AJHM Volume 2 Issue 2 (Apr-Jun 2018) CASE REPORT

CASE REPORT

Hydromorphone Precipitating Serotonin Syndrome

Sijie Jason Wang1
1
Concord Hospital, Department of Hospital Medicine, 250 Pleasant St, Concord, NH 03301

Corresponding author: Sijie Jason Wang, MD, Concord Hospital, Department of Hospital Medicine, 250 Pleasant
Street, Concord, NH 03301 ([email protected])

Received: November 17, 2017 Accepted: March 1, 2018 Published: May 25, 2018

Am J Hosp Med 2018 Apr;2(2):2018.010 https://doi.org/10.24150/ajhm/2018.010

Opioid medications are an underappreciated cause of serotonin syndrome. Fentanyl, meperidine,

and methadone are more commonly associated with this potentially life-threatening side effect.
Here, we present the case of a 60-year-old man taking duloxetine, oxycodone as needed, and
long-acting hydromorphone for chronic pain, who developed serotonin syndrome two days after
his hydromorphone dose was increased. Due to severe agitation he required intubation and his
course was notable for marked adrenergic instability. Eventually, he improved after treatment
with benzodiazepines and cyproheptadine. This case highlights a rare synergistic effect from the
combination of hydromorphone, duloxetine, and oxycodone resulting in serotonin syndrome.

OBJECTIVE: (SSRIs), serotonin-norepinephrine reuptake

inhibitors (SNRIs), tricyclics, as well as
To alert clinicians about the risk of illicit substances, such as ecstasy (MDMA)
hydromorphone precipitating serotonin or amphetamines. However, there are a
syndrome when given in conjunction with huge number of other drugs that act upon the
other serotonergic agents. serotonergic system in unpredictable ways,
which may not always be apparent to the
BACKGROUND: prescriber. The syndrome is characterized
by a triad of mental status changes,
Chronic pain is a challenging disorder to autonomic hyperactivity, and neuromuscular
treat and is frequently associated with abnormalities, but not all three need to be
depression and anxiety. Opioids are often present to make the diagnosis.2
combined with serotonergic agents, where Most clinicians would probably not
the serotonergic drugs may be used to treat consider opioids to play a major role in
concomitant psychiatric illness, or directly serotonin syndrome, although certainly
to treat pain itself. However, there remains some specific agents, such as meperidine,
a great deal of uncertainty regarding optimal have become well-known for this effect, as
drug combinations and potentiation of side seen with the unfortunate case of Libby
effects.1 Zion. Nevertheless, the FDA has started to
Serotonin syndrome is a severe warn that all opioids may have this effect.3
adverse reaction, which is typically This case report describes a patient who was
associated with serotonergic drugs, such as taking a regimen for chronic pain with SNRI
selective serotonin reuptake inhibitors and opioids, and unfortunately developed

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AJHM Volume 2 Issue 2 (Apr-Jun 2018) CASE REPORT

severe serotonin syndrome after his In the ED his vitals were noted to be
hydromorphone dose was increased. highly labile. His systolic blood pressures
ranged from 93 to 183 mmHg and diastolic
CASE PRESENTATION: pressures ranged from 52 to 110 mmHg. He
was afebrile. His heart rate ranged from 100
A 60-year-old male presented to the to 140 beats per minute. His respiratory rate
Emergency Department (ED) due to anxiety. was 20 breaths per minute. He appeared
He had a history of coronary artery disease, diaphoretic, could not lay still in the bed,
paroxysmal atrial fibrillation, chronic and was noted to be pacing restlessly.
obstructive pulmonary disease, spinal Cardiopulmonary examination was
stenosis status post L3-L5 decompressive unremarkable except for tachycardia. On
surgery, and residual back pain treated with neurologic exam, he was noted to have
chronic oral narcotics. His medication list is hyperreflexia throughout, inducible
shown in Table 1. He had been noted by his sustained myoclonus in the lower
primary care physician to be highly extremities bilaterally, and bilateral upgoing
compliant with medications and was on a toes. No overt muscle rigidity was noted.
chronic narcotic contract. He was given several doses of
Two days prior to presentation, the intravenous lorazepam (6 mg total), but
patient’s oral hydromorphone dosage had became increasingly combative. He was
been increased from 16 mg to 24 mg/day. finally intubated due to his altered mental
After this medication change, the patient status and concern for airway compromise.
became acutely restless and agitated. He His initial laboratory values,
could not sleep at all the previous night. His including complete blood count,
wife went to work in the morning, and when electrolytes, thyroid stimulating hormone,
she came that home in the evening she found hepatic function tests, and urine drug screen
him incredibly frantic, pacing, anxious, and were unremarkable. His lumbar puncture
unable to sit still. and computed tomography scan of the head
were also unremarkable.

Table 1. Patient’s medication list. All routes are oral unless specified.

Aspirin 81 mg daily
Albuterol metered dose inhaler, 90 mcg/actuation, 2 puffs inhaled every 4-6 hours as needed for
wheezing
Baclofen 10 mg three times daily
Duloxetine 60 mg twice daily
Docusate 100 mg as needed for constipation
Fluticasone-salmeterol 100/50 mcg 1 puff inhaled twice daily
Furosemide 20 mg daily
Hydromorphone sustained-release 24 mg daily
Lisinopril 20 mg daily
Metoprolol succinate 100 mg daily
Oxycodone 5 mg daily as needed for breakthrough pain
Rosuvastatin 40 mg daily
Sildenafil 50 mg as needed for erectile dysfunction
Spironolactone 12.5 mg daily
Warfarin (dose varies)

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AJHM Volume 2 Issue 2 (Apr-Jun 2018) CASE REPORT

The patient’s presentation was felt to It can be diagnosed via the Hunter Criteria,
be consistent with serotonin syndrome which stipulates that the patient must be on a
precipitated by the hydromorphone dose serotonergic agent and meet one of the
increase and fulfilled the Hunter criteria (see following conditions5:
discussion). He was sedated with  Spontaneous clonus
midazolam and dexmedetomidine, and  Inducible clonus PLUS agitation or
cyproheptadine was started at a loading dose diaphoresis
of 12 mg, followed by 4 mg every 6 hours.  Ocular clonus PLUS agitation or
He was extubated on hospital day #3, but diaphoresis
remained delirious for several days  Tremor PLUS hyperreflexia
thereafter. Over the next few days he also  Hypertonia PLUS temperature above
developed mild rhabdomyolysis and had 38°C PLUS ocular clonus or
intermittent fevers as high as 38.3°C with inducible clonus
negative infectious workup.
He was eventually discharged from Symptoms present relatively quickly
the hospital and has since tapered off after a medication is started or a dose is
duloxetine and hydromorphone completely. increased – typically within 24-48 hours.
He remains on a small dose of oxycodone These symptoms occur along a spectrum of
and has been started on gabapentin and severity, which makes both initial diagnosis
medical cannabis. and prevention of progression challenging.
Patients may experience some mild diarrhea
DISCUSSION or tremor which many clinicians may not
associate with serotonin syndrome. Many
The neurotransmitter 5-hydroxytryptamine, patients may not report some of these
otherwise known as serotonin, is synthesized symptoms to their physicians at all. More
from the amino acid tryptophan. Its severe cases can cause autonomic instability,
regulation, metabolism, and reuptake diaphoresis, mydriasis, hyperreflexia,
mechanisms are complex and will not be clonus, or severe agitation as seen in this
discussed in detail here. However, it is case. Interestingly, after his recovery, this
important to recall that the enzyme patient recalled that he felt “like a kettle
monoamine oxidase breaks down serotonin; ready to boil” in the days leading up to the
hence, MAO inhibitors such as phenelzine hydromorphone dose increase which
can precipitate serotonin syndrome. Drugs ultimately precipitated the full-blown
which cause massive release of serotonin syndrome. He did not mention this to his
(such as ecstasy), inhibition of reuptake physician, and it is very possible that even if
(such as SSRIs), or direct receptor agonism he had, his vague complaint may not have
(such as fentanyl and buspirone) can cause been attributed to serotonin syndrome.
serotonin syndrome. It is also important to After all, he was on a stable dose of
recognize that hepatic cytochrome P450 duloxetine, and hydromorphone is not
enzyme inhibitors can increase drug levels.2 typically associated with the syndrome.
For example, in one case, a child taking a There is an increasing evidence that
stable dose of sertraline suffered serotonin all opioids can precipitate serotonin
syndrome after being exposed to syndrome, although the mechanisms are
erythromycin.4 likely hetereogeneous.3,6 This patient’s
Serotonin syndrome is a potentially life- reaction represents a dose-related adverse
threatening side effect of serotonergic drugs. drug reaction caused by hydromorphone

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AJHM Volume 2 Issue 2 (Apr-Jun 2018) CASE REPORT

dose increase in setting of stable chronic References

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