Fentanyl can cause serotonin syndrome

  • Fentanyl3.5 out of 5 stars

Serotonin Syndrome Induced by Fentanyl in a Child: Case Report. Robles LA. Clin Neuropharmacol 2015 Sept-Oct;38:206-8.


When many clinicians think of serotonin syndrome (SS), they consider the usual suspects:

Aside from these common culprits, there are other commonly used drugs whose clear association with serotonin syndrome is less-often realized:

  • Fentanyl
  • Methadone
  • Tramadol
  • Lithium
  • Linezolid
  • Ondansetron
  • Metoclopramide
  • Methylene blue

Since many ICU patients are treated with fentanyl and/or antiemetics such as ondansetron, and have other conditions that can cause altered mental status, the diagnosis is frequently not suspected initially, and causative pharmaceutical agents not discontinued.

This interesting report describes a 7-yead-old boy admitted to the intensive care unit after surgery for an intracerebral hemorrhage.Within 48 hours of admission, he developed the characteristic clinical triad of SS: altered mental status (consistent with his underlying condition,) inducible clonus and tremors, and autonomic instability (hyperthermia, hypertension, tachycardia.) Two days after surgery, clinicians considered the diagnosis of serotonin syndrome. They reviewed the patient’s medications and noted that fentanyl was the only drug he was receiving that was associated with SS. The fentanyl infusion was discontinued and “the patient showed a dramatic improvement” within 60 minutes.

Fentanyl seems to be a weak SSRI. The author argues somewhat persuasively that this patient’s clinical presentation meets the definition of SS according to Hunter’s Criteria. The case would have been stronger if instead of describing a “mild fever” an actual temperature had been provided. The authors claim that this is the first reported case of serotonin syndrome apparently caused by fentanyl alone.

The association of fentanyl with SS is one every clinicians should be aware of.

Related posts:

Bath salts (MDPV): another possible cause of serotonin syndrome

FDA warns about linezolid, methylene blue association with serotonin syndrome

Linezolid and serotonin syndrome

Methylene blue and serotonin syndrome


Loperamide (Imodium) overdose can cause fatal cardiac toxicity


A recent paper described two fatalities associated with overdose of the anti-diarrhea drug loperamide (Imodium.) This drug, once available by prescription only, had been thought so safe that in 1988 it was approved for purchase over-the-counter. Here are some important questions regarding this medication:

  • Why is it sometimes called the “poor man’s methadone”?
  • Why, despite having typical opiate μ-receptor activity, does it generally not cause respiratory or mental status depression?
  • Why is P-glycoprotein (P-gp) important for understanding the pharmacokinetics of loperamide, and what does that have to do with Mr. T?
  • What are the important cardiotoxic effects of loperamide?
  • Why did the FDA recently issue a safety alert warning of “Serious heart problems” that could result from loperamide overdose?

The answers to these questions, and more, can be found in my “Toxicology Rounds” column this month in Emergency Medicine News. To read it, click here.

Related post:

Cardiac effects of loperamide overdose


Acetaminophen and N-acetylcysteine are removed by hemodialysis

3.5 out of 5 stars

Massive acetaminophen overdose: effect of hemodialysis on acetaminophen and acetylcysteine kinetics. Ghannoum M et al. Clin Toxicol 2016 Jul;54:519-22.


As we’ve discussed before, massive acetaminophen [APAP] overdose may be a somewhat different beast from the usual, run-of-the-mill case that reliably responds to N-acetylcysteine [NAC] (if administered at an early stage.)There is evidence that a very large intake of APAP (some say >500 mg/kg) can poison mitochondria, causing severe effects that manifest even before onset of hepatotoxicity. “Massive overdose” is suggested by history of large ingestion in a patient who presents within hours of ingestion, has normal hepatic enzymes and coagulation tests, and is found to have otherwise unexplained metabolic (lactic) acidosis and altered mental status.

The Extracorporeal Treatments in Poisoning (ExTRIP) workgroup has suggested that in cases of massive APAP overdose NAC by itself may not be effective even if administered within 8 hours of ingestion, and recommends adding hemodialysis. This case report lends support to that suggestion.

This interesting case report describes an 80 kg, 18-yo woman who presented an hour after ingesting 100g APAP. Three hours after ingestion her mental status deteriorated and she was intubated. Laboratory tests showed a lactic acidosis (venous pH 7.19, serum lactate8.6 mmil/L.) There was no laboratory evidence of hepatotoxicity or coagulopathy. Initial (90 min) APAP level was 981 μg/mL.

The patient was started on intravenous NAC at 2 hours post-ingestion, along with hemodialysis. Since NAC is removed by dialysis, the 16-hour infusion rate of 6.25 mg/kg/h was doubled during the procedure. The patient did well, was extubated the day after admission, and never developed hepatotoxicity.

The author’s pharmacokinetic calculations demonstrated that hemodialysis significantly decreased the half-life of APAP and removed approximately 50% of the body burden. In addition, 6.5 hours of dialysis removed over 80% of NAC given up to that point, lowering the serum level significantly (despite the increased rate of infusion.) The conclusion:

This case report demonstrates the variable clinical evolution of a patient presenting with massive acetaminophen overdose treated with hemodialysis. While hemodialysis is effective in enhancing acetaminophen and acetylcysteine elimination, its use in the patient described in this report also reversed metabolic acidosis and improved mental status, which are commonly present in such overdose.Our pharmacokinetic data imply that acetylcysteine dosage must be more than double during hemodialysis to compensate for its loss via the dialysate.

The ExTRIP recommendations suggest specific APAP levels for initiating hemodialysis in massive overdose. These levels are not, as far as I can tell, based on any evidence, and seem to be counterproductive. I think it suffices to say that a patient who presents with a clinical picture of massive overdose and has APAP levels in the OMG! range should be considered a candidate — no need to give precise numbers.

Related posts:

Must-read: consider hemodialysis in cases of massive acetaminophen overdose

Early metabolic acidosis and coma in massive acetaminophen overdose





A can’t miss item in the differential diagnosis of neuroleptic malignant syndrome

2 out of 5 stars

Psychiatric Emergencies for Clinicians: Emergency Department Management of Neuroleptic Malignant Syndrome. Wilson MP et al. J Emerg Med 2016;51:66-69.


This review article about neuroleptic malignant syndrome (NMS) is brief but disappointing and misleading on some points. For example, the authors state that:

The majority of cases of NMS develop symptoms within the first week [after starting the offending medication], and virtually all develop symptoms within the first 30 days.

The clinician who takes this statement to the bank could easily miss late-onset NMS occurring as a result of dose change, additional medication, or concurrent illness and dehydration. The clinical scenario the authors present to start the discussion doesn’t even mention the patient’s medications.

On the controversial topic of the role of dantrolene in treating NMS, the paper’s conclusion:

. . .the evidence on the use of dantrolene is contradictory, and all recommend its use.

is gibberish, since “all” doesn’t have a recognizable antecedent The bottom line is that the evidence is indeed contradictory, but many authors recommend use of dantrolene in severe cases since there doesn’t seem to be much downside.

One would hope that a just-published review article would be up-to-date and include important recent information, but the authors do miss a key point. Table 3 lists a differential diagnosis for NMS, but there’s a crucial omission. Anti-NMDA receptor encephalitis can easily be confused with NMS, since it presents with recent-onset psychiatric symptoms that are often treated with neuroleptics. If this diagnosis is not considered it will be missed.

Related posts:

Must-read: Anti-NMDA Receptor Encephalitis

Must-listen podcast: anti-NMDA receptor encephalitis

Rant: ultrasound visualization of pills in the stomach will never make sense

Konstantin Shevtsov/shutterstock.com

Konstantin Shevtsov/shutterstock.com

2 out of 5 stars

Accuracy of Trans-Abdominal Ultrasound in a Simulated Massive Acute Overdose. Sullivan S et al.  Am J Emerg Med 2016 Apr 23 [Epub ahead of print]


As soon as emergency portable bedside ultrasound became feasible approximately three decades ago, toxicologists wondered if it would be a useful modality for visualizing pills in the stomach of overdose patients.

The answer, clearly, is no it would not. This misguided paper illustrates why.

This randomized study had a study group (N=10) and a control group (N=10) ingest 50 enteric-coated placebo capsules plus 1 L fluid, or or 1 L fluid only. Ultrasound imaging of the stomach was performed and interpreted by 3 emergency ultrasound-trained sonographers attires 0, 60, and 90 minutes after ingestion. All subjects fasted for at least 6 hours before the study.

Without going into the weeds with precise numbers (consult the abstract if you’re really interested,) we can say that even under these ideal conditions, the sensitivity and specificity of the test were lousy. This is consistent both with the results of a previous pilot study and with common sense. Furthermore, the authors’ premise is ill-considered:

In many cases, traditional ED decontamination therapy with activated charcoal, whole bowel irrigation with polyethylene glycol, and gastric lavage are limited to the first hour post-ingestion. . . .If effective, ultrasound would allow visualization of ingested capsules in the stomach, and could potentially be used to expand the window of decontamination therapy beyond 60 minutes.

NO! As we’ve discussed before, gastric lavage and whole bowel irrigation (WBI) are outmoded, potentially dangerous interventions that should go the way of ipecac and free-range chicken dung as therapeutic options in poisoned patients.(To read our stand on this issue, click here.) The risk is that visualizing something that looks like it may be pills on the ultrasound might motivate the clinician to take unwise measures to go fishing for it. As for charcoal, the concept that a potential benefit might me limited to 1-hour post-ingestion never made any sense. If there are no contraindications (such as altered mental status or an unprotected airway) activated charcoal is relatively safe and easy to administer and is a reasonable option in potentially serious overdoses even hours after the fact.

We should note that, as the authors mention, most overdose patients do not drink 1 L fluid before presentation to improve imaging of the stomach. Also, they usually are not thoughtful enough to be NPO for at least 6 hours. Wo with poor results under ideal conditions, and no rational justification to pursue the topic, do the authors throw in the towel. NO! They conclude:

Further studies that have larger numbers of participants, recruited from actual patient populations, and address the non-fasting status of emergency department patients would be of benefit to make definitive conclusions.

No, it would not be of benefit. This is madness. Please stop. No more studies are needed. This is a blind alley.

Incidentally, in the course of their work the authors made an observation that confirms common sense: ” . . . although it was not a primary endpoint, we did develop a subjective appreciation for how difficult it is to swallow 50 enteric-coated capsules.

Related post:

Use of ultrasound in toxic ingestions: good idea or wild-goose chase?