Fentanyl: Difference between revisions

{{cs1Cs1 config|name-list-style=vanc|display-authors=6}}

| Watchedfields = changed

| verifiedrevid = 443760208

| image = [[File:Fentanyl2DCSD.svg|frameless|class=skin-invert]]

| alt =

| image2 = Fentanyl-xtal-3D-balls.png

| alt2 = <!--Clinical = data-->

| class = [[Opioid]]

| ATC_prefix = N01

| ATC_suffix = AH01

| ATC_supplemental = {{ATC|N02|AB03}}

<!-- Legal status -->| legal_AU = S8

<!-- Pharmacokinetic data -->| bioavailability = *[[Transdermal]]: 92%

|*[[Intranasal]]: bioavailability = 92% (transdermal)<br />90% (intranasal){{Citation needed|reason=Many external sources mention 50–71%, top google result states 89% (not 90%) but links to a very old study. No valid reasons provided to raise from 65%.|date=November 2023}}<br />50% (buccal)<br />33% (ingestion)<br />100% (intramuscular)<br /> 80% (inhaled)<br />100% (intravenous)

| excretion = Mostly urinary (metabolites, <{{nbsp}}10% unchanged drug)<ref name=AHFS2017/>

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}

<!--Chemical data-->| IUPAC_name = ''N''-phenyl-''N''-[1-(2-phenylethyl)piperidin-4-yl]propanamide

| N O = 21

| density melting_point = 187.15

'''Fentanyl''' is a highly potent synthetic [[piperidine]] [[opioid]] primarily used as an [[analgesic]]. It is 2030 to 4050 times more [[Potency (pharmacology)|potent]] than [[heroin]] and 100 times more potent than [[morphine]];<ref>{{cite webjournal |date=14 November 2018 |title=Fentanyl |urljournal=https://www[[Nature.canadacom]] |volume=9 |issue=1 |doi=10.ca1038/en/healths41398-canada/services/substance019-use/controlled0625-illegal-drugs/fentanyl.html0 |access-datepage=5 November 2023282 |websitepmid=[[Health Canada]]31712552 |archive-datepmc=56848196 November| 2023vauthors |archive-url=https://web.archive.org/web/20231105012202/https://www.canada.ca/en/health-canada/services/substance-use/controlled-illegal-drugs/fentanyl.html |url-status=liveHan Y, Yan W, Zheng Y, Khan MZ, Yuan K, Lu L }}</ref> its primary clinical utility is in [[pain management]] for cancer patients and those recovering from painful surgeries.<ref>{{cite web |date=7 October 2022 |title=Fentanyl |url=https://www.cdc.gov/opioids/basics/fentanyl.html |access-date=20 February 2023 |website=U.S. [[Centers for Disease Control and Prevention]] (CDC) |archive-date=28 April 2022 |archive-url=https://web.archive.org/web/20220428125143/https://www.cdc.gov/opioids/basics/fentanyl.html |url-status=live }}</ref><ref>{{cite web |title=Fentanyl: MedlinePlus Drug Information |url=https://medlineplus.gov/druginfo/meds/a605043.html |access-date=5 November 2023 |website=MedlinePlus |archive-date=27 November 2023 |archive-url=https://web.archive.org/web/20231127155947/https://medlineplus.gov/druginfo/meds/a605043.html |url-status=live }}</ref> Fentanyl is also used as a [[sedative]].<ref name = "Ramos-Matos_2022">{{cite book |vauthors=Ramos-Matos CF, Bistas KG, Lopez-Ojeda W |chapter=Fentanyl |date=2022 |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK459275/ |title=StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29083586 |access-date=20 February 2023 |archive-date=15 March 2023 |archive-url=https://web.archive.org/web/20230315112647/https://www.ncbi.nlm.nih.gov/books/NBK459275/ |url-status=live }}</ref> Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause [[Drug overdose|overdose]].<ref>{{cite web |date=21 December 2021 |title=Fentanyl |url=https://nida.nih.gov/research-topics/fentanyl |access-date=20 February 2023 |website=National Institute on Drug Abuse |archive-date=20 February 2023 |archive-url=https://web.archive.org/web/20230220094916/https://nida.nih.gov/research-topics/fentanyl |url-status=live }}</ref> Fentanyl works by activating [[μ-opioid receptor]]s.<ref name="AHFS2017">{{cite web |title=Fentanyl, Fentanyl Citrate, Fentanyl Hydrochloride |url=https://www.drugs.com/monograph/fentanyl-fentanyl-citrate-fentanyl-hydrochloride.html |url-status=live |archive-url=https://web.archive.org/web/20171214015004/https://www.drugs.com/monograph/fentanyl-fentanyl-citrate-fentanyl-hydrochloride.html |archive-date=14 December 2017 |access-date=8 December 2017 |publisher=The American Society of Health-System Pharmacists}}</ref> Fentanyl is sold under the brand names '''Actiq''', '''Duragesic''', and '''Sublimaze''', among others.<ref name="National Institute on Drug Abuse_2021">{{cite web |date=1 June 2021 |title=Fentanyl DrugFacts |url=https://nida.nih.gov/publications/drugfacts/fentanyl |access-date=20 February 2023 |website=National Institute on Drug Abuse |archive-date=11 May 2023 |archive-url=https://web.archive.org/web/20230511222756/https://nida.nih.gov/publications/drugfacts/fentanyl |url-status=live }}</ref>

Fentanyl was first synthesized by [[Paul Janssen]] in 1959 and was approved for medical use in the United States in 1968.<ref name=AHFS2017/><ref name=Stan1992>{{cite journal | vauthors = Stanley TH | title = The history and development of the fentanyl series | journal = Journal of Pain and Symptom Management | volume = 7 | issue = 3 Suppl | pages = S3–S7 | date = April 1992 | pmid = 1517629 | doi = 10.1016/0885-3924(92)90047-L | doi-access = free | title-link = doi }}</ref> In 2015, {{convert|1600|kg|lb|abbr=off|sp=us}} were used in healthcare globally.<ref name=UN2016>{{cite report |title=Narcotic Drugs Estimated World Requirements for 2017 / Statistics for 2015 |year=2016 |publisher=United Nations |location=New York |isbn=978-92-1-048163-2 |page=40 |url=https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2016/Narcotic_Drugs_Publication_2016.pdf |access-date=14 December 2017|archive-url=https://web.archive.org/web/20171022041515/https://www.incb.org/documents/Narcotic-Drugs/Technical-Publications/2016/Narcotic_Drugs_Publication_2016.pdf |archive-date=22 October 2017 |url-status=live}}</ref> {{As of|2017}}, fentanyl was the most widely used [[synthetic opioid]] in medicine;<ref>{{cite web |title=Fentanyl and analogues |date=16 October 2017 |website=LverToxLiverTox |url=https://livertox.nlm.nih.gov//FentanylAndAnalogues.htm |access-date=14 December 2017 |url-status=live |archive-url=https://web.archive.org/web/20170107002718/https://livertox.nlm.nih.gov/FentanylAndAnalogues.htm|archive-date=7 January 2017 }}</ref> in 2019, it was the 278th most commonly prescribed medication in the United States, with more than a million prescriptions.<ref>{{cite web |title = The Top 300 of 2019 |website = ClinCalc |url = https://clincalc.com/DrugStats/Top300Drugs.aspx |access-date = 7 October 2022 |archive-date = 12 February 2021 |archive-url = https://web.archive.org/web/20210212142534/https://clincalc.com/DrugStats/Top300Drugs.aspx |url-status = live }}</ref><ref>{{cite web |title = Fentanyl Drug Usage Statistics |website = ClinCalc |url = https://clincalc.com/DrugStats/Drugs/Fentanyl |access-date = 7 October 2022 |archive-date = 11 April 2020 |archive-url = https://web.archive.org/web/20200411201150/https://clincalc.com/DrugStats/Drugs/Fentanyl |url-status = live }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book |title = World Health Organization model list of essential medicines |year = 2021 |edition=22nd list (2021) |publisher = [[World Health Organization]] |location = Geneva, CH |hdl = 10665/345533 |hdl-access=free |id = WHO/MHP/HPS/EML/2021.02 | vauthors = Organization WH }}</ref>

Fentanyl continues to fuel an [[opioid epidemic in the United States|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 [[Drug overdose|overdoses]] to 70,601.<ref name="NIDA_overdose" /> 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.<ref name="www.cbsnews.com_2018">{{cite web|title=Fentanyl overtakes heroin as the No. 1 opioid overdose killer |url=https://www.cbsnews.com/news/fentanyl-no-1-opioid-overdose-killer-over-heroin-vicodin-oxycontin/ |access-date=20 February 2023 |first1=Steven|last1 vauthors = Reinberg S |website=CBS News|publisher=CBS Interactive Inc|date=12 December 2018 |archive-date=12 December 2018 |archive-url=https://web.archive.org/web/20181212202314/https://www.cbsnews.com/news/fentanyl-no-1-opioid-overdose-killer-over-heroin-vicodin-oxycontin/ |url-status=live}}</ref><ref name="NIDA_overdose">{{cite web |date=9 February 2023 |title=Drug Overdose Death Rates |url=https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates |access-date=20 February 2023 |website=National Institute on Drug Abuse |archive-date=23 February 2023 |archive-url=https://web.archive.org/web/20230223163541/https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates |url-status=live }}</ref><ref>{{cite web |title=U.S. Overdose Deaths In 2021 Increased Half as Much as in 2020 – But Are Still Up 15% |url=https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/202205.htm |website=U.S. [[Centers for Disease Control and Prevention]] (CDC) |access-date=5 May 2023 |date=11 May 2022 |archive-date=10 August 2022 |archive-url=https://web.archive.org/web/20220810145038/https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2022/202205.htm |url-status=live }}</ref> Fentanyl constitutes the majority of all drug overdose deaths in the United States since it overtook [[heroin]] in 2018.<ref name="www.cbsnews.com_2018" /> [[FBI Laboratory|The United States National Forensic Laboratory]] estimates fentanyl reports by federal, state, and local [[Crime lab|forensic laboratories]] increased from 4,697 reports in 2014 to 117,045 reports in 2020.<ref name="www.dea.gov" /> Fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin.<ref name="www.dea.gov" /> Fentanyl has been reported in pill form, including pills mimicking [[medication|pharmaceutical]] drugs such as [[oxycodone]].<ref name="www.dea.gov" /> 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.<ref name = "Ramos-Matos_2022" /> In an attempt to reduce the number of overdoses from taking other drugs mixed with fentanyl, drug testing kits, strips, and labs are available.<ref>{{cite web |title=DrugsData.org: Lab Analysis / Drug Checking for Recreational Drugs |url=https://www.drugsdata.org/ |access-date=12 December 2023 |website=DrugsData}}</ref><ref>{{cite web | vauthors = Nasir A |title=Drug Checking | work = DanceSafe |url=https://dancesafe.org/drug-checking/ |access-date=12 December 2023 |language=en-US}}</ref> Fentanyl's ease of manufacture and high potency makes it easier to produce and [[smuggling|smuggle]], resulting in fentanyl replacing other abused [[narcotic]]s and becoming more widely used.<ref>{{cite web |vauthors=Falco G |date=8 January 2023 |title=China's Role in Illicit Fentanyl Running Rampant on US Streets |url=https://trone.house.gov/2023/01/08/chinas-role-in-illicit-fentanyl-running-rampant-on-us-streets/ |access-date=20 February 2023 |website=Congressman David Trone |archive-date=16 February 2023 |archive-url=https://web.archive.org/web/20230216071828/https://trone.house.gov/2023/01/08/chinas-role-in-illicit-fentanyl-running-rampant-on-us-streets/ |url-status=live }}</ref>

Intravenous fentanyl is often used for [[anesthesia]] and as an [[analgesic]].<ref>{{cite book |vauthors = Brunton LL, Hilal-Dandan R, Knollmann BC |date=5 December 2017 |title=Goodman & Gilman's: The pharmacological basis of therapeutics |isbn=978-1-259-58473-2 |edition=13th |location=New York, NY | publisher = McGraw-Hill Education |oclc=993810322}}</ref> To induce anesthesia, it is given with a [[sedative-hypnotic]], like [[propofol]] or [[thiopental]], and a [[euphoria|euphoriant]].<ref name="Gropper_2019">{{cite book |vauthors = Gropper MA, Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Cohen LH, Leslie K |date=7 October 2019 |title=Miller's Anesthesia |edition=9th |location=Philadelphia, PA | publisher = Elsevier |isbn=978-0-323-61264-7 |oclc=1124935549}}</ref> To maintain anesthesia, inhaled anesthetics and additional fentanyl may be used.<ref name="Gropper_2019" /> These are often given in 15–30{{nbsp}}minute intervals throughout procedures such as [[endoscopy]] and [[surgeries]] and in emergency rooms.<ref>{{cite journal | vauthors = Godwin SA, Burton JH, Gerardo CJ, Hatten BW, Mace SE, Silvers SM, Fesmire FM | title = Clinical policy: procedural sedation and analgesia in the emergency department | journal = Annals of Emergency Medicine | volume = 63 | issue = 2 | pages = 247–58.e18 | date = February 2014 | pmid = 24438649 | doi = 10.1016/j.annemergmed.2013.10.015 }}</ref><ref>{{cite journal | vauthors = Smith HS, Colson J, Sehgal N | title = An update of evaluation of intravenous sedation on diagnostic spinal injection procedures | journal = Pain Physician | volume = 16 | issue = 2 Suppl | pages = SE217–SE228 | date = April 2013 | pmid = 23615892 | doi = 10.36076/ppj.2013/16/SE217 | url = http://www.painphysicianjournal.com/current/pdf?article=MTg4MQ%3D%3D&journal=74 | url-status = live | access-date = 1 May 2017 | archive-url = https://web.archive.org/web/20151019192759/http://www.painphysicianjournal.com/current/pdf?article=MTg4MQ%3D%3D&journal=74 | archive-date = 19 October 2015 | doi-access = free | title-link = doi }}</ref>

Fentanyl is sometimes given intrathecally as part of [[spinal anaesthesia|spinal anesthesia]] or epidurally for [[epidural anaesthesia]] and [[epidural analgesia|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.<ref>{{cite journal | vauthors = Bujedo BM | title = Current evidence for spinal opioid selection in postoperative pain | journal = The Korean Journal of Pain | volume = 27 | issue = 3 | pages = 200–209 | date = July 2014 | pmid = 25031805 | pmc = 4099232 | doi = 10.3344/kjp.2014.27.3.200 }}</ref> It is widely used in [[Obstetrics|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.<ref name="Moisés_2005">{{cite journal | vauthors = Moisés EC, de Barros Duarte L, de Carvalho Cavalli R, Lanchote VL, Duarte G, da Cunha SP | title = Pharmacokinetics and transplacental distribution of fentanyl in epidural anesthesia for normal pregnant women | journal = European Journal of Clinical Pharmacology | volume = 61 | issue = 7 | pages = 517–522 | date = August 2005 | pmid = 16021436 | doi = 10.1007/s00228-005-0967-9 | s2cid = 26065578 }}</ref> 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 [[Stimulant]].<ref name="Moisés_2005" /> For this reason, shorter -acting agents such as [[alfentanyl]] or [[remifentanil]] may be more suitable in the context of inducing general anaesthesia.<ref>{{cite journal | vauthors = White LD, Hodsdon A, An GH, Thang C, Melhuish TM, Vlok R | title = Induction opioids for caesarean section under general anaesthesia: a systematic review and meta-analysis of randomised controlled trials | journal = International Journal of Obstetric Anesthesia | volume = 40 | pages = 4–13 | date = November 2019 | pmid = 31230994 | doi = 10.1016/j.ijoa.2019.04.007 | hdl = 10072/416502 | s2cid = 181816438 | url = https://researchonline.nd.edu.au/cgi/viewcontent.cgi?article=2384&context=med_article | hdl-access = free | access-date = 23 May 2022 | archive-date = 22 May 2022 | archive-url = https://web.archive.org/web/20220522185407/https://researchonline.nd.edu.au/cgi/viewcontent.cgi?article=2384&context=med_article | url-status = live }}</ref>

The bioavailability of intranasal fentanyl is about 70–90%, but with some imprecision due to clotted nostrils, pharyngeal swallow, and incorrect administration. For both emergency and palliative use, intranasal fentanyl is available in doses of 50, 100, 200, 400(PecFent){{nbsp}}μg. In emergency medicine, safe administration of intranasal fentanyl with a low rate of side effects and a promising pain-reducing effect was demonstrated in a prospective observational study in about 900{{nbsp}}out-of-hospital patients.<ref>{{cite journal | vauthors = Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS | title = Safety of intranasal fentanyl in the out-of-hospital setting: a prospective observational study | journal = Annals of Emergency Medicine | volume = 63 | issue = 6 | pages = 699–703 | date = June 2014 | pmid = 24268523 | doi = 10.1016/j.annemergmed.2013.10.025 }}</ref>

It is also used in the [[Pain management|management]] of [[chronic pain]] including [[Euphoria]].<ref>{{cite journal | vauthors = Plante GE, VanItallie TB | title = Opioids for cancer pain: the challenge of optimizing treatment | journal = Metabolism | volume = 59 | issue = Suppl 1 | pages = S47–S52 | date = October 2010 | pmid = 20837194 | doi = 10.1016/j.metabol.2010.07.010 }}</ref> Often, [[transdermal patch]]es are used.<ref name="www.dea.gov">{{cite web |title=Fentanyl |type=factsheet |publisher=[[Drug Enforcement Administration]] |url=https://www.dea.gov/factsheets/fentanyl |access-date=4 December 2018 |archive-date=4 December 2018 |archive-url=https://web.archive.org/web/20181204053826/https://www.dea.gov/factsheets/fentanyl |url-status=live }}</ref> The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72{{nbsp}}hours, allowing for long-lasting pain management.<ref name="AC-Durogesic2">{{cite book | veditors = Jasek W |year=2007 |title=Austria-Codex |edition=62nd |publisher=Österreichischer Apothekerverlag |isbn=978-3-85200-181-4 |location=Vienna, AU |pages=2621{{nbsp}}ff |language=de}}</ref> Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.<ref name="AC-Durogesic2" /> Each patch should be changed every 72{{nbsp}}hours.<ref>{{cite web |title=Fentanyl patches (Durogesic) for chronic pain |website=NPS Medicinewise |date=August 2006 |url=https://www.nps.org.au/radar/articles/fentanyl-patches-durogesic-for-chronic-pain#:~:text=The%20patch%20should%20be%20changed,and%20100%20micrograms%20per%20hour. |access-date=7 December 2021 |archive-date=7 December 2021 |archive-url=https://web.archive.org/web/20211207205934/https://www.nps.org.au/radar/articles/fentanyl-patches-durogesic-for-chronic-pain#:~:text=The%20patch%20should%20be%20changed,and%20100%20micrograms%20per%20hour. |url-status=live }}</ref> Rate of absorption is dependent on a number of factors. Body temperature, skin type, amount of body fat, and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption, and route of administration. Under normal circumstances, the patch will reach its full effect within 12 to 24{{nbsp}}hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain.<ref name="AC-Durogesic2" /> It is unclear if fentanyl gives long-term pain relief to people with [[neuropathic pain]].<ref>{{cite journal | vauthors = Derry S, Stannard C, Cole P, Wiffen PJ, Knaggs R, Aldington D, Moore RA | title = Fentanyl for neuropathic pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 5 | pages = CD011605 | date = October 2016 | pmid = 27727431 | pmc = 6457928 | doi = 10.1002/14651858.CD011605.pub2 }}</ref>

A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow patients to control the administration of fentanyl through the skin to treat postoperative pain.<ref name="pmid15914877">{{cite journal | vauthors = Koo PJ | title = Postoperative pain management with a patient-controlled transdermal delivery system for fentanyl | journal = American Journal of Health-System Pharmacy | volume = 62 | issue = 11 | pages = 1171–1176 | date = June 2005 | pmid = 15914877 | doi = 10.1093/ajhp/62.11.1171 | url = http://www.medscape.com/viewarticle/505784_2 | url-status = live | access-date = 28 March 2016 | archive-url = https://web.archive.org/web/20180806203216/https://www.medscape.com/viewarticle/505784_2 | archive-date = 6 August 2018 | doi-access = free | title-link = doi }}</ref> The technology consists of a "preprogrammed, self-contained drug-delivery system" that uses [[iontophoresis|electrotransport]] technology to administer on-demand doses of 40{{nbsp}}μg of fentanyl hydrochloride over ten minutes. In a 2004 experiment including 189 patients with moderate to severe postoperative pain up to 24{{nbsp}}hours after major surgery, 25% of patients withdrew due to inadequate analgesia. However, the PCTS method proved superior to the placebo, showing lower mean [[Visual analogue scale|VAS]] pain scores and having no significant respiratory depression effects.<ref>{{cite journal | vauthors = Chelly JE, Grass J, Houseman TW, Minkowitz H, Pue A | title = The safety and efficacy of a fentanyl patient-controlled transdermal system for acute postoperative analgesia: a multicenter, placebo-controlled trial | journal = Anesthesia and Analgesia | volume = 98 | issue = 2 | pages = 427–433 | date = February 2004 | pmid = 14742382 | doi = 10.1213/01.ANE.0000093314.13848.7E | s2cid = 24551941 | doi-access = free | title-link = doi }}</ref>

* Simultaneous use of CNS depressants like benzodiazepines (i.e. [[alprazolam]], [[diazepam]], [[clonazepam]]), barbiturates, alcohol, and inhaled anesthetics

* Early carbon dioxide retention causingcauses cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces the protein binding of fentanyl, releasing yet more fentanyl.

Wooden chest syndrome is reversed by naloxone and is believed to be caused by a release of [[noradrenaline]], which activates [[alpha-adrenergic receptors|α-adrenergic receptors]] and also possibly via an activation of [[Acetylcholine receptors|cholinergic receptors]].<ref name="Torralva">{{cite journal | vauthors = Torralva R, Janowsky A | title = Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 371 | issue = 2 | pages = 453–475 | date = November 2019 | pmid = 31492824 | pmc = 6863461 | doi = 10.1124/jpet.119.258566 | url = https://jpet.aspetjournals.org/content/jpet/371/2/453.full-text.pdf | access-date = 9 August 2021 | publisher = [[American Society for Pharmacology and Experimental Therapeutics]] | publication-place = [[Rockville, Maryland|Rockville]], [[Maryland]], United States of America | oclc = 1606914 | veditors = Trew KD, Dodenhoff R, Vore M, Siuciak JA, Perry J, Wood C, Blumer J | archive-url = https://web.archive.org/web/20200309222939/https://jpet.aspetjournals.org/content/jpet/371/2/453.full-text.pdf | archive-date = 9 March 2020 | lccn = sf80000806 }}</ref>

=== "Fentanyl fold" posture ===

Fentanyl poses an exceptionally high overdose risk in humans, since the amount required to cause [[toxicity]] is unpredictable.<ref name = "Ramos-Matos_2022" /> In its pharmaceutical form, most overdose deaths attributed solely to fentanyl occur at [[Serum (blood)|serum]] concentrations at a mean of 0.025{{nbsp}}μg/mL, with a range 0.005–0.027{{nbsp}}μg/mL.<ref>{{cite journal | vauthors = Cheema E, McGuinness K, Hadi MA, Paudyal V, Elnaem MH, Alhifany AA, Elrggal ME, Al Hamid A | title = Causes, Nature and Toxicology of Fentanyl-Associated Deaths: A Systematic Review of Deaths Reported in Peer-Reviewed Literature | journal = Journal of Pain Research | volume = 13 | pages = 3281–3294 | date = 7 December 2020 | pmid = 33324089 | pmc = 7732170 | doi = 10.2147/JPR.S280462 | doi-access = free | title-link = doi }}</ref> In contexts of poly-substance use, blood fentanyl concentrations of approximately 7{{nbsp}}ng/mL or greater have been associated with fatalities.<ref>{{cite web|title=Fentanyl drug profile|publisher=European Monitoring Centre for Drugs and Drug Addiction|url=https://www.emcdda.europa.eu/publications/drug-profiles/fentanyl_en#:~:text=The%20estimated%20lethal%20dose%20of,poly-substance%20use%20was%20involved.|access-date=10 September 2022|archive-date=10 September 2022|archive-url=https://web.archive.org/web/20220910035457/https://www.emcdda.europa.eu/publications/drug-profiles/fentanyl_en#:~:text=The%20estimated%20lethal%20dose%20of,poly-substance%20use%20was%20involved.|url-status=live}}</ref> Over 85% of overdoses involved at least one other drug, and there was no clear correlation showing at which level the mixtures were fatal. The dosages of fatal mixtures varied by over three magnitudes in some cases. This extremely unpredictable volatility with other drugs makes it especially difficult to avoid fatalities.<ref> name="pmid31304441">{{cite journal | vauthors = Drummer OH | title = Fatalities caused by novel opioids: a review" | journal = Forensic Sciences Research | volume = 4 | issue = 2 | pages = 95–110 | date = 2019 | pmid = 31304441 | pmc = 6609322 | doi = 10.1080/20961790.2018.1460063 }}</ref>

Fentanyl has started to make its way into heroin as well as illicitly manufactured opioids and benzodiazepines. Fentanyl contamination in cocaine, methamphetamine, [[ketamine]], MDMA, and other drugs is common.<ref>{{cite news |vauthors=Scaccia A |date=9 October 2018 |title=How Fentanyl is contaminating America's cocaine supply |magazine=[[Rolling Stone]] |url=https://www.rollingstone.com/culture/culture-features/fentanyl-cocaine-how-contamination-happens-735155/ |access-date=5 November 2018 |archive-date=6 November 2018 |archive-url=https://web.archive.org/web/20181106053222/https://www.rollingstone.com/culture/culture-features/fentanyl-cocaine-how-contamination-happens-735155/ |url-status=live }}</ref><ref>{{cite web |vauthors=Daly M |date=30 July 2019 |title=Exclusive data reveals just how often Fentanyl is in cocaine |website=Vice |url=https://www.vice.com/en_us/article/nea898/how-much-fentanyl-is-actually-in-cocaine |access-date=9 January 2020 |archive-date=24 January 2020 |archive-url=https://web.archive.org/web/20200124015237/https://www.vice.com/en_us/article/nea898/how-much-fentanyl-is-actually-in-cocaine |url-status=live }}</ref> A kilogram of heroin laced with fentanyl may sell for more than US$100,000, but the fentanyl itself may be produced far more cheaply, for about US$6,000 per kilogram. While Mexico and China are the primary source countries for fentanyl and fentanyl-related substances trafficked directly into the United States, India is emerging as a source for finished fentanyl powder and fentanyl precursor chemicals.<ref>{{cite news |vauthors=Chang A |date=3 December 2018 |title=What it means for the U.S. that China will label Fentanyl as 'a controlled substance' |publisher=[[NPR]] |department=All Things Considered |url=https://www.npr.org/2018/12/03/673022614/what-it-means-for-the-u-s-that-china-will-label-fentanyl-as-a-controlled-substan |access-date=6 December 2018 |archive-date=6 December 2018 |archive-url=https://web.archive.org/web/20181206025755/https://www.npr.org/2018/12/03/673022614/what-it-means-for-the-u-s-that-china-will-label-fentanyl-as-a-controlled-substan |url-status=live }}</ref><ref>{{cite web |date=January 2020 |title=Fentanyl Flow to the United States |url=https://www.dea.gov/sites/default/files/2020-03/DEA_GOV_DIR-008-20%20Fentanyl%20Flow%20in%20the%20United%20States_0.pdf |access-date=24 July 2019 |website=U.S. [[Drug Enforcement Administration]] |archive-date=30 September 2022 |archive-url=https://web.archive.org/web/20220930135741/https://www.dea.gov/sites/default/files/2020-03/DEA_GOV_DIR-008-20%20Fentanyl%20Flow%20in%20the%20United%20States_0.pdf |url-status=live }}</ref> The United Kingdom illicit drug market is no longer reliant on China, as domestic fentanyl production is replacing imports.<ref>{{cite news |author-first1=Jamie|author-last1 vauthors = Grierson J |title=Coronavirus triggers UK shortage of illicit drugs |date=12 April 2020 |department=Society |newspaper=[[The Guardian]] |url=https://www.theguardian.com/society/2020/apr/12/coronavirus-triggers-uk-shortage-of-illicit-drugs |access-date=23 April 2020 |archive-date=9 May 2020 |archive-url=https://web.archive.org/web/20200509113021/https://www.theguardian.com/society/2020/apr/12/coronavirus-triggers-uk-shortage-of-illicit-drugs |url-status=live }}</ref>

The intravenous dose causing 50% of opioid-naive experimental subjects to die ({{LD50}}) is "3{{nbsp}}mg/kg in rats, 1{{nbsp}}mg/kg in cats, 14{{nbsp}}mg/kg in dogs, and 0.03{{nbsp}}mg/kg in monkeys."<ref>{{cite web |title=Fentanyl citrate injection, USP |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016619s034lbl.pdf |access-date=3 March 2019 |archive-date=31 October 2020 |archive-url=https://web.archive.org/web/20201031000544/https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016619s034lbl.pdf |url-status=live }}</ref> The LD₅₀ in mice has been given as 6.9{{nbsp}}mg/kg by intravenous administration, 17.5{{nbsp}}mg/kg intraperitoneally, 27.8{{nbsp}}mg/kg by oral administration.<ref>{{cite journal | vauthors = Gupta PK, Yadav SK, MauryaBhutia CKYD, GuptaSingh PKP, JainRao AKP, Gujar NL, Ganesan K, Bhattacharya R | title = Synthesis and biologicalcomparative evaluationbioefficacy of someN-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and novelits 1-substituted fentanyl analogs in Swiss albino mice | journal =Medicinal InterdisciplinaryChemistry ToxicologyResearch | volume date=1 7August | issue = 22013 | pages volume= 93–10222 | date issue= June 20148 | pmid pages= 261098853888–3896 | pmc doi= 442772110.1007/s00044-012-0390-6 | doi url= https://link.springer.com/article/10.24781007/intoxs00044-2014012-00130390-6 |language=en |issn=1554-8120}}</ref> The LD₅₀ in humans is unknown.<ref>{{cite web|url=https://www.drugbank.ca/drugs/DB00813|title=Fentanyl|publisher=Drugbank|access-date=18 January 2019|archive-date=11 July 2017|archive-url=https://web.archive.org/web/20170711073330/https://www.drugbank.ca/drugs/DB00813|url-status=live}}</ref>

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 toConcerning overdose deaths in pediatric cases, numbers are also concerning. Based on a report by the JAMA networkNetwork, 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."<ref>{{cite web | url = https://reliefweb.int/report/world/unodc-world-drug-report-2023b | title = UNODC World Drug Report 2023 | work = ReliefWeb | access-date = 26 June 2023 }}</ref><ref name="pmid37155161">{{cite journal | vauthors = Gaither JR | title = National Trends in Pediatric Deaths From Fentanyl, 1999-2021 | journal = JAMA Pediatrics | volume = 177 | issue = 7 | pages = 733–735 | date = July 2023 | pmid = 37155161 | doi = 10.1001/jamapediatrics.2023.0793 | pmc = 10167597 }}</ref>

In the late 2010s, some media outlets began to report stories of police officers being hospitalisedhospitalized after touching powdered fentanyl, or after brushing it from their clothing.<ref>{{cite news |vauthors=Ross C |date=9 August 2017 |title=Are people really falling ill from touching fentanyl? In most cases, scientists say no |website=Stat News |url=https://www.statnews.com/2017/08/09/fentanyl-falling-ill |access-date=7 August 2021 |archive-date=7 August 2021 |archive-url=https://web.archive.org/web/20210807091036/https://www.statnews.com/2017/08/09/fentanyl-falling-ill/ |url-status=live }}</ref><ref name="wpbump">{{cite news |vauthors=Bump P |title=Analysis {{!}} Why you're hearing so much about fentanyl these days |url=https://www.washingtonpost.com/politics/2022/07/15/why-youre-hearing-so-much-about-fentanyl-these-days/ |access-date=16 September 2022 |newspaper=[[The Washington Post]] |date=15 July 2022 |archive-date=15 July 2022 |archive-url=https://web.archive.org/web/20220715220749/https://www.washingtonpost.com/politics/2022/07/15/why-youre-hearing-so-much-about-fentanyl-these-days/ |url-status=live }}</ref> [[Topical]] (or transdermal; via the skin) and [[Inhalation|inhalative]] exposure to fentanyl is extremely unlikely to cause intoxication or overdose (except in cases of prolonged exposure with very large quantities of fentanyl), and first responders such as paramedics and police officers are at minimal risk of fentanyl poisoning through accidental contact with intact skin.<ref>{{cite press release | work = American College of Medical Toxicology | title = Position Statement on Fentanyl Exposure | url = https://www.acmt.net/cgi/page.cgi/_zine.html/Press_Releases/ACMT_Position_Statement_on_Fentanyl_Exposure | archive-url = https://web.archive.org/web/20180831011606/https://www.acmt.net/cgi/page.cgi/_zine.html/Press_Releases/ACMT_Position_Statement_on_Fentanyl_Exposure | archive-date = 31 August 2018 | date = 18 July 2017 }}</ref><ref>{{cite journal | vauthors = Thors L, Öberg L, Forsberg E, Wigenstam E, Larsson A, Bucht A | title = Skin penetration and decontamination efficacy following human skin exposure to fentanyl | journal = Toxicology in Vitro | volume = 67 | pages = 104914 | date = September 2020 | pmid = 32540164 | doi = 10.1016/j.tiv.2020.104914 | bibcode = 2020ToxVi..6704914T | s2cid = 219704174 }}</ref> A 2020 article from the [[Journal of Medical Toxicology]] stated that "the consensus of the scientific community remains that illness from unintentional exposures is extremely unlikely, because opioids are not efficiently absorbed through the skin and are unlikely to be carried in the air."<ref>{{cite journal | vauthors = Herman PA, Brenner DS, Dandorf S, Kemp S, Kroll B, Trebach J, Hsieh YH, Stolbach AI | title = Media Reports of Unintentional Opioid Exposure of Public Safety First Responders in North America | journal = Journal of Medical Toxicology | volume = 16 | issue = 2 | pages = 112–115 | date = April 2020 | pmid = 32096007 | pmc = 7099103 | doi = 10.1007/s13181-020-00762-y }}</ref> The [[American College of Medical Toxicology]] and the [[American Academy of Clinical Toxicology]] issued a joint report in 2017 asserting the risk of fentanyl overdose via incidental transdermal exposure is very low, and it would take 200 minutes200  minutes of breathing fentanyl at the highest airborne concentrations to yield a therapeutic dose, but not a potentially fatal one.<ref>{{cite journal | vauthors = Moss MJ, Warrick BJ, Nelson LS, McKay CA, Dubé PA, Gosselin S, Palmer RB, Stolbach AI | title = ACMT and AACT position statement: preventing occupational fentanyl and fentanyl analog exposure to emergency responders | journal = Clinical Toxicology | volume = 56 | issue = 4 | pages = 297–300 | date = April 2018 | pmid = 28872357 | doi = 10.1080/15563650.2017.1373782 | pmc = 5711758 }}</ref><ref>{{cite journal | vauthors = Del Pozo B, Sightes E, Kang S, Goulka J, Ray B, Beletsky LA | title = Can touch this: training to correct police officer beliefs about overdose from incidental contact with fentanyl | journal = Health & Justice | volume = 9 | issue = 1 | pages = 34 | date = November 2021 | pmid = 34817717 | pmc = 8612110 | doi = 10.1186/s40352-021-00163-5 | doi-access = free | title-link = doi }}</ref> The effects being reported in these cases, including rapid heartbeat, [[hyperventilation]] and chills, were not symptoms of a fentanyl overdose, and were more commonly associated with a [[panic attack]].<ref>{{cite news |title=State Departments Issue Guidance Around Fentanyl Exposure |url=https://www.tn.gov/behavioral-health/news/2022/8/24/state-departments-issue-guidance-around-fentanyl-exposure-.html |access-date=16 September 2022 |work=State of Tennessee |archive-date=13 September 2022 |archive-url=https://web.archive.org/web/20220913201552/https://www.tn.gov/behavioral-health/news/2022/8/24/state-departments-issue-guidance-around-fentanyl-exposure-.html |url-status=live }}</ref>

A 2021 paper expressed concern that these physical fears over fentanyl may inhibit effective emergency response to overdoses by causing responding officers to spend additional time on unnecessary precautions, and that the media coverage could also perpetuate a wider social stigma that people who use drugs are dangerous to be around.<ref>{{cite journal | vauthors = Del Pozo B, Sightes E, Kang S, Goulka J, Ray B, Beletsky LA | title = Can touch this: training to correct police officer beliefs about overdose from incidental contact with fentanyl | journal = Health & Justice | volume = 9 | issue = 1 | pages = 34 | date = November 2021 | pmid = 34817717 | pmc = 8612110 | doi = 10.1186/s40352-021-00163-5 | doi-access = free | title-link = doi }}</ref> A 2020 survey of first responders in [[New York (state)|New York]] found that 80% believed “briefly touching fentanyl could be deadly.”<ref>{{cite journal | vauthors = Persaud E, Jennings CR | title = Pilot Study on Risk Perceptions and Knowledge of Fentanyl Exposure Among New York State First Responders | journal = Disaster Medicine and Public Health Preparedness | volume = 14 | issue = 4 | pages = 437–441 | date = August 2020 | pmid = 31571559 | doi = 10.1017/dmp.2019.95 }}</ref>

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.<ref>{{cite web |title=Increases in Fentanyl Drug Confiscations and Fentanyl-related Overdose Fatalities HAN 00384 |work=Health Alert Network |url=https://emergency.cdc.gov/han/han00384.asp |publisher=U.S. Centers for Disease Control and PreventationPrevention |access-date=21 December 2022 |date=15 October 2015 |archive-date=21 December 2022 |archive-url=https://web.archive.org/web/20221221170401/https://emergency.cdc.gov/han/han00384.asp |url-status=live }}</ref> A subsequent HAN Alert was issued in July 2018, warning of rising numbers of deaths due to fentanyl abuse and mixing with non-opioids.<ref>{{cite web |title=Rising Numbers of Deaths Involving Fentanyl and Fentanyl Analogs, Including Carfentanil, and Increased Usage and Mixing with Non-opioids – 00413 |work=Health Alert Network (HAN) |url=https://emergency.cdc.gov/han/han00413.asp |publisher=U.S. Centers for Disease Control and PreventationPrevention |access-date=21 December 2022 |date=11 July 2018 |archive-date=21 December 2022 |archive-url=https://web.archive.org/web/20221221170401/https://emergency.cdc.gov/han/han00413.asp |url-status=live }}</ref> A December 2020 HAN Advisory warned of:

# localLocal need to expand the distribution and use of naloxone and overdose prevention education,

# expandExpand awareness, access, and availability of treatment for substance use disorders,

# interveneIntervene early with individuals at the highest risk for overdose, and

Another initiative is a [[social media]] campaign from the United States [[Drug Enforcement Administration]] (DEA) called "One Pill Can Kill".<ref name=onepill>{{cite web |title=One Pill Can Kill |url=https://www.dea.gov/onepill |access-date=15 November 2023 |website=U.S. [[Drug Enforcement Administration]] |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115200822/https://www.dea.gov/onepill |url-status=live}}</ref> This social media campaign's goal is to spread awareness of the prevalence of counterfeit pills that are being sold in America that areis leading to the large overdose epidemic in America. This campaign also shows the difference between counterfeit pills and real pills.

The structures of opioids share many similarities. Whereas opioids like codeine, [[hydrocodone]], oxycodone, and hydromorphone are synthesized by simple modifications of morphine, fentanyl, and its relatives are synthesized by modifications of [[meperidine]].<ref name="Hemmings_2018">{{cite book | vauthors = Hemmings HC, Egan TD |date = 19 October 2018 |title=Pharmacology and Physiology for Anesthesia: Foundations and clinical application |isbn=978-0-323-56886-9 |edition=2nd |location=Philadelphia, PA | publisher = Elsevier |oclc=1063667873}}</ref> Meperidine is a fully synthetic opioid, and other members of the phenylpiperidine family like alfentanil and sufentanil are complex versions of this structure.<ref name="Hemmings_2018"/>

[[List of fentanyl analogues|Fentanyl analogs]] are types of fentanyl with various chemical modifications on any number of positions of the molecule, but still maintain, or even exceed, its pharmacological effects. Many fentanyl analogs are termed "designer drugs" because they are synthesized solely to be used in an illicit mannerillicitly. Carfentanil, a fentanyl analog, has an additional carboxylic acid group attached to the 4 position. Carfentanil is 20–30 more times as potent as fentanyl, and is common in the illicit drug chain. The drug is commonly used to tranquilize elephants and other large animals.<ref>{{cite journal | vauthors = Zawilska JB, Kuczyńska K, Kosmal W, Markiewicz K, Adamowicz P | title = Carfentanil – from an animal anesthetic to a deadly illicit drug | journal = Forensic Science International | volume = 320 | pages = 110715 | date = March 2021 | pmid = 33581655 | doi = 10.1016/j.forsciint.2021.110715 | s2cid = 231918983 }}</ref>

Fentanyl, like other opioids, acts on opioid receptors. These receptors are [[G protein-coupled receptor|G-protein-coupled receptors]], which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus.<ref name="Hemmings_2018" /> The extracellular N-terminus is important in differentiating different types of binding substrates.<ref name="Hemmings_2018" /> When fentanyl binds, downstream signaling leads to the inhibitory effects, such as decreased [[Cyclic adenosine monophosphate|cAMP]] production, decreased calcium ion influx, and increased potassium efflux.<ref name="Hemmings_2018" /> This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation of [[Nociception|nociceptive]] signals, resulting in analgesic effects.<ref name="Suzuki17" /><ref>{{cite web|url=https://www.drugbank.ca/drugs/DB00813|title=Fentanyl|website=www.drugbank.ca|access-date=18 January 2019|archive-date=11 July 2017|archive-url=https://web.archive.org/web/20170711073330/https://www.drugbank.ca/drugs/DB00813|url-status=live}}</ref>{{unreliable medical source|date=July 2024}}

As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine.<ref name="Suzuki17">{{cite journal | vauthors = Suzuki J, El-Haddad S | title = A review: Fentanyl and non-pharmaceutical fentanyls | journal = Drug and Alcohol Dependence | volume = 171 | pages = 107–116 | date = February 2017 | pmid = 28068563 | doi = 10.1016/j.drugalcdep.2016.11.033 }}</ref> It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to more easily penetrate the [[central nervous system]].<ref name="Yaksh_2011" /><ref name="Mayes_2006">{{cite journal | vauthors = Mayes S, Ferrone M | title = Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 12 | pages = 2178–2186 | date = December 2006 | pmid = 17164395 | doi = 10.1345/aph.1H135 | url = http://www.medscape.com/viewarticle/549359_3 | url-status = live | access-date = 17 December 2010 | s2cid = 24454875 | archive-url = https://web.archive.org/web/20121001210131/http://www.medscape.com/viewarticle/549359_3 | archive-date = 1 October 2012 }}</ref> It attenuates "second pain" with primary effects on slow-conducting, unmyelintatedunmyelinated C-fibers and is less effective on neuropathic pain and "first pain" signals through small, myelinated A-fibers.<ref name="Hemmings_2018" />

Fentanyl and fentanyl analogues can be qualitatively detected in drug samples using commercially available fentanyl testing strips or spot reagents. Following the principles of harm reduction, this test is to be used directly on drug samples as opposed to urine. To prepare a sample for testing, approximately 10&nbsp;mg of the drug, about the size of hair on Abraham Lincoln's head on a penny, should be diluted into 1 teaspoon, or 5&nbsp;mL, of water.<ref>{{cite web | vauthors = Cunningham C | date = 22 March 2023 | title = Fentanyl Test Strip Guidance | url = https://oasas.ny.gov/system/files/documents/2023/03/fentanyl_test_strip_guidance_0.pdf | access-date = 3 October 2023 | publisher = State of New York | archive-date = 19 April 2023 | archive-url = https://web.archive.org/web/20230419163310/https://oasas.ny.gov/system/files/documents/2023/03/fentanyl_test_strip_guidance_0.pdf | url-status = live }}</ref> Research in Dr. Lieberman's lab at the University of Notre Dame has reported false positive results on BTNX fentanyl testing strips with [[methamphetamine]], [[MDMA]], and [[diphenhydramine]].<ref>{{cite journal | vauthors = Lockwood TE, Vervoordt A, Lieberman M | title = High concentrations of illicit stimulants and cutting agents cause false positives on fentanyl test strips | journal = Harm Reduction Journal | volume = 18 | issue = 1 | pages = 30 | date = March 2021 | pmid = 33750405 | doi = 10.1186/s12954-021-00478-4 | pmc = 7941948 | doi-access = free | title-link = doi }}</ref> The [[sensitivity and specificity]] of fentanyl test strips vary depending on the concentration of fentanyl tested, particularly from 10–25010 to 250&nbsp;ng/mL.<ref>{{cite journal | vauthors = Bergh MS, Øiestad ÅM, Baumann MH, Bogen IL | title = Selectivity and sensitivity of urine fentanyl test strips to detect fentanyl analogues in illicit drugs | journal = The International Journal on Drug Policy | volume = 90 | pages = 103065 | date = April 2021 | pmid = 33333419 | doi = 10.1016/j.drugpo.2020.103065 | doi-access = free | title-link = doi }}</ref>

Fentanyl is a 4-anilopiperidine class synthetic opioid.<ref>{{cite journal | vauthors = Vardanyan RS, Hruby VJ | title = Fentanyl-related compounds and derivatives: current status and future prospects for pharmaceutical applications | journal = Future Medicinal Chemistry | volume = 6 | issue = 4 | pages = 385–412 | date = March 2014 | pmid = 24635521 | pmc = 4137794 | doi = 10.4155/fmc.13.215 }}</ref> The synthesis of Fentanyl is accomplished by one of four main methods as reported in the scientific literature: the Janssen, Siegfried, Gupta, or Suh method.<ref>{{cite journal | vauthors = Valdez CA | title = Gas Chromatography-Mass Spectrometry Analysis of Synthetic Opioids Belonging to the Fentanyl Class: A Review | journal = Critical Reviews in Analytical Chemistry | volume = 52 | issue = 8 | pages = 1938–1968 | date = 17 November 2022 | pmid = 34053394 | doi = 10.1080/10408347.2021.1927668 | s2cid = 235255612 | doi-access = free | title-link = doi }}</ref><ref>{{cite web |title=News: April 2022 – UNODC: Three precursors of the most common synthesis routes used in illicit fentanyl manufacture now under international control |url=https://www.unodc.org/LSS/Announcement/Details/b152bda5-5d71-4f7e-9d68-1bdd9af04a83 |access-date=15 November 2023 |website=www.unodc.org |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115232130/https://www.unodc.org/LSS/Announcement/Details/b152bda5-5d71-4f7e-9d68-1bdd9af04a83 |url-status=live }}</ref>

The original synthesis as patented in 1964 by Paul Janssen involves the 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.<ref>{{cite web |date=18 June 2020 |title=Fentanyl Synthesis |url=https://gpatindia.com/fentanyl-synthesis-sar-mcqstructurechemical-properties-and-therapeutic-uses/ |url-status=live |archive-url=https://archive.today/20221228231415/https://gpatindia.com/wp-content/uploads/2020/06/fentanyl-synthesis.png |archive-date=28 December 2022 |website=GPTA India}}</ref>

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{{nbsp}}hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.<ref>{{cite web |vauthors=Mandal A |veditors=SRobertson S |title=Fentanyl History |url=https://www.news-medical.net/health/Fentanyl-History.aspx |website=News-Medical.net |publisher=AZoNetwork |access-date=27 January 2023 |date=11 April 2010 |archive-date=27 January 2023 |archive-url=https://web.archive.org/web/20230127211932/https://www.news-medical.net/health/Fentanyl-History.aspx |url-status=live }}</ref>

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.<ref>{{cite web|title=ACTIQ® (fentanyl citrate) oral transmucosal lozenge (1968 version revised in 2011)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020747s033lbl.pdf|publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=26 December 2017|date=December 2011|archive-url=https://web.archive.org/web/20170210123603/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020747s033lbl.pdf|archive-date=10 February 2017|url-status=live}}</ref>

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{{nbsp}}kg in 2015 and 2016 to only 731.,452{{nbsp}}kg in 2021, a nearly 68.2% decrease.<ref>{{cite web |title=2022 Aggregate Production Quota History for Selected Substances |url=https://www.deadiversion.usdoj.gov/quotas/quota_history.pdf |archive-url=https://web.archive.org/web/20230119052906/https://www.deadiversion.usdoj.gov/quotas/quota_history.pdf |archive-date=19 January 2023 |url-status=live}}</ref>

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, then-President [[Andrés Manuel López Obrador]] insistsinsisted that the main source of this synthetic drug is [[Asia]]. He believesstated that the crisis of a lack of family values in the United States drives people to use the drug.<ref>{{cite news |title=As fentanyl crisis grows, U.S.-Mexico divide deepens |newspaper=[[The Washington Post]] |url=https://www.washingtonpost.com/world/2023/04/29/mexico-us-fentanyl/ |access-date=1 May 2023 |archive-date=29 April 2023 |archive-url=https://web.archive.org/web/20230429142455/https://www.washingtonpost.com/world/2023/04/29/mexico-us-fentanyl/ |url-status=live }}</ref>

[[Substance abuse|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 [[clandestine chemistry|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.<ref>{{cite magazine |vauthors=Ducharme J |date=3 December 2018 |title=China has promised to crack down on Fentanyl. Here's what that could mean for overdose deaths in the U.S. |magazine=[[Time (magazine)|Time]] |url=httphttps://time.com/5469231/china-fentanyl-controlled-substance/ |access-date=6 December 2018 |archive-date=6 December 2018 |archive-url=https://web.archive.org/web/20181206031948/http://time.com/5469231/china-fentanyl-controlled-substance/ |url-status=live }}</ref>

Non-medical use of fentanyl by individuals without opioid tolerance can be very dangerous and has resulted in numerous deaths.<ref name=DEA2015>{{cite web |title=Fentanyl |date=March 2015 |publisher=U.S. [[Drug Enforcement Administration]] |url=http://www.deadiversion.usdoj.gov/drug_chem_info/fentanyl.pdf |access-date=2 June 2016 |archive-url=https://web.archive.org/web/20160611072817/http://www.deadiversion.usdoj.gov/drug_chem_info/fentanyl.pdf |archive-date=11 June 2016 |url-status=live }}</ref> 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.<ref>{{cite journal | vauthors = Mars SG, Rosenblum D, Ciccarone D | title = Illicit fentanyls in the opioid street market: desired or imposed? | journal = Addiction | volume = 114 | issue = 5 | pages = 774–780 | date = May 2019 | pmid = 30512204 | pmc = 6548693 | doi = 10.1111/add.14474 }}</ref>

Beginning in 2015, Canada has seen a number ofseveral 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.<ref>{{cite web |title = Lethal fentanyl profiting gangs in Western Canada while deaths climb |date = 6 August 2015 |website = CTV News |url = https://www.ctvnews.ca/canada/lethal-fentanyl-profiting-gangs-in-western-canada-while-deaths-climb-1.2505470 |vauthors = Burgmann T |access-date = 16 July 2022 |archive-date = 17 July 2022 |archive-url = https://web.archive.org/web/20220717024447/https://www.ctvnews.ca/canada/lethal-fentanyl-profiting-gangs-in-western-canada-while-deaths-climb-1.2505470 |url-status = live }}</ref> Traces of the drug have also been found in other recreational drugs, including cocaine, [[MDMA]], and heroin. The drug has been implicated in the deaths of people from all walks of life—from homeless individuals to professionals—including teens and young parents.<ref>{{cite web |title = Fentanyl doesn't discriminate, killing the homeless and young professionals |date = 22 August 2015 |newspaper = [[Edmonton Journal]] |url = https://edmontonjournal.com/news/local-news/fentanyl-doesnt-discriminate-killing-the-homeless-and-young-professionals |archive-url = https://web.archive.org/web/20161220132537/http://edmontonjournal.com/news/local-news/fentanyl-doesnt-discriminate-killing-the-homeless-and-young-professionals |archive-date = 20 December 2016}}</ref> Because of the rising deaths across the country, especially in [[British Columbia]] where 1,716{{nbsp}}deaths were reported in 2020 and 1,782 from January to October{{nbsp}}2021,<ref>{{cite news |vauthors=Mangione K, Hasegawa R |date=9 December 2021 |title=2021 is now B.C.'s deadliest year in the opioid crisis, with 2{{nbsp}}months of data left to collect |website=[[CTV News]] |url=https://bc.ctvnews.ca/2021-is-now-b-c-s-deadliest-year-in-the-opioid-crisis-with-2-months-of-data-left-to-collect-1.5700104 |access-date=25 December 2021 |archive-date=25 December 2021 |archive-url=https://web.archive.org/web/20211225152051/https://bc.ctvnews.ca/2021-is-now-b-c-s-deadliest-year-in-the-opioid-crisis-with-2-months-of-data-left-to-collect-1.5700104 |url-status=live }}</ref> [[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.<ref>{{cite news |title=Winnipeg Naloxone-distribution program could prevent fentanyl deaths |website=[[CBC News]] |url=http://www.cbc.ca/news/canada/manitoba/winnipeg-naloxone-distribution-program-could-prevent-fentanyl-deaths-1.3197131 |access-date=16 January 2018 |url-status=live |archive-url=https://web.archive.org/web/20180531104801/http://www.cbc.ca/news/canada/manitoba/winnipeg-naloxone-distribution-program-could-prevent-fentanyl-deaths-1.3197131 |archive-date=31 May 2018 }}</ref> In 2018, [[Global News]] reported allegations that [[Canada–China relations|diplomatic tensions]] between Canada and China hindered cooperation to seize imports, with Beijing being accused of inaction.<ref>{{cite news |vauthors=Cooper S, Bell S, Russell A |date=1 December 2018 |title=China won't stop flood of fentanyl into Canada, sources say |department=National |newspaper=[[Global News]] |place=Canada |url=https://globalnews.ca/news/4658188/fentanyl-china-canada-diplomatic-tensions/ |access-date=21 July 2021 |archive-date=13 June 2021 |archive-url=https://web.archive.org/web/20210613085610/https://globalnews.ca/news/4658188/fentanyl-china-canada-diplomatic-tensions/ |url-status=live }}</ref>

Recent investigations and convictions of members of the [[Sinaloa drug cartel]] by federal agencies made a clear connection between illegal arms trafficking from the U.S. to Mexico and the smuggling of fentanyl into the U.S. Mexico had repeatedly made official complaints due to the fact thatsince illegal guns are easily purchased for example in Arizona and as far north as Wisconsin and even Alaska, according to U.S. intelligence sources, and transported onto Mexican territory through a chain of American brokers and couriers often financed by those drug cartels that also engage in money laundering. Therefore, the lack of arms controls in the U.S. has directly contributed to the U.S. opioid overdose crisis.<ref>{{cite web | url = https://www.atf.gov/news/pr/convicted-felon-arrested-attempting-trade-fentanyl-four-firearms | title = Felon Arrested for Attempting To Trade Fentanyl for Four Firearms | date = 6 September 2023 | work = ATF.gov | access-date = 16 December 2023 }}</ref><ref>{{cite web | url = https://home.treasury.gov/news/press-releases/jy1523 | title = Treasury Sanctions Individuals Linked to CJNG's Arms Trafficking, Fuel Theft, and Money Laundering | work = home.treasury.gov | access-date = 16 December 2023 }}</ref><ref>{{cite web | url = https://www.cbsnews.com/news/mexican-drug-cartels-american-weapons-smuggled-across-border/ | title = Mexican drug cartels pay Americans to smuggle weapons across the border, intelligence documents show | work = CBS News | date = 18 September 2023 | access-date = 16 December 2023 }}</ref>

* On 20 August 2020, American singer, songwriter, and musician [[Justin Townes Earle]] died from an accidental overdose caused by cocaine laced with fentanyl.<ref>{{cite news | vauthors = Bernstein J | date = 1 December 2020 | magazine = [[Rolling Stone]] | title = Justin Townes Earle death ruled an accidental drug overdose | url = https://www.rollingstone.com/music/music-country/justin-townes-earle-cause-of-death-fentanyl-1097043/ | access-date = 29 December 2020 | archive-date = 9 November 2021 | archive-url = https://web.archive.org/web/20211109000140/https://www.rollingstone.com/music/music-country/justin-townes-earle-cause-of-death-fentanyl-1097043/ | url-status = live }}</ref>

* {{cite journal | vauthors = Tschirhart JN, Zhang S | title = Fentanyl-Induced Block of hERG Channels Is Exacerbated by Hypoxia, Hypokalemia, Alkalosis, and the Presence of hERG1b | journal = Molecular Pharmacology | volume = 98 | issue = 4 | pages = 508–517 | date = October 2020 | pmid = 32321735 | doi = 10.1124/mol.119.119271 | ref = pmid32321735PMID 32321735 | s2cid = 216084895 | doi-access = free | title-link = doi }}