What could be causing a patient's symptoms of nocturnal sweating, tremors, fatigue, insomnia, and blurry vision after recently starting duloxetine (Cymbalta), while also taking hydroxyzine (Vistaril), tizanidine (Zanaflex), amitriptyline (Elavil), aripiprazole (Abilify), and tramadol (Ultram)?

Serotonin Syndrome from Polypharmacy

This patient is most likely experiencing serotonin syndrome caused by the dangerous combination of duloxetine (an SNRI) with tramadol, compounded by amitriptyline—all three medications increase serotonin activity and create a high-risk drug interaction. 1, 2

Primary Diagnosis: Serotonin Syndrome

The constellation of symptoms—nocturnal sweating (diaphoresis), tremors (shakes), insomnia, fatigue, and blurry vision—are classic manifestations of serotonin syndrome, particularly when duloxetine was recently initiated in a patient already taking tramadol. 1, 2

Key Clinical Features Present:

• Autonomic hyperactivity: Diaphoresis (sweating) and tachycardia are hallmark features 1, 2
• Neuromuscular changes: Tremors (shakes) indicate neuromuscular hyperactivity 1, 2
• Mental status changes: Fatigue and insomnia suggest altered mental status 1
• Mydriasis: Blurry vision may reflect pupillary dilation 2

High-Risk Drug Combination:

• Duloxetine + Tramadol: This is a documented dangerous combination. Duloxetine inhibits serotonin reuptake while tramadol both inhibits serotonin reuptake AND releases serotonin, creating additive serotonergic effects 3, 2, 4
• Adding Amitriptyline: This tricyclic antidepressant further increases serotonergic activity, compounding the risk 5
• Case precedent: A published case report documented serotonin syndrome from tramadol combined with venlafaxine (another SNRI similar to duloxetine), presenting with agitation, confusion, severe shivering, diaphoresis, myoclonus, hyperreflexia, mydriasis, tachycardia, and fever 2

Immediate Management Algorithm

Step 1: Discontinue Offending Agents

• Stop duloxetine immediately as the most recently added serotonergic agent 1, 2
• Consider stopping or reducing tramadol given its dual mechanism (serotonin reuptake inhibition + serotonin release) 2, 4
• Do NOT abruptly stop amitriptyline due to discontinuation syndrome risk, but plan gradual taper 5

Step 2: Monitor for Progression

• Assess for severe serotonin syndrome features: fever >38°C, seizures, muscle rigidity, altered consciousness, arrhythmias 1
• If severe features present: Immediate hospitalization with continuous cardiac monitoring is mandatory 1
• If mild-moderate features: Close outpatient monitoring with daily follow-up for 48-72 hours 1, 2

Step 3: Supportive Care

• Hydration and symptomatic treatment for diaphoresis and tremors 1
• Benzodiazepines (patient already has hydroxyzine, which may help with agitation) 2

Alternative Contributing Factors (Less Likely)

Duloxetine-Specific Side Effects:

While duloxetine alone can cause these symptoms, the combination with tramadol makes serotonin syndrome far more likely:

• Common duloxetine side effects: Diaphoresis, tremor, insomnia, dizziness, blurred vision 5, 1, 3
• However: The severity and clustering of symptoms shortly after initiation, combined with tramadol co-administration, strongly suggests serotonin syndrome rather than simple side effects 1, 2

Anticholinergic Effects from Amitriptyline:

• Amitriptyline causes blurred vision, but typically also causes dry mouth and constipation (not sweating) 5
• The presence of diaphoresis argues against pure anticholinergic toxicity 5

Critical Pitfalls to Avoid

• Do not dismiss as "adjustment period": Serotonin syndrome can progress to life-threatening complications including seizures, arrhythmias, and death 1
• Do not add more medications: Avoid adding agents to "treat" individual symptoms without addressing the underlying drug interaction 1, 2
• Do not rechallenge with duloxetine while on tramadol: This combination should be avoided 2, 4
• Monitor for discontinuation syndrome: When stopping duloxetine, expect dizziness, headache, nausea, paresthesia, irritability, and insomnia for 1-2 weeks 1

Long-Term Medication Reconciliation

This patient is on an excessive polypharmacy regimen with multiple overlapping mechanisms:

• Three serotonergic agents: Duloxetine, amitriptyline, tramadol 1, 3, 2
• Three sedating agents: Hydroxyzine, tizanidine, amitriptyline 5
• Aripiprazole: Adding dopaminergic effects 5

A comprehensive medication review and deprescribing strategy is urgently needed to reduce polypharmacy burden and prevent future drug interactions. 2, 4