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Critical Review Report:
VALERYLFENTANYL
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
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© World Health Organization 2019 All rights reserved.
This is an advance copy distributed to the participants of the 42nd 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. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use.
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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 ......................................................................................................................................................... 9
2. Chemistry ...................................................................................................................................................... 9
A. Chemical Name ................................................................................................................................................................... 9 B. Chemical Structure ............................................................................................................................................................. 9 C. Stereoisomers ....................................................................................................................................................................... 9 D. Methods and Ease of Illicit Manufacturing .............................................................................................................. 9 E. Chemical Properties ........................................................................................................................................................... 9 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 ............................................................................................................................... 12
A. Animal Studies................................................................................................................................................................... 12 B. Human Studies .................................................................................................................................................................. 12
8. Abuse Potential .......................................................................................................................................... 12
A. Animal Studies................................................................................................................................................................... 12 B. Human Studies .................................................................................................................................................................. 13
9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use ............ 13
10. Listing on the WHO Model List of Essential Medicines .......................................................................... 13
11. Marketing Authorizations (as a Medicinal Product) .............................................................................. 13
12. Industrial Use ............................................................................................................................................. 13
13. Non-Medical Use, Abuse and Dependence ............................................................................................. 13
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14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence ....... 13
15. Licit Production, Consumption and International Trade ........................................................................ 13
16. Illicit Manufacture and Traffic and Related Information ....................................................................... 13
17. Current International Controls and Their Impact ................................................................................... 14
18. Current and Past National Controls ......................................................................................................... 14
19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the
Substance ................................................................................................................................................... 14
References ................................................................................................................................................... 15
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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), INCB, UNODC, and Member States for providing relevant information for the review of substances.
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Executive Summary Valerylfentanyl first appeared in toxicological assays in 2016 and through 2018, it has been reported in 6 countries worldwide, including North America, Europe, and Asia. It is being sold as heroin, an adulterant in heroin, or as counterfeit pills. Few fatalities have been attributed to this substance although confiscations of drug containing valerylfentanyl appear to be increasing in some states in the U.S. Receptor binding data show that valerylfentanyl binds selectively to the mu subtype of opioid receptors with low nanomolar affinity relative to kappa and delta opioid receptors. Functional binding assays suggest that valerylfentanyl is a partial agonist at mu and kappa opioid receptors and an antagonist at delta receptors. However, in vivo pharmacology studies in rodents and non-human primates suggest that valerylfentanyl is a full mu agonist. No pharmacokinetic studies of valerylfentanyl are reported in the preclinical or clinical scientific literature. Valerylfentanyl appears to be less potent than other illicit mu agonists with a chemical structure that is similar to fentanyl. As such, 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 valerylfentanyl suggests that it has high abuse potential and poses a serious public health threat. Substance identification: Valerylfentanyl (N-(1-phenethylpiperidin-4-yl)-N-phenylpentanamide) is also known as valeryl fentanyl, NIH 10488, pentanoyl fentanyl, pentanyl fentanyl, and phenylvaleramide. WHO review history: The WHO has not previously reviewed valerylfentanyl. Chemistry: No reports on the methods and ease of illicit manufacturing of valerylfentanyl are available in the scientific literature. Ease of convertibility into controlled substances: No reports of conversion of valerylfentanyl into other controlled substances were found in the scientific literature. Similarity to known substances / Effects on the central nervous system: Valerylfentanyl has a chemical structure similar to fentanyl and receptor binding and behavioral profiles in preclinical models consistent with selective activity at mu opioid receptors compared to delta and kappa receptors. General pharmacology: Preclinical behavioral pharmacology studies demonstrated that valerylfentanyl: 1) suppressed withdrawal symptoms in morphine-dependent monkeys, 2) produced antinociceptive effects in mice, and 3) shared discriminative stimulus effects with oxycodone in mice. The antinociceptive and discriminative stimulus effects of valerylfentanyl were antagonized by naltrexone, suggesting that it produced its effects through opioid receptors. Preclinical studies further demonstrated that valerylfentanyl was less potent than oxycodone in the drug discrimination assay, slightly more potent than morphine in the warm-water tail-withdrawal assay (potency ratio of valerylfentanyl to morphine: 1.22), and much less potent than fentanyl in both assays (e.g., the potency ratio of valerylfentanyl to fentanyl in the warm-water tail-withdrawal assay was 0.0125). The duration of its antinociceptive action was similar to several other fentanyl analogs: the % maximum possible effect was <25% 2 hours after the highest cumulative dose tested; this duration of action was shorter than morphine and fentanyl. Unlike several other mu-receptor-selective opioid agonists, however, valerylfentanyl did not increase locomotor activity. Overall, the pharmacology and toxic effects of valerylfentanyl are likely to be similar to fentanyl, although controlled studies of its respiratory depressant effects have not been performed. Toxicology: Preclinical evaluations of the acute or chronic toxicological effects of valerylfentanyl have not been conducted.
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Adverse reactions in humans: One forensic report exists in which valerylfentanyl was identified. Dependence potential: Based on a single-dose suppression study in monkeys, valerylfentanyl may produce physical dependence similar to morphine. Abuse potential: The abuse potential of valerylfentanyl has been evaluated in a rodent drug discrimination assay. Specifically, valerylfentanyl produced full substitution in mice trained to discriminate oxycodone from saline; this effect was antagonized by naltrexone. Unlike other mu opioid agonists, however, valerylfentanyl did not increase locomotor activity in mice. Therapeutic applications / usefulness: None. It 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: Valerylfentanyl is not listed as an essential medicine. Marketing authorizations: None. Industrial use: Valerylfentanyl is available commercially for research and forensic purposes and as an analytical reference standard. Non-medical use: One forensic report exists in which valerylfentanyl was identified. Nature and magnitude of public health problems: One valerylfentanyl-related death was reported in the U.S. in 2016. Licit production, consumption, and international trade: None. Illicit manufacture and traffic: The U.S. Drug Enforcement Agency (DEA) identified valerylfentanyl for the first time in 2016 (52 reports of drug chemistry analyses; NFLIS Brief, 2017) and in 2019, the DEA described a seizure of approximately 70 pounds of heroin and fentanyl in the Bronx and Yonkers, NY (https://www.dea.gov/press-releases/2019/01/31/approximately-70-pounds-heroin-and-fentanyl-seized-wholesale-distribution; accessed August 16, 2019). Valerylfentanyl was identified in the confiscated drugs. Five people were arrested, one of whom was connected to a narcotics supply organization based in Mexico.
Current international controls and their impact: Valerylfentanyl 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: Valerylfentanyl was scheduled by the Chinese government on March 1, 2017. It was also temporarily placed into Schedule 1 by the DEA on February 1, 2018. The impact of valerylfentanyl scheduling is difficult to determine at present.
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1. Substance identification
A. International Nonproprietary Name (INN)
Valerylfentanyl
B. Chemical Abstract Service (CAS) Registry Number
122882-90-0
C. Other Chemical Names
N-[1-(2-phenylethyl)-4-piperidyl]-N-phenylvaleramide hydrochloride N-(1-phenethylpiperidin-4-yl)-N-phenylpentanamide hydrochloride N-Phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]pentanamide [ACD/IUPAC Name] N-Phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]pentanamid [German] [ACD/IUPAC Name] N-Phényl-N-[1-(2-phényléthyl)-4-pipéridinyl]pentanamide [French] [ACD/IUPAC Name] Pentanamide, N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]- [ACD/Index Name]
D. Trade Names
None
E. Street Names
Seizures of drug in New Jersey in 2016 and 2017 that were verified to contain valerylfentanyl were stamped with the following (Daily Drug Environment Report, May 3, 2016, ROIC201605-03841F; Daily Drug Environment Report, May 17, 2016, ROIC201605-04269F; Daily Drug Environment Report, July 14, 2016, ROIC2016-06174F; Weekly Drug Environment Report, September 9, 2016, ROIC201609-08066F; Weekly Drug Environment Report, November 4, 2016, ROIC201611-09978F; Weekly Drug Environment Report, January 23, 2017, ROIC201701-00742F):
• Hands Up and Twitter & Bird (image) (contained valerylfentanyl);
• # and Red Bull (contained furanylfentanyl/valerylfentanyl/U-47700);
• No Evil (contained heroin/valerylfentanyl/furanylfentanyl);
• New York Post (contained valerylfentanyl/U-47700);
• Paw print image (contained heroin/valerylfentanyl and heroin/valerylfentanyl/furanylfentanyl);
• Fendi and Fendi logo (contained aceytlfentanyl/furanylfentanyl/valerylfentanyl/U-47700);
• Beats by Dr Dre, Unstoppable (contained heroin/furanylfentanyl/valerylfentanyl/U-47700)
Seizures of drug in Texas that were verified to contain valerylfentanyl were white powder, 77 unmarked white pills, and 512 white pills marked with “WATSON 853” (Microgram Bulletin LE, January 2017, 50(1): 1-8)
F. Physical Appearance
Valerylfentanyl is a dry white powder.
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G. WHO Review History
Valerylfentanyl has not been reviewed previously by the WHO.
2. Chemistry
A. Chemical Name
IUPAC Name: N-(1-phenethylpiperidin-4-yl)-N-phenylpentanamide CA Index Name: Not found
B. Chemical Structure
Molecular Formula: C24H32N2O Molecular Mass: 364.533 g/mol
C. Stereoisomers
Unknown
D. Methods and Ease of Illicit Manufacturing
No reports on the methods and ease of illicit manufacturing of valerylfentanyl are available in the scientific literature.
E. Chemical Properties
Melting point 202.08°C (mean or weighted MP)
Boiling point 484.35°C (adapted Stein & Brown method)
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Solubility Water solubility at 25°C (mg/L): 1.759
(http://www.chemspider.com/Chemical-Structure.10551383.html?rid=0b7be1dd-79c4-4999-8037-262b8064ef8a; accessed August 18, 2019)
F. Identification and Analysis
Valerylfentanyl can be detected in whole blood by a liquid chromatography-tandem mass spectrometry-based method (Strayer et al., 2018) with a level of detection < 0.100 ng/mL. Furthermore, Moody et al. (2018) described a LC-MS/MS method for detecting valerylfentanyl with a minimum limit of detection at 0.025 ng/ml. A direct enzyme-linked immunosorbent assay (ELISA) has also been developed against fentanyl in whole blood that cross-reacts with several fentanyl analogs, including valerylfentanyl (Guerrieri et al., 2019). Although some assays exist for synthetic fentanyl analogs such as valerylfentanyl, the number of deaths related to these substances is likely to be underestimated because many laboratories use assays that are not specific or sensitive enough for these substances or the tests are not performed at all (Moody et al., 2018).
3. Ease of Convertibility into Controlled Substances
No reports of conversion of valerylfentanyl into other controlled substances were found.
4. General Pharmacology
A. Routes of Administration and Dosage
Powder containing valerylfentanyl has been obtained by regulatory agencies in the U.S. (https://www.dea.gov/press-releases/2019/01/31/approximately-70-pounds-heroin-and-fentanyl-seized-wholesale-distribution; accessed August 16, 2019). No information about route of administration and dosage of valerylfentanyl in humans is available, although given its powder form and easy solubility in water, use of valerylfentanyl via intranasal, intravenous, and other parenteral routes of administration seems feasible. Seizures of valerylfentanyl in powder and pill form also suggest use by parenteral and oral routes of administration (see Section 1.E. above). In preclinical models, valerylfentanyl is pharmacologically active via the subcutaneous route of administration.
Preclinical studies showed that valerylfentanyl was less potent than fentanyl and oxycodone, and equipotent with morphine, depending on the assay.
The binding affinities (Ki±SEM) of valerylfentanyl in rat brain tissue for mu-, delta-, and kappa-opioid receptors were 53.0±5.13, 3,450±247, and 1,960±62 nM, respectively (Baumann et al., 2018). Thus, valerylfentanyl was 65- and 37-fold more selective for mu- than delta- or kappa-opioid receptors, respectively (Baumann et al., 2018).
In radioligand binding assays conducted on rat mu opioid receptors transfected into Chinese hamster ovary (CHO) cells and human delta and kappa receptors transfected into
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CHO cells, valerylfentanyl Ki values were 2.16±0.84, 1,660±170, and 467±26 nM for mu, delta, and kappa receptors, respectively (Janowsky, 2016). Displacement studies revealed that valerylfentayl was the least potent drug tested in assays of mu, delta, and kappa receptor binding (Janowsky, 2016). In [35S]GTPγS functional binding assays, valerylfentanyl appeared to be a partial agonist at mu and kappa receptors and an antagonist at delta receptors (Janowsky, 2016).
An earlier evaluation of valerylfentanyl concluded that it was inactive in the electrically stimulated mouse vas deferens assay at concentrations ranging between 10-8 M to 3x10-9 M (Woods et al., 1988). It also did not alter responses to sufentanil, although it did displace specific [3H]-etorphine binding with an EC50 of 215 nM (Woods et al., 1988).
B. Pharmacokinetics
No controlled pharmacokinetic studies of valerylfentanyl have been reported. However, its duration of antinociception in mice after the highest cumulative dose tested was shorter than morphine and fentanyl (Varshneya et al., 2019).
C. Pharmacodynamics
As described in more detail below (Sections 7.A. and 8.A.), valerylfentanyl has been examined in multiple behavioral assays in rodents and primates (Aceto et al., 1988; Jacobson, 1988; Varshneya et al., 2019; Walentiny et al., 2019; Woods et al., 1988). These studies suggest that the pharmacology of valerylfentanyl is consistent with activity at mu opioid receptors: it shared discriminative stimulus effects with oxycodone and produced antinociceptive effects, both of which were antagonized by naltrexone (Varshneya et al., 2019; Walentiny et al., 2019). Valerylfentanyl also suppressed withdrawal symptoms in morphine-dependent monkeys (Aceto et al., 1988). One unusual finding was that valerylfentanyl did not increase locomotor activity in mice (Varshneya et al., 2019), a prototypical effect produced by mu opioid agonists.
5. Toxicology
No formal toxicology studies have been performed with valerylfentanyl.
6. Adverse Reactions in Humans
No controlled clinical studies have been conducted with valerylfentanyl. Because valerylfentanyl and fentanyl have similar chemical structures, adverse reactions associated with the compound are expected to be similar to fentanyl (e.g., respiratory depression, although formal studies of this effect have not been performed). In 2016, 1 confirmed fatality associated with valerylfentanyl was reported in the U.S., based on post-mortem toxicology (Moody et al., 2018). However, the exact cause of death is not clear. One case of a fatal overdose in New Jersey was reported in 2017 where drug containing heroin, valerylfentanyl, and furanylfentanyl was found at the scene (the drug was stamped as “No Evil”; Weekly Drug Environment Report, January 23, 2017, ROIC201701-00742F).
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7. Dependence Potential
A. Animal Studies
Monkeys received 3 mg/kg s.c. morphine every 6 hours for at least 90 days in order to induce physical dependence (Aceto et al., 1988). A single dose of a test drug was administered approximately 15 hours after the last dose of morphine in order to determine whether it would suppress the withdrawal symptoms that emerged. In this single-dose suppression test, valerylfentanyl (NIH 10488; 5 mg/kg s.c.) reduced withdrawal symptoms, which demonstrated cross-dependence between valerylfentanyl and morphine (Aceto et al., 1988). A dose of 2.5 mg/kg produced partial suppression of withdrawal. Valerylfentanyl was approximately equipotent with morphine at time of peak effect and its duration of action was 2.5 hours. Convulsions occurred in one animal an hour after administration of the highest dose. Within the first 30 min after dose administration, jaw sag and ataxia also were observed (Aceto et al., 1988).
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, valerylfentanyl fully substituted for oxycodone (Walentiny et al., 2019). At doses that produced full substitution, rates of responding significantly decreased and Straub tail was observed. Valerylfentanyl was the least potent among the drugs that were tested with the following rank order of potency: ocfentanil > fentanyl > 3-furanyl fentanyl ≈ crotonylfentanyl > oxycodone > valerylfentanyl. Pretreatment with 1 mg/kg naltrexone antagonized the lowest valerylfentanyl dose that substituted for oxycodone. In phenylquinone and tailflick tests in mice, the ED50 values for valerylfentanyl were 2.4 and 5.4 mg/kg, respectively (Jacobson, 1988). In the hotplate test in mice, the ED50 was 7.5 mg/kg (5.4-10.3 mg/kg; Woods et al., 1988). In adult male Swiss Webster mice, valerylfentanyl produced dose-related increases in antinociception in a warm-water tail withdrawal assay (Varshneya et al., 2019). Naltrexone (1 mg/kg) antagonized the antinociceptive effects of valerylfentanyl and increased its ED50 for this effect by 11.9 fold. The order of potency for antinociception was: isobutyrylfentanyl > fentanyl > para-methoxybutyrylfentanyl > crotonylfentanyl > para-fluorobutyrylfentanyl > thiophenefentanyl > valerylfentanyl > morphine > benzodioxolefentanyl. At the highest cumulative doses tested, fentanyl- and morphine-induced antinociception was above 50% maximum possible effect 2 hours after administration. The antinociceptive effects of valerylfentanyl was of
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much shorter duration (Varshneya et al., 2019). Unlike the other opioids tested, valerylfentanyl did not increase locomotor activity (Varshneya et al., 2019).
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
Valerylfentanyl is not approved in any country for therapeutic use.
10. Listing on the WHO Model List of Essential Medicines
Valerylfentanyl is not included in the WHO Model List of Essential Medicines.
11. Marketing Authorizations (as a Medicinal Product)
Valerylfentanyl 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
Valerylfentanyl is available for use in research and for forensic purposes as an analytical reference standard.
13. Non-Medical Use, Abuse and Dependence
The magnitude of misuse and abuse of valerylfentanyl is unknown. Given the structural similarity between valerylfentanyl and fentanyl, as well as its pharmacology in preclinical models, it is expected that valerylfentanyl has high potential for non-medical use, abuse, and dependence.
14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence
Valerylfentanyl was identified in one postmortem case between October 2016 and September 2017 in the U.S. (Moody et al., 2018). One case of a fatal overdose in New Jersey was reported in 2017 where drug containing heroin, valerylfentanyl, and furanylfentanyl was found at the scene (the drug was stamped as “No Evil”; Weekly Drug Environment Report, January 23, 2017, ROIC201701-00742F). In 2018 and 2019, valerylfentanyl was detected in 1 post-mortem case and in 2 cases of driving under the influence of drugs, all in the U.S. (UNODC Report, 2019).
15. Licit Production, Consumption and International Trade
Valerylfentanyl does not appear to have licit medicinal or veterinary use in any country.
16. Illicit Manufacture and Traffic and Related Information
The National Forensic Laboratory Information System (NFLIS) of the U.S. Drug Enforcement Agency (DEA) identified valerylfentanyl for the first time in 2016 (52 reports of drug chemistry analyses; NFLIS Brief, 2017).
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Seizures of drug in Texas that were verified to contain valerylfentanyl were white powder, 77 unmarked white pills, and 512 white pills marked with “WATSON 853” (Microgram Bulletin LE, January 2017, 50(1): 1-8). Multiple reports of drug seizures containing valerylfentanyl, most often in combination with other illicit opioids, were also reported in New Jersey in 2016 and 2017. NFLIS data reported in 2018 showed that valerylfentanyl was identified in 2 of 748,357 reports, one of which was in New York City (NFLIS, 2018). From January 1 through December 31, 2017, valerylfentanyl was identified in New Jersey (3 counts) and Pennsylvania (2 counts; U.S. DEA Diversion Control Division, 2018). A press release by the U.S. DEA on January 31, 2019 describes seizure of approximately 70 pounds of heroin and fentanyl in the Bronx and Yonkers, NY (https://www.dea.gov/press-releases/2019/01/31/approximately-70-pounds-heroin-and-fentanyl-seized-wholesale-distribution; accessed August 16, 2019). Valerylfentanyl was identified in the confiscated drugs. Five people were arrested, one of whom was connected to a narcotics supply organization based in Mexico. Internationally, between 2016 and 2018, valerylfentanyl was reported in 6 countries in North America, Europe, and Asia, 9 reports in 2016, 2 reports in 2017, and 1 report in 2018 (UNODC Report, 2019).
17. Current International Controls and Their Impact
Valerylfentanyl 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 – as of February 1, 2018) Valerylfentanyl was temporarily placed into Schedule 1 by the DEA on February 1st, 2018 [21 CFR Part 1308, Docket No. DEA-475]. The impact of valerylfentanyl scheduling is difficult to determine at present. In a press release dated February 17, 2017, the DEA reported that the Chinese government controlled valerylfentanyl, which took effect on March 1, 2017 (https://www.dea.gov/press-releases/2017/02/17/china-announces-scheduling-controls-carfentanil-and-other-fentanyl; accessed August 16, 2019).
19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance
None.
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References 1. Aceto M, Bowman E, Harris L, May E (1988) Dependence studies of new compounds in the rhesus
monkey, rat, and mouse, 1987. NIDA Res Monogr 81, 485-542 (p.527-528).
2. Guerrieri D, Kjellqvist F, Kronstrand R, Green H (2019) Validation and cross-reactivity data for fentanyl analogs with the immunalysis fentanyl ELISA. J Anal Toxicol 43, 18-24.
3. Jacobson A (1988) Biological evaluation of compounds for their physical dependence potential and
abuse liability: XI. Drug testing program of the Committee on Problems of Drug Dependence, Inc. (1987). NIDA Res Monogr 81, 466-484 (p.480).
4. Janowsky A (2016) Valeryl Fentanyl N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]-pentanamide,
mononhydrochloride: Binding and Functional Activity at Delta, Kappa and Mu Opioid Receptors. Unpublished data.
5. Moody MT, Diaz S, Shah P, Papsun D, Logan BK (2018) Analysis of fentanyl analogs and novel
synthetic opioids in blood, serum/plasma, and urine in forensic casework. Drug Test Anal 10: 1358-1367. doi:10.1002/dta.2393.
6. United Nations Office on Drugs and Crime Report on New Psychoactive Substances Under Review
at the 42nd Expert Committee Meeting on Drug Dependence (ECDD), 2019.
7. 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 19 Sep 2019 from https://www.nflis.deadiversion.usdoj.gov/
8. Strayer KE, Antonides HM, Juhascik MP, Daniulaityte R, Sizemore IE (2018) LC-MS/MS-based
method for the multiplex detection of 24 fentanyl analogues and metabolites in whole blood at sub ng mL-1 concentrations. ACS Omega 3: 514-523.
9. U.S. Drug Enforcement Administration, Diversion Control Division. (2018). Table 3. State counts for
fentanyl and fentanyl-related substances: 2017. Retrieved from the NFLIS Public Resource Library at https://www.nflis.deadiversion.usdoj.gov/Resources/NFLISPublicResourceLibrary.aspx
10. U.S. Drug Enforcement Administration, Diversion Control Division. (2017). NFLIS Brief: Fentanyl and
Fentanyl-Related Substances Reported in NFLIS, 2015– 2016. Springfeld, VA: U.S. Drug Enforcement Administration. https://www.nflis.deadiversion.usdoj.gov/DesktopModules/
11. ReportDownloads/Reports/11350_R1_NFLIS_Research_Brief_Fentanyl. pdf. Accessed August 16, 2019.
12. 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.
13. 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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14. Woods JH, Medzihradsky F, Smith C, Winger G, France C (1988) Evaluation of new compounds for opioid activity. NIDA Res Monogr 90, 421-467 (p.443).
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Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances Refer to separate Annex 1: Report on WHO questionnaire for review of psychoactive substances
