Fentanyl: Biological Mechanisms, Surgical Applications and Side Effects

Fentanyl is a synthetic opioid drug that is 50 to 100 times more potent than morphine and exhibits vastly different properties and pharmacokinetics.¹ The Belgian pharmaceutical company Janssen Pharmaceutica first developed fentanyl in 1959.² In the 1960s, fentanyl was introduced into medical practice as an anesthetic agent, and is now used for both anesthesia and analgesia.² Fentanyl is classified as a United States Drug Enforcement Administration (DEA) Schedule II drug, which means that it has “a high potential for abuse, with use potentially leading to severe psychological or physical dependence.”³ In December 2018, the Centers for Disease Control and Prevention (CDC) pronounced fentanyl the deadliest drug in America due to its potency, addictive properties and role in the opioid crisis.⁴ Because of fentanyl’s potential to cause rapid death, anesthesia providers should understand its biological mechanisms, surgical applications and side effects.⁴

The molecular formula for fentanyl, also known as fentanyl citrate, is C₂₂H₂₈N₂O.⁵ Fentanyl is lipophilic, meaning that it tends to spread to fatty tissues and thus has greater bioavailability than hydrophilic (water-soluble) drugs.⁵ Like other opioids, fentanyl binds to the m-opioid receptor in the central nervous system (CNS), thus reducing neuronal excitability.⁵ However, fentanyl also serves as an agonist for other opioid receptors such as the delta and kappa receptors.¹ Activation of these opioid receptors produces analgesia, while increases in the release of dopamine elicits exhilaration and relaxation effects.¹ Fentanyl is metabolized extensively in the liver and intestines via the enzyme CYP3A4.⁵ Less than 11 percent of the dose is excreted through urine and feces as inactive metabolites or as unchanged drug.⁵ Fentanyl metabolism, elimination and duration of effects may be affected by medications or substances that inhibit the CYP3A4 enzyme.⁶

Fentanyl comes in several forms, which allow it to serve a variety of purposes.⁷ When used to treat breakthrough pain for patients who use opioids on a long-term basis, fentanyl comes as a lozenge on a handle, a sublingual tablet, a film and a buccal tablet.⁷ Fentanyl is also administered intravenously, intramuscularly, transdermally as skin patches, intranasally via a nasal spray and intrathecally.¹ In contrast to other opioid drugs, fentanyl is less common as an oral tablet or powder.¹ For surgical procedures, fentanyl can be used preoperatively, during surgery and in the immediate postoperative period.⁵ Before surgery, fentanyl provides anxiolysis and relaxation.⁵ In combination with other anesthetic drugs, fentanyl is useful for procedures that require patients to be lightly anesthetized or awake.⁵ However, it may be administered with oxygen and a muscle relaxant to provide anesthesia without the use of additional anesthetic agents.⁵ Fentanyl can prevent or relieve postoperative emergence delirium.⁵ Clearly, fentanyl has various uses as an analgesic and anesthetic drug.

Unfortunately, fentanyl’s many uses are accompanied by many side effects. Fentanyl’s side effects are similar to those of heroin, including euphoria, confusion, drowsiness, nausea, visual disturbances or hallucinations, delirium and constipation.¹ Serious adverse effects include addiction, hypotension, coma, respiratory depression and death.¹ Fentanyl and its derivatives can produce rigidity in the diaphragm, chest wall and upper airway—known as “wooden chest syndrome” (WCS)—within a narrow dosing range.⁴ WCS can be fatal and causes rapid death without proper airway management.⁴ Because fentanyl is so potent and overdose is likely, anesthesia providers must be extremely diligent when providing patients with fentanyl.⁸ Patients who have respiratory issues or liver failure or who are using drugs such as alcohol, antibiotics or antifungal agents may not be able to use fentanyl.¹ Fentanyl can be habit forming, so patients should be educated about its proper use and addictive properties.⁷

Fentanyl is an extremely potent synthetic opioid that is used for analgesia and anesthesia. By activating certain opioid receptors, fentanyl inhibits neuronal activity. Fentanyl is primarily used for analgesia in combination with other anesthetics. Fentanyl’s side effects range from drowsiness and nausea to coma, respiratory depression and even death. Because fentanyl is a highly addictive substance, anesthesiology professionals should prescribe it cautiously.

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2.         Dale E, Ashby F, Seelam K. Report of a patient chewing fentanyl patches who was titrated onto methadone. BMJ Case Reports. 2009;2009:bcr01.2009.1454.

3.         United States Drug Enforcement Administration. Drug Scheduling. Drug Information 2020; https://www.dea.gov/drug-scheduling.

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5.         Fentanyl. PubChem Database. Web: National Center for Biotechnology Information; 2020.

6.         Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate. Anesthesiology. 2004;101(3):729–737.

7.         Fentanyl. MedlinePlus. Bethesda, MD: National Institutes of Health; October 15, 2019.

8.         Simmons B, Kuo A. 40—Analgesics, Tranquilizers, and Sedatives. In: Brown DL, ed. Cardiac Intensive Care (Third Edition). Philadelphia: Elsevier; 2019:421–431.e425.