Roth Dovepress NSAIDs, ibuprofen was associated with the highest rate of adverse cardiovascular outcomes (11.7 per 100 person- years), followed by diclofenac (9.3 per 100 person-years), and naproxen (8.5 per 100 person-years).35 and/or anticoagulants) receive one of the following analgesics for pain: acetaminophen (not to exceed 4 g/day), a topical NSAID, a nonselective oral NSAID plus a gastroprotective agent, or a COX-2 inhibitor.38 Renal adverse events In addition to gastrointestinal and cardiovascular risks, all oral NSAIDs also confer a serious risk of renal adverse events.3 Although comparative data are limited, some studies suggest that fenoprofen and indomethacin may have greater nephro- toxicity than the other nonselective NSAIDs.3 Renal adverse events associated with oral NSAIDs include electrolyte reten- tion, reduced glomerular filtration, nephritic syndrome, renal papillary necrosis, hyperkalemia, and chronic renal failure.3 Although renal adverse events related to NSAIDs are rare in the population at large, their likelihood increases dramatically in high-risk patients, such as older adults, especially those with concurrent conditions, including underlying volume depletion, renal insufficiency, congestive heart failure, and diabetes.3 Significant increases in blood urea nitrogen and creatinine clearance have been observed in older patients, even after discontinuation of NSAIDs.3 Osteoarthritis guidelines The adverse events associated with use of oral (systemic) NSAIDs are well established and have been studied in both clinical and observational trials. Guidelines for the manage- ment of osteoarthritis provide suggestions for minimizing the risks of oral NSAID use. The American Geriatrics Soci- ety guidelines recommend that nonselective NSAIDs and COX-2 selective NSAIDs be used rarely and with extreme caution, only in patients who have been carefully selected to minimize risk of gastrointestinal, cardiovascular, or renal adverse events, and only when safer alternative therapies have failed.36 These guidelines caution that older individu- als taking nonselective NSAIDs and individuals on aspirin therapy taking COX-2 selective agents should take a proton pump inhibitor or misoprostol for gastroprotection. The American College of Gastroenterology cautions against the use of oral NSAID therapy in patients at high risk for gas- trointestinal bleeding, even in conjunction with misoprostol and a proton pump inhibitor, and strongly recommends that safer alternatives to oral NSAID therapy be utilized.37 The American Academy of Orthopedic Surgeons guidelines sug- gest that patients with symptomatic osteoarthritis of the knee and increased gastrointestinal risk (age $60 years, comorbid medical conditions, history of peptic ulcer disease, history of gastrointestinal bleeding, concurrent use of corticosteroids, 128 submit your manuscript | www.dovepress.com Dovepress Topical NSAIDs in osteoarthritis: potential for risk reduction Nonselective NSAIDs are available as oral formulations which produce systemic levels of drug and as topical formula- tions which deliver drug to the local target tissue and result in significantly lower levels of systemic absorption relative to oral therapy.7 Whereas plasma drug concentrations after administration of topical NSAIDs are comparatively low (generally ,10% of that after oral administration), local drug concentrations in target tissues are high.7,39 Lower plasma concentrations of active drug after application of topical NSAIDs appear to be associated with a lower risk of systemic adverse events compared with oral formulations.39 However, data vary among the available topical agents. Only diclofenac topical solution has been compared with oral diclofenac in head-to-head trials, in which diclofenac topical solution estab- lished comparable efficacy and a lower incidence of systemic adverse events compared with oral diclofenac.40,41 Topical diclofenac, in gel and solution formulations, is the only topical NSAID currently approved by the Food and Drug Administration for the management of osteoarthritis.42,43 Although other topical salicylates are available over the coun- ter to treat joint pain and were recommended in the American College of Rheumatology guidelines in 2000, these agents do not have the evidence base of diclofenac to support their use, possibly because of poor skin penetration properties,2,42,43 and being nonacetylated salicylates with absent prostaglandin inhibition, they are weak analgesics.44 In clinical practice, topical NSAIDs are used for the many patients with osteoarthritis who require NSAID therapy but desire or need to minimize the risk of systemic adverse events or who prefer topical to oral dosing.42,45 A recent review by Haroutiunian et al reported that the incidence of severe gastrointestinal adverse events is three times lower with topical diclofenac compared with oral diclofenac, and that its systemic effects across the board were generally infrequent and did not differ from placebo in the great major- ity of trials.7 Another recent systematic review by Makris et al evaluated the safety of topical NSAIDs in older adults with osteoarthritis. These authors concluded that the use of topical NSAIDs resulted in fewer severe gastrointestinal adverse events compared with oral NSAIDs in older adults.46 Both of these reviews included data from a wide range of Clinical Interventions in Aging 2011:6