Safest Medication to Combine with Lyrica (Pregabalin) for Migraine Treatment
NSAIDs, particularly naproxen sodium (500-825 mg at onset), represent the safest and most evidence-based option to combine with pregabalin for migraine treatment, as they have no significant drug interactions with pregabalin and provide first-line efficacy for mild-to-moderate attacks. 1, 2
Primary Recommendation: NSAIDs
Naproxen sodium is the preferred NSAID choice because it has strong evidence for migraine efficacy, can be dosed 500-825 mg at onset (repeated every 2-6 hours as needed, maximum 1.5 g/day), and has no pharmacokinetic interactions with pregabalin 1, 2
Ibuprofen (400-800 mg) or aspirin (900-1000 mg) are acceptable alternatives with similar safety profiles when combined with pregabalin 3, 1
Limit NSAID use to no more than twice weekly to prevent medication-overuse headache, which can develop with frequent use and lead to daily headaches 1
Second-Line Option: Triptans
Triptans (sumatriptan, rizatriptan, naratriptan, or zolmitriptan) are safe to combine with pregabalin for moderate-to-severe migraine attacks, as there are no significant drug interactions between these medication classes 3, 1
Sumatriptan can be dosed as 50-100 mg orally, 6 mg subcutaneously, or 5-20 mg intranasally depending on attack severity and presence of nausea/vomiting 3, 1
Restrict triptan use to no more than twice weekly to avoid medication-overuse headache 1, 4
Adjunctive Antiemetic Therapy
Metoclopramide 10 mg can be added 20-30 minutes before the NSAID or triptan to provide synergistic analgesia beyond just treating nausea, as it has direct analgesic effects through dopamine receptor antagonism 1
Prochlorperazine 10 mg (oral or IV) is an alternative antiemetic with comparable efficacy to metoclopramide 1
Medications to Avoid with Pregabalin
Avoid opioids (hydromorphone, oxycodone, etc.) and butalbital-containing compounds as they lead to medication-overuse headache, dependency, and loss of efficacy, particularly problematic when combined with pregabalin's sedative effects 1, 4
Avoid benzodiazepines (lorazepam, diazepam) as they have additive CNS depressant effects with pregabalin, increasing risk of sedation, dizziness, and respiratory depression 1
Exercise caution with multiple sedating medications, as pregabalin itself causes dizziness and somnolence in many patients 5
Critical Context About Pregabalin for Migraine
Pregabalin lacks robust evidence for migraine prevention in adults - a Cochrane review found no published controlled trials demonstrating efficacy, and one small open-label study (47 patients) showed only modest benefit with significant dropout due to side effects 5, 6
Gabapentin (pregabalin's predecessor) was definitively shown to be ineffective for migraine prophylaxis in pooled analysis of controlled trials, suggesting pregabalin may have limited utility for this indication 5
If pregabalin is being used for migraine prevention, consider transitioning to evidence-based preventive agents such as propranolol (80-240 mg/day), topiramate (50 mg twice daily), or candesartan, which have strong guideline support 7
Practical Treatment Algorithm
For mild-to-moderate migraine: Start with naproxen sodium 500-825 mg at onset when pain is still mild 1, 2
For moderate-to-severe migraine: Use a triptan (sumatriptan 50-100 mg or rizatriptan 10 mg) at onset, potentially combined with naproxen for synergistic effect 1, 8
If nausea is prominent: Add metoclopramide 10 mg given 20-30 minutes before the analgesic 1
If using acute medications more than twice weekly: Transition to evidence-based preventive therapy rather than continuing pregabalin, which lacks strong efficacy data 7, 5
Key Pitfall to Avoid
Do not allow the patient to increase frequency of acute medication use (NSAIDs, triptans, or combination therapy) beyond twice weekly, as this creates medication-overuse headache that will worsen the underlying migraine pattern and reduce treatment responsiveness 1, 7