Other Some 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.
Under normal circumstances, the patch will reach its full effect within 12 to 24 hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine
or oxycodone) to handle breakthrough pain.
 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.
 Other factors that increase the risk of respiratory depression are: • High fentanyl doses • Sleep • Older age • Simultaneous use of CNS depressants like benzodiazepines,
barbiturates, alcohol, and inhaled anesthetics • Hyperventilation • Decreased CO2 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.
 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
Naloxone (also known as Narcan) can reverse the effects of an opioid overdose; however, because fentanyl is so potent, multiple doses might be necessary.
 Topical (or transdermal; via the skin) and inhalative exposure to fentanyl is extremely unlikely to cause intoxication or overdose (except in cases of prolonged exposure
with very large quantities of fentanyl), and first responders such as paramedics and police officers are at minimal risk of fentanyl poisoning through accidental contact with intact skin.
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 out-of-hospital patients.
The CDC recommended the following four actions to counter this rise: 1. local need to expand the distribution and use of naloxone and overdose prevention education, 2.
expand awareness, access, and availability of treatment for substance use disorders, 3. intervene early with individuals at highest risk for overdose, and 4. improve detection of overdose outbreaks to facilitate more effective response.
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.
 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.
 It is widely used in 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.
 Palliative care 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.
 In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formulation of an inert alcohol gel infused with
select fentanyl doses, which are worn to provide constant administration of the opioid over a period of 48 to 72 hours.
• Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels.
 A 2021 paper expressed concern that these physical fears over fentanyl may inhibit effective emergency response to overdoses by causing responding officers to spend additional
time on unnecessary precautions, and that the media coverage could also perpetuate a wider social stigma that people who use drugs are dangerous to be around.
 It attenuates “second pain” with primary effects on slow-conducting, unmyelintated C-fibers and is less effective on neuropathic pain and “first pain” signals through
small, myelinated A-fibers.
However, the PCTS method proved superior to the placebo, showing lower mean VAS pain scores and having no significant respiratory depression effects.
 Fentanyl’s ease of manufacture and high potency makes it easier to produce and smuggle, resulting in fentanyl replacing other abused narcotics and becoming more widely
 In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.
 Depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose.
 Over 85% of overdoses involved at least one other drug, and there was no clear correlation showing at which level the mixtures were fatal.
 • Pronunciation: /ˈfɛntənɪl/ or /ˈfɛntənəl/; Trade names: Actiq, Duragesic, Sublimaze, others, AHFS/Drugs.com; Monograph: MedlinePlus, a605043; License data: EU EMA:
by INN, US DailyMed: Fentanyl; Pregnancy category: AU: C; Dependence liability: High; Routes of administration; Buccal, epidural, intramuscular, intrathecal, intravenous, sublingual, transdermal; Drug class: Opioid; ATC code: N01AH01 (WHO)
N02AB03 (WHO); Legal status: AU: S8 (Controlled drug), BR: Class A1 (Narcotic drugs), CA: Schedule I, DE: Anlage III (Special prescription form required), UK: Class A, US: Schedule II, UN: Narcotic Schedule I, EU: Rx-only; Pharmacokinetic
data: Bioavailability: 92% (transdermal), 65% (intranasal), 50% (buccal), 33% (ingestion), 100% (intramuscular), 80% (inhaled)100% (intravenous); Protein binding: 80–85%; Metabolism: Liver, primarily by CYP3A4; Onset of action: 5 minutes;
Elimination half-life: IV: 6 mins (T1/2 α), 1 hours (T1/2 β), 16 hours (T1/2 ɣ), Intranasal: 15-25 hours, Transdermal: 20–27 hours, Sublingual (single dose): 5–13.5 hours, Buccal: 3.2-6.4 hours; Duration of action: IV: 30–60 minutes;
Excretion: Mostly urinary (metabolites,
< 10% unchanged drug); Identifiers: CAS Number: 437-38-7 ; PubChem CID: 3345; IUPHAR/BPS: 1626; DrugBank: DB00813 ; ChemSpider: 3228 ; UNII: UF599785JZ; KEGG: D00320 ; ChEBI: CHEBI:119915 ; ChEMBL: ChEMBL596 ; PDB ligand: 7V7 (PDBe, RCSB PDB); CompTox
Dashboard (EPA): DTXSID9023049 ; ECHA InfoCard: 100.006.468 Medical uses Anesthesia Intravenous fentanyl is often used for anesthesia and as an analgesic.
 Wooden chest syndrome is unique to the most powerful opioids—which today comprise fentanyl and its analogs—while other less-powerful opioids like heroin produce mild
rigidity of the respiratory muscles to a much lesser degree.
Because fentanyl is 50 to 100 times more potent than morphine, its primary clinical utility is in pain management for cancer patients and those recovering from painful surgical
 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).
), which can trigger the release and absorption of too much medication and cause potentially deadly complications.
 A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow patients to control administration of fentanyl through the skin to treat
 Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity.
 The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.
 The technology consists of a “preprogrammed, self-contained drug-delivery system” that uses electrotransport technology to administer on-demand does of 40 µg of fentanyl
hydrochloride over ten minutes.
 As of 2017, fentanyl was the most widely used synthetic opioid in medicine; in 2019, it was the 278th most commonly prescribed medication in the United States, with
more than a million prescriptions.
 After receiving a bolus dose of fentanyl, people can also experience paradoxical coughing, which is a phenomenon that is not well understood.
 The LD50 in humans is unknown, but it is estimated that the lethal dose may be as low as 2 mg in some people depending on body size, tolerance, and past usage.
 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.
 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.
“ The effects being reported in these cases, including rapid heartbeat, hyperventilation and chills, were not symptoms of a fentanyl overdose, and were more commonly associated
with a panic attack.
 In July 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, and advised that they should be folded, with the adhesive side in, before being discarded.
 The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management.
 Following the patch, a flavored lollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name of Actiq, becoming the first quick-acting
formation of fentanyl for use with chronic breakthrough pain.
At high doses, the drug may act on the fetus to cause postnatal respiratory distress.
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.
 A 2020 article from the Journal of Medical Toxicology stated that “the consensus of the scientific community remains that illness from unintentional exposures is
extremely unlikely, because opioids are not efficiently absorbed through the skin and are unlikely to be carried in the air.
 A December 2020 HAN Advisory warned of: 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.
The Marquis Color test may also be used to detect the presence of fentanyl.
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 section below.
The different delivery systems used by different makers will also affect individual rates of absorption, and route of administration.
 Chronic pain It is also used in the management of chronic pain including cancer pain.
 Respiratory depression The most dangerous adverse effect of fentanyl is respiratory depression, that is, decreased sensitivity to carbon dioxide leading to
reduced rate of breathing, which can cause anoxic brain injury or death.
 Regional anesthesia Fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min.)
 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.
 In contexts of poly-substance use, blood fentanyl concentrations of approximately 7 ng/ml or greater have been associated with fatalities.
 Therapeutic effects • Pain relief: Primarily, fentanyl provides the relief of pain by acting on the brain and spinal μ-receptors.
Lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets.
 A portion of the Janssen Method is shown below, in this instance, to synthesize a related opioid.
 In the US, fentanyl and fentanyl analogs caused over 29,000 deaths in 2017, a large increase over the previous four years.
Fentanyl is especially useful for concomitant treatment in palliative care settings where pain and shortness of breath are severe and need to be treated with high strength
 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.
 Fentanyl continues to fuel an epidemic of synthetic opioid drug overdose deaths in the United States.
 In the U.S., fentanyl is a Schedule II controlled substance per the Controlled Substance Act.
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.. The United Kingdom illicit drug market is no longer reliant on China, as domestic fentanyl production is replacing imports.
Body temperature, skin type, amount of body fat, and placement of the patch can have major effects.
 • Sedation: Fentanyl produces sleep and drowsiness, as the dosage is increased, and can produce the δ-waves often seen in natural sleep on electroencephalogram.
 All of these factors allow it to rapidly cross cellular membranes, contributing to its quick effect in the body and the central nervous system.
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