In this episode I’ll discuss the clinical relevance of the linezolid-fentanyl drug interaction in critically ill patients.

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Before we begin, I’d like to share a pearl from my book, A Pharmacist’s Guide To Inpatient Medical Emergencies: Instead of thinking faster (which can lead to errors), think ahead! Anticipate and prepare for the worst-case scenario.

Many clinical decision support systems list linezolid and fentanyl as a contraindicated combination. This is due to the risk of serotonin syndrome.

Linezolid was originally discovered as an antidepressant via the drug’s mild, reversible inhibition of monoamine oxidase. It is this status as a monoamine oxidase inhibitor (MAOI) that confers the risk of serotonin syndrome. When monoamine oxidase is inhibited, synaptic concentrations of serotonin can reach toxic levels.

Serotonin syndrome

I discussed serotonin syndrome and other medication related causes of severe hyperthermia back in episode 40.

Serotonin syndrome presents like neuroleptic malignant syndrome. A thorough review of a patient’s medication list and history of present illness differentiates these conditions.

The Hunter Criteria is often used for the diagnosis of serotonin syndrome. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet ONE of the following conditions:

1. Spontaneous clonus

2. Inducible clonus PLUS agitation or diaphoresis

3. Ocular clonus PLUS agitation or diaphoresis

4. Tremor PLUS hyperreflexia

5. Hypertonia PLUS temperature above 38ºC PLUS ocular clonus or inducible clonus

Linezolid induced serotonin syndrome

Linezolid has been implicated as a cause of serotonin syndrome by itself, or in combination with other serotonergic agents.

One retrospective review found a 3% incidence (2 of 72 patients) of serotonin syndrome in patients taking linezolid and selective serotonin reuptake inhibitors (SSRIs).

Case reports I’ve reviewed of serotonin syndrome from linezolid suggest the interaction usually is mild and resolves quickly. I was unable to locate within Pubmed a single case of fatal serotonin syndrome in a patient receiving linezolid.

The worst outcome I could find in a published case was that of a 47 year-old female who experienced mild serotonin syndrome from linezolid and sertraline. 45 days later she was started on linezolid again and sertraline was held. After 9 days of linezolid, she developed confusion, myoclonus, incoordination, and cardiopulmonary arrest, leaving the patient in a coma.

Fentanyl induced serotonin syndrome

Synthetic opioids such as fentanyl and meperidine have serotonergic activity. These synthetic opioids are referred to as phenylpiperidines – the same structural class as the SSRI paroxetine.

While fentanyl has been reported to cause serotonin syndrome, the incidence is likely minuscule. One review found that 4 out of 4,538 patients who received fentanyl and another serotonergic agent developed serotonin syndrome.

Linezolid + fentanyl induced serotonin syndrome

No case reports in Pubmed describe serotonin syndrome resulting from linezolid and fentanyl together. In 2013, a case of serotonin syndrome from 3 serotonergic agents was published.

A 68 year-old woman on fentanyl and amitriptyline was prescribed linezolid. Within 24 hours she developed restlessness, diaphoresis, tremor, shivering, myoclonus, and high fever (40°C), as well as gradual mental status disorders with disorientation, confusion, and coma. She required intubation due to respiratory failure. A few hours after linezolid was stopped she began to improve. Within 48 hours she was extubated. Her mental status gradually returned to normal.

Is the linezolid-fentanyl interaction clinically relevant to critical care patients?

The last thing a critically ill patient needs is a complication from drug therapy such as serotonin syndrome. But there will be patients who need both linezolid and fentanyl for legitimate reasons. If both linezolid and fentanyl are needed, and alternative medications are not equally safe and effective, I do not consider the combination a contraindication.

I am comfortable with this decision for the following reasons:

Linezolid and fentanyl together as the only serotonergic agents have not been reported to cause serotonin syndrome. Nearly all cases of serotonin syndrome with linezolid appear mild or reversible. The intense monitoring that critically ill patients receive with 1:2 nurse:patient ratios allow for rapid detection and treatment of serotonin syndrome should it occur.

If the combination is used, I advise the nurse and physician to monitor for signs of tremor, myoclonus, hyperthermia, rigidity, hyperreflexia, incoordination, confusion or coma.

When there is a 3rd serotonergic medication involved, I am much more hesitant to use linezolid.

My tolerance for risk of the linezolid-fentanyl interaction often changes outside of critical care settings. Monitoring is less intense with a higher nurse to patient ratio. Additionally, alternatives to either medication are much easier to find outside of the ICU.

If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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