Remitch (nalfurafine) / Toray, Tanabe Pharma - LARVOL DELTA

Kappa opioids suppress histaminergic itch by inhibiting mediodorsal thalamus-projecting claustrum glutamatergic neurons. (PubMed, Sci Adv) - "Conditional knockdown of KORs in CLAGlu neurons or the CLAGlu-MD circuit diminishes Nalfurafine's antipruritic effects. These findings provide insight into the neural circuits involved in histaminergic itch and the action of KOR agonists."

Journal

Comparative Efficacy and Tolerability of Pharmacological Agents for Cholestatic Pruritus in Primary Biliary Cholangitis: A Systematic Review and Network Meta-Analysis (ACG 2026) - "(c) Any adverse events: rifampin, sertraline, naltrexone, and linerixibat carried significantly higher adverse event rates versus placebo; nalfurafine 5 mg was the safest agent (P-score 0.82). Fourteen RCTs across 9 active treatment nodes were included. On continuous pruritus reduction, rifampin ranked first (SMD -4.21 [95% CI -7.12, -1.29]; P-score 0.90), followed by linerixibat (SMD -2.68 [-4.55, -0.80]; P-score 0.69) and naltrexone (SMD -2.62 [-4.73, -0.51]; P-score 0.68). For responder rate, rifampin led (RR 2.80 [1.29-6.05]), while linerixibat combined a significant responder rate (RR 1.69 [1.20-2.38]) with the highest P-score among well-powered trials (0.53)."

Retrospective data • Review • Dermatology • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Anrikefon vs Nalfurafine for Sleep Quality in Hemodialysis Patients With CKD-aP (clinicaltrials.gov) - P4 | N=50 | Recruiting | Sponsor: Zhujiang Hospital | Not yet recruiting ➔ Recruiting

Enrollment open • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Efficacy of Nalfurafine for Chronic Kidney Disease-Associated Pruritus in Twice-Weekly Hemodialysis Patients: A Randomized Controlled Trial (clinicaltrials.gov) - P4 | N=36 | Not yet recruiting | Sponsor: Indonesia University

New P4 trial • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

A zinc deficiency leads to non-inflammatory pruritus by modifying opioid receptor signaling. (PubMed, J Dermatol Sci) - "Our data strongly suggest that a ZD is an independent cause of NIP, which could be resolved by zinc supplementation. In addition, mouse model revealed that zinc plays a critical role in modification of opioid receptor-mediated signaling. This study reveals for the first time that zinc is crucially related to pruritus via opioid receptors."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Dermatitis • Dermatology • Inflammation • Pruritus

An Exploratory Study Comparing Anrikefon with Nalfurafine in Improving Sleep Quality Among CKD-aP Patients Undergoing Hemodialysis: An Open-Label Randomized Controlled Clinical Trial (ChiCTR) - P4 | N=50 | Sponsor: Zhujiang Hospital of Southern Medical University; Zhujiang Hospital of Southern Medical University

New P4 trial • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Effects of repeated nalfurafine and VZTK35 treatments on fentanyl/cocaine mixture self-administration in a rat drug-vs.-food choice procedure. (PubMed, Psychopharmacology (Berl)) - "While candidate medications are needed for fentanyl and cocaine co-use, these results do not support the further evaluation of these KOR agonists for this purpose. However, these methods provide an empirical preclinical framework for studying fentanyl and cocaine interactions on reinforcement endpoints."

Journal • Preclinical • Addiction (Opioid and Alcohol)

EFFICACY AND SAFETY OF NALFURAFINE FOR REFRACTORY PRURITUS IN HEMODIALYSIS PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS (ISN-WCN 2026) - "Its use may represent a valuable addition to current management strategies. Further studies should clarify the influence of dialysis adequacy and middle-molecule clearance on treatment response to optimize patient outcomes."

Retrospective data • Review • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

ANALYSIS OF THE EFFICACY AND SAFETY OF NALFURAFINE HYDROCHLORIDE FOR TREATING CHRONIC KIDNEY DISEASE-ASSOCIATED PRURITUS IN HEMODIALYSIS PATIENTS (ISN-WCN 2026) - "Multivariate ordered logistic regression analysis indicated that the frequency of hemodiafiltration was an independent factor associated with the antipruritic efficacy of nalfurafine hydrochloride(OR=0.24, 95%CI 0.06∼0.90, P=0.035). Download: Download high-res image (92KB)Download: Download full-size imageDownload: Download high-res image (302KB)Download: Download full-size imageDownload: Download high-res image (198KB)Download: Download full-size imageDownload: Download high-res image (119KB)Download: Download full-size imageConclusion Nalfurafine hydrochloride effectively relieves pruritus symptoms in HD patients and has a good safety profile."

Clinical • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

EFFECTS OF DIFELIKEFALIN ON INFLAMMATORY RESPONSES AND RENAL DYSFUNCTION IN A RAT MODEL OF RENAL ISCHEMIA- REPERFUSION-INDUCED ACUTE KIDNEY INJURY (ISN-WCN 2026) - "Difelikefalin suppressed all elevated cytokines to the same levels as those in the sham group, U-50488H showed moderate efficacy by suppressing 6 of 13 cytokines, and nalfurafine hydrochloride exhibited a poor inhibitory effect, affecting only 1 of 13 cytokines.Conclusion These findings indicate that difelikefalin has anti-inflammatory and renoprotective effects in a rat acute kidney injury model, and that there is variable anti-inflammatory efficacy among KOR agonists.The content of this abstract was submitted to the 69th Annual Meeting of the Japanese Society for Dialysis Therapy, held in June 2024 in Yokohama, and it was published in BMC Nephrology (Takeuchi H, et al. 2025 Jul 1; 26(1): 307).I have potential conflict of interest to disclose.Employee of Kissei Pharmaceutical Co., Ltd.I did not use generative AI and AI-assisted technologies in the writing process."

Preclinical • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • CSF2 • IFNG • IL10 • IL12A • IL13 • IL17A • IL18 • IL1B • IL2 • IL4 • IL5 • IL6 • IL7 • TNFA

NALFURAFINE FOR REFRACTORY UREMIC AND CHOLESTATIC PRURITUS IN A HEMODIALYSIS PATIENT: A CASE REPORT (ISN-WCN 2026) - "During her course, she experienced recurrent spontaneous bacterial peritonitis (pathogen: vancomycin-resistant Enterococcus faecium) necessitating multiple courses of broad-spectrum antibiotics (including cefoperazone-sulbactam, meropenem, daptomycin, linezolid)...Initially suspected as a drug allergy, all potential culprit medications were discontinued, and prednisone was administered...Despite trials of various standard therapies including antihistamines, intensified hemodialysis with hemoperfusion, gabapentin, ursodeoxycholic acid, sertraline, topical tacrolimus ointment, and achieving targets for phosphate and parathyroid hormone control, the generalized pruritus remained refractory...This outcome underscores its mechanistic advantage and potential therapeutic value in challenging clinical scenarios involving mixed-origin pruritus.Conclusion In conclusion, nalfurafine presents a promising therapeutic option for refractory pruritus of mixed uremic and cholestatic..."

Case report • Clinical • Chronic Kidney Disease • Dermatology • Fibrosis • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Nephrology • Pruritus • Renal Disease • Urticaria

NOVEL KAPPA OPIOID RECEPTOR AGONISTS AS REMYELINATION REAGENTS (ADPD 2026) - "Accumulating evidence indicates that kappa opioid receptor (KOR) agonists, e.g. nalfurafine (NLF), are attractive therapeutic targets with myelin repair promoting properties and the ability to drive differentiation of oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS)... Kappa opioid receptor agonists as novel remyelination agents seem promising treatment for multiple sclerosis. Further drug development campaign is warranted to move forward to the market."

CNS Disorders • Inflammation • Multiple Sclerosis • Solid Tumor

Prevalence and influencing factors of chronic kidney disease-associated pruritus in patients undergoing maintenance hemodialysis (PubMed, Zhonghua Yi Xue Za Zhi) - "Topical emollients (27.30%, 993/3 638) and gabapentin (13.80%, 502/3 638) were the most frequently used antipruritic agents, whereas the κ-opioid receptor agonist nalfurafine hydrochloride was used in only 1.35% (49/3 638) of patients. The occurrence of CKD-aP is related to calcium-phosphorus metabolic disorder and low BMI. Compared with mild-to-moderate pruritus, patients with severe pruritus showed a higher prevalence of sleep disturbances, cardiovascular disease, and cerebrovascular disease."

Journal • Addiction (Opioid and Alcohol) • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Dermatology • Metabolic Disorders • Nephrology • Pruritus • Renal Disease • Sleep Disorder • Vascular Neurology

Anrikefon vs Nalfurafine for Sleep Quality in Hemodialysis Patients With CKD-aP (clinicaltrials.gov) - P4 | N=50 | Not yet recruiting | Sponsor: Zhujiang Hospital

New P4 trial • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Pain signaling via sensory neurons drives breast cancer progression through neuropeptide release and κ-opioid counter-regulation. (PubMed, Pharmacol Res) - "Conversely, in vitro treatment with dynorphin enhanced the cytotoxic efficacy of docetaxel, accompanied by the inhibition of PI3K-Akt signaling, whereas in vivo administration of the peripherally restricted KOR agonist nalfurafine methiodide markedly suppressed tumor growth. These findings establish a bidirectional neural-tumor axis in breast cancer progression. Therapeutically, combined blockade of CGRP/SP signaling with peripheral KOR agonism may present a novel strategy to enhance chemotherapy efficacy in TNBC patients."

Journal • Breast Cancer • Oncology • Pain • Palliative care • Solid Tumor • Transplantation • Triple Negative Breast Cancer

EXPLORING KAPPA OPIOID RECEPTOR MUTATIONS IN IBD: FROM MOLECULAR PHARMACOLOGY TO DRUG DISCOVERY (CCCongress 2026) - "A focused ligand panel will include FDA-approved therapeutics (e.g. difelikefalin, anrikefon, nalfurafine), experimental drug candidates (e.g., sialorphin), and in-house designed peptides (e.g. helianorphin-19, DNCP-β-NalA). Nat Commun. 2023 Dec 6;14(1):8064."

Addiction (Opioid and Alcohol) • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

Genome-Wide Association Studies Data and Transcriptomics Data Link Herpes Simplex Virus 1 Infection and Parkinson's Disease. (PubMed, Parkinsons Dis) - "The upregulated shared gene set between HSV-1 infection and PD is mainly enriched in neuroinflammation, while the downregulated shared gene set is mainly enriched in stem cell and cellular metabolism, and the drug repurposing targeted the shared molecular signature nalfurafine. HSV-1 infection is related to PD, and these two diseases had shared molecular signature such as neuroinflammation and stem cell, which could be targeted for drug repurposing."

Journal • CNS Disorders • Herpes Simplex • Infectious Disease • Inflammation • Keratitis • Movement Disorders • Ocular Inflammation • Ophthalmology • Parkinson's Disease

Development and Application of an LC-MS Method for the Pharmacokinetics and Pharmacodynamics of Oral Therapeutic Efficacy of Nalfurafine. (PubMed, Basic Clin Pharmacol Toxicol) - "Our findings demonstrate that oral administration of Nalf is pharmacokinetically favourable and effectively reduces disease disability and promotes remyelination in the EAE model. This study supports the clinical development of oral Nalf as a potential treatment for MS, offering an effective and noninvasive alternative to injections."

Journal • PK/PD data • Addiction (Opioid and Alcohol) • CNS Disorders • Immunology • Multiple Sclerosis

Nalmefene enhances the remyelinating ability of nalfurafine when administered therapeutically at very low doses during experimental autoimmune encephalomyelitis. (PubMed, Clin Transl Immunology) - "This finding was supported by a bioinformatic analysis response that highlighted the myelination benefits of the suboptimal dose combination while the optimal dose combination of NalF/NalM stimulated increased immunomodulatory activity. Findings from this study indicate that the remyelinating and immunomodulatory effects of the KOR agonist NalF can be significantly enhanced through interactions with the MOR antagonist NalM in a distinct dose-dependent manner."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis

Inhibitory effects of a κ-opioid receptor agonist and neurokinin-3 receptor antagonist on testosterone secretion in male rats. (PubMed, Theriogenology) - "Co-administration of nalfurafine and fezolinetant further suppressed testosterone levels, with significant reductions observed in the 0.01 + 1, 0.01 + 3, and 0.1 + 3 mg/kg groups at 2-6, 2-6, and 2-8 h, respectively. These findings demonstrate that the oral administration of nalfurafine and fezolinetant alone and in combination effectively suppresses testosterone secretion in male mammals."

Journal • Preclinical

Nalfurafine is Aversive at Antinociceptive Doses in Mice. (PubMed, Pharmacol Res Perspect) - "Neither nalfurafine nor U50,488 showed a separation between their antinociceptive and aversive effects, contradicting the hypothesis that nalfurafine is a nonaversive analgesic in mice. The findings caution against assuming nalfurafine is a nonaversive KOPr agonist for use in preclinical research."

Journal • Preclinical • CNS Disorders • Pain

Structural and dynamic insights into the biased signaling mechanism of the human kappa opioid receptor. (PubMed, Nat Commun) - "Here we show, using multiple complementary methods, shared residues that determine β-arrestin recruitment by nalfurafine and U-50,488H...Furthermore, MD simulations revealed that the four mutants tend to adopt conformations with reduced β-arrestin recruitment activity. Our research findings provide a foundation for enhancing KOR-mediated therapeutic effects while minimizing unwanted side effects by targeting specific residues within the KOR ligand-binding pocket, including K2275.40 and Y3127.34, which have previously been implicated in biased signaling."

Journal • Anesthesia • Pain

Pruritus in Uremic Patients: Approaches to Alleviating a Common Symptom in Chronic Kidney Disease. (PubMed, Life (Basel)) - "Difelikefalin, a κ-opioid receptor agonist, represents a breakthrough in systemic treatment, demonstrating efficacy with a favorable safety profile. Another opioid-based therapy, nalfurafine, has shown notable symptom relief in multiple clinical studies, with a low risk of abuse. Sertraline, an antidepressant, offers another alternative, although its delayed onset remains a limitation...Further research, including comparative and long-term studies, is essential to refine treatment algorithms and improve patient outcomes. By integrating new pharmacologic and nonpharmacologic options, CKD-aP management is shifting toward a more tailored and effective approach that addresses the individual needs of each patient."

Journal • Review • Chronic Kidney Disease • Dermatology • Inflammation • Nephrology • Pruritus • Renal Disease

Anti-inflammatory and renoprotective effects of difelikefalin, a kappa opioid receptor agonist, in a rat model of renal ischemia-reperfusion-induced acute kidney injury. (PubMed, BMC Nephrol) - "These findings indicate that difelikefalin has anti-inflammatory and renoprotective effects in a rat acute kidney injury model, with varying anti-inflammatory efficacy among KOR agonists."

Journal • Preclinical • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury

KOR agonists for the treatment and/or prevention of opioid use disorder and cocaine use disorder. (PubMed, Pharmacol Biochem Behav) - "Subsequently, nalfurafine and recently triazole 1.1 and oxa-noribogaine, three centrally acting KOR agonists devoid of such side effects, have been studied in animal models of OUD and CUD...Oxa-noribogaine suppressed cue-induced reinstatement of morphine and fentanyl seeking...Therefore, a combination of a KOR agonist and a MOR agonist or a compound with dual KOR/MOR agonist activities when used as analgesics will deter escalation use of MOR agonists, thus prevent OUD, and KOR agonists may be useful for treatment of cocaine abuse and relapse. Importantly, KOR agonists with no or fewer side effects of typical KOR agonists should be further investigated in animal models of OUD and CUD, particularly those that simulate stress-, cue- and drug priming-induced relapse for potential clinical development."

Journal • Review • Addiction (Opioid and Alcohol) • Anesthesia • CNS Disorders • Depression • Pain • Psychiatry • Substance Abuse