Repeated topical administration of morphine daily produces tolerance within three days. Ketamine alone has little effect in the radiant heat tailflick assay. However, with administered with morphine, topical ketamine prevented the development of morphine tolerance in a dose-dependent manner. Furthermore, topical ketamine also slowly reversed pre-existing morphine tolerance. These observations imply that topical morphine tolerance is mediated, at least in part, through peripheral N-methyl-D-aspartate (NMDA) receptors and raises the possibility of the use of topical NMDA receptor antagonists clinically.