SpR topic

Sarika Hanchanale

21/08/2013

Case A 55 year old female with Ca lung was presented at day hospice in a very

agitated state. Her friend said that she had vomiting and diarrhoea just started in the last day. On examination she was diaphoretic, pulse 150, temperature 38.9, BP 160/100. On examination- slow, continuous, horizontal, eye movements and she was hyperreflexic (most prominently in the lower extremities). Medications- Fentanyl patch, Fluoxetine, Diclofenac, prn oramorph. What is the most likely diagnosis?

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Serotonin toxicity/syndrome

Learning Outcomes• Describe basic pathophyisology• List the medications causing toxicity• Describe the clinical features• List the differential diagnosis• Explain the management

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Serotonin

• 5HT-neurotransmitter• Found in CNS, Gastrointestinal tract and

platelets• GIT- regulates gut movement (90% of

serotonin is found in enterochromaffin cells in gut)

• CNS neurons- regulation of mood, sleep and appetite, thermoregulation (serotonin is mainly produced in midline raphe nucluei found in the brainstem from midbrain to medulla)

• Platelet- helps in haemostasis and blood clotting

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Physiology

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5HT receptor subtype(Boyer and Shanon, 2005)

Type Action

5-HT1A Neuronal inhibition, regulation of sleep, feeding, thermoregulation, hyperactivity associated with anxiety, hypoactivity associated with depression

5-HT1D Locomotion, muscle tone

5-HT2A Neuronal excitation, learning, peripheral vasoconstriction, platelet aggregation

5-HT2B Stomach contraction

5-HT3 Nausea and vomiting, anxiety

5-HT4 Gastrointestinal motility

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Serotonin toxicity

• Serotonin toxicity occurs due to increase in serotonin activity in CNS

• Excessive ingestion of drugs which increase central and peripheral concentration of serotonin

• Severe toxicity is more likely to occur secondary to combination of two or more serotonergic drugs

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Drugs with serotoninergic potency

• Antidepressants-MAOI, SSRIs, SNRIs (serotonin reuptake inhibitors)

• Psychostimulants (increase serotonin release from neurons)

• Other drugs-H1 antihistamines(serotonin reuptake inhibitors)

• Opioids

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Clinical features

• Neuromuscular hyperactivity-tremor, clonus, hyperreflexia, spasticity (marked in legs), ocular clonus

• Altered mental status-agitation, hypomania, delirium

• Autonomic hyperactivity-sweating, fever, tachycardia, hypertension, tachypnoea, sialorrhoea, diarrhoea

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Hunter’s serotonin toxicity criteria (Dunkley et al, 2003)

Serotonergic medications (within past 5 weeks) Serotonin toxicity

Spontaneous clonus Yes

Inducible clonus and either agitation or diaphoresis Yes

Ocular clonus and agitation or diaphoresis Yes

Tremor and hyperreflexia Yes

Hypertonic and temp>38 and have ocular clonus or inducible clonus

Yes

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Evaluation

• Drug history• Ask about herbal medications-St John’s Wort, OTC

drugs (cough remedies containing dextromothorphan) and elicit drugs such as MDMA, ecstasy-these can cause or contribute to toxicity

• Clinical signs• In severe cases, blood tests can show metabolic

acidosis, rhabdomyolysis, renal failure and DIC

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Differential diagnosis

• Neuroleptic malignant syndrome• Anticholinergic toxicity• Malignant hyperthermia• Encephalitis, meningitis

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Difference between ST and NMS

ST• Serotonin excess• Rapid onset of action after

the drug administration• Autonomic dysfunction • altered mental status• Hyperkinesia, tremor, clonus• Responds to serotonin

blockade • Resolution in 24 h

NMS• Dopamine blockade• Slow onset of action after

drug administration• Autonomic dysfunction • altered mental status• Bradykinesia/extrapyramidal

lead pipe rigidity• Responds to dopamine

agonist• Resolution in days-weeks

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Treatment of serotonin toxicity

• Discontinue the medication (toxicity resolves in 24 hrs)

• ABC....• Symptomatic treatment-Benzodiazepines for agitation, myoclonus and seizures5-HT2A antagonists

-Chlorpromazine 50-100mg im-Olanzapine 10mg im-Cyproheptadine 12mg po stat followed by 8mg q6h and 2mg

q2h prn until symptoms resolve (tablets can be crushed and given via NG tube)

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Treatment

• Stabilisation of BP- for hypotension from MAOI interactions, give low doses of sympathomimetic (adrenaline, noradrenaline), for hypertension- give short acting agents like nitroprusside, esmolol

• Severe cases are managed in ICU

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• Ann Pharmacother. 2012 Dec;46(12):1712-6. doi: 10.1345/aph.1Q748. Epub 2012 Dec 4.

• Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors.Nelson EM, Philbrick AM.

• OBJECTIVE:• To investigate the nature of the interaction between selective serotonin reuptake inhibitors (SSRIs) and tramadol to

mitigate or avoidserotonin syndrome.• DATA SOURCES:• PubMed, Ovid MEDLINE, and International Pharmaceutical Abstracts from January 1990 to August 2012 were searched. Key

words used were tramadol, antidepressive agents, antidepressants, drug interactions, selective serotonin uptake inhibitors, and serotonin syndrome.

• DATA SYNTHESIS:• Published documentation describing the interaction between tramadol and SSRIs and its relevance to serotonin

syndrome is limited to a few case reports and 1 case series. While both tramadol and SSRIs increase the amount of serotonin in the brain, the interaction is much more complicated. Tramadol is metabolized through CYP2D6 enzymes and all SSRIs are inhibitors of these enzymes. Inhibitors of CYP2D6 can increase the concentration of tramadol in the blood and thus increase its effects on serotonin in the brain, contributing to the development of serotonin syndrome. CYP2D6 poor metabolizers are at a greater risk of serotonin syndrome and an inadequate analgesic effect.

• CONCLUSIONS:• Coadministration of tramadol and SSRIs has caused serotonin syndrome. An attempt should be made to identify individuals

who are poor metabolizers of CYP2D6 and avoid this combination in those patients. When SSRIs and tramadol must be used in combination, it is critical that patients be aware of the signs and symptoms of serotonin syndrome, should they occur.

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.• Ann Clin Psychiatry. 2012 Nov;24(4):310-8.• Overview of serotonin syndrome.• Iqbal MM, Basil MJ, Kaplan J, Iqbal MT.• METHODS:• The authors conducted a MEDLINE search for the period covering 1955 to 2011.• RESULTS:• SS commonly occurs after the use of serotonergic agents alone or in combination with monoamine oxidase inhibitors. SS

classically consists of a triad of signs and symptoms broadly characterized as alteration of mental status, abnormalities of neuromuscular tone, and autonomic hyperactivity. However, all 3 triads of SS may not occur simultaneously. Clinical manifestations are diverse and nonspecific, which may lead to misdiagnosis. SS can range in severity from mild to life-threatening. Most cases of SS are mild and resolve with prompt recognition and supportive care. Management of SS involves withdrawal of the offending agent(s), aggressive supportive care to treat hyperthermia and autonomic dysfunction, and occasionally the administration of serotonin antagonists--cyproheptadine or chlorpromazine. Patients with moderate and severe cases of SS require inpatient hospitalization.

• CONCLUSIONS:• Psychiatrists, clinicians, and general practitioners must develop increased awareness of SS due to the current increase in

the use of serotonergic agents in clinical practice. As SS is a manifestation of adverse pharmacology, it is not considered an idiosyncratic drug reaction, making it predictable and highly preventable. Most cases of SS are mild and easily managed. With prompt recognition and supportive care, more severe cases of SS have a favorable prognosis.

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Opioids and serotonin syndrome• Oxycodone+SSRI/SNRI- SS, mechanism not clear-oxycodone does not

stimulate serotonin release or inhibit reuptake, only 4-5 case reports, oxycodone changed to morphine and symptoms improved

• Fentanyl +SSRI/SNRI-SS, review of case reports by Janseen (maufacturer)

letter June 2013 (Ireland)-Summary-This communication is being distributed to alert you to the possibility of serotonin syndrome when serotonergic drugs are administered concomitantly with the Company’s fentanyl-containing products, including Durogesic DTrans Transdermal Patch. If serotonin syndrome is suspected, rapid discontinuation of the Durogesic Dtrans Transdermal Patch should be considered. The information is being sent in agreement with the Irish Medicines Board. Mechanism not clear (http://www.imb.ie/images/uploaded/documents/DHCP-letter-Durogesic%20DTrans-june-2013-CLEAN%20FINAL%20letter%20approved%20by%20the%20IMB%20.pdf)

• Methadone+SSRI-SS-case reports

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Summary

• Remember about drug interactions especially opioids+ SSRI

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References • Boyer EW, Shannon M. The serotonin syndrome. Engl J

Med 2005;356(23):2437.• Christopher F. Recognition and treatment of serotonin syndrome Can Fam

Physician. 2005; 54(7): 988–992.• 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(9):635–42.

• Rastogi R, Swarm RA, Patel TA. Case scenario: opioid association with serotonin syndrome: implications to the practitioners. Anesthesiology. 2011 Dec;115(6):1291-8.

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