What is the recommended treatment with Calcitonin Gene-Related Peptide (CGRP) inhibitors for an adult patient with chronic or episodic migraines who has tried other treatments without success?

CGRP Inhibitors for Migraine Treatment

Direct Answer

For adults with chronic or episodic migraine who have failed other treatments, use CGRP monoclonal antibodies (fremanezumab, galcanezumab, or eptinezumab) as third-line preventive therapy, or consider oral gepants (rimegepant, ubrogepant, zavegepant, or atogepant) for acute treatment or prevention, with the choice primarily driven by cost and route of administration preference. 1, 2

Treatment Algorithm by Clinical Scenario

For Acute Episodic Migraine (Failed First-Line Therapy)

• First-line treatment failure: If combination therapy with a triptan plus NSAID or acetaminophen has failed or is not tolerated, consider CGRP antagonist-gepants (rimegepant, ubrogepant, or zavegepant) for acute treatment 1
• Evidence caveat: Gepants may have lower likelihood of pain freedom at 2 hours compared to triptan-NSAID combinations (low-certainty evidence), but they represent a reasonable alternative when triptans are contraindicated or ineffective 1, 3
• Timing: Begin treatment as soon as possible after migraine onset 1

For Migraine Prevention (Episodic or Chronic)

Step 1: Confirm indication for preventive therapy

• Migraine occurring ≥2 days per month despite optimized acute treatment warrants preventive medication 4

Step 2: First-line preventive options (try these first)

• Beta-blockers (propranolol, metoprolol), topiramate, or candesartan 1, 4
• For chronic migraine specifically: topiramate is the drug of first choice due to much lower cost 1

Step 3: Second-line options (if first-line fails)

• Amitriptyline, valproate (avoid in women of childbearing potential), or flunarizine 1, 4

Step 4: Third-line CGRP-targeted therapy (after 2-3 failed preventive medications)

CGRP Monoclonal Antibodies (mAbs) - Preferred for prevention:

• Fremanezumab, galcanezumab, or eptinezumab receive the strongest recommendations as they directly bind CGRP peptide 2
• Erenumab (binds CGRP receptor) also effective but carries hypertension risk - monitor blood pressure 2, 3
• Dosing examples: Galcanezumab 240 mg loading dose (two 120 mg injections), then 120 mg monthly 5; Fremanezumab per FDA labeling 6
• Expected benefit: Reduce migraine days by approximately 0.8-2.3 days per month compared to placebo 2
• Time to assess efficacy: 3-6 months 4

Oral Gepants - Alternative for prevention:

• Atogepant (daily oral dosing): Effective for episodic migraine prevention, with 60 mg dose showing greatest reduction in monthly migraine days (mean difference -1.48 days) 2, 7
• Rimegepant: Can be used for both acute treatment and prevention 2

Key Efficacy Comparisons

CGRP mAbs vs. Traditional Preventives

• May reduce migraine frequency by 0.76-0.80 fewer days per month compared to valproate or topiramate (low-certainty evidence) 2, 3
• Major advantage: Significantly fewer discontinuations due to adverse events compared to topiramate (162 fewer events per 1000 treated people) 3
• Higher likelihood-to-help-versus-harm ratio than propranolol or topiramate for episodic migraine, and higher than onabotulinumtoxinA or topiramate for chronic migraine 8

Real-World Effectiveness

• 50% responder rate (≥50% reduction in migraine days): 27.6-61.4% of patients with chronic migraine 9
• Conversion from chronic to episodic migraine: 40.88% of cases 9
• Medication overuse cessation: 29-88% of patients 9

Safety Profile

Common adverse events (generally mild to moderate):

• Injection-site reactions for mAbs 3
• Constipation (9% in real-world data), nausea 3, 10, 7
• Upper respiratory tract infection 3

Specific safety concern:

• Erenumab: Risk of developing or worsening hypertension based on post-marketing surveillance - monitor blood pressure 2, 3

Hypersensitivity reactions:

• Can occur days after administration and may be prolonged 5
• If serious hypersensitivity occurs, discontinue immediately and initiate appropriate therapy 5

Overall tolerability:

• Discontinuation rates due to adverse events are low 3
• No new safety signals identified in combination therapy with onabotulinumtoxinA 10

Critical Cost Considerations

This is the major limiting factor for CGRP therapies:

• Oral gepants: $4,959-$5,994 annually for oral formulations; $8,800 for intranasal zavegepant 3
• CGRP mAbs: $7,071-$22,790 annually 2, 3
• Traditional preventives: Substantially less expensive 3

Clinical implication: The American College of Physicians explicitly recommends prescribing less costly medications when appropriate 3, 4. Insurance often requires failure of 2-3 traditional preventives before approving CGRP therapies 1

Special Populations and Situations

Chronic Migraine with Medication Overuse Headache (MOH)

• Rule out and manage MOH first through medication withdrawal (abrupt withdrawal preferred except for opioids) 1
• Once MOH is ruled out, initiate preventive therapy 1
• CGRP therapies help 29-88% of patients stop medication overuse 9

Obesity as Negative Predictor

• Obesity is the main negative predictor of response to anti-CGRP mAbs 9
• Consider topiramate preferentially in obese patients due to weight loss effects 1

Combination Therapy

• OnabotulinumtoxinA + CGRP mAb: For chronic migraine resistant to monotherapy, combination treatment shows additional clinically meaningful benefits (mean decrease 3.5-4.0 monthly migraine days over 6-12 months) 10
• 45.1% of patients had clinically meaningful improvement in migraine-related disability after ~6 months of combination therapy 10
• Well tolerated with no new safety signals 10

Pregnancy and Lactation

• Discuss adverse effects of all pharmacologic treatments during pregnancy and lactation with patients of childbearing potential 1
• Valproate is strictly contraindicated in women of childbearing potential 4

Critical Pitfalls to Avoid

Medication overuse headache:

• Limit simple analgesics to <15 days/month and triptans to <10 days/month 1
• Educate patients preemptively about this risk 1

Premature discontinuation:

• Assess efficacy only after adequate trial: 2-3 months for most preventives, 3-6 months for CGRP mAbs 4

Ignoring contraindications:

• Never use opioids or butalbital for acute migraine treatment 1, 4
• Monitor blood pressure with erenumab 2

Cost barriers:

• Ensure prior authorization requirements are met (typically 2-3 failed preventives) before prescribing CGRP therapies 1

Route of Administration Preferences

• Patients generally prefer oral treatments over injectables (moderate-certainty evidence) 2
• Oral options: Atogepant (daily for prevention), rimegepant, ubrogepant, zavegepant (acute treatment) 2
• Injectable options: Erenumab, fremanezumab, galcanezumab (monthly or quarterly subcutaneous) 5, 6
• IV option: Eptinezumab (quarterly infusion) 2

When to Refer to Specialist

• Chronic migraine diagnosis and management typically requires specialist referral 1
• Patients failing multiple preventive medications should be referred before initiating CGRP therapies 1
• Complex cases with multiple comorbidities (depression, anxiety, chronic pain) benefit from specialist management 1