Sunday, August 1, 2010

Safety, Efficacy of TOPICAL NSAIDs Examined

Superficially applied (topical) nonsteroidal anti-inflammatory drugs (NSAIDs) are often used for musculoskeletal strains, sprains, and pains. Their main appeal is presumed safety in providing pain relief without NSAID-associated systemic adverse effects; however, this needs careful consideration, especially in older persons.

Thomas Massey, from the University of Oxford, United Kingdom, and colleagues conducted a Cochrane Systematic Review to evaluate the evidence from randomized, double-blind, controlled trials of the efficacy and safety of topically applied NSAIDs for relief of acute pain [Massey et al. 2010]. Inclusion criteria were controlled trials in adults with strains, sprains, or sports or overuse-type injuries, with 10 or more participants in each treatment group, and treatment application at least once daily. They identified 47 qualifying studies, enrolling a total of 3,455 participants, and comparing topical NSAID gel, spray, or cream versus a similar placebo.

The evidence from this large number of studies indicated that about 60% to 70% of patients will have successful pain control during 7 days with a topical NSAID, compared with 40% using placebo; the high placebo response may be because acute conditions like sprained ankles tend to get better on their own. From another perspective, one of every 4 to 5 persons appropriately treated with a topical NSAID would be expected to experience at least a 50% reduction in pain during 1 to 2 weeks (NNT=4.5; 95% CI: 3.9-5.3). There appeared to be little difference in analgesic efficacy between topical diclofenac, ibuprofen, ketoprofen, and piroxicam; however, indomethacin was less effective than the others and benzydamine was no better than placebo. Topical aspirin formulations were not considered in the review.

Local adverse events at the site of application were not significantly worse with topical NSAIDs than with topical placebo; they were mild and transient, and occurred in about 6% of participants. Systemic adverse events (eg, stomach upset or nausea) and study dropouts due to adverse effects were uncommon, occurring no more frequently with topical NSAID than placebo, and no serious adverse events were reported in any of the trials. However, there were insufficient data to directly compare individual topical NSAIDs with the same NSAIDs in oral formulation.

In a second recently reported systematic review, Makris and colleagues at Yale University School of Medicine [2010], examined adverse effects associated with topical NSAID use in older adults with osteoarthritis (OA). Their broad literature search, which included other types of reports in addition to controlled trials, yielded 19 eligible articles for inclusion. Overall, older patients using topical NSAIDs reported up to 39% application site adverse effects and up to roughly 18% systemic adverse events. Five cases of warfarin potentiation with topical agents were reported, with 1 resulting in gastrointestinal bleeding. In formal clinical trials, dropout rates due to adverse effects ranged from 0 to 21% among elderly patients using topical agents compared with 0 to 25% in those taking oral NSAIDs and 0 to 16% in the placebo groups.

Makris et al. conclude that, although topical NSAIDs appear to be safer than oral NSAIDs (eg, fewer severe gastrointestinal adverse events), a substantial proportion of older adults report systemic problems with topical agents. For example, study withdrawal rates due to adverse events with topical agents are comparable to those of oral NSAIDs. Given these observations, the researchers believe further data are needed to determine the incremental safety and efficacy benefits of topical NSAIDs compared with other treatment modalities in older adults with OA.

Massey et al. [2010] note that topical NSAIDs for pain relief remain somewhat controversial in pain practice. While plasma concentrations found after topical NSAID application are only a fraction (usually less than 5%) of the plasma levels following oral NSAID administration, there is no certain knowledge of lower effects with topical NSAIDs on cardiac or renal failure [both of which are associated with oral NSAID use and discussed elsewhere in our series on NSAID safety]. In some parts of the world (eg, much of Western Europe) topical NSAIDs have been widely available for many years without prescription and extensively used, and evidence for their safety is considered adequate. In other locales they are regarded as little more than placebo, with any apparent benefit attributed to the process of rubbing at the site of the affected area. In England 3.8 million prescriptions for topical NSAIDs were dispensed in 2009 and in the United States their use was uncommon until relatively recently when the Food and Drug Administration began licensing topical nonsteroidal products in 2007.

The review by Makris et al. [2010] of topical NSAIDs in older persons is of some concern, although they included less rigorous accounts — eg, case reports and observational studies — along with clinical trials. Apparently, this population of patients may be much more sensitive to the adverse effects of NSAIDs whether delivered topically or systemically. Groups like the American Geriatrics Society have advised against the use of NSAIDs or COX-2 inhibitors and, instead, favor opioid analgesics for elderly patients with moderate-to-severe pain or diminished quality of life due to pain [AGS Panel 2009]. Further safety studies of topical NSAIDs in this population would seem appropriate.

> AGS Panel on Persistent Pain in Older Persons. Pharmacological Management of Persistent Pain in Older Persons. American Geriatrics Society. J Am Geriatr Soc 2009 [
access available here].
> Makris UE, Kohler MJ, Fraenkel L. Adverse effects of topical nonsteroidal antiinflammatory drugs in older adults with osteoarthritis: a systematic literature review. J Rheumatol. 2010(Jun);37(6):1236-1243 [
abstract here].
> Massey T, Moore DS, McQuay HJ. Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev. 2010(Jun);6(CD007402) [
abstract here].