Thursday, October 11, 2012

Topical NSAIDs for Chronic Musculoskeletal Pain?

Topical NSAIDsAccording to a recently reported Cochrane systematic review and meta-analysis, topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) provide relief of chronic osteoarthritis pain in the knee or hand that is comparable to oral NSAID formulations and significantly better than placebo. However, there was no evidence for topical NSAIDs benefitting any other chronic pain conditions and the availability of high quality research data overall was limited; adequate data could be found only for topical diclofenac.

For this study, Sheena Derry, PhD, from the University of Oxford in the United Kingdom and colleagues searched the literature on the use of topical NSAIDs in chronic musculoskeletal pain [Derry et al. 2012]. They selected only a) randomized, double blind trials with placebo or active comparators, b) which included at least 10 participants in each treatment arm, c) were of high methodological quality, and d) had a duration of at least 2 weeks. All NSAID agents in any topical formulation (eg, solutions, cream, gel, patch) were eligible, with the exception of salicylates (eg, aspirin), which the researchers note are “no longer classified as topical NSAIDs.”

The search revealed information on 7,688 participants in 34 eligible studies, 23 of which compared a topical NSAID with placebo. The following NSAIDs were examined in at least one trial: diclofenac, ibuprofen, piroxicam, felbinac, nimesulide, and ketoprofen — some are not marketed in the United States.

Topical NSAIDs were overall significantly more effective than placebo for reducing pain due to chronic musculoskeletal conditions; however, the best data were for topical diclofenac in osteoarthritis of the hand and knee, where the number-needed-to-treat, or NNT, for at least 50% pain relief or its equivalent during 8-to-12 weeks compared with placebo was 6.4 for the solution and 11 for the gel formulation. There were too few data of good quality to calculate NNTs for any other individual topical NSAIDs compared with placebo.

Direct comparisons of any topical NSAIDs with an oral NSAID formulation did not show any differences in efficacy. There was an increase in local adverse effects (mostly mild skin reactions) with topical NSAIDs compared with placebo or oral NSAIDs, but no increase in serious adverse events. As might be expected, gastrointestinal adverse events with topical NSAIDs did not differ from placebo, and were much less frequent than with oral NSAIDs.

The researchers conclude that topical NSAIDs generally appear to provide good levels of pain relief, but the base of good quality evidence is very limited. Topical diclofenac appears equivalent to oral NSAIDs in knee and hand osteoarthritis, but there is no evidence for other chronic painful conditions. The incidence of local adverse effects is increased with topical NSAIDs, but gastrointestinal adverse events are reduced compared with oral NSAIDs.

CLINICAL COMMENTARY: For treating chronic pain conditions there is increasing interest in alternatives to opioids and other drugs that have misuse and abuse potential or may incur troublesome adverse effects when used long-term. Oral NSAIDs are sometimes viewed as a reasonable option but they carry significant risks of gastrointestinal, renal, and cardiovascular adverse effects, particularly in certain populations such as the elderly. Therefore, topical analgesic formulations containing opioids [discussed in a previous UPDATE here] and NSAIDs as examined in this present study may offer significant advantages.

An obvious advantage of topical formulations is that the drug stays close to the site of application and systemic levels in the blood and more remote tissues remain relatively low. Of course, a disadvantage is that topical agents only may be most effective when pain is localized and nearer to the body surface.

According to background information provided by Derry et al. [2012], the use of topical NSAIDs in pain management practice was once controversial. Yet, in some parts of the world they have been available for many years, widely accessible without prescription, prominently advertised, extensively used, and the limited evidence for their use is considered adequate. In other parts of the world they have only become licensed in recent years. In the USA, the Food and Drug Administration first licensed topical nonsteroidal products in 2007 and, in England, the National Institute for Health and Clinical Excellence (NICE) first recommended topical therapies in its guidelines for osteoarthritis in 2008.

The use of topical NSAIDs in acute and chronic musculoskeletal pain has been supported by previous systematic reviews. However, this present review and meta-analysis by Derry and colleagues, focusing exclusively on the highest-quality research evidence, provides limited support for the benefits of topical NSAIDs. As so frequently occurs in the pain management field, this study exemplifies the lack of adequate research rather than a firm foundation on which to base clinical decision making. And, in this context, diclofenac is not necessarily the only topical NSAID of value — it is the only one with sufficient research evidence to reach firm conclusions.

The longest trials examined by Derry et al. were 8-to-10 weeks, which is likely insufficient when considering the treatment of chronic conditions. In these longer trials, the NNTs for topical diclofenac solution and gel ranged from 6.4 to 11, respectively; that is, for every 6 to 11 patients treated with the respective formulation compared with placebo 1 additional person would achieve treatment success. However, according to some experts, such NNTs represent only relatively small clinical effect sizes, comparable to a Cohen’s d of 0.30 or less [see Citrome 2008; also see Effect Size discussion here].

Of further concern, data in the Derry et al. report show that NNTs for topical diclofenac overall were all statistically significant but increased in size as trial length increased: 2-3 weeks (NNT=5.0); 4-6 weeks (NNT=5.2); 8-12 weeks (NNT=10). It is uncertain whether this represents a waning of efficacy over time or a regression to the mean due to the natural course of musculoskeletal pain; either way, longer controlled trials are needed as confirmation.

Additionally, a major concern with topical NSAIDs appears to be localized skin reactions at the point of application. The calculated number-needed-to-harm, or NNH, for this adverse effect was 16 (ie, for every 16 persons treated 1 additional patient would experience the side effect). Another way of looking at this is the benefit-to-harm ratio calculated as NNH/NNT [discussed in UPDATE here]. For topical diclofenac formulations this ratio would be 2.5 to 1.5, meaning that for roughly every 2 to 3 patients who benefit from the therapy at least 1 additional patient would experience a skin reaction. Some patients may consider this merely a minor nuisance, whereas for others it might be a therapy-limiting condition.

Clearly, the use of topical NSIAD analgesics is another area of pain management in need of more and better research. While there may be considerable potential of this therapy for select pain conditions of some duration, the present base of good-quality evidence for judging clinical effectiveness and safety in everyday practice seems inadequate.

> Citrome L. Compelling or irrelevant? Using number needed to treat can help decide. Acta Psychiatr Scand. 2008;117(6):412-419 [
article here].
> Derry S, Moore RA, Rabbie R. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews. 2012, Issue 9 [
abstract here].

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