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

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

The efficacy and safety of kappa opioid receptor (KOR) agonists in patients with uraemic pruritus: a systematic review and network meta-analysis. (PubMed, Clin Kidney J) - "For the secondary endpoint, all four doses of difelikefalin were associated with higher rates of adverse events compared with placebo, while other interventions showed rates comparable to those of placebo and did not present statistically significant differences. In summary, difelikefalin at doses of 0.25 µg/kg and 0.5 µg/kg, along with nalfurafine at 0.25 µg/kg and 0.5 µg/kg, can be considered recommended therapeutic options for UP treatment."

Journal • Retrospective data • Addiction (Opioid and Alcohol) • Dermatology • Pruritus

Keratinocyte-TRPV1 sensory neuron interactions in a genetically controllable mouse model of chronic neuropathic itch. (PubMed, Proc Natl Acad Sci U S A) - "Here, we describe a profound chronic itch phenotype in transgenic mice expressing the tetracycline transactivator (tTA) gene within the Phox2a lineage. Phox2a; tTA mice exhibit intense, localized scratching and regional skin lesions, controllable by the tTA inhibitor, doxycycline. As gabapentin and the kappa opioid receptor agonist, nalfurafine, but not morphine, significantly reduce scratching, this phenotype has a pharmacological profile of neuropathic pruritus...In contrast denervation induced loss of all cutaneous input rapidly blocks scratching. These findings identify the cellular, molecular, and topographic basis of a robust and chronic sensory neuron-dependent and gabapentin-responsive neuropathic itch that is initiated by genetic factors within keratinocytes."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Dermatology • Pruritus • HOXB5 • TRPV1

Effectiveness of Nemolizumab for Refractory Pruritus in a Pediatric Patient With Atopic Dermatitis After Biliary Atresia Surgery. (PubMed, Cureus) - "Chronic pruritus following biliary atresia (BA) surgery significantly impairs quality of life, and conventional treatments, including ursodeoxycholic acid, nalfurafine, and antihistamines, often provide insufficient relief. Sleep disturbances resolved, allowing discontinuation of multiple medications, and her overall well-being significantly improved. This case highlights the potential role of IL-31 in cholestatic pruritus and suggests that IL-31 blockade with nemolizumab may be an effective therapeutic option for refractory pruritus in pediatric patients with BA, warranting further investigation into its broader clinical applications beyond AD."

Journal • Atopic Dermatitis • CNS Disorders • Dermatitis • Dermatology • Hepatology • Immunology • Liver Failure • Pediatrics • Pruritus • Sleep Disorder

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

Clinical study on the efficacy and safety of nalfurafine hydrochloride in the treatment of Chinese patients with chronic liver disease complicated with pruritus related to cholestasis (ChiCTR) - P4 | N=60 | Not yet recruiting | Sponsor: Tianjin University Central Hospital(Tianjin Third Central Hospital); Tianjin University Central Hospital(Tianjin Third Central Hospital)

New P4 trial • Cholestasis • Dermatology • Hepatology • Pruritus

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