Fentanyl
Fentanyl is a potent synthetic piperidine opioid primarily used as an analgesic. It is 50 times more potent than heroin and 100 times more potent than morphine;[8] its primary clinical utility is in pain management for cancer patients and those recovering from painful surgeries.[9][10] Fentanyl is also used as a sedative.[11] Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose.[12] Fentanyl works by activating μ-opioid receptors.[6] Fentanyl is sold under the brand names Actiq, Duragesic and Sublimaze, among others.[13]
Clinical data
/ˈfɛntənɪl/ or /ˈfɛntənəl/
Actiq, Duragesic, Sublimaze, others
- AU: C
High[1]
Very High[2]
- AU: S8 (Controlled drug)
- BR: Class A1 (Narcotic drugs)
- CA: Schedule I
- DE: Anlage III (Special prescription form required)
- NZ: Class B
- UK: Class A
- US: WARNING[3]Schedule II
- UN: Narcotic Schedule I
- EU: Rx-only
92% (transdermal)
90% (intranasal)
50% (buccal)
33% (ingestion)
100% (intramuscular)
80% (inhaled)
100% (intravenous)
80–85%[4]
5 minutes[5]
Mostly urinary (metabolites, < 10% unchanged drug)[6]
C22H28N2O
336.479 g·mol−1
1.1 g/cm3
87.5 °C (189.5 °F)
Pharmaceutical fentanyl's adverse effects are identical to those of other narcotic opioids,[14] including addiction, confusion, respiratory depression (which, if extensive and untreated, may lead to arrest), drowsiness, nausea, visual disturbances, dyskinesia, hallucinations, delirium, a subset of the latter known as "narcotic delirium", narcotic ileus, muscle rigidity, constipation, loss of consciousness, hypotension, coma, and death.[11] Alcohol and other drugs (e.g., cocaine and heroin) can synergistically exacerbate fentanyl's side effects. Naloxone (also known as Narcan) can reverse the effects of an opioid overdose; however, because fentanyl is so potent, multiple doses might be necessary.[13]
Fentanyl was first synthesized by Paul Janssen in 1959 and was approved for medical use in the United States in 1968.[6][15] In 2015, 1,600 kilograms (3,500 pounds) were used in healthcare globally.[16] As of 2017, fentanyl was the most widely used synthetic opioid in medicine;[17] in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions.[18][19] It is on the World Health Organization's List of Essential Medicines.[20]
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.[21] 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.[22][21][23] Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtook heroin in 2018.[22] 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.[24] Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin.[24] Fentanyl has been reported in pill form, including pills mimicking pharmaceutical drugs such as oxycodone.[24] 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.[11] In an attempt to reduce the number of overdoses from taking other drugs mixed with fentanyl, drug testing kits, strips and labs are available.[25][26] 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.[27]
Medical uses[edit]
Anesthesia[edit]
Intravenous fentanyl is often used for anesthesia and as an analgesic.[28] To induce anesthesia, it is given with a sedative-hypnotic, like propofol or thiopental, and a muscle relaxant.[29] To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used.[29] These are often given in 15–30 minute intervals throughout procedures such as endoscopy and surgeries and in emergency rooms.[30][31]
For pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia.[29] Balancing this medication and titrating the drug based on expected stimuli and the person's responses can result in stable blood pressure and heart rate throughout a procedure and a faster emergence from anesthesia with minimal pain.[29]
Regional anesthesia[edit]
Fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min) and intermediate duration of action (60–120 min).[32] Spinal administration of hyperbaric bupivacaine with fentanyl may be the optimal combination. The almost immediate onset of fentanyl reduces visceral discomfort and even nausea during the procedure.[33]
Obstetrics[edit]
Fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anaesthesia and analgesia. Because of fentanyl's high lipid solubility, its effects are more localized than morphine, and some clinicians prefer to use morphine to get a wider spread of analgesia.[34] It is widely used in obstetrical anesthesia because of its short time to action peak (about 5 minutes), the rapid termination of its effect after a single dose, and the occurrence of relative cardiovascular stability.[35] In obstetrics, the dose must be closely regulated in order to prevent large amounts of transfer from mother to fetus. At high doses, the drug may act on the fetus to cause postnatal respiratory distress.[35] For this reason, shorter acting agents such as alfentanyl or remifentanil may be more suitable in the context of inducing general anaesthesia.[36]
History[edit]
Fentanyl was first synthesized in Belgium by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959.[136] It was developed by screening chemicals similar to pethidine (meperidine) for opioid activity.[137] 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).[138] Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil Laboratories under the trade name Sublimaze.[139]
In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formulation of an inert alcohol gel infused with select fentanyl doses, which are worn to provide constant administration of the opioid over a period of 48 to 72 hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.[140]
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.[141]
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.[142] 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.[142]
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.[143]
Society and culture[edit]
Legal status[edit]
In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.[144]
In the Netherlands, fentanyl is a List I substance of the Opium Law.[145]
In the U.S., fentanyl is a Schedule II controlled substance per the Controlled Substance Act. Distributors of Abstral are required to implement an FDA-approved risk evaluation and mitigation strategy (REMS) program.[146][147] In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.[148][149][150]
In Canada, fentanyl is considered a schedule I drug as listed in Canada's Controlled Drugs and Substances Act.[151]
Estonia is known to have been home to the world's longest documented fentanyl epidemic, especially following the Taliban ban on opium poppy cultivation in Afghanistan.[152]
A 2018 report by The Guardian indicated that many major drug suppliers on the dark web have voluntarily banned the trafficking of fentanyl.[153]
The fentanyl epidemic has erupted in a highly acrimonious dispute between the U.S. and Mexican governments. While U.S. officials blame the flood of fentanyl crossing the border primarily on Mexican crime groups, President Andrés Manuel López Obrador insists that the main source of this synthetic drug is Asia. He believes that the crisis of a lack of family values in the United States drives people to use the drug.[154]
Recreational use[edit]
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.[155]
Fentanyl analogues may be hundreds of times more potent than heroin. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin or oxycodone, which can lead to overdose. Many fentanyl overdoses are initially classified as heroin overdoses.[156] Recreational use is not particularly widespread in the EU except for Tallinn, Estonia, where it has largely replaced heroin. Estonia has the highest rate of 3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.[157]
Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies. The gel from inside the patches is sometimes ingested or injected.[158]
Another form of fentanyl that has appeared on the streets is the Actiq lollipop formulation. The pharmacy retail price ranges from US$15 to US$50 per unit based on the strength of the lozenge, with the black market cost ranging from US$5 to US$25, depending on the dose.[159] The attorneys general of Connecticut and Pennsylvania have launched investigations into its diversion from the legitimate pharmaceutical market, including Cephalon's "sales and promotional practices for Provigil, Actiq and Gabitril."[159]
Non-medical use of fentanyl by individuals without opioid tolerance can be very dangerous and has resulted in numerous deaths.[158] Even those with opiate tolerances are at high risk for overdoses. Like all opioids, the effects of fentanyl can be reversed with naloxone, or other opiate antagonists. Naloxone is increasingly available to the public. Long acting or sustained release opioids may require repeat dosage. Illicitly synthesized fentanyl powder has also appeared on the United States market. Because of the extremely high strength of pure fentanyl powder, it is very difficult to dilute appropriately, and often the resulting mixture may be far too strong and, therefore, very dangerous.[160]
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.[161]
Veterinary use[edit]
Fentanyl is commonly used for analgesia and as a component of balanced sedation and general anesthesia in small animal patients. In addition, its efficacy is higher than many other pure-opiate and synthetic pure-opioid agonists regarding vomiting, depth of sedation, and cardiovascular effects when given as a continuous infusion as well as a transdermal patch.[251][252][253] As with other pure-opioid agonists, fentanyl has been associated with dysphoria in dogs.[254]
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.[255] 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.[256] The drug is also approved in Europe.[257]