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Ewa Greenier, MPH, MBAValentina Lukyanova, PhD Lynn Reede, CRNA, DNP, MBA

Serotonin Syndrome: Fentanyl and Selective SerotoninReuptake Inhibitor Interactions

PRACTICE NEWS

What Is SerotoninSyndrome?Serotonin syndrome is a potentiallyfatal condition associated withincreased serotonergic activity in thecentral nervous system that can beattributed to certain drugs, interac-tions between drugs, or intentionaloverdose.1 The terms serotonintoxicity and serotonin syndrome areoften used interchangeably. Gillmanreasons that the term serotonin tox-

icity is more accurate, as it reflects“the broad spectrum of serotonin-related side effects progressing totoxicity.”2,3 As serotonin syndrome isused predominantly in the literatureand anesthesia-related texts, we willuse the term serotonin syndrome throughout this article.

Serotonin syndrome is often char-acterized by a triad of symptoms,which include altered mental status,neuromuscular hyperactivity, and

autonomic instability or hyperactiv-ity.4 The symptoms can range frommild to severe and can be fatal ifleft untreated.5 Table 1 provides asummary of mild, moderate, andsevere symptoms associated withserotonin syndrome. Patients maybe discharged following anesthesiawith unrecognized symptoms ofserotonin syndrome. After cessa-tion of the drugs responsible for thissyndrome, symptoms usually abate

within 24 hours. However, in severecases, it can take up to several daysfor symptoms to abate.6

What Causes Serotonin Syn-drome?A large number of drugs with seroto-nergic activity have been implicatedin serotonin syndrome (see Table2). Antidepressants known as sero-tonin reuptake inhibitors (SSRIs) aremost commonly responsible for this

condition.7

 SSRIs work by increasingthe levels of serotonin in the brain,which can be effective for treatingdepression. However, when used incombination with other serotoner-gic drugs, SSRIs can significantlyincrease the levels of serotonin inthe central nervous system, whichmay result in subsequent serotoninsyndrome.5 

Incidence

According to the 2012 AnnualReport of the American Associationof Poison Control Centers’ NationalPoison Data, 47,115 people reportedtoxicity related to SSRIs, resulting in1,723 moderate adverse events, 152major adverse events, and 7 deaths.8 However, these numbers are likelyto be underestimated as serotoninsyndrome may be confused withother medical conditions, especiallyif symptoms are mild.9 Furthermore,

Serotonin syndrome is a rare but potentially fatal

adverse drug reaction associated with increased sero- 

tonergic activity in the central nervous system. It ischaracterized by a triad of symptoms, which include

altered mental status, neuromuscular hyperactivity,

and autonomic instability or hyperactivity. Due to the

potential of rapid onset, it is important for clinicians to

recognize the signs and symptoms of serotonin syn- 

drome. Serotonin syndrome symptoms may resemble

other conditions. Although this article focuses on sero- 

tonin syndrome as a result of an adverse interaction

of selective serotonin reuptake inhibitors (SSRI) and

fentanyl, it is important for not only anesthesia pro- 

fessionals, but all clinicians—such as those in emer- 

gency medicine and critical care—to be aware of thissyndrome and its management. This article discusses

the clinical manifestations of the serotonin syndrome

and highlights reported cases of serotonin syndrome

specifically related to an interaction between SSRIs

and fentanyl, a commonly used opioid in anesthesia

practice.

Keywords:   Fentanyl, serotonin syndrome, serotonin

toxicity, SSRI.

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healthcare providers may not beaware of this condition and/or theinteractions among prescribed

drugs.10 Given the common prescrip-tion of SSRIs for treating depressionand other conditions, the incidenceof serotonin syndrome will likelyincrease in the future.

Fentanyl and SSRI InteractionCase reports suggest that sero-tonin syndrome may be caused byan interaction between fentanyland SSRIs. The exact mechanisms

through which this reaction occursare not fully understood.6 Fentanylis commonly used in most anesthe-sia techniques as an analgesic. Itsshort half-life makes it an appeal-ing drug choice in anesthesia.6,11 Inpatients already taking other SSRIs,the administration of fentanyl mayprecipitate serotonin syndrome.Fentanyl and other phenylpiperidineopioids (eg, meperidine, tramadol,sufentanil, alfentanil, and remifent-

anil) seem to be weak SSRIs and mayalso enhance serotonin release.Current research regarding the

interaction between fentanyl, SSRIs,and serotonin syndrome is basedon case studies, several of whichhave been summarized in Table 3. Case studies are prone to researchbias and limited generalizability.Nevertheless, case studies can helpidentify the important areas forfurther investigations involving sys-

tematically collected data. The casesdescribed here suggest that patientstaking SSRIs are at an increasedrisk for serotonin syndrome follow-ing fentanyl administration. Mostof these patients developed severesymptoms and required emergencycare.

Clinical Findings of Sero-tonin Syndrome

Serotonin syndrome can mani-fest in a variety of ways, includingmental status changes, autonomichyperactivity, and neuromuscularabnormalities.12 Mild symptoms mayinclude mild hypertension, tachy-cardia, and tremor that can rapidlyprogress to more severe symptoms,such as delirium, neuromuscularrigidity, and hyperthermia.7,10,13 People of all age groups, includ-ing newborns and older adults, can

develop this condition.

1

 Cliniciansneed to pay close attention to warn-ing signs in cases of suspectedserotonin syndrome. The mostimportant signs include clonus andgeneralized hyperreflexia that can beaccompanied by rigidity, especiallyin the lower extremities.1 Changesin mental state and autonomic func-tions can also be observed in patientswith moderate to severe serotoninsyndrome.5 

Table 2. Drugs Associated With Serotonin Syndrome (adapted from

Isbister et al, 2007)5 

Serotonin Selective serotonin reuptake inhibitors: fluoxetine, fluvox-

reuptake inhibitors amine, paroxetine, citalopram, sertraline, escitalopram

  Other antidepressants: venlafaxine, clomipramine,

imipramine

  Opioid analgesics: pethidine, tramadol, fentanyl,

dextromethorphan

  Herbal products: St. John’s wort

Monoamine oxidase Irreversible monoamine oxidase A inhibitors: phenelzine,inhibitors tranylcypromine

Reversible monoamine oxidase A inhibitors: moclobemide

Others: linezolid

Serotonin-releasing Fenfluramine

  Amphetamines

  Methylenedioxymethamphetamine (MDMA; ecstasy)

Miscellaneous Lithium

Tryptophan

agents

Mild  Akathisia

  Anxiety

  Diaphoresis

  Hyperreflexia

  Mild hypertension

  Mydriasis

  Myoclonus

  Restlessness  Shivering

  Tachycardia

  Tremor

Moderate  Symptoms as above, and 

  Agitation

  Easily startled

  Hyperactive bowel sounds

  Hypervigilance

  Increased confusion

  Inducible clonus

  Myoclonus

  Ocular clonus  Pressured speech

  Temperature of at least 40° C

Severe  Symptoms as above, and 

  Acute respiratory distress

syndrome

  Coma

  Delirium

  Diffuse intravascular clotting

  Disseminated intravascular

coagulopathy

  Dramatic swings in pulse rate

and blood pressure

  Elevation of serum

aminotransaminases and

creatinine

  Hypertension (can deteriorate

to shock)

  Hypotonicity

  Metabolic acidosis

  Muscle rigidity

  Myoglobinuria

  Renal failure

  Respiratory failure

  Rhabdomyolysis

  Seizures

  Spontaneous clonus

  Tachycardia

  Temperature greater than

41.1° C

Table 1. Signs, Symptoms, and

Complications of Serotonin

Syndrome10,13,16,19

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DiagnosisCurrently, there are two main diag-nostic criteria to establish serotonin

syndrome: the Sternbach’s criteriaand the Hunter Serotonin Toxicitycriteria. Developed in 1991, theSternbach’s criteria include 10clinical features, and require threeof these 10 features to be presentto establish the diagnosis clinically(see Table 4). While the Sternbach’scriteria can be useful in recognizingearly signs of serotonin syndrome,it has been criticized for its lackof specificity of symptoms, which

can also be found in other medicalconditions.12,14 More recently, theHunter Serotonin Toxicity Criteriawas developed and consists of simplebut accurate decision rules.14 TheHunter’s criteria, with its emphasison clonus as the most important fea-ture of serotonin syndrome, appearmore sensitive (84% vs 75%) andmore specific (97% vs 96%) thanSternbach’s criteria. Not surprisingly,the Hunter’s criteria are considered

to be the preferred diagnostic tool.The onset of symptoms is typi-cally rapid, with symptoms oftenoccurring within minutes of drugadministration, dosage change, oroverdose.10 Approximately 60% ofserotonin syndrome cases presentwithin 6 hours of drug therapy.10 There are no laboratory tests avail-able for diagnosis of serotoninsyndrome.7,15 Laboratory and diag-nostic testing is used to rule out

alternative explanations for theobserved signs and symptoms.7 Serotonin syndrome may initially

resemble other conditions, such asadverse drug reactions, meningo-encephalitis, severe sepsis, deliriumtremens, heat stroke, neurolepticmalignant syndrome, sympatho-mimetic toxicity, anticholinergicpoisoning, or malignant hyperther-mia.5,7,15 Examination of specificneurological symptoms and rulingout other conditions will aid theclinician in making the differentialdiagnosis.5

ManagementInitial management of serotoninsyndrome consists of supportivecare and cessation of serotonergicdrugs.5,15 Supportive managementto address symptoms may preventsecondary complications. Earlymanagement includes stabilizationof vital signs, administration of oxy-gen and IV fluids, and continuouscardiac monitoring.13 The course

of treatment can vary based on theseverity of the case. Many casestend to resolve within 24 hoursafter initiation of supportive careand discontinuation of serotonergicdrugs.10,13 Symptoms may persistlonger if the patient is taking medica-tions with longer half-lives, activemetabolites, or a protracted durationof action.10 Benzodiazepines, suchas diazepam or midazolam, may beused to control agitation or tremor

for cases of any severity level.10,13,16

Mild cases, which can be char-acterized by mild hypertension,

tachycardia, mydriasis, diaphoresis,shivering, tremor, myoclonus, andhyperreflexia,13 may not requirehospitalization, as supportive careand drug cessation can be enoughfor symptoms to subside.7,15 Supportive care can aid in the pre-vention of secondary complicationssuch as rhabdomyolysis, renal fail-ure, and disseminated intravascularcoagulation.15 Patient vital signs,kidney function, and electrolytes

should be monitored.15

 Progressively increased toxic-ity several hours after ingestion ofserotonergic drugs can be notedin patients with moderate cases.15 Moderate cases can be character-ized by a temperature >40º C (104ºF), hyperactive bowel sounds,ocular clonus, agitation, hyper-vigilance, and pressured speech.13 Those with moderate serotoninsyndrome should be observed for

a period of 6-12 hours.

5,15

 Patientswith moderate cases should havecardiorespiratory and thermal abnor-malities corrected and may benefitfrom 5-HT2A antagonist administra-tion.10 Patients with moderate tosevere cases are typically treatedwith cyproheptadine.7 Additionally,olanzapine or chlorpromazine areother drug options, but are not rou-tinely used due to their potentialside effects and toxicity.7 In par-

  Sternbach Hunter

Must exhibit at least 3 of the 10 following features, with the Must use serotonergic drug, in addition to 1 or more of the following:

addition of or increase in a known serotonergic agent:

• Mental status changes • Spontaneous clonus

• Agitation • Inducible clonus with agitation or diaphoresis

• Myoclonus • Ocular clonus with agitation or diaphoresis

• Hyperreflexia • Tremor and hyperreflexia

• Diaphoresis • Hypertonia, temperature above 100.4° F (38° C) with ocular or

• Shivering inducible clonus

• Tremor

• Diarrhea

• Incoordination

• Fever

Table 4. Diagnostic Criteria for Serotonin Syndrome

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ticular, caution should be taken ifchlorpromazine is being consideredto treat symptoms for patients withhypotension or neuroleptic malig-nant syndrome.10,16 

Rapid deterioration of a patient’scondition signals the need for an

immediate, aggressive treatment.10 Severe cases can be characterizedby a temperature >41.1º C (106ºF), dramatic swings in blood pres-sure and pulse rate, delirium, andmuscle rigidity.13 For severe cases,the patient should be admitted tothe intensive care unit with a focuson hemodynamic stability and man-agement of symptoms.5,15 The same5-HT2A antagonist drug regimenmay be used for severe symptoms,

although patients who becomehyperthermic may also requireimmediate sedation and intubationusing a nondepolarizing neuro-muscular blocking agent.10,13,16 Succinylcholine use is not adviseddue to the risk of arrhythmia fromhyperkalemia associated with rhab-domyolysis.10,13,16 Active coolingis recommended, as antipyreticagents will not be effective in thesecases.13,15-17 Hyperthermia due to

serotonin syndrome is caused bymuscle hypermetabolism and not bycentral nervous system effects.13,16 Dantrolene, used to treat malignanthyperthermia, has not been shownto be an effective treatment optionfor serotonin syndrome in animalmodels.13,18 

Management of a patient experi-encing serotonin syndrome is a teameffort. Once a case is identified, inaddition to the interprofessional

team, consultation with a medicaltoxicologist, clinical pharmacolo-gist, or a poison control center cansupport clinicians in the decision-making process regarding drug-druginteractions, potential side effects,and ongoing patient management.10 

Implications for AnesthesiaPracticeThe intent of this article is to raiseawareness of serotonin syndrome: its

causes, clinical manifestations, andtreatment options. Because fentanylis widely used in anesthesia prac-tice and has the potential to resultin serotonin syndrome if combinedwith other serotonergic drugs, wehighlighted several examples of cases

resulting from SSRI and fentanylinteraction. Through a thoroughpatient assessment and evaluation,an anesthesia provider should beaware of potentially problematicdrugs, herbal supplements, or illicitdrugs that patients are taking. Dueto the prevalent use of serotonergicdrugs, clinicians need to be aware ofthe signs and symptoms of serotoninsyndrome and how to differentiateit from other conditions. Clinicians

also need to remain vigilant forsigns and symptoms, as serotoner-gic properties of certain drugs maynot be well established.4 If pos-sible, multidrug regimens should beavoided, or one serotonergic drug bediscontinued prior to the administra-tion of another. In the case of drugsrequired for sedation or general anes-thesia, communication is importantamong all clinicians in the patientcare team about the patient’s drugs,

the planned anesthetic, the require-ments of the planned procedure, andthe overall course of treatment.

Predicting serotonin syndromeis difficult. Patient and caregivereducation regarding the symptoms isalso important for early recognition.Clinicians treating patients who aretaking multiple drugs should edu-cate their patients on the potentialsigns and symptoms of serotoninsyndrome and appropriate steps

to take should symptoms occur.

16

 Patients should periodically reviewall of their prescribed and over-the-counter drugs and supplements withtheir clinician or pharmacist.

If a patient experiences serotoninsyndrome, the clinician or facilitymay consider voluntary reporting ofthe case to the U.S. Food and DrugAdministration (FDA) through theMedWatch program, found onlineat www.fda.gov/Safety/MedWatch/ .

MedWatch is a voluntary program

that aids the FDA in identifyingtrends of side effects, adverse drugevents, and other quality-relatedproblems associated with medica-tions or devices.

Early recognition of symptoms,

discontinuation of serotonergicdrugs, and immediate treatment

can mitigate complications due toserotonin syndrome and yield afavorable prognosis for patients suf-fering from this condition. Througheducation and heightened aware-ness, safety can be increased forthose patients who may be at an

increased risk for experiencing sero-tonin syndrome.

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  2. Gillman PK. Monoamine oxidase inhibi-tors, opioid analgesics and serotonin tox-icity. Br J Anaesth. 2005;95(4):434-441.

  3. Gillman PK. The spectrum con-cept of serotonin toxicity. Pain Med. 2004;5(2):231-232; author reply 233.

  4. Thanacoody R. Serotonin syndrome. Medi-cine. 2011;40(2):63-64.

  5. Isbister GK, Buckley NA, Whyte IM.Serotonin toxicity: a practical approachto diagnosis and treatment. Med J Aust. 2007;187(6):361-365.

  6. Kirschner R, Donovan JW. Serotoninsyndrome precipitated by fentanyl dur-ing procedural sedation. J Emerg Med. 2010;38(4):477-480.

  7. Ables AZ, Nagubilli R. Prevention,recognition, and management of sero-tonin syndrome. Am Fam Physician. 2010;81(9):1139-1142.

  8. Mowry JB, Spyker DA, Cantilena LR Jr,Bailey JE, Ford M. 2012 Annual Report ofthe American Association of Poison Con-trol Centers’ National Poison Data System(NPDS): 30th Annual Report. Clin Toxicol(Phila). 2013;51(10):949-1229.

  9. Rastogi R, Swarm RA, Patel TA. Case sce-nario: opioid association with serotonin

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 10. Boyer EW, Shannon M. The sero-tonin syndrome. N Engl J Med. 2005;352(11):1112-1120.

 11. Alkhatib AA, Peterson KA, Tuteja AK.Serotonin syndrome as a complicationof fentanyl sedation during esopha-gogastroduodenoscopy. Dig Dis Sci.2010;55(1):215-216.

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Serotonin syndrome. Ochsner J. 2013;13(4):533-540.

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 15. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT.Overview of serotonin syndrome.  Ann ClinPsychiatry. 2012;24(4):310-318.

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 Adv Crit Care. 2013;24(1):15-20; quiz21-12.

 17. Isbister GK, Buckley NA. The patho-physiology of serotonin toxicity in animalsand humans: implications for diagnosisand treatment. Clin Neuropharmacol. 2005;28(5):205-214.

 18. Nisijima K, Yoshino T, Yui K, Katoh S.Potent serotonin (5-HT)(2A) receptorantagonists completely prevent the devel-opment of hyperthermia in an animalmodel of the 5-HT syndrome. Brain Res. 2001;890(1):23-31.

 19. Frank C. Recognition and treatment ofserotonin syndrome. Can Fam Physician. 2008;54(7):988-992.

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AUTHORS

Ewa Greenier, MPH, MBA, is a professionalpractice specialist for the AANA, providing staffsupport for Practice Committee activities in ParkRidge, Illinois. Email: egreenier@aana.com.

 Valentina Lukyanova, PhD, is a research

analyst for the AANA, providing research sup-

port for Practice Committee activities in Park

Ridge, Illinois. Email: vlukyanova@aana.com.

Lynn Reede, CRNA, DNP, MBA, is a senior

director for the AANA, providing staff leader-

ship to the AANA’s Practice Committee in the

development and revision of evidence-based

anesthesia clinical practice guidelines, position

statements, standards and member resources,

in Park Ridge, Illinois. Email: lreede@aana.com.

ACKNOWLEDGMENT

The authors would like to thank John J. Nagel-

hout, CRNA, PhD, FAAN and Nina McLain,

CRNA, PhD for their clinical review and feed-

back on the content of this article.