Transdermal delivery of the potent analgesic dihydroetorphine: Kinetic analysis of skin permeation and analgesic effect in the hairless rat

Dihydroetorphine is an extraordinarily strong opioid analgesic. To assess i ts effectiveness after topical application in hairless rats we have examine d the kinetic analysis of skin permeation through excised skin and the in-v itro reservoir effect of skin, and have investigated the predictability of plasma concentration and analgesic effect following in-vivo transdermal app lication. Dihydroetorphine was moderately permeable from an aqueous suspension throug h excised hairless rat skin. Dihydroetorphine flux from drug-dispersed pres sure-sensitive adhesive tape was threefold that from the applied aqueous su spension. The fluxes through the abdominal and the dorsal skin during tape application fitted the Fickian diffusion equation well after the tape was r emoved peeling off the outer layer of the stratum corneum. The relationship between the plasma concentration and the analgesic effect was examined for four different rates of infusion of dihydroetorphine. A non-linear pharmac okinetic disposition was observed. Following abdominal (0 . 28 cm(2), 20 ug ) and dorsal (0 . 50 cm(2), 35 mug) applications of the dihydroetorphine ta pe, plasma concentration (0 .2-0 .8 ng mL(-1)) and analgesic effect were ma intained at a suitable level, for more than 8 h, until removal of the tape. These profiles were predictable using the combined equation for percutaneo us absorption, disposition and the analgesic effect, but the analgesic effe ct was slightly lower than the predicted value. The results show that it was possible to control the plasma concentration a nd the analgesic effect of dihydroetorphine by topical application of the a nalgesic using pressure sensitive adhesive tape in the hairless rat. It was possible to predict the result using mathematical modelling.