Olanzapine (Zyprexa) for Headache Management
Olanzapine is not recommended for routine headache management and has no role in standard migraine or tension-type headache treatment according to current clinical practice guidelines. 1, 2
Evidence Base and Clinical Context
The 2023 VA/DoD headache management guidelines and 2025 acute headache treatment guidelines make no mention of olanzapine as a treatment option for any headache type, despite comprehensive reviews of pharmacologic interventions. 1, 2 This absence from evidence-based guidelines is significant, as these documents systematically evaluated all available treatments with sufficient evidence.
Limited Research Evidence
While olanzapine lacks guideline support, small open-label studies have explored its use in highly specific scenarios:
Cluster Headache (Not Migraine)
- One small open-label trial (n=5) found olanzapine 5-10 mg reduced cluster headache pain by at least 80% in 4 of 5 patients, with pain relief typically within 20 minutes. 3
- This was an abortive treatment for cluster headache specifically, not migraine or tension-type headache. 3
Refractory Chronic Daily Headache
- A retrospective chart review (n=50) of patients with refractory headache who had failed at least four preventive medications showed olanzapine 2.5-35 mg daily reduced headache days from 27.5 to 21.1 days per month. 4
- These were highly selected patients with refractory disease, not typical headache presentations. 4
Critical Limitations and Safety Concerns
These studies represent the lowest quality evidence (open-label, small sample sizes, no placebo control) and cannot support clinical recommendations. The research predates modern headache treatment standards by over 20 years. 3, 4
Significant Adverse Effects
- Olanzapine frequently causes weight gain, sedation, and anticholinergic effects. 5
- Active surveillance is required for elevated transaminases, increased blood pressure, and QT prolongation. 5
- These risks far outweigh any potential benefit for routine headache management. 5
Evidence-Based Alternatives
For acute migraine treatment, use NSAIDs (ibuprofen 400-800 mg, naproxen 500-825 mg) as first-line therapy for mild-to-moderate attacks, and add triptans for moderate-to-severe attacks or when NSAIDs fail. 2
For preventive therapy when needed (≥2 attacks per month with disability), use propranolol 80-240 mg/day, topiramate, or amitriptyline 30-150 mg/day as first-line options. 1, 6
Standard Treatment Algorithm
- Mild-to-moderate migraine: NSAIDs + antiemetic (metoclopramide 10 mg or prochlorperazine 25 mg) 2
- Moderate-to-severe migraine: Triptan + NSAID combination (superior to either alone) 2
- IV treatment: Metoclopramide 10 mg IV + ketorolac 30 mg IV 2
- Limit all acute medications to ≤2 days per week to prevent medication-overuse headache 1, 2
Clinical Bottom Line
Do not use olanzapine for headache management. It has no established role in evidence-based headache treatment, carries significant adverse effects, and effective alternatives with robust evidence exist. 1, 2 The only potential exception would be cluster headache refractory to all standard treatments in consultation with a headache specialist, but even this lacks guideline support. 3