Fentanyl was first synthesized by Paul Janssen in 1959 and was approved for medical use in the United States in 1968. In 2015, 1,600 kilograms (3,500 pounds) were used in healthcare globally. As of 2017 , fentanyl was the most widely used synthetic opioid in medicine; in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions. It is on the World Health Organization's List of Essential Medicines.
Fentanyl was first synthesized in Belgium by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959. It was developed by screening chemicals similar to pethidine (meperidine) for opioid activity. The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 stoichiometric ratio). Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil Laboratories under the trade name Sublimaze.
The original synthesis as patented in 1964 by Paul Janssen involves synthesis of benzylfentanyl from N-Benzyl-4-Piperidone. The resulting benzylfentanyl is used as feedstock to norfentanyl. It is norfentanyl that forms fentanyl upon reaction with phenethyl chloride.
Following the patch, a flavored lollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain.
Russian Spetsnaz security forces are suspected to have used a fentanyl analogue, or derivative (suspected to be carfentanil and remifentanil ), to rapidly incapacitate people in the Moscow theater hostage crisis in 2002. The siege was ended, but many hostages died from the gas after their health was severely taxed during the days long siege. The Russian Health Minister later stated that the gas was based on fentanyl, but the exact chemical agent has not been clearly identified.
Some heroin dealers mix fentanyl powder with heroin to increase potency or compensate for low-quality heroin. In 2006, illegally manufactured, non-pharmaceutical fentanyl often mixed with cocaine or heroin caused an outbreak of overdose deaths in the United States and Canada, heavily concentrated in the cities of Dayton, Ohio; Chicago, Illinois; Detroit, Michigan; and Philadelphia, Pennsylvania.
The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context. In 2006, the United States Food and Drug Administration (FDA) began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008. The FDA reported in April 2012 that twelve young children had died and twelve more had become seriously ill from separate accidental exposures to fentanyl skin patches.
In 2009, the US Food and Drug Administration (FDA) approved Onsolis (fentanyl buccal soluble film), a fentanyl drug in a new dosage form for cancer pain management in opioid-tolerant subjects. It uses a medication delivery technology called BEMA (BioErodible MucoAdhesive), a small dissolvable polymer film containing various fentanyl doses applied to the inner lining of the cheek.
Furthermore, transdermal fentanyl's potency and short duration of action make it popular as an intra-operative and post-operative analgesic in cats and dogs. This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012, a highly concentrated (50 mg/mL) transdermal solution, trade name Recuvyra, has become commercially available for dogs only. It is FDA-approved to provide four days of analgesia after a single application before surgery. It is not approved for multiple doses or other species. The drug is also approved in Europe.
In June 2013, the United States Centers for Disease Control and Prevention (CDC) issued a health advisory to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, a synthetic opioid analog of fentanyl that has never been licensed for medical use. In a separate study conducted by the CDC, 82% of fentanyl overdose deaths involved illegally manufactured fentanyl, while only 4% were suspected to originate from a prescription.
Fentanyl continues to fuel an epidemic of synthetic opioid drug overdose deaths in the United States. From 2011 to 2021, prescription opioid deaths per year remained stable, while synthetic opioid deaths per year increased from 2,600 overdoses to 70,601. Since 2018, fentanyl and its analogues have been responsible for most drug overdose deaths in the United States, causing over 71,238 deaths in 2021. Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtook heroin in 2018. The United States National Forensic Laboratory estimates fentanyl reports by federal, state, and local forensic laboratories increased from 4,697 reports in 2014 to 117,045 reports in 2020. Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin. Fentanyl has been reported in pill form, including pills mimicking pharmaceutical drugs such as oxycodone. Mixing with other drugs or disguising as a pharmaceutical makes it difficult to determine the correct treatment in the case of an overdose, resulting in more deaths. In an attempt to reduce the number of overdoses from taking other drugs mixed with fentanyl, drug testing kits, strips and labs are available. Fentanyl's ease of manufacture and high potency makes it easier to produce and smuggle, resulting in fentanyl replacing other abused narcotics and becoming more widely used.
Beginning in 2015, Canada has seen a number of fentanyl overdoses. Authorities suspected that the drug was being imported from Asia to the western coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets. Traces of the drug have also been found in other recreational drugs, including cocaine, MDMA, and heroin. The drug has been implicated in deaths of people from all walks of life—from homeless individuals to professionals—including teens and young parents. Because of the rising deaths across the country, especially in British Columbia where 1,716 deaths were reported in 2020 and 1,782 from January to October 2021, Health Canada is putting a rush on a review of the prescription-only status of naloxone in an effort to combat overdoses of the drug. In 2018, Global News reported allegations that diplomatic tensions between Canada and China hindered cooperation to seize imports, with Beijing being accused of inaction.
Fentanyl has a US Drug Enforcement Administration (DEA) Administrative Controlled Substances Code Number (ACSCN) of 9801. Its annual aggregate manufacturing quota has significantly reduced in recent years from 2,300.000 kg in 2015 and 2016 to only 731.452 kg in 2021, a nearly 68.2% decrease.
Some increases in fentanyl deaths do not involve prescription fentanyl but are related to illicitly made fentanyl that is being mixed with or sold as heroin. Death from fentanyl overdose continues to be a public health issue of national concern in Canada since September 2015. In 2016, deaths from fentanyl overdoses in the province of British Columbia averaged two persons per day. In 2017 the death rate increased by more than 100% with 368 overdose-related deaths in British Columbia between January and April 2017.
Public health advisories to prevent fentanyl misuse and fatal overdose have been issued by the U.S. Centers for Disease Control (CDC). An initial HAN Advisory, also known as a Health Alert Network Advisory ("provides vital, time-sensitive information for a specific incident or situation; warrants immediate action or attention by health officials, laboratorians, clinicians, and members of the public; and conveys the highest level of importance") was issued during October 2015. A subsequent HAN Alert was issued in July 2018, warning of rising numbers of deaths due to fentanyl abuse and mixing with non-opioids. A December 2020 HAN Advisory warned of:
Fentanyl has been discovered for sale in illicit markets in Australia in 2017 and in New Zealand in 2018. In response, New Zealand experts called for wider availability of naloxone.
Naloxone (sold under the brand name Narcan) can completely or partially reverse an opioid overdose. In July 2014, the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children, and advised that they should be folded, with the adhesive side in, before being discarded. The patches should be kept away from children, who are most at risk from fentanyl overdose. In the US, fentanyl and fentanyl analogs caused over 29,000 deaths in 2017, a large increase over the previous four years.
Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. More than 12 different analogues of fentanyl, all unapproved and clandestinely produced, have been identified in the U.S. drug traffic. In February 2018, the U.S. Drug Enforcement Administration indicated that illicit fentanyl analogs have no medically valid use, and thus applied a "Schedule I" classification to them.
In August 2018, Nebraska became the first American state to use fentanyl to execute a prisoner. Carey Dean Moore, at the time one of the longest-serving death row inmates in the United States, was executed at the Nebraska State Penitentiary. Moore received a lethal injection, administered as an intravenous series of four drugs that included fentanyl citrate, to inhibit breathing and render the subject unconscious. The other drugs included diazepam as a tranquilizer, cisatracurium besylate as a muscle relaxant, and potassium chloride to stop the heart. The use of fentanyl in execution caused concern among death penalty experts because it was part of a previously untested drug cocktail. The execution was also protested by anti-death penalty advocates at the prison during the execution and later at the Nebraska capitol building.
Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In November 2016, the DEA uncovered an operation making counterfeit oxycodone and Xanax from a home in Cottonwood Heights, Utah. They found about 70,000 pills in the appearance of oxycodone and more than 25,000 in the appearance of Xanax. The DEA reported that millions of pills could have been distributed from this location over the course of time. The accused owned a tablet press and ordered fentanyl in powder form from China. A seizure of a record amount of fentanyl occurred on 2 February 2019, by U.S. Customs and Border Protection in Nogales, Arizona. The 254 pounds (115 kg) of fentanyl, which was estimated to be worth US$3.5M, was concealed in a compartment under a false floor of a truck transporting cucumbers. The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF). One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl, which today are classified as Schedule I drugs in the United States. Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is more resistant to metabolic degradation. This results in a drug with an increased duration.
81,230 drug overdose deaths occurred during the 12 months from May 2019 to May 2020, the largest number of drug overdoses for a 12-month interval ever recorded for the U.S. The CDC recommended the following four actions to counter this rise:
In May 2019, China regulated the entire class of fentanyl-type drugs and two fentanyl precursors. Nevertheless, it remains the principal origin of fentanyl in the United States: Mexican cartels source fentanyl precursors from Chinese suppliers such as Yuancheng Group, which are finished in Mexico and smuggled to the United States. Following the 2022 visit by Nancy Pelosi to Taiwan, China halted cooperation with the United States on combatting drug trafficking.
In 2020, the Myanmar military and police confiscated 990 gallons of "methyl fentanyl" [sic], as well as precursors for the illicit synthesis of the drug. According to the United Nations Office on Drugs and Crime, the Shan State of Myanmar has been identified as a major source for fentanyl derivatives. In 2021, the agency reported a further drop in opium poppy cultivation in Burma, as the region's synthetic drug market continues to expand and diversify.
substantial increases in drug overdose deaths across the United States, primarily driven by rapid increases in overdose deaths involving ... illicitly manufactured fentanyl; a concerning acceleration of the increase in drug overdose deaths, with the largest increase recorded from March 2020 to May 2020, coinciding with the implementation of widespread mitigation measures for the COVID-19 pandemic; significant increases in overdose deaths involving methamphetamine.
The Gupta (or 'one-pot') method starts from 4-Piperidone and skips the direct use of 4-ANPP/NPP; rather the compounds are formed only as impurities or temporary intermediates. For the first half of 2021, the U.S. Drug Enforcement Administration found the Gupta method was the predominant synthesis route in their samples of seized fentanyl. In 2022, Braga and coworkers described a synthesis of fentanyl involving continuous flow that uses reagents similar to the ones described for the Gupta procedure.
In 2023, a California police union director was charged with importing synthetic opioids, including fentanyl and tapentadol disguised as chocolate. U.S. law enforcement had been slow in their response to the fentanyl crisis, according to the Washington Post. The response by the federal government to the fentanyl crisis had also faltered, according to the press release. Overdose deaths by fentanyl and other illegally imported opioids were surging since 2019 and are presently a major cause of death in all U.S. states.
In February 2004, a leading fentanyl supplier, Janssen Pharmaceutica Products recalled one lot, and later, additional lots of fentanyl (brand name: Duragesic) patches because of seal breaches that might have allowed the medication to leak from the patch. A series of class II recalls was initiated in March 2004, and in February 2008, the ALZA Corporation recalled their 25 µg/h Duragesic patches due to a concern that small cuts in the gel reservoir could result in accidental exposure of patients or health care providers to the fentanyl gel. In April 2023, Teva Pharmaceuticals USA recalled 13 lots of their Fentanyl Buccal Tablets CII due to missing safety information sheets on how to properly administer their product. The corporation issued a consumer recall report and stressed the importance of safety in the use and administration of opioid therapeutics.
In June 2023, overdose deaths in the U.S. and Canada again reached record numbers. According to a 2023 report from the United Nations Office on Drugs and Crime (UNODC) based in Vienna, the increased numbers of deaths are not related to an increased number of users but to the lethal effects of fentanyl itself. Fentanyl would require a special status as it is considerably more toxic than other widely abused opioids and opiates. With regard to overdose deaths in pediatric cases, numbers are also concerning. Based on a report by JAMA network, 37.5% of all fatal pediatric cases between 1999 and 2021 were related to fentanyl; most of the deaths were among adolescents (89.6%) and children aged 0 to 4 years (6.6%). According to the UNODC, "the opioid crisis in North America is unabated, fueled by an unprecedented number of overdose deaths."