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Topical preparations of capsaicin, the major pungent ingredient of hot pepper, are being used for management of pain and inflammatory disorders. Purpose of this study was to use nanoemulsion as an effective topical drug carrier for in vivo delivery of capsaicin. An oil-in-water nanoemulsion containing capsaicin was prepared by spontaneous emulsification method. Optimized formulation showed a median droplet diameter (d50) of 13-14 nm and was stable for more than 8 months in room and harsh temperature (i.e. 4 and 45 °C). The nanoemulsion was then formulated into topical cream and gel to compare its efficacy and safety profiles with conventional cream of capsaicin. Skin irritation study showed that topical application of capsaicin nanoemulsion was safe and no sign of edema and erythema was observed. The preparation significantly decreased inflammation of rats paw edema compared to the commercial cream and control group, especially in 2nd and 3rd hours of the test. Also, pretreated rats with capsaicin nanoemulsion gel showed very good resistance to the pain caused by heat stimulus. In total, the selected nanoemulsion showed great potential as carrier for topical delivery of capsaicin for improving its analgesic and anti-inflammatory effects. It was also found that the topical gel outperforms the topical cream as dosage form for the nanoemulsion., (Copyright © 2019 Elsevier B.V. All rights reserved.)