OBJECTIVE: Pain is one of the major public health burdens worldwide, however, conventional analgesics are often ineffective. Capsaicin-the active compound of Capsicum species, being responsible for their pungency-has been part of traditional medicine long ago. Capsaicin is a natural agonist of the Transient Receptor Potential Vanilloid 1 receptor-localized on capsaicin-sensitive sensory neurons and strongly involved in pain transmission-, and has been in focus of analgesic drug research for many years. In this study, we aimed to develop a sustained release transdermal patch (transdermal therapeutic system, TTS) combining the advantages of low-concentration capsaicin and diclofenac embedded in an innovative structure, as well as to perform complex preclinical investigations of its analgesic effect. METHODS: Drug delivery properties of the TTS were investigated with Franz cell and flow-through cell tests. Analgesic effect of the TTS was examined in in vivo models of acute postoperative and inflammatory, chronic neuropathic and osteoarthritic pain. RESULTS: Modified silicone polymer matrix-based TTS containing low-concentration capsaicin and diclofenac has been developed, releasing both compounds according to zero-order kinetics. Moreover, capsaicin and diclofenac facilitated the liberation of each other. Combined TTS significantly reduced acute postoperative and inflammatory pain, as well as chronic neuropathic and osteoarthritic pain. Interestingly, in acute postoperative and chronic osteoarthritic pain, capsaicin prolonged and potentiated the pain-relieving effect of diclofenac. CONCLUSIONS: New generation combined low-concentration capsaicin-diclofenac containing TTS can be an effective therapeutic tool in acute and chronic pain states involving neuropathic and inflammatory components.