What preventive therapy should be initiated for an adult with frequent (≥4 headache days per month) or disabling migraines despite adequate acute treatment?

Preventive Therapy for Migraine

When to Initiate Preventive Therapy

Preventive migraine therapy should be initiated when patients have ≥4 migraine days per month or when they have ≥2 migraine days with significant disability despite appropriate use of acute migraine therapies. 1

• The threshold for initiating prevention is ≥2 days per month of migraine-related disability despite optimized acute treatment, according to the most recent guidelines 1
• Additional indications include using acute medications more than twice weekly (≥10 days per month), which creates risk for medication-overuse headache 1
• Contraindication to or failure of acute treatments warrants preventive therapy 1
• Patient preference for prevention is a valid indication even when frequency thresholds are not met 1, 2

First-Line Preventive Medications

Beta-blockers (propranolol 80–240 mg/day, metoprolol, atenolol, or bisoprolol), topiramate, or candesartan should be used as first-line preventive medications. 1, 3

Beta-Blockers

• Propranolol 80–240 mg/day has the strongest evidence among beta-blockers and is FDA-approved for migraine prevention 1, 3
• Metoprolol, atenolol, and bisoprolol are supported by moderate-quality evidence 1, 3
• Beta-blockers without intrinsic sympathomimetic activity are preferred 1
• These agents are particularly appropriate for patients with comorbid hypertension or anxiety 2

Topiramate

• Topiramate is effective for both episodic and chronic migraine prevention 1, 3
• Common side effects include cognitive impairment, paresthesias, and weight loss 2, 3
• Topiramate is teratogenic and should be avoided in women of childbearing potential unless effective contraception is used 1

Candesartan

• Candesartan is recommended as first-line therapy with favorable tolerability 1
• It is particularly useful in patients with comorbid hypertension 2

Second-Line Preventive Medications

Amitriptyline 30–150 mg/day, flunarizine, or (in men) sodium valproate should be used as second-line medications. 1

Amitriptyline

• Amitriptyline is preferred when patients have comorbid depression, anxiety, insomnia, or mixed migraine with tension-type headache 1
• Start at low doses (10–25 mg at bedtime) and titrate gradually to minimize side effects 2
• Common side effects include sedation, dry mouth, constipation, and weight gain 2, 3

Sodium Valproate/Divalproex

• Divalproex 500–1500 mg/day or sodium valproate 800–1500 mg/day are effective preventive agents 1, 3
• These agents are strictly contraindicated in women of childbearing potential due to teratogenic risk 1
• Side effects include weight gain, hair loss, tremor, and hepatotoxicity 2, 3

Third-Line Preventive Medications: CGRP Monoclonal Antibodies

CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab) should be considered as third-line medications after failure of first-line and second-line oral preventives. 1

CGRP Monoclonal Antibodies

• Erenumab, fremanezumab, and galcanezumab received "strong for" recommendations for prevention of episodic or chronic migraine based on robust evidence 1
• These agents resulted in reductions in mean monthly migraine days and abortive medication use in both episodic and chronic migraine 1
• CGRP monoclonal antibodies require 3–6 months to assess efficacy, and patients should not abandon treatment prematurely 4
• Erenumab has been associated with development or worsening of hypertension in postmarketing studies, requiring blood pressure monitoring 1, 5
• Cost and insurance coverage limitations restrict first-line use of these agents 3

Gepants for Prevention

• Atogepant has a "weak for" recommendation for episodic migraine prevention based on evidence from 2466 patients showing reductions in monthly migraine days 1
• Rimegepant has a "neither for nor against" recommendation for episodic migraine prevention 1, 6
• Rimegepant 75 mg every other day demonstrated a reduction of 0.8 monthly migraine days compared to placebo over weeks 9–12, with 49.1% achieving ≥50% reduction in migraine days 6

OnabotulinumtoxinA for Chronic Migraine

OnabotulinumtoxinA (Botox) is the only FDA-approved preventive therapy specifically for chronic migraine (≥15 headache days per month) and should be used as first-line when three oral preventives have failed. 4, 3

• The recommended protocol is 155–195 units injected across 31–39 sites every 12 weeks 4
• OnabotulinumtoxinA is as effective as other medications, is well tolerated, and has lower discontinuation rates 3
• Efficacy should be evaluated after 6–9 months of treatment 4, 2
• This agent is not indicated for episodic migraine (fewer than 15 headache days per month) 1

Non-Pharmacological Preventive Therapies

Neuromodulatory devices, biobehavioral therapy (cognitive-behavioral therapy, biofeedback, relaxation training), and acupuncture should be considered as adjuncts to medication or as stand-alone preventive treatment when medication is contraindicated. 1, 2

• Cognitive-behavioral therapy and biofeedback have favorable evidence profiles 2, 3
• Acupuncture is supported by evidence, though one study showed it was not superior to sham acupuncture 1
• Exercise is supported by varying levels of evidence and can be used in combination with pharmacotherapy 3
• Little to no evidence exists for physical therapy, spinal manipulation, or dietary approaches 1

Nutraceuticals

• Coenzyme Q10, magnesium citrate, and riboflavin have favorable evidence profiles with limited side effects 2
• Magnesium and melatonin have shown effectiveness and are generally well tolerated 3
• These agents can be used as adjuncts to prescription medications or when patients prefer non-prescription options 2

Treatment Principles and Monitoring

Starting and Titrating Therapy

• Start preventive medications at low doses and increase gradually to the recommended daily dose as tolerance permits 7, 8
• Give each treatment an adequate trial of 2–3 months before judging efficacy 7, 2
• Patients must keep a headache diary to objectively assess treatment response 8, 2

Assessing Treatment Success

• Goals include reducing attack frequency by ≥50%, reducing severity and duration, improving responsiveness to acute treatments, and decreasing overall use of acute medications 1, 9
• Critical outcomes are change in mean monthly headache days and mean monthly migraine days from baseline 1
• Patient-reported outcomes regarding disability and quality of life are essential in evaluating effectiveness 4

Duration of Therapy

• If treatment is successful, continue for 6–12 months, then attempt to taper the dose to find the minimum effective dose or discontinue 8, 2
• Failure of one preventive treatment does not predict failure of other drug classes 4

Critical Pitfalls to Avoid

• Do not delay preventive therapy while trialing multiple acute strategies—this undermines timely control of migraine 4
• Avoid sodium valproate/divalproex in all women of childbearing potential due to teratogenic risk 1
• Ensure patients are not overusing acute medications (≥10 days/month for triptans, ≥15 days/month for NSAIDs), as this reduces effectiveness of preventive treatments and perpetuates chronic migraine 1, 4
• Do not abandon CGRP monoclonal antibodies prematurely—efficacy requires 3–6 months to assess, and responder rates may increase after the second or third infusion 4
• Monitor blood pressure in patients taking erenumab due to postmarketing reports of hypertension development or worsening 1, 5
• Address modifiable risk factors including obesity, excessive caffeine, sleep deprivation, stress, and psychiatric comorbidities, as these perpetuate migraine 4, 3