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{{Short description|Opioid medication}}
'''Fentanyl''' is a [[narcotic]] [[analgesic]], first synthesized in [[Belgium]] in the late [[1950s]], with an analgesic potency of about 80 times that of [[morphine]]. It was introduced into medical practice in the [[1960s]] as an intravenous [[anesthetic]] under the trade name of Sublimaze®.
{{redirect|Fent}}
{{Use dmy dates|date=July 2024}}
{{Use American English|date=July 2021}}
{{Cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 443760208
| image = [[File:Fentanyl2DCSD.svg|frameless|class=skin-invert]]
| alt =
| image2 = Fentanyl-xtal-3D-balls.png
| alt2 = <!--Clinical data-->
| pronounce = [[Help:IPA/English|/ˈfɛntənɪl/]] or /ˈfɛntənəl/
| tradename = Actiq, Duragesic, Sublimaze, others
| Drugs.com = {{drugs.com|monograph|fentanyl-citrate}}
| MedlinePlus = a605043
| DailyMedID = Fentanyl
| pregnancy_AU = C
| dependency_liability = High<ref>{{cite book |vauthors=Bonewit-West K, Hunt SA, Applegate E |year=2012 |title=Today's Medical Assistant: Clinical and administrative procedures |publisher=Elsevier Health Sciences |page=571 |isbn=978-1-4557-0150-6 |url=https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |access-date=20 August 2019 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110030031/https://books.google.com/books?id=YalYPI1KqTQC&pg=PA571 |url-status=live }}</ref>
| addiction_liability = Very High<ref name="PMID 28735776">{{cite journal | vauthors = Ciccarone D | title = Fentanyl in the US heroin supply: A rapidly changing risk environment | journal = The International Journal on Drug Policy | volume = 46 | pages = 107–111 | date = August 2017 | pmid = 28735776 | pmc = 5742018 | doi = 10.1016/j.drugpo.2017.06.010 }}</ref>
| routes_of_administration = [[Buccal mucosa|Buccal]], [[epidural]], [[Intramuscular injection|intramuscular]], [[intrathecal]], [[Intravenous therapy|intravenous]], [[sublingual]], [[Transdermal patch|transdermal]]
| class = [[Opioid]]
| ATC_prefix = N01
| ATC_suffix = AH01
| ATC_supplemental = {{ATC|N02|AB03}}
 
<!-- Legal status -->| legal_AU = S8
[[Image:Fentanyl.png]]
| legal_AU_comment =
| legal_BR = Class A1
| legal_BR_comment =
| legal_CA = Schedule I
| legal_CA_comment =
| legal_DE = Anlage III
| legal_DE_comment =
| legal_NZ = Class B
| legal_NZ_comment =
| legal_UK = Class A
| legal_UK_comment =
| legal_US = Schedule II
| legal_US_comment =
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Instanyl EPAR | website=European Medicines Agency (EMA) | date=20 July 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/instanyl | access-date=11 September 2024}}</ref><ref>{{cite web | title=Effentora EPAR | website=European Medicines Agency (EMA) | date=4 April 2008 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/effentora | access-date=12 October 2024}}</ref>
| legal_UN = N I<!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->
 
<!-- Pharmacokinetic data -->| bioavailability = *[[Transdermal]]: 92%
Thereafter, two other fentanyl analogues were introduced; alfentanil (Alfenta&reg;), an ultra-short (5-10 minutes) acting analgesic, and sufentanil (Sufenta&reg;), an exceptionally potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery.
*[[Intranasal]]: 90%{{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}}
*[[Buccal administration|Buccal]]: 50%
*[[Oral administration|By mouth]]: 33%
*[[Inhalation]]: 80%
*[[Intramuscular]]: 100%
*[[Intravenous]]: 100%
| protein_bound = 80–85%<ref>{{cite journal |vauthors = Bista SR, Haywood A, Hardy J, Lobb M, Tapuni A, Norris R |title = Protein binding of fentanyl and its metabolite nor-fentanyl in human plasma, albumin and α-1 acid glycoprotein |journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems |volume = 45 |issue = 3 |pages = 207–212 |date = March 2015 |pmid = 25314012 |doi = 10.3109/00498254.2014.971093 |s2cid = 21109003 }}</ref>
| metabolism = [[Liver]], primarily by [[CYP3A4]]
| onset = 5{{nbsp}}minutes<ref name=Cl2010>{{cite book |title=Clinically Oriented Pharmacology |edition=2nd |year=2010 |publisher=Quick Review of Pharmacology |page=172 |url=https://books.google.com/books?id=PaOhT_4zBL8C&pg=PA172}}</ref>
| elimination_half-life = {{Abbr|IV|Intravaneous}}: 6{{nbsp}}mins (T1/2 α)<br /> 1{{nbsp}}hours (T1/2 β)<br /> 16{{nbsp}}hours (T1/2 ɣ)<br />Intranasal: 15–25{{nbsp}}hours<ref name=AHFS2017/><br />Transdermal: 20–27{{nbsp}}hours<ref name=AHFS2017/><br />Sublingual (single dose): 5–13.5{{nbsp}}hours<ref name=AHFS2017/><br />Buccal: 3.2–6.4{{nbsp}}hours<ref name=AHFS2017/>
| duration_of_action = {{Abbr|IV|Intravaneous}}: 30–60{{nbsp}}minutes<ref name=Cl2010/><ref>{{cite web |title=Guideline for administration of fentanyl for pain relief in labour |publisher=RCP |url=http://rcp.nshealth.ca/sites/default/files/clinical-practice-guidelines/fentanyl.pdf |access-date=7 October 2015 |url-status=live |archive-url=https://web.archive.org/web/20160304100402/http://rcp.nshealth.ca/sites/default/files/clinical-practice-guidelines/fentanyl.pdf |archive-date=4 March 2016 |quote=Onset of action after I.V. administration of Fentanyl is 3–5{{nbsp}}minutes; duration of action is 30–60{{nbsp}}minutes. }}</ref>
| excretion = Mostly urinary (metabolites, <{{nbsp}}10% unchanged drug)<ref name=AHFS2017/>
 
<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}
Today, fentanyls are extensively used for [[anesthesia]] and [[analgesia]]. Duragesic&reg;, for example, is a fentanyl transdermal patch used in chronic pain management, and Actiq&reg; is a solid formulation of fentanyl citrate on a stick that dissolves slowly in the mouth for transmucosal absorption. Actiq&reg; is intended for [[opiate]]-tolerant individuals and is effective in treating breakthrough pain in cancer patients. Carfentanil (Wildnil&reg;) is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals.
| CAS_number = 437-38-7
| PubChem = 3345
| IUPHAR_ligand = 1626
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00813
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3228
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = UF599785JZ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00320
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 119915
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| PDB_ligand = 7V7
| ChEMBL = 596
 
<!--Chemical data-->| IUPAC_name = ''N''-phenyl-''N''-[1-(2-phenylethyl)piperidin-4-yl]propanamide
Illicit use of pharmaceutical fentanyls first appeared in the mid-[[1970s]] in the medical community and continues to be a problem in the [[United States]]. To date, over 12 different analogues of fentanyl have been produced clandestinely and identified in the U.S. drug traffic. The biological effects of the fentanyls are indistinguishable from those of [[heroin]], with the exception that the fentanyls may be hundreds of times more potent. Fentanyls are most commonly used by intravenous administration, but like heroin, they may also be smoked or snorted.
| C = 22
| H = 28
| N = 2
| O = 1
| smiles = O=C(CC)N(C1CCN(CC1)CCc2ccccc2)c3ccccc3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H28N2O/c1-2-22(25)24(20-11-7-4-8-12-20)21-14-17-23(18-15-21)16-13-19-9-5-3-6-10-19/h3-12,21H,2,13-18H2,1H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PJMPHNIQZUBGLI-UHFFFAOYSA-N
| density = 1.1
| melting_point = 87.5
}}
 
<!-- Definition and medical uses -->
In [[1979]], fentanyl was at the center of a major scandal in the sport of [[horse racing]], as tests of urine samples revealed the presence of the drug in hundreds of [[thoroughbred]] race horses, most of whom had raced at East Coast racetracks (in addition to its analgesic effects, fentanyl has a powerful stimulant effect on horses). The scandal resulted in the horses in question being disqualified from races in which they had either won or had earned a share of the purse, and the purse money was redistributed.
'''Fentanyl''' is a highly potent synthetic [[piperidine]] [[opioid]] primarily used as an [[analgesic]]. It is 30 to 50 times more [[Potency (pharmacology)|potent]] than [[heroin]] and 100 times more potent than [[morphine]];<ref>{{cite journal |date=14 November 2018 |title=Fentanyl |journal=[[Nature.com]] |volume=9 |issue=1 |doi=10.1038/s41398-019-0625-0 |page=282 |pmid=31712552 |pmc=6848196 | vauthors = Han 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>
 
<!--Noted effects and mechanism -->
The incapacitating agent used by Russian security forces in the October 2002 [[Moscow theatre siege]] incident was a fentanyl derivative,
Pharmaceutical fentanyl's adverse effects are identical to those of other opioids and [[narcotics]],<ref>{{cite web |title=Fentanyl: Uses, Warnings & Side Effects |url=https://my.clevelandclinic.org/health/drugs/18085-fentanyl-injection |access-date=5 November 2023 |website=Cleveland Clinic |archive-date=5 November 2023 |archive-url=https://web.archive.org/web/20231105011856/https://my.clevelandclinic.org/health/drugs/18085-fentanyl-injection |url-status=live }}</ref> including [[addiction]], [[confusion]], [[hypoventilation|respiratory depression]] (which, if extensive and untreated, may lead to [[respiratory arrest]]), [[drowsiness]], [[nausea]], visual disturbances, [[dyskinesia]], [[hallucination]]s, [[delirium]], a subset of the latter known as "narcotic delirium", [[ileus|narcotic ileus]], [[hypertonia|muscle rigidity]], [[constipation]], [[unconsciousness|loss of consciousness]], [[hypotension]], [[coma]], and death.<ref name = "Ramos-Matos_2022" /> [[Alcohol (drug)|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, but because fentanyl is so potent, multiple doses might be necessary.<ref name="National Institute on Drug Abuse_2021" />
according to a statement issued by the Russian Health Minister Yuri Shevchenko.
 
<!-- History and medical use -->
----
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=LiverTox |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>
==External links:==
 
* [http://www.usdoj.gov/dea/concern/fentanyl.html US DOJ information: fentanyl]
<!-- Illegal use -->
* [http://news.bbc.co.uk/1/hi/world/europe/2377563.stm BBC news report]
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 | 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>
 
== Medical uses ==
 
=== Anesthesia ===
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>
 
For pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia.<ref name="Gropper_2019"/> 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.<ref name="Gropper_2019"/>
 
=== Regional anesthesia ===
Fentanyl is the most commonly used [[Intrathecal administration|intrathecal]] opioid because its lipophilic profile allows a quick onset of action (5–10 min) and intermediate duration of action (60–120 min).<ref>{{cite book |vauthors=Gudin MA, López R, Estrada J, Ortigosa E |chapter=Neuraxial Blockade: Subarachnoid Anesthesia |date=28 November 2011 |title=Essentials of Regional Anesthesia |pages=261–291 |place=New York, NY |publisher=Springer New York |doi=10.1007/978-1-4614-1013-3_11 |isbn=978-1-4614-1012-6 |chapter-url=http://dx.doi.org/10.1007/978-1-4614-1013-3_11 |access-date=4 July 2021 |archive-date=8 February 2023 |archive-url=https://web.archive.org/web/20230208191557/https://link.springer.com/chapter/10.1007/978-1-4614-1013-3_11 |url-status=live }}</ref> 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.<ref>{{cite journal |vauthors=Buggy D |date=1 July 2008 |type=book review |title=Anesthesiology: Longnecker DE, Brown DL, Newman MF, Zapol WM, Editors, McGraw Hill, New York (2007) {{text|ISBN}}: 978-0-07-145984-6, 2278 pp, hardcover, $249{{nbsp}}... |journal=Regional Anesthesia and Pain Medicine |volume=33 |issue=4 |page=380 |publisher=BMJ Journals |doi=10.1016/j.rapm.2008.03.003 |issn=1098-7339 |url=https://rapm.bmj.com/content/33/4/380 |access-date=18 July 2021 |archive-date=18 July 2021 |archive-url=https://web.archive.org/web/20210718162807/https://rapm.bmj.com/content/33/4/380 |url-status=live }}</ref>
 
=== Obstetrics ===
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 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>
 
=== Pain management ===
[[File:PecFent 100mcg.jpg|thumb|A fentanyl nasal spray with a strength of 100{{nbsp}}μg per use]]
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>
 
In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.<ref name="ReferenceA">{{cite journal | vauthors = Murphy A, O'Sullivan R, Wakai A, Grant TS, Barrett MJ, Cronin J, McCoy SC, Hom J, Kandamany N | title = Intranasal fentanyl for the management of acute pain in children | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD009942 | date = October 2014 | pmid = 25300594 | pmc = 6544782 | doi = 10.1002/14651858.CD009942.pub2 }}</ref> Furthermore, a 2017 study suggested the efficacy of fentanyl lozenges in children as young as five, weighing as little as 13{{nbsp}}kg. Lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets.<ref>{{cite journal | vauthors = Coombes L, Burke K, Anderson AK | title = The use of rapid onset fentanyl in children and young people for breakthrough cancer pain | journal = Scandinavian Journal of Pain | volume = 17 | issue = 1 | pages = 256–259 | date = October 2017 | pmid = 29229211 | doi = 10.1016/j.sjpain.2017.07.010 | s2cid = 8577873 }}</ref>
 
==== Chronic pain ====
It is also used in the [[Pain management|management]] of [[chronic pain]].<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>
 
==== Breakthrough pain ====
Sublingual fentanyl dissolves quickly and is absorbed through the [[sublingual]] mucosa to provide rapid analgesia.<ref name="trib">{{cite web |title=Abstral sublingual tablets |date=May 2016 |publisher=UK Electronic Medicines Compendium |url=http://www.medicines.org.uk/emc/medicine/21371/SPC/Abstral+Sublingual+Tablets/ |url-status=live |access-date=1 May 2017 |archive-url=https://web.archive.org/web/20170323181204/http://www.medicines.org.uk/emc/medicine/21371/SPC/Abstral+Sublingual+Tablets/ |archive-date=23 March 2017 }}</ref> Fentanyl is a highly lipophilic compound,<ref name="trib" /><ref>{{cite journal | vauthors = | title = Abstral (Fentanyl Sublingual Tablets for Breakthrough Cancer Pain) | journal = P & T | volume = 36 | issue = 2 | pages = 2–28 | date = February 2011 | pmid = 21560267 | pmc = 3086091 }}</ref> which is well absorbed sublingually and generally well tolerated.<ref name="trib" /> Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity.<ref>{{cite journal | vauthors = Ward J, Laird B, Fallon M |year=2011 |title=The UK breakthrough cancer pain registry: Origin, methods and preliminary data |journal=BMJ Supportive & Palliative Care |volume=1 |page=A24 |doi=10.1136/bmjspcare-2011-000020.71 |s2cid=73185220}}</ref>
 
==== Palliative care ====
[[File:A generic fentanyl transdermal patch, with a release rate of 12mcg per hour, applied to the skin (cropped).jpg|thumb|A fentanyl transdermal patch with a release rate of 12 micrograms per hour, on a person's arm]]
In [[palliative care]], transdermal fentanyl patches have a definitive, but limited role for:
* people already stabilized on other opioids who have persistent swallowing problems and cannot tolerate other parenteral routes such as subcutaneous administration.
* people with moderate to severe [[Renal failure|kidney failure]].<ref>{{cite journal | vauthors = Roy PJ, Weltman M, Dember LM, Liebschutz J, Jhamb M | title = Pain management in patients with chronic kidney disease and end-stage kidney disease | journal = Current Opinion in Nephrology and Hypertension | volume = 29 | issue = 6 | pages = 671–680 | date = November 2020 | pmid = 32941189 | pmc = 7753951 | doi = 10.1097/MNH.0000000000000646 }}</ref>
* troublesome side effects of oral morphine, [[hydromorphone]], or [[oxycodone]].<ref>{{cite journal | vauthors = Aurilio C, Pace MC, Pota V, Sansone P, Barbarisi M, Grella E, Passavanti MB | title = Opioids switching with transdermal systems in chronic cancer pain | journal = Journal of Experimental & Clinical Cancer Research | volume = 28 | pages = 61 | date = May 2009 | issue = 1 | pmid = 19422676 | pmc = 2684533 | doi = 10.1186/1756-9966-28-61 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Minami S, Kijima T, Nakatani T, Yamamoto S, Ogata Y, Hirata H, Shiroyama T, Koba T, Komuta K | title = Opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch for patients with stable thoracic malignancy-related pain | journal = BMC Palliative Care | volume = 13 | issue = 1 | pages = 46 | date = 8 October 2014 | pmid = 25313295 | pmc = 4195703 | doi = 10.1186/1472-684X-13-46 | doi-access = free | title-link = doi }}</ref>
 
When using the transdermal patch, patients must be careful to minimize or avoid external heat sources (direct sunlight, heating pads, etc.), which can trigger the release and absorption of too much medication and cause potentially deadly complications.<ref>{{cite web |title=Fentanyl (Transdermal Route) Precautions |url=https://www.mayoclinic.org/drugs-supplements/fentanyl-transdermal-route/precautions/drg-20068152 |website=Mayo Clinic |access-date=19 January 2023 |archive-date=19 January 2023 |archive-url=https://web.archive.org/web/20230119051903/https://www.mayoclinic.org/drugs-supplements/fentanyl-transdermal-route/precautions/drg-20068152 |url-status=live }}</ref>
 
==== Combat medicine ====
[[Usaf|USAF]] [[United States Air Force Pararescue|Pararescue]] [[combat medic]]s in Afghanistan used fentanyl lozenges in the form of lollipops on combat casualties from [[Improvised explosive device|IED]] blasts and other trauma.<ref name="Shachtman_2009">{{cite magazine| vauthors = Shachtman N |date=10 September 2009|title=Airborne EMTs Shave Seconds to Save Lives in Afghanistan|url=https://www.wired.com/dangerroom/2009/09/airborne_emts_in_astan/|url-status=live|department=Danger Room|magazine=[[Wired (magazine)|Wired]]|archive-url=https://web.archive.org/web/20100706140612/http://www.wired.com/dangerroom/2009/09/airborne_emts_in_astan|archive-date=6 July 2010|access-date=1 July 2010 }}</ref> The stick is taped to a finger and the lozenge put in the [[Buccal administration|cheek]] of the person. When enough fentanyl has been absorbed, the (sedated) person generally lets the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.<ref name="Shachtman_2009" />
 
==== Breathing difficulties ====
Fentanyl is used to help relieve shortness of breath ([[dyspnea]]) when patients cannot tolerate morphine, or whose breathlessness is refractory to morphine. Fentanyl is useful for such treatment in [[palliative care]] settings where pain and shortness of breath are severe and need to be treated with strong opioids. [[Nebulizer|Nebulized]] fentanyl citrate is used to relieve end-of-life dyspnea in [[hospice]] settings.<ref>{{cite journal | vauthors = van Dijk M, Mooren KJ, van den Berg JK, van Beurden-Moeskops WJ, Heller-Baan R, de Hosson SM, Lam-Wong WY, Peters L, Pool K, Kerstjens HA | title = Opioids in patients with COPD and refractory dyspnea: literature review and design of a multicenter double blind study of low dosed morphine and fentanyl (MoreFoRCOPD) | journal = BMC Pulmonary Medicine | volume = 21 | issue = 1 | pages = 289 | date = September 2021 | pmid = 34507574 | pmc = 8431258 | doi = 10.1186/s12890-021-01647-8 | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Simon ST, Köskeroglu P, Gaertner J, Voltz R | title = Fentanyl for the relief of refractory breathlessness: a systematic review | journal = Journal of Pain and Symptom Management | volume = 46 | issue = 6 | pages = 874–886 | date = December 2013 | pmid = 23742735 | doi = 10.1016/j.jpainsymman.2013.02.019 | doi-access = free | title-link = doi }}</ref>
 
=== Other ===
Some [[Route of administration|routes of administration]] such as nasal sprays and inhalers generally result in a faster onset of high blood levels, which can provide more immediate analgesia but also more severe side effects, especially in overdose. The much higher cost of some of these appliances may not be justified by marginal benefit compared with buccal or oral options. Intranasal fentanyl appears to be equally effective as IV morphine and superior to intramuscular morphine for the management of acute hospital pain.<ref name="ReferenceA" />
 
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>
 
== Adverse effects ==
[[File:2 milligrams of fentanyl on pencil tip. A lethal dose for most people. US Drug Enforcement Administration.jpg|thumb|upright=1.0|A two&nbsp;[[milligram]] dose of fentanyl powder (on [[pencil]] tip) is a lethal amount for most people.<ref name=onepill/>]]
[[File:2023-Drug-od-death-rates-2.jpg|thumb|Overall, drug overdose deaths in the United States rose from 2019 to 2021 with more than 106,000 drug overdose deaths reported in 2021. Deaths involving synthetic opioids other than methadone (primarily fentanyl) continued to rise with 70,601 overdose deaths reported in 2021. Those involving stimulants, including cocaine or psychostimulants with abuse potential (primarily methamphetamine), also continued to increase with 32,537 overdose deaths in 2021 (Source: CDC WONDER).<ref name="NIDA_overdose" />]]
Fentanyl's most common side effects, which affect more than 10% of people, include nausea, vomiting, constipation, dry mouth, [[somnolence]], confusion, and [[asthenia]] (weakness). Less frequently, in 3–10% of people, fentanyl can cause abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, anxiety, depression, flu-like symptoms, [[dyspepsia]] (indigestion), [[dyspnea|shortness of breath]], [[hypoventilation]], [[apnoea]], and urinary retention. Fentanyl use has also been associated with [[aphasia]].<ref name="urlDrugs@FDA: FDA Approved Drug Products" /> Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less [[histamine]]-mediated itching, than morphine.<ref name="Mayes_2006" /> In rare cases, [[serotonin syndrome]] is associated with fentanyl use. Existing studies advise medical practitioners to exercise caution when combining [[selective serotonin reuptake inhibitor]] (SSRI) drugs with fentanyl.<ref>{{cite journal | vauthors = Kirschner R, Donovan JW | title = Serotonin syndrome precipitated by fentanyl during procedural sedation | journal = The Journal of Emergency Medicine | volume = 38 | issue = 4 | pages = 477–480 | date = May 2010 | pmid = 18757161 | doi = 10.1016/j.jemermed.2008.01.003 }}</ref><ref>{{cite journal | vauthors = Ailawadhi S, Sung KW, Carlson LA, Baer MR | title = Serotonin syndrome caused by interaction between citalopram and fentanyl | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 32 | issue = 2 | pages = 199–202 | date = April 2007 | pmid = 17381671 | doi = 10.1111/j.1365-2710.2007.00813.x | doi-access = free | title-link = doi }}</ref>
 
The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.<ref name="pmid295585">{{cite journal | vauthors = Smydo J | title = Delayed respiratory depression with fentanyl | journal = Anesthesia Progress | volume = 26 | issue = 2 | pages = 47–48 | year = 1979 | pmid = 295585 | pmc = 2515983 }}</ref><ref name="pmid6116461">{{cite journal | vauthors = van Leeuwen L, Deen L, Helmers JH | title = A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression | journal = Der Anaesthesist | volume = 30 | issue = 8 | pages = 397–399 | date = August 1981 | pmid = 6116461 }}</ref><ref name="pmid4053723">{{cite journal | vauthors = Brown DL | title = Postoperative analgesia following thoracotomy. Danger of delayed respiratory depression | journal = Chest | volume = 88 | issue = 5 | pages = 779–780 | date = November 1985 | pmid = 4053723 | doi = 10.1378/chest.88.5.779 | s2cid = 1836168 }}</ref><ref name="pmid7113633">{{cite journal | vauthors = Nilsson C, Rosberg B | title = Recurrence of respiratory depression following neurolept analgesia | journal = Acta Anaesthesiologica Scandinavica | volume = 26 | issue = 3 | pages = 240–241 | date = June 1982 | pmid = 7113633 | doi = 10.1111/j.1399-6576.1982.tb01762.x | s2cid = 9232457 }}</ref> In 2006, the [[Food and Drug Administration|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.<ref>{{cite journal|title=Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use |journal=Drug Safety Update |volume=2 |issue=2 |date=September 2008 |page=2 |url=http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON025631 |url-status=dead |archive-url=https://web.archive.org/web/20150101054043/http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON025631 |archive-date=1 January 2015}}</ref> 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.<ref name="children">{{cite web |title=Fentanyl patch can be deadly to children |date=19 April 2012 |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.drugs.com/fda-consumer/fentanyl-patch-can-be-deadly-to-children-214.html |access-date=30 July 2013 |archive-url=https://web.archive.org/web/20130725092458/http://www.drugs.com/fda-consumer/fentanyl-patch-can-be-deadly-to-children-214.html |archive-date=25 July 2013 |url-status=live }}</ref>
 
=== Respiratory depression ===
The most dangerous adverse effect of fentanyl is respiratory depression,<ref>{{cite journal |vauthors = Topacoglu H, Karcioglu O, Cimrin AH, Arnold J |title = Respiratory arrest after low-dose fentanyl |journal = Annals of Saudi Medicine |volume = 25 |issue = 6 |pages = 508–510 |date = Nov 2005 |pmid = 16438465 |pmc = 6089740 |doi = 10.5144/0256-4947.2005.508}}</ref> that is, decreased sensitivity to carbon dioxide leading to reduced rate of breathing, which can cause anoxic brain injury or death. This risk is decreased when the airway is secured with an [[endotracheal tube]] (as during anesthesia).<ref name="Hemmings_2018" /> This risk is higher in specific groups, like those with [[obstructive sleep apnea]].<ref name="Hemmings_2018" />
 
Other factors that increase the risk of respiratory depression are:<ref name="Hemmings_2018" />
* High fentanyl doses
* Simultaneous use of [[methadone]]
* Sleep
* Older age
* Simultaneous use of CNS depressants like benzodiazepines (i.e. [[alprazolam]], [[diazepam]], [[clonazepam]]), barbiturates, alcohol, and inhaled anesthetics
* Hyperventilation
* Decreased CO<sub>2</sub> levels in the serum
* Respiratory [[acidosis]]
* Decreased fentanyl clearance from the body
* Decreased blood flow to the liver
* Renal insufficiency
 
Sustained release fentanyl preparations, such as patches, may also produce unexpected delayed [[respiratory depression]].<ref name="pmid9472602">{{cite journal |vauthors = McLoughlin R, McQuillan R |title = Transdermal fentanyl and respiratory depression |journal = Palliative Medicine |volume = 11 |issue = 5 |pages = 419 | date = September 1997 |pmid = 9472602 |doi = 10.1177/026921639701100515 }}</ref><ref name="pmid7484044">{{cite journal |vauthors = Bülow HH, Linnemann M, Berg H, Lang-Jensen T, LaCour S, Jonsson T |title = Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl |journal = Acta Anaesthesiologica Scandinavica |volume = 39 |issue = 6 |pages = 835–839 |date = August 1995 |pmid = 7484044 |doi = 10.1111/j.1399-6576.1995.tb04180.x |s2cid = 22781991 }}</ref><ref name="pmid14694924">{{cite journal |vauthors = Regnard C, Pelham A |title = Severe respiratory depression and sedation with transdermal fentanyl: four case studies |journal = Palliative Medicine |volume = 17 |issue = 8 | pages = 714–716 |date = December 2003 |pmid = 14694924 |doi = 10.1191/0269216303pm838cr |s2cid = 32985050 }}</ref> The precise reason for sudden respiratory depression is unclear, but there are several hypotheses:
* Saturation of the body fat compartment in people with rapid and profound body fat loss (people with cancer, cardiac or infection-induced [[cachexia]] can lose 80% of their body fat).
* Early carbon dioxide retention causes cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces the protein binding of fentanyl, releasing yet more fentanyl.
* Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels.
 
Another related complication of fentanyl overdoses includes the so-called [[wooden chest syndrome]], which quickly induces complete respiratory failure by paralyzing the thoracic muscles, explained in more detail in the [[#Muscle rigidity|Muscle rigidity section]] below.
 
===Heart and blood vessels===
* ''Bradycardia:'' Fentanyl decreases the heart rate by increasing [[Vagus nerve|vagal nerve tone]] in the brainstem, which increases the [[Parasympathetic nervous system|parasympathetic]] drive.<ref name="Hemmings_2018" />
* ''Vasodilation:'' It also vasodilates arterial and venous blood vessels through a central mechanism, by primarily slowing down vasomotor centers in the brainstem. To a lesser extent, it does this by directly affecting blood vessels.<ref name="Hemmings_2018" /> This is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure.<ref name="Hemmings_2018" /> It does not affect the contractility of the heart when regular doses are administered.<ref name="Hemmings_2018" />
 
=== Muscle rigidity ===
If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult.<ref name="Hemmings_2018" /> The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers.<ref name="Hemmings_2018" />
 
==== Wooden chest syndrome ====
A prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known as [[wooden chest syndrome]].<ref>{{cite book |vauthors=Chambers D, Huang CL, Matthews G |date=1 September 2019 |title=Basic Physiology for Anaesthetists |edition=2nd |chapter=Section 2 – Respiratory physiology: Chapter 25: Anaesthesia and the lung |orig-year=2015 |publisher=[[Cambridge University Press]] |publication-place=[[Cambridge]], UK |pages=107–110 |oclc=1088737571 |doi=10.1017/CBO9781139226394.027 |isbn=978-1-108-46399-7 |chapter-url=https://books.google.com/books?id=5ma8BQAAQBAJ&pg=PA107 |access-date=9 August 2021 |url=https://books.google.com/books?id=5ma8BQAAQBAJ |via=[[Google Books]] |archive-date=8 February 2023 |archive-url=https://web.archive.org/web/20230208191600/https://books.google.com/books?id=5ma8BQAAQBAJ |url-status=live }}</ref> The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.<ref>{{cite journal | vauthors = Burns G, DeRienz RT, Baker DD, Casavant M, Spiller HA | title = Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse? | journal = Clinical Toxicology | volume = 54 | issue = 5 | pages = 420–423 | date = June 2016 | pmid = 26999038 | doi = 10.3109/15563650.2016.1157722 | publisher = [[American Academy of Clinical Toxicology|American Academy of Clinical Toxicology (AACT)]] / European Association of Poisons Centres and Clinical Toxicologist / [[Taylor & Francis]] | publication-place = [[McLean, Virginia|McLean]], [[Virginia (state)|VA]] | veditors = Seifert SA, Buckley N, Seger D, Thomas S, Caravati EM | s2cid = 23149685 | oclc = 8175535 }}</ref>
 
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 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>
 
Wooden chest syndrome is unique to the most powerful opioids{{mdash}}which today comprise fentanyl and its analogs{{mdash}}while other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree.<ref>{{cite journal |title=Chest wall rigidity in fentanyl abuse: illicit fentanyl could be a major factor in sudden onset of this potentially lethal adverse event |access-date=9 August 2021 |vauthors=Petrou I |date=1 September 2016 |volume=33 |issue=9 |journal=Contemporary Pedriatics |publisher=Intellisphere, LLC./ MJH Life Sciences (Multimedia Medical LLC) |issn=8750-0507 |publication-place=[[Cranbury, New Jersey|Cranbury]], [[New Jersey]], United States of America |via=Gale Academic OneFile |url-access=subscription |url=https://link.gale.com/apps/doc/A464982083/AONE?u=anon~4087cc99 |oclc=10956598 |veditors=Levine L, Tan TQ, Shippoli J }}{{Dead link|date=February 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="Torralva" />
 
=== "Fentanyl fold" posture ===
There are many reports of fentanyl users adopting a "folded" posture.
 
Daniel Ciccarone of UCSF said what he calls the “nod” is a common side effect of opioid use, and later notes that "nods have always happened to varying degrees with other opioids, particularly heroin. The nods with fentanyl, however, seem to be more extreme. And it's often a sign that a person has taken too strong a dose".<ref>{{Cite web | vauthors = Toledo A, Greene CM |date=July 17, 2024 |title=Here's why fentanyl users on S.F.'s streets are bent over |url=https://www.sfchronicle.com/sf/article/fentanyl-fold-drug-user-19561190.php |website=San Francisco Chronicle}}</ref>
He also said "the fentanyl fold falls into the umbrella of a severe spinal deformity that can cause functional disability and can drive mental anguish" which is a factor given the socioeconomic status and more fragile mental health of drug users typically when compared to non-users.
 
== Overdose ==
{{Further|Opioid overdose|U.S. drug overdose death rates and totals over time}}
[[File:Fentanyl. 2 mg. A lethal dose in most people.jpg|thumb|upright=0.8|2&nbsp;mg of fentanyl (white powder to the right) is a [[lethal dose]] in most people.<ref>{{cite web | url = https://www.dea.gov/galleries/drug-images/fentanyl | archive-url = https://web.archive.org/web/20181008000027/https://www.dea.gov/galleries/drug-images/fentanyl | archive-date = 8 October 2018 | title = Fentanyl. Image 4 of 17 | work = U.S. [[Drug Enforcement Administration]] | quote = photo illustration of 2 milligrams of fentanyl, a lethal dose in most people }}</ref> A [[US penny]] is 19 mm (0.75 in) wide.]]
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>
 
[[Naloxone]] (sold under the brand name Narcan) can completely or partially reverse an opioid overdose.<ref>{{cite web |title=Narcan (Naloxone hydrochloride injection) |website=RxList |url=https://www.rxlist.com/narcan-side-effects-drug-center.htm |access-date=3 March 2020 |archive-date=24 October 2019 |archive-url=https://web.archive.org/web/20191024004929/https://www.rxlist.com/narcan-side-effects-drug-center.htm |url-status=live }}</ref> In July{{nbsp}}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,<ref>{{cite news |title=Fentanyl patches warning |website=[[Pharmaceutical Journal]] |url=http://www.pharmaceutical-journal.com/news-and-analysis/notice-board/fentanyl-patches-warning/20066029.article |access-date=28 March 2016 |archive-url=https://web.archive.org/web/20160408211133/http://www.pharmaceutical-journal.com/news-and-analysis/notice-board/fentanyl-patches-warning/20066029.article |archive-date=8 April 2016 |url-status=live }}</ref> 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.<ref>{{cite news |title=MHRA warns about fentanyl patches after children exposed |website=[[Pharmaceutical Journal]] |url=http://www.pharmaceutical-journal.com/news-and-analysis/news-in-brief/mhra-warns-about-fentanyl-patches-after-children-exposed/20065930.article |access-date=28 March 2016 |url-status=live |archive-url=https://web.archive.org/web/20160409000816/http://www.pharmaceutical-journal.com/news-and-analysis/news-in-brief/mhra-warns-about-fentanyl-patches-after-children-exposed/20065930.article |archive-date=9 April 2016 }}</ref> In the US, fentanyl and [[:Category:Synthetic opioids|fentanyl analogs]] caused over 29,000{{nbsp}}deaths in 2017, a large increase over the previous four years.<ref name=NYT2017>{{cite news | vauthors = Katz J |date=2 September 2017 |title=The first count of Fentanyl deaths in 2016 – up 540% in three years |newspaper=[[The New York Times]] |url=https://www.nytimes.com/interactive/2017/09/02/upshot/fentanyl-drug-overdose-deaths.html |access-date=4 September 2017 |url-status=live |archive-url=https://web.archive.org/web/20170904123700/https://www.nytimes.com/interactive/2017/09/02/upshot/fentanyl-drug-overdose-deaths.html |archive-date=4 September 2017 }}</ref><ref name="NIDA-deaths">{{cite report |url=http://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates |title=Overdose Death Rates |date=29 January 2021 |publisher=[[National Institute on Drug Abuse]] (NIDA) |access-date=22 November 2017 |archive-url=https://web.archive.org/web/20151128091723/http://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates |archive-date=28 November 2015 |url-status=live}}</ref>
 
[[File:Actiq-30-pack-600mcg-fentanyl-base.jpg|thumb|A package of 30 lozenges, 600{{nbsp}}[[Microgram|mcg]] of fentanyl, each]]
 
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.<ref>{{cite press release |date=9 August 2021 |title=Reported law enforcement encounters testing positive for Fentanyl increase across U.S. |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |url=https://www.cdc.gov/drugoverdose/deaths/fentanyl-encounters/index.html |access-date=3 March 2022 |archive-date=2 March 2022 |archive-url=https://web.archive.org/web/20220302132959/http://www.cdc.gov/drugoverdose/deaths/fentanyl-encounters/index.html |url-status=live }}</ref> Death from fentanyl overdose continues to be a public health issue of national concern in Canada since September 2015.<ref>{{cite news |title=Fentanyl Overdose |date=20 May 2016 |website=[[The Huffington Post]] |url=http://www.huffingtonpost.ca/news/fentanyl-overdose |access-date=4 June 2016 |archive-url=https://web.archive.org/web/20160605035409/http://www.huffingtonpost.ca/news/fentanyl-overdose/ |archive-date=5 June 2016 |url-status=dead }}</ref> In 2016, deaths from fentanyl overdoses in the province of [[British Columbia]] averaged two persons per day.<ref>{{cite report |title=Fentanyl-detected in illicit drug overdose deaths, January 1, 2012 to April 30, 2016 |publisher=British Columbia Coroners Service |url=http://www2.gov.bc.ca/assets/gov/public-safety-and-emergency-services/death-investigation/statistical/fentanyl-detected-overdose.pdf |access-date=9 June 2016 |archive-url=https://web.archive.org/web/20160625235638/http://www2.gov.bc.ca/assets/gov/public-safety-and-emergency-services/death-investigation/statistical/fentanyl-detected-overdose.pdf |archive-date=25 June 2016 |url-status=dead }}</ref> In 2017 the death rate increased by more than 100% with 368 overdose-related deaths in British Columbia between January and April 2017.<ref>{{cite news |title=Fentanyl contributed to hundreds of deaths in Canada so far this year |date=31 July 2017 |website=Global News |url=http://globalnews.ca/news/3637148/fentanyl-overdoses-canada-2017/ |access-date=14 September 2017 |url-status=live |archive-url=https://web.archive.org/web/20170914082850/http://globalnews.ca/news/3637148/fentanyl-overdoses-canada-2017/ |archive-date=14 September 2017 }}</ref>
[[File:FENTANYL FLOW TO THE UNITED STATES 2019.png|thumb|250x250px|Illegal fentanyl flow to the US from various regions in 2019]]
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 | 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 LD<sub>50</sub> 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, Bhutia YD, Singh P, Rao P, Gujar NL, Ganesan K, Bhattacharya R |title=Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice |journal=Medicinal Chemistry Research |date=1 August 2013 |volume=22 |issue=8 |pages=3888–3896 |doi=10.1007/s00044-012-0390-6 |url=https://link.springer.com/article/10.1007/s00044-012-0390-6 |language=en |issn=1554-8120}}</ref> The LD<sub>50</sub> 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. Concerning overdose deaths in pediatric cases, numbers are also concerning. Based on a report by the 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."<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>
 
=== False reports by police of poisonings through secondary exposure ===
In the late 2010s, some media outlets began to report stories of police officers being hospitalized 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  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>
 
Many experts in toxicology are skeptical of police truly overdosing through mere touch. "This has never happened," said Dr. Ryan Marino, an [[Emergency medicine|emergency]] and [[addiction medicine]] physician at [[Case Western Reserve University]]. "There has never been an overdose through skin contact or accidentally inhaling fentanyl."<ref>{{cite news | vauthors = Mann B |title=Cops say they're being poisoned by fentanyl. Experts say the risk is 'extremely low' |url=https://www.npr.org/2023/05/16/1175726650/fentanyl-police-overdose-misinformation |access-date=27 November 2023 |archive-date=27 November 2023 |archive-url=https://web.archive.org/web/20231127123606/https://www.npr.org/2023/05/16/1175726650/fentanyl-police-overdose-misinformation |url-status=live }}</ref>
 
=== Prevention ===
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 Prevention |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 Prevention |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:
 
<blockquote>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.<ref name="HAN438">{{cite web |title=Increase in Fatal Drug Overdoses Across the United States Driven by Synthetic Opioids Before and During the COVID-19 Pandemic – HAN 00438 – Health Alert Network Advisory |url=https://emergency.cdc.gov/han/2020/han00438.asp |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |access-date=21 December 2022 |date=17 December 2020 |archive-date=20 December 2022 |archive-url=https://web.archive.org/web/20221220222711/https://emergency.cdc.gov/han/2020/han00438.asp |url-status=live }}</ref></blockquote>
 
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:<ref name="HAN438" />
# Local need to expand the distribution and use of naloxone and overdose prevention education,
# Expand awareness, access, and availability of treatment for substance use disorders,
# Intervene early with individuals at the highest risk for overdose, and
# improve detection of overdose outbreaks to facilitate more effective response.<ref name="HAN438" /><ref>{{cite web |date=2 October 2021 |title=Fentanyl {{!}} CDC's Response to the Opioid Overdose Epidemic {{!}} CDC |url=https://www.cdc.gov/opioids/basics/fentanyl.html |access-date=27 April 2022 |publisher=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>
 
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 is leading to the large overdose epidemic in America. This campaign also shows the difference between counterfeit pills and real pills.
 
== Pharmacology ==
{{See also|Opioid#Pharmacology}}
 
=== Classification ===
Fentanyl is a synthetic opioid in the [[phenylpiperidine]] family, which includes [[sufentanil]], [[alfentanil]], [[remifentanil]], and [[carfentanil]].<ref name="Yaksh_2011">{{cite book | vauthors = Yaksh T, Wallace M |year=2011 |title=Goodman & Gilman's: The Pharmacological Basis of Therapeutics |publisher=McGraw-Hill |isbn=978-0-07-162442-8 |location=New York, NY}}</ref><ref>{{cite book | vauthors = Katzung BG |year=2017 |title=Basic & Clinical Pharmacology |edition=14th |location=New York, NY | publisher = McGraw-Hill |isbn=978-1-259-64115-2 |oclc=1015240036}}</ref> Some [[List of fentanyl analogues|fentanyl analogues]], such as carfentanil, are up to 10,000 times [[Equianalgesic#Opioid equivalency table|stronger than morphine]].<ref name=UN2017CND>{{cite press release |title=Commission on Narcotic Drugs takes decisive step to help prevent deadly fentanyl overdoses |date=16 March 2017 |publisher=Commission on Narcotic Drugs, United Nations Office on Drugs and Crime |url=http://www.unodc.org/unodc/en/frontpage/2017/March/commission-on-narcotic-drugs-takes-decisive-step-to-help-prevent-deadly-fentanyl-overdoses.html |access-date=19 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20170320052640/http://www.unodc.org/unodc/en/frontpage/2017/March/commission-on-narcotic-drugs-takes-decisive-step-to-help-prevent-deadly-fentanyl-overdoses.html |archive-date=20 March 2017 }}</ref>
 
=== Structure-activity ===
[[File:Fentanyl numbering.svg|right|thumb|The chemical structure of fentanyl has been used as a basis in modern chemistry for the discovery and nomenclature of many new fentanyl analogues, sometimes called fentalogs.]]
 
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"/>
 
Like other opioids, fentanyl is a weak base that is highly lipid-soluble, protein-bound, and protonated at physiological pH.<ref name="Hemmings_2018"/> All of these factors allow it to rapidly cross cellular membranes, contributing to its quick effect in the body and the central nervous system.<ref name="Mayes_2006"/><ref name="Yaksh_2011"/>
 
=== Fentanyl analogs ===
[[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 illicitly. Carfentanil, a fentanyl analog, has an additional carboxylic acid group attached to the 4 position. Carfentanil is 20–30 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>
 
=== Mechanism of action ===
{| class="wikitable" style = "float: right; clear: right; margin-left:15px; text-align:center"
|+Fentanyl at opioid receptors<ref name="pmid8114680">{{cite journal | vauthors = Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T | title = Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors | journal = Molecular Pharmacology | volume = 45 | issue = 2 | pages = 330–334 | date = February 1994 | pmid = 8114680 }}</ref>
! colspan="3" |[[Binding affinity|Affinities]], {{abbrlink|K<sub>i</sub>|Inhibitor constant}}
!Ratio
|-
!{{abbrlink|MOR|μ-opioid receptor}}
!{{abbrlink|DOR|δ-opioid receptor}}
!{{abbrlink|KOR|κ-opioid receptor}}
!MOR:DOR:KOR
|-
|0.39 nM
|>1,000 nM
|255 nM
|1:>2564:654
|}
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 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, unmyelinated C-fibers and is less effective on neuropathic pain and "first pain" signals through small, myelinated A-fibers.<ref name="Hemmings_2018" />
 
Fentanyl can produce the following clinical effects strongly, through μ-receptor agonism:<ref name = "Butterworth_2018">{{cite book | vauthors = Butterworth IV JV, Wasnick JD, MacKey DC |date = 21 August 2018 |title=Morgan & Mikhail's Clinical Anesthesiology |edition=6th |isbn=978-1-259-83442-4 |place=New York, NY | publisher = McGraw-Hill Education |oclc=1039081701}}</ref>
* Supraspinal analgesia (μ<sub>1</sub>)
* Respiratory depression (μ<sub>2</sub>)
* Physical dependence
* Muscle rigidity
 
It also produces sedation and spinal analgesia through Κ-receptor agonism.<ref name = "Butterworth_2018" />
 
=== Therapeutic effects ===
* Pain relief: Primarily, fentanyl provides the relief of pain by acting on the brain and spinal μ-receptors.<ref name="Hemmings_2018" />
* Sedation: Fentanyl produces sleep and drowsiness, as the dosage is increased, and can produce the [[Delta waves|δ-waves]] often seen in natural sleep on [[electroencephalogram]].<ref name="Hemmings_2018" />
* Suppression of the cough reflex: Fentanyl can decrease the struggle against an [[endotracheal tube]] and excessive coughing by decreasing the cough reflex, becoming useful when intubating people who are awake and have compromised airways.<ref name="Hemmings_2018" /> After receiving a bolus dose of fentanyl, people can also experience paradoxical coughing, which is a phenomenon that is not well understood.<ref name="Hemmings_2018" />
 
=== Detection in biological fluids ===
Fentanyl may be measured in blood or urine to monitor for abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Commercially available [[immunoassay]]s are often used as initial screening tests, but chromatographic techniques are generally used for confirmation and quantitation. The [[Marquis reagent|Marquis Color test]] may also be used to detect the presence of fentanyl. Using [[formaldehyde]] and [[sulfuric acid]], the solution will turn purple when introduced to opium drugs. Blood or plasma fentanyl concentrations are expected to be in a range of 0.3–3.0 μg/L in persons using the medication therapeutically, 1–10 μg/L in intoxicated people, and 3–300 μg/L in victims of acute overdosage.<ref>Baselt, R. (2017) ''Disposition of Toxic Drugs and Chemicals in Man'', 11th edition, Biomedical Publications, Foster City, CA, pp. 883–886.</ref> [[Paper spray ionization|Paper spray-mass spectrometry]] (PS-MS) may be useful for initial testing of samples.<ref>{{cite journal | vauthors = Vandergrift GW, Hessels AJ, Palaty J, Krogh ET, Gill CG | title = Paper spray mass spectrometry for the direct, semi-quantitative measurement of fentanyl and norfentanyl in complex matrices | journal = Clinical Biochemistry | volume = 54 | pages = 106–111 | date = April 2018 | pmid = 29432758 | doi = 10.1016/j.clinbiochem.2018.02.005 }}</ref><ref>{{cite journal | vauthors = Vandergrift GW, Hessels AJ, Palaty J, Krogh ET, Gill CG | title = Paper spray mass spectrometry for the direct, semi-quantitative measurement of fentanyl and norfentanyl in complex matrices | journal = Clinical Biochemistry | volume = 54 | pages = 106–111 | date = April 2018 | pmid = 29432758 | doi = 10.1016/j.clinbiochem.2018.02.005 | id = 10.25316/IR-4343 }}</ref>
 
=== Detection for harm reduction purposes ===
[[File:Fentanyl-test-strip.jpg|thumb|Image of testing strip instructions from the harm reduction organization Dance Safe]]
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 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>
 
== Synthesis ==
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>
 
=== Janssen ===
[[File:Benzoylbenzylfentanyl synth.png|thumb|upright|Portion of the Janssen Method of synthesis, to synthesize a related opioid]]
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>
 
=== Siegfried ===
[[Image:NPP to fentanyl.svg|thumb|Siegfried Method from NPP through 4-ANPP to fentanyl]]
The Siegfried method involves the initial synthesis of [[N-phenethyl-4-piperidone|''N''-phenethyl-4-piperidone]] (NPP). This intermediate is [[Reductive amination|reductively aminated]] to [[4-anilino-N-phenethylpiperidine|4-anilino-''N''-phenethylpiperidine]] (4-ANPP). Fentanyl is produced following the reaction of 4-ANPP with an acyl chloride.<ref>{{cite web |title=Synthesis of Fentanyl |url=https://erowid.org/archive/rhodium/chemistry/fentanyl.html |website=Rhodium |publisher=Siegfried |access-date=24 January 2023 |archive-date=5 August 2022 |archive-url=https://web.archive.org/web/20220805104925/https://www.erowid.org/archive/rhodium/chemistry/fentanyl.html |url-status=live }}</ref> The Siegfried method has been used in the early 2000s to manufacture fentanyl in both domestic and foreign clandestine laboratories.<ref>{{cite web |title=Designation of Benzylfentanyl and 4-Anilinopiperidine, Precursor Chemicals Used in the Illicit Manufacture of Fentanyl, as List I Chemicals |url=https://www.federalregister.gov/documents/2020/04/15/2020-07064/designation-of-benzylfentanyl-and-4-anilinopiperidine-precursor-chemicals-used-in-the-illicit |website=Federal Register |access-date=28 January 2023 |date=15 April 2020 |archive-date=5 November 2021 |archive-url=https://web.archive.org/web/20211105125231/https://www.federalregister.gov/documents/2020/04/15/2020-07064/designation-of-benzylfentanyl-and-4-anilinopiperidine-precursor-chemicals-used-in-the-illicit |url-status=live }}</ref>
 
=== Gupta ===
[[File:GuptaFent2.jpg|thumb|Gupta Method from [[4-Piperidone]] to fentanyl]]
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.<ref>{{cite journal |vauthors=Gupta P |date=9 November 2005 |title=A Convenient One-Pot Synthesis of Fenta4nyl |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200549130 |access-date=24 January 2023 |journal=ChemInform |volume=36 |issue=49 |doi=10.1002/chin.200549130 |archive-date=24 January 2023 |archive-url=https://web.archive.org/web/20230124235847/https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200549130 |url-status=live }}</ref> For the first half of 2021, the [[Drug Enforcement Administration|U.S. Drug Enforcement Administration]] found the Gupta method was the predominant synthesis route in their samples of seized fentanyl.<ref>{{cite web |title=Fentanyl Profiling Program Report |url=https://www.dea.gov/sites/default/files/2022-05/FPP%20Report%20January%202022.pdf |publisher=Drug Enforcement Administration |access-date=25 January 2023 |pages=1–2 |archive-date=25 January 2023 |archive-url=https://web.archive.org/web/20230125211947/https://www.dea.gov/sites/default/files/2022-05/FPP%20Report%20January%202022.pdf |url-status=live }}</ref> 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.<ref name = "Braga_2022">{{cite journal | vauthors = Braga FC, Ramos TO, Brocksom TJ, de Oliveira KT | title = Synthesis of Fentanyl under Continuous Photoflow Conditions | journal = Organic Letters | volume = 24 | issue = 45 | pages = 8331–8336 | date = November 2022 | pmid = 36346151 | doi = 10.1021/acs.orglett.2c03338 | s2cid = 253396263 }}</ref>
 
=== Suh ===
The Suh (or 'total synthesis') method skips the direct use of piperidine precursors in favor of creating the ring system in-situ.<ref name="pmid9875518">{{cite journal | vauthors = Suh YG, Cho KH, Shin DY | title = Total synthesis of fentanyl | journal = Archives of Pharmacal Research | volume = 21 | issue = 1 | pages = 70–2 | date = February 1998 | pmid = 9875518 | doi = 10.1007/BF03216756 | s2cid = 31408546 }}</ref>
 
== History ==
Fentanyl was first synthesized in Belgium by [[Paul Janssen]] under the label of his relatively newly formed [[Janssen Pharmaceutica]] in 1959.<ref name=JanssenHist>{{cite journal | vauthors = López-Muñoz F, Alamo C | title = The consolidation of neuroleptic therapy: Janssen, the discovery of haloperidol and its introduction into clinical practice | journal = Brain Research Bulletin | volume = 79 | issue = 2 | pages = 130–141 | date = April 2009 | pmid = 19186209 | doi = 10.1016/j.brainresbull.2009.01.005 | s2cid = 7720401 }}</ref> It was developed by screening chemicals similar to [[pethidine]] (meperidine) for opioid activity.<ref name="Bla2005">{{cite journal | vauthors = Black J | title = A personal perspective on Dr. Paul Janssen | journal = Journal of Medicinal Chemistry | volume = 48 | issue = 6 | pages = 1687–1688 | date = March 2005 | pmid = 15771410 | doi = 10.1021/jm040195b | url = http://www.pauljanssenaward.com/janssen/A_Personal_Perspective.pdf#zoom=100 | url-status = dead | archive-url = https://web.archive.org/web/20071010091139/http://www.pauljanssenaward.com/janssen/A_Personal_Perspective.pdf | archive-date = 10 October 2007 }}</ref> The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 [[stoichiometry|stoichiometric ratio]]).<ref>{{cite web | title=Sublimaze- fentanyl citrate injection, solution | website=DailyMed | date=21 April 2008 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8944ea18-016e-4971-876d-2365fac190ea | access-date=10 July 2024}}</ref><ref>{{cite web | title=Actiq- fentanyl citrate lozenge | website=DailyMed | date=18 December 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90b94524-f913-48b3-3771-7b2fcffd888a | access-date=10 July 2024}}</ref> Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by [[McNeil Consumer Healthcare|McNeil Laboratories]] under the brand name Sublimaze.<ref>{{cite journal | vauthors = | title = Fentanyl (sublimaze) | journal = Clinical Pharmacology and Therapeutics | volume = 9 | issue = 5 | pages = 704–706 | date = September 1968 | pmid = 5676808 | doi = 10.1002/cpt196895704 | s2cid = 9743189 }}</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 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 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>
 
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.<ref name="onsolis">{{cite web|title=Questions and Answers about Onsolis (fentanyl buccal soluble film)|url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm172039.htm|publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=26 December 2017|date=16 July 2009|archive-url=https://web.archive.org/web/20170722191120/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm172039.htm|archive-date=22 July 2017|url-status=dead}}</ref> 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]].<ref name=onsolis/>
 
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>
 
== Society and culture ==
 
=== Legal status ===
In the UK, fentanyl is classified as a controlled Class A drug under the [[Misuse of Drugs Act 1971]].<ref>{{cite web|url=http://www.legislation.gov.uk/ukpga/1971/38/schedule/2|title=Misuse of Drugs Act 1971|access-date=22 March 2017|archive-url=https://web.archive.org/web/20121114181829/http://www.legislation.gov.uk/ukpga/1971/38/schedule/2|archive-date=14 November 2012|url-status=live}}</ref>
 
In the Netherlands, fentanyl is a List I substance of the [[Opium Law]].<ref>{{cite web |title=Opiumwet |trans-title=Opium Act |url=https://wetten.overheid.nl/BWBR0001941/2009-07-01#BijlageI |website=Ministerie van Binnenlandse Zaken en Koninkrijksrelaties |trans-website=Ministry of the Interior and Kingdom Relations |access-date=19 January 2023 |language=nl |archive-date=19 January 2023 |archive-url=https://web.archive.org/web/20230119041050/https://wetten.overheid.nl/BWBR0001941/2009-07-01#BijlageI |url-status=live }}</ref>
 
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 [[Specialty drugs#Risk evaluation and mitigation strategies (REMS)|risk evaluation and mitigation strategy]] (REMS) program.<ref name="relayhealth_2011">{{cite web |url=http://www.relayhealth.com/news-and-events/press/ProStrakan-Chooses-RelayHealth-for-Approved-Abstral-REMS-Program-.html#sthash.GRwKE7Wc.dpuf |title=RelayHealth's pharmacy connectivity network and reach, aligned with McKesson Specialty Care Solutions' REMS expertise, expands cancer patients' access to pain therapy |date=20 January 2011 |access-date=5 November 2015 |location=Atlanta |archive-url=https://web.archive.org/web/20160129072751/http://www.relayhealth.com/news-and-events/press/ProStrakan-Chooses-RelayHealth-for-Approved-Abstral-REMS-Program-.html#sthash.GRwKE7Wc.dpuf |archive-date=29 January 2016 |url-status=dead }}</ref><ref name="pharmaceuticalcommerce">{{cite news | vauthors = Shelley S |date=22 April 2011 |title=With a few stumbles, REMS begins to hit its atride |website=Pharmaceutical Commerce |url=http://www.pharmaceuticalcommerce.com/brand_communications?articleid=2389%22%20%5Ct%20%22_blank |access-date=5 November 2015 | url-status=dead | archive-url = https://web.archive.org/web/20160129174603/http://www.pharmaceuticalcommerce.com/brand_communications?articleid=2389%22%20%5Ct%20%22_blank |archive-date=29 January 2016 }}</ref> In order to curb misuse, many health insurers have begun to require [[Managed care|precertification and/or quantity limits]] for Actiq prescriptions.<ref>{{cite web | title = Procedures, programs and drugs that require precertification: Participating provider precertification list | url = https://www.aetna.com/content/dam/aetna/pdfs/health-care-professionals/2021-precert-list-july.pdf | publisher = Aetna Inc. | access-date = 4 July 2021 | archive-date = 9 July 2021 | archive-url = https://web.archive.org/web/20210709183129/https://www.aetna.com/content/dam/aetna/pdfs/health-care-professionals/2021-precert-list-july.pdf | url-status = dead }}</ref><ref>{{cite web | title = Notice regarding precertification requirement | date = 5 November 2007 | publisher = BlueCross BlueShield of Arizona | url = http://www.azblue.com/pdfs/medications/pharmacy/QlList.pdf | archive-url = https://web.archive.org/web/20080828155557/http://www.azblue.com/pdfs/medications/pharmacy/QlList.pdf | archive-date = 28 August 2008}}</ref><ref>{{cite web | title = Medications requiring precertification | publisher = Oxford Health Plans | url = https://www.oxhp.com/druglist/drug_precert_list.html | archive-url = https://web.archive.org/web/20061015232701/https://www.oxhp.com/druglist/drug_precert_list.html | archive-date=15 October 2006}}</ref>
 
In Canada, fentanyl is considered a schedule{{nbsp}}I drug as listed in Canada's [[Controlled Drugs and Substances Act]].<ref>{{cite web |title=Canada's Controlled Drugs and Substances Act |website=Canada Justice Laws Website |url=http://laws.justice.gc.ca/eng/acts/C-38.8/page-12.html#h-34 |access-date=8 September 2018 |archive-date=28 September 2018 |archive-url=https://web.archive.org/web/20180928212208/http://laws.justice.gc.ca/eng/acts/C-38.8/page-12.html#h-34 |url-status=live }}</ref>
 
[[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.<ref>{{cite web | vauthors = Naylor A | date = 6 January 2020 | title = What we can learn from a tiny Baltic country's two-decade Fentanyl crisis | website = Vice | url = https://www.vice.com/en/article/k7ea93/estonia-fentanyl-crisis-what-says-about-us | access-date = 31 January 2021 | archive-date = 8 March 2021 | archive-url = https://web.archive.org/web/20210308162515/https://www.vice.com/en/article/k7ea93/estonia-fentanyl-crisis-what-says-about-us | url-status = live }}</ref>
 
A 2018 report by ''[[The Guardian]]'' indicated that many major drug suppliers on the [[dark web]] have voluntarily banned the trafficking of fentanyl.<ref>{{cite news |vauthors=Townsend M |date=1 December 2018 |title=Dark web dealers voluntarily ban deadly fentanyl |newspaper=[[The Guardian]] |url=https://www.theguardian.com/society/2018/dec/01/dark-web-dealers-voluntary-ban-deadly-fentanyl |access-date=3 December 2018 |archive-date=2 December 2018 |archive-url=https://web.archive.org/web/20181202232730/https://www.theguardian.com/society/2018/dec/01/dark-web-dealers-voluntary-ban-deadly-fentanyl |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]] insisted that the main source of this synthetic drug is [[Asia]]. He stated 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>
 
=== Recreational use ===
[[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=https://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>
 
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.<ref name="pmid16909503">{{cite journal | vauthors = Boddiger D | title = Fentanyl-laced street drugs "kill hundreds" | journal = Lancet | volume = 368 | issue = 9535 | pages = 569–570 | date = August 2006 | pmid = 16909503 | doi = 10.1016/S0140-6736(06)69181-2 | s2cid = 39788629 | doi-access = free | title-link = doi }}</ref> 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.<ref>{{cite news |title=Synthetic drug fentanyl causes overdose boom in Estonia |date=30 March 2012 |website=[[BBC News Online]] |url=https://www.bbc.co.uk/news/world-europe-17524945 |access-date=21 June 2018 |archive-url=https://web.archive.org/web/20180728214747/https://www.bbc.co.uk/news/world-europe-17524945 |archive-date=28 July 2018 |url-status=live }}</ref>
 
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.<ref name=DEA2015 />
 
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.<ref name="trib2">"{{cite web | vauthors = Mims B |date = 11 November 2004 |title = Painkiller is topic of inquiry |newspaper = [[The Salt Lake Tribune]] |url = http://opioids.com/fentanyl/actiq.html |archive-url = https://web.archive.org/web/20071224161858/http://opioids.com/fentanyl/actiq.html |archive-date=2007-12-24}}</ref> 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."<ref name="trib2" />
 
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>
 
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]].<ref>{{cite journal | title = Nonpharmaceutical fentanyl-related deaths—multiple states, April 2005 – March 2007 | journal = MMWR Morb Mortal Wkly Rep | volume = 57 | issue = 29 | pages = 793–6 | date = July 2008 | pmid = 18650786 | url = https://www.cdc.gov/mmwr/PDF/wk/mm5729.pdf | author1 = Centers for Disease Control Prevention (CDC) | access-date = 2 December 2022 | archive-date = 2 December 2022 | archive-url = https://web.archive.org/web/20221202101157/https://www.cdc.gov/mmwr/PDF/wk/mm5729.pdf | url-status = live }}</ref>
 
[[BTMPS]] was detected as an adulterant in illicitly sold fentanyl in the United States in 2024.<ref>{{cite web |title=BTMPS |url=https://www.cfsre.org/nps-discovery/monographs/bis2266-tetramethyl-4-piperidyl-sebacate |website=The Center for Forensic Science Research & Education}}</ref>
 
=== Enforcement ===
{{Further|Anti-fentanyl legislation in the United States|United States sanctions against China#Sanctions on producers of fentanyl precursors|China and the opioid epidemic in the United States}}
[[Image:deafentanyl.jpg|thumb|Fentanyl powder (23% fentanyl) seized by police in [[Ohio]], United States<ref>{{cite web |title=DEA Microgram Bulletin |date=June 2006 |publisher=U.S. [[Drug Enforcement Administration]] |department=Office of Forensic Sciences |place=Washington, DC |url=http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0606/mg0606.html |access-date=22 June 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090721101918/http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0606/mg0606.html|archive-date=21 July 2009}}</ref>]]
 
Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In November{{nbsp}}2016, the DEA uncovered an operation making counterfeit oxycodone and [[Alprazolam|Xanax]] from a home in [[Cottonwood Heights, Utah]]. They found about 70,000{{nbsp}}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.<ref>{{cite news | vauthors = Tanner C |date=2016 |title=Thousands of fentanyl pills confiscated in Utah drug raid |newspaper=[[The Salt Lake Tribune]] |url=http://www.sltrib.com/news/4623595-155/thousands-of-fentanyl-pills-confiscated-in |access-date=23 November 2016 |url-status=live |archive-url=https://web.archive.org/web/20161124094546/http://www.sltrib.com/news/4623595-155/thousands-of-fentanyl-pills-confiscated-in |archive-date=24 November 2016 }}</ref><ref>{{cite web |title=Cottonwood Heights drug bust one of the largest in Utah history |date=22 November 2016 |website=Fox 13 |url=http://fox13now.com/2016/11/22/dea-investigating-drug-operation-near-cottonwood-heights-school/ |url-status=live |access-date=23 November 2016 |archive-url=https://web.archive.org/web/20161123142646/http://fox13now.com/2016/11/22/dea-investigating-drug-operation-near-cottonwood-heights-school/ |archive-date=23 November 2016}}</ref> A seizure of a record amount of fentanyl occurred on 2 February 2019, by [[U.S. Customs and Border Protection]] in [[Nogales, Arizona]]. The {{convert|254|lbs|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.<ref>{{cite news |title=U.S. border officers make largest-ever fentanyl bust: 254{{nbsp}}pounds hidden under cucumbers |date=31 January 2019 |newspaper=[[The Washington Post]] |url=https://www.washingtonpost.com/world/national-security/us-border-officials-announce-largest-ever-fentanyl-seizure/2019/01/31/a43eeb62-258c-11e9-90cd-dedb0c92dc17_story.html |access-date=8 June 2020 |archive-date=8 June 2020 |archive-url=https://web.archive.org/web/20200608203341/https://www.washingtonpost.com/world/national-security/us-border-officials-announce-largest-ever-fentanyl-seizure/2019/01/31/a43eeb62-258c-11e9-90cd-dedb0c92dc17_story.html |url-status=live }}</ref> The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially [[α-Methylfentanyl|α-methylfentanyl]] (AMF).<ref name="deadiversion.usdoj.gov"/> One US Department of Justice publication lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,<ref>{{cite journal | vauthors = Kram TC, Cooper DA, Allen AC | title = Behind the identification of China White | journal = Analytical Chemistry | volume = 53 | issue = 12 | pages = 1379A–1386A | date = October 1981 | pmid = 7294353 | doi = 10.1021/ac00235a003 }}</ref> which today are classified as [[Schedule I drug]]s in the United States.<ref name="deadiversion.usdoj.gov">{{cite web |title = List of Schedule I Drugs |publisher = U.S. Department of Justice |url = http://www.deadiversion.usdoj.gov/schedules/listby_sched/sched1.htm |archive-url = https://web.archive.org/web/20100109203853/http://www.deadiversion.usdoj.gov/schedules/listby_sched/sched1.htm |archive-date = 9 January 2010 }}</ref> 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.<ref name="pmid4420811">{{cite journal | vauthors = Van Bever WF, Niemegeers CJ, Janssen PA | title = Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2-phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide | journal = Journal of Medicinal Chemistry | volume = 17 | issue = 10 | pages = 1047–1051 | date = October 1974 | pmid = 4420811 | doi = 10.1021/jm00256a003 }}</ref>
 
In June 2013, the United States [[Centers for Disease Control and Prevention]] (CDC) issued a health advisory<ref>{{cite web |title=Recommendations for Laboratory Testing for Acetyl Fentanyl and Patient Evaluation and Treatment for Overdose with Synthetic Opioids | author = CDC Health Alert Network |date=20 June 2013 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |url=http://emergency.cdc.gov/HAN/han00350.asp |access-date=20 June 2013 |archive-url=https://web.archive.org/web/20130624113939/http://emergency.cdc.gov/HAN/han00350.asp |archive-date=24 June 2013 |url-status=dead }}</ref> 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.<ref>{{cite report |title=Characteristics of Fentanyl overdose — Massachusetts, 2014–2016 |publisher=U.S. [[Centers for Disease Control and Prevention]] (CDC) |date=14 April 2017}}</ref>
 
Beginning in 2015, Canada has seen several 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>
 
Fentanyl has been discovered for sale in illicit markets in Australia in 2017<ref>{{cite news | vauthors = Bonini T |date=13 October 2017 |title=Could fentanyl be Australia's next deadly drug epidemic? |website=ABC News (Australia) |url=http://www.abc.net.au/news/2017-10-13/could-fentanyl-be-australias-next-deadly-drug-epidemic/9048530 |access-date=6 April 2018 |archive-url=https://web.archive.org/web/20180508164151/http://www.abc.net.au/news/2017-10-13/could-fentanyl-be-australias-next-deadly-drug-epidemic/9048530 |archive-date=8 May 2018 |url-status=live }}</ref> and in New Zealand in 2018.<ref>{{cite web |title=Fentanyl found at New Zealand festival |date=20 March 2018 |website=KnowYourStuffNZ |url=https://knowyourstuff.nz/2018/03/20/fentanyl-found-at-new-zealand-festival/ |access-date=6 April 2018 |url-status=live |archive-url=https://web.archive.org/web/20180407115814/https://knowyourstuff.nz/2018/03/20/fentanyl-found-at-new-zealand-festival/ |archive-date=7 April 2018 }}</ref> In response, New Zealand experts called for wider availability of naloxone.<ref>{{cite news | vauthors = Buchanan J |date=27 March 2018 |title=NZ's 'deadly' indifference to drug overdose antidote |website=HealthCentral NZ |url=http://healthcentral.nz/opinion-julian-buchanan-nzs-deadly-indifference-to-drug-overdose-antidote/ |access-date=6 April 2018 |url-status=live |archive-url=https://web.archive.org/web/20180407054328/http://healthcentral.nz/opinion-julian-buchanan-nzs-deadly-indifference-to-drug-overdose-antidote/ |archive-date=7 April 2018 }}</ref>
 
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 [[Precursor (chemistry)|precursors]] from Chinese suppliers such as [[Yuancheng Group]], which are finished in Mexico and smuggled to the United States.<ref>{{cite news |vauthors=Feng E |date=17 November 2020 |title='We Are Shipping To The U.S.': Inside China's Online Synthetic Drug Networks |work=[[NPR]] |url=https://www.npr.org/2020/11/17/916890880/we-are-shipping-to-the-u-s-china-s-fentanyl-sellers-find-new-routes-to-drug-user |access-date=1 October 2022 |archive-date=1 October 2022 |archive-url=https://web.archive.org/web/20221001144517/https://www.npr.org/2020/11/17/916890880/we-are-shipping-to-the-u-s-china-s-fentanyl-sellers-find-new-routes-to-drug-user |url-status=live }}</ref><ref name="brookings-3-22">{{cite web |vauthors=Felbab-Brown V |date=23 March 2022 |title=China and synthetic drugs control: Fentanyl, methamphetamines, and precursors |url=https://www.brookings.edu/research/china-and-synthetic-drugs-control-fentanyl-methamphetamines-and-precursors/ |access-date=23 September 2022 |website=Brookings |archive-date=23 September 2022 |archive-url=https://web.archive.org/web/20220923083453/https://www.brookings.edu/research/china-and-synthetic-drugs-control-fentanyl-methamphetamines-and-precursors/ |url-status=live }}</ref><ref name="dea-2020">{{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=4 October 2022 |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> Following the [[2022 visit by Nancy Pelosi to Taiwan]], China halted cooperation with the United States on combatting drug trafficking.<ref>{{cite web |vauthors=Lo K |date=29 September 2022 |title=White House confirms China has stopped cooperating on anti-drug measures |url=https://www.scmp.com/news/china/diplomacy/article/3194183/white-house-confirms-china-has-stopped-cooperating-anti-drug |access-date=1 October 2022 |website=[[South China Morning Post]] |archive-date=1 October 2022 |archive-url=https://web.archive.org/web/20221001071714/https://www.scmp.com/news/china/diplomacy/article/3194183/white-house-confirms-china-has-stopped-cooperating-anti-drug |url-status=live }}</ref>
 
India has also emerged as a source of fentanyl and fentanyl precursors,<ref name="dea-2020" /> where Mexican cartels have already developed networks for the import of synthetic drugs. It is possible that fentanyl and precursor production may disperse to other countries, such as [[Nigeria]], [[South Africa]], [[Indonesia]], [[Myanmar]], and the [[Netherlands]].<ref name="brookings-3-22" />
 
In 2020, the [[Myanmar military]] and police confiscated 990 gallons of "methyl fentanyl"{{sic}}, as well as [[Precursor (chemistry)|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.<ref>{{cite web |vauthors = Beech H, Nang S |date = 19 May 2020 |title = Raids reveal massive fentanyl production in Myanmar |newspaper = [[The New York Times]] |url = https://www.nytimes.com/2020/05/19/world/asia/myanmar-drug-raid-fentanyl.html |access-date = 2 May 2021 |archive-date = 8 June 2021 |archive-url = https://web.archive.org/web/20210608052805/https://www.nytimes.com/2020/05/19/world/asia/myanmar-drug-raid-fentanyl.html |url-status = live }}</ref><ref>{{cite report | title = UNODC report: Opium production drops again in Myanmar as the synthetic drug market expands | website = [[UNODC]] (Myanmar) | url = https://www.unodc.org/southeastasiaandpacific/en/2021/02/myanmar-opium-survey-report-launch/story.html | access-date = 2 May 2021 | archive-date = 4 March 2021 | archive-url = https://web.archive.org/web/20210304124958/https://www.unodc.org/southeastasiaandpacific/en/2021/02/myanmar-opium-survey-report-launch/story.html | url-status = live }}</ref>
 
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.<ref>{{cite web | url = https://www.cnn.com/2023/03/30/us/california-police-union-executive-drug-scheme-opioids/index.html | title = A California police union director is being charged with importing opioids, including fentanyl, disguised as chocolate and wedding favors | archive-url = https://web.archive.org/web/20230402201933/https://www.cnn.com/2023/03/30/us/california-police-union-executive-drug-scheme-opioids/index.html | archive-date=2 April 2023 | work = CNN | date = 31 March 2023 | access-date = 2 April 2023 }}</ref><ref>{{cite news | url = https://www.washingtonpost.com/investigations/interactive/2022/dea-fentanyl-failure/ | title = Cause of death: Washington faltered as fentanyl gripped America | archive-url = https://web.archive.org/web/20230325131141/https://www.washingtonpost.com/investigations/interactive/2022/dea-fentanyl-failure/ | archive-date=25 March 2023 | newspaper = [[The Washington Post]] | access-date = 2 April 2023 }}</ref>
 
According to the national archives and the [[Drug Enforcement Administration|DEA]], direct fentanyl shipments from China have stopped since 2022.<ref>{{cite web |date=10 May 2022 |title=DEA zeroes in on China as fentanyl deaths soar – CBS News |url=https://www.cbsnews.com/news/fentanyl-china-mexico-drug-enforcement-administration/ |access-date=15 November 2023 |website=CBS News |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115231610/https://www.cbsnews.com/news/fentanyl-china-mexico-drug-enforcement-administration/ |url-status=live }}</ref><ref>{{cite web |title=DHS Investigation Leads to Indictments Against China-Based Companies and Employees for Fentanyl Trafficking {{!}} Homeland Security |url=https://www.dhs.gov/news/2023/10/03/dhs-investigation-leads-indictments-against-china-based-companies-and-employees |access-date=15 November 2023 |website=U.S. Department of Homeland Security|archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115231610/https://www.dhs.gov/news/2023/10/03/dhs-investigation-leads-indictments-against-china-based-companies-and-employees |url-status=live }}</ref> The majority of illicit fentanyl and analogues now entering the U.S. from Mexico are final products in form of "tablets" and adulterated heroin from previously synthesized fentanyl. From the sophistication of full [[chemical synthesis|fentanyl synthesis]] and acute toxicity in laboratory environments, 'clandestine' labs in Mexico relate to making an illicit dosage form from available fentanyl rather than the synthesis itself. Based on further research by investigators, fentanyl and analogues are likely synthesized in labs that have the appearance of a legal entity, or are diverted from pharmaceutical laboratories.<ref>{{cite web | url = https://www.reuters.com/article/us-usa-trump-opioid-indictments-idUKKBN1CM22B | title = U.S. indicts major Chinese traffickers and three Americans for selling fentanyl online | archive-url = https://web.archive.org/web/20230405070000/https://www.reuters.com/article/us-usa-trump-opioid-indictments-idUKKBN1CM22B | archive-date=5 April 2023 | date = 17 October 2017 | work = Reuters | access-date = 4 April 2023 }}</ref><ref>{{cite web | url = https://trone.house.gov/2023/01/08/chinas-role-in-illicit-fentanyl-running-rampant-on-us-streets/ | title = China's Role in Illicit Fentanyl Running Rampant on US Streets | 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/ | archive-date=16 February 2023 | work = trone.house.gov | date = 8 January 2023 | access-date = 4 April 2023 }}</ref><ref>{{cite web | url = https://www.wilsoncenter.org/article/briefing-senate-foreign-relations-committee-countering-illicit-fentanyl-trafficking-hearing | title = Briefing on the Senate Foreign Relations Committee Countering Illicit Fentanyl Trafficking Hearing | archive-url = https://web.archive.org/web/20230405062732/https://www.wilsoncenter.org/article/briefing-senate-foreign-relations-committee-countering-illicit-fentanyl-trafficking-hearing | archive-date=5 April 2023 | work = Wilson Center | access-date = 4 April 2023 }}</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 since 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>
 
=== Brand names ===
Brand names include Sublimaze,<ref name="urlDrugs@FDA: FDA Approved Drug Products">{{cite web |title=Fentanyl |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=fentanyl&SearchType=BasicSearch |url-status=live |access-date=4 September 2013 |archive-url=https://web.archive.org/web/20130313061008/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.SearchAction&SearchTerm=fentanyl&SearchType=BasicSearch |archive-date=13 March 2013}}</ref> Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,<ref>{{cite web |title=Introducing Onsolis |website=Onsolis.com |url=http://www.onsolis.com |url-status=live |access-date=28 July 2010 |archive-url=https://web.archive.org/web/20100722034245/http://www.onsolis.com/ |archive-date=22 July 2010}}</ref> Instanyl,<ref>{{cite report |title=Instanyl |publisher=[[European Medicines Agency]] |url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf |url-status=live |access-date=28 July 2010 |archive-url=https://web.archive.org/web/20120520054824/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000959/WC500033142.pdf |archive-date=20 May 2012}}</ref> Abstral,<ref>{{cite web |title=Abstral |url=http://newdrugreview.com/index.php/analgesic-drugs/abstral-fentanyl |url-status=dead |access-date=7 January 2011 |archive-url=https://web.archive.org/web/20110714180154/http://newdrugreview.com/index.php/analgesic-drugs/abstral-fentanyl|archive-date=14 July 2011}}</ref> Lazanda<ref>{{cite web |title=Lazanda (fentanyl nasal spray) CII |publisher=Lazanda.com |url=http://www.lazanda.com/ |url-status=live |access-date=14 May 2012 |archive-url=https://web.archive.org/web/20120425063819/http://www.lazanda.com/ |archive-date=25 April 2012}}</ref> and others.<ref name="urlFentanyl - Drugs.com">{{cite web |title=Fentanyl |website=Drugs.com |url=https://www.drugs.com/international/fentanyl.html |url-status=live |access-date=23 January 2018 |archive-url=https://web.archive.org/web/20180616103343/https://www.drugs.com/international/fentanyl.html |archive-date=16 June 2018}}</ref>
 
=== Economics ===
In the United States, the 800 mcg tablet was 6.75 times more expensive as of 2020 than the lozenge.<ref>{{cite web|title=Fentanyl Buccal|url=https://www.goodrx.com/fentanyl-buccal?dosage=800mcg&form=buccal-tablet&label_override=fentanyl+buccal&quantity=1|access-date=27 May 2020|archive-date=31 July 2020|archive-url=https://web.archive.org/web/20200731044214/https://www.goodrx.com/fentanyl-buccal?dosage=800mcg&form=buccal-tablet&label_override=fentanyl+buccal&quantity=1|url-status=live}}</ref><ref>{{cite web |title=Fentanyl Citrate Generic Actiq |url=https://www.goodrx.com/fentanyl-citrate?dosage=800mcg&form=lozenge&label_override=fentanyl+citrate&quantity=1 |website=GoodRx |access-date=27 May 2020 |archive-date=31 July 2020 |archive-url=https://web.archive.org/web/20200731065535/https://www.goodrx.com/fentanyl-citrate?dosage=800mcg&form=lozenge&label_override=fentanyl+citrate&quantity=1 |url-status=live }}</ref> As of 2023, the average cost for an injectable fentanyl solution (50&nbsp;mcg/mL) is around [[USD|US]]$17 for a supply of 20 milliliters, depending on the pharmacy.<ref>{{cite web |title=Fentanyl Prices, Coupons, Copay & Patient Assistance |url=https://www.drugs.com/price-guide/fentanyl |website=Drugs.com |access-date=26 January 2023 |archive-date=26 January 2023 |archive-url=https://web.archive.org/web/20230126185041/https://www.drugs.com/price-guide/fentanyl |url-status=live }}</ref> In a 2020 report by the [[Australian Institute of Criminology]], a 100-microgram transdermal patch was valued from between [[AUD|AU]]$75 and AU$450 on illicit markets.<ref>{{cite web |vauthors=Broadhurst R, Ball M, Trivedi H |title=Fentanyl availability on darknet markets |url=https://www.aic.gov.au/sites/default/files/2020-05/ti590_fentanyl_availability_on_darknet_markets.pdf |access-date=26 January 2023 |page=1 |date=February 2020 |archive-date=26 January 2023 |archive-url=https://web.archive.org/web/20230126185041/https://www.aic.gov.au/sites/default/files/2020-05/ti590_fentanyl_availability_on_darknet_markets.pdf |url-status=live }}</ref> Furthermore, in another 2020 study, the average price per gram of non-pharmaceutical fentanyl on various [[cryptomarket]]s was US$1,470.40 for offerings of less than five grams; the average for offers over five grams was US$139.50. In addition, on [[Dream Market|DreamMarket]] furanfentanyl (Fu-F), the most common analog on said market, the average price per gram was US$243.10 for retail listings and US$26.50 per gram for wholesale listings.<ref>{{cite journal | vauthors = Lamy FR, Daniulaityte R, Barratt MJ, Lokala U, Sheth A, Carlson RG | title = Listed for sale: Analyzing data on fentanyl, fentanyl analogs and other novel synthetic opioids on one cryptomarket | journal = Drug and Alcohol Dependence | volume = 213 | pages = 108115 | date = June 2020 | pmid = 32585419 | pmc = 7736148 | doi = 10.1016/j.drugalcdep.2020.108115 }}</ref>
 
=== Storage and disposal ===
The fentanyl patch is one of a few medications that may be especially harmful, and in some cases fatal, with just one dose, if misused by a child.<ref>{{cite journal |author=Office of the Commissioner |date=26 January 2022 |title=Accidental Exposures to Fentanyl Patches Continue to Be Deadly to Children |url=https://www.fda.gov/consumers/consumer-updates/accidental-exposures-fentanyl-patches-continue-be-deadly-children |journal=FDA |access-date=12 April 2022 |archive-date=12 April 2022 |archive-url=https://web.archive.org/web/20220412190113/https://www.fda.gov/consumers/consumer-updates/accidental-exposures-fentanyl-patches-continue-be-deadly-children |url-status=live }}</ref><ref name="fda-disp">{{cite web|url=https://www.fda.gov/drugs/safe-disposal-medicines/disposal-unused-medicines-what-you-should-know|title=Disposal of Unused Medicines: What You Should Know|date=1 February 2019|publisher=U.S. [[Food and Drug Administration]] (FDA)|access-date=2 September 2019|archive-date=2 September 2019|archive-url=https://web.archive.org/web/20190902064935/https://www.fda.gov/drugs/safe-disposal-medicines/disposal-unused-medicines-what-you-should-know|url-status=live}}</ref> Experts have advised that any unused fentanyl patches be kept in a secure location out of children's sight and reach, such as a locked cabinet.
 
In [[British Columbia]], [[Canada]], where there are environmental concerns about toilet flushing or garbage disposal, [[pharmacists]] recommend that unused patches be sealed in a [[child-proof]] container that is then returned to a [[pharmacy]].<ref name="bcpharm">{{cite web|url=https://www.bcpharmacists.org/fentanyl-patches|title=Safe Disposal of Fentanyl Patches|date=2019|publisher=College of Pharmacists of British Columbia|access-date=2 September 2019|archive-date=2 September 2019|archive-url=https://web.archive.org/web/20190902144426/https://www.bcpharmacists.org/fentanyl-patches|url-status=live}}</ref> In the United States where patches cannot always be returned through a medication take-back program, [[Flush toilet|flushing]] is recommended for fentanyl patches, because it is the fastest and surest way to remove them from the home to prevent ingestion by children, pets or others not intended to use them.<ref name="fda-disp" /><ref name="fda-flush">{{cite web|url=https://www.fda.gov/drugs/disposal-unused-medicines-what-you-should-know/drug-disposal-flush-potentially-dangerous-medicine#FlushList|title=Drug Disposal: Flush Potentially Dangerous Medicine (Flush list)|date=19 December 2018|publisher=U.S. [[Food and Drug Administration]] (FDA)|access-date=2 September 2019|archive-date=4 September 2019|archive-url=https://web.archive.org/web/20190904234712/https://www.fda.gov/drugs/disposal-unused-medicines-what-you-should-know/drug-disposal-flush-potentially-dangerous-medicine#FlushList|url-status=live}}</ref>
 
=== Notable deaths ===
* On 25 September 2003, American [[professional wrestling|professional wrestler]] [[Anthony Durante]], also known as "Pitbull #2", died from a fentanyl-induced overdose.<ref>{{cite book | vauthors = Williams SE |date=1 March 2006 |title=Hardcore History: The Extremely Unauthorized Story of ECW |url=https://books.google.com/books?id=kiMCOJKZtvAC&pg=PT252 |publisher=[[Skyhorse Publishing|Sports Publishing]] |page=211 |isbn=978-1-59670-021-5}}</ref>
* On 24 May 2009, [[Wilco]] guitarist [[Jay Bennett]] died from an accidental overdose of fentanyl.<ref>{{cite news |url= http://www.memphisflyer.com/SingAllKinds/archives/2009/05/14/is-wilcos-jeff-tweedy-living-the-life-he-sings-about|title= Is Wilco's Jeff Tweedy Living the Life He Sings About? |date= 14 May 2009 | vauthors = Lisle A |publisher= Memphis Flyer |access-date= 24 May 2009}}</ref><ref>{{cite news|url=http://www.chicagobreakingnews.com/2009/06/coroner-painkiller-killed-ex-wilco-member.html |title=Coroner: Painkiller killed ex-Wilco member |date=23 June 2009 | vauthors = Kot G |author-link=Greg Kot |newspaper=[[Chicago Tribune]] |access-date=23 June 2009 |url-status=dead |archive-url=https://web.archive.org/web/20090625053327/http://www.chicagobreakingnews.com/2009/06/coroner-painkiller-killed-ex-wilco-member.html |archive-date=25 June 2009 }}</ref><ref>{{cite web | work = [[NME]] | url = https://www.nme.com/news/wilco/45547 | title = Ex-Wilco guitarist died of a drug overdose, says coroner: Jay Bennett had been taking pain medication | archive-url = https://web.archive.org/web/20160303201517/http://www.nme.com/news/wilco/45547 | archive-date=3 March 2016 }}</ref>
* On 24 May 2010, [[Slipknot (band)|Slipknot]] bassist [[Paul Gray (American musician)|Paul Gray]] died from an overdose of morphine and fentanyl.<ref>{{cite news| vauthors = Crumb MJ |title= Slipknot bassist died of an overdose of morphine|agency=Associated Press|publisher=MSNBC|date=21 June 2010|url=http://today.msnbc.msn.com/id/37836072/ns/today-entertainment/|archive-url=https://web.archive.org/web/20100624024552/http://today.msnbc.msn.com/id/37836072/ns/today-entertainment/|url-status=dead|archive-date=24 June 2010|access-date=21 June 2010}}</ref>
* On 21 April 2016, musician [[Prince (musician)|Prince]] died and medical examiners concluded he had accidentally overdosed on fentanyl.<ref name="NYTprince" /> Fentanyl was among many substances identified in counterfeit pills recovered from his home, including some that were mislabeled as Watson 385, a combination of [[Hydrocodone/paracetamol|hydrocodone and paracetamol]].<ref name="NYTprince">{{cite news | vauthors = Eligon J, Kovaleski SF |date=2 June 2016 |title=Prince died from accidental overdose of opioid painkiller |newspaper=[[The New York Times]] |url=https://www.nytimes.com/2016/06/03/arts/music/prince-death-overdose-fentanyl.html |access-date=1 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20170805222747/https://www.nytimes.com/2016/06/03/arts/music/prince-death-overdose-fentanyl.html |archive-date=5 August 2017 }}</ref><ref>{{cite web |title=Official: Mislabeled pills found at Prince's estate contained fentanyl |newspaper=[[Chicago Tribune]] |date=22 August 2016 |url=http://www.chicagotribune.com/entertainment/ct-prince-death-investigation-20160821-story.html|access-date=22 August 2016 |url-status=live |archive-url=https://web.archive.org/web/20160822053540/http://www.chicagotribune.com/entertainment/ct-prince-death-investigation-20160821-story.html |archive-date=22 August 2016 }}</ref>
* On 21 April 2016, American author and journalist [[Michelle McNamara]] died from an accidental overdose; medical examiners determined fentanyl was a contributing factor.<ref>{{cite news |vauthors=Mizoguchi K |date=3 February 2017 |title=Patton Oswalt reveals wife died due to prescription medications and undiagnosed heart condition |magazine=[[People (magazine)|People]] |url=http://people.com/celebrity/patton-oswalt-wife-cause-of-death/ |access-date=5 November 2017 |archive-date=11 April 2018 |archive-url=https://web.archive.org/web/20180411161423/http://people.com/celebrity/patton-oswalt-wife-cause-of-death/ |url-status=live }}</ref><ref name=APNews-CauseOfDeath-2017>{{cite news |vauthors=McCartney A |date=3 February 2017 |title=Oswalt says heart condition, meds killed wife |publisher=[[Associated Press]] |url=https://apnews.com/cb50f829c93348e2adf9c2b71cc112d3 |access-date=30 April 2018 |archive-date=30 April 2018 |archive-url=https://web.archive.org/web/20180430114344/https://apnews.com/cb50f829c93348e2adf9c2b71cc112d3 |url-status=live }}</ref>
* On 11 November 2016, Canadian video game composer [[Saki Kaskas]] died of a fentanyl overdose;<ref name="vancouriersaki"/> he had been battling heroin addiction for over a decade.<ref name="vancouriersaki">{{cite news |vauthors=Kurucz J |date=18 June 2019 |title=Completing Vancouver musician's album cathartic for those he left behind |newspaper=[[Vancouver Courier]] |url=https://www.vancourier.com/news/completing-vancouver-musician-s-album-cathartic-for-those-he-left-behind-1.23859396 |access-date=21 January 2020 |archive-date=21 October 2020 |archive-url=https://web.archive.org/web/20201021004640/https://www.vancourier.com/news/completing-vancouver-musician-s-album-cathartic-for-those-he-left-behind-1.23859396 |url-status=live }}</ref>
* On 15 November 2017, American rapper [[Lil Peep]] died of an accidental fentanyl overdose.<ref>{{cite news |title=Toxic combo of prescription drugs killed rapper |date=8 December 2017 |newspaper=[[The New York Times]] |url=https://nytimes.com/aponline/2017/12/08/us/ap-us-lil-peep-cause-of-death.html |access-date=9 December 2017 |url-status=dead |archive-url=https://web.archive.org/web/20171210015603/https://www.nytimes.com/aponline/2017/12/08/us/ap-us-lil-peep-cause-of-death.html |archive-date=10 December 2017}}</ref><ref>{{cite news | vauthors = Brown A |date=16 November 2017 |title=Lil Peep, hero to the emo and hip-hop scenes, dies of suspected overdose at 21 |newspaper=[[Los Angeles Times]] |url=http://www.latimes.com/entertainment/music/la-et-ms-lil-peep-obituary-20171116-story.html |access-date=16 November 2017 |url-status=live |archive-url=https://web.archive.org/web/20171118080606/http://www.latimes.com/entertainment/music/la-et-ms-lil-peep-obituary-20171116-story.html |archive-date=18 November 2017 }}</ref>
* On 19 January 2018, the [[Los Angeles County Department of Medical Examiner]] said musician [[Tom Petty]] died from an accidental drug overdose as a result of mixing medications that included fentanyl, acetyl fentanyl, and despropionyl fentanyl (among others). He was reportedly treating "many serious ailments" that included a broken hip.<ref>{{cite news|url=https://www.nytimes.com/2018/01/19/arts/music/tom-petty-cause-death-opioid-overdose.html|title=Tom Petty Died From Accidental Drug Overdose Involving Opioids, Coroner Says | vauthors = Coscarelli J |date=2018 |newspaper=[[The New York Times]] |access-date=20 January 2018|issn=0362-4331|archive-url=https://web.archive.org/web/20180120025725/https://www.nytimes.com/2018/01/19/arts/music/tom-petty-cause-death-opioid-overdose.html|archive-date=20 January 2018|url-status=live}}</ref>
* On 7 September 2018, American rapper [[Mac Miller]] died from an accidental overdose of fentanyl, cocaine and alcohol.<ref name=cause>{{cite news |title=Mac Miller's cause of death: Accidental Fentanyl, cocaine overdose |date=5 November 2018 |magazine=[[Rolling Stone]] |url=https://www.rollingstone.com/music/music-news/mac-miller-cause-of-death-fentanyl-cocaine-alcohol-751974/ |access-date=5 November 2018 |archive-date=5 November 2018 |archive-url=https://web.archive.org/web/20181105202930/https://www.rollingstone.com/music/music-news/mac-miller-cause-of-death-fentanyl-cocaine-alcohol-751974/ |url-status=live }}</ref>
* On 16 December 2018, American tech entrepreneur [[Colin Kroll]], founder of social media video-sharing app [[Vine (service)|Vine]] and quiz app [[HQ (video game)|HQ Trivia]], died from an overdose of fentanyl, heroin, and cocaine.<ref>{{cite news | vauthors = Paybarah A |date=3 October 2019 |title='Mike's candyshop': Behind the overdose death of HQ Trivia's Colin Kroll |newspaper=[[The New York Times]] |url=https://www.nytimes.com/2019/10/03/nyregion/colin-kroll-hq-trivia-overdose.html |archive-url=https://web.archive.org/web/20191003172004/https://www.nytimes.com/2019/10/03/nyregion/colin-kroll-hq-trivia-overdose.html |archive-date=3 October 2019 |url-access=subscription |url-status=live|access-date=29 April 2021|issn=0362-4331}}</ref>
* On 1 July 2019, American baseball player [[Tyler Skaggs]] died from [[pulmonary aspiration]] while under the influence of fentanyl, [[oxycodone]], and alcohol.<ref>{{cite web|url=https://www.latimes.com/sports/angels/story/2019-08-30/tyler-skaggs-autopsy-report-fentanyl-oxycodone-alcohol-angels-rusty-hardin|title=Tyler Skaggs' autopsy: Fentanyl, oxycodone and alcohol led to death by choking on vomit|date=30 August 2019|work=Los Angeles Times|access-date=30 August 2019|archive-date=30 August 2019|archive-url=https://web.archive.org/web/20190830194259/https://www.latimes.com/sports/angels/story/2019-08-30/tyler-skaggs-autopsy-report-fentanyl-oxycodone-alcohol-angels-rusty-hardin|url-status=live}}</ref>
* On 1 January 2020, American rapper, singer, and songwriter [[Lexii Alijai]] died from accidental toxicity resulting from the combination of alcohol and fentanyl.<ref>{{cite web|title=Accidental overdose killed St. Paul rapper Lexii Alijai|url=https://www.mprnews.org/story/2020/01/28/autopsy-st-paul-rapper-lexii-alijai-died-of-accidental-overdose|access-date=26 June 2021|publisher=MPR News|date=28 January 2020 |archive-date=26 June 2021|archive-url=https://web.archive.org/web/20210626123846/https://www.mprnews.org/story/2020/01/28/autopsy-st-paul-rapper-lexii-alijai-died-of-accidental-overdose|url-status=live}}</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>
* On 24 August 2020, [[Riley Gale]], frontman for the Texas metal band [[Power Trip (band)|Power Trip]], died as a result of the toxic effects of fentanyl in a manner that was ruled accidental.<ref>{{cite magazine | url=https://www.rollingstone.com/music/music-news/riley-gale-power-trip-singer-dead-obit-1049964/ | title=Riley Gale, Singer for Thrash Metal Band Power Trip, Dead at 34 | magazine=[[Rolling Stone]] | date=25 May 2021 | access-date=19 May 2022 | archive-date=8 November 2021 | archive-url=https://web.archive.org/web/20211108082912/https://www.rollingstone.com/music/music-news/riley-gale-power-trip-singer-dead-obit-1049964/ | url-status=live }}</ref>
* On 2 March 2021, American musician [[Mark Goffeney]], also known as "Big Toe" (because being born [[Amelia (birth defect)|without arms]], he played [[guitar]] with his feet), died from an overdose of fentanyl.<ref>{{cite web | vauthors = Goffeney A |title=Statement from a family member. |url=http://bigtoerocks.com/ |publisher=Big Toe Rocks |access-date=18 August 2021}}</ref><ref>{{cite web | vauthors = Raferty M |date=14 March 2021 |title=PASSAGES: MARK GOFFENEY, 'BIG TOE' MUSICIAN WITHOUT ARMS |url=https://www.eastcountymagazine.org/passages-mark-goffeney-%E2%80%9Cbig-toe%E2%80%9D-musician-without-arms |archive-url=https://web.archive.org/web/20230218221919/https://www.eastcountymagazine.org/passages-mark-goffeney-%E2%80%9Cbig-toe%E2%80%9D-musician-without-arms |archive-date=18 February 2023 |access-date=18 February 2023 |magazine=East County Magazine}}</ref>
* On 22 April 2021, [[Digital Underground]] frontman, rapper, and musician [[Shock G]] died from an accidental overdose of fentanyl, meth, and alcohol.<ref>{{cite magazine|vauthors=Atkinson K|url=https://www.billboard.com/music/rb-hip-hop/digital-underground-shock-g-cause-of-death-9585758/|title=Digital Underground's Shock G Cause of Death Revealed|date=10 June 2021|magazine=Billboard|access-date=16 July 2022|archive-date=31 August 2022|archive-url=https://web.archive.org/web/20220831130806/https://www.billboard.com/music/rb-hip-hop/digital-underground-shock-g-cause-of-death-9585758/|url-status=live}}</ref>
* On 6 September 2021, actor [[Michael K. Williams]], who performed as [[Omar Little]] on the [[HBO]] drama series ''[[The Wire]]'', died from an overdose of fentanyl, [[parafluorofentanyl]], heroin, and cocaine.<ref>{{cite web |vauthors=Moshtaghian A |date=24 September 2021 |title=Michael K. Williams' cause of death determined by medical examiner |url=https://www.cnn.com/2021/09/24/entertainment/michael-k-williams-cause-of-death/index.html |access-date=8 March 2022 |website=CNN |archive-date=17 March 2022 |archive-url=https://web.archive.org/web/20220317231733/https://www.cnn.com/2021/09/24/entertainment/michael-k-williams-cause-of-death/index.html |url-status=live }}</ref><ref>{{cite web|url=https://deadline.com/2021/09/michael-k-williams-cause-of-death-accidental-overdose-1234844098/|title=Michael K. Williams' Died From Accidental Overdose, New York Medical Examiner Says|work=Deadline Hollywood|vauthors=Cordero R, Hipes P|date=24 September 2021|access-date=24 September 2021|archive-date=24 September 2021|archive-url=https://web.archive.org/web/20210924194521/https://deadline.com/2021/09/michael-k-williams-cause-of-death-accidental-overdose-1234844098/|url-status=live}}</ref>
* On 28 September 2022, rapper [[Coolio]] (Artis Leon Ivey, Jr.) died from an accidental overdose of fentanyl, heroin, and methamphetamine.<ref>{{cite web |date=6 April 2023 |title=Coroner says rapper Coolio died at 59 from effects of several drugs |url=https://abc7.com/coolio-cause-of-death-gangtas-paradise-artis-leon-ivey-jr-drug-overdose/13095817/ |access-date=15 June 2023 |website=ABC7 Los Angeles |archive-date=26 April 2023 |archive-url=https://web.archive.org/web/20230426232513/https://abc7.com/coolio-cause-of-death-gangtas-paradise-artis-leon-ivey-jr-drug-overdose/13095817/ |url-status=live }}</ref>
* On 31 July 2023, [[Angus Cloud]], best known for his portrayal of [[List of Euphoria characters#Fezco|Fezco]] on the [[HBO]] drama series ''[[Euphoria (American TV series)|Euphoria]]'', died from an accidental overdose of methamphetamine, cocaine, fentanyl, and benzodiazepines.<ref>{{cite web |vauthors=Franklin M |date=21 September 2023 |title=Angus Cloud's Cause of Death Revealed: Actor Overdosed on Fentanyl, Cocaine and More |url=https://variety.com/2023/tv/news/angus-cloud-cause-of-death-overdose-drugs-1235684153/ |access-date=25 September 2023 |website=Variety |archive-date=21 September 2023 |archive-url=https://web.archive.org/web/20230921173635/https://variety.com/2023/tv/news/angus-cloud-cause-of-death-overdose-drugs-1235684153/ |url-status=live }}</ref>
* On 15 September 2023, [[Fentanyl daycare incident|an infant died at a daycare center]] in The Bronx, New York City, due to fentanyl contamination, which is also believed to have caused sickness in other children.<ref name=":1">{{cite news |date=19 September 2023 |title=US child dies from fentanyl kept under nursery nap mat |work=BBC News |url=https://www.bbc.com/news/world-us-canada-66861588 |access-date=20 September 2023 |archive-date=20 September 2023 |archive-url=https://web.archive.org/web/20230920000740/https://www.bbc.com/news/world-us-canada-66861588 |url-status=live }}</ref>
* On 22 March 2024, Mark D'Wit was sentenced to a minimum of 37 years imprisonment for murdering Stephen and Carol Baxter in [[Essex]], England on 9 April 2023 by giving them drinks laced with fentanyl.<ref>{{cite news |url=https://www.theguardian.com/uk-news/2024/mar/22/fentanyl-poisoner-jailed-couple-murder-essex |title=Fentanyl poisoner jailed for at least 37 years for murder of couple in Essex |newspaper=[[The Guardian]] | vauthors = Rawlinson K |date=22 March 2024}}</ref>
 
=== Governmental usage ===
In August 2018, Nebraska became the first American state to use fentanyl to [[capital punishment|execute]] a prisoner.<ref name="BBC News_2018">{{cite news |title=Nebraska first to use fentanyl in execution |date=14 August 2018 |website=[[BBC News]] |url=https://www.bbc.com/news/world-us-canada-45185687 |access-date=15 August 2018 |archive-date=15 August 2018 |archive-url=https://web.archive.org/web/20180815025008/https://www.bbc.com/news/world-us-canada-45185687 |url-status=live }}</ref><ref>{{cite news |title=Nebraska becomes first state to use fentanyl in execution |date=14 August 2018 |website=[[NBC News]] |url=https://www.nbcnews.com/storyline/lethal-injection/nebraska-set-become-first-state-use-fentanyl-execution-n900576 |access-date=15 August 2018 |archive-date=14 August 2018 |archive-url=https://web.archive.org/web/20180814234427/https://www.nbcnews.com/storyline/lethal-injection/nebraska-set-become-first-state-use-fentanyl-execution-n900576 |url-status=live }}</ref><ref name="National Public Radio">{{cite news |title=Nebraska carries out 1st execution using Fentanyl in U.S. |website=[[National Public Radio]] |url=https://www.npr.org/2018/08/14/638250649/nebraska-prepares-to-carry-out-first-execution-using-fentanyl |access-date=15 August 2018 |archive-date=14 August 2018 |archive-url=https://web.archive.org/web/20180814235530/https://www.npr.org/2018/08/14/638250649/nebraska-prepares-to-carry-out-first-execution-using-fentanyl |url-status=live }}</ref> [[Execution of Carey Dean Moore|Carey Dean Moore]], at the time one of the longest-serving [[Capital punishment in the United States|death row]] [[Prisoner|inmates]] in the United States,<ref>{{cite news |title=Nebraska will make history in its execution of a death row inmate |date=14 August 2018 |magazine=[[Newsweek]] |url=https://www.newsweek.com/carey-dean-moore-nebraska-fentanyl-lethal-injection-death-row-execution-1071741 |access-date=15 August 2018 |archive-date=14 August 2018 |archive-url=https://web.archive.org/web/20180814232910/https://www.newsweek.com/carey-dean-moore-nebraska-fentanyl-lethal-injection-death-row-execution-1071741 |url-status=live }}</ref> was executed at the [[Nebraska State Penitentiary]]. Moore received a [[lethal injection]], administered as an [[Drug injection|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 besilate|cisatracurium besylate]] as a muscle relaxant, and [[Potassium chloride (medical use)|potassium chloride]] to stop the heart.<ref name="The New York Times_2018">{{cite news |title=Fentanyl used to execute Nebraska inmate, in a first for U.S. |date=14 August 2018 |newspaper=[[The New York Times]] |url=https://www.nytimes.com/2018/08/14/us/carey-dean-moore-nebraska-execution-fentanyl.html |url-access=subscription |url-status=live |access-date=15 August 2018 |archive-url=https://web.archive.org/web/20180814182425/https://www.nytimes.com/2018/08/14/us/carey-dean-moore-nebraska-execution-fentanyl.html |archive-date=14 August 2018}}</ref><ref name="Nebraska executes inmate using powerful opioid fentanyl_2018">{{cite news |title=Nebraska executes inmate using powerful opioid fentanyl |date=14 August 2018 |department=PBS NewsHour |publisher=[[Public Broadcasting System]] |url=https://www.pbs.org/newshour/nation/nebraska-executes-inmate-using-powerful-opioid-fentanyl |access-date=15 August 2018 |archive-date=15 August 2018 |archive-url=https://web.archive.org/web/20180815013302/https://www.pbs.org/newshour/nation/nebraska-executes-inmate-using-powerful-opioid-fentanyl |url-status=live }}</ref> The use of fentanyl in execution caused concern among death penalty experts because it was part of a previously untested [[Lethal injection#Drugs|drug cocktail]].<ref name="BBC News_2018"/><ref name="National Public Radio"/> The execution was also protested by [[Anti-Death Penalty Movement in the United States|anti-death penalty]] advocates at the prison during the execution and later at the [[Nebraska State Capitol]].<ref name="The New York Times_2018"/><ref name="Nebraska executes inmate using powerful opioid fentanyl_2018"/>
 
Russian [[Spetsnaz]] security forces are suspected to have used a fentanyl analogue, or derivative (suspected to be carfentanil and remifentanil),<ref>{{cite journal | vauthors = Riches JR, Read RW, Black RM, Cooper NJ, Timperley CM | title = Analysis of clothing and urine from Moscow theatre siege casualties reveals carfentanil and remifentanil use | journal = Journal of Analytical Toxicology | volume = 36 | issue = 9 | pages = 647–656 | date = 2012 | pmid = 23002178 | doi = 10.1093/jat/bks078 | doi-access = free | title-link = doi }}</ref> 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.<ref>{{cite news |date=27 October 2002 |title=Gas 'killed Moscow hostages' |url=http://news.bbc.co.uk/2/hi/europe/2365383.stm |access-date=7 April 2023 |archive-date=31 July 2017 |archive-url=https://web.archive.org/web/20170731010211/http://news.bbc.co.uk/2/hi/europe/2365383.stm |url-status=live }}</ref><ref name="gas">{{cite news |url=https://pqasb.pqarchiver.com/washingtonpost/access/224294031.html?dids=224294031:224294031&FMT=ABS&FMTS=ABS:FT&fmac=&date=Oct+28%2C+2002&author=Susan+B.+Glasser+and+Peter+Baker&desc=Gas+in+Raid+Killed+115+Hostages |title=115 Hostages in Moscow Killed by Gas |newspaper=The Washington Post |date=27 October 2002 |archive-url=https://web.archive.org/web/20070313010058/https://pqasb.pqarchiver.com/washingtonpost/access/224294031.html?dids=224294031:224294031&FMT=ABS&FMTS=ABS:FT&fmac=&date=Oct+28%2C+2002&author=Susan+B.+Glasser+and+Peter+Baker&desc=Gas+in+Raid+Killed+115+Hostages |archive-date=13 March 2007 }}</ref> The Russian Health Minister later stated that the gas was based on fentanyl,<ref>{{cite news |title=Russia names Moscow siege gas |date=31 October 2002 |publisher=[[BBC News]] |url=http://news.bbc.co.uk/2/hi/europe/2377563.stm |access-date=18 May 2018 |url-status=live |archive-url=https://web.archive.org/web/20180619064228/http://news.bbc.co.uk/2/hi/europe/2377563.stm |archive-date=19 June 2018 }}</ref> but the exact chemical agent has not been clearly identified.<ref>{{cite web | url=https://www.history.com/news/opioid-chemical-weapons-moscow-theater-hostage-crisis | title=How Opioids Were Used as Weapons During the Moscow Theater Hostage Crisis | date=5 October 2023 | access-date=15 November 2023 | archive-date=15 November 2023 | archive-url=https://web.archive.org/web/20231115230951/https://www.history.com/news/opioid-chemical-weapons-moscow-theater-hostage-crisis | url-status=live }}</ref>
 
=== Recalls ===
In February{{nbsp}}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{{nbsp}}II recalls was initiated in March{{nbsp}}2004, and in February{{nbsp}}2008, the [[ALZA Corporation]] recalled their 25{{nbsp}}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.<ref name="recall">{{cite web |title=Pricara recalls 25{{nbsp}}mcg/hr Duragesic (Fentanyl transdermal system) c{{nbsp}}II pain patches |date=12 February 2008 |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.fda.gov/oc/po/firmrecalls/pricara02_08.html |url-status=live |access-date=10 May 2008 |archive-url=https://web.archive.org/web/20080513124253/https://www.fda.gov/oc/po/firmrecalls/pricara02_08.html |archive-date=13 May 2008}}</ref> 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<ref>{{cite web | title = Teva Issues Voluntary Nationwide Recall of Specific Lots of FENTANYL Buccal Tablets CII to the Consumer Level | work = Teva Pharmaceuticals USA, Inc. | date = 27 April 2023 | url = https://www.tevausa.com/globalassets/us-files---global/fentanyl-citrate-recall-04-2023-_consumer-letter-27-apr-2023.pdf }}</ref> and stressed the importance of safety in the use and administration of opioid therapeutics.<ref>{{cite web |work=Office of Regulatory Affairs |date=28 April 2023 |title=Teva Initiates Voluntary Nationwide Recall of Specific Lots of FENTANYL Buccal Tablets CII Due to a Labeling Error |url=https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/teva-initiates-voluntary-nationwide-recall-specific-lots-fentanyl-buccal-tablets-cii-due-labeling |access-date=15 November 2023 |publisher=U.S. Food and Drug Administration |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115231609/https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/teva-initiates-voluntary-nationwide-recall-specific-lots-fentanyl-buccal-tablets-cii-due-labeling |url-status=live }}</ref><ref>{{cite web |title=Teva Initiates Voluntary Nationwide Recall of Specific Lots of FENTANYL Buccal Tablets CII Due to a Labeling Error |url=https://www.usatoday.com/recalls/food-and-drug/FDA-irhQWXH5y0Q/ |access-date=15 November 2023 |website=USA Today |archive-date=15 November 2023 |archive-url=https://web.archive.org/web/20231115231723/https://www.usatoday.com/recalls/food-and-drug/FDA-irhQWXH5y0Q/ |url-status=live }}</ref>
 
== Veterinary use ==
Fentanyl is commonly used for analgesia and as a component of balanced [[sedation]] and general [[Veterinary anesthesia|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]].<ref>{{cite journal | vauthors = Kukanich B, Clark TP | title = The history and pharmacology of fentanyl: relevance to a novel, long-acting transdermal fentanyl solution newly approved for use in dogs | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 35 | issue = Suppl 2 | pages = 3–19 | date = August 2012 | pmid = 22731771 | doi = 10.1111/j.1365-2885.2012.01416.x | doi-access = free | title-link = doi }}</ref><ref>{{cite journal | vauthors = Gutierrez-Blanco E, Victoria-Mora JM, Ibancovichi-Camarillo JA, Sauri-Arceo CH, Bolio-González ME, Acevedo-Arcique CM, Marin-Cano G, Steagall PV | title = Postoperative analgesic effects of either a constant rate infusion of fentanyl, lidocaine, ketamine, dexmedetomidine, or the combination lidocaine-ketamine-dexmedetomidine after ovariohysterectomy in dogs | journal = Veterinary Anaesthesia and Analgesia | volume = 42 | issue = 3 | pages = 309–318 | date = May 2015 | pmid = 25039918 | doi = 10.1111/vaa.12215 }}</ref><ref>{{cite journal | vauthors = Pettifer GR, Dyson DH | title = Comparison of medetomidine and fentanyl-droperidol in dogs: sedation, analgesia, arterial blood gases and lactate levels | journal = Canadian Journal of Veterinary Research | volume = 57 | issue = 2 | pages = 99–105 | date = April 1993 | pmid = 8490814 | pmc = 1263601 }}</ref> As with other pure-opioid agonists, fentanyl has been associated with [[dysphoria]] in dogs.<ref>{{cite journal | vauthors = Becker WM, Mama KR, Rao S, Palmer RH, Egger EL | title = Prevalence of dysphoria after fentanyl in dogs undergoing stifle surgery | journal = Veterinary Surgery | volume = 42 | issue = 3 | pages = 302–307 | date = April 2013 | pmid = 23231071 | doi = 10.1111/j.1532-950X.2012.01080.x }}</ref>
 
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.<ref>{{cite web | vauthors = Lee L | title = Perioperative Pain Management |url=https://www.westernu.edu/mediafiles/veterinary/vet-anesthesia-analgesia/perioperative-pain-management.pdf |access-date=19 January 2023 |archive-url=https://web.archive.org/web/20230119044903/https://www.westernu.edu/mediafiles/veterinary/vet-anesthesia-analgesia/perioperative-pain-management.pdf |archive-date=19 January 2023 |page=11 |url-status=live}}</ref> This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012, a highly concentrated (50{{nbsp}}mg/mL) [[transdermal]] solution, brand name Recuvyra, has become commercially available for dogs only. It is approved by the [[Food and Drug Administration]] to provide four days of analgesia after a single application before surgery. It is not approved for multiple doses or other species.<ref>{{cite web |title=Original new animal drug application: Recuvyra |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM314828.pdf |access-date=22 September 2014 |url-status=live |archive-url=https://web.archive.org/web/20150904122554/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/UCM314828.pdf |archive-date=4 September 2015}}</ref> The drug is also approved in Europe.<ref>{{cite web |title=Recuvyra |publisher=European Medicines Agency |url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/veterinary/medicines/002239/vet_med_000245.jsp&mid=WC0b01ac058008d7a |access-date=28 March 2016 |url-status=live |archive-url=https://web.archive.org/web/20160304193130/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fveterinary%2Fmedicines%2F002239%2Fvet_med_000245.jsp&mid=WC0b01ac058008d7a8 |archive-date=4 March 2016 }}</ref>
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin}}
* {{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 = PMID 32321735 | s2cid = 216084895 | doi-access = free | title-link = doi }}
{{refend}}
 
== External links ==
{{Spoken Wikipedia|Fentanyl.ogg|date=1 December 2011}}
{{Commons category}}
* {{cite report | title = Fentanyl |date = 8 July 2021 |publisher = [[National Institute for Occupational Safety and Health]] (NIOSH) |url = https://www.cdc.gov/niosh/ershdb/EmergencyResponseCard_29750022.html }}
 
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{{Analgesics}}
{{Opioid receptor modulators}}
{{Xenobiotic-sensing receptor modulators}}
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