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Emergency Medicine Australasia (2015) ••, ••–••
doi: 10.1111/1742-6723.12521
CASE LETTER
Serotonin toxicity caused by the interaction of fentanyl
and serotonergic medications
Dear Editor,
A 19-year-old woman was transferred
to the ED from an external Day Procedure Unit having been emergently
intubated following a tonic episode
after elective general anaesthesia for
molar extraction. Her past medical
history included depression, and her
regular medications were amitriptyline
25 mg, citalopram 60 mg and pantoprazole 20 mg.
General anaesthesia was achieved
with sevoflurane and iv fentanyl
75 mcg, propofol 125 mg and midazolam 2 mg with a laryngeal mask airway
(LMA). During the case, the patient received iv kefazolin 1 g, dexamethasone
8 mg, paracoxib 40 mg and ondansetron 4 mg, and 15 mL 0.5% bupivocaine was infiltrated locally. On
LMA removal post-procedure, she
had generalised tonicity with jaw
trismus, tachycardia (111/min), hypertension (172/83 mmHg) and oxygen
saturations of 88% on room air. She
was subsequently intubated with iv
fentanyl 100 mcg, propofol 50 mg
and rocuronium 50 mg. She received
further iv fentanyl 80 mcg and
rocuronium 20 mg, and a propofol infusion was commenced prior to transfer to the ED.
On arrival in the ED, the patient was
sedated with normal haemodynamics.
She had signs of neuromuscular
excitation with bilateral increased
lower limb tone, hyperreflexic knee
and ankle jerks with sustained ankle
clonus.
A computed tomography head scan
was normal and an electroencephalogram 4 h after arrival demonstrated
severe diffuse encephalopathy consistent with medication effect.
The patient was managed in Intensive Care prior to an uneventful
extubation, and she was discharged
from hospital the following day.
The patient’s clinical presentation
was consistent with serotonin toxicity
from her serotonergic medications
(amitriptyline, a tricyclic antidepressant, and citalopram, a selective
serotonin re-uptake inhibitor) with the
additional administration of fentanyl,
a phenylpiperidine opioid, which is also
a serotonin re-uptake inhibitor. Differential diagnoses included malignant hyperthermia; however, neuromuscular
hyper-reactivity signs including clonus
are not consistent with this. Primary
seizure was also considered, but this
was not consistent with clinical signs
or electroencephalogram findings. Her
hypoxia was likely a consequence of
restricted ventilation due to respiratory
muscle spasm, which may have occurred because of serotonin toxicity or
fentanyl usage.
Serotonin toxicity is a spectrum of
clinical signs occurring due to increased serotonin concentrations
within the central nervous system.
Neuromuscular excitation, autonomic
nervous system excitation and mental
state changes form the triad of clinical
features1 with some neuromuscular
changes, for example, clonus or
tremor and hyperreflexia being essential for diagnosis of serotonin toxicity.2 A number of drug classes are
implicated as causative agents including monoamine oxidase inhibitors,
serotonin releasing agents (e.g. serotonin re-uptake inhibitors, tricyclic
antidepressants and phenylpiperidine
opioids) and miscellaneous drugs
including lithium.1
Serotonin toxicity is a concentrationdependent event with onset depending
on pharmacokinetics and pharmacodynamics of the specific serotonergic
agent. With this case, serotonin toxicity
developed rapidly corresponding to the
rapid onset of action of parenterally administered fentanyl.
Serotonin toxicity has been reported
previously where patients treated with
serotonergic agents have received fentanyl.3,4 In a retrospective analysis
conducted by Koury et al.,5 4538 patients given fentanyl while on a
serotonergic drug were compared with
a cohort of 107 507 patients on a serotonergic agent who did not receive
fentanyl. Although the incidence of
serotonin toxicity was low, the rate
within the cohort receiving fentanyl
was 18 times higher, which was statistically significant.
Fentanyl is widely used in a variety
of situations within the ED. With increasing usage of serotonin-releasing
antidepressants,6 ED staff must be
aware of the cumulative impact
phenylpiperidone opioids have in precipitating serotonin toxicity. For patients prescribed regular serotonergic
agents, alternate opioid classes should
be utilised if there is no specific indication for fentanyl. If fentanyl is administered, increased vigilance should be
observed for the development of serotonin toxicity.
Acknowledgement
CBP is supported by a QEMRF Research Fellowship.
Competing interests
CBP is a section editor for Emergency
Medicine Australasia.
References
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Buckley NA, Dawson AH, Isbister GK.
Serotonin syndrome. BMJ 2014; 348:
g1626.
Dunkley EJ, Isbister GK, Sibbritt D,
Dawson AH, Whyte IM. The Hunter
Serotonin Toxicity Criteria: simple
and accurate diagnostic decision rules
for serotonin toxicity. QJM 2003; 96:
635–42.
Ailawadhi S, Sung KW, Carlson LA,
Baer MR. Serotonin syndrome caused
by interaction between citalopram
and fentanyl. J. Clin. Pharm. Ther.
2007; 32: 199–202.
Rang S, Field J, Irving C. Serotonin
toxicity caused by an interaction
© 2015 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine
2
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CASE LETTER
between fentanyl and paroxetine. Can.
J. Anesth. 2008; 55: 521–5.
Koury KM, Becky BA, Gulur P. Incidence of serotonin syndrome in
patients treated with fentanyl on serotonergic agents. Pain Physician 2015;
18: E27–E30.
Buckley NA, Whyte IM, Dawson AH,
Isbister G. A prospective cohort study
of trends in self poisoning, Newcastle,
Australia, 1987–2012: plus ça change,
plus c’est la même chose. Med. J. Aust.
2015; 202: 438–42.
Melanie C ARMITAGE,1
Kathryn I WOOLFIELD1 and
Colin B PAGE1,2,3
1
Emergency Department, Princess
Alexandra Hospital, Brisbane,
Queensland, Australia, 2Clinical
Toxicology Research Group,
University of Newcastle, Newcastle,
New South Wales, Australia, and
3
School of Medicine, University
of Queensland, Brisbane,
Queensland, Australia
© 2015 Australasian College for Emergency Medicine and Australasian Society for Emergency Medicine