Fentanyl is one of the most powerful opioid analgesics with a potency approximately 81 times that of morphine. Fentanyl has an LD₅₀ of 3.1 milligrams per kilogram in rats and 0.03 milligrams per kilogram in monkeys. The LD₅₀ in humans, by intravenous injection in an opiate-naive individual (without tolerance), is 0.5-1 milligrams. It is also a highly abused drug, as a result being categorized as a Schedule II drug in the United States.

History

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, eventually reaching record profits of over a billion dollars gross sales in 2004, following prescription practices extending beyond chronic cancer and non-cancer malignant pain.

Following the patch, a flavored-lollipop of fentanyl citrate mixed with inert fillers on a stick was introduced under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with breakthrough chronic 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.

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 affording 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 (510 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.