Emerging Treatments for Episodic and Chronic Migraine
CGRP-targeted therapies—including monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) and oral gepants (atogepant, rimegepant)—represent the most significant emerging treatments for migraine prevention, with strong evidence supporting their use as second- or third-line options after traditional preventives fail. 1
CGRP Monoclonal Antibodies (mAbs)
Strong Evidence for Prevention
Fremanezumab, galcanezumab, and erenumab receive "strong for" recommendations from both the American College of Physicians and VA/DoD for prevention of episodic or chronic migraine, demonstrating reductions in mean monthly migraine days by approximately 3.4-4.7 days compared to baseline. 1, 2, 3
Eptinezumab (intravenous) receives a "weak for" recommendation from VA/DoD for episodic or chronic migraine prevention, offering an alternative route of administration for patients who prefer quarterly infusions over self-injection. 1
These agents reduce migraine frequency by approximately 0.8-2.3 days per month compared to placebo, with favorable safety and tolerability profiles. 4, 5, 6
Mechanism Distinctions Matter
Fremanezumab, galcanezumab, and eptinezumab are humanized monoclonal antibodies that directly bind to the CGRP peptide itself, neutralizing free bioavailable CGRP. 4
Erenumab differs by binding to the CGRP receptor rather than the peptide, which may increase risk for development or worsening of hypertension—an important safety consideration when selecting among agents. 4
Clinical Trial Data
In episodic migraine trials, galcanezumab 120 mg monthly (with 240 mg loading dose) reduced migraine days by 4.3-4.7 days from a baseline of approximately 9 days per month, with 59-62% of patients achieving ≥50% reduction in migraine frequency. 2
Fremanezumab demonstrated similar efficacy with both monthly (225 mg) and quarterly (675 mg) dosing regimens, reducing migraine days by 3.4-3.7 days compared to 2.2 days with placebo. 3
Oral CGRP Receptor Antagonists (Gepants)
For Prevention
Atogepant receives a "weak for" recommendation from VA/DoD for episodic migraine prevention, with the 60 mg daily dose showing the greatest reduction in monthly migraine days (mean difference -1.48 days). 1, 4, 7
Rimegepant has "insufficient evidence" for prevention according to VA/DoD guidelines, though it is FDA-approved for this indication. 1
These oral agents competitively block the CGRP receptor without affecting CGRP peptide levels, offering daily oral dosing as an alternative to injectable therapies. 4, 6
For Acute Treatment
Rimegepant and ubrogepant receive "weak for" recommendations from VA/DoD for acute episodic migraine treatment, providing an alternative to triptans. 1, 4
These agents are particularly valuable for patients who cannot tolerate or have contraindications to triptans. 5
OnabotulinumtoxinA (Botox)
OnabotulinumtoxinA receives a "weak for" recommendation specifically for chronic migraine prevention (≥15 headache days per month), but is recommended against for episodic migraine. 1, 8
FDA-approved for prophylaxis of headache in adults with chronic migraine, requiring specialist administration with specific injection protocols. 8
Patients should receive at least 2-3 treatment cycles before being classified as non-responders. 8
Treatment Algorithm for Emerging Therapies
First-Line Traditional Preventives Remain Standard
For episodic migraine: Consider beta-blockers (propranolol), antiseizure medications (topiramate, valproate), or ARBs (candesartan, telmisartan) as first-line options due to lower cost and established efficacy. 1
For chronic migraine: Topiramate is preferred first-line due to proven efficacy and lower cost ($100-300 annually vs. $7,071-22,790 for CGRP therapies). 4, 8
Second/Third-Line: CGRP-Targeted Therapies
Initiate CGRP mAbs when 2-3 traditional preventives have failed or are contraindicated, as most insurance requires documented failure of traditional agents before approval. 4, 8
Choose among CGRP mAbs based on:
Consider oral gepants (atogepant) for patients preferring oral daily therapy over injections, though efficacy may be slightly lower than mAbs. 4, 7
Special Populations
For chronic migraine with obesity: Topiramate is particularly beneficial due to weight loss effects. 4, 8
For patients with medication overuse headache (MOH): Rule out and manage MOH first through medication withdrawal before initiating preventive therapy. 4, 8
For women of childbearing potential: Discuss adverse effects during pregnancy and lactation, as safety data for CGRP therapies in pregnancy remain limited. 4
Switching Among CGRP Therapies
If one CGRP mAb fails, switching to another may be viable due to pharmacological differences in target (peptide vs. receptor), structure, and pharmacokinetics. 9
Evaluate response after 3-6 months of treatment before declaring failure. 7
Consider pausing preventive treatment after 6-12 months of success to assess continued need. 7
Critical Cost Considerations
CGRP mAbs cost $7,071-22,790 annually compared to $100-300 for traditional preventives, making cost-effectiveness a major consideration. 4
Oral gepants cost $4,959-5,994 annually, positioning them between traditional preventives and mAbs. 4, 7
The American College of Physicians recommends prescribing less costly medications when appropriate, reserving CGRP therapies for third-line use. 4
Common Pitfalls to Avoid
Do not use CGRP therapies as first-line agents unless traditional preventives are contraindicated—insurance will deny coverage and cost-effectiveness is poor. 4, 8
Monitor for medication overuse headache with acute CGRP antagonists (threshold ≥10 days per month). 7
Do not declare treatment failure prematurely—allow 3-6 months for full therapeutic effect before switching agents. 7
Screen for hypertension before and during erenumab therapy due to increased risk compared to other CGRP mAbs. 4
Ensure adequate trial of traditional preventives (2-3 agents at therapeutic doses for sufficient duration) before advancing to CGRP therapies to satisfy insurance requirements and optimize cost-effectiveness. 4, 8