Download What is the risk of developing Serotonin Syndrome following

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



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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