1. SpR topic Sarika Hanchanale 21/08/2013

2. 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? 21/08/2013

3. Serotonin toxicity/syndrome Learning Outcomes Describe basic pathophyisology List the medications causing toxicity Describe the clinical features List the differential diagnosis Explain the management 21/08/2013

4. 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 21/08/2013

5. Physiology 21/08/2013

6. 5HT receptor subtype (Boyer and Shanon, 2005) TypeAction 5-HT 1A Neuronal inhibition, regulation of sleep, feeding, thermoregulation, hyperactivity associated with anxiety, hypoactivity associated with depression 5-HT 1D Locomotion, muscle tone 5-HT 2A Neuronal excitation, learning, peripheral vasoconstriction, platelet aggregation 5-HT 2B Stomach contraction 5-HT 3 Nausea and vomiting, anxiety 5-HT 4 Gastrointestinal motility 21/08/2013

7. 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 21/08/2013

8. 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 21/08/2013

9. 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 21/08/2013

10. Hunter’s serotonin toxicity criteria (Dunkley et al, 2003) Serotonergic medications (within past 5 weeks)Serotonin toxicity Spontaneous clonusYes Inducible clonus and either agitation or diaphoresisYes Ocular clonus and agitation or diaphoresisYes Tremor and hyperreflexiaYes Hypertonic and temp>38 and have ocular clonus or inducible clonus Yes 21/08/2013

11. 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 21/08/2013

12. Differential diagnosis Neuroleptic malignant syndrome Anticholinergic toxicity Malignant hyperthermia Encephalitis, meningitis 21/08/2013

13. 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 21/08/2013

14. Treatment of serotonin toxicity Discontinue the medication (toxicity resolves in 24 hrs) ABC.... Symptomatic treatment -Benzodiazepines for agitation, myoclonus and seizures 5-HT 2A 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) 21/08/2013

15. 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 21/08/2013

16. Ann Pharmacother. 2012 Dec;46(12):1712-6. doi: 10.1345/aph.1Q748. Epub 2012 Dec 4. Ann Pharmacother. Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors.Nelson EM, Philbrick AM.Nelson EMPhilbrick 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. 21/08/2013

17. . Ann Clin Psychiatry. 2012 Nov;24(4):310-8. Ann Clin Psychiatry. Overview of serotonin syndrome. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Iqbal MMBasil MJKaplan JIqbal 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. 21/08/2013

18. 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) 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 21/08/2013

19. Summary Remember about drug interactions especially opioids+ SSRI 21/08/2013

20. 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. Rastogi RSwarm RAPatel TA Anesthesiology. 21/08/2013