Nalfurafine (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

) (brand name Remitch; former developmental code names TRK-820, AC-820, MT-9938) is an

antipruritic Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit the itching (Latin: ''pruritus'') often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those ...

(anti-itch drug) that is marketed in

Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...

for the treatment of

uremic pruritus Uremic pruritus is caused by chronic kidney failure and is the most common internal systemic cause of itching. Nalfurafine, an orally-administered, centrally-acting κ-opioid receptor agonist, is approved to treat the condition in Japan. See al ...

in individuals with

chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

undergoing

hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...

. It acts as a potent, selective, centrally-penetrant

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

(KOR)

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

, and is the first and currently the only selective KOR agonist to have been approved for clinical use. It has also been dubiously referred to as the "first non-

narcotic The term narcotic (, from ancient Greek ναρκῶ ''narkō'', "to make numb") originally referred medically to any psychoactive compound with numbing or paralyzing properties. In the United States, it has since become associated with opiates ...

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...

drug" in history.

History

Nalfurafine was derived from

structural modification Molecular modification is chemical alteration of a known and previously characterized lead compound for the purpose of enhancing its usefulness as a drug. This could mean enhancing its specificity for a particular body target site, increasing its ...

of the

opioid antagonist An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist that acts on one or more of the opioid receptors. Naloxone and naltrexone are commonly used opioid antagonist drugs which are competitive antagonists that bind to the o ...

naltrexone Naltrexone, sold under the brand name Revia among others, is a medication primarily used to manage alcohol or opioid use disorder by reducing cravings and feelings of euphoria associated with substance use disorder. It has also been found t ...

. It was first synthesized and characterized in 1998, and was approved for clinical use in

as an

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

drug under the brand name Remitch in 2009. The developer of nalfurafine also sought approval in

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...

under the brand name Winfuran, but the

Marketing Authorization Application Marketing Authorisation Application (MAA) is an application submitted by a drug manufacturer seeking marketing authorisation, that is permission to bring a medicinal product (for example, a new medicine or generic medicine) to the market. MAA is pa ...

was declined by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...

. The drug was originally developed as an

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

surgery Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...

, but while effective in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s of

nociception Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, co ...

, it was repurposed as an antipruritic at lower treatment doses due to an apparently unacceptable incidence of

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...

effects in humans. As of 2015, nalfurafine is also in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s for the treatment of

cholestatic pruritus Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cholangitis, primary sclerosing cholangitis, obstructive choledocholithiasis, carcinoma of the bile duct, c ...

in Japan for patients with

chronic liver disease Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. "Chronic liver disease" refers to disease ...

, and for the treatment of uremic pruritus in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...

Effects

Unlike other KOR agonists, nalfurafine does not produce

hallucinogenic Hallucinogens are a large, diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mood, and perception as well as other changes. Most hallucinogens can be categorize ...

effects in humans. Single

intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have ...

s of up to 30 µg are well tolerated by humans, whereas a dose of 40 µg produced "moderate behavioral/psychological side effects" (possibly referring to sedation), though apparently did not produce any psychotomimetic or dysphoric effects. In rodents, a low dose of nalfurafine (10–40 µg/kg) was found not to produce

conditioned place preference Conditioned place preference (CPP) is a form of Pavlovian conditioning used to measure the motivational effects of objects or experiences. This motivation comes from the pleasurable aspect of the experience, so that the brain can be reminded of th ...

or aversion, though a high dose (80 µg/kg) did induce significant place aversion. The most common

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

of low-dose nalfurafine seen in clinical trials was

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

(observed in 10–15% of patients), with few other adverse effects observed. In addition, tolerance to the antipruritic effects of nalfurafine was not found after treatment of patients with the drug for one year, and nalfurafine has shown no evidence of either

physical Physical may refer to: *Physical examination In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally co ...

nor

psychological dependence Psychological dependence is a cognitive disorder that involves emotional–motivational withdrawal symptoms—e.g. anxiety and anhedonia—upon cessation of prolonged drug abuse or certain repetitive behaviors. It develops through frequent exp ...

in humans. The drug also shows lower evidence of tolerance for effects such as analgesia and sedation in animals relative to other KOR agonists. In animals, nalfurafine produces anti-scratch,

antinociceptive Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...

, sedative, and

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

effects.

Mechanism of action

Nalfurafine is an orally active, centrally acting, highly potent, selective

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

of the

(KOR) (K_i = 75 pM; EC₅₀ = 25 pM). As touched on above, nalfurafine shows atypical properties as a KOR agonist relative to other drugs. Notably, it does not completely substitute for the prototypical KOR agonist

U-50488 U-50488 is a drug which acts as a highly selective κ-opioid agonist, but without any μ-opioid antagonist effects. It has analgesic, diuretic and antitussive effects, and reverses the memory impairment produced by anticholinergic Anticholi ...

in rodents, indicating qualitative differences in the discriminative effects of the two compounds. Moreover, unlike U-50488, it produces neither conditioned place aversion or preference in rodents. The drug is a 4,5-epoxy

morphinan Morphinan is the prototype chemical structure of a large chemical class of psychoactive drugs, consisting of opiate analgesics, cough suppressants, and dissociative hallucinogens, among others. Structure Morphinan has a phenanthrene core stru ...

derivative, and is structurally unique relative to other KOR agonists. Nalfurafine may be a

biased agonist Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand (biochemistry), ligand-dependent selectivity for certain signal transduction pathway ...

of the KOR or a KOR subtype-selective agonist. Indeed, it has been found to act as a biased agonist of the KOR, preferring activation of β-arrestin signaling ''in vitro'', but paradoxically, β-arrestin appears to be responsible for KOR agonist-induced aversion, and nalfurafine furthermore shows paradoxical effects ''in vivo'' that are not consistent with its ''in vitro'' profile. As such, more research is needed to clarify the distinct mechanisms and effects of this drug. Nalfurafine has been found ''in vitro'' to bind to the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

and to possess weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...

activity at this site, albeit with much lower

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...

relative to the KOR. However, ''in vivo'', nalfurafine has shown no indications of MOR agonism or antagonism in animals or humans, including no evidence of rewarding or reinforcing effects or physical dependence.

Research

Nalfurafine has been found to be effective in a variety of

s relevant to

drug abuse Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...

, and dependence, and may represent a novel potential treatment for these maladies. In rodents, the drug attenuates the discriminative and rewarding effects of

cocaine Cocaine (from , from , ultimately from Quechuan languages, Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly recreational drug use, used recreationally for its euphoria, euphoric effects. It is primarily obtained from t ...

and the rewarding and locomotor effects of

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

, and diminishes the

mecamylamine Mecamylamine ( INN, BAN; or mecamylamine hydrochloride (USAN); brand names Inversine, Vecamyl) is a non-selective, non-competitive antagonist of the nicotinic acetylcholine receptors (nAChRs) that was introduced in the 1950s as an antihypertensi ...

-precipitated aversive effect of

nicotine withdrawal Nicotine withdrawal is a group of symptoms that occur in the first few weeks after stopping or decreasing use of nicotine. Symptoms include intense cravings for nicotine, anger or irritability, anxiety, depression, impatience, trouble sleeping, ...

References

{{Opioidergics Tertiary alcohols Alkene derivatives Carboxamides Antipruritics Biased ligands 4,5-Epoxymorphinans 3-Furyl compounds Kappa-opioid receptor agonists Phenols Semisynthetic opioids Cyclopropanes

History

Effects

Mechanism of action

Research

See also

References