Drug Enforcement Administration

Diversion Control Division

January 2023
Fentanyl
(Trade Names: Actiq®, FentoraTM, Duragesic®)

Introduction: Fentanyl patches are abused by removing the gel contents from the
Fentanyl is a potent synthetic opioid. It was introduced into patches and then injecting or ingesting these contents. Patches have
medical practice as an intravenous anesthetic under the trade also been frozen, cut into pieces and placed under the tongue or in the
name of Sublimaze in the 1960s. cheek cavity for drug absorption through the oral mucosa. Used
patches are attractive to abusers as a large percentage of fentanyl
Licit Uses: remains in these patches even after a 3-day use. Fentanyl oral
According to IQVIA National Prescription Audit™, total transmucosal lozenges and fentanyl injectables are also diverted and
prescriptions dispensed for fentanyl were approximately 6.5 million abused.
in 2015, 5.0 million in 2017, 3.2 million in 2019, 2.7 million in 2020, Abuse of fentanyl initially appeared in mid-1970s and has increased
and 2.4 million in 2021. During the height of the opioid epidemic, in recent years. There have been reports of deaths associated with
in 2016 and 2017, the number of fentanyl prescriptions dispensed abuse of fentanyl products.
were approximately 6.0 million and 5.0 million, respectively. According to the Centers for Disease Control and Prevention (CDC)
Fentanyl pharmaceutical products are currently available as oral in 2020, more than 56,000 deaths involving synthetic opioids (other than
transmucosal lozenges, commonly referred to as fentanyl methadone) occurred in the United States, which is more deaths than
“lollipops” (Actiq®), effervescent buccal tablets (Fentora™), from any other drug class. Synthetic opioid-involved death rates
sublingual tablets (Abstral®), sublingual sprays (Subsys™), nasal increased by over 56% from 2019 to 2020 and accounted for over 82%
sprays (Lazanda®), transdermal patches (Duragesic®), and of all opioid-involved deaths in 2020. The rate of overdose deaths
injectable formulations. Oral transmucosal lozenges and involving synthetic opioids was more than 18 times higher in 2020 than
effervescent buccal tablets are used for the management of in 2013. While the synthetic opioid category does include other
breakthrough cancer pain in patients who are already receiving substances such as tramadol, fentanyl largely dominates the category.
opioid medication for their underlying persistent pain. Transdermal Also, as annually reported by the DEA National Drug Threat
patches are used in the management of chronic pain in patients Assessment, in March 2021, states with the greatest amounts of
who require continuous opioid analgesia. Fentanyl citrate fentanyl seized in 2019 were either clustered along the Southwest
injections are administered intravenously, intramuscularly, spinally, border, or were located in the Mid-Atlantic, Great Lakes, or Northeast
or epidurally for potent analgesia and anesthesia. Because of a areas of the United States..
concern about deaths and overdoses resulting from fentanyl
transdermal patches (Duragesic® and generic versions), on July Illicit Distribution:
15, 2005, the Food and Drug Administration issued safety Licit fentanyl is diverted via theft, fraudulent prescriptions, and illicit
warnings and reiterated the importance of strict adherence to the distribution by patients, physicians, and pharmacists.
guidelines for the proper use of these products. Illicitly manufactured fentanyl is chiefly responsible for the current
domestic crisis. According to the National Forensic Laboratory
Chemistry: Information System (NFLIS) database, which does not distinguish
Fentanyl (N-phenyl-N-[1-(2-phenylethyl)-4- between pharmaceutical and illicitly manufactured fentanyl, the annual
piperidinyl]propanamide) is a water-soluble solid that exists in a number of fentanyl reports in 2017 was 61,628 and 89,894 in 2018,
crystal or crystalline powder form. which were analyzed by federal, state and local forensic laboratories in
the United States. Fentanyl reports continued to rise in 2019 with
107,966 reports, and again in 2020 with 125,119 reports. In 2021,
159,645 fentanyl drug reports were submitted to NFLIS. Preliminary
findings indicate a greater increase with 86,414 reports of fentanyl
identified in 2018.

Clandestine Manufacture:
From April 2005 to March 2007, an outbreak of fentanyl overdoses
and deaths occurred. The Centers for Disease Control and Prevention
Pharmacology: (CDC)/Drug Enforcement Administration (DEA) surveillance system
Fentanyl is about 100 times more potent than morphine as an reported 1,013 confirmed non-pharmaceutical fentanyl-related deaths.
analgesic. It is a µ-opioid receptor agonist with high lipid solubility Most of these deaths occurred in Delaware, Illinois, Maryland, Michigan,
and a rapid onset and short duration of effects. Fentanyl rapidly Missouri, New Jersey, and Pennsylvania. Consequently, DEA
crosses the blood-brain barrier. It is similar to other µ-opioid immediately undertook the development of regulations to control
receptor agonists (like morphine or oxycodone) in its precursor chemicals used by clandestine laboratories to illicitly
pharmacological effects and produces analgesia, sedation, manufacture fentanyl. In 2007, DEA published an Interim Final Rule to
nausea, vomiting, itching, and respiratory depression. Fentanyl designate N-phenethyl-4-piperidone (NPP) – a precursor to fentanyl, as
appears to produce muscle rigidity with greater frequency than a list I chemical. DEA also completed a scheduling action to designate
other opioids. Unlike some µ-opioid receptor agonists, fentanyl 4-anilino-N-phenethylpiperidine (ANPP) as a schedule II immediate
does not cause histamine release and has minimal depressant precursor in 2010. After the control of ANPP, the number of fentanyl-
effects on the heart. related deaths declined until 2013. In effort to address the continued
evolution of precursors used in the illicit manufacture of fentanyl, DEA
Illicit Uses: recently completed regulations to add benzylfentanyl and 4-
Fentanyl is abused for its intense euphoric effects. Fentanyl anilinopiperidine (4-AP) as list I chemicals and to control norfentanyl, as a
can serve as a direct substitute for heroin in opioid dependent schedule II immediate precursor to fentanyl.
individuals. However, fentanyl is a very dangerous substitute for
heroin because it is much more potent than heroin and results in Control Status:
frequent overdoses that can lead to respiratory depression and Fentanyl is controlled in schedule II of the Controlled Substances
death. Act.

Comments and additional information are welcomed by the Drug and