Expert Committee on Drug Dependence Thirty-ninth Meeting Geneva, 6-10 November 2017 Expert Peer Review for Carfentanil 1. Comments based on the review report a. Evidence on dependence and abuse potential Dependence potential: Carfentanil is a synthetic opioid agonist belonging to the 4- anilidopiperidine class of synthetic opioid analgesics that includes fentanyl, sufentanil, alfentanil, and remifentanil. It is described as an analogue of fentanyl considered to be one of the most potent opioids known. Information from the pre-review report did not demonstrate data on the dependence potential of carfentanil; controlled animal or human studies in this regard have not been performed. On the other hand the pharmacodynamic similarities between carfentanil and very potent opioid agonists are clearly described with selective binding of carfentanil to the μ, δ and κ opioid receptors. Its peculiar chemical and pharmacokinetic properties account for its easy and rapid absorption, rapid onset of action, longer lasting effects and extremely higher potency. The latter is related to its serious human health hazard; with carfentanil having a qualitative potency of 10,000 times that of morphine and 100 times that of fentanyl. Abuse potential: There is lack of published preclinical or clinical abuse liability studies with carfentanil. There is also no data regarding the comparative euphoric effects of carfentanil in spite of its increased analgesic potency but laboratory studies in humans with fentanyl (which has pharmacologic effects related to carfentanil) demonstrate subjective effects comparable with other μ receptor agonists like heroine and alfentanil. However, considering the pharmacologic similarities between carfentanil and other very potent opioids, abuse of carfentanil is likely to occur. b. Risks to individual and society because of misuse The clinical features of carfentanil toxicity in humans are similar to those seen following toxicity with opioids and include sedation, dizziness and profound respiratory depression. Apnoea and death can occur following an overdose. Respiratory depression is typically rapid and severe and is related to its extreme potency; opioid antagonists such as naloxone or naltrexone are usually required to reverse the effects. Page 1 of 5
In some reported cases, several doses of naloxone and even infusions were required because of its unusually high potency. The risk of toxicity, overdose and death, has been associated with the difficulty in diluting the substance and the use of routes of administration with high bioavailability (such as injecting, insufflation, and inhalation). The risk has also been found to be more in persons inexperienced with its dosing, those with no or limited tolerance to opioids, administration of the drug while alone and the use of other central nervous system depressants at the same time (such as other opioids, benzodiazepines, gabapentanoids, and alcohol). Reports of toxicity due to snorting of carfentanil inadvertently (where it was believed to be cocaine or other substances) were also described. This is not uncommon because carfentanil is typically added to or sold as heroin, other opioids or prescription pills in the illicit market and many users unaware they are taking carfentanil. There are also reports that carfentanil-laced cocaine is being sold in the United States. The extreme potency of carfentanil makes it inappropriate for use in humans. As a result carfentanil was intended for large-animal use only, being marketed as a general anaesthetic agent. Misuse in humans has been associated with an increasing number of fatalities. It s often fatal effects especially in combination with other substances have contributed to the peculiar street names given to these combinations such as gray death, drop dead and serial killer. The pre-review report documented a substantial increase in the reports of fatal overdoses involving carfentanil. It was also stated that carfentanil contributed enormously to the opioid epidemic in the United States. However, the exact incidence rate of carfentanil overdoses could not be described in the report especially since most toxicology examinations for suspected opioid overdose deaths do not routinely test for carfentanil and other emerging fentanyl analogs. The report stated that the rate of carfentanil-related incidents may be underestimated due to lack of detection. For instance in Miami-Dade County, carfentanil was initially missed in 104 of the 134 cases until a more sensitive method was used to facilitate detection. In 2002, after the chemical aerosol spray by Russian military personnel to raid hostageholding Chechen terrorists in Moscow mass fatalities were recorded. Carfentanil and remifentanil were detected on clothing and urine samples of survivors. Its availability has raised concerns over its potential use as a weapon of mass destruction by terrorist groups or by countries as a tool of war for offensive or defensive applications. c. Magnitude of the problem in countries (misuse, illicit production, smuggling etc.) Following the first case of carfentanil seizures reported in 2012 in Latvia, it was linked to a spate of deaths among injecting drug users in that country. The pre-review reported that between November 2016 and May 2017, acute intoxications with confirmed exposure to carfentanil were reported by France and Lithuania. Although the analytical detection of other substances was not reported, these intoxications were Page 2 of 5
considered life-threatening in 2 cases and required hospitalization of all three patients. Additionally, a total of 48 deaths with confirmed exposure to carfentanil were reported by Belgium (1 case), Estonia (6), Finland (1), Lithuania (7), Norway (1), Sweden (3), and the United Kingdom (29). The cases occurred between November 2016 and the first half of 2017; at least 57 % of the deaths occurred in the United Kingdom between February and May 2017. Carfentanil was also detected in overdose deaths in Ohio, Florida and Hamilton County. In Hamilton County, carfentanil accounted for at least 8 overdose deaths between July and September 2016. In Hillsborough County, Florida, deaths from fentanyl and fentanyl analogs increased by more than twofold between 2014-16 and carfentanil was identified and ruled to be the cause of 2 overdose deaths alone or in combination with other drugs in 2016. In Miami-Dade County, carfentanil was detected in 134 overdose deaths starting in July 2016. The report described the threat posed by carfentanil to public health as serious. Illicit production of carfentanil was also demonstrated in the report along with illicit on-line markets. Certain internet sites were noted to provide information on both illicit purchase and importation of carfentanil; users being encouraged to buy as a result of its relatively cheaper price compared to heroin. The report also stated that clandestinely manufactured carfentanil had been shipped via mail services from China to Canada, the U.S., and Mexico, where they were used as adulterants in other controlled substances such as heroin, cocaine, and methamphetamine. Prior to the rescheduling of carfentanil in China, Canadian authorities reported seizure of a one kilogram shipment from China equivalent to 50 million lethal doses. Seizures of carfentanil were reported in many other countries- Canada, Australia, Belgium, Estonia, Germany, Finland, Latvia, Lithuania, Sweden and in the United Kingdom. In some cases carfentanil was found alone or detected in a mixture with heroin, medications, other opioids e.g. methadone or other psychoactive substances e.g. alpha-php. Both powder and liquid mixtures were identified. d. Need of the substance for medical (including veterinary) practice Carfentanil is used as an anaesthetic agent for large animals in veterinary medicine. Extreme caution and use of protective equipment is strictly advised during exposure of veterinary workers to carfentanil. It has no known therapeutic use in humans. e. Need of the substance for other purposes (e.g. industrial) No data on other uses. No known industrial use. f. Measures taken by countries to curb misuse The pre-review report stated that carfentanil has been placed under National Control in the United States (Schedule II of the Controlled Substances Act along with e.g. codeine and morphine), Canada (Schedule I along with e.g. codeine and morphine), the UK Page 3 of 5
(Schedule 2, Class A substance along with cocaine, methadone and morphine) and Australia (S8 along with methadone and morphine). On March 1, 2017 carfentanil was added to the list of controlled substances in China; prior to this date it was legally manufactured and sold to other countries. In Germany, carfentanil is classified as a narcotic and is only authorized for scientific use. Carfentanil is also controlled under various control legislations in Belgium, Cyprus, Czech Republic, Denmark, Estonia, Germany, Ireland, Latvia, Lithuania, Sweden, the United Kingdom, Norway, Austria, Hungary and Poland. It is controlled under medicines legislation in Finland but it is not under any national control measures in Bulgaria, Croatia, France, Greece, Italy, Luxembourg, Malta, the Netherlands, Portugal, Romania, Slovakia, Slovenia and Spain. g. Impact if this substance is scheduled The administrative burdens on veterinary and research institutions following strict scheduling of carfentanil will be offset by likely reduction in the harms due to the abuse potential. Scheduling should have limited impact on legitimate veterinary and research use. Scheduling would also be one method to place uniform limitations on the use of carfentanil for countries who are signatories to International Conventions. There will be control measures on manufacturing, exportation, importation and distribution. In addition, diversion will be limited and trafficking will be interrupted. Countries will have the laboratory capacity to identify it. 2. Are there absent data that would be determinative for scheduling? There is no absent data that would determinative for scheduling. 3. Other comments or opinions No additional comments. 4. Expert reviewer s view on scheduling with rational Carfentanil is one of the most potent synthetic opioids. It is convertible into sufentanil and alfentanil which are two very potent opioid analgesics. Although there are no controlled preclinical and clinical studies on the abuse and dependence liability of carfentanil, it is pharmacologically similar to fentanyl, sufentanil, alfentanil, and remifentanil which are Schedule I drugs under the U.N. 1961 Single Convention on Narcotic Drugs. It is therefore Page 4 of 5
liable to similar abuse and productive of similar ill effects as some of these substances which are already in Schedule I. Carfentanil has therapeutic uses in animals; it is mainly used as an anaesthetic in large animals. There is however information regarding its capacity to induce significant harm in humans, including death. As a result of its extreme potency, potential harmful uses on a large scale basis and pharmacological similarity to substances in Schedule I under the U.N. 1961 Single Convention on Narcotic Drugs, it would be appropriate to consider scheduling carfentanil likewise. Based on this, I recommend that the Expert Committee should proceed to a critical review of carfentanil. Page 5 of 5