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

Improvement in Uncomfortable Dialysis-Related Symptoms Such as Daytime Itching, Nighttime Itching, Restless Legs and Leg Muscle Cramps by Switching from HD to OHDF Through Enhanced Removal Efficacy of Medium-Molecular-Weight Substances. (ERA 2025) - "All participants were receiving pharmacological treatment, including Nalfurafine hydrochloride (2.5 µg/day), Clonazepam (0.5 mg/day), and Shakuyakukanzoto extract (6.0 g/day). Transition from HD to OHDF resulted in a slight decrease in serum albumin concentrations; however, no significant decline in Kt/V was observed, and the marked reduction in the removal rates of small to middle-weight substances was not evident. The removal efficiencies of β2-microglobulin and α1- microglobulin significantly improved, consequently the overall patients experienced an improvement in dialysis-related symptoms. Therefore, HDF treatment has demonstrated the potential to enhance the QOL for dialysis patients suffering from uncomfortable dialysis-related symptoms."

Clinical • Diabetes • Insomnia • Metabolic Disorders • Movement Disorders • Pruritus • Restless Legs Syndrome • B2M

Chronic kidney disease-associated pruritus combined with anxiety and depression treated with nalfurafine hydrochloride: a case report (PubMed, Zhonghua Nei Ke Za Zhi) - No abstract available

Journal • Chronic Kidney Disease • CNS Disorders • Depression • Dermatology • Mood Disorders • Nephrology • Pruritus • Psychiatry • Renal Disease

Nalfurafine reverses fentanyl-induced muscle rigidity and respiratory depression without affecting sedation in rats: decoupling respiration from sedation. (PubMed, J Appl Physiol (1985)) - "Nalfurafine is a promising therapeutic candidate able to reverse fentanyl-induced muscle rigidity and respiratory depression without affecting sedation or the response to painful stimuli, potentially improving the safety and efficacy of fentanyl in specific clinical settings. We could not, however, confirm that this effect was mediated via κOR."

Journal • Preclinical • Anesthesia • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

G protein Inactivation as a Mechanism for Addiction Treatment. (PubMed, Biol Psychiatry) - "Both nalfurafine and nalmefene have long histories of safety and use in humans and could potentially be repurposed for the treatment of dynorphin-mediated stress disorders."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Psychiatry • Substance Abuse

Insufficient Control of Cholestatic Pruritus in Primary Biliary Cholangitis (PBC) With Current Therapies: Baseline Data From the East Asian Population Enrolled in the Phase 3 GLISTEN (Global Linerixibat Itch STudy of Efficacy and safety iN PBC) Study (APASL 2025) - P3 | "Participants are either pruritus treatment-naïve, have received prior pruritus therapy or continue stable concomitant therapies commonly used for PBC and/or pruritus, except for obeticholic acid...Antihistamines were the most common type of prior medication taken for pruritus among East Asian participants (20%), while prior use of bile acid binding resins was low (3%; 2 participants from China) and none had received opioid antagonists, selective serotonin reuptake inhibitors or rifampicin... Prior use of bile acid binding resins was low in the GLISTEN population, despite its first-line position in treatment guidelines in many countries, including China. Similarly, use of nalfurafine was low among Japanese participants, despite being approved in Japan for treating pruritus in chronic liver diseases. Regardless of the use of multiple off-label therapies that may impact pruritus, including fibrates, participants showed evidence of ongoing moderate–severe pruritus,..."

Clinical • P3 data • Dermatology • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Therapeutic Effects of Topical Tramadol liposomal gel (TrLG) and Tramadol hydrochloride solution (TrHC) on Symptoms of Chronic Pruritus: BALB/c Mice Preclinic Model (AAD 2025) - "[1] Substances such as nalfurafine, difelikefalin, and nalbuphine, which are also kappa opioid receptor (KOR) agonists, are currently used in clinical studies for treating chronic pruritus. [2-4] In this study, we evaluated Tramadol hydrochloride solution (TrHC) and Tramadol liposomal gel (TrLG), another kappa opioid receptor (KOR) agonist and centrally acting opioid analgesic used for treating moderate acute or chronic pain [5], on a murine model of chronic pruritus."

Preclinical • Atopic Dermatitis • Dermatology • Immunology • Pain • Pruritus

Kappa opioid receptor internalisation-induced p38 nuclear translocation suppresses glioma progression. (PubMed, Br J Anaesth) - "This combined molecular, cellular, and in vivo approach supports use of KOP receptor agonists as potential adjuvant therapeutics for glioma."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • Transplantation

Comparison of effect and mechanism between nalfurafine hydrochloride and narrow-band ultraviolet B phototherapy in the treatment of pruritus in hemodialysis patients. (PubMed, Ann Med) - "There were no side effects in both treatment groups. Nalfurafine could be an alternative treatment option compared with NB-UVB as an oral medication in pruritis in hemodialysis patients, especially those with hyperphosphatemia."

Clinical • Journal • CNS Disorders • Dermatology • Mental Retardation • Metabolic Disorders • Nephrology • Pruritus • Psychiatry • Renal Disease

INSUFFICIENT CONTROL OF CHOLESTATIC PRURITUS IN PRIMARY BILIARY CHOLANGITIS (PBC) WITH CURRENT THERAPIES: BASELINE DATA FROM THE ONGOING PHASE 3 GLISTEN (GLOBAL LINERIXIBAT ITCH STUDY OF EFFICACY AND SAFETY IN PBC) TRIAL (AASLD 2024) - P3 | "Participants are either treatment-naïve, have received prior therapy or continue stable concomitant therapies commonly used for PBC and/or pruritus, except for obeticholic acid...Overall, 97% of participants were receiving ursodeoxycholic acid...In total, 42% of participants were receiving concomitant therapy that may reduce pruritus, including 22% receiving fibrates, 10% selective serotonin reuptake inhibitors, 8% bile acid binding resins, 6% antihistamines, 4% gabapentin, 3% rifampin, 3% naltrexone, 3% pregabalin, and 2% nalfurafine. Prior use of bile acid binding resins was low in the GLISTEN population despite its first-line position in treatment guidelines. Regardless of the use of multiple "off label" therapies, participants living with PBC globally had evidence of ongoing moderate–severe pruritus, underscoring the unmet need for a symptom-specific therapy targeting pruritus in PBC."

Clinical • P3 data • Dermatology • Fibrosis • Hepatology • Immunology • Primary Biliary Cholangitis • Pruritus

Hair Loss in a Hemodialysis Patient after Repetitive Use of the Antipruritic Drug Nalfurafine: Implications of Impaired Angiogenesis for Hair Loss. (PubMed, Intern Med) - "His hair loss was completely ameliorated for the next five months. We speculated that κ-opioid receptor activation by nalfurafine caused blood capillary regression around the hair follicles, leading to cessation of hair growth and subsequent hair fallout."

Journal • Alopecia • Dermatology • Pruritus • Renal Disease

Stimulation of kappa opioid receptors in the nucleus accumbens promotes feeding behavior in mice: acute restoration of feeding during anorexia induced by 5-fluorouracil. (PubMed, Eur J Pharmacol) - "However, neither the orexin OX1 receptor antagonist YNT-1310 nor the non-selective orexin receptor antagonist suvorexant inhibited the increase in food intake induced by nalfurafine. Reduced food intake at 2 days following 5-fluorouracil administration was alleviated across the first 3 h following daily injection of nalfurafine, though daily food intake was not influenced. These results indicate that nalfurafine promotes feeding behavior through stimulation of κ opioid receptors in the nucleus accumbens and may be a candidate for reducing anorexia due to anti-cancer agents."

Journal • Preclinical • Anorexia • Oncology

Kappa opioids inhibit spinal output neurons to suppress itch. (PubMed, Sci Adv) - "We then show that the kappa opioid receptor agonist nalfurafine relieves itch by selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide a population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch."

Journal • GRP-10

Characterising Kappa Opioid Receptor Expression in Multiple Sclerosis (ECTRIMS 2024) - "CPZ and rapamycin were removed at day 84. On days 85-126 mice were treated with either the KOR agonist nalfurafine (0.1 mg/kg/day) or vehicle and brain tissue was collected for analysis at experimental endpoint (day 126)... The current study validates the KOR system as therapeutic target for MS and confirms KORs ability to modulate astrogliosis in preclinical models of demyelination."

CNS Disorders • Multiple Sclerosis • Solid Tumor

Clinical Research Progress on Using κ-Opioid Receptor Agonists to Treat Uremic Pruritus (PubMed, Sichuan Da Xue Xue Bao Yi Xue Ban) - "Recently, there is growing evidence showing that κ-opioid receptor agonists, including nalfurafine, difelikefalin, and nalbuphine, can effectively and safely reduce itching symptoms in patients with refractory uremic pruritus. Herein, we reviewed the epidemiology, pathogenesis, clinical symptoms, and treatment strategies of uremic pruritus, and summarized in detail the progress in clinical research on the use of κ-opioid receptor agonists, including nalfurafine, difelikefalin, and nalbuphine, in the management of patients with uremic pruritus."

Journal • Review • Chronic Kidney Disease • CNS Disorders • Depression • Dermatology • Nephrology • Pruritus • Psychiatry • Renal Disease • Sleep Disorder

NIH HEAL Initiative Preclinical Screening Platform for Pain Program and Data Sharing (IASP 2024) - "(PGI), carbamazepine (3-300 mg/kg, PO), celecoxib (3-100 mg/kg, PO), diazepam (1-30 mg/kg, PO), diclofenac sodium (1-100 mg/kg, PO), duloxetine hydrochloride (3-100 mg/kg, PO), gabapentin (10-300 mg/kg, PO), ketoprofen (0.3-10 mg/kg, PO), morphine sulfate (0.3-10 mg/kg, SC), naproxen sodium (1-100 mg/kg, PO), nalfurafine hydrochloride (1-3,000 µg/kg, SC), pregabalin (10-100 mg/kg, PO), and resatorvid (1-100 mg/kg, SC) were evaluated using the PSPP workflow, including in vitro assessment of safety and abuse liability and protein binding and in vivo assessment of pharmacokinetics, side effect profile, efficacy in pain-related models, and/or abuse liability. The PSPP program and public-facing website (https://pspp.ninds.nih.gov/) are resources available to the global community developing potential pain therapeutics with the goal of accelerating the development of new, non-opioid, non-addictive pain therapeutics. The program website details the optimized and validated..."

Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Pain • Psychiatry

Peripheral administration of a κ-opioid receptor agonist nalfurafine inactivates gonadotropin-releasing hormone pulse generator activity in goats. (PubMed, Neurosci Lett) - "These results suggest that nalfurafine inhibits the activity of the GnRH pulse generator in the ARC, thus suppressing pulsatile LH secretion. Therefore, nalfurafine could be used as a reproductive inhibitor in mammals."

Journal

Effects of Selective and Mixed-Action Kappa and Delta Opioid Receptor Agonists on Pain-Related Behavioral Depression in Mice. (PubMed, Molecules) - "IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

Nalfurafine promotes myelination in vitro and facilitates recovery from cuprizone + rapamycin-induced demyelination in mice. (PubMed, Glia) - "Primary mouse (C57BL/6J) OPC-containing cultures were treated with nalfurafine (0.6-200 nM), clemastine (0.01-100 μM), T3 (30 ng/mL), or vehicle for 5 days. Partial recovery was observed on both the horizontal bar and complex running wheel tests over time, which was facilitated by nalfurafine treatment. Taken together, these data highlight the potential of nalfurafine as a remyelination-promoting therapeutic."

Journal • Preclinical • CNS Disorders • Multiple Sclerosis • Solid Tumor

Systematic Structure-Activity Relationship Study of Nalfurafine Analogues toward Development of Potentially Nonaddictive Pain Management Treatments. (PubMed, J Med Chem) - "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."

Journal • Addiction (Opioid and Alcohol) • Pain

Microdosing Partial Agonists Inactivates Kappa Opioid Receptors - An Alternative Strategy for Human Trials (CPDD 2024) - "KOR-mediated analgesia, aversion, fentanyl withdrawal, prolactin release, diuresis, and antipruritic effects were assessed (n = 6-16)...This response was blocked by naloxone (opioid antagonist), JNK-IN-8 (JNK inhibitor), or MJ33 (PRDX6 inhibitor)... These findings suggest that chronic low-dose treatment with nalfurafine or nalmefene could offer a safer, more targeted approach to KOR inactivation, with fewer side effects compared to competitive KOR antagonists. The observed tissue-specific effects, with no interference in diuretic or antipruritic responses, indicate tissue-specific selectivity. The lower doses required for KOR inactivation may minimize off-target adverse effects, making them attractive candidates for prolonged use and highlighting their potential to promote stress resilience with therapeutic selectivity."

Addiction (Opioid and Alcohol) • CNS Disorders • Cognitive Disorders • Mood Disorders • Psychiatry • Tobacco Addiction • PRDX6

Nalfurafine is Aversive at Analgesic Doses - Non-Clinical Evidence to Indicate It is Not an Atypical Kappa Opioid Receptor Agonist (CPDD 2024) - "Nalfurafine and U50,488 were both aversive at analgesic doses contradicting the hypothesis that nalfurafine is atypical because it produces analgesia without dysphoria/dissociation. Nalfurafine was well tolerated in clinical trials. The divergence between non clinical and clinical findings could be indication (pruritis versus thermal algesia), locus of therapeutic effect, species difference, or respective doses required for efficacy."

Clinical • Addiction (Opioid and Alcohol) • CNS Disorders • Pain • Pruritus

Efficacy and safety of different systemic drugs in the treatment of uremic pruritus among hemodialysis patients: a network meta-analysis based on randomized clinical trials. (PubMed, Front Med (Lausanne)) - "Drugs including cromolyn sodium, dexchlorpheniramine, difelikefalin, gabapentin, hydroxyzine, ketotifen, melatonin, montelukast, nalbuphine, nalfurafine, nemolizumab, nicotinamide, pregabalin, sertraline, thalidomide, and placebo were assessed. This study suggests considering gabapentin treatment when facing a patient suffering from UP. This study provides a reference for the selection of drug therapy for UP patients receiving hemodialysis."

Clinical • Retrospective data • Review • Dermatology • Pruritus • Renal Disease

Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination. (PubMed, Clin Transl Immunology) - "In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits. This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine-fingolimod combination providing enhanced benefits."

Journal • CNS Disorders • Immunology • Inflammation • Multiple Sclerosis • CD4

Effects of the novel selective κ-opioid receptor agonist NP-5497-KA on morphine-induced reward-related behaviors. (PubMed, Sci Rep) - "Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. Nalfurafine (10 μg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects."

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

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys. (PubMed, Psychopharmacology (Berl)) - "These results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse."

Journal • Addiction (Opioid and Alcohol) • Pain