Editing Fentanyl (section)

== 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]], [[apnoea]], and urinary retention. Fentanyl use has also been associated with [[aphasia]].<ref name="urlDrugs@FDA: FDA Approved Drug Products" /> Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less [[histamine]]-mediated itching, than morphine.<ref name="Mayes_2006" /> In rare cases, [[serotonin syndrome]] is associated with fentanyl use. Existing studies advise medical practitioners to exercise caution when combining [[selective serotonin reuptake inhibitor]] (SSRI) drugs with fentanyl.<ref>{{cite journal | vauthors = Kirschner R, Donovan JW | title = Serotonin syndrome precipitated by fentanyl during procedural sedation | journal = The Journal of Emergency Medicine | volume = 38 | issue = 4 | pages = 477–480 | date = May 2010 | pmid = 18757161 | doi = 10.1016/j.jemermed.2008.01.003 }}</ref><ref>{{cite journal | vauthors = Ailawadhi S, Sung KW, Carlson LA, Baer MR | title = Serotonin syndrome caused by interaction between citalopram and fentanyl | journal = Journal of Clinical Pharmacy and Therapeutics | volume = 32 | issue = 2 | pages = 199–202 | date = April 2007 | pmid = 17381671 | doi = 10.1111/j.1365-2710.2007.00813.x | doi-access = free | title-link = doi }}</ref>

The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.<ref name="pmid295585">{{cite journal | vauthors = Smydo J | title = Delayed respiratory depression with fentanyl | journal = Anesthesia Progress | volume = 26 | issue = 2 | pages = 47–48 | year = 1979 | pmid = 295585 | pmc = 2515983 }}</ref><ref name="pmid6116461">{{cite journal | vauthors = van Leeuwen L, Deen L, Helmers JH | title = A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression | journal = Der Anaesthesist | volume = 30 | issue = 8 | pages = 397–399 | date = August 1981 | pmid = 6116461 }}</ref><ref name="pmid4053723">{{cite journal | vauthors = Brown DL | title = Postoperative analgesia following thoracotomy. Danger of delayed respiratory depression | journal = Chest | volume = 88 | issue = 5 | pages = 779–780 | date = November 1985 | pmid = 4053723 | doi = 10.1378/chest.88.5.779 | s2cid = 1836168 }}</ref><ref name="pmid7113633">{{cite journal | vauthors = Nilsson C, Rosberg B | title = Recurrence of respiratory depression following neurolept analgesia | journal = Acta Anaesthesiologica Scandinavica | volume = 26 | issue = 3 | pages = 240–241 | date = June 1982 | pmid = 7113633 | doi = 10.1111/j.1399-6576.1982.tb01762.x | s2cid = 9232457 }}</ref> In 2006, the [[Food and Drug Administration|United States Food and Drug Administration]] (FDA) began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008.<ref>{{cite journal|title=Fentanyl patches: serious and fatal overdose from dosing errors, accidental exposure, and inappropriate use |journal=Drug Safety Update |volume=2 |issue=2 |date=September 2008 |page=2 |url=http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON025631 |url-status=dead |archive-url=https://web.archive.org/web/20150101054043/http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON025631 |archive-date=1 January 2015}}</ref> The FDA reported in April 2012 that twelve young children had died and twelve more had become seriously ill from separate accidental exposures to fentanyl skin patches.<ref name="children">{{cite web |title=Fentanyl patch can be deadly to children |date=19 April 2012 |publisher=U.S. [[Food and Drug Administration]] (FDA) |url=https://www.drugs.com/fda-consumer/fentanyl-patch-can-be-deadly-to-children-214.html |access-date=30 July 2013 |archive-url=https://web.archive.org/web/20130725092458/http://www.drugs.com/fda-consumer/fentanyl-patch-can-be-deadly-to-children-214.html |archive-date=25 July 2013 |url-status=live }}</ref>

=== Respiratory depression ===
The most dangerous adverse effect of fentanyl is respiratory depression,<ref>{{cite journal |vauthors = Topacoglu H, Karcioglu O, Cimrin AH, Arnold J |title = Respiratory arrest after low-dose fentanyl |journal = Annals of Saudi Medicine |volume = 25 |issue = 6 |pages = 508–510 |date = Nov 2005 |pmid = 16438465 |pmc = 6089740 |doi = 10.5144/0256-4947.2005.508}}</ref> that is, decreased sensitivity to carbon dioxide leading to reduced rate of breathing, which can cause anoxic brain injury or death. This risk is decreased when the airway is secured with an [[endotracheal tube]] (as during anesthesia).<ref name="Hemmings_2018" /> This risk is higher in specific groups, like those with [[obstructive sleep apnea]].<ref name="Hemmings_2018" />

Other factors that increase the risk of respiratory depression are:<ref name="Hemmings_2018" />
* High fentanyl doses
* Simultaneous use of [[methadone]]
* Sleep
* Older age
* Simultaneous use of CNS depressants like benzodiazepines (i.e. [[alprazolam]], [[diazepam]], [[clonazepam]]), barbiturates, alcohol, and inhaled anesthetics
* Hyperventilation
* Decreased CO<sub>2</sub> levels in the serum
* Respiratory [[acidosis]]
* Decreased fentanyl clearance from the body
* Decreased blood flow to the liver
* Renal insufficiency

Sustained release fentanyl preparations, such as patches, may also produce unexpected delayed [[respiratory depression]].<ref name="pmid9472602">{{cite journal |vauthors = McLoughlin R, McQuillan R |title = Transdermal fentanyl and respiratory depression |journal = Palliative Medicine |volume = 11 |issue = 5 |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, by primarily slowing down vasomotor centers in the brainstem. To a lesser extent, it does this by directly affecting blood vessels.<ref name="Hemmings_2018" /> This is much more profound in patients who have an already increased sympathetic drive, like patients who have high blood pressure or congestive heart failure.<ref name="Hemmings_2018" /> It does not affect the contractility of the heart when regular doses are administered.<ref name="Hemmings_2018" />

=== Muscle rigidity ===
If high boluses of fentanyl are administered quickly, muscle rigidity of the vocal cords can make bag-mask ventilation very difficult.<ref name="Hemmings_2018" /> The exact mechanism of this effect is unknown, but it can be prevented and treated using neuromuscular blockers.<ref name="Hemmings_2018" />

==== Wooden chest syndrome ====
A prominent idiosyncratic adverse effect of fentanyl also includes a sudden onset of rigidity of the abdominal muscles and the diaphragm, which induces respiratory failure; this is seen with high doses and is known as [[wooden chest syndrome]].<ref>{{cite book |vauthors=Chambers D, Huang CL, Matthews G |date=1 September 2019 |title=Basic Physiology for Anaesthetists |edition=2nd |chapter=Section 2 – Respiratory physiology: Chapter 25: Anaesthesia and the lung |orig-year=2015 |publisher=[[Cambridge University Press]] |publication-place=[[Cambridge]], UK |pages=107–110 |oclc=1088737571 |doi=10.1017/CBO9781139226394.027 |isbn=978-1-108-46399-7 |chapter-url=https://books.google.com/books?id=5ma8BQAAQBAJ&pg=PA107 |access-date=9 August 2021 |url=https://books.google.com/books?id=5ma8BQAAQBAJ |via=[[Google Books]] |archive-date=8 February 2023 |archive-url=https://web.archive.org/web/20230208191600/https://books.google.com/books?id=5ma8BQAAQBAJ |url-status=live }}</ref> The syndrome is believed to be the main cause of death as a result of fentanyl overdoses.<ref>{{cite journal | vauthors = Burns G, DeRienz RT, Baker DD, Casavant M, Spiller HA | title = Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse? | journal = Clinical Toxicology | volume = 54 | issue = 5 | pages = 420–423 | date = June 2016 | pmid = 26999038 | doi = 10.3109/15563650.2016.1157722 | publisher = [[American Academy of Clinical Toxicology|American Academy of Clinical Toxicology (AACT)]] / European Association of Poisons Centres and Clinical Toxicologist / [[Taylor & Francis]] | publication-place = [[McLean, Virginia|McLean]], [[Virginia (state)|VA]] | veditors = Seifert SA, Buckley N, Seger D, Thomas S, Caravati EM | s2cid = 23149685 | oclc = 8175535 }}</ref>

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

Wooden chest syndrome is unique to the most powerful opioids{{mdash}}which today comprise fentanyl and its analogs{{mdash}}while other less-powerful opioids like heroin produce mild rigidity of the respiratory muscles to a much lesser degree.<ref>{{cite journal |title=Chest wall rigidity in fentanyl abuse: illicit fentanyl could be a major factor in sudden onset of this potentially lethal adverse event |access-date=9 August 2021 |vauthors=Petrou I |date=1 September 2016 |volume=33 |issue=9 |journal=Contemporary Pedriatics |publisher=Intellisphere, LLC./ MJH Life Sciences (Multimedia Medical LLC) |issn=8750-0507 |publication-place=[[Cranbury, New Jersey|Cranbury]], [[New Jersey]], United States of America |via=Gale Academic OneFile |url-access=subscription |url=https://link.gale.com/apps/doc/A464982083/AONE?u=anon~4087cc99 |oclc=10956598 |veditors=Levine L, Tan TQ, Shippoli J }}{{Dead link|date=February 2023 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name="Torralva" />

=== "Fentanyl fold" posture ===
There are many reports of fentanyl users adopting a "folded" posture.<ref>{{Cite web | vauthors = Ward J |title=It's an odd side effect of opioid abuse: Why are fentanyl users bent over. Here's why |url=https://www.desertsun.com/story/news/nation/california/2024/07/19/what-is-the-fentanyl-fold-how-to-treat-opioid-overdoses/74471357007/ |access-date=26 February 2025 |website=The Desert Sun |language=en-US}}</ref>

Daniel Ciccarone of UCSF said what he calls the “nod” is a common side effect of opioid use, and later notes that "nods have always happened to varying degrees with other opioids, particularly heroin. The nods with fentanyl, however, seem to be more extreme. And it's often a sign that a person has taken too strong a dose".<ref>{{Cite web | vauthors = Toledo A, Greene CM |date=17 July 2024 |title=Here's why fentanyl users on S.F.'s streets are bent over |url=https://www.sfchronicle.com/sf/article/fentanyl-fold-drug-user-19561190.php |website=San Francisco Chronicle}}</ref> 
He also said "the fentanyl fold falls into the umbrella of a severe spinal deformity that can cause functional disability and can drive mental anguish" which is a factor given the socioeconomic status and more fragile mental health of drug users typically when compared to non-users.

Adulteration of fentanyl with [[xylazine]], also known as 'tranq', can exacerbate postural problems.<ref>{{Cite web |title=The Zombie Drug {{!}} Psychology Today |url=https://www.psychologytoday.com/intl/blog/addiction-outlook/202406/the-zombie-drug |access-date=26 February 2025 |website=www.psychologytoday.com |language=en}}</ref><ref>{{Cite journal | vauthors = Dinis-Oliveira RJ |date=March 2024 |title=New Choking Epidemic Trends in Psychoactive Drugs: The Zombifying Combination of Fentanyl and Xylazine Cause Overdoses and Little Hope in Rehabilitation |journal=Psychoactives |language=en |volume=3 |issue=1 |pages=132–136 |doi=10.3390/psychoactives3010009 |doi-access=free |issn=2813-1851}}</ref>