Fentanyl

Article Author:
Carlos Ramos-Matos
Article Editor:
Wilfredo Lopez-Ojeda
Updated:
10/16/2017 6:39:51 PM
PubMed Link:
Fentanyl

Indications

A strong 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, it is most often used as a sedative in intubated patients, as well as in severe cases of pain in patients with renal failure owing 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, 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 can also be given perioperatively. Lastly, fentanyl uses can be extended to the treatment of epilepsy. That is, in combination with certain neuroleptic medications as part of therapeutic neuroleptanalgesia.

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 regarded to the control of emotions, pain, and speaking to the point of its infamous addictive properties, reward. Biochemically, it is referred to as a Mu-selective opioid agonist. However, it has the capabilities 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, produce 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.

Administration

Fentanyl is typically administered intravenously (IV), intramuscularly (IM), transdermally (TD) as skin patches (Durogesic DTrans; Fencino; Fentalis), intranasally (IN) in the form of a volatile nasal spray (Instanyl or PecFent, and intrathecally (IT). It is also available as a buccal soluble thin film (Breakyl), which can dissolve in the mouth, similarly to the sublingual tablets (Abstral or Recivit). However, in contrast to other opiates, it is less common to find forms of the synthetic drug as oral tablets or powders. A novel medication currently being used to address the gastrointestinal (GI) side effects without counteracting its primary analgesic aims is Relistor. The latter 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.

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 which complicate the patient’s prognosis.

Contraindications

The use of fentanyl is contraindicated in patients,

  • 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 hypoventilation 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 to any of the 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 since 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.

Monitoring

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 be monitored closely and frequently. Also, consider lowering the dose of fentanyl. Similarly, when using fentanyl citrate injection along with CYP3A4 inducer medications, or stopping the CYP3A4 inhibitors, an undesirable reduction in fentanyl plasma concentrations may occur, thus 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.

Toxicity

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 should be performed accordingly. An opioid drug antagonist such as naloxone is also indicated to correct OIRD symptoms. Commonly, repetitive doses are required since the respiratory depression may overcome with time the effects of the antagonist drug, namely with opiates such as fentanyl in which increased receptor affinity may be noted as compared to other opiates. Thus, the therapeutic approach is continued 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. Naloxone is commonly administered IV, IM, IN or subcutaneously (SC). More recently, a caveat regarding the intranasal route for naloxone administration has been posed. Since the incidence of obstructive nasal pathology is relatively high in patients who experience serious OIRD, relevant instances of treatment failures have been documented 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.