Do patients need to be on oral (per oral) migraine medications before starting migraine injection therapy with onabotulinumtoxinA (Botox)?

No Oral Migraine Medications Required Before Starting Botox Injections

You do not need to be on oral migraine preventive medications before starting onabotulinumtoxinA (Botox) injections for chronic migraine, though most guidelines recommend trying 2-3 oral preventive medications first due to cost considerations and patient preference for oral routes. 1

Evidence-Based Treatment Sequencing

Guideline Recommendations on Treatment Order

• The 2025 American College of Physicians guideline suggests using oral preventive medications (β-blockers like metoprolol or propranolol, valproate, venlafaxine, or amitriptyline) before CGRP-mAbs or CGRP antagonist-gepants, primarily based on cost differences rather than efficacy differences. 1

• The European Headache Federation recommends that patients should preferably have tried 2-3 other migraine prophylactics before starting onabotulinumtoxinA, but this is not an absolute requirement. 2

• The 2023 VA/DoD Clinical Practice Guideline suggests onabotulinumtoxinA injection for prevention of chronic migraine without mandating prior oral medication trials. 3

Why Guidelines Recommend Trying Oral Medications First

• Cost considerations: OnabotulinumtoxinA has substantially higher costs compared to oral preventive medications like propranolol, amitriptyline, or valproate. 1

• Patient preference: Evidence shows patients probably prefer oral treatments over injectable medications when effectiveness is similar (moderate-certainty evidence). 1

• Insurance requirements: Most regulatory and insurance restrictions require failure of 2-3 other preventive medications before approving onabotulinumtoxinA coverage. 3

Clinical Scenarios Where Botox Can Be Started Without Prior Oral Medications

Acceptable Situations for Direct Botox Initiation

• Contraindications to oral medications: When patients have medical conditions that preclude use of standard oral preventives (e.g., β-blockers contraindicated in asthma, valproate contraindicated in pregnancy planning). 1

• Previous intolerance: When patients have documented adverse reactions or intolerance to multiple oral preventive medication classes. 2

• Medication overuse headache: OnabotulinumtoxinA can be initiated in patients with concurrent medication overuse, either before or during withdrawal from overused medications. 2

• Patient receiving concurrent oral preventives: It is acceptable to start onabotulinumtoxinA while patients continue their current oral preventive medications—93% of patients in real-world studies received concurrent oral preventives when starting Botox. 4

Important Clinical Considerations

Medication Overuse Management

• Patients with medication overuse should ideally be withdrawn from overused medications before initiating onabotulinumtoxinA if feasible, but if withdrawal is not feasible, onabotulinumtoxinA can be initiated from the start or before withdrawal. 2

• In real-world practice, 80% of patients starting onabotulinumtoxinA met criteria for medication overuse, and 61.9% successfully discontinued medication overuse after the first year of Botox treatment. 4

Treatment Protocol Requirements

• OnabotulinumtoxinA should be administered according to the PREEMPT injection protocol: 155-195 units to 31-39 sites every 12 weeks. 2

• Patients should receive at least 2-3 treatment cycles before being classified as non-responders, as clinical benefit may take time to manifest. 2, 5

• Response should be defined as at least 30% reduction in headache days per month, though other factors like headache intensity, disability, and patient preferences should also be considered. 2

Concurrent Oral Preventive Medications

• It is common and acceptable to continue oral preventive medications when starting onabotulinumtoxinA—in long-term real-world data, 48.6% of patients were able to discontinue concurrent oral preventives after sustained Botox treatment. 4

• The decision to continue or discontinue oral preventives should be individualized based on response to onabotulinumtoxinA over time. 4

Common Pitfalls to Avoid

• Don't delay Botox unnecessarily: While trying oral medications first is reasonable for cost and preference reasons, don't force patients through multiple failed oral medication trials if they have contraindications or documented intolerance. 2

• Don't stop Botox too early: Allow for adequate treatment duration (2-3 cycles minimum) before declaring treatment failure, as response may take up to 15 days after each injection to manifest. 5

• Don't ignore medication overuse: Address medication overuse headache concurrently with Botox treatment rather than delaying Botox initiation. 2

• Don't use Botox for episodic migraine: OnabotulinumtoxinA is only indicated for chronic migraine (≥15 headache days per month) and is ineffective for episodic migraine. 3