Carfentanil

Substance identification
Chemically, carfentanil is Methyl 1-(2-phenylethyl)-4-[phenyl(propanoyl) amino]piperidine-4-carboxylate. Carfentanil has no stereoisomers.

Previous review
Carfentanil has not been previously pre-reviewed or critically reviewed. A critical review was initiated due to a notification from a Party to the Conventions concerning the scheduling of a substance.

Similarity to known substances and effects on the central nervous system
Carfentanil contains a carboxymethyl group in the fourth position of the piperidine ring of fentanyl, a drug regulated under Schedule I of the 1961 Single Convention on Narcotic Drugs. Carfentanil can be easily converted into sufentanil and alfentanil, which are Schedule I drugs under the 1961 Convention on Narcotic Drugs. Carfentanil binds with high affinity to μ-opioid receptors, and less so to δ- and κ-opioid receptors. Similar to other μ-opioid agonists, it depresses the respiratory centre, produces analgesia, and causes drowsiness, nausea, miosis and sedation. As an analgesic, carfentanil is approximately 10 000 times more potent than morphine. The pharmacodynamic effects of carfentanil can be reversed by opioid antagonists, such as naloxone and naltrexone although re-narcotization can occur.

Dependence potential
Carfentanil has been demonstrated to prevent and alleviate signs of withdrawal in the morphine-dependent rhesus monkey indicating its cross-dependency with morphine. No controlled dependence studies in human subjects have been reported.

Actual abuse and/or evidence of likelihood of abuse
No controlled experimental studies have been conducted investigating the abuse potential of carfentanil. In vitro and in vivo studies present carfentanil as a typical μ-opioid agonist, similar in its pharmacology to the controlled substance, fentanyl. Its pharmacokinetic properties account for its easy and rapid absorption, rapid onset of action and extreme potency. The latter is related to its serious hazardousness to human health, because carfentanil has a qualitative potency 10 000 times that of morphine and 100 times that of fentanyl.

Carfentanil has been detected in powder form in 618 seizures in Europe, amounting to nearly 2.7 kg of seized material (equivalent to 27 000 kg of morphine). It has also been identified in seizures in North America, where it has been sold as counterfeit oxycodone or alprazolam tablets. Carfentanil is used as an adulterant of other controlled substances such as heroin, cocaine and metamfetamine. Carfentanil has been associated with hundreds of deaths in North America and in Europe. Estimates of its lethality are challenging because carfentanil is not always routinely tested for following overdose and because the concentrations are typically extremely low in biological samples. Carfentanil has been placed under some form of national regulation by numerous countries in different regions.

Therapeutic usefulness
Carfentanil has been used in veterinary medicine since 1986, primarily for immobilizing large animals, because of its extreme potency. Etorphine, another opioid compound used in veterinary medicine for immobilizing large animals, is in Schedule I and IV of the Single Convention on Narcotic Drugs, 1961, but is less dangerously potent than carfentanil. Labelled carfentanil ([11C]-carfentanil) is used as a positron emission tomography (PET) radiotracer. It has no approved therapeutic use in humans.

Recommendation
Carfentanil is convertible into sufentanil and alfentanil, two very potent opioid analgesics controlled as Schedule I drugs under the 1961 Convention on Narcotic Drugs. It is a μ-opioid receptor agonist, and its pharmacodynamic and clinical effects are similar to those of fentanyl but it is about 100 times more potent. It binds to opioid receptors, and produces respiratory depression, decreased consciousness, antinociception and miosis. The substance has been associated with hundreds of deaths and nonfatal intoxications globally, and is a significant concern in a number of countries. Due to the extremely small doses that induce lethal effects, it poses a particularly serious threat to public health.

Carfentanil is a compound liable to similar abuse and with similar ill effects to controlled opioids such as fentanyl that are included in Schedule I of the Single Convention on Narcotic Drugs of 1961. There is sufficient evidence that it is being or is likely to be abused so as to constitute a public health and social problem warranting the placing of the substance under international control. Thus, because it meets the required condition of similarity, it is recommended that carfentanil (Methyl 1-(2-phenylethyl)-4-[phenyl(propanoyl)amino]piperidine- 4-carboxylate) be placed in Schedule I of the Single Convention on Narcotic Drugs, 1961, as consistent with Article 3, paragraph 3 (iii) of that Convention in that the substance is liable to similar abuse and productive of similar ill effects to drugs in Schedule I.

The Committee recognized the impact that international scheduling could have on veterinary access to carfentanil in relation to its therapeutic use in large animals. However, the Committee was particularly concerned about the extreme potency of the substance and the serious risk to public health. The Committee felt that the therapeutic advantages did not offset the severe threat to human health. As such, and taking into consideration that substances in Schedule IV afford Parties the opportunity to adopt special measures for drugs with particularly dangerous properties, the Committee recommended that carfentanil (Methyl 1-(2-phenylethyl)-4-[phenyl(propanoyl)amino]piperidine-4-carboxylate) be placed in Schedule IV of the UN Single Convention on Narcotic Drugs, 1961.