US Pharm. 2016;41(10):55-58.
Acetyl fentanyl, N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide, is an analogue of the potent opioid analgesic fentanyl.1 It may also be referred to as nonpharmaceutical fentanyl.2 Some common street names for acetyl fentanyl include China White, Apache, China girl, dance fever, friend, goodfella, jackpot, murder 8, TNT, and Tango and Cash.3 The chemical structure of acetyl fentanyl is very similar to fentanyl’s. The substance is also referred to as desmethyl fentanyl due to a missing methyl group in its structure compared to that of fentanyl.4 Acetyl fentanyl is manufactured, distributed, and sold illicitly, and may be mixed with heroin or other agents. It may be marketed as heroin, oxycodone (OxyContin), or fentanyl to unsuspecting buyers. Fentanyl is 50 to 100 times more potent than morphine.5 When mixed with other substances, such as heroin, it can have additive toxic effects.
According to the CDC’s Health Alert Network, some states have reported a rise in fatalities associated with acetyl fentanyl since 2012.6 There have been reports of over 700 overdose deaths attributed to fentanyl and acetyl fentanyl from 2013 to 2014.7 It is conceivable that the number is much higher, since some state health departments are reporting even greater numbers, particularly in the eastern United States. Ohio reported 514 fentanyl overdoses in 2014, and Maryland reported 185. In addition, most medical examiners do not test for acetyl fentanyl unless specifically asked to do so.7,8 Data from the National Forensic Laboratory Information System reported an increase in the number of drug seizures in some states for acetyl fentanyl from 618 in 2012 to 4,585 in 2014.6,9
Acetyl fentanyl, like fentanyl, binds to mu opioid receptors, causing agonist effects.1 Studies suggest that its potency is 5 to 15 times that of heroin.10 Clinical effects are similar to those of other opioid agents, including analgesia, as well as euphoria, altered mood, miosis, drowsiness, cough suppression, decreased gastro-intestinal motility, and respiratory depression. Adverse effects of fentanyl may include nausea, itching, dizziness, or altered mental status, and may progress to more severe toxicity.11
Tolerance and Dependence
Similar to other opioid agents, repeated use can lead to tolerance, with escalating doses required for an effect.11 Acetyl fentanyl may also serve as a substitute for heroin or other opioids in opioid-dependent persons, because of agonism of the same mu opioid receptors. Additionally, individuals may believe they are using heroin and inadvertently become tolerant to or dependent on the more potent opioid, such that a return to unadulterated heroin no longer provides the expected effects.12 While withdrawal has not been specifically described, given its affinity for opioid receptors, an opioid withdrawal pattern would be expected, with anxiety, sweating, abdominal discomfort, nausea/vomiting, diarrhea, shivering, and piloerection.
Clinical studies evaluating the pharmacologic effects of acetyl fentanyl specifically in humans are lacking.11 Its toxicity is similar to that of other opioids, with lethargy progressing to coma, respiratory depression leading to apnea, bradycardia, and hypotension.11,12 Death is usually due to respiratory arrest. Users may be at greater risk of severe effects if they believe they are using heroin but have actually purchased the more potent acetyl fentanyl or a mixture of the two.
The effects of acetyl fentanyl can be potentiated by other central nervous system (CNS) depressants, including other opioids. When it is used with alcohol, synergistic effects occur. Benzodiazepines also have an additive and possibly synergistic effect on CNS and respiratory depression.11 When these are taken with stimulants, rapid respiratory depression may ensue at the point that the stimulant properties resolve.13 Use of HIV protease inhibitors, such as ritonavir, may reduce the elimination of acetyl fentanyl and increase plasma levels.11
The CDC recommends testing using enzyme-linked immuno-sorbent assay (ELISA) for those patients showing symptoms consistent with opioid overdose. If the test is positive, confirmatory testing is recommended using gas chromatography–mass spectrometry (GC-MS) testing on specimens to confirm or rule out fentanyl and its analogues, including acetyl fentanyl.14
Treatment With Naloxone
Pharmacists should counsel patients, family members, and caregivers to become familiar with signs of opioid overdose as well as to understand the instructions for administering a reversal agent. Opiate overdose should be sus-pected in any patient presenting with the triad of mental status depression, miosis, and respiratory depression. In the nonhospital setting, 911 should be contacted immediately.15 See SIDEBAR 1 for patient case studies.
Naloxone is an opioid receptor antagonist indicated for the treat-ment of respiratory depression (overdose) due to an opioid agent, including fentanyl derivatives such as acetyl fentanyl.12 It is FDA-approved for use in opioid reversal. Ready access to this medication can save lives.16
Naloxone is available in several dosage forms, including IV, injectable (IM/SC), and nasal spray. Typical starting doses are 0.1 to 0.2 mg IV. Onset is rapid, within minutes if not faster. If no response is seen, the dose may be repeated or increased every 2 to 3 minutes until respiratory status improves. Due to the potency of acetyl fentanyl, doses of 2 to 5 mg or more may be required.17
Some forms of naloxone are now available for use outside of clinical settings for overdose management. Evzio is a kit with two prefilled, single-use, auto-injectors of 0.4 mg/0.4 mL of naloxone, for IM or SC use only. The instructions include print as well as an electronic voice tutorial on how to administer the drug.18
Naloxone is also available for intranasal administration for use outside of clinical settings. Narcan nasal spray is a kit with two single-use 4 mg/0.1 mL doses of naloxone.19 In addition, naloxone has been administered off-label intranasally via atomizer at doses of 2 mg.20
Naloxone may precipitate withdrawal in the setting of lower potency opioids or high doses, characterized by anxiety, sweating, abdominal discomfort, diarrhea, shivering, and piloerection. If respiratory depression is not present or has reversed, additional naloxone is not indicated, as other agents could be contributing to CNS depression, and concomitant withdrawal could be detrimental. The effects of naloxone last 30 to 90 minutes, and may abate while long-acting opiate drugs (including fentanyl derivatives) are still present, resulting in recurrent symptoms that may require treatment.21 Thus, all patients should be observed in a healthcare facility beyond the effects of naloxone. Patients who receive naloxone should be cautioned to avoid opiates until the naloxone has been cleared, as they may not feel an initial effect due to receptor blockade and then suddenly become symptomatic.21
Additional treatment hinges on supportive care, including cardiopulmonary support and resuscitation. The use of naloxone does not preclude ongoing respiratory assistance while awaiting a response. Intubation and mechanical ventilation may be required in patients with no response to naloxone, particularly when cointoxicants are considered or the picture is unclear.21
Acetyl fentanyl and other new psychoactive substances (NPS), as referenced by the United Nations Office on Drugs and Crime,22 are sold primarily through the Internet, in head shops, and on the street as “legal.” These products are often labeled “not for human consumption” to try to skirt state and federal laws in the U.S. Acetyl fentanyl and other NPS pose a significant regulatory challenge at both the federal and the state level because the products are continually morphing chemically to evade regulations.
Federal Regulations: According to data from the FDA, almost 40% of legitimate drugs sold in the U.S. are imported from abroad, and nearly 80% of the raw ingredients to manufacture licit drugs are imported as well.23 In addition to these legitimate products, a great deal of raw material to make NPS is also being shipped to the U.S. from overseas. Regulations are there-fore crucial to protect the drug supply from adulteration and misbranding.
The FDA Safety and Innovation Act, signed into law in 2012, expands the FDA’s authority to protect the drug supply chain. It has some new provisions under Title XI, Subtitle D–Synthetic Drugs (sections 1152 and 1153), to specifically deal with the threat to public safety from NPS.24 In July 2015, under federal regulation 21 CFR Part 1308 and its emergency scheduling authority, the Drug Enforcement Administration (DEA) temporarily classified acetyl fentanyl and its salts and isomers as a Schedule I drug with a high potential for abuse.25 Other federal laws dealing with NPS include the Synthetic Drug Abuse Prevention Act and the Controlled Substance Analogue Act (21 USC 802 and 813).26
State Regulations: States have had to learn to be creative in combating the regulatory challenges posed by NPS. According to the National Conference of State Legislatures, most states are using either individual bans, general bans to prohibit synthetic drugs, or analogue laws. Analogue laws rely on banning substances based on the substance having properties chemically similar to a regulated Schedule I or II drug. Some states also delegate administrative authority to the state’s board of pharmacy to ban NPS or place them in a Schedule I category until legislative action can be taken. States have also used agricultural laws or “nuisance abatement laws” to combat sale and distribution.27 Currently, 34 states use analogue laws to ban NPS according to the National Alliance for Model State Drug Laws.28
Many states have passed Good Samaritan laws to allow bystanders, such as family and friends, to administer naloxone to overdose victims until emergency medical services arrive.29 Some states have also initiated collaborative practice agreements with pharmacies to dispense naloxone. These agreements allow a practitioner to delegate a pharmacist to “initiate, modify, and monitor” naloxone therapy. In addition, many states have recently adopted statewide standing order legislation that allows pharmacists to dispense naloxone without the need for a prescription.29
Helpful Resources and Additional Information for Pharmacists
Medical professionals are often missing critical toxicologic and clinical information about NPS that pose health threats from drug-drug interactions, adverse reactions, or overdose that is important in making treatment decisions.30 Although there is a wealth of information available online, it is important for pharmacists to have access to credible sources as a tool in patient education. Refer to SIDEBAR 2 for more information on new and emerging issues with NPS and acetyl fentanyl.
Acetyl fentanyl is among a growing list of NPS posing significant health threats to public safety in the U.S. Regulatory challenges represent an added layer of complication in keeping these products out of the hands of the public. Pharmacists can play a fundamental role in providing education regarding risks of use of these emerging psychoactive substances as well as stand at the forefront in providing naloxone for overdose treatment.
1. Drug Enforcement Administration (DEA). Office of Diversion Control. Drug and chemical evaluation section. Acetyl fentanyl. July 2015. www.deadiversion.usdoj.gov/drug_chem_info/acetylfentanyl.pdf. Accessed February 21, 2016.
2. CDC. Nonpharmaceutical fentanyl-related deaths—multiple states, April 2005–March 2007. July 25, 2008. MMWR Morb Mortal Wkly Rep. 2008;57(29):793-796. www.cdc.gov/mmwr/preview/mmwrhtml/mm5729a1.htm. Accessed March 14, 2016.
3. National Institute on Drug Abuse. Fentanyl. www.drugabuse.gov/drugs-abuse/fentanyl. Accessed February 21, 2016.
4. World Health Organization. Acetyl fentanyl. Critical review report. Agenda item 5.2. Expert Committee on Drug Dependence. Thirty-seventh meeting. Geneva, 16-20 November 2015. www.who.int/medicines/access/controlled-substances/5.2_Acetylfentanyl_CRev.pdf. Accessed February 22, 2016.
5. National Institute on Drug Abuse. Fentanyl use in combination with street drugs leading to death in some cases. June 2006. www.drugabuse.gov/about-nida/directors-page/messages-director/2006/06/fentanyl-use-in-combination-street-drugs-leading-to-death-in-some-cases. Accessed February 21, 2016.
6. CDC Health Alert Network. Increases in fentanyl drug confiscations and fentanyl-related overdose fatalities. CDCHAN-00384. October 26, 2015. http://emergency.cdc.gov/han/han00384.asp. Accessed February 21, 2016.
7. DEA. National heroin threat assessment summary. DEA Intelligence Report. April 2015. www.dea.gov/divisions/hq/2015/hq052215_National_Heroin_Threat_Assessment_Summary.pdf. Accessed February 21, 2016.
8. DEA. DEA issues nationwide alert on fentanyl as threat to health and public safety. Headquarters News. March 18, 2015. www.dea.gov/divisions/hq/2015/hq031815.shtml. Accessed February 22, 2016.
9. National Forensic Laboratory Information System. Special Report: Opiates and Related Drugs Reported in NFLIS, 2009–2014. July 2015. http://ndews.umd.edu/sites/ndews.umd.edu/files/NFLIS-SR-Opioids.pdf. Accessed February 22, 2016.
10. Higashikawa Y, Suzuki S. Studies on 1-(2-phenethyl)-4-(N-propionylanilino) piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other analogues. Forensic Toxicol. 2008;26(1):1-5.
11. European Monitoring Centre for Drugs and Drug Addiction. Fentanyl drug profile. www.emcdda.europa.eu/publications/drug-profiles/fentanyl. Accessed March 8, 2016.
12. Stogner JM. The potential threat of acetyl fentanyl: legal issues, contaminated heroin, and acetyl fentanyl “disguised” as other opioids. Ann Emerg Med. 2014;64(6):637-639.
13. Galea S, Nandi A, Coffin PO, et al. Heroin and cocaine dependence and the risk of accidental non-fatal drug overdose. J Addict Dis. 2006;25(3):79-87.
14. CDC Health Alert Network. Recommendations for laboratory testing for acetyl fentanyl and patient evaluation and treatment for overdose with synthetic opioids. June 20, 2013. http://stacks.cdc.gov/view/cdc/25259. Accessed February 24, 2016.
15. Kim D, Irwin KS, Khoshnood K. Expanded access to naloxone: options for critical response to the epidemic of opioid overdose mortality. Am J Public Health. 2009;99(3):402-407.
16. Doyon S, Aks SE, Schaeffer S. Expanding access to naloxone in the United States. J Med Toxicol. 2014;10(4):431-434.
17. Roberts JR. Acetyl fentanyl: new drug of abuse more common than assumed. Emerg Med News. 2013;35:1-28.
18. Evzio (naloxone hydrochloride) auto-injector prescribing information. Richmond VA: Kaleo, Inc; April 2014. http://evzio.com/pdfs/Evzio%20PI.PDF. Accessed September 1, 2016.
19. Narcan (naloxone hydrochloride) nasal spray prescribing information. Radnor, PA: Adapt Pharma, Inc; February 2016. www.narcan.com/pdf/NARCAN-Prescribing-Information.pdf. Accessed September 1, 2016.
20. Wermeling DP. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Ther Adv Drug Saf. 2015;6(1):20-31.
21. Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146-155.
22. United Nations Office on Drugs and Crime. UNODC early warning advisory (EWA) on new psychoactive substances (NPS). www.unodc.org/LSS/Home/NPS. Accessed February 23, 2016.
23. Barlas S. FDA starts new light-touch inspections for some imports. P T. 2014;39(6):384-385.
24. FDA Safety and Innovation Act. S.3187. January 3, 2012. www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf. Accessed February 23, 2016.
25. DEA. Office of Diversion Control. Schedules of controlled substances: temporary placement of acetyl fentanyl into Schedule I. 21 CFR Part 1308. Fed Regist. 2015;80(137):42381-42385. www.deadiversion.usdoj.gov/fed_regs/rules/2015/fr0717_7.htm. Accessed February 22, 2016.
26. Santos AG; DEA. Synthetic drug trafficking and abuse trends. July 13-14, 2013. Pharmacy Diversion Awareness Conference (PDAC). Portland, Oregon. www.deadiversion.usdoj.gov/mtgs/pharm_awareness/conf_2013/july_2013/asantos2.pdf. Accessed February 23, 2016.
27. National Conference of State Legislatures. Synthetic drug threats. January 13, 2015. www.ncsl.org/research/civil-and-criminal-justice/synthetic-drug-threats.aspx#2. Accessed February 23, 2016.
28. National Alliance for Model State Drug Laws. Controlled substance analogs statutory comparison and compilation. October 30, 2012. www.namsdl.org/library/7C341200-1C23-D4F9-74CEC9BE0E87F653/. Accessed February 23, 2016.
29. The Network for Public Health Law. Legal interventions to reduce overdose mortality: naloxone access and overdose Good Samaritan laws. www.networkforphl.org/_asset/qz5pvn/network-naloxone-10-4.pdf June 2016. Accessed August 31, 2016.
30. Lank PM, Pines E, Mycyk MB. Emergency physicians’ knowledge of cannabinoid designer drugs. West J Emerg Med. 2013;14(5):467-470.
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