The most well-known of all the NSAIDS, aspirin, has been used for over 100 years to control various forms of inflammation and today Americans consume over 80 billion tablets of aspirin a year. NSAIDS are available in OTC and prescription forms. Common OTC forms are ibuprofen, naproxen, aspirin, and acetaminophen. Those available with a prescription include celecoxib (Celbrex®), diclofenac (Votaren®), etodolac (Lodine®), indomethacin (Indocid®), ketoprofen (Orudis®) and Rofecoxib (Vioxx®) to name a few. While many topical forms of NSAIDs including Voltaren Emulgel, Indocid (indomethacin), Nidol (nimesulide), Feldene gelw (piroxicam), Oruvailw (ketoprofen), and Pennsaidw (diclofenac) are available in Europe and elsewhere without prescription, in the U. S. none are available as either OTC or prescription drugs (23). One topical prescription NSAID that has received FDA approval in the U. S. is Solareze® (diclofenac) which is indicated for the treatment of actinic keratoses (24). Perhaps due the availability of topical NSAIDS in Europe but not in the U. S., a number of non-FDA approved topical NSAID products have now emerged for sale without a prescription on various Web sites. These include such products as ProzReliefw (12% ibuprofen) and IbuCream (10% ibuprofen).
When one examines the published data on the efficacy of topical NSAIDS in treating various inflammatory symptoms, the results show considerable disparity. A statistical analysis of clinical data from a wide number of trials with various topical NSAID preparations for treating inflammation associated with arthritis concluded that while relief from symptoms was higher in the NSAID group versus the placebo group for the first two weeks, after that time, there was no measurable difference between the two treatment groups (25). Many other reports, however, do suggest that topical NSAID treatment for joint pain provides relief beyond that observed with the placebo group (26,27). A very recent clinical study with over 200 patients suffering from knee osteoarthritis found that the topical application of diclofenac provided significantly more effective relief from pain and stiffness than the vehicle control group (28). In another recent study, the product, Nidolw, which contains 2% of the COX-2 inhibitor, nimesulide, was found to be significantly more effective than topical diclofenac in reducing the pain of shoulder periarthritis (29). Considering that few studies have yet to evaluate topical formulations containing newer NSAIDs, including the specific COX-2 inhibitors, and considering that few topical formulations for NSAIDs have been developed and optimized, there is a considerable amount of research to be carried out to fully assess the efficacy of topical NSAIDs in treating inflammation (30,31). Certainly, it seems likely that a topical preparation of a potent NSAID that delivers adequate levels of an effective COX inhibitor through the skin would likely be effective in treating a variety of inflammatory conditions in which PGE-2 is indicated as a causative factor. Such products would be preferred over the use of oral dosing because of minimal risk topically applied NSAIDs present for stomach irritation.
The mechanism of action of NSAIDs involves the inhibition of prostaglandin production, particularly PGE-2. The common target for NSAIDS is the enzyme
cyclooxygenase (COX), which exists in two forms, COX-1, and COX-2. While most older versions of NSAIDS including aspirin, ibuprofen, and acetaminophen are not selective inhibitors of any particular form of COX, newer drugs have been designed to target primarily COX-2. The effort to design COX-2 specific inhibitors stems from findings that COX-1 plays a protective role in preserving the stomach lining, and thus, NSAIDs that target both COX-1 and COX-2 can erode the stomach lining and cause ulcer formation when taken orally (32,33). This deleterious side effect would however, likely be significantly reduced with topically applied NSAIDS. If so, COX inhibitors, whether specific for COX-2 or not, could be used with equal effectiveness in treating symptoms of inflammation.
Perhaps one of the most obvious and effective uses of a topical NSAID would be to treat the symptoms associated with sunburn. This type of inflammation is primarily driven by the UVR-induced production of PGE-2, which, as mentioned above, causes vasodilation, enhances sensitivity of nerve endings, causes histamine release from mast cells, and stimulates the production of additional inflammatory mediators in fibroblasts. By blocking or reducing the UVR-induced production of PGE-2 from keratinocytes and fibroblasts it should be possible to minimize the onset and progression of a sunburn. Thus, it seems likely that the topical use of a COX inhibitor might be able to not only slow the progression of a sunburn but decrease the magnitude of the UVR induced erythema. At present in the U. S. there are no topical prescription or OTC drugs that either effectively prevent the onset of sunburn (other than sunscreens that simply block UVR at the skin’s surface) or eliminate existing erythema resulting from a sunburn. Topical steroids have been shown to reduce the onset of erythema resulting from a minimal erythema dose (MED) of 2 but are ineffective at higher MED values (34). Further, they cannot reverse existing UVR-induced erythema.
Studies with topical NSAIDs have shown that these are effective in both retarding the onset of UVR-induced erythema and decreasing the magnitude of the sunburn response. Topical indomethacin (1%) if administered immediately after sun exposure is more effective than steroids, being able to block the onset of sunburn produced by a 6 MED dose of UVB radiation (34). Further, topical application of the COX-2 inhibitor, celecoxib, after UVB irradiation of skin reduced erythema, edema, PGE-2 levels, the number of sunburn cells, and dermal infiltration of neutrophils (35). The topical NSAID, diflofenac (branded Solareze®), which is approved for use in the U. S. to treat actinic keratoses, has been shown to reduce sunburn symptoms when applied within four hours of the initial onset of sunburn (36). It is quite likely that other NSAIDS would be similarly effective in reducing the intensity of a sunburn if applied topically, and may also show the same efficacy as topical diclofenac in treating actinic keratoses. Interestingly, several studies implicate PGE-2 as a causative factor in skin cancer, and results from mouse experiments show that topical application of a PGE-2 inhibitor lowers the UVB-induced number of papillomas detectable 12 weeks after UVB dosing (37-40).