Fentanyls Continue to Replace Heroin in the Drug Arena: the Cases of Ocfentanil and Carfentanil
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Forensic Toxicol DOI 10.1007/s11419-017-0379-4 REVIEW ARTICLE Fentanyls continue to replace heroin in the drug arena: the cases of ocfentanil and carfentanil 1 1 1 1 Nektaria Misailidi • Ioannis Papoutsis • Panagiota Nikolaou • Artemisia Dona • 1 1 Chara Spiliopoulou • Sotiris Athanaselis Received: 2 June 2017 / Accepted: 23 July 2017 Ó The Author(s) 2017. This article is an open access publication Abstract concern for public safety. The authorities should take the Purpose Ocfentanil and carfentanil are two potent syn- appropriate actions to avoid the expansion of this threat by thetic opioids that are analogues of fentanyl and are taking proper and prompt measures. actively involved in the recent fentanyl crisis. The aim of this review is to provide all the available information on Keywords Ocfentanil Á Carfentanil Á Synthetic opioids Á these two fentanyl analogues. Gray deaths Á Toxicology Á Legal status Methods All reviewed information was gathered through a detailed search of PubMed and the World Wide Web using relevant keywords. Introduction Results Like most of the members of the family of fen- tanyls, they are either sold as heroin to unsuspecting users New psychoactive substances (NPS) are a group of sub- or used extensively to lace heroin street samples. Despite stances that are sold in pure form or as a mixture with other the fact that ocfentanil was studied clinically in the early drugs of abuse and are widely abused. Most of these sub- 1990s, it did not manage to find its place in clinical prac- stances are not controlled under the 1961 Single Conven- tice. On the other hand, carfentanil is mainly used today as tion on Narcotic Drugs or the 1971 Single Convention on an anesthetic agent in large animals. Ocfentanil and car- Psychoactive Substances [1]. The rapid spread of NPS in fentanil are used and abused extensively, mainly in Europe the illegal drug market poses a significant risk for the and in the United States. As a result, they are the cause of public health and seems to present a serious matter of some verified intoxication cases and deaths worldwide. concern because of a high number of these drugs emerging This review provides information concerning chemistry, every year [2, 3]. Synthetic opioids hold a significant synthesis, prevalence, pharmacology, and toxicology, as position among NPS as they are highly potent drugs that well as the current legal status of these two fentanyl ana- are often sold as heroin to unsuspected drug users [3]. logues. Analytical methods developed for the determina- Among them, fentanyl is an important substance that is tion of ocfentanil and carfentanil in biological specimens used extensively as a powerful pain killer and is also and seized materials, as well as related intoxication and abused by a large number of drug addicts [4, 5]. More than lethal cases are also presented. 1400 fentanyl analogues have been synthesized over the Conclusions Ocfentanil and carfentanil are undeniably years in order to mimic fentanyl’s opioid effects and out- very dangerous opioid drugs and a very serious matter of smart the law because fentanyl is a controlled substance in most countries internationally [6, 7]. Two hundred of these analogues have been studied pharmacologically, 12 of & Panagiota Nikolaou which have entered the illegal drug market during the last 5 [email protected] years [6]. Ocfentanil is a short-acting fentanyl analogue that was 1 Department of Forensic Medicine and Toxicology, Faculty of Medicine, National and Kapodistrian University of Athens, firstly described in a US patent by Huang et al. [8]. It had 75 Mikras Asias, 115 27 Athens, Greece been studied for its analgesic activity and was found to be 123 Forensic Toxicol more potent than fentanyl and with fewer adverse effects, and Applied Chemistry (IUPAC) name is N-(2-fluo- regarding cardiovascular effects and respiratory depression rophenyl)-2-methoxy-N-[1-(2-phenylethyl)-piperidin-4-yl] [9]. The drug has also been studied as a supplement in acetamide, but it can also been found under the names 1-(2- general anesthesia [10]. Ocfentanil was the cause of some phenylethyl)-4-[N-(2-fluorophenyl)methoxyac- verified intoxication cases and deaths, mainly in Europe, etamido]piperidine hydrochloride, N-(2-fluorophenyl)-2- and threatens to be an imminent hazard to the public safety methoxy-N-[1-(2-phenylethyl)-4-piperidinyl]acetamide, [6, 11–15]. Some ocfentanil-related cases have been also ocfentanyl, ocfentanilo, UNII-MX52WBC8EV and A-3217 presented at different scientific conferences [16–18]. [53]. Ocfentanil is sold either as its base with the molecular Carfentanil is the most potent of the commercially formula C22H27FN2O2 (molecular weight 370.46 g/mol) or available fentanyl analogues [19, 20]. It was synthesized in as its hydrochloric acid salt C22H27FN2O2 HCl (molecular 1974 by a group of chemists at Janssen Pharmaceuticals, weight 406.9 g/mol) in a white or brown crystalline pow- and since then it has been used in veterinary medicine as a der form [50, 53, 54]. The Chemical Abstracts Service tranquilizer for the sedation of large animals [21–29]. (CAS) number of ocfentanil is 101343-69-5 [53–55]. It has Carfentanil has been pharmacologically studied mostly in a melting point of 183–184 °C, and there are no data animals, but also in humans [23, 28–39]. Some evidence regarding its boiling point [8, 54]. The drug is soluble in suggests that it has been used as a chemical weapon by the aqueous media at a pH below 7 (pKa = 7.82) and stable to Russian military, while attempting to subdue a terrorist moderate heat and light, if stored properly [10, 54]. siege of the Moscow Theater [40, 41]. Carfentanil is often used to adulterate heroin, fentanyl, and other drugs of Synthesis abuse [19, 42, 43]. During recent years, this fentanyl ana- logue has been responsible for a significant number of The synthesis of ocfentanil was first described in US patent accidental intoxication cases and deaths mostly in the number 4,584,303 by Huang et al. [8]. Initially 1-phe- United States [40, 44–46]. Intentional intake of carfentanil nethyl-4-piperidone reacts with 2-fluoro aniline. The does not seem to happen very often, because most drug resulting compound is a Schiff base that is reduced to the users are well informed about its potency and its harmful corresponding diamine, by sodium borohydride or lithium potential [47–49]. aluminum hydride. The acylation of the secondary amino The aim of this review is to provide all the available group with 2-methoxyacetyl chloride (methyl chlorofor- information on ocfentanil and carfentanil, regarding their mate) leads to the final product by yielding 1-(2-pheny- chemistry, synthesis, prevalence, pharmacology, toxicol- lethyl)-4-[N-(2-fluorophenyl)methoxyacetamido]piperi- ogy, and their current legal status. Analytical methods for dine. The whole synthetic route is presented in Fig. 2 the determination of ocfentanil and carfentanil in biological [8, 51]. specimens and seized materials, as well as related intoxi- cations and fatal cases are also presented. All the reviewed Prevalence and use information was gathered through a detailed search of PubMed and the World Wide Web using the keywords Despite the fact that ocfentanil had been studied clinically ‘‘ocfentanil’’, ‘‘carfentanil’’, ‘‘pharmacology’’, ‘‘toxicol- during early 1990s, it did not manage to find its place in ogy’’, ‘‘intoxications’’, ‘‘fatalities’’, ‘‘determination’’, ‘‘bi- clinical practice [10, 56–58]. As a drug of abuse, it ological fluids’’, and ‘‘legal status’’. emerged recently on the illegal drug market along with other fentanyl analogues [12–14, 59]. Ocfentanil was among the 81 NPS that were reported to the Early Warning Ocfentanil System (EWS) of European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in 2013, after the drug Chemistry was identified in a seizure made by Dutch police, which might have been intended for sale as ‘‘synthetic heroin’’, in Ocfentanil is a synthetic analogue of fentanyl (Fig. 1) that October 2013. A related alert for ocfentanil was issued by possesses a methoxy group instead of a methyl group and a EMCDDA and Europol in the same year [44, 60]. fluorine atom on the ortho position of the aniline group According to the Early Warning Advisory (EWA) of the [50, 51]. Ocfentanil and ocfentanilum (in Latin) are the United Nations Office of Drugs and Crime (UNODC), proposed international nonproprietary names given by the ocfentanil is among the 14 fentanyl analogues that have World Health Organization (WHO) in accordance with been reported in Europe within 2012–2016 and it is among article 3 of the Procedure for the Selection of Recom- the 15 different synthetic opioids that have been reported to mended International Nonproprietary Names for Pharma- EMCDDA during 2009–2015 [6, 15]. The National Drug ceutical Substances [52]. Its International Union of Pure EWS (NDEWS) also issued an alert for ocfentanil among 123 Forensic Toxicol Fig. 1 Structures of fentanyl, ocfentanil, and carfentanil Fig. 2 Synthesis of ocfentanil according to Huang et al. [8] other fentanyl analogues [61]. It has been associated with acid [12, 13, 50, 59, 65, 69–71]. In many cases, ocfentanil is some intoxication cases and deaths mostly in Europe used to adulterate heroin; thus heroin users can be exposed to [6, 11–14, 62]. Ocfentanil has also been reported in Fin- ocfentanil without knowing it [12–14, 50, 59, 65, 68–71, 75]. land, France, Ireland, Luxembourg, Spain, Sweden, and the Cases in which fentanyls are sold under the guise of heroin United Kingdom [6, 59, 63–66]. The drug is also among are common worldwide [6]. In some, ocfentanil was labeled other synthetic opioids that are a current matter of concern and sold in the darknet as heroin or ‘‘synthetic heroin’’ in the United States and Canada [67, 68].