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Last Update: March 16, 2021.

Continuing Education Activity

Fentanyl is a potent synthetic opioid, which, similar to morphine, produces analgesia but to a greater extent. This robust pharmacologic agent is typically 50 to 100 times more potent. A dose of only 100 micrograms can produce equivalent analgesia to approximately 10 mg of morphine. However, fentanyl exhibits vastly different properties and pharmacokinetics. Clinically, its most common use is as a sedative in intubated patients and severe cases of pain in patients with renal failure due to its primarily hepatic elimination. At times, fentanyl may also be indicated to treat chronic pain patients who have developed tolerance to opiates. When used as a sedative, drug administration is most commonly via a drip. Lastly, fentanyl uses can extend to the treatment of epilepsy. That is, in combination with certain neuroleptic medications as part of therapeutic neuroleptanalgesia. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, monitoring, and toxicity of fentanyl so that providers can direct patient therapy to optimal outcomes.


  • Identify the mechanism of action of fentanyl.
  • Summarize the approved indications for pain control therapy with fentanyl.
  • Review the contraindications and adverse event profile of fentanyl.
  • Explain interprofessional team strategies for improving care coordination and communication to advance fentanyl therapy and improve outcomes and minimize adverse events and misuse, especially in light of the ongoing opioid crisis.
Access free multiple choice questions on this topic.


Fentanyl is a strong synthetic opioid, similar to morphine but produces analgesia to a greater extent. This robust pharmacologic agent is typically 50 to 100 times more potent. A dose of only 100 micrograms can produce equivalent analgesia to approximately 10 mg of morphine. However, fentanyl exhibits vastly different properties and pharmacokinetics. Clinically, its most frequent use is as a sedative in intubated patients and severe cases of pain in patients with renal failure due to its primarily hepatic elimination. At times, clinicians may also use fentanyl to treat chronic pain patients who have developed tolerance to opiates. When used as a sedative, it is most commonly administered as a drip, owing to its versatility in titration scenarios. It may often require large doses when used as a sedative in patients with mechanical ventilation requirements. As pre-medication for procedures, namely those anticipated to cause discomfort, fentanyl is also an option perioperatively. Lastly, fentanyl use can extend to the treatment of epilepsy. That is, in combination with certain neuroleptic medications as part of therapeutic neuroleptanalgesia.[1][2][3]

Mechanism of Action

Fentanyl is similar to other opioid drugs. Fentanyl molecules target a subclass of opioid receptor systems in the body, many of which are localized in the brain within specialized neuroanatomical structures, particularly involving the control of emotions, pain, and speaking to the point of its infamous addictive properties, reward. Biochemically, it is a Mu-selective opioid agonist. However, it has the capability to activate other opioid system receptors such as the delta and potentially the kappa-receptors. Consequently, the activation of these receptors, particularly the Mu-receptors, produces analgesia. Also, the neurotransmitter dopamine (Da) is increased in the reward areas of the brain, which elicits the stereotypical exhilaration and relaxation effects, and is typically associated with the addiction to the drug.[4]


Fentanyl is typically administered intravenously (IV), intramuscularly (IM), transdermally (TD) as skin patches, intranasally (IN) in the form of a volatile nasal spray, and intrathecally (IT). It is also available as a buccal soluble thin film (Breakyl), which can dissolve in the mouth, similar to the sublingual tablets. However, in contrast to other opiates, it is less common to find forms of synthetic drugs as oral tablets or powders. A new medication currently being used to address the gastrointestinal (GI) side effects without counteracting its primary analgesic aims acts selectively on the GI mu-opioid receptors and can aid in alleviating constipation while still providing pain relief, a dilemma previously treated off-label in some hospitals by suspending a vial of naloxone in ice water and taking the mix enterally. The transdermal patch is for the long-term management of pain. 

Adverse Effects

Fentanyl's side effects are similar to those of heroin, which produce euphoria, confusion, respiratory depression (which, if extensive and untreated, may lead to arrest), drowsiness, nausea, visual disturbances, dyskinesia, hallucinations, delirium, a subset of the latter known as "narcotic delirium," analgesia, constipation, narcotic ileus, muscle rigidity, constipation, addiction, loss of consciousness, hypotension, coma, and even death. Alcohol and other drugs (i.e., cocaine, heroin) can synergistically exacerbate fentanyl's side effects, creating multi-layered clinical scenarios that can be complex to manage. These substances, taken together, generate undesirable conditions that complicate the patient's prognosis.[5][6][7]


The use of fentanyl is contraindicated in patients in the following situations:

  • After operative interventions in the biliary tract, as these may slow hepatic elimination of the drug.
  • With respiratory depression or obstructive airway diseases (i.e., asthma, COPD, obstructive sleep apnea, obesity hyperventilation, also know as, Pickwickian syndrome)
  • With liver failure
  • With known intolerance to fentanyl or other morphine-like drugs, including codeine
  • With known hypersensitivity (i.e., anaphylaxis) or any common drug delivery excipients (i.e., sodium chloride, sodium hydroxide). 

The drug fentanyl should not be used concomitant with certain medications such as CYP3A4 inhibitors like macrolide antibiotics or azole-antifungal agents, and protease inhibitors may increase plasma concentrations of fentanyl, extending the opioid drug action and exacerbating the opioid-induced respiratory depression (OIRD). On the other hand, the cessation of a CYP3A4 inducer medication (i.e., carbamazepine, phenytoin) in patients treated with fentanyl citrate injections may potentially increase fentanyl plasma concentrations prolonging the opioid adverse reactions.


When using fentanyl citrate injections along with medications such as CYP3A4 inhibitors or stopping the CYP3A4 inducers in patients treated with fentanyl injections, the patients should receive frequent and close monitoring. Also, consider lowering the dose of fentanyl. Similarly, when using fentanyl citrate injection in conjunction with CYP3A4 inducer medications, or stopping the CYP3A4 inhibitors, an undesirable reduction in fentanyl plasma concentrations may occur, thereby decreasing its systemic efficacy. The use of fentanyl citrate injection with CYP3A4 inducers or stopping the CYP3A4 inhibitor will require close and repetitive monitoring of the patient. Also, consider augmenting the dose of fentanyl, as needed.


Typically, a fentanyl overdose manifests as an extrapolation of its pharmacological side effects. Although the clinical scenarios may vary among patients, one of the main concerns is the level of expression of OIRD. In such cases, oxygen administration and respiratory assistance are a priority. An opioid drug antagonist such as naloxone can help to correct OIRD symptoms. Commonly, repeated doses are necessary since, over time, respiratory depression may overcome the effects of the antagonist drug, particularly with opiates such as fentanyl, in which increased receptor affinity may be present as compared to other opiates. Thus, the therapeutic approach should continue until a normal respiratory rate coincides with appropriate oxygen saturation levels. Naloxone/naltrexone are robust opioid antagonists that function by blocking µ-receptors. The FDA has approved these antidote medications for emergency treatment of patients with known or suspected opioid overdose experiencing respiratory and/or central nervous system (CNS) depression. Common routes of naloxone administration include IV, IM, IN, or subcutaneous (SC). More recently, researchers have posed a caveat regarding the intranasal route for naloxone administration. Since the incidence of obstructive nasal pathology is relatively high in patients who experience serious OIRD, there is documentation of relevant instances of treatment failures when using the IN formulations.

Also, an IV neuromuscular blocker may be employed in cases of severe muscular rigidity to assist the controlled respiration treatments.

Enhancing Healthcare Team Outcomes

Fentanyl is a widely used narcotic in the hospital environment. However, with recent concerns about opiate overdose and toxicity, all interprofessional healthcare team members who prescribe, administer, or dispense this medication should be familiar with the drug's adverse effects and how to reverse them. This includes all clinicians, mid-level practitioners, nurses, and pharmacists. When prescribing fentanyl, the duration should be short, and the patient continually assessed for compliance and/or diversion. Healthcare workers should be aware of new prescribing laws governing opioids, and unlike the past, empirical prescribing of narcotics can lead to legal troubles, including loss of prescription privilege.[8][9] With interprofessional coordination of activities and open communication, fentanyl therapy can be successful and adverse events avoided or managed if they arise. [Level 5]

Review Questions


Glick JL, Christensen T, Park JN, McKenzie M, Green TC, Sherman SG. Stakeholder perspectives on implementing fentanyl drug checking: Results from a multi-site study. Drug Alcohol Depend. 2019 Jan 01;194:527-532. [PubMed: 30551090]
Wakeman SE, Chang Y, Regan S, Yu L, Flood J, Metlay J, Rigotti N. Impact of Fentanyl Use on Buprenorphine Treatment Retention and Opioid Abstinence. J Addict Med. 2019 Jul/Aug;13(4):253-257. [PubMed: 30550392]
Hagedorn H, Kenny M, Gordon AJ, Ackland PE, Noorbaloochi S, Yu W, Harris AHS. Advancing pharmacological treatments for opioid use disorder (ADaPT-OUD): protocol for testing a novel strategy to improve implementation of medication-assisted treatment for veterans with opioid use disorders in low-performing facilities. Addict Sci Clin Pract. 2018 Dec 13;13(1):25. [PMC free article: PMC6293521] [PubMed: 30545409]
Comer SD, Cahill CM. Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019 Nov;106:49-57. [PMC free article: PMC7233332] [PubMed: 30528374]
Gallagher R. Opioid-Related Harms: Simplistic Solutions to the Crisis Ineffective and Cause Collateral Damage. Health Serv Insights. 2018;11:1178632918813321. [PMC free article: PMC6256311] [PubMed: 30505147]
Ochalek TA, Parker MA, Higgins ST, Sigmon SC. Fentanyl exposure among patients seeking opioid treatment. J Subst Abuse Treat. 2019 Jan;96:23-25. [PMC free article: PMC6447297] [PubMed: 30466544]
Mars SG, Rosenblum D, Ciccarone D. Illicit fentanyls in the opioid street market: desired or imposed? Addiction. 2019 May;114(5):774-780. [PMC free article: PMC6548693] [PubMed: 30512204]
Bakovic M, Nestic M, Mayer D. Death by band-aid: fatal misuse of transdermal fentanyl patch. Int J Legal Med. 2015 Nov;129(6):1247-52. [PubMed: 26055040]
Manchikanti L, Sanapati J, Benyamin RM, Atluri S, Kaye AD, Hirsch JA. Reframing the Prevention Strategies of the Opioid Crisis: Focusing on Prescription Opioids, Fentanyl, and Heroin Epidemic. Pain Physician. 2018 Jul;21(4):309-326. [PubMed: 30045589]
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Bookshelf ID: NBK459275PMID: 29083586


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