Headache Cocktail for Patients Unable to Tolerate NSAIDs
For patients unable to tolerate NSAIDs, the recommended headache cocktail is acetaminophen 1000 mg combined with metoclopramide 10 mg IV, which provides efficacy equivalent to oral sumatriptan 100 mg for moderate to severe migraine. 1, 2
First-Line Combination Therapy (NSAID-Intolerant Patients)
Acetaminophen 1000 mg + Metoclopramide 10 mg IV is the primary recommendation when NSAIDs cannot be used 1, 2:
- Acetaminophen 1000 mg provides pain relief with NNT of 5.0 for 2-hour headache relief (56% response vs 36% placebo) 3
- Metoclopramide 10 mg IV provides synergistic analgesia beyond just treating nausea, with direct analgesic effects through central dopamine receptor antagonism 2, 4
- This combination achieves short-term efficacy equivalent to oral sumatriptan 100 mg 1
- Critical advantage: Fewer serious/severe adverse events compared to sumatriptan (NNH 32 favoring the combination) 1
Alternative First-Line Options
If the acetaminophen-metoclopramide combination is insufficient or contraindicated:
Prochlorperazine 10 mg IV can be substituted for metoclopramide 2, 4:
- Comparable efficacy to metoclopramide for headache relief 2
- May have slightly better efficacy profile (rated 4 vs 2 for metoclopramide in clinical impression) 4
- Monitor for akathisia and consider prophylactic diphenhydramine if this side effect is a concern 5
Second-Line Triptan Strategy (When Acetaminophen Alone Fails)
Add a triptan to acetaminophen when adequate acetaminophen dosing provides insufficient relief 1:
- Oral triptans with strong evidence: sumatriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan, naratriptan, frovatriptan 1
- For severe nausea/vomiting: Use non-oral triptan formulations (subcutaneous sumatriptan 6 mg, intranasal sumatriptan, or intranasal zolmitriptan) 1, 4
- Subcutaneous sumatriptan 6 mg provides highest efficacy (59% pain-free at 2 hours) with fastest onset (~15 minutes) 4
Critical contraindications to triptans 6:
- Coronary artery disease or risk factors requiring cardiovascular evaluation
- Uncontrolled hypertension
- History of stroke or TIA
- Hemiplegic or basilar migraine
- Peripheral vascular disease
Third-Line Options for Refractory Cases
When both acetaminophen-antiemetic combinations and triptans fail or are contraindicated 1, 2:
CGRP Antagonists (Gepants):
- Rimegepant, ubrogepant, or zavegepant 1, 2
- Considered for moderate to severe migraine when combination therapy inadequate 1
Dihydroergotamine (DHE):
Lasmiditan (Ditan):
- Reserved for patients who fail all other options 1, 2
- Causes sedation; patients cannot drive for 8 hours after use 2
Treatment Algorithm by Severity
Mild to Moderate Migraine:
- Acetaminophen 1000 mg (can add caffeine for synergistic effect) 2, 7
- If inadequate: Add metoclopramide 10 mg 2
Moderate to Severe Migraine:
- Acetaminophen 1000 mg + Metoclopramide 10 mg IV 1, 2
- If inadequate after 2 hours: Add triptan or switch to triptan + acetaminophen 1
- If still inadequate: CGRP antagonist or DHE 1, 2
Severe Migraine with Vomiting:
- Non-oral triptan (subcutaneous sumatriptan 6 mg or intranasal formulation) + antiemetic 1, 4
- Alternative: DHE intranasal + antiemetic 1, 2
Critical Pitfalls to Avoid
Medication Overuse Headache 1, 2:
- Limit acute treatment to ≤2 days per week (≤10 days/month for triptans, ≤15 days/month for acetaminophen) 1, 4
- Frequent use paradoxically worsens headache frequency 1
Avoid Opioids and Butalbital 1, 2:
- Lead to dependency, rebound headaches, and loss of efficacy 2, 4
- No role in routine migraine management 1
Timing of Administration 1, 4:
- Begin treatment as early as possible in the attack 1
- Medications are most effective when taken while pain is still mild 4
Special Considerations
If headaches occur frequently (≥2 attacks/month causing ≥3 days disability, or requiring acute medication >2 days/week) 1, 4:
- Initiate preventive therapy with propranolol 80-240 mg/day, amitriptyline 30-150 mg/day, or divalproex sodium 500-1500 mg/day 1
Pregnancy/Lactation 1: