Date Published: June 12, 2017
Publisher: Public Library of Science
Author(s): Kenya Kamimura, Takeshi Yokoo, Hiroteru Kamimura, Akira Sakamaki, Satoshi Abe, Atsunori Tsuchiya, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa, Shuji Terai, Tatsuo Kanda.
Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, κ-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients.
A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 μg/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment.
Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at ≥20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses. Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.
Many cases of chronic liver disease are accompanied by pruritus caused by cholestasis, which cause systemic itching without any skin lesions. The symptoms cause both physical and mental stress and affect the quality life (QOL) of the patients. The mechanism of pruritus includes upregulation of the μ-opioid receptor system and suppression of the κ-opioid receptor system. Therefore, anti-histamines and sedatives show insufficient effects. Pruritus has also been seen and extensively studied in hemodialysis patients  and recently, therapeutic effect of κ-opioid receptor agonist, nalfurafine hydrochloride, on the itching by modulating the central nervous signals, have been reported in the hemodialysis patients [2, 3].
Pruritus is a symptom that can cause disruption of daily activities, sleep, and worsen QOL in patients. It is classified into two main types: peripheral and central. Peripheral pruritus is caused by the activation of mast cells releasing histamine through C fibers, and central pruritus is caused by the activation of μ-opioid receptors by various agonists, including β-endorphin, encephalin, and more. Scratching further activates C fibers and worsens the symptom for both types of pruritus. Central pruritus can be observed in patients on hemodialysis and in those with chronic liver diseases [7, 10, 11]; however, no effective treatments had been developed. It has been reported that chronic liver diseases are accompanied with pruritus, and it impairs activity and sleep, and causes malaise and cramping limbs, thereby affecting QOL [4–7, 10, 11]. It was recently reported that lysophosphatidic acid (LPA) and autotaxin (ATX), which is involved in the production of LPA, are involved in the development of central pruritus in cases of PBC . More recently, the presence of ATX stimulating factors has also been reported . Our study showed a higher rate of itching in PBC patients, likely due to this mechanism. The reasons for a relatively lower level of Hb in patients with pruritus remain unclear.