162; 26% and 28/164; 17% respectively). Adverse event withdrawals were rare (4/162 and 8/164 respectively).

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.

Figure 2: Results of 12-week comparison of topical diclofenac and placebo

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

Oral control, 12 weeks [3]
The basic design features of the third study were similar to the placebocontrolled trials, except that here the design was double-dummy, with oral diclofenac 150 mg 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 years and 58% were women. The two groups were well matched at baseline. Sixty-one percent completed the 12 weeks. Of those withdrawing, adverse events contributed 20% with topical and 25% with oral diclofenac, while lack of efficacy contributed 9% and 3% respectively.

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 eesponder was defined as a patient with a 50% or greater improvement in pain or function that was 20 mm or more on a 100 mm VAS, or 20% or greater improvement in at least two of pain, function, or patient global assessment that was 10 mm or more on a 100 mm VAS.

Figure 3: Results of 12-week comparison of topical and oral diclofenac

Application site reactions occurred almost uniquely in patients using active topical diclofenac. Dry skin (27%), rash (12%), and pruritus (6%) 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 (Table 1). These gastrointestinal adverse events were also more
likely to be severe with oral than topical diclofenac (Table 1). 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% 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.

Table 1: Adverse events over 12 weeks with topical and oral diclofenac

Laboratory changes were also more common for oral compared with topical diclofenac (Table 2). Elevations in liver enzymes and reduced haemoglobin gave NNH values of 7 to 14 (Table 2). Clinically significant elevations of three times the upper limit of normal or more occurred more frequently with oral diclofenac (1%, 5% and 4% with AST, ALT and GGT) than topical diclofenac (0.4%, 1.1%
and 1,.4% respectively).

Table 2: Laboratory adverse events with topical and oral diclofenac

Comment
These are important milestones in our thinking about the evidence for topical NSAIDs in chronic painful conditions like osteoarthritis of the knee. They provide 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. The DMSO vehicle together with the diclofenac led to many local adverse events, probably more
so than seen typically with gels, creams, or sprays.

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. By now we have become used to the gastrointestinal adverse events, but it is still interesting to see the high rate of 10% of reduced haemoglobin with oral diclofenac, as well as the common elevations in liver enzymes and
reduced creatinine clearance.

With doubts about the efficacy of paracetamol in osteoarthritis (Bandolier 128), 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.

References:
1. AA Bookman et al. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized 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 randomized controlled study. Journal of Rheumatology 2004 31: 2002-2012.

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