Fentanyl

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Fentanyl
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. mass	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 by CYP3A4
Half life	7 hours (range 3–12 h)
Excretion	Urine
Therapeutic considerations
Pregnancy cat.	C(US)
Legal status	Schedule II(US)
Dependence Liability	Moderate - High
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, and, 0.03 milligrams per kilogram in monkeys. The LD₅₀ in humans is not known. In the United States, fentanyl is a Schedule II drug.

[edit] Chemistry

[edit] 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 acylation reaction between ANPP and propionic anhydride led to the fentanyl

[edit] Analogues

The pharmaceutical industry has developed several analogues of fentanyl:

• Alfentanil (trade name Alfenta), an ultra-short acting (5–10 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.

[edit] Therapeutic use

Fentanyls are extensively used for anesthesia and analgesia, most often in the operating room and intensive care unit. Duragesic, by Janssen Pharmaceutica, is a fentanyl transdermal patch used in chronic pain management. Duragesic patches work by releasing fentanyl into body 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 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 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]
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. The development of small fentanyl buccal pellets may be much more practical.

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, according to the prescribing information,^[4] is quicker absorption into the bloodstream at lower dosage levels.

Fentanyl is frequently given intrathecally as part of spinal anesthesia or epidurally for epidural anesthesia and analgesia. It is also used as a sedative.

[edit] Adverse effects

Like other lipid soluble drugs, the pharmacokinetics of fentanyl are poorly understood. The manufacturers acknowledge there is no data on the pharmacokinetics of fentanyl in elderly, 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 and respiratory deaths since the 1980s.^{[citation needed]} 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.

In palliative care fentanyl has a definite, but limited, role for:

• Patients already stabilised on other opioids but who cannot swallow
• Patients with moderate to severe renal failure

Fentanyl is not considered a first line opioid in palliative care—morphine remains the first line choice, and safer opiate derivatives such as oxycodone and hydromorphone are usually tried before resorting to fentanyl.

[edit] Illicit use

Fentanyl powder seized by a Lake County Deputy Sheriff in Painesville, Ohio, where a male subject had been discovered unresponsive and struggling to breathe

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 longer 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 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 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, Milwaukee, Camden, Chicago,^[5] Little Rock, and Dallas.^[6] The mixture of fentanyl and heroin is known as "magic", among other names, on the street.^[7]

Both Actiq and Duragesic are becoming as popular as OxyContin in pharmacy burglaries and robberies.^{[citation needed]} 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.^{[citation needed]}

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.^[8] 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 OxyContin tablets containing fentanyl instead of oxycodone, as well as bulk fentanyl and other drugs.^[9][10]

The "china white" form of fentanyl refers to the clandestinely produced analogue alpha-methyl fentanyl (AMF).^[11] 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.^[12]

[edit] References

[edit] See also

• Psychoactive drug

[edit] External links

• Description of use of Fentanyl in Russia as an incapacitating weapon. See also Moscow theater hostage crisis
• US DEA information: fentanyl
• BBC news report on Russian siege story
• Amid fentanyl deaths, investigation, addicts keep using in the Chicago Defender
• Lancaster Online story - New Killer: Fentanyl-Heroin Mix
• Links to external chemical sources