What are the indications for cyproheptadine?

Indications for Cyproheptadine

Cyproheptadine is indicated for severe serotonin syndrome as a serotonin2A receptor antagonist, gastrointestinal symptoms in mast cell activation syndrome (MCAS), and allergic rhinitis, with additional off-label uses for appetite stimulation and PTSD-related nightmares.

Primary FDA-Approved Indication

Allergic Rhinitis

• Cyproheptadine is a first-generation H1-antihistamine approved for treating allergic-type symptoms and rhinorrhea 1
• The anticholinergic effects provide better control of rhinorrhea compared to second-generation antihistamines 1
• Common dosing is 4 mg three times daily in adults, with 2 mg/5 mL syrup available for pediatric patients aged 2 years and older 1
• Important caveat: First-generation antihistamines like cyproheptadine cause significant sedation (9-11% incidence), impair driving ability, and can lead to cognitive decline, particularly in elderly patients 1

Critical Emergency Indication

Severe Serotonin Syndrome

• Cyproheptadine is the preferred antidote for severe serotonin syndrome, functioning as a serotonin2A receptor antagonist 1, 2
• The American Academy of Pediatrics specifically recommends cyproheptadine over chlorpromazine for severe cases 1
• Adult dosing: Start with 12 mg orally, followed by 2 mg every 2 hours for continuing symptoms, with maintenance dosing of 8 mg every 6 hours (total 12-24 mg over 24 hours) 1, 2
• Pediatric dosing: 0.25 mg/kg per day 1, 2
• Critical consideration: No parenteral form exists, but tablets can be crushed and administered via nasogastric tube 1
• Warning: May cause hypotension and sedation; patients can deteriorate rapidly requiring ICU-level monitoring 1, 2
• Serotonin syndrome has an 11% mortality rate with complications including rhabdomyolysis, metabolic acidosis, renal failure, and seizures 1, 2

Mast Cell Disorders

Mast Cell Activation Syndrome (MCAS)

• Cyproheptadine is recommended for gastrointestinal symptoms in MCAS due to its dual H1-antihistamine and antiserotonergic properties 1
• The Journal of Allergy and Clinical Immunology guidelines note it may help with diarrhea and nausea specifically 1
• Mechanism: Blocks both histamine H1 receptors and serotonin receptors, providing broader symptom control than standard antihistamines 1
• Important limitation: Evidence shows it may not be more beneficial than other antihistamines like diphenhydramine for general MCAS symptoms 1

Off-Label Indications with Guideline Support

PTSD-Related Nightmares

• The American Academy of Sleep Medicine position paper addresses cyproheptadine for combat-related nightmares 1
• Dosing ranges from 2-24 mg nightly, with median effective doses of 16-24 mg in veterans 1
• Evidence is conflicting: One case series showed elimination of nightmares in 3 of 4 patients within days, while another study of 16 patients showed no significant improvement 1
• Side effects include fatigue, restlessness, and paradoxically worsening nightmares in some patients 1

Erythromelalgia

• Limited evidence supports use for primary erythromelalgia with partial symptom relief 1
• Mechanism: Serotonin antagonist properties may help with pain and hot skin symptoms 1
• Evidence quality is poor: Only case reports of 2 patients showing effectiveness, while a survey found 0 of 3 patients benefited 1

Appetite Stimulation (Orexigenic Effect)

• Widely used off-label for appetite stimulation despite lack of formal authorization in many countries 3
• Safety profile: Considered generally safe with mild neurological effects (drowsiness) being most common 3
• Hepatotoxicity is uncommon to rare (0.27-1.4 per 1000 patients), but very rare cases of liver failure have been reported requiring monitoring 3

Important Safety Considerations

Contraindications and Warnings

• Cognitive decline risk is especially concerning in elderly patients due to anticholinergic effects 1
• May impair driving ability and school performance even without subjective awareness of sedation 1
• Anticholinergic effects include dry mouth, dry eyes, constipation, urinary retention, and risk of narrow-angle glaucoma 1
• Rare but serious: Aggression and violent behavior reported in children, likely related to serotonin antagonism 4
• Fatal overdoses have been reported, particularly in combination with other CNS depressants 5

Drug Interactions

• Avoid concomitant use with alcohol and other CNS-active substances as this enhances performance impairment 1
• In serotonin syndrome, avoid indirect sympathomimetics like dopamine; use direct-acting agents (phenylephrine, norepinephrine) instead 1

Monitoring Requirements

• For orexigenic use: Monitor hepatic function due to rare hepatotoxicity risk 3
• For serotonin syndrome: Requires ICU-level monitoring with preparation for rapid deterioration, intubation, and paralysis with non-depolarizing agents if needed 1, 2
• Avoid succinylcholine in severe serotonin syndrome due to hyperkalemia and rhabdomyolysis risks 2