Serotonin Syndrome
The most likely diagnosis is serotonin syndrome (option 3). This patient presents with the classic triad of neuromuscular abnormalities (tremors, myoclonus, hyperreflexia manifesting as allodynia), mental status changes (visual hallucinations), and autonomic hyperactivity after combining multiple serotonergic agents—duloxetine (SNRI), amitriptyline (TCA), and morphine—all of which can precipitate this potentially life-threatening condition 1, 2.
Diagnostic Reasoning
The clinical presentation meets Hunter Criteria for serotonin syndrome, which requires exposure to a serotonergic agent plus one of the following: tremor and hyperreflexia (both present in this patient), spontaneous clonus, inducible clonus with agitation or diaphoresis, ocular clonus with agitation or diaphoresis, or hypertonia with temperature >38°C and ocular/inducible clonus 2, 3. The patient's myoclonus is particularly diagnostic, occurring in 57% of serotonin syndrome cases and considered highly specific when combined with hyperreflexia in the setting of serotonergic drug use 1, 2.
Key Serotonergic Culprits in This Case:
- Duloxetine (SNRI): Potent serotonin reuptake inhibitor that can cause serotonin syndrome even as monotherapy 4
- Amitriptyline (TCA): Enhances central serotonergic responses, particularly dangerous in combination with other agents 5
- Morphine: Opioid analgesics are well-documented precipitants of serotonin syndrome 1, 6
- Ondansetron: 5-HT3 antagonist that contributes to serotonergic activity 1
The combination of multiple serotonergic medications creates additive risk, with symptoms typically developing within 6-24 hours of starting or increasing doses 2, 7.
Why Not the Other Options?
Anticholinergic Toxicity (Option 1):
This is ruled out by the presence of hyperreflexia and myoclonus—anticholinergic toxicity causes decreased bowel sounds, urinary retention, dry mucous membranes, and absent reflexes, not hyperreflexia 1. Additionally, scopolamine (the only anticholinergic agent) would not explain the neuromuscular hyperactivity seen here.
Opioid-Induced Toxicity (Option 2):
Pure opioid toxicity presents with the classic triad of miosis, respiratory depression, and decreased level of consciousness 8. While morphine can cause CNS excitation and convulsions at high doses, it does not cause the hyperreflexia, clonus, and autonomic instability characteristic of this presentation 8. The visual hallucinations and allodynia point away from simple opioid toxicity.
Neuroleptic Malignant Syndrome (Option 4):
NMS requires exposure to antipsychotic medications and presents with lead-pipe rigidity (not hyperreflexia), delirium, and hyperthermia developing over days to weeks—not the acute 2-day onset seen here 1, 2. The patient is not on any neuroleptic agents.
Immediate Management Algorithm
Step 1: Discontinue ALL serotonergic agents immediately (duloxetine, amitriptyline, morphine, ondansetron) 2, 3
Step 2: Initiate supportive care:
- Administer benzodiazepines (first-line for agitation and neuromuscular symptoms) 1, 3
- Provide IV fluids for autonomic instability 3
- Implement external cooling measures (cooling blankets, not antipyretics which are ineffective) 1, 3
- Avoid physical restraints—they worsen hyperthermia and lactic acidosis through isometric muscle contractions 1, 3
Step 3: For moderate-to-severe symptoms, add cyproheptadine:
- Initial dose: 12 mg orally, followed by 2 mg every 2 hours until symptom improvement 2, 3
- Maintenance: 8 mg every 6 hours after initial control 2
- Continue until the clinical triad resolves (typically 24-48 hours) 2, 3
Step 4: Monitor for complications:
- Rhabdomyolysis (elevated CPK) 1, 2
- Metabolic acidosis 1
- Renal failure 1
- Seizures 1
- Disseminated intravascular coagulopathy 2
Critical Pitfalls to Avoid
Do not restart serotonergic agents prematurely—symptoms must completely resolve before considering reintroduction of any serotonergic medication, and never restart the same combination 3.
Do not use succinylcholine if intubation is required—use non-depolarizing agents to avoid hyperkalemia and worsening rhabdomyolysis 2.
Do not use indirect sympathomimetics (like dopamine) for hypotension—use direct-acting agents like phenylephrine or norepinephrine instead 2.
Recognize that approximately 25% of patients require ICU admission with intubation and mechanical ventilation, and the mortality rate is 11% 1, 3. This patient requires continuous cardiac monitoring and close observation for rapid deterioration 2, 3.
The onset on day 2 after starting IV morphine, combined with the pre-existing serotonergic polypharmacy (duloxetine + amitriptyline), created the perfect storm for serotonin syndrome 5, 7. The visual hallucinations represent altered mental status, and the allodynia reflects the neuromuscular hyperactivity component of the syndrome 1, 2.