(Trans)dermal delivery of opioids: a structure-permeability relationship

Recent studies showed that morphine is locally effective in the local treatment of post herpetic neuralgia. However, no information has been available in literature on the ability of human skin to retain morphine derivatives. The present study investigated the effect of four different substituents (i.e., 3-methoxyl, 6-carbonyl, 14-hydroxyl groups and 7,8-didehydro), on in vitro penetration through human skin. The effect of the selected substituents and their synergistic effects, statistically evaluated, were elucidated in relation to physico-chemical parameters and molecular dynamic simulations. The 3-methoxyl group, determining a significant increase of flux and at the same time a reduction of skin retention, plays a key role in governing the penetration of morphine derivatives. Moreover, the docking analyses suggested that a ceramide-based computational model might be suitable for describing the affinity of opioid to be retained into the human epidermis. The overall results suggested that hydromorphone could be a good alternative to morphine since it has a greater affinity for human epidermis as well as a relatively higher potency.