Critical Review Report:

Expert Committee on Drug Dependence Forty-second Meeting Geneva, 21-25 October 2019

This report contains the views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the World Health Organization 42nd ECDD (2019): Crotonylfentanyl

© World Health Organization 2019 All rights reserved.

nd This is an advance copy distributed to the participants of the 42 Expert Committee on Drug Dependence, before it has been formally published by the World Health Organization. The document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means without the permission of the World Health Organization.

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42nd ECDD (2019): Crotonylfentanyl Contents Acknowledgements ...... 5 Executive Summary ...... 6 1. Substance identification ...... 8 A. International Nonproprietary Name (INN) ...... 8 B. Chemical Abstract Service (CAS) Registry Number ...... 8 C. Other Chemical Names ...... 8 D. Trade Names ...... 8 E. Street Names ...... 8 F. Physical Appearance...... 8 G. WHO Review History ...... 8 2. Chemistry ...... 8 A. Chemical Name ...... 8 B. Chemical Structure ...... 8 C. Stereoisomers ...... 9 D. Methods and Ease of Illicit Manufacturing ...... 9 E. Chemical Properties ...... 10 F. Identification and Analysis ...... 10 3. Ease of Convertibility into Controlled Substances ...... 10

4. General Pharmacology ...... 10 A. Routes of Administration and Dosage ...... 10 B. Pharmacokinetics ...... 11 C. Pharmacodynamics ...... 11 5. Toxicology ...... 11

6. Adverse Reactions in Humans ...... 11

7. Dependence Potential ...... 11 A. Animal Studies...... 11 B. Human Studies ...... 11 8. Abuse Potential ...... 11 A. Animal Studies...... 11 B. Human Studies ...... 12 9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use ...... 12

10. Listing on the WHO Model List of Essential Medicines ...... 12

11. Marketing Authorizations (as a Medicinal Product) ...... 12

12. Industrial Use ...... 12

13. Non-Medical Use, Abuse and Dependence ...... 12

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42nd ECDD (2019): Crotonylfentanyl 14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence ...... 12

15. Licit Production, Consumption and International Trade ...... 13

16. Illicit Manufacture and Traffic and Related Information ...... 13

17. Current International Controls and Their Impact ...... 13

18. Current and Past National Controls ...... 13

19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance ...... 13

References ...... 14

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42nd ECDD (2019): Crotonylfentanyl Acknowledgements

This document was produced for the WHO Expert Committee on Drug Dependence (ECDD) under the overall direction of the WHO Secretariat led by Dr Gilles Forte (Division of Access to Medicines, Vaccines, and Pharmaceuticals). The document was written by Professor Sandra Comer under the technical direction of Dr Dilkushi Poovendran (Division of Access to Medicines, Vaccines, and Pharmaceuticals). The report was edited by Professor Kim Wolff. The member state questionnaire was produced under the technical direction of Ms Judith Sprunken (Division of Access to Medicines, Vaccines, and Pharmaceuticals).

The WHO Secretariat would also like to thank the European Monitoring Centre for Drugs and Drug Addiction (EMCCDA), International Narcotics Control Board (INCB), United Nations Office of Drugs and Crime (UNODC), and Member States for providing relevant information for the review of substances.

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42nd ECDD (2019): Crotonylfentanyl Executive Summary

Crotonylfentanyl is an isomer of and has a chemical structure that is similar to . It first appeared in toxicological assays in 2017 and has only been reported in the U.S. through 2018. No fatalities have been attributed to this substance although confiscations of drug containing crotonylfentanyl are reported in several states throughout the U.S. Preclinical behavioral pharmacology studies demonstrated that its effects were antagonized by , suggesting that it has activity at receptors. Its profile of effects is similar to other mu opioid agonists in that it substituted for in a drug discrimination assay, produced antinociception, and increased locomotor activity. No data are available on the respiratory depressant effects of crotonylfentanyl but overall, its pharmacology and toxic effects are likely to be similar to fentanyl. It currently has no legitimate medical or veterinary uses and is relatively easy to manufacture. The totality of data currently available on crotonylfentanyl suggests that it has high abuse potential and poses a serious public health threat.

Substance identification: Crotonylfentanyl ((2E)-N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-2- butenamide) is a structural isomer of cyclopropylfentanyl, which was synthesized by Paul Janssen as described in the patent literature in 1965 (U.S.) and 1968 (France). It is also known as crotonyl fentanyl.

WHO review history: The WHO has not previously reviewed crotonylfentanyl.

Chemistry: The proprioamide group of fentanyl is replaced by a 2-butenamide group for crotonylfentanyl. It can be synthesized from 4-Anilino-N-phenethylpiperidine (4-ANPP), which is also used to make fentanyl and other fentanyl analogues.

Ease of convertibility into controlled substances: No reports of conversion of crotonylfentanyl into other controlled substances were found in the scientific literature.

Similarity to known substances / Effects on the central nervous system: Crotonylfentanyl is a structural isomer of cyclopropylfentanyl and has a chemical structure that is similar to fentanyl. Preclinical behavioral pharmacology studies demonstrated that its effects were antagonized by naltrexone, suggesting that it has activity at opioid receptors. Its profile of effects is similar to other mu opioid agonists in that it substituted for oxycodone in a drug discrimination assay, produced antinociception, and increased locomotor activity. No data are available on the respiratory depressant effects of crotonylfentanyl.

General pharmacology: Studies in rodents suggest that the pharmacology of crotonylfentanyl is consistent with activity at mu opioid receptors: it shared discriminative stimulus effects with oxycodone, produced antinociceptive effects, and increased locomotor activity, all of which were antagonized by naltrexone. Its duration of antinociceptive action appeared to be longer than other fentanyl analogues, such as , but comparable to . Crotonylfentanyl was less potent than fentanyl and more potent than oxycodone and morphine (e.g., the potency ratio for crotonylfentanyl to fentanyl was 0.354 and crotonylfentanyl to morphine was 34.5 in the warm-water tail-withdrawal assay in mice).

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42nd ECDD (2019): Crotonylfentanyl

Toxicology: Neither preclinical nor clinical evaluations of the acute or chronic toxicological effects of crotonylfentanyl have been conducted.

Adverse reactions in humans: No reports are available on adverse reactions to crotonylfentanyl.

Dependence potential: The dependence potential of crotonylfentanyl has not been evaluated.

Abuse potential: The abuse potential of crotonylfentanyl has been evaluated in rodents using assays of drug discrimination, antinociception, and locomotor activity. These studies suggest that crotonylfentanyl has abuse potential similar to other mu opioid agonists with a potency less than fentanyl and greater than oxycodone.

Therapeutic applications / usefulness: Crotonylfentanyl is listed by the International Narcotics Control Board as a fentanyl-related substance with no known legitimate uses.

Listing on WHO Model List of Essential Medicines: Crotonylfentanyl is not listed as an essential medicine.

Marketing authorizations: None.

Industrial use: Crotonylfentanyl is available commercially for research and forensic purposes and as an analytical reference standard.

Non-medical use: No reports are available on the non-medical use of crotonylfentanyl.

Nature and magnitude of public health problems: The public health impact of crotonylfentanyl is unknown.

Licit production, consumption, and international trade: None.

Illicit manufacture and traffic: No information is available on the illicit manufacture and trafficking of crotonylfentanyl.

Current international controls and their impact: Crotonylfentanyl has not been subject to international control under the 1971 United Nations Convention on Psychotropic Substances or the 1961 Single Convention on Narcotic Drugs.

Current and past national controls: Crotonylfentanyl was included in the temporary scheduling of fentanyl analogues into Schedule 1 by the U.S. DEA on February 6, 2018 [21 CFR Part 1308, Docket No. DEA-476], as clarified by the DEA on April 18, 2019.

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42nd ECDD (2019): Crotonylfentanyl 1. Substance identification

A. International Nonproprietary Name (INN) Crotonylfentanyl

B. Chemical Abstract Service (CAS) Registry Number 760930-59-4 free base

C. Other Chemical Names (E)-N-(1-phenethylpiperidin-4-yl)-N-phenylbut-2-enamide; (2E)-N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]but-2-enamide; (2E)-N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-2-butenamide [ACD/IUPAC] (2E)-N-Phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-2-butenamid [German ACD/IUPAC] (2E)-N-Phényl-N-[1-(2-phényléthyl)-4-pipéridinyl]-2-buténamide [French ACD/IUPAC] 2-Butenamide, N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-, (2E)- [ACD/Index Name]

D. Trade Names None

E. Street Names None Other names and code names: crotonyl fentanyl

F. Physical Appearance Crotonylfentanyl is a yellow crystalline solid powder.

G. WHO Review History Crotonylfentanyl has not been reviewed previously by the WHO.

2. Chemistry

A. Chemical Name IUPAC Name: (2E)-N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-2-butenamide CA Index Name: Not found

B. Chemical Structure Free base:

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42nd ECDD (2019): Crotonylfentanyl

Molecular Formula: C23H28N2O Molecular Mass: 348.5 g/mol

C. Stereoisomers Crotonylfentanyl (B) and cyclopropylfentanyl (A) are structural isomers (see figure below excerpted from Maher et al., 2018). The proprioamide group of fentanyl (C) is replaced by a 2- butenamide group for crotonylfentanyl and a cyclopropane-carboxamide group for cyclopropylfentanyl. Two additional isomers of crotonylfentanyl have been reported, Z- crotonylfentanyl and E-crotonylfentanyl (Mallette et al., 2019; see Section 2.D. below).

D. Methods and Ease of Illicit Manufacturing

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42nd ECDD (2019): Crotonylfentanyl As excerpted above from Mallette et al. (2019), crotonylfentanyl was synthesized from 4-Anilino- N-phenethylpiperidine (4-ANPP; 1). Two isomers of crotonylfentanyl were obtained: Z- crotonylfentanyl (3) and E-crotonylfentanyl (2), as well as 3-butenylfentanyl (4), the latter of which was a previously unknown compound. Due to the sensitive nature of the subject matter, the exact synthesis procedures were not described.

E. Chemical Properties Melting point 195.06°C (mean or weighted MP)

Boiling point 476.32°C (adapted Stein & Brown method)

Solubility Water solubility at 25°C (mg/L): 1.5784

(http://www.chemspider.com/Chemical-Structure.8648371.html; accessed August 18, 2019)

F. Identification and Analysis Because the structure and chromatographic behavior of crotonylfentanyl and cyclopropylfentanyl are so similar, additional analytical techniques are required to differentiate these substances (Bierly and Graf, 2017). Specifically, high performance liquid chromatography with diode array UV detection (HPLC-DAD), high performance liquid chromatography-tandem mass spectrometry (LC- MS/MS), and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QToF-MS) can be used to differentiate the two compounds, as described by Maher et al. (2018). Evaluation of both chromatographic retention time and UV spectral analysis are needed to differentiate these isomers. Other analytical methods to differentiate crotonylfentanyl and cyclopropylfentanyl also have been described (Bergh et al., 2019; Lee et al., 2019; Mallette et al., 2019).

3. Ease of Convertibility into Controlled Substances No reports of conversion of crotonylfentanyl into other controlled substances were found.

4. General Pharmacology

A. Routes of Administration and Dosage Preclinical studies have established that crotonylfentanyl is less potent than fentanyl (Varshneya et al., 2019; Walentiny et al., 2019) and more potent than oxycodone (Walentiny et al., 2019) when given subcutaneously. No information about route of administration and dosage of crotonylfentanyl in humans is available but given its powder form and easy solubility in water, use of crotonylfentanyl via intranasal, intravenous, and other parenteral routes of administration seems feasible.

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42nd ECDD (2019): Crotonylfentanyl B. Pharmacokinetics No controlled pharmacokinetic studies of crotonylfentanyl have been reported. At the highest cumulative doses tested, the antinociceptive effects of crotonylfentanyl were above 50% maximum possible effect 2 hours after administration, which was similar to fentanyl and morphine (Varshneya et al., 2019).

C. Pharmacodynamics Studies in rodents (described in more detail below in Section 8.A.) suggested that the pharmacology of crotonylfentanyl was consistent with activity at opioid receptors: it shared discriminative stimulus effects with oxycodone, produced antinociceptive effects, and increased locomotor activity, all of which were antagonized by naltrexone (Varshneya et al., 2019; Walentiny et al., 2019). The overall profile of behavioral effects produced by crotonylfentanyl suggests that it is a mu agonist.

5. Toxicology No formal toxicology studies have been performed with crotonylfentanyl.

6. Adverse Reactions in Humans No controlled clinical studies have been conducted with crotonylfentanyl and no reports of fatal or non-fatal overdoses exist, so adverse reactions in humans due to crotonylfentanyl are unknown.

7. Dependence Potential

A. Animal Studies No preclinical dependence potential studies were found in the published literature.

B. Human Studies No clinical dependence potential studies were found in the published scientific literature.

8. Abuse Potential

A. Animal Studies In adult male C57BL/6J mice trained to discriminate 1.3 mg/kg s.c. oxycodone from saline, crotonylfentanyl fully substituted for oxycodone (Walentiny et al., 2019). At the dose that produced full substitution (0.32 mg/kg), the rate of responding significantly decreased. Crotonylfentanyl was less potent than fentanyl and more potent than oxycodone in this assay. Among the drugs that were tested, the following rank order of potency was observed: ocfentanil > fentanyl > 3-furanyl fentanyl ≈ crotonylfentanyl > oxycodone > valerylfentanyl. Pretreatment with 1 mg/kg naltrexone antagonized the lowest crotonylfentanyl dose that substituted for oxycodone (Walentiny et al., 2019).

In adult male Swiss Webster mice, crotonylfentanyl produced dose-related increases in antinociception in a warm-water tail withdrawal assay and locomotor activity (Varshneya et al.,

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42nd ECDD (2019): Crotonylfentanyl 2019). Naltrexone (1 mg/kg) antagonized the antinociceptive effects of crotonylfentanyl and increased its ED50 for this effect by 6.27 fold. The order of potency for antinociception was: isobutyrylfentanyl > fentanyl > para-methoxybutyrylfentanyl > crotonylfentanyl > para- fluorobutyrylfentanyl > thiophenefentanyl > valerylfentanyl > morphine > benzodioxolefentanyl. More specifically, the potency ratio for crotonylfentanyl to fentanyl was 0.354 and crotonylfentanyl to morphine was 34.5. At the highest cumulative doses tested, the antinociceptive effects of fentanyl, morphine, and crotonylfentanyl were above 50% maximum possible effect 2 hours after administration; the other drugs tested produced antinociception of much shorter duration (Varshneya et al., 2019). Consistent with its discriminative stimulus effects, crotonylfentanyl was less potent than fentanyl in producing antinociception and locomotor activity.

B. Human Studies No clinical abuse potential studies were found in the published scientific literature.

9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use Crotonylfentanyl is not approved in any country for therapeutic use.

10. Listing on the WHO Model List of Essential Medicines Crotonylfentanyl is not included in the WHO Model List of Essential Medicines.

11. Marketing Authorizations (as a Medicinal Product) Crotonylfentanyl is not approved in any country as a medicinal product. It is listed by the International Narcotics Control Board as a fentanyl-related substance with no known legitimate uses.

12. Industrial Use Crotonylfentanyl is available commercially for research and forensic purposes and as an analytical reference standard.

13. Non-Medical Use, Abuse and Dependence Because of the difficulties associated with positively identifying crotonylfentanyl in standard assays, the magnitude of misuse and abuse of the drug is unknown. Given the structural similarity between crotonylfentanyl and fentanyl, however, as well as its preclinical behavioral pharmacology, it is expected that crotonylfentanyl has high potential for non-medical use, abuse, and dependence.

14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence No reports of crotonylfentanyl-related misuse, abuse, or dependence were found.

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42nd ECDD (2019): Crotonylfentanyl 15. Licit Production, Consumption and International Trade Crotonylfentanyl does not have licit medicinal or veterinary use in any country.

16. Illicit Manufacture and Traffic and Related Information Few reports of illicit manufacture and trafficking of crotonylfentanyl are available. NFLIS data reported in 2018 showed that crotonylfentanyl was identified 78 of 748,357 reports and in combination with cyclopropylfentanyl in 193 of 748,357 reports (NFLIS, 2018). At the state and city level, crotonylfentanyl was identified in Minnesota (10 of 5,861 counts), Chicago (14 of 23,287 counts), Miami (48 of 11,140 counts in combination with cyclopropylfentanyl), Boston (3 of 9,860 counts and 5 of 9,860 counts in combination with cyclopropylfentanyl), Cincinnati (1 of 3,634 counts), and Minneapolis (10 of 3,140 counts). From January 1 through December 31, 2017, crotonylfentanyl was identified in Maryland (1 count), New Jersey (1 count), and Ohio (39 counts). Crotonylfentanyl in combination with cyclopropylfentanyl was reported in Florida (35 counts), Maryland (3 counts), Massachusetts (4 counts), New Jersey (4 counts), and Ohio (31 counts; U.S. DEA Diversion Control Division, 2018).

Cyclopropylfentanyl, a compound that is structurally very similar to crotonylfentanyl, also was seized by authorities in Canada where approximately 5-7% of urine samples testing positive for fentanyl also tested positive for cyclopropylfentanyl and its dealkylated nor metabolite, cyclopropylnorfentanyl [8 of 104 samples in November 2017 (7.7%), 4 of 79 samples from February to October 2017 (5.1%), and 56 of 1048 samples collected over an 8-day period in 2017 (5.3%)] (Palaty et al., 2018). The authors acknowledged, however, that their assay does not differentiate cyclopropylfentanyl from crotonylfentanyl. Although the high levels of cyclopropylfentanyl in the urine samples (median 24 ng/ml; range 1-3200 ng/ml) supported the view that it was deliberately being added to illicit , the authors concluded that it was unlikely that illicit crotonylfentanyl was deliberately being sold in “significant amounts.”

17. Current International Controls and Their Impact Crotonylfentanyl has not been subject to international control under the 1971 United Nations Convention on Psychotropic Substances or the 1961 Single Convention on Narcotic Drugs.

18. Current and Past National Controls US: Schedule I (temporary)

Crotonylfentanyl was included under the temporary scheduling of fentanyl analogues into Schedule 1 by the U.S. DEA on February 6, 2018 [21 CFR Part 1308, Docket No. DEA-476] and as clarified on April 18, 2019.

19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance None.

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42nd ECDD (2019): Crotonylfentanyl References

1. Bergh MS-S, Bogen IL, Wohlfarth A, Wilson SR, Oiestad AML (2019) Crotonylfentanyl by methods commonly available in the forensic laboratory. Ther Drug Monit 41: 519-527.

2. Bierly J and Graf K (2017) Cyclopropyl/crotonyl fentanyl and methoxyacetyl fentanyl. Society of Forensic Toxicologists, Inc., ToxTalk®, 41, Issue 4, 11.

3. Drug Enforcement Administration, Department of Justice. “Chemical Names of Previously Controlled Fentanyl-Related Substances.” Federal Register Document 2019-07457 filed 4- 18-19.

4. Lee J, Krotulski AJ, Fogarty MF, Papsun DM, Logan BK (2019) Chromatographic separation of the isobaric compounds cyclopropylfentanyl, crotonylfentanyl, methacrylfentanyl, and para-methacrylfentanyl for specific confirmation by LC-MS/MS. J Chromatography B 1118- 1119: 164-170.

5. Maher S, Elliott SP, George S (2018) The analytical challenge of cyclopropylfentanyl and crotonylfentanyl: An approach for toxicological analysis. Drug Test Anal 1-5.

6. Mallette JR, Casale JF, Hays PA (2019). Characterization and differentiation of cyclopropylfentanyl from E-crotonylfentanyl, Z-crotonylfentanyl, and 3-butenylfentanyl. Science & Justice 59: 67-74.

7. Palaty J, Konforte D, Karakosta T, Wong E, Stefan C (2018). Rapid identification of cyclopropyl fentanyl/crotonyl fentanyl in clinical urine specimens: A case study of clinical laboratory collaboration in Canada. Clin Biochem 53: 164-167.

8. U.S. Drug Enforcement Administration, Diversion Control Division. (2018, December 21). National Forensic Laboratory Information System (NFLIS-Drug) 2018 Midyear Drug Reports, by Nation, State, and Metropolitan Statistical Area [NFLIS-Drug Data Query System analysis]. Retrieved 7 September 2019 from https://www.nflis.deadiversion.usdoj.gov/

9. Varshneya NB, Walentiny M, Moisa LT, Walker TD, Akinfiresoye LR, Beardsley PM (2019) Opioid-like antinociceptive and locomotor effects of emerging fentanyl-related substances. Neuropharmacol 151: 171-179.

10. Walentiny DM, Moisa LT, Beardsley PM (2019) Oxycodone-like discriminative stimulus effects of fentanyl-related drugs of abuse in mice. Neuropharmacol 151: 210-216.

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