DEA/OD/ODE page 1 of 10 April 27

, 201 5 Acetyl Fentanyl

Background Information and Evaluation of ‘ Three Factor Analysis ’ (Factor s 4, 5 and 6) for T emporary S cheduling

Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement

Administration, 8701 Morrissette Drive, Springfield, VA 22152

April 2015

Introduction

N

- (1

- phenethylpiperidin

- 4

- yl)

- N

- phenylacetamide ( acetyl fentanyl) is a potent opioid analgesic and has no accepted medical use in the United States

. Since 2013, b oth law enforcement and public health reports demonstrate the illicit use and distribution of this substance. Reports indicate that acetyl fentanyl is available on the il licit market as a powder or in tablet form which mimic pharmaceutical opiate products. In powder form, the identity of the substance may go unknown to the end user as it may be marketed as heroin or mixed with heroin. Recent reports indicate that acetyl fentanyl is available over the I nternet

.
Acetyl fentanyl was first mentioned in a book chapter in 1968 by Janssen and Van der Eycken . I t exhibits a typical morphine

- like profile in animals

. Data show that the analgesic potency of acetyl fentanyl is up to 15.7 times greater than that of morphine in mice as evaluated using an acetic acid writhing method (Higashikawa and Suzuki , 2008)

. Since 2013, adverse effects due to acetyl fentanyl toxicity have been reported in humans

. Similar to other opi oids (i.e. heroin, oxycodone, hydrocodone, fentanyl, etc.) , acetyl fentanyl induces respiratory depression which may lead to death in an overdose event

. DEA is currently aware of 39 confirmed fatalities in which acetyl fentanyl was a contributing factor. These fatalities occurred in California (1), Louisiana (14), North Carolina (7), Oregon (1), Pennsylvania (1) and Rhode Island (15)

. The extent of abuse and mortality associated with acetyl fentanyl is likely to be underestimated since it is not included in most drug screens. In addition, the identity of fentanyl and acetyl fentanyl cannot be distinguished by commonly used drug screens including enzy me

- linked immunosorbent assay ( ELISA ). Further confi rmatory testing (i.e. mass spectrometry) is required to identify acetyl fentanyl (CDC, 2013).

R eports of overdose and fatalities associated with abuse of acetyl fentanyl have been recorded

. T he Rhode Island Department of Health reported 1 5 fatalities associated with acetyl fentanyl in 2013. The ages of the decedents ranged from 19 to 57 years. Acetyl fentanyl was involved in seven fatalities in North Carolina in 2014. Two fatal overdoses and one death associated with acetyl fentanyl were reported from St. Tammany Parish, Louisiana in 2014 and one fatal overdose was reported in Oregon in September 2014. Eleven o verdose deaths involving acetyl fentanyl have been reported fromDEA/OD/ODE page 2 of 10 April 27

, 201 5

Jefferson Parish, Louis i ana in 2013 and 2014. San Diego County, California re ported one death due to acute acetyl fentanyl intoxication in November 2014.

With no legitimate medical use and limited pharmacological information, acetyl fentanyl has emerged on the illicit drug market and is being abused for its opioid properties. To protect the public health and safety, the Drug Enforcement Administration (DEA) is temporarily placing acetyl fentanyl in Schedule I of the Controlled Substances Act (CSA). With respect to finding an imminent hazard to the public safety, DEA has considere d the three factors required under the CSA for the temporary scheduling of acetyl fentanyl. 21 U.S.C. 811(h)(3) and 811(c)(4)

- (6).

Acetyl F entany l

Fentanyl Acetyl F entanyl

Figure 1 . Chemical Structure s of Fentanyl and Acetyl Fentanyl

Acetyl fentanyl is a synthetic opioid in the phenyl piperidine class which includes fentanyl. Acetyl fentanyl differs in chemical structure from fentanyl by one carbon atom and two hydrog en atoms. Fentanyl possesses a phenyl propanamide functionality whereas acetyl fentanyl has a phenyl acetamide group (Figure 1)

. A cetyl fentanyl has also been referred to as desmethyl fentanyl , likely due to the removal of a methylene group from the chemical structure of fentanyl.

Fact or 4. H istory and C urrent P attern of A buse

Clandestinely produced substances structurally related to the Schedule II opioid analgesic fentanyl, were trafficked and abused on the West Coast in the late 1970 s and
1980 s

. Alpha

- methylfentanyl, the first fentanyl analogue identified in California, wasDEA/OD/ODE page 3 of 10 April 27

, 201 5

placed into Schedule I of the CSA in September 1981. Following the control of alpha

methylfentanyl, DEA identified several other fentanyl analogues ( See Appendix A ) in
submiss ions to forensic laboratories

. These substances were temporarily control led under
the CSA after finding that they posed an imminent hazard to public safety

.

The first laboratory su bmission of acetyl fentanyl was recorded in Maine in April 2013 according to the National Forensic Laboratory Information System 1 (NFLIS)

. Acetyl fentanyl was first r eported to DEA ’s System to Retrieve Information from Drug
Evidence 2 ( STRIDE )

, in Septembe r of 2013 from exhibits obtained through a controlled purchase in Louisiana

. I n October 2013

, an exhibit collected from a controlled purchase of suspected oxycodone tablets in Rhode Island contain ed acetyl fentanyl as the primary
substance. STARLiMS (a web

- based, commercial laboratory information management system that is in transition to replace STRIDE) and STRIDE report ed eight additional
seizures in 2014 , in Colorado, Florida

, Georgia , and Washington

. NFLIS registered eight reports containing acet yl fentanyl in 2013, in Louisiana, Maine, and North Dakota, and
30 in 2014

, in Florida, Illinois, Louisiana, Maine, New Jersey, Ohio, Oregon, Pennsylvania , and Virginia

.

I n August 2013, the Centers for Disease Control and Prevention ( CDC ) published
an article in its Morbidity and Mortality Weekly Report documenting a series of 14 fatalities related to acetyl fentanyl that occurred between March and May 2013 (CDC, 2013)

. Ten overdose fatalities in the months of March and April 2013 tested positive fo r fentanyl in blood by ELISA, however fentanyl was not detected by confirmatory gas chromatography/mass spectromet ry ( GC/MS ) analysis. Th ese data were consistent with acetyl fentanyl. During the field investigation by the CDC and Rhode Island public
heal th officials, two more fatalities were associated with acetyl fentanyl. Of these 12 fatalities, intravenous administration was suspected in at least four of these deaths. Acetyl fentanyl was the only substance detected in one decedent and was found in

co mbination with other substances such as cocaine, other opioids, ethanol and/or benzodiazepines in ten of the decedents. Importantly, fentanyl w as not detected by GC/MS in any of these fatalities. Two additional fatalities involving acetyl fentanyl

occurr ed in May 2013 (CDC, 2013), and one additional fatality in December 2013

1 NFLIS is a program of the DEA that collects drug identification results from drug cases analyzed by other F ederal

, S tate, and local forensic laboratories

. NFLIS

, other federal, state
, and local forensic drug reports

were queried on 02/03/2015 (data are still being reported for November 2014 and December 2014 )

. 2 STRIDE collected the results of drug evidence analyzed at DEA laboratories and reflects evidence submitted by the DEA, other Federal law enforcement agencies, and some local law enforcement agencies. STRIDE data was queried through 09 / 30/2014 by date submitted to Federal forensic laboratories. Since October 1 , 2014, STARLiMS replaced STRIDE as the DEA laboratory drug evidence data system of record. DEA laboratory data submitted after September 30, 2014 are reposited in STARLiMS.DEA/OD/ODE page 4 of 10 April 27

, 201 5

(Rhode Island Department of Health, personal communication) increasing the number of deaths associated with acetyl fentanyl in Rhode Island to 15 through 2013.

I n February 2014 , t h e North Carolina Department of Health and Human Services issued a health advisory related to acetyl fentanyl following at least three deaths related to
th is synthetic drug. Toxicologists at the Office of the Chief Medical Examiner detected acetyl fentanyl in biological samples associated with deaths that occurred in January in Sampson, Person and Transylvania counties. In July and August 2014, four additional
fatalities inv olving acetyl fentanyl were reported. Deaths involving acetyl fentanyl have also been reported in California (1), Louisiana (14), Oregon (1) and Pennsylvania (1).

A significant seizure of acetyl fentanyl occurred in April 2013 during a law
enforcement investigation in Montreal, Canada. Approximately three kilograms of acetyl fentanyl in powder form and approximately 11,000 tablets containing acetyl fentanyl
were seized. Given that a typical dose of acetyl fentanyl is in the microgram range, a
three ki logram quantity could potentially produce millions of dosage units.

In the United States, tablets that mimic pharmaceutical opiate products have been reported in multiple states, including Rhode Island, Colorado, Georgia, Florida and Washington. Recent reports indicate that acetyl fentanyl in powder form is available over
the I nternet and has been shipped to addresses within the United States.

The pattern of abuse of fentanyl analogues

, including acetyl fent anyl, parallels
that of heroin and prescription opioid abusers

. S eizures of acetyl fentanyl have been encountered both in powder and in tablet form. It is also supported by the profile of many fatal overdose reports that document intravenous route of administration and
histories of d rug abuse (CDC, 2013; medical examiner report communicated by Chief Medical Examiner, Chapel Hill, North Carolina ).

Factor 5. S cope, D uration, and S ignificance of A buse

Fatalities associated with acetyl fentanyl have been reported in six states in 2013 and 2014, including California, Louisiana, North Carolina, Oregon, Pennsylvania, and
Rhode Island

. STARLiMS and STRIDE , database s capturing drug evidence information
from DEA forensic laboratories, ha ve a total of 10 drug reports in which acetyl fentanyl

was identified in six cases for analyzed drugs submitted from January 2010

– December
2014 from Colorado, Florida, Georgia

, Louisiana, Rhode Island and Washington

. (query date: February 3, 2015 )

.DEA/OD/ODE page 5 of 10 April 27

, 201 5 Populations likely to abuse acetyl fentanyl are likely to coincide with populations abusing prescription opi oid analgesics and heroin , however the presence of acetyl fentanyl may be unknown to the end user

. According to the National Survey on Drug Use and Health (NSDUH 3 ), in 201 3 , the number of persons aged 12 or older who are current (used within the past month) nonmedical users of pain relievers (opioids) were 4. 5 million and the number of current users of heroin w as 289,000 . The NSDUH data also indicate that in 201 3 an estimat ed 1.9 million persons aged 12 or older were classified with past year substance use disorder (dependence and abuse) of pain relievers and the corresponding number for heroin was 517,000 . This population is likely to be at risk of abusing acetyl fentanyl. Because acetyl fentanyl is an opioid, individuals who initiate ( i.e. use an illicit drug for the first time) acetyl fentanyl abuse are likely to be at risk of developing substance use disorder, overdose and death similar to that of other opioid analgesic s (e.g., fentanyl, morphine

, etc. ).

Further

, because abusers of acetyl fentanyl are likely to obtain the drug through unknown sources, the identity, purity, and quantity are uncertain, thus posing significant adverse health risks to its users. This ris k is particularly heightened by the fact that acetyl fentanyl is a highly potent opioid (15.7

- fold more than that of morphine as tested in mice using an acetic acid writhing method ) (Higashikawa and Suzuki, 2008) . Thus

, small changes in the amount and purity of the substance could potentially lead to overdose and death

.

Factor 6. What, if A ny, R isk T here I s to the P ublic H ealth

Acetyl fentanyl exhibits a pharmacological profile similar to that of fentany l and
other μ

- opioid receptor agonist s ( Jac o bson, 1987; Higashikawa and Suzuki, 2008)

. In a study using tail flick ( ED 50 = 0.3 mg/kg/s.c.; morphine, ED 50 = 5.8 mg/kg/s.c. ) and phenylquinone writhing tests ( ED 50 = 0.05 mg/kg/s.c.; morphine, ED 50 = 0.23 mg/k g/s.c. ) acetyl fentanyl produced opioid

- like analgesic response in mice ( Jacobson, 1987). Acetyl

fentanyl has been shown to completely suppress the signs of withdrawal in morphine

dependent monkeys with a single dose

. In this study, a cetyl fentanyl rapid ly but briefly (90
min ute ), substituted completely for morphine at 0.5 mg/kg . At peak effect, a cetyl fentanyl is
considered to be six times as potent as the reference standard morphine ( Jacobson, 1987 )

. In another study using a different mouse writhing model, a cetyl fentanyl also demonstrated

3 The National Survey on Drug Use and Health, formerly known as the National House hold Survey on Drug Abuse (NHSDA), is conducted annually by the Department of Health and Human Services Substance Abuse and Mental Health Services Administration (SAMHSA). It is the primary source of estimates of the prevalence and incidence of nonmedical use of pharmaceutical drugs, illicit drugs, alcohol, and tobacco use in the United States. The survey is based on a nationally representative sample of the civilian, non

institutionalized population 12 years of age and older. The survey excludes homeles s people who do not use shelters, active military personnel, and residents of institutional group quarters such as jails and hospitals. The NSDUH provides yearly national and state level estimates of drug abuse, and includes prevalence estimates by lifetim e (i.e., ever used), past year and past month abuse or dependence.DEA/OD/ODE page 6 of 10 April 27

, 201 5

a potent μ

- opioid receptor agonist effect with an effective dose ( ED 50 ) of 0.021 mg/kg, making it 1/3 as potent as fentanyl (ED 50 =0.0061 mg/kg) and 15.7 times as potent as morphine (ED 50 =0.33 mg/kg)

. In addition, i n vivo pharmacology studies performed in mice suggest that the range between ED 50 and lethal dose ( LD 50 ) of acetyl fentanyl is narrower than that of morphine and fentanyl (acetyl fentanyl: ED 50 = 0.021 mg/kg, LD 50 =9.3 mg/kg; morphine: ED 50 =0.33 mg/kg, LD 50 =470 mg/kg; fentanyl: ED 50 =0.0061 LD 50 , LD 50 =62 mg/kg ), increasing the risk of fatal overdose (Higashikawa and Suzuki, 2008) . In view of this narrow dose range of acetyl fentanyl and its high potency, its a buse is likely to pose quantitatively greater ris ks to the public health and safety than traditional opioid analgesic s such as morphine.

Based on the above pharmacological data, the a buse of acetyl fentanyl leads to the same qualitative public health risks as heroin , fentanyl and other opioid analgesic s

. The public health risks attendant to the abuse of heroin and other opioid analgesic s are well

established (i.e. Brunton et al., 2010 ; Martin, 1977 ; Maxwell, 2011 ). The abuse of opioid analgesic s has resulted in large numbers of treatment admissions (Ling et al., 2011 ; SAMHSA, 2012 ), emergency department visits (Cai et al., 2010 ; SAMHSA, 2013 ), and fatal overdoses (Paulozzi, 2012 ; CDC, 2014 ).

According to the Treatment Episode Data Set (TEDS) 4 of the Substance Abuse and Mental Health Services Administration (SAMHSA) 5 , in 201 2 , the number of persons aged
12 or older admitted for the treatment for heroin as the primary substance of abuse was 285,451 and the corresponding number for other opioid a nalgesic s (“Other opiates/synthetics”) was 1 69

, 868 . The 201 2 numbers for other opioid analgesic s were over five

- fold higher than the corresponding numbers in 2000 (28,326 admissions) (SAMHSA,
2012 , 2014 )

.

According to the Drug Abuse Warning Network (DAW N) 6 of the SAMHSA , in 2011, the numbe r of emergency department (ED) visits involving abuse of heroin was

4 TEDS is a program coordinated and managed by the Substance Abuse and Mental Health Services Administration (SAMHSA). This database includes information on treatment admissions that are routinely collected by states to monitor their individual substance abuse treatment systems. Thus, TEDS includes data primarily from treatment facilities that receive public funds. TEDS includes information on demographic variables including age, gender, race and ethnicity. TEDS also reports on the top three drugs of abuse at the time of admission. TEDS does not include all drugs that may have been abused prior to admission. States and jurisdictions can choose whether or not to report the detailed listi ng. 5 The Substance Abuse and Mental Health Services Administration (SAMHSA) is a branch of the U.S. Department of Health and Human Services (HHS). It is charged with improving the quality and availability of prevention, treatment, and rehabilitative serv ices in order to reduce illness, death disability, and cost to society resulting from substance abuse and mental illness.
6 The Drug Abuse Warning Network (DAWN) is a public health surveillance system that monitors drug related hospital emergency departmen t (ED) visits to track the impact of drug use, misuse, and abuse in theDEA/OD/ODE page 7 of 10 April 27

, 201 5

258,482 and the corresponding number for opioid analgesics (“Narcotic Pain Relievers”)

w as 420,040. In 2011

, ED visits involving opioid analgesics were 153 percent more than in
2004 (SAMHSA, 2013)

.

Prescription opi oid analgesic

- related deaths have increased in the past 15 years

. F rom 1999 to 201 3 , the number of U.S. drug poisoning deaths involving any opioid analgesic (e.g., oxyco done, methadone, or hydrocodone) more than quadrupled, from 1.4 to 5.1 per 100,000 population , accounting for 37 % (16,235 opioid deaths ) of the 43,982 drug poisoning deaths in 201 3 (CDC, 201 5 ). Prescription opi oid analgesic

- related deaths were recently di scussed by DEA (DEA, 2014)

. In the decade from 2002 to 2011, the annual number of drug poisoning deaths involving heroin doubled, from 2,089 deaths in 2002 to 4,397 deaths in 2011 ( CDC, 2014)

.

Similar to heroin and other opioid analgesic s, acetyl fentany l has been associated
with numerous fatalities. Thirty nine confirmed deaths associated with acetyl fentanyl
ab use have been reported in six states in 2013 and 2014, including California, Louisiana, North Carolina, Oregon, Pennsylvania, and Rhode Island . This indicates that acetyl fentanyl

poses an imminent hazard to public safety.

Conclusion of 3

- Factor Analysis

After a careful review of the scientific literature, Factors 4, 5, and 6, NFLIS, STRIDE, and other law enforcement data and other sources of information, it is evident that acetyl fentanyl is trafficked and abused

, and that it pose s a n imminent hazard to public safety

. DEA has considered the three criteria for placing a substance into Schedule I of the CSA (21 U.S.C. 812). The data avail able and reviewed for acetyl fentanyl indicate s that acetyl fentanyl , including its isomers, esters, ethers, salts, and salts of isomers, esters and
ethers pose s an imminent hazard to public safety and health, has no currently accepted
medical use in treatment in the United States, and lack s accepted safety for use under medical supervision.

United States. It is sponsored by the SAMHSA and c ollects data on drug

- related emergency department (ED) visits from a nationally representative sample of hospitals in the U.S. and a selection of metropolitan

areas

. A DAWN case is any ED visit involving recent drug use that is implicated in the ED visit. DAWN captures both ED visits that are directly caused by drugs and those in which drugs are a contributing factor but not the direc t cause of the ED visit. Annually, DAWN produces estimates of drug

- related visits to hospital EDs for the nation as a whole and for selected metropolitan areas.DEA/OD/ODE page 8 of 10 April 27

, 201 5

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.DEA/OD/ODE page 10 of 10 April 27

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Appendix A. Control and Emergency Control of Substances Structurally related to Fentanyl.

Appendix A