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Medicines Q&As UKMi Q&A 94.5 What is the risk of developing Serotonin Syndrome following concomitant use of tramadol with selective serotonin reuptake inhibitors (SSRIs)? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date updated: May 2014 Background Serotonin (5- hydroxytryptamine, 5-HT) is a neurotransmitter with receptors in the central nervous system, on the surface of platelets and on the vascular endothelium (1). Neurotransmission involving serotonin is responsible for a large range of functions. In the central nervous system, serotonin assists in the regulation of wakefulness, mood, affective behaviour, food intake, thermoregulation, migraine, emesis, sexual behaviour, regulation of nociception, and motor tone. In the periphery, the serotonergic system assists in the regulation of vascular tone, gastro-intestinal activity and platelet activity (2). Serotonin syndrome (also known as ‘serotonin toxicity’) occurs as a result of excess agonist activity at central and peripheral nervous system serotonin receptors. Effects result in clinical findings which range from barely perceptible to lethal (3). Serotonin syndrome is described in more detail in UKMI Q & A 219: What is serotonin syndrome and which medicines cause it? Briefly, serotonin syndrome is characterized by three groups of symptoms (2): 1. Neuromuscular hyperactivity—hyperreflexia, clonus, myoclonus, tremor and rigidity 2. Autonomic hyperactivity—hyperreflexia, tachycardia and diaphoresis 3. Altered mental state—agitation, anxiety, hypomania, and confusion Patients with mild manifestations may present with subacute or chronic symptoms, whereas severe cases may progress rapidly to death (2). Groups of drugs that have been associated with serotonin syndrome include those which may inhibit reuptake or breakdown (selective serotonin reuptake inhibitors (SSRIs);, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants),and those that increase serotonin release or are serotonin agonists for example opioid analgesics or some antibiotics (2). A combination of agents increasing serotonin by different mechanisms, such as by inhibition of serotonin uptake and serotonin metabolism, is associated with an increased risk of the syndrome. Symptoms usually occur following initiation of therapy or increases in dose of a drug that can increase serotonin levels (7). The increasing availability and use of antidepressant agents with serotonergic properties has possibly contributed to the increased number of reports of this syndrome in recent years. Other potential causes such as infections, metabolic disturbances, substance abuse, or withdrawal need to be excluded (8). Differential diagnoses include malignant hyperthermia, anticholinergic poisoning, and neuroleptic malignant syndrome (2). Answer: Tramadol is a centrally acting analgesic structurally related to codeine and morphine. It is an agonist of the µ opioid receptor. In addition, tramadol inhibits serotonin reuptake and norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord (4). Tramadol may cause serotonin syndrome particularly when it is used at high doses or in combination with other agents increasing serotonin levels (5). The manufacturers of tramadol state that co-administration Available through NICE Evidence Search at www.evidence.nhs.uk with serotonergic drugs, e.g. SSRIs or MAOIs, may lead to an increase of serotonin-associated effects, which can include serotonin syndrome (6). Published cases involving tramadol and SSRIs causing serotonin syndrome are listed in Appendix 1. In the majority of these patients recovered, usually after withdrawal of one or more of the drugs, but in two cases the combination was fatal. There are two possible explanations for this interaction that leads to serotonin syndrome in some individuals. The first of these is that tramadol is primarily metabolised in the liver by the isoenzyme Cytochrome P450 2D6 (also known as CYP2D6) (9). SSRIs are known to have an inhibitory effect on CYP2D6 (10), which could therefore result in elevated serum concentrations of tramadol, increasing the risk of excessive serotonergic effects. The second and possibly more likely explanation is that the CYP2D6 system is deficient or absent in up to 10% of the population (8), which would mean that these individuals have increased blood levels of tramadol following a normal dose, and exposure to SSRIs would result in increased serotonergic activity and an increased tendency to develop serotonin syndrome. This may explain why the serotonin syndrome only develops in a minority of patients given such a combination. Summary There is a risk of developing serotonin syndrome following concomitant use of tramadol with SSRIs. This may be more frequent than with other combinations of serotonergic drugs due to inhibition of tramadol metabolism by these antidepressants in addition to the combined serotonergic effect. Although the inhibition of the metabolism of tramadol through CYP2D6 by SSRIs may explain this interaction, the potential for up to 10% of the population to be poor metabolisers of CYP2D6 substrates may explain why this reaction seems to be of significance in only a minority of patients. There are only a limited number of case reports in the literature which suggests the risk may be low, however serotonin syndrome can have serious consequences if undetected. There does not seem to be a strong pattern to determine which patients may be predisposed to the development of serotonin syndrome. In addition, several of the milder symptoms of serotonin syndrome are non-specific and this may mean the syndrome is relatively common but largely undiagnosed. Symptoms of serotonin syndrome developed within a few days of addition of the SSRI to tramadol therapy or vice versa, and mostly resolved within days to a few weeks (up to four) of discontinuation of the serotonergic agents but there have been fatalities Patients and healthcare professionals should be aware of the potential for serotonin syndrome and monitor for any of the symptoms of serotonin syndrome on initiation and dose increases of all serotonergic medications, but particularly where combinations of such agents are used. It may be appropriate to use lower doses of the second agent initially, and any increase in dose should be monitored closely. Limitations Only published case reports in foreign languages that were obtainable and translatable have been included. Case reports of serotonin syndrome following concomitant use of tramadol and antidepressants that act on more than one neurotransmitter system (e.g. venlafaxine, duloxetine and some tricyclic agents) were not included in this review. References 1. 2. 3. 4. 5. 6. 7. Jones D, Story D. Serotonin Syndrome and the Anaesthetist. Anaesth Intensive Care 2005; 33: 181–7 Boyer E, Shannon M. Current Concepts: The Serotonin Syndrome. N Engl J Med 2005; 352: 1112–1120 Isbister G, Whyte I. Serotonin toxicity and malignant hyperthermia: role of 5-HT2 receptors. Br J Anaesth 2002; 88: 603–604 Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879–923 WHO. Tramadol—Safety experience. WHO Drug Information 2003; 17(1): 22 January 2011 Zydol 50mg capsules—Summary of Product Characteristics. Grunenthal Ltd. (Available via http://emc.medicines.org.uk [accessed on 15/11/2011] . UKMi Q & A 219: What is serotonin syndrome and which medicines cause it? accessed via NHS Evidence, May 2014, at http://www.evidence.nhs.uk/search?q=UKMi+serotonin+syndrome 8. Mason B, Blackburn K. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997; 31: 175–177 Available through NICE Evidence Search at www.evidence.nhs.uk 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. Egberts A, ter Borgh J, Brodie-Meijer C. Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997; 12: 181–182 Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. Am J Psychiatry 2004; 161: 1129 Peacock L, Wright F. Serotonin syndrome secondary to tramadol and citalopram. Am J Psychiatry 2004;161:1129. Pilgrim J, Gerostamoulos D, Drummer O. Deaths involving contra-indicated and inappropriate combinations of serotonergic drugs. Int J Legal med 2011:125:803-15. Kesavan S, Sobala G. Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med 1999; 92: 474–475 Gonzalez-Pinto A , Imaz H, Perez de Heredia J, Gutierrez M, Mico J. Mania and tramadol-fluoxetine combination. Am J Psychiatry 2001; 158: 964–5 Lange-Asschenfeldt C, Weigmann H, Hiemke C, Mann K. Serotonin syndrome as a result of fluoxetine in a patient with tramadol abuse: Plasma level correlated symptomatology. J Clin Psychopharmacol 2002;22: 440– 441 Ledoux M, Braslow K, Brown T. C-reactive protein and serotonin syndrome. Am J Psychiatry 2004; 161: 1499 Devulder J, De Laat M, Dumoulin K, Renson A, Rolly G. Nightmares and hallucinations after long tem intake of tramadol combined with antidepressants. Acta Clinica Belgica 1996; 51: 184–186 Lantz M, Buchalter E, Giambanco V. Serotonin syndrome following the administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998; 13: 343–345 Mittino D, Mula M, Monaco F. Serotonin syndrome associated with tramadol-sertraline coadministration. Clin Neuropharmacol 2004; 27: 150–151 Sauget D, Franco PS, Amaniou M, Mazere J, Dantoine T. Possible syndrome sérotoninergique induit par l’association de tramadol à de la sertraline chez une femme âgée. Therapie (2002) 57, 309–10 per Stockley I [updated periodically]. Drug Interactions. London, Pharmaceutical Press. Available from www.medicinescomplete.com [accessed on-line 21.11.11] Nayyar N. Serotonin syndrome associated with sertraline tramadol and trazodone abuse. Indian J Psychiatry 2009; 2009;51:68. Nelson E, Philbrick A. Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Ann Pharmacother 2012; 46:1712-1716. Quality Assurance Prepared by Louise Nolan, Trent Medicines Information Service, Leicester Royal Infirmary Updated by Laura Kearney, Trent Medicines Information Service, Leicester Royal Infirmary Updated by Susan Carr, Trent Medicines Information Service, Leicester Royal Infirmary May 2014 Contact [email protected] Date first prepared 24 November 2005 Dates revised 21 December 2011 (94.3) 5 March 2012 (94.4), May 2014 (94.5) Checked by Vanessa Chapman Acting Director, Trent Medicines Information Service, Leicester Royal Infirmary Date of check May 2014 Search strategy Embase 1996: (“tramadol + serotonin-syndrome + antidepressant-agent”) Medline 1950: (“tramadol + serotonin-syndrome + antidepressive-agent”) IDIS (“serotonin syndrome + tramadol”, “antidepressants-SSRIs + serotonin syndrome” and “tramadol + antidepressants-SSRIs” Internet Search (www.google.com; “tramadol and serotonin syndrome”) Available through NICE Evidence Search at www.evidence.nhs.uk Medicines Q&As Appendix 1 Case reports of serotonin syndrome following concomitant use of tramadol with SSRIs are outlined in the table below. No case reports of serotonin syndrome developing in patients taking concomitant tramadol and escitalopram or fluvoxamine were located. Patient Tramadol dose SSRI dose Other medicines Symptoms Outcome Ref Unknown Tremor, restlessness, fever, confusion, visual hallucinations Symptoms resolved following tramadol discontinuation 10 Full recovery after both drugs removed. 11 Tramadol and citalopram 70 yrs, female 50mg daily added to therapy Citalopram 10mg daily 78 yrs female Unknown Citalopram dose & duration unknown 71 yrs female unknown Citalopram dose unknown Codeine, diazepam, ibuprofen Unknown. Findings at autopsy: pulmonary and cerebral oedema Death 12 Tramadol and fluoxetine 31 yrs, female 100–200mg daily started four weeks prior to symptom presentation Fluoxetine 20mg daily Unknown Tremor of right hand spread to face Both fluoxetine and tramadol discontinued. Symptom improvement 7 days later. 13 72 yrs, female 150mg daily started 18 days prior to symptom presentation Fluoxetine 20mg daily Unknown Feeling nervous, pyrexic, piloerection, muscular contractions, agitated, euphoric, hyperactive, insomnia. Physical symptoms resolved 3 days after tramadol discontinuation, although mental state still affected. Fluoxetine treatment stopped and antipsychotic treatment started. Symptoms resolved 2 weeks later. 14 44 yrs, female 400mg daily, self increased to 800mg daily prior to admission Fluoxetine 20mg daily started 10 days prior to admission, self increased to 80mg daily Unknown Disorientated, confused, visual hallucinations, continuous tremor, mydriasis, hyper-reflexia, and ataxic, unsteady gait. Fluoxetine discontinued, plus gradual dose reduction of tramadol, leading to complete symptom remission. 15 53 yrs, male Dose not stated Dose not stated, but added into existing therapy, 6 days prior to symptom presentation Trazodone Clonazepam Confusion, visual hallucinations, gastrointestinal distress, fever tachycardia, oedema, and rash. Fluoxetine, tramadol, and trazodone discontinued. Treatment with cyproheptadine commenced. 14 days later, patient symptom free. 16 26, male Unknown Unknown Diazepam oxycodone Unknown. Pulmonary oedema on autopsy Death 12 Available through NICE Evidence Search at www.evidence.nhs.uk Tramadol and paroxetine 47 yrs, male 100mg, symptoms started 12 hours after taking first dose. Paroxetine 20mg daily Unknown Shivering, diaphoresis, myoclonus, subcomatose Tramadol discontinued, paroxetine dose halved. Consciousness regained 12 hours later; other symptoms disappeared after a week. 9 66 yrs, male Unknown, started 2 months prior to symptom presentation Paroxetine 30mg daily Dosulepin Nightmares and hallucinations. Paroxetine discontinued with no effect. Dosulepin discontinued with no effect. Tramadol discontinued and symptoms resolved. 17 78 yrs, female 150mg daily, 3–4 days prior to symptom presentation Paroxetine 20mg daily Unknown Nausea, diaphoresis, irritability, muscle weakness, confusion. Both medicines stopped, symptoms resolved after 4–5 days. Paroxetine restarted 2 weeks later. 16 88 yrs, female 100–200mg daily a few days before symptom presentation Paroxetine 10mg daily Unknown Nausea, vomiting, diaphoresis, confusion, insomnia, dizziness Both medicines discontinued, symptoms resolved after 4–5 days. 17 55 yrs, female 200mg daily, increased to 800mg daily by the patient due to increasing pain Paroxetine 20mg daily increased to 80mg daily by the patient. Alprazolam, Treatment for arthritis and diabetes (details not given) Agitation, arousal, confusion, slurred and pressured speech, two tonic-clonic seizures, delusions, elated and labile effect, ankle clonus, increased muscle tone, tachycardia, increased blood pressure, dilated pupils Both medicines discontinued. Symptoms resolved, although symptoms of mania took 8 weeks to resolve following treatment with sodium valproate and olanzapine. 18 Tramadol and sertraline 75 yrs, female 150mg daily Sertraline 50mg (single dose given) unknown confusion, myoclonic jerks Sertraline discontinued and symptoms remitted after a few days. 19 42 yrs, female 300mg daily at time of diagnosis (patient had been self increasing the dose). Symptoms started 3 weeks after tramadol initiated. Sertraline 100mg daily Unknown Tachycardia, altered mental state, gastrointestinal disturbances. Symptoms resolved 24–36 hours after stopping tramadol and reducing sertraline to 50mg daily. 8 88 yrs, female 100mg daily, increased to 400mg daily. Started 10 days before symptom onset. Sertraline 50mg daily, increased to 100mg daily. Dextropropoxyphene Paracetamol Others (not listed) Confusion, alterations in cognitive function, tremor, co-ordination problems, muscle weakness. Sertraline withdrawn and tramadol dose reduced to 200mg daily. Patient recovered after 2 weeks. 20 55 yrs, male Dose unknown, 4-5 days Sertraline dose unknown, 1 year Trazodone Recovered within 24 hours 22 Available through NICE Evidence Search at www.evidence.nhs.uk