||It has been suggested that Abstral, Actiq and Duragesic be merged into this article. (Discuss) Proposed since April 2013.|
|Systematic (IUPAC) name|
|Trade names||Actiq, Duragesic, Fentora, Sublimaze and others|
|Pregnancy cat.||C (US)|
|Legal status||Controlled (S8) (AU) Class A (UK) Schedule II (US)|
|Dependence liability||Moderate – high|
|Routes||TD, IM, IV, oral transmucosal, sublingual, buccal|
|Metabolism||hepatic, primarily by CYP3A4|
|Half-life||(IV)= 10-20 mins (T1/2 β)
2-4 hours (T1/2 ɣ)
Intranasal = 6.5 mins
Transdermal = 20–27 h
|Excretion||60% Urinary (metabolites, <10% unchanged drug)|
|ATC code||N01 N02|
|Mol. mass||336.471 g/mol|
|Melt. point||87.5 °C (190 °F)|
|(what is this?)|
Fentanyl (also known as fentanil, brand names Sublimaze, Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis, Instanyl, Abstral, Lazanda and others) is a potent, synthetic opioid analgesic with a rapid onset and short duration of action. It is a strong agonist at the μ-opioid receptors. Historically it has been used to treat breakthrough pain and is commonly used in pre-procedures as a pain reliever as well as an anesthetic in combination with a benzodiazepine.
Fentanyl is approximately 100 times more potent than morphine, with 0.1 milligrams (mg) of fentanyl approximately equivalent to 10 mg of morphine and 75 mg of pethidine (meperidine) in analgesic activity.[dead link]
Fentanyl was first synthesized by Paul Janssen in 1960 following the medical inception of pethidine several years earlier. Janssen developed fentanyl by assaying analogues of the structurally related drug pethidine for opioid activity. The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 stoichiometry), which entered the clinical practice as a general anaesthetic under the trade name Sublimaze in the 1960s. Following this, many other fentanyl analogues were developed and introduced into medical practice, including sufentanil, alfentanil, remifentanil, and lofentanil.
In the mid-1990s, fentanyl was first introduced for widespread palliative use with the clinical introduction of the Duragesic patch, followed in the next decade by the introduction of the first quick-acting prescription formations of fentanyl for personal use, the Actiq lollipop and Fentora buccal tablets. Through the delivery method of transdermal patches, as of 2012[update] fentanyl was the most widely used synthetic opioid in clinical practice, with several new delivery methods currently in development, including a sublingual spray for cancer patients.
Fentanyl and its derivatives are used recreationally. Deaths have resulted from both recreational and medical use, some because of malfunctioning patches.
Intravenous fentanyl is extensively used for anesthesia and analgesia, most often in operating rooms, intensive care units and in the prehospital medical setting. The concept of a general anesthetic is based upon a balance between an opioid and a hypnotic agent. Hence, fentanyl is used mainly for induction of anaesthesia alongside a hypnotic agent like propofol. It is also administered in combination with a benzodiazepine, such as midazolam, to produce procedural sedation for endoscopy, cardiac catheterization, oral surgery, etc., and is often used in the management of chronic pain including cancer pain.
Fentanyl transdermal patch (Durogesic/Duragesic/Matrifen) is used in chronic pain management. The patches work by releasing fentanyl into body fats, which then slowly release the drug into the bloodstream over 48 to 72 hours, allowing for long-lasting relief from pain. The patches are available in generic form, which has made them available at lower cost. Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is 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 or oxycodone) to handle breakthrough pain.
Fentanyl lozenges (Actiq) are a solid formulation of fentanyl citrate on a 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 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 swabbed on the mucosal surfaces inside the mouth—inside of the cheeks, under and on the tongue and gums—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%. These are now available in the United States in generic form, through an FTC consent agreement. However, most patients find that 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.
During 2008-09, a wide range of fentanyl preparations became 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.
On July 16, 2009, the FDA approved Onsolis (BEMA Fentanyl) for breakthrough cancer pain. Onsolis incorporates "bioerodible mucoadhesive" technology, a small soluble film that contains fentanyl, which is placed on the inside cheek of the mouth.
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 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.
Fentanyl's major side-effects (more than 10% of patients) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion, asthenia (weakness), 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 (indigestion), dyspnea (shortness of breath), hypoventilation, apnea, and urinary retention. Fentanyl use has also been associated with aphasia.
Like other lipid-soluble drugs, the pharmacodynamics of fentanyl are poorly understood. The manufacturers acknowledge that there are no data on the pharmacodynamics of fentanyl in elderly, cachectic, or debilitated patients, frequently the type of patient for whom transdermal fentanyl is being used. This may explain the increasing number of reports of respiratory depression events since the late 1970s. In 2006 the U.S. 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 young children had died or become seriously ill from accidental exposure to a fentanyl skin patch.
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.
Storage and disposal
Fentanyl is one of a small number of drugs that may be especially harmful, and in some cases fatal, with just one dose, if used by someone other than the person for whom the drug was prescribed. All fentanyl medicine should be kept in a secure location that is out of children’s sight and reach, such as a locked cabinet.
When they cannot be disposed of through a drug take-back program, flushing is recommended for fentanyl medicines because it is the fastest and surest way to remove these potent medicines from the home so they cannot harm children, pets, and others not intended to use them.
Fentanyl patches should be flushed down the toilet as soon as they are removed from the body, and unused fentanyl patches should be flushed as soon as they are no longer needed. Detailed "Instructions for Use", with complete information on how to apply, use, and dispose of fentanyl patches, are available on the FDA website.
Overdoses and fatalities
A number of fatal fentanyl overdoses have been directly tied to the drug over a period of 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 become 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 U.S. Food and Drug Administration (FDA) has issued public health advisories related to fentanyl patch dangers. Manufacturers affected include Janssen Pharmaceutica Products, L.P.; Alza Corporation; Actavis South Atlantic, LLC; Sandoz; and Cephalon, Inc.
Fentanyl has an LD50 of 3.1 milligrams per kilogram (mg/kg) in rats, and an LD50 of 0.03 mg/kg in monkeys.
In 2009, the former guitarist for the band Wilco, Jay Bennett, died in his sleep of an overdose of the drug via Duragesic time-release patches prescribed for him. In 2010, band Slipknot's bassist Paul Gray overdosed and died after abusing a mixture of fentanyl and morphine, for which there was no evidence of a prescription. An inquest jury found by a majority verdict of 3-2 that an overdose of fentanyl was responsible for the death by misadventure of Anita Chan Lai-ling, 69, who died on October 17, 2007, after she was given an overdose of fentanyl. On June 27, 2005, Laurence Harvey's daughter Domino Harvey was found unconscious in her bathtub, and the Los Angeles County Coroner's office determined that she had overdosed on fentanyl. In 2009 27-year-old Hayley Fisher, a midwife at King Edward Memorial Hospital for Women in Australia, died after injecting herself with fentanyl.
The synthesis of fentanyl by Janssen Pharmaceutica was achieved in four steps, starting from 4-piperidinonehydrochloride. The sequence commenced with N-alkylation of 4-piperidinone with 2-phenylethylbromide to give N-phenethyl-4-piperidinone (NPP). Reductive amination of NPP using aniline and sodium borohydride afforded 4-anilino-N-phenethylpiperidine (ANPP). Finally, N-acylation of the secondary amine with propionic anhydride provided fentanyl.
Structural analogs of fentanyl include:
- Alfentanil (trade name Alfenta), an ultra-short-acting (five- to 10-minute) analgesic.
- Sufentanil (trade name Sufenta), a potent analgesic (five to 10 times more potent than fentanyl) for use in specific surgeries and surgery in heavily opioid-tolerant/opioid-dependent patients. Its binding affinity is high enough to theoretically break through a buprenorphine blockade to offer pain relief from acute trauma in patients taking high-dose buprenorphine.
- 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.
- Lofentanil is an analogue of fentanyl with a potency slightly greater than that of carfentanil.
- 3-Methylfentanyl (thought to be the active constituent of Kolokol-1, a chemical weapon)
- α-Methylfentanyl (see below)
Mechanism of action
Fentanyl provides some of the effects typical of other opioids through its agonism of the opioid receptors. Its strong potency in relation to that of morphine is largely due to its high lipophilicity, per the Meyer-Overton correlation. Because of this, it can more easily penetrate the CNS.
Fentanyl binds μ-opioid G-protein-coupled receptors, which inhibit pain neurotransmitter release by decreasing intracellular Ca2+ levels.
Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959. In the 1960s, fentanyl was introduced as an intravenous anesthetic under the trade name of Sublimaze. In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formation 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. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into the medical practice.
Following the patch, a flavored lollipop of fentanyl citrate mixed with inert fillers was introduced under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain. More recently, fentanyl has been developed into an effervescent tab for buccal absorption much like the Actiq lollipop, followed by a buccal spray device for fast-acting relief and other delivery methods currently in development.
A fentanyl product has been approved by the US Food and Drug Administration (FDA) for breakthrough cancer pain called Onsolis. It uses a drug delivery technology called BEMA (fentanyl buccal soluble film) on a small disc placed in the mouth. Unlike many other fentanyl products, the drug cannot be abused by crushing and inhaling.
||The examples and perspective in this section deal primarily with the United States and do not represent a worldwide view of the subject. (September 2011)|
Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. United States authorities classify fentanyl as a narcotic and an opioid. To date, more than 12 different analogues of fentanyl have been produced clandestinely and identified in the U.S. drug traffic. The biological effects of the fentanyl analogues 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.
The use of fentanyl has caused death. Fentanyl analogues may be hundreds of times more potent than street heroin, and tends to produce significantly more respiratory depression, making it somewhat more dangerous than heroin to users. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin, often leading to overdoses. Many fentanyl overdoses are initially classified as heroin overdoses. In Estonia, due to its high rate of recreational use, fentanyl causes more deaths nationwide than traffic accidents.
Fentanyl is sometimes 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.
Another dosage form of fentanyl that has appeared on the streets is the Actiq fentanyl lollipops, which are sold under the street name of "percopop". The pharmacy retail price ranges from US$15 to US$50 per unit (based on strength of lozenge), with the black market cost anywhere from US$20 to US$80 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. 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 United States 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, therefore, very dangerous.
Some heroin dealers mix fentanyl powder with heroin to increase potency or compensate for low-quality heroin. In 2006, illegally manufactured, non-pharmaceutical fentanyl often mixed with cocaine or heroin caused an outbreak of overdose deaths in the United States, heavily concentrated in the cities of Dayton, (Ohio), Chicago, Detroit, and Philadelphia, as well as Baltimore, Pittsburgh, St. Louis, Milwaukee, and Camden (New Jersey). Little Rock and Dallas were also affected. The mixture of fentanyl and heroin is known as "magic" or "the bomb", among other names, on the street.
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 was seized by Border Patrol agents in California from a vehicle that had entered from Mexico. Mexico is the source of much of the illicit fentanyl for sale in the U.S. However, in April 2006, there was one domestic fentanyl lab discovered by law enforcement in Azusa, California. The lab was a source of counterfeit 80-mg OxyContin tablets containing fentanyl instead of oxycodone, as well as bulk fentanyl and other drugs.
The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF). This Department of Justice document lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl, which today are classified as Schedule I drugs in the United States. Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is relatively more resistant to metabolic degradation. This results in a drug with an increased duration.
In June 2013, the United States' Centers for Disease Control and Prevention (CDC) issued a health advisory to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, a novel, injected, non-prescription synthetic opioid analog of fentanyl.
The Danish Army uses the fentanyl stick in military operations as a painkiller. The war documentary Armadillo (2010) features an interview with a Danish medic who tells of using fentanyl on a severely wounded soldier in Afghanistan.
It is alleged that Mossad agents used "levofentanyl" in their 1997 attempt to kill Hamas leader Khalid Mishal. However, since fentanyl is achiral (i.e., has no "levo-" form), the substance was probably fentanyl itself, a fentanyl analogue, or another opioid. However, it could have been a non-opioid sedative or unknown drug.
A gas, it is presumed, based on a derivative of fentanyl was used in 2002 in the Moscow theatre hostage crisis to incapacitate Chechen terrorist attackers (and their hostages) too quickly for them to retaliate. More than 15% of those affected died, including 117 of the 800 hostages.
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