What are the next best treatment options for a 30-year-old female of childbearing age with new onset migraines (8 months ago), progressively worsening, and unresponsive to preventative medications propranolol (beta blocker) or topiramate (anticonvulsant), with a normal magnetic resonance imaging (MRI) scan?

Next Best Treatment Options for Progressive Migraines Unresponsive to Propranolol and Topiramate

For this 30-year-old woman of childbearing age with progressive migraines failing two first-line preventive agents, the next step is to switch to a different first-line preventive medication—specifically amitriptyline 30-150 mg/day or divalproex/valproate—while simultaneously optimizing acute treatment with combination triptan plus NSAID therapy. 1

Critical Contraindication Alert for Women of Childbearing Age

• Valproate/divalproex is absolutely contraindicated in women of childbearing potential unless no other suitable treatment exists and effective contraception is used, as it causes serious birth defects (spina bifida/neural tube defects in 1-2% of exposed pregnancies), decreased IQ in offspring, and increased risk of autism and ADHD 2
• The FDA explicitly states that women of childbearing age must not take valproate to prevent migraine headaches 2
• If valproate is considered despite these risks, the patient must use highly effective contraception and be fully counseled on teratogenic risks 2

Recommended Treatment Algorithm

First Priority: Switch Preventive Medication

Amitriptyline is the preferred next preventive agent for this patient, given the absolute contraindication of valproate in women of childbearing potential 1, 2:

• Start amitriptyline at 30 mg at bedtime, titrating up to 30-150 mg/day based on response and tolerability 1, 3
• Amitriptyline has documented high efficacy with mild to moderate adverse events and is particularly useful for patients with mixed migraine and tension-type headache 3, 4
• Allow an adequate trial of 2-3 months at therapeutic dose before declaring treatment failure 5, 1
• Common side effects include sedation, dry mouth, and weight gain, but these can be managed with dose adjustment 6

Second Priority: Optimize Acute Treatment

While establishing preventive therapy, ensure optimal acute treatment:

• Prescribe combination therapy with a triptan (sumatriptan 50-100 mg, rizatriptan 10 mg, or eletriptan 40 mg) PLUS naproxen sodium 500 mg to be taken at migraine onset 7, 8
• This combination is superior to either agent alone, with 130 more patients per 1000 achieving sustained pain relief at 48 hours 8
• Add metoclopramide 10 mg taken 20-30 minutes before the triptan/NSAID combination for synergistic analgesia and to address nausea 8
• Strictly limit all acute medications to no more than 2 days per week (10 days per month) to prevent medication-overuse headache, which can paradoxically worsen migraine frequency 7, 8, 1

Third-Line Options if Amitriptyline Fails

If amitriptyline fails after an adequate 2-3 month trial:

• Consider CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, or eptinezumab) as third-line preventive therapy, which require 3-6 months for efficacy assessment 1
• Alternative second-line oral agents include venlafaxine (SNRI), though it has less supporting evidence than amitriptyline 9, 10
• Candesartan (ARB) is another option with emerging evidence for migraine prevention 1, 4

Critical Assessment: Rule Out Medication-Overuse Headache

• Before escalating preventive therapy, assess whether the patient is using acute medications more than 2 days per week, as medication-overuse headache (MOH) can cause progressive worsening and treatment resistance 7, 8
• MOH is defined as headache occurring ≥15 days per month for at least 3 months in patients with preexisting headache disorder due to overuse of acute medication 7
• The threshold varies by medication: ≥15 days/month for NSAIDs, ≥10 days/month for triptans 7, 8

Important Considerations for Childbearing Age

• Discuss pregnancy plans and contraception before initiating any preventive medication 7, 2
• If pregnancy is planned or possible, avoid valproate entirely and use amitriptyline with caution, discussing risks and benefits 2
• Topiramate (which she already failed) also carries teratogenic risk and should be avoided in pregnancy 5
• If the patient becomes pregnant while on preventive therapy, immediately contact her healthcare provider to reassess the treatment plan 2

Common Pitfalls to Avoid

• Do not declare preventive treatment failure before allowing 2-3 months at therapeutic dose—premature switching prevents adequate assessment of efficacy 5, 1
• Do not allow the patient to increase frequency of acute medication use in response to treatment failure—this creates a vicious cycle of MOH 8
• Do not prescribe opioids or butalbital-containing compounds, as they have questionable efficacy, lead to dependency, cause rebound headaches, and result in loss of efficacy over time 7, 8
• Do not use valproate without explicit discussion of teratogenic risks and confirmation of highly effective contraception in this woman of childbearing age 2

Lifestyle Modifications to Emphasize

• Maintain regular sleep schedule with sufficient and consistent sleep 7
• Stay well hydrated and maintain regular meals 7
• Engage in regular moderate to intense aerobic exercise 7
• Manage stress with relaxation techniques or mindfulness practices 7
• Identify and avoid individual migraine triggers through detailed history 7