Dovepress topical NSAID preparations, including agents not currently available in the US.7,46 In the US, diclofenac is available topically as a gel and as a solution for the management of osteoarthritis.42,43 A number of placebo-controlled studies have examined the safety and efficacy of these two topical diclofenac formulations individually. Topical diclofenac solution with dimethylsulfoxide Several randomized controlled trials have shown that topi- cal diclofenac solution with a dimethylsulfoxide penetration enhancer (Pennsaid®, Mallinckrodt Inc, Hazelwood, MO) is effective and well tolerated in the treatment of signs and symptoms of knee osteoarthritis. Three vehicle-controlled studies, ranging in length from 4–12 weeks, established the ability of topical diclofenac solution to improve pain scores, physical function, patient global assessment, stiffness, and pain on walking.47–49 The most common adverse events were local skin irritation, such as dryness.47–49 Skin dryness may be due to the potential of dimethylsulfoxide to dissolve skin lipids, and may be countered by the application of skin emollients. However, the effect of emollients on skin dryness has not been specifically evaluated.40 Topical diclofenac solution is also unique among the diclofenac formulations available in the US, in that it has been compared with oral diclofenac in head-to-head trials including osteoarthritis of the knee. In two 12-week active- controlled studies comparing topical diclofenac solution with oral diclofenac, topical diclofenac produced pain relief in patients with osteoarthritis comparable with pain relief experienced with oral diclofenac.40,41 In addition, topical diclofenac solution was associated with fewer systemic adverse events compared with oral diclofenac. In a study by Tugwell et al, patients treated with topical diclofenac solution had a significantly lower incidence of gastrointestinal adverse events compared with patients receiving oral diclofenac, including dyspepsia (15% versus 26%, P = 0.001), abdomi- nal pain (12% versus 22%, P = 0.0008), nausea (8% versus 13%, P = 0.04), and diarrhea (9% versus 17%, P = 0.001).41 Incidence of abnormal liver function (aspartate transami- nase, 2% versus 10%, P = 0.0001; alanine transaminase, 5% versus 17%, P , 0.0001) and altered laboratory parameters (eg, creatinine clearance, an indicator of renal effects) also occurred less frequently with topical diclofenac solution.41 Topical diclofenac solution demonstrated similar safety advantages in a study by Simon et al, in which only 6.5% of patients treated with topical diclofenac solution experienced gastrointestinal adverse events, compared with 23.8% of Clinical Interventions in Aging 2011:6 Nonsteroidal anti-inflammatory drug gastropathy those receiving oral diclofenac (dyspepsia, 2.6% versus 4.0%; abdominal pain, 3.2% versus 7.3%; nausea, 0% versus 2.0%; diarrhea, 1.3% versus 4.6%).40 The incidence of cardiovas- cular events was comparably low among patients receiving oral diclofenac and treated with topical diclofenac solution (,2%), as was the incidence of hypertension (1.3%).40 Very large, longer-term studies would likely be needed to detect a difference in the incidence of cardiovascular effects between topical diclofenac solution and oral diclofenac therapy. Topical diclofenac gel Diclofenac gel 1% (Voltaren® gel, Endo Pharmaceuticals Inc, Chadds Ford, PA) has been studied in placebo-controlled studies to determine efficacy and safety in the treatment of pain associated with osteoarthritis. Diclofenac gel was significantly more effective than placebo in three studies (one 3-week and two 12-week), as would be expected.50–52 In all three trials, the incidence of gastrointestinal adverse events was similar between patients treated with diclofenac gel (ranging from 0% to 5.9%) and patients treated with placebo (ranging from 1.7% to 5.0%).50–52 One study noted a higher incidence of cardiovascular events among patients treated with diclofenac gel compared with placebo (four events versus one event), although these events were deemed unrelated to treatment.51 The rates of gastrointestinal adverse events occurring in these studies of diclofenac gel are substantially lower than those with oral diclofenac treatment in other trials including osteoarthritis.40,41 Observed discontinuation rates due to adverse reactions were only slightly higher for diclofenac gel versus placebo (5% versus 3%).53 The most common cause for discontinuation was application site reactions.53 The incidence of adverse events demonstrated in a long-term trial (up to 1 year) was similar to incidence in the placebo-controlled studies.53 In this long-term trial, application site dermatitis was observed in 11% of patients and led to discontinuation for 6% of patients.53 Summary Osteoarthritis remains a prevalent yet too often unsafely treated disease, due to the well documented, systemic adverse events associated with the ubiquitous use of oral (systemic) NSAID therapy.8,13 It is estimated that almost half of the adult population may develop symptomatic osteoarthritis of the knee by the age of 85 years.54 Oral NSAIDs, widely used in the treatment of osteoarthritis, are associated with significant gastrointestinal adverse events, which the introduction of COX-2 selective NSAIDs has not completely eliminated.3,13 NSAID gastropathy remains a silent threat, despite various efforts to manage it. 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