UKMi Q&A 94.4
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 Prepared: 21 December 2011
Serotonin (5- hydroxytryptamine, 5-HT) is a neurotransmitter with receptors in the nervous system, on the surface of platelets and on the vascular endothelium (1).
Serotonin neurotransmission is responsible for a large range of functions. In the central nervous system, serotonin assists in the regulation of wakefulness, affective behaviour, food intake, thermoregulation, migraine, emesis, sexual behaviour, regulation of nociception, and motor tone. In the periphery, the serotonin system assists in the regulation of vascular tone and gastro-intestinal activity (2).
Drugs may affect serotonin levels through inhibition of serotonin reuptake (e.g. selective serotonin reuptake inhibitors, SSRIs) and metabolism (e.g. monoamine oxidase inhibitors, MAOIs) at the postsynaptic receptor (3).
Serotonin syndrome occurs as a result of excess agonist activity at central and peripheral nervous system serotonin receptors. Excess serotonergic activity produces a spectrum of clinical findings from barely perceptible to lethal (4).
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 monoamine oxidase inhibitors, SSRIs, tricyclic antidepressants, opiate analgesics, and antibiotics (2).
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 (5).
From the NHS Evidence website www.evidence.nhs.uk

Tramadol may cause serotonin syndrome particularly when it is used at high doses or in combination with other agents increasing serotonin levels (6). The manufacturers of tramadol state that co-administration with serotonergic drugs, e.g. SSRIs or MAOIs, may lead to an increase of serotonin-associated effects, which can include serotonin syndrome (7).
A combination of agents increasing serotonin by different mechanisms, such as by inhibition of serotonin uptake and serotonin metabolism, is associated with a high risk of the syndrome (3). Symptoms usually occur following initiation of therapy or increases in dose of a drug that can increase serotonin levels (3).
The increasing availability of antidepressant agents with serotonergic properties has increased the 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 neuromuscular malignant syndrome (2).
Patient
A number of the case reports of serotonin syndrome following concomitant use of tramadol with SSRIs are outlined in Table 1 below.
Tramadol dose SSRI dose Other medicines
Symptoms Outcome Ref
Tramadol and citalopram
Citalopram 10mg daily Unknown Tremor, restlessness, fever, confusion, visual hallucinations
Symptoms resolved following tramadol discontinuation
10 70 yrs, female 50mg daily added to therapy
Tramadol and fluoxetine
31 yrs, female 100
–200mg daily started four weeks prior to symptom presentation
72 yrs, female 150mg daily started 18 days prior to symptom presentation
Fluoxetine 20mg daily
Fluoxetine 20mg daily
Unknown Tremor of right hand spread to face Both fluoxetine and tramadol discontinued.
Symptom improvement 7 days later.
11
12
44 yrs, female 400mg daily, self increased to 800mg daily prior to admission
Fluoxetine 20mg daily started10 days prior to admission, self increased to
80mg daily
53 yrs, male Dose not stated Dose not stated, but added into existing therapy, 6 days prior to symptom presentation
Unknown
Unknown
Trazodone
Clonazepam
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.
Disorientated, confused, visual hallucinations, continuous tremor, mydriasis, hyper-reflexia, and ataxic, unsteady gait.
Confusion, visual hallucinations, gastro-intestinal distress, fever tachycardia, oedema, and rash.
Fluoxetine discontinued, plus gradual dose reduction of tramadol, leading to complete symptom remission.
Fluoxetine, tramadol, and trazodone discontinued. Treatment with cyproheptadine commenced. 14 days later, patient symptom free.
13
14

Tramadol and paroxetine
47 yrs, male 100mg, symptoms started 12 hours after taking first dose.
66 yrs, male
Paroxetine 20mg daily
Unknown, started 2 months prior to symptom presentation
Paroxetine 30mg daily
78 yrs, female 150mg daily, 3
–4 days prior to symptom presentation
88 yrs, female 100 –200mg daily a few days before symptom presentation
Paroxetine 20mg daily
Paroxetine 10mg daily
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.
Unknown
Dosulepin
Unknown
Unknown
Shivering, diaphoresis, myoclonus, subcomatose
Nightmares and hallucinations.
Nausea, diaphoresis, irritability, muscle weakness, confusion.
Nausea, vomiting, diaphoresis, confusion, insomnia, dizziness
Tramadol discontinued, paroxetine dose halved. Consciousness regained 12 hours later, other symptoms disappeared after a week.
Paroxetine discontinued with no effect.
Dosulepin discontinued with no effect.
Tramadol discontinued and symptoms resolved.
Both medicines stopped, symptoms resolved after 4 –5 days. Paroxetine restarted 2 weeks later.
Both medicines discontinued, symptoms resolved after 4
–5 days.
Alprazolam,
Treatment for arthritis and diabetes
(details not given)
Agitation, arousal, confusion, slurred and pressured speech, two tonicclonic 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.
Tramadol and sertraline
75 yrs, female 150mg daily Sertraline 50mg
(single dose given)
Sertraline 100mg daily 42 yrs, female 300mg daily at time of diagnosis (patient had been self increasing the dose). Symptoms started 3 weeks after tramadol initiated.
88 yrs, female 100mg daily, increased to 400mg daily. Started
10 days before symptom onset.
Sertraline 50mg daily, increased to 100mg daily. unknown
Unknown confusion, myoclonic jerks
Tachycardia, altered mental state, gastro-intestinal disturbances.
Dextropropoxyphene
Paracetamol
Others
(not listed)
Confusuion, alterations in cognitive function, tremor, co-ordination problems, muscle weakness.
Sertraline discontinued and symptoms remitted after a few days.
Symptoms resolved 24
–36 hours after stopping tramadol and reducing sertraline to
50mg daily.
Sertraline withdrawn and tramadol dose reduced to 200mg daily. Patient recovered after 2 weeks.
Table 1: Case reports of serotonin syndrome following concomitant use of tramadol with SSRIs.
No case reports of serotonin syndrome developing in patients taking concomitant tramadol and escitalopram or fluvoxamine were located.
9
17
16
17
18
15
8
19

One proposed mechanism for the development of serotonin syndrome following concomitant administration of tramadol with SSRIs is a metabolic interaction which potentiates the serotonergic effects of tramadol. Among other mechanisms, tramadol is metabolised in the liver by CYP2D6, an isoenzyme of cytochrome P450 (9). SSRIs are known to have an inhibitory effect on CYP2D6 (10), which can result in elevated serum concentrations of tramadol. An alternative explanation is that the CYP2D6 system is absent in up to 10% of the population (8), which may explain why the serotonin syndrome only develops in a minority of patients given this combination.
 There is a risk of developing of 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 as well as the combined serotonergic effect.
 The inhibition of the metabolism of tramadol through CYP2D6 by SSRIs may explain this inetarction. Alternatively, 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 small number of patients.
 There are only a limited number of case reports in the literature suggesting the risk may be low, however serotonin syndrome can be serious if undetected and there does not seem to be a strong pattern in determining which patients may be predisposed to the development of serotonin syndrome. In addition, several of the symptoms of serotonin syndrome are non-specific and this may mean the syndrome is largely undiagnosed.
 In all the case reports symptoms developed within a few days of addition of the SSRI to tramadol therapy or vice versa, and equally symptoms resolved within days to a few weeks of discontinuation of the serotonergic agents. 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.
 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 and duloxetine) were not included.
1. Jones D, Story D. Serotonin Syndrome and the Anaesthetist. Anaesth Intensive Care 2005; 33: 181
–7
2. Boyer E, Shannon M. Current Concepts: The Serotonin Syndrome. N Engl J Med 2005; 352: 1112 –1120
3. ADRAC. Serotonin Syndrome. Aust Adv Drug Reactions Bull 2004; 23: 3
–4
4. Isbister G, Whyte I. Serotonin toxicity and malignant hyperthermia: role of 5-HT(2) receptors. Br J Anaesth
2002; 88: 603
–604
5. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43: 879 –923
6. WHO. Tramadol
—Safety experience. WHO Drug Information 2003; 17(1): 22
7. Zydol 50mg capsules —Summary of Product Characteristics. Grunenthal Ltd. Accessed via http://emc.medicines.org.uk
[accessed on 15/11/2011] Date of revision: January 2011.
8. Mason B, Blackburn K. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997; 31: 175
–177
9. Egberts A, ter Borgh J, Brodie-Meijer C. Serotonin syndrome attributed to tramadol addition to paroxetine therapy. Int Clin Psychopharmacol 1997; 12: 181
–182
10. Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. Am J
Psychiatry 2004; 161: 1129
11. Kesavan S, Sobala G. Serotonin syndrome with fluoxetine plus tramadol. J R Soc Med 1999; 92: 474 –475
12. 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
13. 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
From the NHS Evidence website www.evidence.nhs.uk

14. Ledoux M, Braslow K, Brown T. C-reactive protein and serotonin syndrome. Am J Psychiatry 2004; 161:
1499
15. Mittino D, Mula M, Monaco F. Serotonin syndrome associated with tramadol-sertraline coadministration. Clin
Neuropharmacol 2004; 27: 150
–151
16. 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
17. Lantz M, Buchalter E, Giambanco V. Serotonin syndrome following the administration of tramadol with paroxetine. Int J Geriatr Psychiatry 1998; 13: 343
–345
18. John A, Koloth R. Severe serotonin toxicity and manic switch induced by combined use of tramadol and paroxetine. Aust NZ J Psychiatry 2007; 41: 192
–3.
19. Sauget D, Franco PS, Amaniou M, Mazere J, Dantoin e 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]
Louise Nolan, Trent Medicines Information Service, Leicester Royal Infirmary
Updated by Laura Kearney, Trent Medicines Information Service, Leicester Royal Infirmary
medicines.info@uhl-tr.nhs.uk
24 November 2005
21 December 2011 (94.3) with minor revision 5 March 2012 (94.4)
Peter Golightly
Director, Trent Medicines Information Service, Leicester Royal Infirmary
15 January 2012 (94.3); 7 March 2012(94.4).

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”

In-house database (DiScan and Mi databank)

Manufacturer (Grunethal/AKOS Ltd, Holly Sawney —Pharmacovigilance Project Manager,
30/07/07, email)
 Internet Search (Google; “tramadol and serotonin syndrome”)

Pharmline (“[tramadol or analgesics-narcotic] + [antidepressants or noradrenaline-serotonin reuptake inhibitors or serotonin reuptake inhibitors or antidepressantstricyclic]”, “tramadol + serotonin”)