View source for Fentanyl

{{Short description|Opioid medication}}
{{Hatnote group|
{{Redirect|Fent}}
{{Confuse|Femtanyl}}
}}
{{Globalize|1=article|2=United States|date=February 2025}}
{{Use American English|date=July 2021}}
{{Use dmy dates|date=February 2026}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| image = Fentanyl.svg
|image_class=skin-invert-image
| alt = 
| image2 = Fentanyl-xtal-3D-balls.png
| image_class2 = bg-transparent
| alt2 = 

<!-- Clinical data -->
| pronounce = [[Help:IPA/English|/ˈfɛntəˌnɪl/]]
| tradename = 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>
| 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
| 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 = [[Controlled Substances Act#Schedule II|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 = SE: Förteckning II<ref>{{Cite web|url=https://fass.se/product/20070609000057|title=Fentanyl Sandoz (Depotplåster 12 mikrog/timme) • Översikt &#124; FASS Patient|website=fass.se}}</ref>

<!-- Pharmacokinetic data -->
| bioavailability = *[[Transdermal]]: 90–92%<ref name="Transdermal Bio">{{cite journal | vauthors = Taylor KP, Singh K, Goyal A | title = Fentanyl Transdermal | journal = StatPearls | location = [[Saint James School of Medicine]] & [[University of Kansas Medical Center]] | date = 6 July 2023 | pmid = 32310428 | url = https://www.ncbi.nlm.nih.gov/books/NBK555968/ | access-date = 12 July 2025 | publisher = StatPearls Publishing }}</ref><ref name="Varvel_1989">{{cite journal | title = Absorption Characteristics of Transdermally Administered Fentanyl | journal = Anesthesiology | volume = 70 | issue = 6 | pages = 928–934 | date = 1 June 1989 | pmid = 2729633 | doi = 10.1097/00000542-198906000-00008 | vauthors = Varvel JR, Shafer SL, Hwang SS, Coen PA, Stanski DR }}</ref>
* [[Intranasal]]: 89%<ref name="Intranasal Bio">{{cite journal | vauthors = Nakhaee S, Saeedi F, Mehrpour O | title = Clinical and pharmacokinetics overview of intranasal administration of fentanyl | journal = Heliyon | volume = 9 | issue = 12 | article-number = e23083 | date = December 2023 | pmid = 38144320 | pmc = 10746457 | doi = 10.1016/j.heliyon.2023.e23083 | bibcode = 2023Heliy...923083N | doi-access = free | issn = 2405-8440 }}</ref>
* [[Buccal administration|Buccal]]: 51% (tablets), 71% (film)<ref name="Buccal & Oral Bio">{{cite journal | vauthors = Vasisht N, Gever LN, Tagarro I, Finn AL | title = Single-Dose Pharmacokinetics of Fentanyl Buccal Soluble Film | journal = Pain Medicine | volume = 11 | issue = 7 | pages = 1017–1023 | date = July 2010 | pmid = 20492573 | pmc = 2955962 | doi = 10.1111/j.1526-4637.2010.00875.x }}</ref>
* [[Sublingual]]: 54% (Abstral tablets), 76% (spray)<ref name="Sublingual tablet Bio">{{cite journal | vauthors = Beng Stephen Lim C, Schug SA, Bruce Sunderland V, James Paech M, Liu Y | title = A Phase I Pharmacokinetic and Bioavailability Study of a Sublingual Fentanyl Wafer in Healthy Volunteers | journal = Anesthesia and Analgesia | volume = 115 | issue = 3 | pages = 554–559 | date = September 2012 | pmid = 22584544 | doi = 10.1213/ANE.0b013e3182575cbf }}</ref><ref name="Sublingual Spray Bio">{{cite journal | vauthors = Taylor D | title = Single-dose fentanyl sublingual spray for breakthrough cancer pain | journal = Clinical Pharmacology: Advances and Applications | volume = 5 | pages = 131–141 | date = July 2013 | pmid = 23901300 | pmc = 3726301 | doi = 10.2147/CPAA.S26649 | doi-access = free }}</ref>
* [[Oral administration|Oral]]: 35%<ref name="Buccal & Oral Bio" />
* [[Inhalation]]: 56–96% <ref name="Inhalation Bio">{{cite journal | vauthors = Mather LE, Woodhouse A, Ward ME, Farr SJ, Rubsamen RA, Eltherington LG | title = Pulmonary administration of aerosolized fentanyl: pharmacokinetic analysis of systemic delivery | journal = British Journal of Clinical Pharmacology | volume = 46 | issue = 1 | pages = 37–43 | date = July 1998 | pmid = 9690947 | pmc = 1873979 | doi = 10.1046/j.1365-2125.1998.00035.x }}</ref>
* [[Intramuscular|IM]] & [[Intravenous|IV]]: 100%<ref name="Transdermal Bio" /><ref name="IM & IV dosing">{{cite web | title = Fentanyl Citrate Injection, USP | date = November 2012 | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/016619s034lbl.pdf | website = FDA.gov | publisher = Food and Drug Administration | access-date = 12 July 2025 | 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>
| 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]]
* [[Norfentanyl]]
* [[4-ANPP|Despropionylfentanyl]] (minor)
* Hydroxyfentanyl (minor)
* Hydroxynorfentanyl (minor secondary metabolite)
| 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 (T<sub>1/2</sub> α)<br /> 1{{nbsp}}hours (T<sub>1/2</sub> β)<br /> 16{{nbsp}}hours (T<sub>1/2</sub> ɣ){{citation needed|date=February 2025}}<br />Intranasal: 15–25{{nbsp}}hours<ref name=AHFS2017/><br />Transdermal: 20–27{{nbsp}}hours<ref name=AHFS2017/><br />Sublingual: 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 = 437-38-7
| PubChem = 3345
| IUPHAR_ligand = 1626
| DrugBank = DB00813
| ChemSpiderID = 3228
| UNII = UF599785JZ
| KEGG = D00320
| ChEBI = 119915
| PDB_ligand = 7V7
| ChEMBL = 596

<!-- Chemical data -->
| IUPAC_name = ''N''-phenyl-''N''-[1-(2-phenylethyl)piperidin-4-yl]propanamide
| C = 22
| H = 28
| N = 2
| O = 1
| smiles = O=C(CC)N(C1CCN(CC1)CCc2ccccc2)c3ccccc3
| 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 = PJMPHNIQZUBGLI-UHFFFAOYSA-N
| density = 1.1
| melting_point = 87.5
}}

<!-- Definition and medical uses -->
'''Fentanyl''' is a highly potent synthetic [[opioid]] of the [[piperidine]] family, used primarily as [[analgesic|pain medication]]. It is 50 to 100 times more potent than [[morphine]]. Its primary clinical use is in pain management for cancer patients and those recovering from surgery.<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]] for [[intubated]] patients.<ref name="Ramos-Matos_2022">{{cite book |vauthors=Ramos-Matos CF, Bistas KG, Lopez-Ojeda W |chapter=Fentanyl |date=2022 |chapter-url=https://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> Fentanyl has a short duration of action. 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> Brand names include '''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 }}</ref>

<!-- History and medical use -->
Fentanyl was first synthesized by [[Paul Janssen]] in 1960 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 |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="WHO24th">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list | year = 2025 | hdl = 10665/382243 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | hdl-access = free | doi = 10.2471/B09474 | doi-access = free | id = License: CC BY-NC-SA 3.0 IGO }}</ref>

<!--Noted effects and mechanism -->
The effects of fentanyl are similar to those of other opioids, causing sedation and analgesia at clinical doses. The most common adverse effects are [[respiratory depression]], [[emesis]], and [[asthenia]]. [[Bradycardia]] and [[apnea]] are uncommon side effects but are serious and can lead to death outside of clinical settings. Fentanyl exerts its actions as an agonist of the [[μ-opioid receptor]] and [[κ-opioid receptor]]. The μ-receptor agonism is responsible for the respiratory depression and generalized analgesia whilst the κ-receptor agonism is responsible for sedation and spinal analgesia. Fentanyl is a potent μ-receptor agonist but has less [[binding affinity|affinity]] for the κ-receptor.

<!-- Illegal use -->
Fentanyl is contributing to an [[opioid epidemic in the United States|epidemic of synthetic opioid drug overdose deaths in the United States]]. From 2011 to 2021, overdose deaths involving prescription opioid (natural and semi-synthetic opioids and [[methadone]]) per year remained stable, while synthetic opioid (primarily fentanyl) associated overdose deaths per year increased from 2,600 [[Drug overdose|overdoses]] to 70,601.<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 }}</ref> Fentanyl was involved in the most drug overdose deaths in the United States in 2018.<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> [[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" /> Emerging [[adulterant]]s have further complicated the evolving fentanyl supply.

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 |archive-date=11 December 2023 |archive-url=https://web.archive.org/web/20231211153641/https://drugsdata.org/ |url-status=live }}</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 |archive-date=1 August 2022 |archive-url=https://web.archive.org/web/20220801071523/https://dancesafe.org/drug-checking/ |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 | publisher = McGraw-Hill Education |oclc=993810322}}</ref> To induce anesthesia, it is given with a [[sedative]] like [[propofol]] or [[thiopental]].<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| 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, using fentanyl 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 |publisher=Springer |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 |url-access=subscription }}</ref>

=== Obstetrics ===
Fentanyl is sometimes given intrathecally as part of [[spinal anaesthesia|spinal anesthesia]] or epidurally for [[epidural anesthesia]] 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 [[neonatal withdrawal]].<ref name="Moisés_2005" /> For this reason, shorter-acting agents such as [[alfentanil]] or [[remifentanil]] may be more suitable in the context of inducing general anesthesia.<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}}[[Microgram|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, or 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 | article-number = 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 |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 | article-number = CD011605 | date = October 2016 | pmid = 27727431 | pmc = 6457928 | doi = 10.1002/14651858.CD011605.pub2 }}</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 | article-number = 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 | article-number = 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 ====
[[File:Fentanylové lízatko.jpg|thumb|Fentanyl lollipops Actiq 200 mcg]]

[[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/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 [[Shortness of breath|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 | article-number = 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: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]], [[apnea]], 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 |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 serious adverse effect of fentanyl is respiratory depression, although it is rare in clinical settings.<ref name="saudi">{{cite journal | vauthors = Topacoglu H, Karcioglu O, Cimrin AH, Arnold J | date = Nov 2005 | title = Respiratory arrest after low-dose fentanyl | journal = Annals of Saudi Medicine | volume = 25 | issue = 6 | pages = 508–510 | doi = 10.5144/0256-4947.2005.508 | pmc = 6089740 | pmid = 16438465 }}</ref> Respiratory depression entails decreased sensitivity to carbon dioxide, leading to a reduced rate of breathing which, if untreated and severe, can cause anoxic brain injury or death. Fentanyl stimulates MORs (mu-opioid receptors) in the preBötzinger Complex located in the ventrolateral medulla of the brainstem, which can depress ventilation.<ref name=":0">{{cite journal | vauthors = Palkovic B, Marchenko V, Zuperku EJ, Stuth EA, Stucke AG | date = November 2020 | title = Multi-Level Regulation of Opioid-Induced Respiratory Depression | journal = Physiology | volume = 35 | issue = 6 | pages = 391–404 | doi = 10.1152/physiol.00015.2020 | pmc = 7864237 | pmid = 33052772 }}</ref> A study found that 100 µg/kg fentanyl given to rats, which in proportion to a dose in humans is 5 µg/kg, resulted in an EEG recording showing higher theta power levels, which significantly correlates to the slowing of respiratory rate.<ref name=":0" /><ref>{{cite journal | vauthors = Montandon G, Qin W, Liu H, Ren J, Greer JJ, Horner RL | date = January 2011 | title = PreBotzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression | journal = The Journal of Neuroscience | volume = 31 | issue = 4 | pages = 1292–1301 | doi = 10.1523/JNEUROSCI.4611-10.2011 | pmc = 6623620 | pmid = 21273414 }}</ref> This risk is decreased when the airway is secured with an [[endotracheal tube]], as during anesthesia.<ref name="Hemmings_2018" /> The 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 include:<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 |page = 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, primarily by 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-date=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" />

== Overdose ==
{{Further|Opioid overdose|U.S. drug overdose death rates and totals over time}}
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 0.007{{nbsp}}μg/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.<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, synthetic opioids (including fentanyl) were detected in 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> 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 according to the DEA]]
Fentanyl has started to be mixed into 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/article/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 name="dea-2020" /> 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 |url-access=subscription |archive-date=19 January 2022 |access-date=4 November 2024 |archive-url=https://web.archive.org/web/20220119171631/https://link.springer.com/article/10.1007/s00044-012-0390-6 |url-status=live }}</ref> The safety margin{{efn|Ratio of LD<sub>50</sub> to ED<sub>50</sub>}} in rats is ~280. The LD<sub>50</sub> in humans is unknown.<ref name="auto">{{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>

In 2023, overdose deaths in the US and Canada reached record numbers.<ref name="mmwr-2024-12-05">{{cite journal | vauthors = Tanz LJ, Stewart A, Gladden RM, Ko JY, Owens L, O'Donnell J | title = Detection of Illegally Manufactured Fentanyls and Carfentanil in Drug Overdose Deaths – United States, 2021-2024 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 73 | issue = 48 | pages = 1099–1105 | date = December 2024 | pmid = 39636782 | doi = 10.15585/mmwr.mm7348a2 | pmc = 11620336 }}</ref> While overdoses involving fentanyl in the United States have decreased in 2024, the overall percentage of overdoses involving fentanyl has remained stable between 70% and 80% from 2021-2024.<ref name="mmwr-2024-12-05" /> According to a 2023 report from the [[United Nations Office on Drugs and Crime]] (UNODC), the increased numbers of deaths are not related to an increased number of users but to the lethal effects of fentanyl itself. In an article published by [[Los Alamos National Laboratory]], researchers state, "Because of the very high strength of pure fentanyl powder, it's hard to [[concentration|dilute]] precisely, so small inaccuracies in weight can cause huge variation between batches, and it's all too easy for someone to get too much."<ref>{{Cite web |vauthors=Hutterer E |title=Fighting Fentanyl Overdose and the Opioid Crisis {{!}} LANL |url=https://www.lanl.gov/media/publications/1663/1224-fighting-fentanyl-overdose |access-date=16 April 2025 |website=Eleanor Hutterer |date=24 December 2024 |language=en |archive-date=17 March 2025 |archive-url=https://web.archive.org/web/20250317222544/https://www.lanl.gov/media/publications/1663/1224-fighting-fentanyl-overdose |url-status=live }}</ref>
[[File:US timeline. Opioid deaths.jpg|thumb|Number of yearly U.S. [[opioid overdose]] deaths from all opioid drugs.]]
In a report published in [[JAMA Pediatrics]], 37.5% of all fatal pediatric opioid poisonings between 1999 and 2021 were related to fentanyl; most of the deaths were among adolescents (89.6%) (15–19 years) 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 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 | pmc = 10167597 | doi = 10.1001/jamapediatrics.2023.0793 | quote = Fentanyl was implicated in 5194 of 13 861 (37.5%) fatal pediatric opioid poisonings between 1999 and 2021. Most deaths were among adolescents aged 15 to 19 years (89.6%) and children aged 0 to 4 years (6.6%). For all ages, 43.8% of deaths occurred at home, and 87.5% were unintentional. Coingestion of benzodiazepines was implicated in 17.1% of deaths [.] }}</ref>{{medrs|date=January 2026|reason=Primary article, although it is simply an analysis of statistics}}

=== Prevention ===
[[File:Fentanyl_Test_Strip_Tutorial.webm|thumb|Fentanyl Test Strip Tutorial]]

Public health advisories to prevent fentanyl misuse and fatal overdose have been issued by the US [[Centers for Disease Control and Prevention]] (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]] (CDC) |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]] (CDC) |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 US. 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.
# 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>

== Pharmacology ==
{{See also|Opioid#Pharmacology}}

=== Classification ===
Fentanyl is a synthetic opioid in the [[phenylpiperidine]] family that has high [[protein binding]] and [[lipophilicity]].<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}}</ref><ref>{{cite book | vauthors = Katzung BG |year=2017 |title=Basic & Clinical Pharmacology |edition=14th |location=New York | publisher = McGraw-Hill |isbn=978-1-259-64115-2 |oclc=1015240036}}</ref>

=== Structure-activity ===
[[File:Fentanyl numbering.svg|class=skin-invert-image|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 | 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"/>

Fentanyl is a weak [[Base (chemistry)|base]] that is highly [[Lipophilicity|lipid-soluble]], [[Plasma protein binding|protein-bound]], and protonated at [[PH#pH of various body fluids|physiological pH]].<ref name="Hemmings_2018"/> All of these factors allow it to rapidly cross [[Cell membrane|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 methyl ester 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 | article-number = 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 | doi = 10.1016/S0026-895X(25)09932-8 | 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 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">{{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><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}}

The affinity of fentanyl to the μ-opioid receptor is similar to that of morphine. The reasons for fentanyl's increased potency ''in vivo'' are unclear, however differences in efficacy and pharmacokinetics may be involved.<ref>{{cite journal | vauthors = Kelly E, Sutcliffe K, Cavallo D, Ramos-Gonzalez N, Alhosan N, Henderson G | date = April 2023 | title = The anomalous pharmacology of fentanyl | journal = British Journal of Pharmacology | volume = 180 | issue = 7 | pages = 797–812 | doi = 10.1111/bph.15573 | pmid = 34030211 }}</ref> It has high lipid solubility, allowing it to penetrate more easily 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 | url-access = subscription }}</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 | publisher = McGraw-Hill Education |oclc=1039081701}}</ref>
* Supraspinal analgesia (μ<sub>1</sub>)
* [[Hypoventilation|Respiratory depression]] (μ<sub>2</sub>)
* Physical dependence
* [[Hypertonia|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 [[Blood plasma|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 | hdl = 10613/5492 | id = 10.25316/IR-4343 | hdl-access = free }}</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 should be diluted into {{tspUS|1}} 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 | article-number = 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 | article-number = 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-[[Aniline|anilino]]piperidine class synthetic opioid.<ref name="auto"/> 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|class=skin-invert-image|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|4-piperodone]]. The resulting benzylfentanyl is used as feedstock to [[norfentanyl]]. It is norfentanyl that forms fentanyl upon reaction with a phenethyl halide.<ref>{{Cite patent|number=US3141823A|title=Method for producing analgesia|gdate=1964-07-21|invent1=Janssen|invent2=Francis|inventor1-first=PA|inventor2-first=JG|url=https://patents.google.com/patent/US3141823A/en}} {{Webarchive|url=https://web.archive.org/web/20250609144112/https://patents.google.com/patent/US3141823A/en |date=9 June 2025 }}</ref><ref>{{cite web |date=18 June 2020 |title=Fentanyl Synthesis |url=https://gpatindia.com/fentanyl-synthesis-sar-mcqstructurechemical-properties-and-therapeutic-uses/ |website=GPTA India}}</ref>

=== Siegfried ===
[[File:NPP to fentanyl.svg|class=skin-invert-image|thumb|Siegfried method from NPP through 4-ANPP to fentanyl]]
The Siegfried method, initially described in 1978 and later published on [[The Hive (website)|The Hive]], involves the initial synthesis of [[N-phenethyl-4-piperidone|''N''-phenethyl-4-piperidone]] (NPP).<ref>{{cite journal | vauthors = Weedn VW, Elizabeth Zaney M, McCord B, Lurie I, Baker A | title = Fentanyl-related substance scheduling as an effective drug control strategy | journal = Journal of Forensic Sciences | volume = 66 | issue = 4 | pages = 1186–1200 | date = July 2021 | pmid = 33951192 | pmc = 8360110 | doi = 10.1111/1556-4029.14712 }}</ref> 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 was used in the early 2000s to illicitly manufacture fentanyl in the USA and other countries.<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|class=skin-invert-image|thumb|Gupta method from [[4-Piperidone|4-piperidone]] to fentanyl]]
The Gupta (or 'one-pot') method starts from [[4-Piperidone|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 PK, Ganesan K, Pande A, Malhotra RC |date=2005 |title=A convenient one pot synthesis of fentanyl |journal=Journal of Chemical Research |volume=2005 |issue=7 |pages=452–453 |doi=10.3184/030823405774309078 |doi-access=free|pmc= |pmid= }}</ref><ref>{{cite journal |vauthors=Gupta PK, Ganesan K, Pande A, Malhotra RC |date=9 November 2005 |title=A Convenient One-Pot Synthesis of Fentanyl |url=https://onlinelibrary.wiley.com/doi/abs/10.1002/chin.200549130 |access-date=24 January 2023 |journal=ChemInform |volume=36 |issue=49 |article-number=chin.200549130 |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 |url-access=subscription }}</ref> For the first half of 2021, the [[Drug Enforcement Administration|US 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=U.S. 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 with [[photoredox catalysis]] 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 = 70–72 | 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]] (Demerol) 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 | 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 | archive-date=10 July 2024 | archive-url=https://web.archive.org/web/20240710043815/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=90b94524-f913-48b3-3771-7b2fcffd888a | url-status=live }}</ref> Fentanyl citrate entered medical use as a general anesthetic 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 [[buccal administration|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}}</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 reduced from 2,300{{nbsp}}kg in 2015 and 2016 to 731{{nbsp}}kg in 2021, a 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 ===
Effective from May 2019, China officially classified all forms of fentanyl as controlled narcotics.<ref>{{Cite web |title= Fentanyl Flow to the United States | date = January 2020 | id = DEA-DCT-DIR-008-20 | work = DEA Intelligence Report | publisher = U.S. Drug Enforcement Division |url= https://www.dea.gov/sites/default/files/2020-03/DEA_GOV_DIR-008-20%20Fentanyl%20Flow%20in%20the%20United%20States_0.pdf |archive-url= https://web.archive.org/web/20250306072958/https://www.dea.gov/sites/default/files/2020-03/DEA_GOV_DIR-008-20%20Fentanyl%20Flow%20in%20the%20United%20States_0.pdf |archive-date= 6 March 2025 |access-date=10 March 2025 |url-status=live }}</ref>

In the UK, fentanyl is classified as a controlled Schedule II, 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 US, fentanyl is a Schedule II controlled substance per the [[Controlled Substances 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 }}</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 | 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 }}</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 name=lgc1>{{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> Some fentanyl precursors, such as the [[piperidone]]s (after October 2023) have been banned under its [[Precursor Control Regulations]],<ref name="ggc1">{{cite news |url=https://gazette.gc.ca/rp-pr/p1/2023/2023-10-28/html/notice-avis-eng.html |title=Canada Gazette, Part 1, Volume 157, Number 43: GOVERNMENT NOTICES |date=28 October 2023 |archive-date=14 May 2025 |access-date=23 May 2025 |archive-url=https://web.archive.org/web/20250514184024/https://gazette.gc.ca/rp-pr/p1/2023/2023-10-28/html/notice-avis-eng.html |url-status=live }}</ref> which have been in place at least since November 2016.<ref name="ggc2">{{cite news |url=https://gazette.gc.ca/rp-pr/p2/2016/2016-11-30/html/sor-dors294-eng.html |title=Canada Gazette – Regulations Amending the Precursor Control Regulations (Fentanyl Precursors) |date=30 November 2016 |archive-date=29 December 2024 |access-date=23 May 2025 |archive-url=https://web.archive.org/web/20241229235431/https://gazette.gc.ca/rp-pr/p2/2016/2016-11-30/html/sor-dors294-eng.html |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 US 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>

{{Anchor|Actiq}}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>

Another form of fentanyl that has appeared on the streets is the [[Lollipop#Medicinal use|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 in 2007, 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. As with 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; 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]]. Deaths were heavily concentrated in the cities of [[Dayton, Ohio|Dayton]], Ohio; [[Chicago, Illinois|Chicago]], Illinois; [[Detroit, Michigan|Detroit]], Michigan; and [[Philadelphia, Pennsylvania|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 = 793–796 | 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>

=== 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 |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>]]

The fentanyl supply chain in Mexico consists of a vast and elusive network, potentially involving hundreds of players. U.S. and Mexican anti-narcotics officials acknowledge that the exact number is unknown. Some brokers operate as specialists within major cartels, while others act independently. A major challenge in disrupting this trade lies in the global chemical industry. Many of the compounds used to manufacture fentanyl have legitimate industrial applications, classifying them as dual-use chemicals. These substances are often unregulated or only lightly controlled in key countries such as the United States, Mexico, and China. This regulatory gap enables brokers to evade detection, navigating between the legal chemical trade and the illicit drug market to acquire the necessary precursors.<ref>{{Cite web|url=https://www.reuters.com/investigates/special-report/drugs-fentanyl-brokers/|title=The shadowy 'brokers' helping Mexico's cartels smuggle fentanyl chemicals from China|website=[[Reuters]] |date=18 December 2024 }}</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|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|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 }}</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/article/lethal-fentanyl-profiting-gangs-in-western-canada-while-deaths-climb/ |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://www.ctvnews.ca/vancouver/article/2021-is-now-bcs-deadliest-year-in-the-opioid-crisis-with-2-months-of-data-left-to-collect/ |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 |author1=Knowyourstuffnz }}</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> Bilateral talks on fentanyl later resumed in [[APEC United States 2023|San Francisco in 2023]] when then [[President of the United States|U.S. President]] [[Joe Biden]] and [[General Secretary of the Chinese Communist Party|CCP General Secretary]] [[Xi Jinping]] met. In the past several months before February 2025, China also began scheduling fentanyl precursors that are internationally banned, aligning with efforts to restrict the flow of chemicals used in fentanyl production as well as the drug itself. These actions are intended to strengthen efforts to curb drug trafficking and disrupt the supply chain more effectively. In February 2025, US president Trump imposed a 10% [[Second Trump tariffs|tariff]] on Chinese imports, claiming the move as a way "to pressure China into taking action on fentanyl" but experts have expressed concern that these tariffs could reverse the progress made under the Biden administration and weaken the international cooperation necessary to combat global drug trafficking.<ref>{{Cite web |vauthors=Ortiz E |date=4 March 2025 |title=Trump says tariffs were enacted to curb fentanyl, but U.S. overdose deaths are already declining |url=https://www.nbcnewyork.com/news/national-international/trump-says-tariffs-to-curb-fentanyl-but-us-overdose-deaths-declining/6173140/?os=io....sxj9oul9no_journeys=true&ref=app |access-date=10 March 2025 |work=NBC New |location=New York |language=en-US |archive-date=11 July 2025 |archive-url=https://web.archive.org/web/20250711010612/https://www.nbcnewyork.com/news/national-international/trump-says-tariffs-to-curb-fentanyl-but-us-overdose-deaths-declining/6173140/?ref=app&os=io....sxj9oul9no_journeys%3Dtrue |url-status=live }}</ref><ref>{{Cite news | vauthors = Hawkins A |date=4 February 2025 |title=Is the China-US fentanyl pipeline really responsible for the US opioid crisis? |url=https://www.theguardian.com/society/2024/nov/26/is-the-china-us-fentanyl-pipeline-really-responsible-for-the-us-opioid-crisis |access-date=10 March 2025 |work=The Guardian |language=en-GB |issn=0261-3077}}</ref><ref>{{Cite news | vauthors = Green HH |date=8 March 2025 |title=Trump policies could fuel illicit drug trade despite vow to curb fentanyl |url=https://www.theguardian.com/us-news/2025/mar/08/trump-policies-drug-trade-fentanyl |access-date=10 March 2025 |work=The Guardian |language=en-GB |issn=0261-3077}}</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 the 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 prefer to make 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 | date = 24 February 2023 | access-date = 4 April 2023 }}</ref>

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. The guns are 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 | archive-date = 22 February 2024 | archive-url = https://web.archive.org/web/20240222174607/https://www.atf.gov/news/pr/convicted-felon-arrested-attempting-trade-fentanyl-four-firearms | url-status = live }}</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 | archive-date = 16 December 2023 | archive-url = https://web.archive.org/web/20231216003519/https://home.treasury.gov/news/press-releases/jy1523 | url-status = live }}</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 | archive-date = 16 December 2023 | archive-url = https://web.archive.org/web/20231216003519/https://www.cbsnews.com/news/mexican-drug-cartels-american-weapons-smuggled-across-border/ | url-status = live }}</ref>

The [[opioid epidemic in the United States]] is largely fueled by drugs smuggled from Mexico; approximately 98% of fentanyl entering the U.S. comes from Mexico.<ref>{{Cite web |vauthors=Devlin K, Ma Y |date=4 March 2025 |title=How does fentanyl get into the US? |url=https://www.bbc.com/news/articles/cvg93nn1e6go |access-date=4 March 2025 |website=[[BBC News]] |language=en-GB |archive-date=3 March 2025 |archive-url=https://web.archive.org/web/20250303201413/https://www.bbc.com/news/articles/cvg93nn1e6go |url-status=live }}</ref> In January 2025, President Trump said that [[2025 United States trade war with Canada and Mexico|tariffs on Mexico]] were intended to reduce the U.S. trade deficit and force the country to secure its border with the U.S. against fentanyl smuggling and [[illegal immigration into the United States|illegal immigration]].<ref>{{Cite news | vauthors = Kaye D |date=1 February 2025 |title=Here's What to Know About Trump's Tariffs |url=https://www.nytimes.com/2025/02/01/business/trump-tariffs-canada-mexico-china.html |url-status=live |archive-url=https://web.archive.org/web/20250203162720/https://www.nytimes.com/2025/02/01/business/trump-tariffs-canada-mexico-china.html |archive-date=3 February 2025 |access-date=2 February 2025 |work=[[The New York Times]] |language=en-US |issn=0362-4331}}</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=https://www.accessdata.fda.gov/scripts/cder/daf/ |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 |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 | article-number = 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 }}</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>

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, preventing 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}}</ref>

===State usage as weapon===
====US death penalty====
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]], then 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 theater siege====
Russian [[Spetsnaz]] security forces are [[Moscow hostage crisis chemical agent|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=https://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=https://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>

== Veterinary use ==
Fentanyl is commonly used for analgesia and as a component of balanced [[sedation]] and general [[Veterinary anesthesia|anesthesia]] in small animal patients.<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> The short-acting nature, wide safety profile, lower rate of adverse effect compared to other opioids, and high potency make fentanyl one of the most effective and common analgesics in veterinary medicine; the ability to reduce the [[minimum alveolar concentration]] leads to fentanyl being commonly used in dogs that are elderly or have cardiovascular issues.<ref name="saunders">{{cite book|pages=318–321|title=Saunders Handbook of Veterinary Drugs| vauthors = Papich M |publisher=Elsevier|date=2016|isbn=978-0-323-24485-5|edition=4th}}</ref><ref name="lamont"/><ref>{{cite book | vauthors = Floriano DA, Shelby AM | title=Small Animal Anesthesia Techniques | chapter=Section II: Drug formulary | publisher=Wiley | date=15 November 2022 | isbn=978-1-119-71082-0 | doi=10.1002/9781119710868.s2 | url=https://onlinelibrary.wiley.com/doi/10.1002/9781119710868.s2 | pages=320–321}}</ref> Due to its short duration and quick onset, fentanyl is commonly used as a constant rate infusion or as a transdermal patch, with the latter being able to last 3 to 4 days. Fentanyl can provide sedation for dogs. Fentanyl is less common and has more adverse effects in livestock and equine compared to cats and dogs.<ref name="lamont">{{cite book|isbn=978-1-119-83027-6 | vauthors = Simon BT, Lizarraga I |chapter=Opioids | veditors = Lamont L, Grimm K, Robertson S, Love L, Schroeder C |title=Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones | date = 11 September 2024 |pages=378–379|publisher=Wiley Blackwell}}</ref> In horses at analgesic doses [[tachycardia]], restlessness, and excitement occur. Subcutaneous administration often causes pain, but a bicarbonate solution exists which does not cause pain when given subcutaneously.<ref name="saunders"/>

Fentanyl is highly [[lipophilic]], about 1000 times more than [[morphine]]. In dogs it has low [[protein binding]] of 15.6% and a half-life of 2–6 hours. In cats the half-life is 2.5 hours. Fentanyl has poor oral bio-availability due to it being metabolized by the liver. Transdermal and transmucosal formulations are common for out-patients, although the latter's efficacy is not well supported by evidence.<ref name="saunders"/>

==Notes==
{{notelist}}

== 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 web | url=https://www.dea.gov/factsheets/fentanyl | publisher = U.S. Drug Enforcement Administration (DEA) | title = Fentanyl}}
* {{Cite web | url = https://www.euda.europa.eu/publications/drug-profiles/fentanyl_en | publisher = European Union Drugs Agency (EUDA) | title = Fentanyl }}
* {{cite web | url=https://nida.nih.gov/research-topics/fentanyl | archive-url=https://web.archive.org/web/20220606183456/https://nida.nih.gov/research-topics/fentanyl | archive-date=6 June 2022 | publisher=National Institute on Drug Abuse (NIDA) |title=Fentanyl| date=21 December 2021 }}
* {{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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