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Carfentanil

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Carfentanil or carfentanyl, sold under the brand name Wildnil, is an extremely potent opioid analgesic used in veterinary medicine to anesthetize large animals such as elephants and rhinoceroses.<ref name="pmid33581655">Template:Cite journal</ref> It is a structural analogue of the opioid analgesic fentanyl. It is typically administered in this context by tranquilizer dart.<ref name="pmid33581655" /> Carfentanil has also been used in humans to image opioid receptors.<ref name="pmid33581655" /> It has additionally been used as a recreational drug, typically by injection, insufflation, or inhalation.<ref name="pmid33581655" /> Deaths have been reported in association with carfentanil.<ref name="pmid33581655" /><ref name="pmid29367860" />

Effects and side effects of carfentanil in humans are similar to those of other opioids and include euphoria, relaxation, pain relief, pupil constriction, drowsiness, sedation, slowed heart rate, low blood pressure, lowered body temperature, loss of consciousness, and suppression of breathing.<ref name="pmid33581655" /> The effects of carfentanil, including overdose, can be reversed by the opioid antagonists naloxone and naltrexone, though higher doses than usual may be necessary compared to other opioids.<ref name="pmid33581655" /><ref name="pmid29367860" /><ref name="EMCDDA">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Rp Carfentanil is a structural analogue of the synthetic opioid analgesic fentanyl.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It acts as an ultrapotent and highly selective agonist of the μ-opioid receptor.<ref name="pmid33581655" />

Carfentanil was first synthesized in 1974 by a team of chemists at Janssen Pharmaceuticals which included Paul Janssen.<ref name="Janssen Tribute">Template:Cite journal</ref> It was introduced into veterinary medicine in 1986.<ref name="pmid33581655" /> Carfentanil is legally controlled in most jurisdictions.<ref name="pmid29367860" />

UsesEdit

Veterinary useEdit

Chosen for its high therapeutic index, carfentanil was first sold in 1986 under the brand name "Wildnil" for use in combination with an α2-receptor agonist as a tranquilizing agent<ref name="EMCDDA" />Template:Rp for ungulates like hippos, rhinos, and elephants, and large carnivores.<ref name="Janssen Tribute" /><ref name="lamont"/><ref name="jacobson">Template:Cite journal</ref> 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.<ref name="lamont"/><ref name="WHO Report">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid30666589">Template:Cite journal</ref> Since then, etorphine has become the standard tranquilizing agent for large mammals, with diprenorphine as the preferred reversal agent. Diprenorphine was also used previously to reverse the effects of carfentanil.<ref>Template:Cite journal</ref>

Clinical useEdit

Carfentanil has been used at doses of less than 7 μg as a radiotracer for positron emission tomography imaging of the μ-opioid receptor in the brain in humans.<ref name="pmid33581655" />

PharmacologyEdit

PharmacodynamicsEdit

Carfentanil acts as a highly selective agonist of the μ-opioid receptor.<ref name="pmid2982931">Template:Cite journal</ref> It showed affinity values (Ki) of 0.051 nM for the μ-opioid receptor, 4.7 nM for the δ-opioid receptor, and 13 nM for the κ-opioid receptor in rat brain.<ref name="pmid2982931" /> Thus, carfentanil displayed 90- and 250-fold selectivity for the μ-opioid receptor over the δ-opioid receptor and the κ-opioid receptor, respectively.<ref name="pmid2982931" /> 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.<ref name="pmid30666589" /> Carfentanil appears to have higher affinity for the μ1-opioid receptor over the μ2-opioid receptor.<ref name="pmid33581655" /> Carfentanil has approximately 10,000 times the analgesic potency of morphine, 4,000 times the potency of heroin, and 20 to 100 times the potency of fentanyl in animal studies.<ref name="pmid33581655" /><ref name="pmid29367860" /><ref name="pmid30666589" /> The effects of carfentanil are reversed by μ-opioid receptor antagonists like naloxone and naltrexone, though higher than normal doses of these agents may be necessary in humans due to the extremely high potency of carfentanil.<ref name="pmid33581655" /><ref name="pmid29367860">Template:Cite journal</ref>

PharmacokineticsEdit

A lipophilic chemical that can easily cross the blood–brain barrier, carfentanil has a very rapid onset of action and is longer acting than fentanyl.<ref name="EMCDDA" />Template:Rp Its elimination half-life in humans was 42 to 51 minutes following an intravenous bolus at an average dose of 1.34 μg (19 ng/kg).<ref name="pmid33581655" /><ref name="pmid29367860" /> However, in a case study of recreational exposure, the half-lives of carfentanil and its metabolite norcarfentanil were estimated to be 5.7 hours and 11.8 hours, respectively.<ref name="pmid33581655" /><ref>Template:Cite journal</ref>

ChemistryEdit

File:Fentanyl numbering.svg
Nomenclature for derivatives of fentanyl

Carfentanil is an analogue of fentanyl and is also known as (4Template:Nbhmethoxycarbonyl)fentanyl. Related analogues of fentanyl include 4Template:Nbhphenylfentanyl, lofentanil (3Template:Nbhmethylcarfentanyl), N-methylnorcarfentanil, R-30490 (4Template:Nbhmethoxymethylfentanyl), sufentanil, and thiafentanil.

HistoryEdit

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 naltrexone was administered. The veterinarian was hospitalised but made a full recovery within a day.<ref name="lamont"/>

Increase in illicit useEdit

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File:Fentanyl. 2 mg. A lethal dose in most people.jpg
CitationClass=web }}</ref> but is predicted to be much smaller.<ref name=2018Oct26>Template:Cite journal 26 October 2018. From the conclusion: "Postmortem concentrations seemed to correlate with their potency, although the presence of other CNS depressants, such as ethanol and benzodiazepines has to be taken into account."</ref> Diameter of a US penny is 19.05 mm, or 0.75 inches.

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, West Virginia, Indiana, Kentucky and Florida.<ref name ="Time_Ohio">Template:Cite magazine</ref> In 2017, a Milwaukee, Wisconsin man died from a Carfentanil overdose, likely taken unknowingly with another illegal drug such as heroin or cocaine.<ref>Template:Cite news</ref> Carfentanil is most often taken with heroin 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.<ref name="AP_Weber" />

Importation from ChinaEdit

Authorities in Latvia and Lithuania reported seizing Carfentanil as an illicit drug in the early 2000s.<ref name="AP_Weber" /><ref name="Europe">Template:Cite journal</ref>

Around 2016, the United States and Canada reported a dramatic increase in shipment of carfentanil and other strong opioid drugs to customers in North America from Chinese chemical supply firms. In June 2016, the Royal Canadian Mounted Police 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 cartridges for HP LaserJet printers.<ref name="AP_Weber">Template:Cite news</ref>

Carfentanil was not a controlled substance in China until 1 March 2017,<ref>Template:Cite news</ref> and until then was manufactured legally and sold openly over the Internet, being actively marketed by several Chinese chemical companies.<ref name="AP_Weber" />

Moscow theater hostage crisisEdit

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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 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.<ref>Template:Cite journal</ref> Researchers had previously surmised from the available evidence that the Moscow emergency services had not been informed of the use of the agent, despite being instructed to bring opioid antagonists 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 naloxone and naltrexone 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 during the incident.<ref>Template:Cite journal</ref>

Potential as a chemical weaponEdit

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.<ref name="AP_Weber" />

Society and cultureEdit

Legal statusEdit

CanadaEdit

Carfentanil 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.<ref name="lamont"/>

ChinaEdit

Carfentanil has been controlled in China since 1 March 2017.<ref name="EMCDDA" />Template:Rp The trade war between China and the United States has included controversy over the effectiveness of this control.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref><ref>Template:Cite news</ref>

GermanyEdit

Carfentanil and its stereoisomers and salts are controlled by the Betäubungsmittelgesetz as a Anlage I substance and can only be used with the special permission of the authorities.

United StatesEdit

Carfentanil is classified as Schedule II under the Controlled Substances Act 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.).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Carfentanil requires approval from the Drug Enforcement Agency for veterinary use.<ref name="lamont">Template:Cite book</ref> 1081|publisher=Wiley Blackwell}}</ref>

United KingdomEdit

Carfentanil has been specifically controlled as a Class A drug since 1986.<ref name=ABC>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

See alsoEdit

ReferencesEdit

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