The results of this study support the high efficacy and safety of S-flurbiprofen plaster (SEPP) in the treatment of osteoarthritis. The optimal tested dose of SFPP was determined to be 40 mg.

Osteoarthritis (OA) is a painful and inflammatory condition that impairs the overall functioning and significantly affects the quality of life. It is a highly prevalent disease with higher incidence rates in the aged population. The pharmacological treatment for symptomatic OA includes the usage of non-steroidal anti-inflammatory drugs (NSAIDs), but they are associated with risk of adverse reactions such as gastrointestinal disorders. The risk of the gastrointestinal disorders can be lowered by topical administration of NSAIDs as they indicate lower systemic concentration and avoid the direct action on the gastrointestinal mucosa. It was determined that there is a need of an effective formulation that employs the favorable characteristics of topical NSAIDs. In this study, a novel topical NSAID patch formulation was developed and was defined as SFPP. The efficacy of this topical formulation was increased by selection of the potent cyclooxygenase inhibitory NSAID S-flurbiprofen. To increase the penetration of this formulation in deep tissues, a tape-type patch with superior percutaneous absorption was selected as the dosage form, along with additional efforts to maximize the formulation performance. The evidence from in vivo studies suggests that SFPP was superior in terms of percutaneous absorption, analgesic, and anti-inflammatory effects when compared with existing NSAID patch products. A study conducted in healthy adult males demonstrated that SFPP provides sustained and stable plasma levels of S-flurbiprofen and another survey conducted in OA patients proved greater synovial transfer of S-flurbiprofen compared with that of an existing flurbiprofen patch formulation.

Rationale behind the research:

NSAID patches show much less gastrointestinal side effects as compared to oral NSAIDs, whereas its percutaneous absorption is not adequate for the expression of clinical efficacy at a satisfactory level. This study was conducted to examine the optimal dose of SFPP in treatment of OA.

Objective:

To determine the efficacy and safety of S-SFPP as compared to placebo in treatment of osteoarthritis.

Study outcome measures:

• Primary outcomes: The measurement of improvement in knee pain on rising from the chair assessed by visual analog scale (VAS)
• Secondary outcomes: The measurement of total clinical symptoms score (the change from baseline; ΔtCS)
• Other endpoints:  Change in knee pain on walking assessed by VAS pain scores, global assessment by both investigator and patient and adverse effects evaluation for determining safety

Time Points:  At baseline, and after 2 weeks.

Study outcomes

Baseline: There were no statistically significant differences observed at baseline

Primary outcomes:

• VAS change in knee pain from baseline to trial end was dose-dependent, least squares mean was 29.5, 31.5, 32.0, and 35.6 mm in the placebo and SFPP 10, 20, and 40 mg, respectively. A significant difference was observed between placebo and SFPP 40 mg (P=0.001) {Fig 1}

• The proportion of the patients who achieved 50% pain relief was 72.4% in 40 mg and 51.2% in placebo (p<0.001)

Secondary outcomes:

• The least squares mean (95% confidence interval) of ΔtCS of SFPP 40 mg group was 6.5 (5.9–7.0), which was significantly larger than that of placebo group 5.3 (4.7–5.9) {Fig 2}

Other outcomes:

• In all other endpoints, SFPP 40 mg showed significant improvement compared with placebo
• The least squares mean of ΔwVAS of SFPP 40 mg group was 19.7 (17.1–22.3) mm which was significantly larger than that of placebo group 14.8 (12.2–17.5) mm (P=0.005) {Fig 3}

• The incidence of AEs was not different across all four groups, and no severe AEs were observed
  

In the present study, clinically relevant pain scores were obtained between all the groups, especially in 40 mg group. A 6.1 mm statistical difference was detected in ΔrVAS between SFPP 40 mg and placebo which was smaller than the estimated value of 9.1 mm at the planning stage. This difference was also smaller than those reported in the results of two comparative studies of diclofenac patch and placebo. Both studies followed same inclusion criteria and the pain scores at baseline were also similar in both studies, but there exists a difference between ΔrVAS scores. The reason behind this was a high content of peppermint oil in the present study as compared to diclofenac study.

Peppermint oil is used in the current research to improve trans dermal absorption of SFP. The proportion of patients who achieved moderate improvement (achieved 30% pain reduction) was very high (75.6%–84.3%). A statistically significant difference between SFPP 40 mg and placebo were obtained between other efficacy outcomes that include the assessments by patients (rVAS, wVAS, and patient's global assessment) and investigators (clinical symptoms and investigator's global assessment). The safety assessment indicates that SFPP was well tolerated and the adverse effects were drug-related, and there were no intergroup differences. These AEs reported might not be causally related to S-flurbiprofen because no consistent trend depending on doses was observed. These AEs might have been related to physical stimuli, such as irritation upon patch removal. The study results indicate that there was a low incidence of the gastrointestinal disorder, but there exists increment in BUN levels that can lead to renal disorders. No incidence of photosensitivity was observed in the present study. Therefore, it can be concluded that SFPP is efficacious and possess safety at an optimal tested dose of 40 mg.