Nalfurafine

Currently, the only clinically successful k agonist drug has been TRK-820 (nalfurafine hydrochloride) (Toray, Fig. 6). Almost all of the U-50,488H derivatives apparently had side effects that were different from that of morphine,... 

Nalfurafine hydrochloride is a first-in-class, nonaddictive opioid drug that is used as an antipruritic for severe itching associated with hemodialysis. This drug was launched in Japan in 2009. It has a unique morphinan structure that is rarely observed in typical and traditional opioid k agonists. The design rationale for this characteristic compound was described in a previous study [7, 28], and would be of interest to researchers in the opioid field. We will summarize the rationale in Sect. 4. 

Patients on hemodialysis often complain of an intractable pruritus (uremic pruritus). Indeed, the consequent sleep disorder can impair the quality of life. Clinical and preclinical data suggested that the p opioid system induced itching, but not the k system. The antipruritic efficacy of nalfurafine hydrochloride (general name of TRK-820) was demonstrated for patients on hemodialysis in two multicenter, randomized, double-blind, placebo-controlled, clinical studies in Europe [66]. 

After the Phase HI study, a 1-year open-label study showed that nalfurafine hydrochloride (5 pg, p.o.) provided antipruritic effects for 211 patients on hemodialysis with itching that was resistant to currently available treatments. These results suggested that tolerance to the antipruritic effect of the agent was not observed, at least after 1 year of treatment. It is noteworthy that nalfurafine hydrochloride exhibited neither physical nor psychological dependency [68]. 

This novel drug was officially approved for clinical use in January 2009 by the Ministry of Health, Labour, and Welfare of Japan. This is the first pharmaceutical success ever achieved for a selective opioid k agonist. All the other compounds derived from modifications of U-50,488H have been withdrawn or halted in early clinical phase development. Furthermore, nalfurafine hydrochloride is recognized as the first nonnarcotic opioid drug in history. 

Nakao K, Mochizuki H (2009) Nalfurafine hydrochloride a new drug for the treatment of uremic pruritus in hemodialysis patients. Drugs Today 45 323-329... 

The second chapter, Opioids in Preclinical and Clinical Trials, by Hiroshi Nagase and Hideaki Fujii, provides a short survey of opioid ligands in development. They also give a detailed history of the drugs, TRK-851 (8-antagonist) and TRK-820 (nalfurafine hydrochloride, K-agonist), which were discovered by their team. 

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