Carfentanil or carfentanyl, formerly sold under the brand name Wildnil, is an extremely potent

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

used in

veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...

to anesthetize large animals such as

elephant Elephants are the largest living land animals. Three living species are currently recognised: the African bush elephant ('' Loxodonta africana''), the African forest elephant (''L. cyclotis''), and the Asian elephant ('' Elephas maximus ...

s and

rhinoceros A rhinoceros ( ; ; ; : rhinoceros or rhinoceroses), commonly abbreviated to rhino, is a member of any of the five extant taxon, extant species (or numerous extinct species) of odd-toed ungulates (perissodactyls) in the family (biology), famil ...

es. It is a structural analogue of the

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

opioid analgesic

fentanyl Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...

.. It is typically administered in this context by

tranquilizer dart A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are central nervous system (CNS) depressants and interact with brain activity, causing its deceleration. Various kinds of sedatives c ...

. Carfentanil has also been used in humans to

image An image or picture is a visual representation. An image can be Two-dimensional space, two-dimensional, such as a drawing, painting, or photograph, or Three-dimensional space, three-dimensional, such as a carving or sculpture. Images may be di ...

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

s. It has additionally been used as a

recreational drug Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...

, typically by

injection Injection or injected may refer to: Science and technology * Injective function, a mathematical function mapping distinct arguments to distinct values * Injection (medicine), insertion of liquid into the body with a syringe * Injection, in broadca ...

, insufflation, or

inhalation Inhalation (or inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

. Deaths have been reported in association with carfentanil. Effects and

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of carfentanil in humans are similar to those of other opioids and include

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

, relaxation,

pain relief Pain management is an aspect of medicine and health care involving relief of pain (pain relief, analgesia, pain control) in various dimensions, from acute and simple to chronic and challenging. Most physicians and other health professionals ...

, pupil constriction,

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

, slowed heart rate, low blood pressure, lowered body temperature,

loss of consciousness Unconsciousness is a state in which a living individual exhibits a complete, or near-complete, inability to maintain an awareness of self and environment or to respond to any human or environmental stimulus. Unconsciousness may occur as the re ...

, and suppression of breathing. The effects of carfentanil, including

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

, can be reversed by 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 ...

naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

and

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

, though higher doses than usual may be necessary compared to other opioids. It acts as an ultrapotent and highly selective

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of 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 ...

. Carfentanil was first synthesized in 1974 by a team of chemists at Janssen Pharmaceuticals which included Paul Janssen. It was introduced into veterinary medicine in 1986. Carfentanil is legally controlled in most jurisdictions.

Uses

Veterinary use

Chosen for its high

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

, carfentanil was first sold in 1986 under the brand name "Wildnil" for use in combination with an α₂-receptor agonist as a tranquilizing agent for

ungulates Ungulates ( ) are members of the diverse clade Euungulata ("true ungulates"), which primarily consists of large mammals with hooves. Once part of the clade "Ungulata" along with the clade Paenungulata, "Ungulata" has since been determined to b ...

like hippos, rhinos, and elephants, and large carnivores. Commercial production of Wildnil ceased in 2003; the drug is now available only in compounded form and not available for veterinary use due to human abuse. Since then,

etorphine Etorphine (M99) is a semi-synthetic opioid possessing an analgesic potency approximately 1,000–3,000 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather the re ...

has become the standard tranquilizing agent for large mammals, with

diprenorphine Diprenorphine (brand name Revivon; former developmental code name M5050), also known as diprenorfin, is a non-selective, high-affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) (with equal affinity) which ...

as the preferred reversal agent. Diprenorphine was also used previously to reverse the effects of carfentanil.

Clinical use

Carfentanil has been used at doses of less than 7 μg as a radiotracer for

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image). Imaging technology is the application of materials and methods to create, preserve, or duplicate images. ...

of the

in the brain in humans.

Pharmacology

Pharmacodynamics

Carfentanil acts as a highly selective

of the

. It showed

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 Pa ...

values (''K''_''i'') of 0.051 nM for the μ-opioid receptor, 4.7 nM for the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

, and 13 nM for the

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, 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 re ...

in rat brain. Thus, carfentanil displayed 90- and 250-fold selectivity for the μ-opioid receptor over the δ-opioid receptor and the κ-opioid receptor, respectively. With human proteins, the affinities were 0.024 nM for the μ-opioid receptor, 3.3 nM for the δ-opioid receptor, and 43 nM for the κ-opioid receptor, demonstrating 140- and 1,800-fold selectivity for the μ-opioid receptor over the δ- and κ-opioid receptors, respectively. Carfentanil appears to have higher affinity for the μ₁-opioid receptor over the μ₂-opioid receptor. Carfentanil has approximately 10,000 times the

potency of

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

, 4,000 times the potency of

heroin Heroin, also known as diacetylmorphine and diamorphine among other names, is a morphinan opioid substance synthesized from the Opium, dried latex of the Papaver somniferum, opium poppy; it is mainly used as a recreational drug for its eupho ...

, and 20 to 100 times the potency of fentanyl in animal studies. The effects of carfentanil are reversed by μ-opioid receptor antagonists like

and

, though higher than normal doses of these agents may be necessary in humans due to the extremely high potency of carfentanil.

Pharmacokinetics

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

chemical that can easily cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, carfentanil has a very rapid onset of action and is longer acting than fentanyl. Its

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

in humans was 42 to 51 minutes following an intravenous bolus at an average dose of 1.34 μg (19 ng/kg). However, in a case study of recreational exposure, the half-lives of carfentanil and its

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

norcarfentanil were estimated to be 5.7 hours and 11.8 hours, respectively.

Chemistry

Carfentanil is an analogue of

and is also known as (4methoxycarbonyl)fentanyl. Related analogues of fentanyl include 4 phenylfentanyl, lofentanil (3methylcarfentanyl), N-methylnorcarfentanil, R-30490 (4methoxymethylfentanyl), sufentanil, and thiafentanil.

History

The first reported case of carfentanil overdose in a person was in 1986 when a veterinarian accidentally splashed 1.5mg carfentanil citrate into his eyes and mouth. Sedation occurred within 2 minutes and

was administered. The veterinarian was hospitalised but made a full recovery within a day.

Increase in illicit use

Over three hundred cases of overdose related to fentanyl and Carfentanil analogues were reported between August and November 2016 in several of the United States, including

Ohio Ohio ( ) is a U.S. state, state in the Midwestern United States, Midwestern region of the United States. It borders Lake Erie to the north, Pennsylvania to the east, West Virginia to the southeast, Kentucky to the southwest, Indiana to the ...

West Virginia West Virginia is a mountainous U.S. state, state in the Southern United States, Southern and Mid-Atlantic (United States), Mid-Atlantic regions of the United States.The United States Census Bureau, Census Bureau and the Association of American ...

Indiana Indiana ( ) is a U.S. state, state in the Midwestern United States, Midwestern region of the United States. It borders Lake Michigan to the northwest, Michigan to the north and northeast, Ohio to the east, the Ohio River and Kentucky to the s ...

Kentucky Kentucky (, ), officially the Commonwealth of Kentucky, is a landlocked U.S. state, state in the Southeastern United States, Southeastern region of the United States. It borders Illinois, Indiana, and Ohio to the north, West Virginia to the ...

and

Florida Florida ( ; ) is a U.S. state, state in the Southeastern United States, Southeastern region of the United States. It borders the Gulf of Mexico to the west, Alabama to the northwest, Georgia (U.S. state), Georgia to the north, the Atlantic ...

. In 2017, a

Milwaukee Milwaukee is the List of cities in Wisconsin, most populous city in the U.S. state of Wisconsin. Located on the western shore of Lake Michigan, it is the List of United States cities by population, 31st-most populous city in the United States ...

Wisconsin Wisconsin ( ) is a U.S. state, state in the Great Lakes region, Great Lakes region of the Upper Midwest of the United States. It borders Minnesota to the west, Iowa to the southwest, Illinois to the south, Lake Michigan to the east, Michig ...

man died from a Carfentanil overdose, likely taken unknowingly with another illegal drug such as

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

. Carfentanil is most often taken with

or by users who believe they are taking heroin. Carfentanil is added to or sold as heroin because it is less expensive, easier to obtain, and easier to manufacture than heroin.

Importation from China

Authorities in Latvia and Lithuania reported seizing Carfentanil as an illicit drug in the early 2000s. Around 2016, the United States and Canada reported a dramatic increase in shipment of carfentanil and other strong

drugs to customers in North America from Chinese chemical supply firms. In June 2016, the

Royal Canadian Mounted Police The Royal Canadian Mounted Police (RCMP; , GRC) is the Law enforcement in Canada, national police service of Canada. The RCMP is an agency of the Government of Canada; it also provides police services under contract to 11 Provinces and terri ...

seized one kilogram of carfentanil shipped from China in a box labeled "printer accessories". According to the Canada Border Services Agency, the shipment contained 50 million potentially lethal doses of the drug, in containers labeled as

toner cartridge A toner cartridge, also called laser toner, is the consumable component of a laser printer. Toner cartridges contain toner powder, a fine, dry mixture of plastic particles, carbon, and black or other coloring agents that make the actual image ...

s for

HP LaserJet LaserJet is a line of laser printers sold by HP Inc. (originally Hewlett-Packard) since 1984. The LaserJet was the world's first commercially successful laser printer. Canon supplies both mechanisms and cartridges for most HP laser printers; so ...

printers. Carfentanil was not a controlled substance in China until 1 March 2017, and until then was manufactured legally and sold openly over the Internet, being actively marketed by several Chinese chemical companies.

Moscow theater hostage crisis

In 2012, a team of researchers at the British chemical and biological defence laboratories at Porton Down found carfentanil and remifentanil in clothing from two British survivors of the 2002

Moscow theater hostage crisis The Moscow theater hostage crisis, also known as the 2002 Nord-Ost siege, was the seizure of the crowded Dubrovka Theater in Moscow by Chechen terrorists on 23 October 2002, resulting in the taking of 912 hostages. The attackers, led by Movs ...

and in the urine from a third survivor. The team concluded that the Russian military had used an aerosol mist of carfentanil and remifentanil to subdue Chechen hostage takers. Researchers had previously surmised from the available evidence that the Moscow

emergency services Emergency services and rescue services are organizations that ensure public safety, security, and health by addressing and resolving different emergencies. Some of these agencies exist solely for addressing certain types of emergencies, while ot ...

had not been informed of the use of the agent, despite being instructed to bring

s to the scene. Unaware that hundreds of patients had been exposed to high doses of strong opioids, the emergency workers failed to bring sufficient quantities of

and

to counteract the effects of carfentanil and remifentanil. One hundred and twenty-five people exposed to the aerosol are confirmed to have died from

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...

during the incident.

Potential as a chemical weapon

The toxicity of carfentanil in humans and its ready commercial availability has raised concerns over its potential use as a chemical weapon of mass destruction by rogue nations and terrorist groups. The toxicity of carfentanil has been compared to that of

nerve gas Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that ...

Legal status

*It is scheduled as Class I drug in Canada. Class I classifications is for drugs that have no approved use in humans and poses a high risk for abuse. *Carfentanil has been controlled in China since 1 March 2017. The

trade war A trade war is an economic conflict often resulting from extreme protectionism, in which states raise or implement tariffs or other trade barriers against each other as part of their commercial policies, in response to similar measures imposed ...

between China and the United States has included controversy over the effectiveness of this control. *In Germany, carfentanil and its

stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms i ...

and

salts In chemistry, a salt or ionic compound is a chemical compound consisting of an assembly of positively charged ions ( cations) and negatively charged ions (anions), which results in a compound with no net electric charge (electrically neutral). ...

are controlled by the

Betäubungsmittelgesetz The Narcotic Drugs Act (, or BtMG) is the controlled substances law of Germany. In common with the Misuse of Drugs Act of 1971 of the United Kingdom and Controlled Substances Acts of the US and Canada, it is a consolidation of prior regulatio ...

as a Anlage I substance and can only be used with the special permission of the authorities. *Carfentanil is classified as Schedule II under the

Controlled Substances Act The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...

in the United States with a DEA ACSCN of 9743 and a 2016 annual aggregate manufacturing quota of 19 grams (less than 0.7 oz.). Carfentanil requires approval from the Drug Enforcement Agency for veterinary use. *Carfentanil has been specifically controlled as a Class A drug since 1986.

References

{{Opioid receptor modulators 1974 introductions Anilides Belgian inventions Carboxylate esters Fentanyl General anesthetics Janssen Pharmaceutica Methyl esters Mu-opioid receptor agonists Piperidines Propionamides Synthetic opioids Veterinary drugs Incapacitating agents

Uses

Veterinary use

Clinical use

Pharmacology

Pharmacodynamics

Pharmacokinetics

Chemistry

History

Increase in illicit use

Importation from China

Moscow theater hostage crisis

Potential as a chemical weapon

Legal status

See also

References