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Fentanyl
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| Systematic (IUPAC) name | |
| N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propanamide | |
| Identifiers | |
| CAS number | 437-38-7 |
| ATC code | N01AH01 N02AB03 |
| PubChem | 3345 |
| DrugBank | APRD00347 |
| Chemical data | |
| Formula | C22H28N2O |
| Mol. weight | 336.471 g/mol |
| Physical data | |
| Melt. point | 87.5 °C (190 °F) |
| Pharmacokinetic data | |
| Bioavailability | 92% (transdermal) 50% (buccal) |
| Protein binding | 80-85% |
| Metabolism | hepatic, primarily CYP3A4 |
| Half life | 7 (range 3-12) hours |
| Therapeutic considerations | |
| Pregnancy cat. | C(US) |
| Legal status | Schedule II(US) |
| Routes | TD, IM, IV, oral, sublingual, buccal |
Fentanyl is an opioid analgesic, first synthesized by Janssen Pharmaceutica (Belgium) in the late 1950s, with an analgesic potency of about 80 times that of morphine. Fentanyl was introduced into medical practice in the 1960s as an intravenous anesthetic under the trade name of Sublimaze. Fentanyl has an LD50 of 3.1 milligrams per kilogram in rats. The LD50 in humans is not known. Fentanyl is a Schedule II drug.
Contents |
Synthesis
The synthesis of fentanyl (N-phenyl-N-(1-phenethyl-4-piperidinyl)propanamide) by Janssen Pharmaceutica was achieved in four steps, starting from 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). A final reaction between ANPP and propionic anhydride led to the fentanyl with a 47% overall yield.
Analogues
The pharmaceutical industry has developed several analogues of fentanyl:
- Alfentanil (Alfenta), an ultra-short acting (5–10 minutes) analgesic,
- Sufentanil (Sufenta), a potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery.
- Remifentanil, currently the shortest acting opioid, has the benefit of rapid offset, even after prolonged infusions.
- Carfentanil (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.
Therapeutic use
All forms of fentanyls are to be used only by opioid-tolerant patients; several deaths have occurred when used by other patients. Today, fentanyls are extensively used for anesthesia and analgesia. Duragesic, by Janssen Pharmaceutica, is a fentanyl transdermal patch used in chronic pain management. Duragesic patches work by releasing fentanyl into subcutaneous fats, which then slowly release the drug into the blood stream over 72 hours, allowing for long lasting relief from pain. In the past few years, the patches have gone generic and are available for lower costs. Duragesic is manufactured in five patch sizes: 12.5 µg/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 and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption.
Actiq, by Cephalon, is a recently-developed solid formulation of fentanyl citrate on a stick in the form of a lollipop that dissolves slowly in the mouth for transmucosal absorption. Actiq is intended for opioid-tolerant individuals and is 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 which is 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, absorption from the alimentary tract being poor. Actiq is available in six dosages, from 200 to 1600 µg in 200 µg increments (excluding 1000 µg and 1400 µg). Actiq is now available in the United states in generic form[1], through an FTC consent agreement[2].
FENTORA™ is a new delivery method of fentanyl; it is an effervescent tablet placed in the cheek and is absorbed through the buccal mucosa. It was introduced on 2006-09-25[3]. One advantage of FENTORA is quicker absorption into the bloodstream at lower dosage levels according to the prescribing information[4].
Fentanyl is frequently given intrathecally as part of spinal anesthesia or epidurally for epidural anesthesia and analgesia.
Illicit use
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 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 there is less of a euphoric 'high' associated with the drug and a stronger analgesic effect. Additionally, fentanyl may be hundreds of times more potent — though in some places, it is sold as heroin, often leading to overdoses. Fentanyl also has a shorter half-life than that of heroin, and is most commonly used orally, but like heroin, can also be smoked, snorted or injected.
Actiq has appeared on the streets under the street name of "percopop". The pharmacy retail price ranges from US$16 to US$50 per unit (based on strength of lozenge), with the black market cost is anywhere from US$20 to US$60 per unit, depending on the strength.
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 late May 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, Milwaukee, Camden, Chicago,[5], and Little Rock. The mixture of fentanyl and heroin is known as "magic", among other names, on the street. [6]
Both Actiq and Duragesic are becoming as popular as OxyContin in pharmacy burglaries and robberies. In the U.S., law enforcement agencies are being instructed in how to tell the difference between Actiq and other medications so they are better able to notice abuse of the drug.
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.[7] 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, CA. The lab was a source of counterfeit 80 mg OxyContin tablets containing fentanyl instead of oxycodone, as well as bulk fentanyl and other drugs.[8],[9]
The "china white" form of fentanyl refers to the clandestinely produced alpha-methyl strain (AMF) [10] . This has been reported in the literature to be twice the strength of regular fentanyl. The main bonus of the alpha-methyl is it provides a site of resistance to metabolic degradation resulting in a drug with an increased duration [11].
References
- ^ Barr Pharmaceuticals (2006-09-27). Barr Launches Generic ACTIQ(R) Cancer Pain Management Product. Press release. Retrieved on 2006-09-30.
- ^ FTC (2004-08-09). With Conditions, FTC Allows Cephalon’s Purchase of CIMA, Protecting Competition for Breakthrough Cancer Pain Drugs. Press release. Retrieved on 2006-09-30.
- ^ Cephalon (2006-09-25). Cephalon Receives FDA Approval of FENTORA(TM) (fentanyl buccal tablet) for the Management of Breakthrough Pain in Patients with Cancer. Press release. Retrieved on 2006-09-30.
- ^ FENTORA™ prescribing information (pdf).
- ^ Press Release by the Chicago Police Department Police report about a death lined to heroin/fentanyl mixture August 24, 2006
- ^ Fentanyl probe nets 3 suspects by Norman Sinclair and Ronald J. Hansen, The Detroit News, June 23, 2006, retrieved June 25, 2006.
- ^ INTELLIGENCE ALERT: HIGH PURITY FENTANYL SEIZED NEAR WESTMORELAND, CALIFORNIA, DEA Microgram, June 2006
- ^ INTELLIGENCE ALERT: LARGE FENTANYL / MDA / TMA LABORATORY IN AZUZA, CALIFORNIA - POSSIBLY THE “OC-80” TABLET SOURCE, DEA Microgram, April 2006.
- ^ INTELLIGENCE ALERT: OXYCONTIN MIMIC TABLETS (CONTAINING FENTANYL) NEAR ATLANTIC, IOWA, DEA Microgram, January 2006.
- ^ Behind the Identification of China White Analytical Chemistry, 53(12), 1379A-1386A (1981)
- ^ J. Med. Chem.; 1974; 17(10); 1047-1051
