Nalfurafine Research Articles

Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments.

Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

WED-327 - Efficacy and safety of nalfurafine hydrochloride for pruritus in patients with chronic liver disease in Japan

WED-327 - Efficacy and safety of nalfurafine hydrochloride for pruritus in patients with chronic liver disease in Japan

Pharmacological Therapy of Pruritus in Primary Biliary Cholangitis

We aim to summarize the current management of pruritus in primary biliary cholangitis (PBC) by evaluating the efficacy and safety of pharmacological therapies. Pruritus is a common symptom of PBC, and evidence regarding the most effective antipruritic agents available is lacking. New pharmacotherapy for PBC has shown promising antipruritic effects. We performed a systematic literature review and meta-analysis including all available double-blind, randomized, placebo-controlled clinical trials that evaluated the efficacy of pharmacotherapy for the symptomatic management of pruritus in PBC. Pruritus was assessed as either a change from baseline or a postintervention score. We included 33 studies and 20 medications. Using the visual analog scale, cholestyramine did not significantly improve pruritus compared with placebo [standardized mean differences (SMD): -0.94, 95% CI: -2.05 to 0.17], whereas rifampin and nalfurafine hydrochloride both significantly improved pruritus (SMD: -3.29, 95% CI: -5.78 to -0.80; n=23 and SMD: -0.58, 95% CI: -1.04 to -0.12). In addition, Bezafibrate and linerixibat significantly improved pruritus (SMD: -1.05, 95% CI: -1.41 to -0.68; n=110 and SMD: -0.31, 95% CI: -0.62 to -0.04, respectively). This effect was also present within the subgroup analysis by pruritus scale, where both bezafibrate and linerixibat significantly improved pruritus compared with placebo (SMD: -1.09, 95% CI: -1.54 to -0.65; P <0.001; visual analog scale; as postintervention score and SMD: -0.31, 95% CI: -0.62 to -0.01; P =0.04; numeric rating scale; as a change from baseline score, respectively). Bezafibrate and Linerixibat are potential second-line antipruritic medications for PBC, particularly those with moderate to severe pruritus.

Nalfurafine Hydrochloride, a κ-Opioid Receptor Agonist, Induces Melanophagy via PKA Inhibition in B16F1 Cells.

Selective autophagy controls cellular homeostasis by degrading unnecessary or damaged cellular components. Melanosomes are specialized organelles that regulate the biogenesis, storage, and transport of melanin in melanocytes. However, the mechanisms underlying melanosomal autophagy, known as the melanophagy pathway, are poorly understood. To better understand the mechanism of melanophagy, we screened an endocrine-hormone chemical library and identified nalfurafine hydrochlorides, a κ-opioid receptor agonist, as a potent inducer of melanophagy. Treatment with nalfurafine hydrochloride increased autophagy and reduced melanin content in alpha-melanocyte-stimulating hormone (α-MSH)-treated cells. Furthermore, inhibition of autophagy blocked melanosomal degradation and reversed the nalfurafine hydrochloride-induced decrease in melanin content in α-MSH-treated cells. Consistently, treatment with other κ-opioid receptor agonists, such as MCOPPB or mianserin, inhibited excessive melanin production but induced autophagy in B16F1 cells. Furthermore, nalfurafine hydrochloride inhibited protein kinase A (PKA) activation, which was notably restored by forskolin, a PKA activator. Additionally, forskolin treatment further suppressed melanosomal degradation as well as the anti-pigmentation activity of nalfurafine hydrochloride in α-MSH-treated cells. Collectively, our data suggest that stimulation of κ-opioid receptors induces melanophagy by inhibiting PKA activation in α-MSH-treated B16F1 cells.

Shorter pruritus period and milder disease stage are associated with response to nalfurafine hydrochloride in patients with chronic liver disease

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima’s pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima’s pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.

Improvement of muscle weakness by nalfurafine hydrochloride (TRK-820), a kappa opioid receptor agonist

Improvement of muscle weakness by nalfurafine hydrochloride (TRK-820), a kappa opioid receptor agonist

Effect of nalfurafine hydrochloride (TRK-820), a kappa opioid receptor agonist, in the treatment of cancer cachexia.

Effect of nalfurafine hydrochloride (TRK-820), a kappa opioid receptor agonist, in the treatment of cancer cachexia.

Effectiveness of a treatment algorithm for hemodialysis-associated pruritus in terms of changes in medications

BackgroundHemodialysis-associated pruritus (HAP) is a serious complication that occurs in 60–80% of hemodialysis patients, which not only decreases quality of life but also worsens prognosis. We have developed a treatment algorithm to take a comprehensive cause-specific approach to HAP and used it at our facility since June 2009. In this treatment algorithm, moisturizers and topical steroids are used depending on skin condition and severity of pruritus; administration of nalfurafine hydrochloride is considered in treatment-resistant cases. If pruritus improves, we attempt to taper topical steroids by switching to lower potency or by dose reduction or discontinuation. Here, we examined the effectiveness of the treatment algorithm over 9 years in terms of changes in medications.MethodsSubjects were hemodialysis patients who received treatment for HAP at our facility: 89 in May 2009 before introduction of the algorithm, and 131 in April 2013, 164 in October 2014, 190 in October 2015, 181 in October 2016, 215 in October 2017, and 224 patients in October 2018 after its introduction. A questionnaire survey was conducted on the presence of pruritus, severity (using a visual analogue scale [VAS] and Shiratori severity scores), frequency, and insomnia due to pruritus. Changes in medications were investigated using medical records and compared.ResultsThe proportion of patients with pruritus decreased significantly from 96.6% in 2009 to 66.8% in 2018 (p < 0.001). Median VAS score significantly decreased from 53.0 mm in 2009 to 24.5 mm in 2018 (p < 0.001), and the proportion of patients with insomnia due to pruritus also significantly decreased from 25.8% in 2009 to 2.2% in 2018 (p < 0.001). The proportion of patients who used moisturizers significantly increased from 34.8 to 89.7% (p < 0.001). The proportion of patients receiving topical steroids decreased from 47.2 to 35.7%, but the difference was not significant (p = 0.085).ConclusionsThe treatment algorithm was shown to be useful for improving HAP, but future challenges were identified, including promoting use of lower potency topical steroids or discontinuation. Further prospective studies are required to confirm the role of each treatment intervention in a comprehensive cause-specific approach to HAP.

Anti-pruritic effect of nemolizumab in hemodialysis patients with uremic pruritus: a phase II, randomized, double-blind, placebo-controlled clinical study

BackgroundThe pathophysiology of uremic pruritus (UP), which is characterized by systemic and intractable itching, remains unclear. As interleukin (IL)-31 may be involved, we conducted a phase II, randomized, controlled study to evaluate nemolizumab (anti-IL-31 receptor A antibody) in Japanese hemodialysis patients with UP.MethodsPatients were randomly assigned (1:1:1:1:1) to one of four double-blind groups (receiving a single subcutaneous injection of nemolizumab 0.125, 0.5, or 2.0 mg/kg, or placebo on Day 1) or an open-label reference group (receiving oral nalfurafine hydrochloride 2.5–5 μg once daily for 12 weeks). The primary endpoint was the difference in the absolute change in pruritus visual analog scale (VAS) at Week 4 between placebo and each nemolizumab group.ResultsThe primary efficacy endpoint was not met. The mean change from baseline with all three nemolizumab doses at Week 1, and with 0.5 mg/kg at Week 4, was greater than with placebo. Least square mean differences (95% confidence intervals) in the absolute changes between the placebo arm and each nemolizumab arm were − 2.4 (− 19.7, 14.9) for 0.125 mg/kg, − 8.7 (− 26.6, 9.2) for 0.5 mg/kg, and 0.4 (− 17.0, 17.8) for 2.0 mg/kg. Secondary efficacy parameters including the Shiratori severity score and 5-D itch score failed to show between-group differences. Patients with higher serum IL-31 levels at screening tended to have greater pruritus VAS reductions following nemolizumab treatment.ConclusionsIn this phase II study in patients with UP, the primary efficacy parameter was not met. Nemolizumab was generally well tolerated with no clinically significant safety concerns.Clinical trial registrationJAPIC: JapicCTI-152961, https://www.clinicaltrials.jp/cti-user/trial/ShowDirect.jsp?japicId=JapicCTI-152961.

Pruritus is common in patients with chronic liver disease and is improved by nalfurafine hydrochloride

Pruritus is known to be a common complication in hepatitis patients, but the exact frequency and degree are not fully elucidated. Thus, we evaluated pruritus of 450 patients with chronic liver disease at our hospital. Pruritus was observed in 240 (53%) of the patients. Pruritus was significantly associated with males (OR = 1.51, P = 0.038) and patients with alkaline phosphatase (ALP) ≥ 200 U/L (OR = 1.56, P = 0.0495) and was significantly less in HBsAg-positive patients (OR = 0.449, P = 0.004). Seasonally, there was no difference in the frequency of pruritus between summer and winter. Of the 24 refractory pruritus patients treated with nalfurafine, 17 (71%) indicated improvement of itch, which is defined as a decrease in the visual analog scale score ≥ 30 mm. Pruritus was improved by nalfurafine both during daytime and nighttime in the Kawashima’s scores evaluation. All patients who received nalfurafine exhibited improved Kawashima’s scores ≥ 1 point during the daytime or nighttime. In conclusion, pruritus occurred in > 50% of patients with chronic liver disease, and predictors of pruritus were males and ALP ≥ 200 U/L. Nalfurafine may be useful for pruritus, regardless of whether daytime or nighttime.

Clinical Profiles of Nalfurafine Hydrochloride for the Treatment of Pruritus Patients.

Nalfurafine hydrochloride is a selective kappa-opioid agonist that has antipruritic effects. Here we describe the clinical trials for treatment of uremic pruritus in dialysis patients and on hepatic pruritus in patients with chronic liver disease. Among cytochrome P-450 (CYP) isoforms in humans, CYP3A4 is the major isoform involved in metabolic decyclopropylmethylation of nalfurafine hydrochloride. Nalfurafine hydrochloride was found to be a substrate for P-glycoprotein (P-gp), but had no inhibitory effects on P-gp-mediated transport. The efficacy of oral nalfurafine hydrochloride at 2.5 and 5μg for refractory pruritus in hemodialysis patients was observed within the first 7days of treatment, and the effects persisted for the 52-week treatment period. Nalfurafine hydrochloride is also effective in the treatment of conventional refractory pruritus in peritoneal dialysis patients. Moreover, nalfurafine hydrochloride at 2.5 and 5μg is effective for the treatment of refractory pruritus in chronic liver disease patients within the first 7days of drug administration. In all the clinical trials, most adverse drug reactions (ADRs) were mild and resolved quickly and there was no clinical safety problem. Following 52weeks of treatment, hemodialysis patients did not develop physical or psychological dependence, indicating no addiction risks. In summary, nalfurafine hydrochloride administered orally at doses of 2.5 and 5μg was safe and effective for treatment of refractory pruritus in patients undergoing hemodialysis or peritoneal dialysis and in chronic liver disease patients.

Signal detection of oral drug-induced dementia in chronic kidney disease patients using association rule mining and Bayesian confidence propagation neural network.

Among the mechanisms responsible for cognitive dysfunction in chronic kidney disease (CKD) are albuminuria and oxidative stress. However, there may be other causes not yet identified. In fact, the full relevance of CKD patient drug use and its relationship to dementia has hardly been barely investigated. We identified drugs affecting cognitive function in CKD patients by analyzing the spontaneous reporting system in Japan using Association rule mining (ARM) and Bayesian confidence propagation neural network (BCPNN). The signal detection criterion used were as follows: case ≥ 3, lift > 1, conviction > 1 (ARM) and IC025 >0 (BCPNN). Drugs with more than 20 cases were valaciclovir (lift: 11.21, conviction: 1.28, IC025: 3.12), amantadine (lift: 19.69, conviction: 1.68, IC025: 3.05), nalfurafine (lift: 8.35, conviction: 1.19, IC025: 2.18), pregabalin (lift: 6.05, conviction: 1.12, IC025: 1.78), and acyclovir (lift: 5.89, conviction: 1.12, IC025: 1.68). This study is the first report to use a large-scale medical database to identify drugs related to oral drugs-induced dementia in CKD.

Clinically utilized kappa-opioid receptor agonist nalfurafine combined with low-dose naltrexone prevents alcohol relapse-like drinking in male and female mice

Alcohol relapse is a treatment goal for alcohol dependence and the target for medications’ development. Clinically utilized nalfurafine (NFF) is a potent and selective kappa- opioid receptor (KOP-r) agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists. We have recently found that NFF reduces excessive alcohol drinking in mice via a KOP-r-mediated mechanism. Here, we further investigated whether NFF alone (1–10 μg/kg) or in combination with naltrexone (NTX, mu-opioid receptor [MOP-r] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. Nalmefene (NMF, clinically utilized KOP-r partial agonist with MOP-r antagonism) was used as a reference compound for the effects on mouse ADE of new NFF + NTX combination. After exposed to 3-week intermittent- access alcohol drinking (two-bottle choice, 24-h access every other day), both male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. NFF prevented the ADE in a dose-dependent manner in both male and female mice. A combination of NFF with NTX reduced the ADE without sex differences at doses lower than those individual effective ones, suggesting synergistic effects between the two compounds. NMF prevented the ADE in both sexes, while selective KOP-r antagonist nor-BNI had no effect. Our new study suggests that a combination of clinically-utilized, potent KOP-r agonist NFF with low-dose NTX has therapeutic potential in alcohol “relapse” treatment.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Combination Therapy in Chronic Hemodialysis Patients with Genotype 2 Hepatitis C Virus Infection

Background: Glecaprevir (nonstructural protein 3/4A protease inhibitor) and Pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-antiviral regimen, was evaluated for safety and efficacy in chronic hemodialysis patients with genotype 2 hepatitis C virus infection. Methods: In this prospective, observational, single-center study at Masuko Memorial Hospital, between November 2017 and December 2018, a total of 8 HD patients with an HCV infection genotype 2 received G/P combination therapy. Age was an average of 67.1 (61 - 75) years and there were four men and two women. It was FIB4 INDX an average of 2.67 (1.5 - 3.34) before the start of therapy. It was quantity of HCV RNA an average of 4.43 (2.1 - 6.5). HCV RNA levels were measured by real-time RCR-based method (COBAS AmpiPrep/COBAS TaqMan HCV Test. 4 cases 12 weeks were 2 cases eight weeks for dosing period. Patients were excluded if they had evidence of hepatocellular carcinoma. This study was approved by the ethics committee of our hospital, while we obtained written consent from the participants after providing a thorough explanation of the contents and methods of this study. Results: 6 patients were available for total dose internal use. As for the HCV RNA of the fourth week, (100%) HCV RNA became negative after administration start of therapy. Rapid virologic response (RVR) achieved all cases. 5 patients achieved 12-week sustained virologic response (SVR12) and were following up the 1 patient. The itching appeared in two cases (33%), but there was symptom improvement in nalfurafine hydrochloride use treatment, and treatment continuation was possible. Conclusion: It is thought that G/P can be given to the HD patients’ safety, but we will accumulate a case in future, and it is thought to be necessary to examine utility and safety.

Su1483 - Effect of a Novel Kappa-Receptor Agonist, Nalfurafine Hydrochloride, on Patients with Chronic Liver Disease

Su1483 - Effect of a Novel Kappa-Receptor Agonist, Nalfurafine Hydrochloride, on Patients with Chronic Liver Disease

Recurrence rates of pruritus after the stop of nalfurafine hydrochloride in chronic liver disease: Preliminary prospective confirmatory trial.

The recurrence rates of pruritus after stopping nalfurafine hydrochloride are unknown in chronic liver disease. A prospective confirmatory trial was carried out to determine the recurrence rates of pruritus after cessation of nalfurafine hydrochloride in chronic liver disease. After pretreatment with nalfurafine hydrochloride for 4weeks or more, 15 consecutive Japanese patients, who confirmed the improvement of pruritus (decrease in the visual analogue scale (VAS) of ≥50mm), were enrolled in the present study. Patients were classified to the continuous group (continuation of nalfurafine hydrochloride for 4weeks) or the discontinuous group (cessation of nalfurafine hydrochloride) at the time of consent to study protocol, by self-determination. The recurrence rates (increase in VAS of ≥25mm after stopping nalfurafine hydrochloride) were 100% (5 of 5 patients) and 0% (0 of 10) in the discontinuous and continuous groups, respectively. In the discontinuous group, 3 patients selected retreatment with nalfurafine hydrochloride as salvage therapy, and they generally recovered to the levels of VAS at the discontinuation of treatment. The present prospective trial showed the high recurrence rates of pruritus after the stop of nalfurafine hydrochloride in chronic liver disease.

Is patient-reported outcome improved by nalfurafine hydrochloride in patients with primary biliary cholangitis and refractory pruritus? A post-marketing, single-arm, prospective study.

Patients with primary biliary cholangitis (PBC) frequently suffer from pruritus, which can severely impair their health-related quality of life (HRQOL). Nalfurafine hydrochloride, a selective κ-opioid receptor agonist, was recently approved in Japan for refractory pruritus in patients with chronic liver diseases, but it still remains unclear whether this treatment improves the patient-reported outcome (PRO) in PBC patients with refractory pruritus. Herein, we conducted a multicenter, post-marketing, single-arm prospective study to investigate the efficacy of nalfurafine in terms of PRO, and the associations of the efficacy with any clinical characteristics. After screening for pruritus in 496 patients with PBC using PBC-40 and the visual analog scale (VAS), we identified 141 patients with moderate to severe pruritus; these were invited to participate in the study. The participants received 2.5μg nalfurafine once daily for 12weeks, and pruritus and HRQOL were assessed in week 12 of this treatment. Generic HRQOL, short form 36, blood chemistries, and serum autotaxin levels were also measured at baseline and at week 12. Forty-four patients participated in this study. The mean PBC-40 itch domain scores and VAS declined during the study period, from 8.56 to 7.63 (P = 0.041) and from 42.9 to 29.3 (P = 0.001) at baseline and at week 12, respectively, indicating a significant effect of nalfurafine. The other domains of PBC-40 and all domains of SF-36 were not significantly altered by this treatment. We failed to find any association between the change in VAS and PBC-40 itch scores and any clinical variable. Serum autotaxin levels were significantly increased during the study period. This study demonstrated that nalfurafine improved pruritus in patients with PBC, independent of their clinical characteristics, but had a limited effect on the PRO.

Therapeutics for Pruritus in Cholestatic Liver Disease: Many Treatments but Few Cures

Pruritus in cholestatic liver disease is commonly encountered and difficult to eradicate. It has a major impact on quality of life and thus is important to address. This article reviews current and future treatment options for cholestatic pruritus. In the last 5 years, the pathogenesis of cholestatic itch has been further clarified via studies of serum autotaxin, which correlates with severity of symptoms and decrease in patients on therapy. New medications under development include apical sodium-dependent bile acid transporters (maralixibat, GSK2330672), fibrates (bezafibrate), and κ-opioid receptor agonists (nalfurafine hydrochloride). While many treatments are available to treat this vexing condition, data to support consistent and dramatic improvement with any one medication is lacking. However, with so many options and several new medications under investigation in clinical trials, symptom relief is an achievable goal for many patients.

THU-223 - Effect of nalfurafine hydrochloride for refractory pruritus in patients with primary biliary cholangitis: a multicenter, post-marketing, single-arm, prospective study

THU-223 - Effect of nalfurafine hydrochloride for refractory pruritus in patients with primary biliary cholangitis: a multicenter, post-marketing, single-arm, prospective study

Post-marketing surveillance study of the safety and efficacy of nalfurafine hydrochloride (Remitch® capsules 2.5 μg) in 3,762 hemodialysis patients with intractable pruritus.

BackgroundIntractable pruritus in hemodialysis patients can significantly decrease their quality of life and is also associated with poor vital prognosis. Although combined multiple causes of intractable pruritus in these patients have been identified, no existing treatments are proven to be sufficiently effective. We conducted a post-marketing surveillance to follow-up and assess the safety and efficacy of nalfurafine, a selective κ-opioid receptor agonist, for the treatment of intractable pruritus in patients undergoing hemodialysis.Patients and methodsHemodialysis patients with intractable pruritus from institutions in Japan who received oral nalfurafine hydrochloride between January 2010 and December 2013 were enrolled in the surveillance. Surveillance was completed in July 2015. Safety data during 1 year after nalfurafine treatment onset, and efficacy data of nalfurafine evaluating the first 12-week treatment period and the following period until 1 year after the initial dose of nalfurafine (using global assessment of the itch improvement by the physician, Visual Analog Scale, and the Shiratori’s severity scores) were collected and analyzed.ResultsIn total, 3,762 patients were analyzed for safety. Adverse drug reactions were experienced by 402/3,762 (10.69%) patients. The most frequent adverse drug reactions were insomnia (127/3,762 [3.38%] patients), constipation (34 [0.90%]), somnolence (32 [0.85%]), dizziness (23 [0.61%]), nausea (13 [0.35%]), and malaise (9 [0.24%]). No patients developed dependence on nalfurafine. Nalfurafine was effective in 82.50% (2,880/3,491) of patients during the first 12 weeks and in 84.95% (2,167/2,551) on treatment during the subsequent period until 1 year after nalfurafine treatment initiation. Statistically significant decreases were reported in the Visual Analog Scale and the Shiratori’s severity scores (p<0.001).ConclusionOral nalfurafine hydrochloride (from 2.5 μg/day to a maximum of 5.0 μg/day) continues to be safe and effective for the treatment of intractable pruritus in hemodialysis patients in real-world clinical settings.