What can I substitute pregabalin (Lyrica) with for a patient with a history of headaches, potential neuropathic pain, epilepsy, or anxiety disorders?

Substitutes for Pregabalin in Headache Management

Pregabalin should not be used for headache prevention, as current evidence suggests against gabapentinoids for this indication—instead, consider first-line preventive agents like candesartan, telmisartan, or CGRP antagonists (erenumab, fremanezumab, galcanezumab) for migraine, or amitriptyline for tension-type headache. 1

Why Pregabalin Is Not Appropriate for Headache

The 2023 VA/DoD Clinical Practice Guideline for Management of Headache explicitly recommends against gabapentin for episodic migraine prevention (weak against recommendation), and there is insufficient evidence for pregabalin in headache disorders 1. Pregabalin is FDA-approved only for neuropathic pain (diabetic peripheral neuropathy, postherpetic neuralgia, spinal cord injury), fibromyalgia, and partial-onset seizures—not headache 2.

Recommended Substitutes Based on Headache Type

For Episodic Migraine Prevention (Strong Recommendations)

First-line options with the strongest evidence:

• Candesartan or telmisartan (angiotensin receptor blockers): Strong recommendation for episodic migraine prevention 1
• CGRP antagonists: Erenumab, fremanezumab, or galcanezumab carry strong recommendations for both episodic and chronic migraine prevention 1

Second-line options (Weak recommendations but evidence-supported):

• Topiramate: Weak recommendation for episodic and chronic migraine prevention 1
• Propranolol: Weak recommendation for migraine prevention 1
• Valproate: Weak recommendation for episodic migraine prevention 1
• Lisinopril: Weak recommendation for episodic migraine prevention 1

For Chronic Migraine Prevention

• OnabotulinumtoxinA injection: Weak recommendation specifically for chronic migraine (not episodic) 1
• CGRP antagonists (erenumab, fremanezumab, galcanezumab): Strong recommendation for chronic migraine 1

For Tension-Type Headache Prevention

• Amitriptyline: Weak recommendation for chronic tension-type headache prevention 1

For Acute Migraine Treatment (Not Prevention)

If the patient needs abortive therapy rather than prevention:

• Triptans: Strong recommendation for eletriptan, frovatriptan, rizatriptan, sumatriptan (oral or subcutaneous), sumatriptan-naproxen combination, or zolmitriptan (oral or intranasal) 1
• Aspirin-acetaminophen-caffeine combination: Strong recommendation for acute migraine treatment 1

If Pregabalin Was Prescribed for Comorbid Conditions

For Neuropathic Pain Component

If the patient has true neuropathic pain (not typical headache):

• Gabapentin: Start 100-300 mg at bedtime, titrate to 1800-3600 mg/day in three divided doses over 3-8 weeks 3, 4
• Duloxetine: 60-120 mg/day, particularly effective for diabetic peripheral neuropathy with NNT of 5.2 5
• Tricyclic antidepressants (amitriptyline, nortriptyline): Standard first-line treatment for neuropathic pain 1, 6

For Anxiety Disorders

If pregabalin was being used off-label for anxiety:

• SSRIs or SNRIs: Evidence insufficient for fluoxetine or venlafaxine specifically for headache prevention, but these are standard anxiety treatments 1

For Epilepsy/Seizure Disorders

If the patient has comorbid epilepsy:

• Topiramate: Has dual benefit for both seizures and migraine prevention 1
• Valproate: Has dual benefit for both seizures and migraine prevention 1

Critical Pitfalls to Avoid

Do not use gabapentin as a substitute for headache prevention, as it also carries a weak recommendation against use for episodic migraine 1. Both gabapentinoids (pregabalin and gabapentin) lack evidence for headache disorders and share identical adverse effect profiles including dizziness (23-46%), somnolence (15-25%), and peripheral edema 3, 4.

Avoid medication overuse headache: The guideline identifies frequent use of analgesics (including for migraine treatment) as a risk factor for medication overuse headache, particularly with headache frequency ≥7 days/month 1. Preventive therapy should be prioritized over frequent abortive medication use 1.

Do not abruptly discontinue pregabalin: If switching from pregabalin, taper gradually over minimum 1 week to avoid withdrawal symptoms 3, 2.