Review

Journal of Pharmacy Practice

2014, Vol. 27(1) 71-78
Serotonin Syndrome: Is It a Reason to Avoid ª The Author(s) 2013
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the Use of Tramadol With Antidepressants? DOI: 10.1177/0897190013504957
jpp.sagepub.com

Susie H. Park, PharmD, BCPP, FCSHP1,

Robin C. Wackernah, PharmD, BCPP2,
and Glen L. Stimmel, PharmD, BCPP3

Abstract
Background: There is a warning associated with all serotonergic antidepressants and its concomitant use with tramadol due to the
concern for a drug–drug interaction resulting in serotonin syndrome (SS). The prescribing of antidepressants with tramadol may
be unnecessarily restricted due to fear of causing this syndrome. Objectives: There are 3 objectives of this review. To (1) review
case reports of SS associated with the combination of tramadol and antidepressant drugs in recommended doses, (2) describe the
mechanisms of the drug interaction, and (3) identify the potential risk factors for SS. Methods: Case reports of SS associated with
tramadol and antidepressants were identified via Cochrane Library, PubMed, and Ovid (through October 2012) using search
terms SS, tramadol, antidepressants, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, venlafaxine, des-
venlafaxine, duloxetine, mirtazapine, milnacipran, trazodone, vilazodone, and bupropion. Cases involving monoamine oxidase
inhibitors (MAOIs) and tricyclic antidepressants were excluded. Results: Nine articles were identified describing 10 cases of
suspected SS associated with therapeutic doses of tramadol combined with an antidepressant. Mechanisms of the drug–drug
interactions involve pharmacodynamic, pharmacokinetic, and possible pharmacogenetic factors. Conclusions: Review of the
available case reports of tramadol combined with antidepressant drugs in therapeutic doses indicates caution in regard to the
potential for SS but does not constitute a contraindication to their use. Tramadol is only contraindicated in combination with
MAOIs but not other antidepressants in common use today. These case reports do suggest several factors associated with a
greater risk of SS, including increased age, higher dosages, and use of concomitant potent cytochrome P450 2D6 inhibitors.
Tramadol can be safely combined with antidepressants; however, monitoring and counseling patients are prudent when starting a
new serotonergic agent or when doses are increased.

Keywords
serotonin syndrome, tramadol, antidepressants, drug–drug interactions, serotonergic

Introduction monotherapy antidepressant use is presented in order to high-

light SS occurring, despite the absence of identifiable drug–
Pharmacists face a number of warnings alerting potential drug–
drug interactions and to determine the risk factors associated
drug interactions from their pharmacy’s computerized data-
with its occurrence.
bases, such as First Databank or Medi-Span. When providers’
software systems issue frequent warnings repeatedly for these
drug interactions, alert fatigue occurs. The challenge is to
determine when an alert represents a true contraindication or
1
merely a caution. When a potential drug–drug interaction is University of Southern California School of Pharmacy, Department of
detected, decisions must be made whether to counsel the Clinical Pharmacy and Pharmaceutical Economics & Policy, Los Angeles,
patient, contact the prescriber, or, in extreme cases, refuse to CA, USA
2
Regis University School of Pharmacy, Rueckert-Hartman College for Health
fill the prescription. One such caution involves the use of tra- Professions, Denver, CO, USA
madol and antidepressant drugs, representing a concern re- 3
University of Southern California School of Pharmacy and Keck School of
garding the potential for serotonin syndrome (SS) with the Medicine, Los Angeles, CA, USA
combination. The purpose of this article is to review SS and its
causes, case reports of the syndrome associated with tramadol Corresponding Author:
Susie H. Park, Department of Clinical Pharmacy and Pharmaceutical Economics
and newer antidepressants in therapeutic doses, and to offer & Policy, University of Southern California School of Pharmacy, 1985 Zonal
recommendations regarding a prudent course of action when Avenue, Los Angeles, CA 90033, USA.
this drug combination is encountered. A brief discussion of Email: susiepar@usc.edu

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72 Journal of Pharmacy Practice 27(1)

Methods Table 1. Criteria for Serotonin Syndrome/Toxicity.a

Identification of Studies Hunter serotonin

Sternbach criteria (1991) toxicity criteria (2003)
A literature review was conducted on published reports of
SS caused by drug interactions between tramadol and com- (A) At least 3 of the following Serotonin toxicity is positive if 1 of
monly prescribed serotonergic antidepressants indexed from clinical features the 5 below criteria are met:
the following databases: Cochrane Library, PubMed, and Mental status changes Spontaneous clonus ONLY
(confusion, hypomania) Inducible clonus AND agitation or
Ovid (through October 2012). SS resulting from drug inter-
Agitation diaphoresis
actions between tramadol and older classes of antidepres- Myoclonus Ocular clonus AND agitation or
sants was not systematically reviewed. Key words related Hyperreflexia diaphoresis
to the topic were searched: serotonin syndrome, tramadol, Diaphoresis Tremor AND hyperreflexia ONLY
antidepressants, drug–drug interactions, and serotonergic. Shivering Hypertonia AND temp >38 C
Specific antidepressants searched include fluoxetine, ser- Tremor AND ocular clonus or inducible
traline, paroxetine, fluvoxamine, citalopram, escitalopram, Diarrhea clonus
Incoordination
venlafaxine, desvenlafaxine, duloxetine, mirtazapine, milna-
Fever
cipran, trazodone, vilazodone, and bupropion. (B) Other etiologies have been ruled
out
(C) A neuroleptic had not been
Background started or increased in dosage
prior to the onset of the signs and
Characterization of SS symptoms listed previously
SS is an adverse drug reaction characterized by neuromuscular a
Listed criteria are based on the addition of, or a dose increase in, a
abnormalities, cognitive changes, and autonomic instability. It serotonergic agent.
is also referred to as ‘‘serotonin toxic syndrome’’ and ‘‘toxic
serotomimetic reaction,’’ suggesting that it is not an idiosyn- symptoms of SS.10 In a review of published cases, cyprohepta-
cratic response.1 It is understood by others, however, to be idio- dine (4-24 mg/d) was the most consistently effective pharma-
syncratic in nature, because SS can emerge from an overdose cologic treatment for SS with rapid resolution occurring in
just as likely as therapeutic doses.2 Usually occurring when 2 90.5% (19 of 21) of patients.11
serotonin (5-HT)-modifying agents are combined, it can also Diagnosis of SS is based on the clinical findings. Clinical
occur with single agent use.3 The incidence of SS appears very manifestations range from dismissive to potentially lethal.9 The
low, estimated as 0.4 cases per 1000 patient-months of antide- majority of the patients developing SS will typically experience
pressant treatment.4 SS is fairly common in medication over- mild symptoms such as anxiety, akathisia, and mild hyperre-
dose, occurring in 15% of the cases.5 flexia. More severe cases present with severe hyperthermia,
Considered an uncommon syndrome of serotonin hypersti- seizure, respiratory arrest, and death.6 Categorized into clusters
mulation,6 SS is presumed to result from high levels of central of signs and symptoms, neuromuscular problems include myo-
nervous system 5-HT. The syndrome is thought to be mediated clonus, hyperreflexia (more common in the lower extremities),
through the specific postsynaptic receptor subtype, 5-HT1A,7 restlessness, muscle rigidity, tremor, and bilateral Babinski
the receptor responsible for antidepressant and anxiolytic signs. Cognitive and behavioral symptoms include confusion,
effects. Stimulation of postsynaptic 5-HT2A receptors may also disorientation, agitation, coma/unresponsiveness, and lethargy.
be involved in producing SS.2 Various mechanisms of Autonomic instability includes diaphoresis, tachycardia, nau-
increased 5-HT include (1) increased availability of the 5-HT sea, vomiting, hyperthermia, and dilated pupils.12 Most litera-
precursor, L-tryptophan, (2) increased release of 5-HT caused ture on SS use either the original criteria described by
by amphetamines, dextromethorphan, and opioid analgesics, Sternbach13 or the newer and more commonly used Hunter cri-
(3) 5-HT reuptake inhibition by antidepressants, St John’s teria14 (Table 1).
Wort, and tramadol, (4) decreased metabolism of 5-HT by There are numerous cases of various serotonergic medica-
monoamine oxidase inhibitors (MAOIs), and (5) postsynaptic tion combinations resulting in suspected SS but very few result-
5-HT receptor agonism from buspirone, triptans, lithium, and ing in death. Life-threatening cases have been associated with
carbamazepine.8 MAOIs combined with SSRIs or serotonin–norepinephrine
The onset of SS ranges from minutes to weeks with resolu- reuptake inhibitors (SNRIs).15 It becomes clinically challen-
tion of minor symptoms within 12 to 24 hours after minor sup- ging to identify therapeutic combinations that should be abso-
portive care and drug withdrawal.6 Without intervention, SS is lutely avoided or are contraindicated when used together versus
unlikely to resolve on its own. Once serotonergic agents are combinations that are relatively safe and only require more
removed, supportive care for elevated temperature and careful monitoring. The well-established combinations of
hyperthermia is the mainstay of treatment. Benzodiazepines are greatest concern include any MAOI with any antidepressant,
recommended for control of agitation.9 Cyproheptadine, a 5- dextromethorphan, select triptans (ie, rizatriptan, sumatriptan,
HT1A/2A receptor antagonist, is used for rapidly managing and zolmitriptan), linezolid (Zyvox1-Pfizer), or meperidine

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Park et al
(Demerol1-Sanofi-Aventis). Interestingly, the first reported
case of SS involved the use of an agent with MAOI-like prop-
erties (iproniazid) with pethidine, a narcotic with 5-HT reup-
take inhibition.16
Tramadol
Co-occurring depression and pain disorders are common.17
Tramadol is a common analgesic medication used in patients
with depression related to chronic pain.18 Analgesics are often
combined with co-analgesic antidepressants to treat chronic
pain conditions (eg, fibromyalgia). In addition, tramadol is
used in combination with SSRIs for managing symptoms of
refractory depression,19 obsessive-compulsive disorder,20,21
and Tourette’s syndrome.22 Tramadol is often considered a
therapeutic option over other opioids within the psychiatric
population due to its lower abuse potential.
Tramadol exerts its analgesic effect as a centrally acting
opioid receptor agonist and a 5-HT and norepinephrine (NE)
reuptake inhibitor.23 First synthesized in 1962, tramadol has
been available for pain treatment in Germany since 1977.24
Available in the United States since April 1995, it is a federally
nonscheduled opioid analgesic25 widely used for moderately
severe pain in therapeutic doses of 50 to 400 mg/d.
Tramadol is hepatically metabolized and O-methylated by the
liver cytochrome P450 isoenzyme 2D6 (CYP2D6).26 Interindi-
vidual differences in tramadol metabolism exist.27 Tramadol has
2 chiral centers (þ) tramadol and () tramadol.26 The effect of
NE and 5-HT reuptake and 5-HT release is mainly mediated by
the parent compounds with () tramadol being 5-fold more
potent in inhibiting NE than inhibiting 5-HT reuptake and the
reverse for (þ) tramadol.28 The monoaminergic component of
analgesia may be mediated by (þ) and () tramadol.28 It is pos-
sible that individual differences in plasma levels of (þ)-O-des-
methyltramadol and ()-O-desmethyltramadol exist because
tramadol metabolism via CYP2D6 is stereospecific.27 This is
an important consideration in predicting which patients may
be more likely to develop SS versus others based on the genetic
differences and their ability to produce different ratios of (þ) and
() tramadol enantiomers.
Tramadol may induce 5-HT release at higher doses29 and
block 5-HT reuptake.30 It is not surprising that there have been
reports of tramadol monotherapy inducing SS without conco-
mitant serotonergic medications.31,32 While tramadol in high
doses alone can cause SS, it is more likely to occur when tra-
madol is combined with other serotonergic agents.
Tramadol and Antidepressant Combinations
There are limited cases of SS in the literature describing the
drug–drug interaction between tramadol and serotonergic anti-
depressants. Table 2 summarizes 10 cases of therapeutic trama-
dol doses used for analgesia combined with antidepressants
resulting in moderate to severe occurrences of SS.18,33-40 Onset
of symptoms ranged from 12 hours40 to several weeks.34 Each
patient’s syndrome resolved with either discontinuation of all
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73
offending serotonergic agents,33,34,38,39 discontinuing only tra-
madol,35,37 discontinuing only the antidepressant,36 discontinu-
ing tramadol and decreasing the daily dose of antidepressant by
half,18,40 or discontinuing all agents and treating with a seroto-
nin antagonist, such as cyproheptadine.39 In all but 1 case,36
tramadol was added after stable doses of antidepressants were
established. There were no cases of fatalities associated with
the combined use of tramadol with a serotonergic antidepres-
sant, and full recovery occurred in all cases.
One case of SS involved a patient who took both venlafaxine
and mirtazapine for 4 months before tramadol was added.34
The authors suggest this was a case of dose-dependent induc-
tion of SS by tramadol. Both have serotonergic properties by
different receptor mechanisms that contribute to antidepressant
effects. A case meeting criteria for SS is described during a
cross-tapering of mirtazapine to venlafaxine41 without trama-
dol. Interestingly, venlafaxine is structurally and pharmacolo-
gically related to tramadol.42 It is possible that venlafaxine
exerts similar serotonergic properties as tramadol, making it
just as likely to be implicated in inducing SS in the absence
of concomitant tramadol.
More than half of the cases involved patients over age
6533,35,36,39 with ages ranging from 70 to 88 years. A 70-year-
old caucasian female taking tramadol 50 mg/d and citalopram
10 mg/d experienced visual hallucinations as well as tremors, rest-
lessness, fever, and confusion. Re-exposure to the same drug com-
bination with identical symptoms a year later led to the conclusion
that the patient experienced drug-induced SS.35 Another case
involved an 88-year-old white female stable on paroxetine 10
mg/d for 3 years who took tramadol 50 mg 4 times daily. After
24 hours, she experienced mild confusion, insomnia, dizziness,
diaphoresis, and vomiting. Both agents were discontinued, cypro-
heptadine 2 mg 3 times daily alleviated the symptoms in 4 to 5
days, and paroxetine 10 mg/d was resumed with acetaminophen
without recurrence of SS-related symptoms.39 None of the 4 cases
involving elderly patients discussed hepatic impairment as a con-
tributing factor to SS. Only 1 case excluded renal impairment by
assessing serum creatinine of the patient who experienced SS.33
Renal and/or hepatic impairment is an important consideration that
requires additional investigation in elderly patients who develop
SS from taking relatively low doses of serotonergic agents.
Causes of Drug–Drug Interaction
Leading to SS
Higher plasma concentrations of tramadol with SSRI or SNRI
antidepressants increase the risk of SS. The manner in which
this occurs can be explained by pharmacodynamic (PD), phar-
macokinetic (PK), and pharmacogenetic (PGx) effects and
interactions. The PD interaction was already discussed via neu-
rotransmitter effects of excessive synaptic serotonin.
Pharmacokinetic Considerations
Concomitantly administered CYP2D6 inhibitors contribute to
the variability of tramadol metabolism. Several cases involve
74
Table 2. Cases of Serotonin Syndrome With Tramadol and Antidepressant Combinations.

Patienta Maximum tramadol

Reference gender, age dose, mg/d Antidepressant(s), mg/db Time to onset Sign and symptoms Outcome

Peacock and Wright33 Female, 78
Houlihan34 Caucasian male, 47
Mahlberg et al35 Caucasian female, 70
Mittino et al36 Female, 75
Gonzalez-Pinto et al37 Female, 72
Kesavan and Sobala38 Female, 31 200 mg, then 400 mg 2 Fluoxetine 20 for 3 years
weeks later
Lantz et al39 White female, 78
White female, 88
NR Citalopram; dose NR NR; occurred after Tachycardia, global myoclonus, Resolved upon d/c of both drugs
tramadol started increased tone, hyperreflexia,
bilateral upgoing plantars
400 Mirtazapine 30; venlafaxine XR *40 days after tramadol Agitation, confusion, shivering, Resolved over 36 hours with IV
300 for 4 months dose increased diaphoresis, myoclonus, hydration and d/c of all 3 drugs
hyperreflexia, mydriasis,
tachycardia, fever
50 Citalopram 10 NR; tramadol started Tremors, restlessness, fever, Resolved after d/c of tramadol
after citalopram confusion, visual hallucinations
50 Sertraline 50 After first sertraline dose Confusion, myoclonic jerks Resolved after d/c of sertraline
150 Fluoxetine 20 for 10 years 18 days after tramadol Agitation, fever, piloerection, Resolved after d/c of tramadol
started muscular contractions
*4 weeks after tramadol Agitation, distress, facial twitching, Discharged after 7 days; recovered
started arm tremor, fever, diaphoresis, fully 2 months after d/c of both
anxiety, shivering drugs
150 Paroxetine 20 3 days after tramadol Nausea, diaphoresis, irritability, Symptoms resolved over 4-5 days
started muscle weakness, confusion, after d/c both drugs
fever, agitation, restlessness,
confusion
200 Paroxetine 10 for 2 years 2 days after tramadol Nausea, diaphoresis, vomiting, Symptoms resolved over 4-5 days
started confusion, insomnia, dizziness after d/c both drugs and treat-
ment with cyproheptadine

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Egberts et al40 Male, 47 100 Paroxetine 20 for 4 months 12 hours after first Shivering, diaphoresis, myoclonus, Resolved in 1 week after d/c of
tramadol dose subcomatose state tramadol and paroxetine dose
halved
Mason and Blackburn18 White female, 42 300 for 3 weeks Sertraline 100 for 1 year NR Confusion, psychosis, sundowning, Resolved 24-36 hours after d/c of
agitation, diaphoresis, tremor tramadol and sertraline dose
halved

Abbreviations: NR, not reported; d/c, discontinuation; IV, intravenous

a
Patient’s ethnicity listed if reported in the case.
b
Duration of antidepressant therapy listed if reported in the case.
Park et al
concomitant use of antidepressants known as moderate-to-potent
inhibitors of CYP2D6 such as paroxetine and fluoxetine. This
suggests there may be PK drug interactions between CYP2D6
inhibitors and tramadol, a substrate for CYP2D6. Concomitant
administration of CYP2D6 inhibitors may reduce metabolic
clearance of tramadol whereby contributing to an increased risk
of SS. In 1 case report of tramadol and paroxetine, the authors
attribute SS, in part, to this drug interaction.40 Caution is advised
when tramadol is coadministered with these antidepressants as
well as other CYP2D6 inhibitors43 such as duloxetine.
Pharmacogenomic Considerations
While drug-induced SS can result from PD and PK factors,
PGx factors are also considered. There are functional poly-
morphisms associated with CYP2D6. Patients who are car-
riers for alleles causing deficient activity of these enzymes
(ie, CYP2D6*1/*4 heterozygous genotype35) may have
lower clearance of substrates because they do not metabo-
lize the substrate efficiently. These persons are referred to
as ‘‘slower/intermediate metabolizers.’’ Tramadol is a sub-
strate of CYP2D6 and is metabolized via O-demethylation.
If a person is a slow metabolizer of CYP2D6 and is taking
tramadol with another agent that inhibits tramadol metabo-
lism (eg, paroxetine), there is a potential for a compounded
effect between PD and PK drug interactions and PGx influ-
ences. Paroxetine increases the area under the curve (AUC)
of (þ) tramadol more than the AUC of () tramadol.44 The
(þ) enantiomer is associated with greater 5-HT reuptake
inhibition that leads to varying levels of 5-HT between
poor, intermediate, and extensive metabolizers. Different
phenotypes to genetic polymorphisms of CY2D6 may
explain why individuals taking relatively low and therapeu-
tic doses of tramadol or a specific antidepressant may be at
greater risk of toxic effects.
With regard to ethnic differences in genetic polymorph-
isms of CYP450 enzymes, caucasians make up about 30%
of heterozygous phenotypes45 with approximately 7% to 9%
of caucasians being poor metabolizers of CYP2D6.46,47
CYP2D6*4 is the most common allele associated with the
poor metabolizer phenotype with an allele frequency of up
to 22% in caucasian populations.45,48 The case reports in
Table 2 show that 5 of the 10 patients are caucasian/white.
The ethnicity of the 5 other cases was not identified. Meta-
bolic ratios are stable in an individual, however, inhibition
or induction from concomitantly administered medications
may increase or decrease the metabolic ratio, respectively.48
The relationship between genetic polymorphisms and ethnic
influences on drug metabolism in addition to impact on
drug–drug interactions contributing to SS needs further
delineation.
Monotherapy Antidepressants Causing SS
SS can occur with low49 or excessive doses50 of a single anti-
depressant in the absence of tramadol or an additional
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75
serotonergic agent. A 29-year-old female taking monotherapy
venlafaxine 37.5 mg/d abruptly developed SS a day after a dose
increase from 18.75 mg. Two weeks after distressing symptoms
resolved with venlafaxine discontinuation and treatment with
intravenous prochlorperazine and lorazepam, the patient
received fluoxetine 20 mg/d for major depressive disorder
without reemergence of SS-related effects.49 A 55-year-old
male ingesting 4.5 g of paroxetine controlled-release tablets
died from complications of SS.50 A toxicology review investi-
gating the effect of SSRIs in overdose and the relative toxicity
of 5 different SSRIs found that SS occurred in 14% of 469
patients who overdosed on an SSRI and that paroxetine contrib-
uted to the highest percentage.5 Additional isolated cases
include consumption of 1950 mg venlafaxine51 as well as a sin-
gle dose of duloxetine 30 mg causing a classic presentation of
SS.52 These selected monotherapy cases illustrate the idio-
pathic nature of SS.
Elderly
Increased age may be a risk factor by itself for SS. Cases of SS
have been attributed to antidepressant monotherapy in the
elderly. Fischer reported a case series of 3 older female patients
taking antidepressants for depression who developed SS from
moclobemide (200 and 600 mg/d) and a 1-time citalopram 20
mg intravenous infusion. Symptoms associated with SS
resolved upon discontinuation of the agents or lowering of the
dose.53 Two cases associated with mirtazapine are reported in a
75-year-old man taking 15 mg/d for 8 days,54 and an 85-year-
old female started on 7.5 mg/d developed signs of SS in 3 days
after the mirtazapine dose was increased to 15 mg/d.55 Both of
these mirtazapine-associated cases resulted in resolution of
symptoms within 24 and 30 hours, respectively, upon drug dis-
continuation. More recently, a 76-year-old man taking milnaci-
pran 50 mg twice daily for fibromyalgia developed SS. This
patient was taking paroxetine 25 mg/d for 5 years without inci-
dent until milnacipran was started.56 Although most symptoms
of SS occur rapidly with up to 60% of patients seeking help
within 6 hours of onset,9 a delayed response may be seen, espe-
cially in older patients. This may be explained by decreases in
5-HT receptors and neurotransmission with increased age.57
Moreover, renal54,55,56 and hepatic54,55 impairment were
excluded as contributing factors to SS in some of these cases
involving the elderly.
Conclusion
A large number of patients take tramadol and antidepressants
concomitantly. A retrospective cohort analysis of prescription
claims observed 20.7% of people who received a tramadol pre-
scription also received an antidepressant within 30 days.58
Based upon careful review of the case reports, SS should be
viewed as an uncommon and unpredictable possible adverse
outcome of combining tramadol with serotonin agonist antide-
pressants. The reports also suggest that additional caution is
needed in elderly patients, when higher doses of either drug are
76
used, and when antidepressants with more potent CYP2D6
inhibitor activity are used. Six of the 10 cases were seen in
patients over 70 years of age, and 5 of the 10 cases involved the
most potent CYP2D6 SSRI inhibitors, fluoxetine and paroxe-
tine. SS is a dose-related adverse event, more commonly seen
in overdose situations compared to therapeutic doses of mono-
therapy use. Tramadol can be safely used with other antidepres-
sants but with careful patient monitoring when starting a new
serotonergic agent or with dose increases.
Nearly every antidepressant contains manufacturer informa-
tion alerting clinicians about the potential drug interaction
between serotonergic drugs and their respective antidepres-
sants. They state that ‘‘caution is advised when the antidepres-
sant is coadministered with other drugs that may affect the
serotonergic neurotransmitter systems, such as tramadol.’’ In
no case is this combination identified as a contraindication as
it is between serotonin reuptake inhibitors (SRIs) or SSRIs and
MAOIs. ‘‘SS’’ is listed as a warning, not a contraindication, for
all SSRIs,59,60 SNRIs,61,62 and other serotonergic receptor
modulators such as mirtazapine63 and vilazodone.64 Concomi-
tant use of tramadol and these newer antidepressants does not
rise to the level of a contraindication.
Concern regarding the potential for SS with tramadol and
antidepressants has caused some clinicians to consider using
bupropion, an antidepressant without direct serotonergic effect.
There is no risk of SS due to bupropion’s primary effect of
dopamine reuptake blockade. For other reasons, however,
bupropion is not a safer alternative antidepressant. Both bupro-
pion and tramadol used alone is associated with an increased
risk of seizures. Bupropion has been associated with increasing
the risk of seizures when used at doses of greater than 450 mg/
d.65 Tramadol alone is associated with causing seizure at higher
doses (600-750 mg/d) and at usual recommended doses (50-
300 mg/d).66 Minimum threshold doses for seizure induced
by tramadol are reported in several postmarketing studies to
be as low as 200 mg/d,67 mid-range of 300-450 mg/d,68 and
as high as 500 mg/d.68,69 Other research, however, does not
indicate an increased risk among persons taking tramadol alone
compared to other analgesics.70 Risk of seizure is increased 2-
to 6-fold, however, among users with comorbidities (ie, history
of alcohol abuse, stroke, and head injury) and concomitant
drugs.71 Moreover, there is a higher risk of seizure when trama-
dol is taken with other substances that lower seizure threshold72
including bupropion,65,73 tricyclic antidepressants,65 and
SSRIs.74 Thus, bupropion does not represent a safer alternative
to other antidepressants when used with tramadol.
Patient Counseling
When tramadol is coadministered with an antidepressant, such
a combination is not a contraindication to their use. Overall, SS
appears to be uncommon when combinations of serotonergic
agents in therapeutic doses are used by a single patient. Factors
associated with a greater risk of SS include increased age,
dosage, and concomitant use of potent CYP2D6 inhibitors.
This indicates that although rare, patients should be counseled
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Journal of Pharmacy Practice 27(1)
to recognize signs and symptoms of SS. An example of how to
counsel about SS may include stating ‘‘Rarely, this combina-
tion of medication might cause uncomfortable symptoms such
as fever, sweating, and muscle jerking or tremor. If this occurs,
contact your prescriber right away.’’ SS is a medication safety
issue that concerns clinicians and patients alike; however,
patients should be reassured that the risk of SS is low.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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