Can you get Serotonin Syndrome from a Cough Medicine?

What do antidepressants, OTC cough medicines, painkillers, ADHD drugs, weight-loss drugs, natural mood remedies, and party drugs have in common?

 

 

Answer: They can all cause Serotonin Syndrome!

A fatal pitfall to be avoided:

Toxic combinations of mood-enhancing substances.

Serotonin Syndrome: a serotonin toxidrome arising from overstimulation of 5HT1A and 5HT2A receptors in central grey nuclei and the medulla.

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Medical Pills

Who is at risk?

Some people are more susceptible to the drugs and supplements that cause serotonin syndrome than are others, but the condition can occur in anyone.

You’re at increased risk of serotonin syndrome if:

  • You’ve recently started taking or increased the dose of a medication known to increase serotonin levels.
  • You take more than one drug including herbal supplements known to increase serotonin levels.
  • You use an illicit substance known to increase serotonin levels.

What types of medications/supplements/substances have been implicated?

Serotonin syndrome most commonly occurs with a combination of serotonergic drugs acting on different sites:

Pharmacological actionClinical subgroupsSpecific drugs examples
Serotonin reuptake inhibitorsSSRISCitalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
Other antidepressants (including serotonin and noradrenaline reuptake inhibitors)Clomipramine, imipramine, desvenlafaxine, venlafaxine, duloxetine
Opioid analgesicsDextromethorphan, tramadol, pethidine, methadone
Herbal preparationSt John’s Wort
Monoamine oxidase inhibitorsIrreversiblePhenelzine, tranylcypromine
reversible MAO-A inhibitorMoclobemide
otherLinezolid, methylene blue
Serotonin releasing drugsSympathomimetic amines (stimulants) available on prescriptionPhentermine, dexamphetamine
Illicit sympathomimetic aminesAmphetamines, methamphetamines, methylenedioxymethamphetamine (MDMA, Ecstasy)
PrecursorsL-tryptophan
MiscellaneousLithium
A Case

A 34 year old mane presented to ED with a three day history of headache and vomiint, and one day of confusion and fevers.

Medical history: chronic back pain due to injury.

Usual medications: methadone 70mg daily, gabapentin 600mg TDS, and citalopram 40mg daily

Recent illness:

  • Tooth extraction one week ago
  • “Head cold” 5 days ago; since recovered

On presentation:

  • T 39.1
  • Sweating
  • Pulse 80 – 140 bpm
  • BP 170/86, 216/102mmHg
  • GCS 12; unable to sustain coherent conversation
  • Dental socket clean
  • Generalised abdo tenderness
  • Dilated, reactive pupils
  • No meningism
  • Bilateral lower limbs: increased tone, brisk reflexes, ankle clonus

Could your patient be at risk of multi-organ-failure and death?

Do not miss these signs of serotonin syndrome:

Clinical presentation

Serotonin toxicity is best characterised by a triad of rapidly progressing clinical effects:

  • neuromuscular excitation— shivering, tremor, akathisia, impaired coordination hyperreflexia, clonus (inducible or spontaneous ocular clonus, myoclonus), hypertonia /rigidity
  • autonomic dysregulation—hyperthermia (mild: less than 38.5 °C; severe: greater than 38.5 °C or rapidly rising), diaphoresis, flushing, mydriasis, tachycardia
  • central nervous system (CNS) effects—agitation, confusion, decreased level of consciousness

This is a medical emergency that can progress to multi-organ failure if not treated within hours. Mortality is around 11%!

Case Continued ....
  • Investigations:
  • WCC 21.1x 10^9 (PMN predominance)
  • CRP 15
  • CXR, AXR – NAD
  • U/A – NAD

Provisional Diagnosis:

Presumed sepsis, ?intracerebral or abdo source. Broad spectrum antibiotics were commenced.

Further  investigations over the next 24h:

  • CT Brain, LP – no evidence of infection
  • Abdo CT – NAD
  • Echo – NAD
  • CK 355IU

Going through history again with a fine-toothed comb:

Night & Day Cold & Cough capsules were taken for a few days before presentation….

Advanced Serotonin Syndrome is a medical emergency that can progress to multi-organ failure if not treated within hours. Mortality is around 11%!.

 

TREATMENT

Most Important
In ALL cases of serotonin toxicity, the number one thing you can do for your patient is to CEASE the inciting agent(s).

Treatment is otherwise mostly supportive.

In mild to moderate serotonin toxicity, aggressive treatment is not required. 60% of all cases resolve within 24hours, with the vast majority resolved within 72hours of cessation of the offending agent/s.

Severe cases of serotonin toxicity may be life-threatening and the patient should be sedated, intubated, paralysed and cooled with intensive care support.

Antidotal therapy with oral cyproheptadine (4-12mg) has been used successfully for serotonin toxicity in anecdotal cases, as have other 5-HT2A antagonists e.g. chlorpromazine.

Sedation with benzodiazepines may also be beneficial.

Case Continued ....

Day & Night Cough & Cold capsules were found to contain Dextromethorphan.

Diagnosis:

Serotonin Syndrome

Management:

Citalopram withheld

Signs & symptoms resolved by 48h

Differential Diagnoses

Although other adverse drug reactions can initially be mistaken for serotonin toxicity, a careful examination for specific neurological features such as clonus and hyperreflexia make it possible to distinguish serotonin syndrome from other conditions.

There are several rare but clinically serious conditions which can present with features commonly shared with serotonin toxicity (ie fever, headache, altered mental status, neuromuscular symptoms). Some differentiating features are outlined table below. The key differentiating feature for serotonin toxicity is neurological excitation, namely hyperreflexia and clonus (inducible or spontaneous), which can be elicited during clinical examination.

Clinical entityKey distinguishing feature(s)
serotonin toxicityneuromuscular clonic excitation
autonomic effects
acute baclofen withdrawalhistory of intrathecal baclofen pump
response to baclofen
anticholinergic deliriumabsence of clonic excitation
bowel sounds absent
dry skin
CNS infectionabsence of clonic excitation
+/- vomiting (encephalitis)
+/- neck stiffness (meningitis)
malignant hyperthermiaabsence of clonic excitation
anaesthetic exposure
neuroleptic malignant syndromeabsence of clonic excitation
bradykinesia
lead-pipe rigidity
other extrapyramidal features

References

Therapeutic Guidelines (2017). Serotonin Syndrome (revised Jul 2012). eTG Complete. Therapeutic Guidelines Limited:  https://tgldcdp.tg.org.au.acs.hcn.com.au/etgAccess

Robertson M (2012). Acute Psychiatric Management. HETI: http://www.heti.nsw.gov.au/Resources-Library/Acute-Psychiatric-Management/

Cameron (2006). “Serotonin syndrome precipitated by an over-the-counter cold remedy”. Australian Prescriber 2006 29:7 11 June 2006

Isbister GK, Buckley NA & Whyte I A (2007). “Serotonin toxicity: a practical approach to diagnosis and treatment”. Medical Journal of Australia 187(6):361-365

Kathryn Teh

Kathryn Teh

I am currently a 4th year trainee with Hunter New England Psychiatry program and have a special interest in Child & Adolescent Psychiatry, particularly with regard to developmental trauma, neurodevelopmental disorders, and the systems issues involving the young person and the people around them.I am psychodynamically informed in my approach to clinical practice whilst also carefully considering the biological basis of illness.I aspire to work at the Tavistock Clinic in London one day.Outside of clinical practice, I am involved with the psychiatry medical education program at the University of Newcastle.Outside of work, I continue to thoroughly partake of organised team sport and have had the pleasure of travelling across the globe as part of this. I have not for a moment regretted travelling down this road of Psychiatry as a specialty; with the opportunity to do rewarding, fulfilling, work whilst maintaining a balanced-lifestyle, a career in Psychiatry has afforded me ample opportunity to build on the two-fold foundations touted by Freud to be the at the heart of human living: to work and to love.
Kathryn Teh

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