Fentanyl 141915 223835622 2008-07-06T01:49:16Z Discospinster 82432 Reverted edits by [[Special:Contributions/24.57.226.179|24.57.226.179]] to last version by Fvasconcellos (using [[WP:HG|Huggle]]) {{drugbox | IUPAC_name = ''N''-(1-(2-phenylethyl)-4-piperidinyl)-''N''-phenyl-propanamide | image = Fentanyl-xtal-2D-skeletal.png | image2 = Fentanyl-xtal-3D-balls.png | CAS_number = 437-38-7 | ATC_prefix = N01 | ATC_suffix = AH01 | ATC_supplemental = {{ATC|N02|AB03}} | PubChem = 3345 | DrugBank = APRD00347 | C = 22 | H = 28 | N = 2 | O = 1 | molecular_weight = 336.471 g/mol | smiles = CCC(=O)N(C1CCN(CCc2ccccc2)CC1)c1ccccc1 | melting_point = 87.5 | bioavailability = 92% (transdermal)<br />50% (buccal)<br />33% (ingestion) | protein_bound = 80-85% | metabolism = [[hepatic]], primarily by [[CYP3A4]] | elimination_half-life = 7 hours (range 3–12 h) | excretion = Urine | pregnancy_US = C | legal_UK = Class A | legal_US = Schedule II | routes_of_administration = [[Transdermal patch|TD]], [[Intramuscular injection|IM]], [[Intravenous therapy|IV]], oral, [[sublingual]], [[buccal mucosa|buccal]] | dependency_liability = Moderate - High}} '''Fentanyl''' is a powerful [[opioid]] [[analgesic]] with a potency approximately 81 times that of [[morphine]]. Fentanyl has an [[LD50|LD<sub>50</sub>]] of 3.1 milligrams per kilogram in rats and 0.03 milligrams per kilogram in monkeys. The LD<sub>50</sub> in humans, by intravenous injection in an opiate-naive individual (without tolerance), is 0.5-1 milligrams. Due to its potency, its ability to subdue pain in a short period of time has warranted it a [[Controlled Substances Act#Schedule II drugs|Schedule II drug]] in the United States. ==History== Fentanyl was first synthesized by [[Janssen Pharmaceutica]] ([[Belgium]]) in 1959, and was one of the first few on a long list of helpful pharmaceuticals produced by [[Paul Janssen]]'s relatively new [[Janssen Pharmaceutica]]. Fentanyl was introduced into medical practice in the 1960s as an intravenous [[anesthetic]] under the trade name of '''Sublimaze'''. ==Chemistry== ===Synthesis=== The synthesis of fentanyl [http://cdb.ics.uci.edu/CHEMDB/Web/cgibin/ChemicalDetailWeb.py?chemical_id=3966642 (''N''-phenyl-''N''-(1-phenethyl-4-piperidinyl)propanamide)] by [[Janssen Pharmaceutica]] was achieved in four steps, starting from [[4-Piperidinone|4-piperidinone]] hydrochloride. The 4-piperidinone hydrochloride was first reacted with [[phenethyl bromide]] to give [[N-phenethyl-4-piperidinone]] (NPP). Treatment of the NPP intermediate with [[aniline]] followed by reduction with [[sodium borohydride]] afforded 4-anilino-''N''-phenethyl-piperidine (ANPP). Finally ANPP and [[propionic anhydride]] are reacted to form the amide product. ===Analogues=== The pharmaceutical industry has developed several analogues of fentanyl: * [[Alfentanil]] (trade name '''Alfenta'''), an ultra-short acting (5&ndash;10 minutes) analgesic, * [[Sufentanil]] (trade name '''Sufenta'''), a potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery. * [[Remifentanil]] (trade name '''Ultiva'''), currently the shortest acting opioid, has the benefit of rapid offset, even after prolonged infusions. * [[Carfentanil]] (trade name '''Wildnil''') is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals such as elephants. ==Therapeutic use== Fentanyls are extensively used for [[anesthesia]] and [[analgesia]], most often in the operating room and intensive care unit. Fentanyl [[transdermal patch]] (Durogesic/Duragesic) is used in chronic pain management. Fentanyl patches work by releasing fentanyl into body fats, which then slowly release the drug into the blood stream over 48 to 72 hours, allowing for long lasting relief from pain. In the past few years, the patches have gone [[Generic drug|generic]] and are available for lower costs. Fentanyl patches are manufactured in five patch sizes: 12.5 [[kilogram#SI multiples|micrograms]]/h, 25 µg/h, 50 µg/h, 75 µg/h, and 100 µg/h. Dosage is based on the size of the patch, since the transdermal absorption rate is generally constant at a constant skin temperature. 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. The typical patch will take effect under normal circumstances usually within 8-12 hours, thus fentanyl patches are often prescribed with another opiate (such as morphine sulfate) to handle breakthrough-pain. Fentanyl lozenges ([[Actiq]]) are a solid formulation of fentanyl citrate on a [[lollipop|stick]] in the form of a lollipop that dissolves slowly in the mouth for transmucosal absorption. These lozenges are intended for opioid-tolerant individuals and are effective in treating [[BTCP|breakthrough cancer pain]]. It is also useful for breakthrough pain for those suffering bone injuries, severe back pain, neuropathy, arthritis, and some other examples of chronic nonmalignant pain. The unit is a berry-flavored lozenge on a stick which is swabbed on the mucosal surfaces inside the mouth&mdash;inside of the cheeks, under and on the tongue and gums&mdash;to release the fentanyl quickly into the system. It is most effective when the lozenge is consumed in 15 minutes. The drug is less effective if swallowed, as despite good absorbance from the small intestine there is extensive first pass metabolism, leading to an oral bioavailability of 33%. Fentanyl lozenges are available in six dosages, from 200 to 1600 µg in 200 µg increments (excluding 1000 µg and 1400 µg). These are now available in the United states in generic form,<ref name=Actiq_generic>{{cite press release | title = Barr Launches Generic ACTIQ(R) Cancer Pain Management Product | publisher = [[Barr Pharmaceuticals]] | date = [[2006-09-27]] | url = http://www.lifesciencesworld.com/news/view/9520 | accessdate = 2006-09-30 }}</ref> through an [[FTC]] consent agreement.<ref name=FTC>{{cite press release | title = With Conditions, FTC Allows Cephalon’s Purchase of CIMA, Protecting Competition for Breakthrough Cancer Pain Drugs | publisher = [[FTC]] | date = [[2004-08-09]] | url = http://www.ftc.gov/opa/2004/08/cimacephalon.htm | accessdate = 2006-09-30 }}</ref><br /> However, most patients find it takes 10-15 minutes to use all of one lozenge, and those with a dry mouth cannot use this route. In addition, nurses are unable to document how much of a lozenge has been used by a patient, making drug records inaccurate. <br /> Over 2008/9 a wide range of fentanyl preparations will become available, including buccal tablets or patches, nasal sprays, inhalers and active transdermal patches (heat or electrical). High quality evidence for their superiority over existing preparations is currently lacking. Some preparations such as nasal sprays and inhalers may result in a rapid response, but the fast onset of high blood levels may compromise safety (see below). In addition the expense of some of these appliances may greatly reduce their cost-effectiveness. <br /> In [[palliative care]] transdermal fentanyl has a definite, but limited, role for: * Patients already stabilized on other opioids who have persistent swallowing problem and cannot tolerate other parenteral routes such as subcutaneous administration. * Patients with moderate to severe [[renal failure]] * Troublesome adverse effects on morphine, hydromorphone or oxycodone. Fentanyl is sometimes given intrathecally as part of [[spinal anesthesia]] or epidurally for [[epidural anesthesia]] and [[epidural analgesia|analgesia]]. Because of fentanyl's high lipid solubility its effects are more localised than morphine and some clinicians prefer to use the morphine to get a wider spread of analgesia. ===Adverse events=== Fentanyl's major side effects (more than 10% of patients) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion, [[asthenia]],and sweating; and, less frequently (3 to 10% of patients), abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, hallucinations, anxiety, depression, flu-like symptoms, [[dyspepsia]], [[dyspnea]], [[hypoventilation]], [[apnea]], and urinary retention. Fentanyl use has also been associated with [[aphasia]].<ref>http://www.drugs.com/pro/fentanyl-transdermal.html#A02A9CB6-35CF-4F01-A980-C3733E0F861A</ref> ===Adverse effects=== Like other lipid soluble drugs, the pharmacodynamics of fentanyl are poorly understood. The manufacturers acknowledge there is no data on the pharmacodynamics of fentanyl in elderly, [[cachexia|cachectic]] or debilitated patients, frequently the type of patient for which transdermal fentanyl is being used. This may explain the increasing number of reports of [[respiratory depression]] events since the late 1970s.<ref>Smydo J. Delayed respiratory depression with fentanyl. Anesthesia Progress. 26(2):47-8, 1979</ref><ref>van Leeuwen L. Deen L. Helmers JH. A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression. Anaesthesist. 30(8):397-9, 1981</ref><ref>Brown DL. Postoperative analgesia following thoracotomy. Danger of delayed respiratory depression. Chest. 88(5):779-80, 1985.</ref><ref>Bulow HH. Linnemann M. Berg H. Lang-Jensen T. LaCour S. Jonsson T. Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl. Acta Anaesthesiologica Scandinavica, 1995; 39(6): 835-9.</ref><ref>Nilsson C. Rosberg B. Recurrence of respiratory depression following neurolept analgesia. Acta Anaesthesiologica Scandinavica. 26(3):240-1, 1982</ref><ref>McLoughlin R. McQuillan R. Transdermal fentanyl and respiratory depression. Palliative Medicine, 1997; 11(5):419.</ref><ref>Regnard C, Pelham A. Severe respiratory depression and sedation with transdermal fentanyl: four case studies. Palliative Medicine, 2003; 17: 714-716.</ref> In 2006 the U.S. [[Food and Drug Administration]] started investigating several respiratory deaths. The precise reason for sudden respiratory depression is unclear, but there are several hypotheses: * Saturation of the body fat compartment in patients with rapid and profound body fat loss (patients with cancer, cardiac or infection-induced [[cachexia]] can lose 80% of their body fat). * Early carbon dioxide retention causing cutaneous vasodilatation (releasing more fentanyl), together with acidosis which reduces 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. Fentanyl has a [[therapeutic index]] of 270.<ref>{{cite web | title = New Anesthetic Agents, Devices, and Monitoring Techniques | url=http://books.google.com/books?id=msYvkdGM6F0C&pg=PA122&lpg=PA122&dq=fentanyl+%22therapeutic+index%22+-narrow+-carfentanil&source=web&ots=CS2ROv70RM&sig=NOOlUEZse377jEhVO4XqLXwKce4 | accessdate = 2007-10-20 }}</ref> ==Illicit use== {{Original research|date=September 2007}} [[Image:deafentanyl.jpg|thumb|right|Fentanyl powder seized by a [[Lake County, Ohio|Lake County]] Deputy Sheriff in [[Painesville, Ohio]], where a male subject had been discovered unresponsive and struggling to breathe]] [[Drug abuse|Illicit use]] of pharmaceutical fentanyls first appeared in the mid-1970s in the medical community and continues in the present. United States authorities classify fentanyl as a [[narcotic]]. To date, over 12 different analogues of fentanyl have been produced [[clandestine chemistry|clandestinely]] and identified in the U.S. drug traffic. The biological effects of the fentanyls are similar to those of [[heroin]], with the exception that many users report a noticeably less euphoric 'high' associated with the drug and stronger sedative and analgesic effects. Because the effects of fentanyl last for only a very short time, it is even more addictive than heroin, and regular users may become addicted very quickly. Additionally, fentanyl may be hundreds of times more potent than street heroin, and tends to produce significantly worse [[respiratory depression]], making it somewhat more dangerous than heroin to users — though in some places, it is sold as heroin, often leading to overdoses. Fentanyl is most commonly used orally, but like heroin, can also be smoked, snorted or injected. Many fentanyl overdoses are initially classified as heroin overdoses.<ref>[Boddiger, D. (2006, August 12). Fentanyl-laced street drugs “kill hundreds”. In EBSCOhost. Retrieved March 7, 2007, from http://proxy.clpccd.cc.ca.us:2271/ehost/ pdf?vid=8&hid=8&sid=e6bcbd34-2854-4beb-bfca-35460dd686e6%40sessionmgr7 ]</ref> Fentanyl is normally sold on the black market in the form of transdermal fentanyl patches such as [[Duragesic]], diverted from legitimate medical supplies. The patches may be cut up and eaten, or the gel from inside the patch smoked. To prevent the removal of the fentanyl base, [[Janssen-Cilag]], the inventor of the Fentanyl patch designed the Durogesic patch. The Durogesic patches contain their Fentanyl throughout the plastic matrix instead of gel incorporated into a reservoir on the patch. Manufacturers such as [[Mylan Laboratories Inc.|Mylan]] have also produced [[Durogesic]] style fentanyl patches that contain the chemical in a silicone matrix, preventing the removal of the fentanyl-containing gel present in other products.[http://www.fda.gov/OHRMS/DOCKETS/dockets/04p0506/04p-0506-c000001-06-Tab-04-Flynn-vol1.pdf] Another dosage form of fentanyl which has appeared on the streets are the fentanyl lollipops [[Actiq]], which are sold under the street name of "percopop". The pharmacy retail price ranges from [[United States dollar|US$]]10 to US$30 per unit (based on strength of lozenge), with the black market cost anywhere from US$15 to US$40 per unit, depending on the strength. Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.[http://www.deadiversion.usdoj.gov/drugs_concern/fentanyl.htm] Even those with opiate tolerances are at high risk for overdoses. Once the fentanyl is in the user's system it is extremely difficult to stop its course because of the nature of absorption. Illicitly synthesized fentanyl powder has also appeared on the US market. Because of the extremely high strength of pure fentanyl powder, it is very difficult to dilute appropriately, and often the resulting mixture may be far too strong and consequently very dangerous. Some heroin dealers mix fentanyl powder with larger amounts of heroin in order to increase potency or compensate for low-quality heroin, and to increase the volume of their product. As of December 2006, a mix of fentanyl and either [[cocaine]] or [[heroin]] has caused an outbreak in overdose deaths in the United States, heavily concentrated in the cities of [[Detroit]], [[Philadelphia]], [[Pittsburgh]], [[St. Louis]], [[Milwaukee]], [[Camden, New Jersey|Camden]], [[Chicago]],<ref>[http://www.chicagopolice.org/MailingList/PressAttachment/releaseheroinhomicide.pdf Press Release by the Chicago Police Department] Police report about a death linked to heroin/fentanyl mixture August 24, 2006</ref> [[Little Rock]], and [[Dallas]].<ref>[http://www.dallasnews.com/sharedcontent/dws/dn/latestnews/stories/122106dnmetsmudrug.2b395050.html SMU student's death blamed on rare drug]</ref> The mixture of fentanyl and heroin is known as "magic", among other names, on the street.<ref>[http://www.detnews.com/apps/pbcs.dll/article?AID=/20060623/METRO/606230339/1003 Fentanyl probe nets 3 suspects] by Norman Sinclair and Ronald J. Hansen, The Detroit News, June 23, 2006, retrieved June 25, 2006.</ref> Several large quantities of illicitly-produced fentanyl have been seized by U.S. law enforcement agencies. In June 2006, 945 grams of 83% pure fentanyl powder were seized by [[Border Patrol]] agents in California from a vehicle which had entered from Mexico.<ref>[http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0606/mg0606.html INTELLIGENCE ALERT: HIGH PURITY FENTANYL SEIZED NEAR WESTMORELAND, CALIFORNIA], DEA Microgram, June 2006</ref> Mexico is the source of much of the illicit fentanyl for sale in the U.S. However, there has been one domestic fentanyl lab discovered by law enforcement, in April 2006 in [[Azusa, California]]. The lab was a source of counterfeit 80 mg [[oxycodone|OxyContin]] tablets containing fentanyl instead of oxycodone, as well as bulk fentanyl and other drugs.<ref>[http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0406/mg0406.html INTELLIGENCE ALERT: LARGE FENTANYL / MDA / TMA LABORATORY IN AZUZA, CALIFORNIA - POSSIBLY THE “OC-80” TABLET SOURCE], DEA Microgram, April 2006.</ref><ref>[http://www.usdoj.gov/dea/programs/forensicsci/microgram/mg0106/mg0106.html INTELLIGENCE ALERT: OXYCONTIN MIMIC TABLETS (CONTAINING FENTANYL) NEAR ATLANTIC, IOWA], DEA Microgram, January 2006.</ref> The "china white" form of fentanyl refers to the clandestinely produced analogue [[Alphamethylfentanyl|α-methylfentanyl]] (AMF).<ref>[http://www.erowid.org/archive/rhodium/chemistry/china.white.identification.html Behind the Identification of China White] Analytical Chemistry, 53(12), 1379A-1386A (1981)</ref> Although AMF is described as having a short duration of action (90 minutes), the main bonus of inserting the α-Me can be thought analogously to phenethylamines and amphetamines. The name amphetamine actually is based on chemical structure: '''a'''lpha '''m'''ethyl '''phe'''ne'''t'''hyl '''amines'''. Thus, the motivation for AMF is that despite the extra difficulty from a synthetic stand-point, the resultant drug is relatively more resistant to metabolic degradation resulting in a drug with an increased duration.<ref>{{cite journal |author=Van Bever W, Niemegeers C, Janssen P |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=J Med Chem |volume=17 |issue=10 |pages=1047–51 |year=1974 |pmid=4420811 |doi=10.1021/jm00256a003}}</ref> This is particularly noteworthy since an article in JPET reported that the main metabolite for fentanyl in vivo is the N-dealkylated metabolite.{{Fact|date=April 2008}} Additionally, AMF is reported to be ''at least'' three times more potent than fentanyl.{{Fact|date=April 2008}} ==Overdoses, recalls and legal action== A number of fatal fentanyl overdoses have been directly tied to the drug over the past several years. In particular, manufacturers of time-release fentanyl patches have come under scrutiny for defective products. While the fentanyl contained in the patches was safe, a malfunction of the patches caused an excessive amount of fentanyl to leak and to be absorbed by patients, resulting in life-threatening side effects and even death. Manufacturers of fentanyl transdermal pain patches have voluntarily recalled numerous lots of their patches and the FDA has issued Public Health Advisories related to the fentanyl patch dangers. Manufacturers affected include Janssen Pharmaceutica Products, L.P.; Alza Corporation; Actavis South Atlantic, LLC; Sandoz; Cephalon, Inc. and Mylan. On June 19, 2007, a $5.5 million jury verdict was awarded in a case against Johnson & Johnson subsidiaries, Alza Corporation and Janssen Pharmaceutica Products, the manufacturers of the Duragesic fentanyl transdermal pain patch. This case, the first Federal trial involving a fentanyl patch, was tried in the Federal District Court for the Southern District of Florida, West Palm Beach Division. Dallas, Texas-based law firm, Heygood, Orr, Reyes, Pearson & Bartolomei, achieved the verdict for the family of a 28-year-old Florida man (Adam Hendelson) who died while wearing a fentanyl transdermal pain patch. ==References== <div class="references-small"><references/> *Lehman, K. A., and D. Zech (eds) ''Transdermal Fentanyl: a new Approach to Prolonged Pain Control'', Berlin; New York: Springer-Verlag (1991) ISBN 0387544402</div> ==See also== *[[Psychoactive drug]] ==External links== * [http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a605043.html National Institute of Health (NIH) Medline Plus: Fentanyl] * [http://www.rxlist.com/cgi/generic/fentanyl.htm RxList: Fentanyl] * [http://www.fda.gov/cder/drug/advisory/fentanyl.htm FDA Public Health Advisory: Fentanyl] * [http://www.usdoj.gov/dea/concern/fentanyl.html US DEA information: fentanyl] * [http://www.cephalon.com/newsroom/news_reader.aspx?ID=1041238 08/16/2007 News Release: Cephalon Announces Positive Results from a Pivotal Study of FENTORA in Opioid-tolerant Patients with Non-cancer Breakthrough Pain] * [http://cns.miis.edu/pubs/week/02110b.htm Description of use of Fentanyl in Russia as an incapacitating weapon. See also [[Moscow theater hostage crisis]]] * [http://news.bbc.co.uk/1/hi/world/europe/2377563.stm BBC news report on Russian siege story] * [http://local.lancasteronline.com/4/24625 Lancaster Online story - New Killer: Fentanyl-Heroin Mix] {{General anesthetics}} {{Analgesics}} {{Opioids}} [[Category:Analgesics]] [[Category:Opioids]] [[Category:Piperidines]] [[bg:Фентанил]] [[cs:Fentanyl]] [[de:Fentanyl]] [[es:Fentanilo]] [[fr:Fentanyl]] [[ko:펜타닐]] [[it:Fentanyl]] [[hu:Fentanil]] [[nl:Fentanyl]] [[ja:フェンタニル]] [[pl:Fentanyl]] [[pt:Fentanil]] [[ro:Fentanyl]] [[ru:Фентанил]] [[fi:Fentanyyli]] [[sv:Fentanyl]] [[th:เฟนทานิล]] [[tr:Fentanil]]