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Chronic pruritus is a common and debilitating symptom associated with many dermatologic conditions and substantially impairs patients’ quality of life (QOL). In fact, the impact of chronic pruritis is thought to be comparable to that of chronic pain. Unfortunately, effective management for chronic pruritus remains limited and primarily consists of nonspecific measures, such as antihistamines and moisturizers.
There has been emerging evidence from various clinical trials demonstrating the efficacy and tolerability of a highly selective kappa-agonist, nalfurafine hydrochloride (TRK-820), for the treatment of pruritus in patients with chronic liver disease. Therefore, we conducted a systematic review to assess the efficacy of this agent in liver disease–associated pruritus.
PubMed and Embase were searched from inception to February 9, 2022, using the keywords “nalfurafine hydrochloride,” “itch,” and “pruritus” without restrictions. Two independent reviewers (authors AB and HOYL) screened and extracted data from all articles, with the supervising author (MK) providing consensus. All full-text single-arm, case-control, cohort, and randomized controlled trials with >10 patients describing the use of nalfurafine hydrochloride for the treatment of liver disease–associated pruritus were included. Editorials, commentaries, guidelines, and reviews were excluded. Outcomes included itch scores, QOL scores, and adverse events. The Cochrane Risk of Bias Tool 2.0 and the National Institutes of Health Pre-Post Study Quality Assessment Tool were applied to assess study quality (
Of 233 unique records, 5 studies were included (
PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram of the study selection process.
Characteristics of included studies.
Study name | Country | Study type (data range) | Type of liver disease | Total participants, N (% female) | Age (years), mean | Treatment | Outcomesa | Study quality |
Yagi et al, 2018 [ |
Japan | Single arm (2015-2016) |
PBCb with refractory pruritus |
44 (89) | 66.8 (SD 12.3) | 2.5 mcg nalfurafine once daily for 12 weeks |
VASc: 42.9 at baseline to 29.3 at the end point ( PBC-40: 8.56 at baseline to 7.63 at the end point ( SF-36e: 42.9 at baseline to 29.3 at the end point ( |
Good |
Akuta et al, 2018 [ |
Japan | Single arm (2015-2017) |
Positive for HBsAgf (n=19) Positive for HCVg antibody (n=70) HCCh (n=44) Others (n=5) |
138 (53) | 66 (range 24-91) | 2.5 mcg nalfurafine once daily for a median of 6.4 (range 1-38) weeks |
93 of 138 (67.4%) patients experienced a clinically relevant decrease in itch severity at the end point compared to baseline, predefined as a >50 mm decrease in their VAS score. This did not vary according to the etiology of liver disease (HBsAg+, HCV+, or HCC; |
Good |
Yoshikawa et al, 2021 [ |
Japan | Single arm (2017-2018) |
HCV (n=12) AFLDi (n=5) NAFLDj (n=1) PBC (n=5) Other (n=1) with refractory pruritus |
24 (50) | 68 (range 18-87) | 2.5 mcg nalfurafine once daily for 12 weeks |
17 of 24 (71%) patients experienced a clinically relevant decrease in itch severity at the end point compared to baseline, predefined as a >30 mm decrease in their VAS score. VAS: 50 at baseline to 25 at the end point ( |
Good |
Kumada et al, 2017 [ |
Japan | Randomized double-blind trial (2010-2012) |
Chronic hepatitis (n=78) Cirrhosis (n=142) PBC (n=87) Others (n=28) with refractory pruritus |
317 (57) | 66.5 (SD 10.6) | 2.5 mcg or 5 mcg nalfurafine once daily for 4 weeks |
Decrease in VAS: 28.56 and 27.46 mm in the 2.5 μg and 5 μg groups at the end point from baseline, respectively, compared to 19.25 mm in the placebo group ( |
Low risk of bias |
Kamimura et al, 2018 [ |
Japan | Single arm (2015-2017) |
PBC (n=11) AFLD (n=2) HCV (n=2) Vanishing bile duct syndrome (n=2) AIHk (n=1) |
11 (78) | 69 (range 45-82) | 2.5 mcg nalfurafine once daily for >20 weeks |
The reduction in pruritus scores was correlated with the time of administration (Pearson correlation coefficient |
Good |
aUnless otherwise indicated comparisons between baseline and the end point across studies were determined using a paired Student
bPBC: primary biliary cholangitis.
cVAS: visual analog scale.
dBoth the SF-36 and PBC-40 are validated tools that assess the symptoms and health-related quality of life in patients with PBC.
eSF-36: 36-Item Short Form Health Survey.
fHBsAg: hepatitis B surface antigen.
gHCV: hepatitis C virus.
hHCC: hepatocellular carcinoma.
iAFLD: alcoholic fatty liver disease.
jNAFLD: nonalcoholic fatty liver disease.
kAIH: autoimmune hepatitis.
In a double-blind randomized controlled trial [
Accounting for a combined 217 patients, 4 single-arm studies found that nalfurafine hydrochloride provided a clinically relevant decrease in itch severity in 67% to 71% of patients [
In conclusion, nalfurafine hydrochloride has demonstrated efficacy in the treatment of liver disease–associated pruritis, significantly reducing itch scores compared to the placebo and improving patient QOL. Its advantage over nonspecific measures is its efficacy in refractory pruritus and favorable side effect profile. Considering this agent’s efficacy and tolerability, and the detrimental effect of refractory pruritus on patient well-being, dermatologists and other physicians should strongly consider this agent for future investigation and eventual use in chronic liver disease–associated pruritus.
Supplementary material.
quality of life
None declared.