One year long-term study on abuse liability of nalfurafine in hemodialysis patients

Abstract

Nalfurafine (nalfurafine hydrochloride, TRK-820, Remitch®) was launched as an anti-pruritic for uremic pruritus in hemodialysis patients in Japan in 2009. Since the drug is an opioid that mainly binds to κ-receptors and possesses κ-agonistic pharmacological properties and also binds partially, but very weakly, to μ-receptors, the abuse liability of the drug was assessed by using questionnaires in patients enrolled in a clinical trial evaluating the efficacy and safety of the drug. The clinical trial was conducted for up to 52 weeks in patients subjected to regular hemodialysis. End-stage renal disease (ESRD) patients with uremic pruritus (n = 146) were administered nalfurafine 5 μg intravenously after each hemodialysis session. 81 ESRD patients without uremic pruritus served as non-treatment controls. All pruritus patients answered the 3 questionnaires of "the Addiction Research Centre Inventory (ARCI)", "modified Short Opiate Withdrawal Scale (SOWS)", which provides a range of signs and symptoms of opiate withdrawal, and Severity of Dependence Scale (SDS), which measures the dependence potential of the drug. The control patients were tested with the ARCI and modified SOWS questionnaires. There were no significant differences between the nalfurafine group and control group in the ARCI and modified SOWS scales. Thus, no evidence of abuse liability was indicated in the results. Also, no significant differences in the blood pressure, respiratory rate, body temperature and pupil diameter were shown between the two groups.

Investigation of the role of βarrestin2 in kappa opioid receptor modulation in a mouse model of pruritus

“…Additionally, the development and characterization of nalfurafine (TRK-820) in the clinic to treat hemodialysis-associated pruritus (Kumagai et al, 2012; Kumagai et al, 2010; Ueno et al, 2013; Wikstrom et al, 2005) supports the therapeutic potential of KOR agonists in treating pruritus. Indeed, there is significant evidence supporting activation of KOR as an avenue for the treatment of itch arising from multiple pruritic effectors in both rodents (Gmerek and Cowan, 1988; Kamei and Nagase, 2001) and non-human primates (Ko and Husbands, 2009; Ko et al, 2003).…”

“…These include pruritus induced by substance P, histamine (Togashi et al, 2002), compound 48/80 (Wang et al, 2005), chloroquine (Inan and Cowan, 2004), scratching secondary to cholestasis (Inan and Cowan, 2006) and KOR antagonist-induced itch (Inan et al, 2009b) all in rodents and intravenously administered morphine in monkeys (Wakasa et al, 2004). Nalfurafine (Remitch®) is also clinically utilized in Japan for the treatment of patients suffering from uremic pruritus (Kumagai et al, 2012; Kumagai et al, 2010; Ueno et al, 2013; Wikstrom et al, 2005). Like nalfurafine, the novel KOR agonist Iso2.1 also prevents the development of itch from multiple pruritogens, specifically KOR antagonist-induced (Figure 3A-B) and chloroquine phosphate-induced pruritus (Figure 3C-D) with a similar efficacy as U50,488H.…”

“…The KOR agonist nalfurafine (Remitch®) is used in treatment of the pruritus associated with chronic renal failure in humans, with intravenous (Ueno et al, 2013; Wikstrom et al, 2005) and oral (Kumagai et al, 2012; Kumagai et al, 2010) efficacy. In hemodialysis patients, nalfurafine can produce long-term suppression of pruritus without significant safety issues (Kumagai et al, 2012) or abuse liability (Ueno et al, 2013).…”

“…In hemodialysis patients, nalfurafine can produce long-term suppression of pruritus without significant safety issues (Kumagai et al, 2012) or abuse liability (Ueno et al, 2013). In mice, KOR agonists are also effective.…”

Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats

“…Since 2009, nalfurafine has been used in Japan for the treatment of uremic pruritus (i.e., Remitch ®: 2.5 μg nalfurafine HCl/tablet; P.O. ), with no reports of dysphoric mood disturbances or abuse liability (Kumagai et al 2010; Kumagai et al 2012; Ueno et al 2013). Similar to prototypical kappa agonists, nalfurafine produces antinociception and diminishes the abuse-related effects of morphine in rodents and primates (Hasebe et al 2004; Ko and Husbands 2009).…”