Picture of Fentanyl molecule

Fentanyl

Chemical Name:
N-(1-phenethyl-4-piperidyl)-N-phenyl-propanamide
Classification:
Opioid
Primary Uses:
Analgesia, anesthesia
Brand Names:
Actiq, Duragesic, Fentora, Sublimaze
Slang:
China White

General Information

Fentanyl, a fast-acting opioid analgesic, was developed by a Belgian pharmaceutical company called Janssen Pharmaceutica in 1960. Fentanyl is extremely strong in small quantities, with it being about 80 times more potent morphine. Shortly after the first synthesis of fentanyl, fentanyl citrate was first made, the active ingredient in the prescription lollipop, Actiq, which is used for breakthrough pain. During the 1960s, doctors began using fentanyl quite frequently as an anesthetic.

Opioid analgesics have assumed a huge role in the practice of general anesthesia during the past thirty years. Before fentanyl, sometimes a morphine-oxygen anesthesia was used; however, problems often occurred in the form of "incomplete amnesia, occasional histamine-related reaction, and marked increases in intra- and postoperative respiratory depression." The invention of fentanyl was a huge breakthrough in the world of general anesthesia. Since then, two potent fentanyl analogues have been introduced into clinical practice—sufentanil and alfentanil.1

Over the past few years, there have been many cases of heroin being mixed with fentanyl and sold on the street. Because of the strength of fentanyl, and inconsistencies in purity and potency, there have been documented deaths and overdoses. If you are an active drug user, please be cautious.

Pharmacology & Pharmacokinetics

Fentanyl acts mostly on the mu-opioid receptors and exerts its primary pharmacologic effects on the central nervous system. The mu-opioid receptors are scattered throughout the brain, spinal cord, and other bodily tissues. The actions of therapeutic value include sedation and analgesia. Other effects include respiratory depression, cough suppression, and pupil constriction. In addition, some common reactions include euphoria, dysphoria, drowsiness, and mood changes.2

The half-life of fentanyl is seven hours, but may range from 3-12 hours. Oral transmucosal fentanyl citrate, such as Oralet by Abbott Laboratories, resulted in a bioavailability ranging from 34% to 59%.3 Transdermal fentanyl has a bioavailability of at least 90%. The use of fentanyl along with strong and moderate cytochrome P450 3A4 inhibitors can cause an increase in plasma concentrations of the opioid, and result in death by respiratory depression.

Chemistry

Synthesis:
The following was the original procedure used by Janssen Pharmaceutica to produce fentanyl:4

  • 4-piperidinone hydrochloride was first reacted with phenethyl bromide to give N-phenethyl-4-piperidinone (NPP).
  • Treatment of the NPP intermediate with aniline.
  • Reduction with sodium borohydride afforded 4-anilino-N-phenethyl-piperidine (ANPP).
  • A final acylation reaction between ANPP and propionic anhydride led to the fentanyl.

Analogues:

  • Alfentanil
    • Opioid analgesic (painkiller) with rapid onset of action
    • Used for surgery
    • Injectable alfentanil marketed under brand name Alfenta
    • Can last around 30 minutes

  • Carfentanil
    • Marked under the name Wildnil as a tranquilizer for large animals
    • 10,000 times stronger than morphine
    • 100 times stronger than fentanyl
    • Discovered by Janssen Pharmaceutica

  • Remifentanil
    • Opioid analgesic (painkiller) marked under the name Ultiva
    • Extremely rapid onset and offset
    • Blood concentration decreases by 50% in 3-6 minutes after a one-minute infusion of remifentanil

  • Sufentanil
    • 5-10 times more potent than fentanyl
    • Marketed as Sufenta and Sufentil
    • Sometimes used during anesthesia
    • Transdermal patch for chronic pain sufferers currently in development
    • Transdermal sufentanil patch will be released by Durect Corporation under the name TRANSDUR™

Legal Status

In the United States, this drug is a Schedule II substance, making it illegal to use or possess without a prescription. Schedule II substances, such as dextroamphetamine, morphine, oxycodone, and cocaine, meet the following criteria according to the Controlled Substances Act:

Side Effects

  • Pain relief
  • Euphoria or dysphoria
  • Mood changes
  • Reduced anxiety
  • Sedation
  • Itching
  • Nausea & vomiting
  • Decreased libido (sex drive)
  • Constipation
  • Facial flushing
  • Sweating
  • Vertigo

Withdrawal

Fentanyl in any form is highly addictive, and users often become mentally and physically dependent. Withdrawal typically begins within 24-36 hours after the last dose and peaks in intensity around 72-96 hours; however, it can start much sooner for chronic users. Withdrawal symptoms include gooseflesh, restless legs and arms, anxiety, nausea, vomiting, depression, muscle aches, insomnia, diarrhea, headaches, and dilated pupils.

Sources

[1] Stanley TH, The history and development of the fentanyl series. Entrez PubMed [1517629]. J Pain Symptom Manage. 1992 Apr;7(3 Suppl):S3-7. Accessed: May 8, 2007.
[2] DrugBank: Fentanyl. DrugBank [APRD00347]. Feb. 2007. Accessed: May 8, 2007.
[3] Melissa Wheeler, M.D., Patrick K. Birmingham, M.D., Ralph A. Lugo, Pharm.D., Corri L. Heffner, R.N., and Charles J. Cote, M.D. The Pharmacokinetics of the Intravenous Formulation of Fentanyl Citrate Administered Orally in Children Undergoing General Anesthesia. International Anesthesia Research Society. Anesth Analg 2004;99:1347-1351. [Abstract] Accessed: May 8, 2007.
[4] Fentanyl. Wikipedia, the free encyclopedia. May 3, 2007. [link] Accessed: May 8, 2007.