Efficacy of Topical 5% Doxepin Cream Compared with Diclofenac Gel and Placebo for Knee Osteoarthritis: A Randomized Double-Blind Clinical Trial

Abstract Background and purpose Osteoarthritis is the most common type of arthritis, and knee osteoarthritis is one of the most important forms, causing symptoms such as knee pain and stiffness, followed by reduced physical performance and a decreased quality of life. Among complementary treatments of interest are new and optimal drugs that can reduce pain and discomfort in patients with fewer side effects. This study aimed to evaluate the efficacy and safety of topical 5% doxepin cream. Methods In this double-blind clinical trial, 60 patients with knee osteoarthritis were selected and randomly assigned to 3 groups of 20. The first group used placebo cream twice daily, the second group used 5% doxepin cream twice daily, and the third group used 1% diclofenac topical gel twice daily. All three groups also took 250–500 mg of naproxen tablets orally daily. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Visual Analogue Scale (VAS) questionnaires were administered at baseline and at six weeks after treatment initiation. Improvement in physical function and reduction in pain were considered a response to treatment. Results This study showed that after the doxepin intervention, in the second group, there was a significant difference in knee pain (P < 0.005), daytime stiffness (P < 0.05), morning stiffness (P < 0.05), and physical performance (P < 0.05) between the groups. In the two groups receiving doxepin cream and diclofenac gel, there was a significant reduction in symptoms (pain and stiffness of the knee) and an improvement in physical performance. Conclusion Topical 5% doxepin cream significantly improved pain, stiffness, and physical function in patients with primary knee osteoarthritis. Although diclofenac demonstrated greater improvement in overall knee pain, topical doxepin also showed clinically meaningful benefits and may represent a promising adjunctive treatment option for symptom management in knee osteoarthritis. Larger randomized controlled trials are warranted to confirm these findings.