Editing Fentanyl (section)

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

=== Classification ===
Fentanyl is a synthetic opioid in the [[phenylpiperidine]] family, which includes [[sufentanil]], [[alfentanil]], [[remifentanil]], and [[carfentanil]].<ref name="Yaksh_2011">{{cite book | vauthors = Yaksh T, Wallace M |year=2011 |title=Goodman & Gilman's: The Pharmacological Basis of Therapeutics |publisher=McGraw-Hill |isbn=978-0-07-162442-8 |location=New York}}</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> Some [[List of fentanyl analogues|fentanyl analogues]], such as carfentanil, are up to 10,000 times [[Equianalgesic#Opioid equivalency table|stronger than morphine]].<ref name=UN2017CND>{{cite press release |title=Commission on Narcotic Drugs takes decisive step to help prevent deadly fentanyl overdoses |date=16 March 2017 |publisher=Commission on Narcotic Drugs, United Nations Office on Drugs and Crime |url=http://www.unodc.org/unodc/en/frontpage/2017/March/commission-on-narcotic-drugs-takes-decisive-step-to-help-prevent-deadly-fentanyl-overdoses.html |access-date=19 March 2017 |url-status=live |archive-url=https://web.archive.org/web/20170320052640/http://www.unodc.org/unodc/en/frontpage/2017/March/commission-on-narcotic-drugs-takes-decisive-step-to-help-prevent-deadly-fentanyl-overdoses.html |archive-date=20 March 2017 }}</ref>

=== Structure-activity ===
[[File:Fentanyl numbering.svg|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"/>

Like other opioids, 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 [[carboxylic acid]] group attached to the 4 position. Carfentanil is 20–30 times as potent as fentanyl and is common in the illicit drug chain. The drug is commonly used to tranquilize elephants and other large animals.<ref>{{cite journal | vauthors = Zawilska JB, Kuczyńska K, Kosmal W, Markiewicz K, Adamowicz P | title = Carfentanil – from an animal anesthetic to a deadly illicit drug | journal = Forensic Science International | volume = 320 | page = 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, like other opioids, acts on opioid receptors. These receptors are [[G protein-coupled receptor|G-protein-coupled receptors]], which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus.<ref name="Hemmings_2018" /> The extracellular N-terminus is important in differentiating different types of binding substrates.<ref name="Hemmings_2018" /> When fentanyl binds, downstream signaling leads to inhibitory effects, such as decreased [[Cyclic adenosine monophosphate|cAMP]] production, decreased calcium ion influx, and increased potassium efflux.<ref name="Hemmings_2018" /> This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation of [[Nociception|nociceptive]] signals, resulting in analgesic effects.<ref name="Suzuki17" /><ref>{{cite web|url=https://www.drugbank.ca/drugs/DB00813|title=Fentanyl|website=www.drugbank.ca|access-date=18 January 2019|archive-date=11 July 2017|archive-url=https://web.archive.org/web/20170711073330/https://www.drugbank.ca/drugs/DB00813|url-status=live}}</ref>{{unreliable medical source|date=July 2024}}

As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine.<ref name="Suzuki17">{{cite journal | vauthors = Suzuki J, El-Haddad S | title = A review: Fentanyl and non-pharmaceutical fentanyls | journal = Drug and Alcohol Dependence | volume = 171 | pages = 107–116 | date = February 2017 | pmid = 28068563 | doi = 10.1016/j.drugalcdep.2016.11.033 }}</ref> It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to 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 }}</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 | id = 10.25316/IR-4343 }}</ref>

=== Detection for harm reduction purposes ===
[[File:Fentanyl-test-strip.jpg|thumb|Image of testing strip instructions from the harm reduction organization Dance Safe]]
Fentanyl and fentanyl analogues can be qualitatively detected in drug samples using commercially available fentanyl testing strips or spot reagents. Following the principles of harm reduction, this test is to be used directly on drug samples as opposed to urine. To prepare a sample for testing, approximately 10&nbsp;mg of the drug should be diluted into 1 teaspoon, or 5&nbsp;mL, of water.<ref>{{cite web | vauthors = Cunningham C | date = 22 March 2023 | title = Fentanyl Test Strip Guidance | url = https://oasas.ny.gov/system/files/documents/2023/03/fentanyl_test_strip_guidance_0.pdf | access-date = 3 October 2023 | publisher = State of New York | archive-date = 19 April 2023 | archive-url = https://web.archive.org/web/20230419163310/https://oasas.ny.gov/system/files/documents/2023/03/fentanyl_test_strip_guidance_0.pdf | url-status = live }}</ref> Research in Dr. Lieberman's lab at the University of Notre Dame has reported false positive results on BTNX fentanyl testing strips with [[methamphetamine]], [[MDMA]], and [[diphenhydramine]].<ref>{{cite journal | vauthors = Lockwood TE, Vervoordt A, Lieberman M | title = High concentrations of illicit stimulants and cutting agents cause false positives on fentanyl test strips | journal = Harm Reduction Journal | volume = 18 | issue = 1 | page = 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 | page = 103065 | date = April 2021 | pmid = 33333419 | doi = 10.1016/j.drugpo.2020.103065 | doi-access = free | title-link = doi }}</ref>