BackgroundTopical nonsteroidal anti-inflammatory drug (NSAID) formulations, which produce less systemic exposure compared with oral formulations, are an option for the management of osteoarthritis (OA). However, the overall safety and efficacy of these agents compared with oral or systemic therapy remains controversial.MethodsTwo 12-week, double-blind, double-dummy, randomized, controlled, multicenter studies compared the safety and efficacy profiles of diclofenac topical solution (TDiclo) with oral diclofenac (ODiclo). Each study independently showed that TDiclo had similar efficacy to ODiclo. To compare the safety profiles of TDiclo and ODiclo, a pooled safety analysis was performed for 927 total patients who had radiologically confirmed symptomatic OA of the knee. This pooled analysis included patients treated with TDiclo, containing 45.5% dimethyl sulfoxide (DMSO), and those treated with ODiclo. Safety assessments included monitoring of adverse events (AEs), recording of vital signs, dermatologic evaluation of the study knee, and clinical laboratory evaluation.ResultsAEs occurred in 312 (67.1%) patients using TDiclo versus 298 (64.5%) of those taking ODiclo. The most common AE with TDiclo was dry skin at the application site (24.1% vs 1.9% with ODiclo; P < 0.0001). Fewer gastrointestinal (25.4% vs 39.0%; P < 0.0001) and cardiovascular (1.5% vs 3.5%; P = 0.055) AEs occurred with TDiclo compared with ODiclo. ODiclo was associated with significantly greater increases in liver enzymes and creatinine, and greater decreases in creatinine clearance and hemoglobin (P < 0.001 for all).ConclusionsThese findings suggest that TDiclo represents a useful alternative to oral NSAID therapy in the management of OA, with a more favorable safety profile.

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Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent. These complications can be life-threatening in at-risk populations such as older adults, who are common users of long-term oral systemic NSAID therapy. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy and serious cardiovascular events. There are currently two topical NSAIDs approved by the US Food and Drug Administration for osteoarthritis-associated pain, as well as for the signs and symptoms of osteoarthritis. This review discusses the relative safety, and the gastrointestinal, cardiovascular, and renal risks of chronic oral or systemic NSAID therapy and topical NSAID formulations in patients with osteoarthritis.

BackgroundThis study aimed to determine the safety of diclofenac sodium topical solution 1.5% (w/w) in 45.5% dimethyl sulfoxide (TDiclo) for the treatment of knee or hand osteoarthritis in persons aged 75 years or older.MethodsA pooled analysis of safety data from seven multicenter, randomized, blinded, Phase III clinical trials (4–12 weeks’ duration) of TDiclo was conducted. The analysis focused on a subset of patients (n = 280) aged 75 years or older with a primary diagnosis of osteoarthritis of the knee (six trials) or hand (one trial). Patients received one of three topical treatments: TDiclo (n = 138); placebo (2.33% or 4.55% dimethyl sulfoxide, n = 39); or control (45.5% dimethyl sulfoxide, n = 103). Treatment groups were compared using Chi-square analysis, Fisher’s Exact test, or analysis of variance.ResultsThe most common adverse events involved the skin or subcutaneous tissue, primarily at the application site. The incidence of dry skin was higher in the TDiclo (36.2%; P < 0.0001) and dimethyl sulfoxide control (18.4%; P = 0.0142) groups than in the placebo group (2.6%); the incidence of other skin or subcutaneous tissue adverse events was similar between the groups. Relatively few patients (<18%) experienced gastrointestinal adverse events, and group differences were not detected. In the TDiclo group, constipation (3.6%), diarrhea (3.6%), and nausea (3.6%) were the most common gastrointestinal adverse events. Cardiovascular and renal/ urinary adverse events were rare, and group differences were not detected. There was one case (0.7%) each of hypertension, spider veins, and vasodilation in the TDiclo group. Changes from baseline to the final visit in blood pressure and hepatic/renal enzyme levels were also similar between the groups.ConclusionTDiclo appears to be well tolerated for the treatment of osteoarthritis in persons aged 75 years or older.

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) may offer a safer alternative to their oral counterparts for the management of osteoarthritis. Diclofenac sodium topical solution with dimethyl sulfoxide (TDiclo) was evaluated in five randomized, controlled trials and is indicated for treatment of the signs and symptoms associated with osteoarthritis of the knee. Three studies showed that TDiclo is superior to placebo and vehicle control with respect to pain, physical function, and perception of osteoarthritis symptoms. Two studies showed that benefits are similar to those of oral diclofenac, with one study demonstrating statistical equivalence. The most common adverse event associated with TDiclo in these studies was dry skin. Incidences of gastrointestinal adverse events and abnormal levels of liver enzymes were lower with TDiclo compared with oral diclofenac in active-controlled studies. Based on these studies, TDiclo represents a practical, evidence-based option for the management of osteoarthritis of the knee.