Fentanyl with Nefazodone Interaction Details

Brand Names Associated with Fentanyl

Brand Names Associated with Nefazodone

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Dec 31, 2023

Interaction Effect

Increased fentanyl plasma concentrations and increased risk of serotonin syndrome

Interaction Summary

Coadministration of nefazodone, which strongly inhibits fentanyl metabolism mediated by CYP3A4 activity, may cause increased plasma concentrations of fentanyl and subsequent increased or prolonged adverse drug effects including sedation and potentially fatal respiratory depression. Fentanyl is proserotonergic and has been associated with serotonin syndrome when coadministered with serotonergic drugs , including SSRIs  and other antidepressants. If possible, consider replacing serotonergic opioids (eg, fentanyl) with non-serotonergic opioids (eg, morphine) . Use of caution and monitoring of patients for signs and symptoms of serotonin syndrome, respiratory depression, and sedation may be warranted.

Severity

Major

Onset

Unspecified

Evidence

Theoretical

How To Manage Interaction

Concomitant use of fentanyl, which is metabolized by CYP3A4, with a strong CYP3A4 inhibitor, such as nefazodone, may increase fentanyl plasma concentrations and thereby increase or prolong adverse events. Carefully monitor patients receiving concomitant fentanyl and nefazodone for signs of sedation and respiratory depression and adjust dosage if warranted. Fentanyl is considered a proserotonergic, synthetic piperidine opioid and has been associated with serotonin syndrome when coadministered with a serotonergic drug. Therefore, use caution with coadministration of fentanyl and a serotonergic drug, such as nefazodone, as this may result in additive serotonergic effects and may increase the risk of serotonin syndrome. If possible, consider replacing serotonergic opioids (eg, fentanyl) with non-serotonergic opioids (eg, morphine) . Monitor patients for symptoms of serotonin syndrome, including neuromuscular abnormalities (eg, hyperreflexia, tremor, muscle rigidity, clonus, peripheral hypertonicity, and shivering), autonomic hyperactivity (eg, tachycardia, mydriasis, diaphoresis, the presence of bowel sounds, and diarrhea), and mental status changes (eg, agitation and delirium). Serotonin syndrome can be life-threatening. If serotonin syndrome develops, discontinue the offending agents and provide supportive care and other therapy as necessary .

Mechanism Of Interaction

Inhibition of CYP3A4-mediated metabolism of fentanyl; additive serotonergic effect

Literature Reports

A) Serotonin syndrome associated with fentanyl use during an esophagogastroduodenoscopy was reported in a 39-year-old woman also taking sertraline 100 mg daily as an outpatient. The patient initially presented with hematemesis and a history of alcoholic cirrhosis. Prior to the esophagogastroduodenoscopy, an octreotide and pantoprazole drip was started, 2 doses of fentanyl 50 micrograms, and 2 doses of midazolam 1 mg were administered. The patient became somnolent and extremely rigid in all four extremities following the procedure, and vecuronium and etomidate were given for immediate intubation. The rigidity progressed with diffuse diaphoresis, horizontal roving eye movements, and a fever of 105 degrees F. Due to the potential for seizure activity, lorazepam 2 mg IV was given with no improvement and a propofol drip was started for continued sedation during intubation. A CPK value of 2800 units/L and an ammonia level of 340 micromols/L indicated rhabdomyolysis. An acute intracranial process was ruled out on a CT scan of the brain and the neurology team made the diagnosis of serotonin syndrome secondary to an interaction between fentanyl and sertraline. Propofol was continued for sedation and the patient received supportive treatment with a cooling blanket and cyproheptadine. After 3 days, the patient's temperature and CPK level normalized and she later extubated with no further complications .

B) Serotonin syndrome following the administration of IV fentanyl during surgical procedures was reported in 2 patients also taking SSRIs (sertraline and escitalopram). The first patient received IV fentanyl (50 micrograms), midazolam (2 mg), and 2 doses propofol (60 mg and 40 mg) in an outpatient surgery center prior to a carpal tunnel release procedure. Postoperatively the patient began shivering and became increasingly agitated for which she was transferred to the emergency department. On presentation the patient was combative, diaphoretic, confused, was unable to follow commands, tachycardic, hypertensive, had hyperreflexia, and ankle clonus. Baseline creatinine kinase rose to 613 units/L on day 2 of hospitalization. The toxicology service treated her with escalating doses of benzodiazepines with no improvement. The patient was subsequently intubated and sedated with a continuous propofol infusion. After 2 days the patient was extubated and by day 3 all symptoms had resolved and the patient was discharged home. The second patient was a 59-year-old woman admitted for an omentectomy for which she received IV fentanyl 250 micrograms, etomidate, vecuronium, morphine and cephazolin. Following extubation the patient became hypoxic and acidotic and was reintubated and transferred to the ICU. On postoperative day 1 she was extubated and later became tachycardic and was unable to follow commands. On examination the patient was agitated and diaphoretic, had patellar hyperreflexia and a bilateral 3 to 4 beat ankle clonus. Laboratory evaluation was remarkable for a peak creatine kinase of 1161 units/L on postoperative day 2. The patient was treated with lorazepam and cyproheptadine with resolution of symptoms after 3 days .

C) A case of postoperative serotonin syndrome following the administration of fentanyl for general anesthesia and post operative analgesia was reported in a 60-year-old woman also receiving paroxetine. Outpatient medications included only paroxetine and thyroxine for a history of depression and hypothyroidism. The patient was admitted for an extensive resection of a recurrent left chest wall myxofibrosarcoma and given propofol and 200 micrograms (mcg) of fentanyl for the induction of anesthesia. The patient also received an additional 800 mcg of fentanyl (intermittent 50 mcg boluses) intraoperatively and a subsequent fentanyl infusion (100 to 200 mcg/hr) for postoperative sedation and analgesia (2545 mcg of fentanyl received over 36 hours). The fentanyl infusion was continued 36 hours postoperatively, at which time intermittent agitation, bilateral hypertonia and hyperreflexia, and bilateral inducible ankle clonus were observed on neurological examination. Symptoms were more severe in the lower limbs and on the right side of the body. A CT scan of the brain was unremarkable and all other examination findings, including a thyroid function test, were within normal limits with the exception of elevated blood pressure (180/90 mmHg), which spontaneously resolved 24 hours after the procedure. Fentanyl was discontinued, and 24 hours later, there was marked improvement in neurological symptoms and complete recovery by postoperative day 4. The patient was ultimately discharged home with no further complications .

Fentanyl Overview

• Fentanyl is used to treat breakthrough pain (sudden episodes of pain that occur despite round the clock treatment with pain medication) in cancer patients at least 18 years of age (or at least 16 years of age if using Actiq brand lozenges) who are taking regularly scheduled doses of another narcotic (opiate) pain medication, and who are tolerant (used to the effects of the medication) to narcotic pain medications. Fentanyl is in a class of medications called narcotic (opiate) analgesics. It works by changing the way the brain and nervous system respond to pain.

Nefazodone Overview

• Nefazodone is used to treat depression. Nefazodone is in a class of medications called serotonin modulators. It works by increasing the amounts of certain natural substances in the brain that are needed to maintain mental balance.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.