The risk of oral NSAID including Cox-2 inhibitors to cause gastrointestinal, renal or cardiovascular adverse events related to systemic drug exposure could be reduced by local application. But only few long-term studies have been published to show safety and efficacy for long-term use of topical NSAID´s. Diractin® (formerly IDEA-033) is a viscous, aqueous formulation for epicutaneous application of ketoprofen based on ultra-deformable, self-regulating carrier (Transfersome ®). This multiple-dose, open label study with treatment periods up to 18 months included 402 patients with joint pain, musculoskeletal pain, stiffness or soft tissue inflammation (age of 61.4 ± 11.5 years). Most of the patients suffered from osteoarthritis (OA) of the knee (68.9%). Diractin® was applied epicutaneously up to twice daily with a maximum dose of 220 mg ketoprofen per a maximum of 2 application sites. The mean pain score at baseline was 5.4 ±1.4 on a 10 point categorical scale. During the study the pain score progressively improved up to week 36 (3.5±1.9) without a substantial further change during the rest of observation period of up to 18 months. The reduction of pain scores between week 0 (baseline) and at all later visits was statistically significant (P < 0.0001). Patients also reported an improvement of quality of life on the EUROQoL. The majority of treatment related adverse events were skin and subcutaneous tissue disorders with the highest frequency reported for erythema (16.7%) and pruritus (2.0%). Systemic ketoprofen exposure remained low throughout the study period with plasma concentrations of less than 1% of what was reported for a single, standard oral dose of 200 mg ketoprofen. There were no occurrences of treatment related serious adverse events and no remarkable changes in laboratory values or vital signs. In summary, Diractin® provided adequate pain relief with a good safety and tolerability profile when used for up to 18 months (72 weeks).