Monthly Injectable Prophylactic Options for Frequent or Disabling Migraine
For adults with frequent or disabling migraine, three CGRP monoclonal antibodies—erenumab, fremanezumab, and galcanezumab—are strongly recommended as monthly injectable prophylactic options, with all three demonstrating robust reductions in monthly migraine days and excellent tolerability. 1
Available Monthly Injectable CGRP Monoclonal Antibodies
The following three agents have strong ("strong for") recommendations from the 2023 VA/DoD guidelines for prevention of episodic or chronic migraine 1:
Erenumab
- Mechanism: Binds directly to the CGRP receptor, blocking receptor activation 2
- Dosing: 70 mg or 140 mg subcutaneous injection monthly 1
- Unique consideration: Post-marketing studies have identified an increased risk for development or worsening of hypertension; prescribing information now includes this warning 1
- Efficacy: Reduces mean monthly migraine days with high-certainty evidence 1
Fremanezumab
- Mechanism: Humanized monoclonal antibody that binds to the CGRP peptide itself, preventing receptor activation 2
- Dosing: 225 mg subcutaneous injection monthly (or 675 mg quarterly as an alternative) 3
- Pharmacokinetics: Steady state achieved by approximately 6 months; half-life approximately 31 days 3
- Efficacy: Reduces monthly migraine days by 1–2 days over placebo in clinical trials, though real-world studies show greater magnitude of benefit 4
- Tolerability: Excellent tolerability profile with mild injection-site reactions as the most common side effect 4
- Special populations: Approved for use in children and adolescents, unique among migraine treatments 4
Galcanezumab
- Mechanism: Humanized monoclonal antibody that binds to the CGRP peptide 2
- Dosing: 120 mg subcutaneous injection monthly (with a 240 mg loading dose at initiation) 5
- Pharmacokinetics: Elimination half-life approximately 27 days; steady state achieved with monthly dosing 5
- Efficacy: Demonstrated statistically significant reductions in monthly migraine headache days, with 62% of patients achieving ≥50% reduction in migraine days in episodic migraine trials 5
Position in Treatment Algorithm
When to Initiate CGRP Monoclonal Antibodies
The 2025 American College of Physicians guidelines recommend CGRP monoclonal antibodies as second-line therapy after failure of first-line conventional preventives (beta-blockers, antiseizure medications, antidepressants), driven primarily by cost considerations rather than efficacy differences. 1, 6
First-line preventive options include:
- Beta-blockers: propranolol 80–240 mg/day or metoprolol 1
- Antiseizure medications: topiramate or valproate 1
- Antidepressants: amitriptyline 30–150 mg/day or venlafaxine 1
- Angiotensin-receptor blockers: candesartan or telmisartan 1
However, the 2023 VA/DoD guidelines upgraded CGRP monoclonal antibodies to "strong for" recommendations based on updated network meta-analysis evidence, reflecting their robust efficacy and superior tolerability. 1
Indications for Preventive Therapy
Preventive therapy is indicated when patients experience 1:
- ≥2 migraine attacks per month producing disability lasting ≥3 days
- Use of acute medication >2 days per week
- Contraindication to or failure of acute treatments
- Uncommon migraine conditions (e.g., hemiplegic migraine, basilar migraine)
- Patient preference for prevention
Comparative Efficacy and Safety
Efficacy
All three CGRP monoclonal antibodies demonstrate similar efficacy 1, 2:
- Reduce mean monthly migraine days by approximately 0.8–2.3 days compared to placebo 2
- Network meta-analysis shows CGRP-mAbs may reduce migraine frequency by 0.76–0.80 fewer days per month compared to valproate or topiramate (low-certainty evidence) 6
- No direct comparative evidence shows superiority of one CGRP-mAb over another 6
In episodic migraine trials:
- 59–62% of patients achieve ≥50% reduction in monthly migraine days 5
- 34–39% achieve ≥75% reduction 5
- 12–16% achieve 100% reduction (complete remission) 5
Safety and Tolerability
CGRP monoclonal antibodies demonstrate excellent tolerability with significantly fewer discontinuations due to adverse events compared to traditional preventives: 6
- 162 fewer discontinuations per 1,000 treated people compared to topiramate (moderate-certainty evidence) 6
- Most common adverse events: injection-site reactions (mild, transient) and upper respiratory tract infections 6
- Serious adverse events are rare 6
Critical safety consideration for erenumab: Monitor blood pressure, as post-marketing studies have identified increased risk for development or worsening of hypertension 1
Administration and Monitoring
Route and Frequency
- All three agents are administered via subcutaneous injection monthly 6
- Fremanezumab offers flexibility with quarterly dosing (675 mg every 3 months) as an alternative to monthly dosing 3
- Patients can self-administer after proper training 5, 3
Time to Efficacy
Therapeutic benefit should be evaluated only after 3–6 months of treatment, as earlier assessment may miss the full effect. 1, 6
Treatment Duration
- After 6–12 months of successful therapy, consider pausing treatment to determine whether preventive therapy can be discontinued 6
- No tapering is required when discontinuing 6
- Success should be quantified by calculating the percentage reduction in monthly migraine days 6
Cost Considerations
Annual costs for CGRP monoclonal antibodies range from $7,071 to $22,790, representing a ~100-fold cost difference compared to conventional preventives ($67–$393 annually). 1, 6
Insurance authorization typically requires:
- Documentation of failure of 2–3 traditional preventive medications 2
- Demonstration that the patient meets criteria for preventive therapy 2
Alternative Injectable Option: OnabotulinumtoxinA (Botox)
For chronic migraine (≥15 headache days per month), onabotulinumtoxinA is the only FDA-approved preventive therapy specifically indicated for this population. 1
Dosing and Administration
- 155–195 units injected across 31–39 sites every 12 weeks 1
- Must be administered by a neurologist or headache specialist 1
Efficacy
- Reduces headache days, headache episodes, cumulative headache hours, and improves quality of life in chronic migraine (high-quality RCT evidence from PREEMPT trials) 1, 7
- Efficacy should be evaluated after 6–9 months of treatment 1
Position in Algorithm
- Recommended as first-line for chronic migraine when three oral preventives have failed 1
- Not effective for episodic migraine (weak against recommendation) 1
Critical Pitfalls to Avoid
Do not discontinue CGRP monoclonal antibodies prematurely: Patients must complete a minimum of 3–6 months before efficacy can be properly assessed 1, 6
Do not use CGRP monoclonal antibodies as first-line therapy unless all conventional preventives are contraindicated, as this conflicts with guideline recommendations and cost-effectiveness principles 1, 6
Do not allow patients to increase frequency of acute medication use in response to treatment failure; instead, transition to preventive therapy while optimizing acute treatment strategy 1
Monitor blood pressure in patients receiving erenumab due to post-marketing reports of hypertension 1
Limit all acute migraine medications to ≤2 days per week (≤10 days per month) to prevent medication-overuse headache, which can paradoxically increase headache frequency 1
Special Populations
Pregnancy and Lactation
Discuss adverse effects of pharmacologic treatments during pregnancy and lactation before initiating therapy 1
Cardiovascular Disease
- CGRP monoclonal antibodies have no vasoconstrictor activity, making them safe options for patients with cardiovascular contraindications to triptans 8
- Fremanezumab has not been associated with development or worsening of hypertension in post-marketing studies, unlike erenumab 6
Pediatric Patients
Fremanezumab is approved for use in children and adolescents, unique among migraine treatments 4