What are the next steps for a patient with migraines who has failed propranolol and topiramate (first-line medications), with concerns about secondary causes, and may have underlying conditions such as thyroid disorders or anemia?

Next Steps for Migraine After Propranolol and Topiramate Failure

When first-line preventive medications (propranolol and topiramate) have failed and secondary causes are concerning, immediately investigate for underlying pathology before escalating to second-line preventive therapy. 1

Immediate Evaluation for Secondary Causes

In patients with apparent late-onset migraine or treatment-refractory migraine, suspect an underlying cause and conduct targeted investigation. 1 This is particularly critical given your concern about secondary causes.

Red Flags Requiring Urgent Workup:

• New-onset or changing headache pattern (especially after age 50) should raise suspicion for secondary headache 1
• Thyroid disorders: Check TSH, free T4 to rule out hypothyroidism or hyperthyroidism as migraine triggers
• Anemia: Check CBC to identify iron deficiency anemia or other hematologic abnormalities that can worsen migraine
• Other metabolic causes: Consider comprehensive metabolic panel, inflammatory markers if clinically indicated

When to Refer to Specialist:

If all treatments fail, question the diagnosis and consider specialist referral. 1 Specialist care is indicated for diagnostically challenging cases, difficult-to-treat migraine, or complications from comorbidities 1.

Second-Line Preventive Medications

Once secondary causes are excluded or addressed, escalate to second-line preventive therapy:

Recommended Second-Line Options:

• Flunarizine (calcium channel blocker) 1
• Amitriptyline 30-150 mg/day - particularly beneficial if mixed migraine and tension-type headache coexist 1
• Sodium valproate (in men only) - strictly contraindicated in women of childbearing potential due to teratogenic risk 1

Start at low doses and titrate slowly to minimize adverse effects while giving each medication an adequate 2-3 month trial. 1, 2

Third-Line Options: CGRP Monoclonal Antibodies

If second-line medications fail or are contraindicated:

Consider CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, or eptinezumab) as third-line medications. 1 These require 3-6 months for efficacy assessment and are typically reserved for patients who have failed multiple other preventive medications 1.

Combination Therapy Strategy

For truly refractory migraine, consider combining a beta-blocker with topiramate if the patient tolerated each individually but failed to respond to monotherapy. 3 A study demonstrated that 75% of patients who failed both medications separately showed response (>50% reduction in frequency) when combined, with 44% achieving excellent (>75%) response 3. However, adverse events led to discontinuation in approximately 17% of patients 3.

Critical Medication Overuse Assessment

Before escalating therapy, rule out medication-overuse headache (MOH) if the patient uses acute medications ≥10 days/month for triptans or ≥15 days/month for NSAIDs. 1 MOH can cause treatment resistance and increasing headache frequency, often resulting in daily headaches 1.

Non-Pharmacological Adjuncts

Consider neuromodulatory devices, biobehavioral therapy, and acupuncture as adjuncts to preventive medication or as stand-alone treatment when medication is contraindicated. 1 These have supporting evidence and can enhance outcomes when combined with pharmacotherapy 1.

Treatment Evaluation Timeline

Evaluate treatment response 2-3 months after initiation or change of preventive treatment, then regularly every 6-12 months. 1 Assess attack frequency, severity, and migraine-related disability using headache calendars 1.

Key Outcome Measures:

• Attack frequency (headache days per month)
• Attack severity (pain intensity)
• Migraine-related disability
• Acute medication use patterns 1

Common Pitfalls to Avoid

• Do not conclude treatment failure prematurely - ensure adequate dosing and duration (2-3 months minimum) before declaring failure 1
• Review adherence - apparent failures may be due to poor adherence or suboptimal dosing 1
• Address comorbidities - thyroid disorders, anemia, and other conditions can undermine preventive therapy effectiveness 2
• Monitor for adverse events - some patients benefit from lower doses with fewer side effects, improving adherence 1