fentanyl fentanyl fentanyl, also spelled fentanil, is a highly potent synthetic piperidine opioid drug primarily used as an analgesic. 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 operations. fentanyl is also used as a sedative. depending on the method of delivery, fentanyl can be very fast acting and ingesting a relatively small quantity can cause overdose. fentanyl works by activating mu-opioid receptors. fentanyl is also commonly known as fentanyl citrate, and is sold under the brand name sublimaze among others. fentanylclinical datapronunciation/ˈfɛntənɪl/ or /ˈfɛntənəl/ trade namesactiq, duragesic, sublimaze, othersahfs/drugs.commonographmedlineplusa605043license data eu ema: by inn us dailymed: fentanyl pregnancycategory au: c dependenceliabilityhighroutes ofadministrationbuccal, epidural, intramuscular, intrathecal, intravenous, sublingual, transdermaldrug classopioidatc coden01ah01 (who) n02ab03 (who)legal statuslegal 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 databioavailability92% (transdermal)65% (intranasal)50% (buccal)33% (ingestion)100% (intramuscular) 80% (inhaled)100% (intravenous)protein binding80–85%metabolismliver, primarily by cyp3a4onset of action5 minuteselimination half-lifeiv: 6 mins (t1/2 α) 1 hours (t1/2 β) 16 hours (t1/2 ɣ)intranasal: 15-25 hourstransdermal: 20–27 hourssublingual (single dose): 5–13.5 hoursbuccal: 3.2-6.4 hoursduration of actioniv: 30–60 minutesexcretionmostly urinary (metabolites, < 10% unchanged drug)identifiers iupac name n-phenyl-n-propanamide cas number437-38-7 ypubchem cid3345iuphar/bps1626drugbankdb00813 ychemspider3228 yuniiuf599785jzkeggd00320 ychebichebi:119915 ychemblchembl596 ypdb ligand7v7 (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid9023049 echa infocard100.006.468 chemical and physical dataformulac22h28n2omolar mass336.479 g·mol−13d model (jsmol)interactive imagedensity1.1 g/cm3melting point87.5 °c (189.5 °f) smiles o=c(cc)n(c1ccn(cc1)ccc2ccccc2)c3ccccc3 inchi inchi=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 ykey:pjmphniqzubgli-uhfffaoysa-n y (verify) pharmaceutical fentanyl's adverse effects resemble those of other narcotic opioids, including addiction, confusion, respiratory depression (which, if extensive and untreated, may lead to arrest), drowsiness, nausea, visual disturbances, dyskinesia, hallucinations, delirium, a subset of the latter known as "narcotic delirium," analgesia, narcotic ileus, muscle rigidity, constipation, loss of consciousness, hypotension, coma, and death. alcohol and other drugs (i.e., cocaine, heroin) can synergistically exacerbate fentanyl's side effects. naloxone (also known as narcan) can reverse the effects of an opioid overdose; however, because fentanyl is so potent, multiple doses might be necessary. fentanyl was first synthesized by paul janssen in 1959 and was approved for medical use in the united states in 1968. in 2015, 1,600 kilograms (3,500 pounds) were used in healthcare globally. 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. it is on the world health organization's list of essential medicines. fentanyl continues to fuel an epidemic of synthetic opioid drug overdose deaths in the united states. while prescription opioid deaths remained stable from 2011 to 2021, synthetic opioid deaths increased from 2,600 overdose deaths per year to 76,238 per year. since 2018, fentanyl and its analogues have been responsible for most drug overdose deaths in the united states, causing over 71,238 deaths in 2021. fentanyl constitutes the majority of all drug overdose deaths in the united states since it overtook heroin in 2018. the united states national forensic laboratory estimates fentanyl reports by federal, state, and local forensic laboratories increased from 4,697 reports in 2014 to 117,045 reports in 2020. fentanyl is often mixed, cut, or ingested alongside other drugs, including cocaine and heroin. fentanyl has been reported in pill form, including pills mimicking pharmaceutical drugs such as oxycodone. 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. 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 used. medical uses anesthesia intravenous fentanyl is often used for anesthesia and as an analgesic. to induce anesthesia, it is given with a sedative-hypnotic, like propofol or thiopental, and a muscle relaxant. to maintain anesthesia, inhaled anesthetics and additional fentanyl may be used. these are often given in 15–30 minute intervals throughout procedures such as endoscopy and surgeries and in emergency rooms. for pain relief after surgery, use can decrease the amount of inhalational anesthetic needed for emergence from anesthesia. 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. regional anesthesia fentanyl is the most commonly used intrathecal opioid because its lipophilic profile allows a quick onset of action (5–10 min.) and intermediate duration of action (60–120 min.). 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. obstetrics fentanyl is sometimes given intrathecally as part of spinal anesthesia or epidurally for epidural anaesthesia and 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. 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. in obstetrics, the dose must be closely regulated in order to prevent large amounts of transfer from mother to fetus. at high doses, the drug may act on the fetus to cause postnatal respiratory distress. for this reason, shorter acting agents such as alfentanyl or remifentanil may be more suitable in the context of inducing general anaesthesia. pain management a fentanyl nasal spray with a strength of 100 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, and 200 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 out-of-hospital patients. in children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated. furthermore, a 2017 study suggested the efficacy of fentanyl lozenges in children as young as five, weighing as little as 13 kg. lozenges are more inclined to be used as the child is in control of sufficient dosage, in contrast to buccal tablets. chronic pain it is also used in the management of chronic pain including cancer pain. often, transdermal patches are used. the patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management. dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature. each patch should be changed every 72 hours. 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 hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain. it is unclear if fentanyl gives long-term pain relief to people with neuropathic pain. breakthrough pain sublingual fentanyl dissolves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia. fentanyl is a highly lipophilic compound, which is well absorbed sublingually and generally well tolerated. such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration, and severe in intensity. 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. people with moderate to severe kidney failure. troublesome side effects of oral morphine, hydromorphone, or oxycodone. 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. combat medicine usaf pararescue combat medics in afghanistan used fentanyl lozenges in the form of lollipops on combat casualties from ied blasts and other trauma. the stick is taped to a finger and the lozenge put in the 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. dyspnea fentanyl can also be used for patients in whom morphine is not tolerated, or whose breathlessness is refractory to morphine. 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 opioids. 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. 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. 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 postoperative pain. 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. in a 2004 experiment including 189 patients with moderate to severe postoperative pain up to 24 hours after major surgery, 25% of patients withdrew due to inadequate analgesia. however, the pcts method proved superior to the placebo, showing lower mean vas pain scores and having no significant respiratory depression effects. adverse effects 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). 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), shortness of breath, hypoventilation, apnoea, and urinary retention. fentanyl use has also been associated with aphasia. despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine. the duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context. in 2006, the 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. the fda reported in april 2012 that twelve young children had died and twelve more made seriously ill from separate accidental exposures to fentanyl skin patches. 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. this risk is decreased when the airway is secured with an endotracheal tube (as during anesthesia). this risk is higher in specific groups, like those with obstructive sleep apnea. 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