In order to develop the transdermal formulations of morphine hydrochloride with high skin permeation rate and prolonged action, several gels and patches containing potent penetration enhancer, laurocapram (Azone), were prepared. Since there was a long lag time period for morphine permeation through the excised hairless rat skin in Azone treatment, N-methyl-2-pyrrolidone was added to the Azone gel or patch as a co-enhancer to increase the skin permeation of morphine hydrochloride, especially in the early phase. The mixed solvent of N-methyl-2-pyrrolidone and water showed cosolvency of morphine hydrochloride, and the co-enhancer could shorten the lag time period of skin permeation of morphine hydrochloride. However, the co-enhancer alone had little effect on the skin permeation of morphine hydrochloride. It was effective only when using with Azone. Coadministration of Azone with the co-enhancer showed high in vitro skin permeation and in vivo blood level of the drug. A marked analgesic effect was found after application of morphine hydrochloride patch containing Azone and N-methyl-2-pyrrolidone. The pharmacological effect was much more prolonged than that after the conventional s.c. injection. From these results, it was predicted that the topical formulations of morphine hydrochloride containing Azone and N-methyl-2-pyrrolidone might be useful for the relief of severe chronic pain in patients.