Erenumab (Aimovig) for Migraine Prevention

Mechanism of Action

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Indications

• Episodic migraine (< 15 headache days/month) — preventive treatment
• Chronic migraine (≥ 15 headache days/month, ≥ 8 of which are migrainous) — preventive treatment

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Dosing

• The 140 mg dose (two 70 mg injections) is the recommended starting dose for chronic migraine
• Administered via autoinjector pen (self-administered)
• No dose adjustment required for renal or hepatic impairment

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Efficacy

• Monthly migraine day (MMD) reduction from baseline over 3 months:
  • Erenumab 70 mg: −4.8 days
  • Erenumab 140 mg: −4.2 days
  • Placebo: −3.1 days (both doses statistically significant vs. placebo)
• Significant reductions in:
  • Acute migraine-specific medication use
  • Proportion of patients achieving ≥50% reduction in MMDs (a key responder threshold)
  • HIT-6 (Headache Impact Test) scores
• In chronic migraine specifically, 70 mg showed a statistically significant −1.67-day reduction in MMDs beyond placebo (p < 0.001)

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Safety Profile

• Well tolerated with low adverse event (AE) rates across trials
• AEs rarely led to treatment discontinuation
• Most common AEs: injection site reactions, constipation
• Constipation is the most clinically notable side effect, occasionally severe enough to discontinue
• No hepatotoxicity signals (unlike some oral preventives)
• No major cardiovascular signals identified in trials, though CGRP has vasodilatory properties — caution is generally advised in patients with recent cardiovascular or cerebrovascular events (limited trial inclusion)

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Place in Therapy

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Comparisons Within the CGRP mAb Class

Erenumab (Aimovig) for Migraine Prevention

Mechanism of Action

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Indications

• Episodic migraine (< 15 headache days/month)
• Chronic migraine (≥ 15 headache days/month, ≥ 8 migrainous)

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Dosing

• 140 mg = two 70 mg autoinjector pens given consecutively
• Patient self-administered; no titration required
• No renal or hepatic dose adjustment needed

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Efficacy

• Reduced acute migraine-specific medication use
• Higher proportion achieving ≥50% MMD reduction (key responder threshold)
• Improved HIT-6 (Headache Impact Test) scores

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Safety

• Overall well tolerated with low adverse event rates; discontinuations due to AEs were rare (Management of Headache, p. 49)
• Most common AEs: injection site reactions, constipation (can occasionally be severe)
• No significant hepatotoxicity or CNS side effects (contrast with topiramate, valproate)
• Cardiovascular caution: CGRP is a vasodilator — use with care in patients with recent MI, stroke, or severe cardiovascular disease (limited trial data in this population)

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Place in Therapy

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CGRP mAb Class Comparison

Migraine Prophylaxis: Clinical Approach

When to Initiate Preventive Treatment

• Attacks significantly interfere with daily life despite adequate acute treatment
• Frequent attacks (generally ≥ 4 migraine days/month is the common threshold)
• Contraindication, failure, or overuse of acute treatments:
  • ≥ 10 days/month: triptans, ergots, opioids, combination analgesics
  • ≥ 15 days/month: NSAIDs, acetaminophen, non-opioid analgesics
• Adverse effects from acute therapies precluding their use
• Patient preference (desire to reduce attack frequency regardless of severity)

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Medication Overuse — A Critical Consideration

• If MOH persists during preventive therapy → escalate dose or switch agent; expert consensus supports adding a second preventive
• CGRP receptor antagonists (ubrogepant, rimegepant) used acutely do not appear to cause MOH — an advantage over traditional acute agents
• Lasmiditan may induce MOH through sensitization mechanisms (clinical data pending)

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Preventive Treatment Options

First-Line Agents (Conventional)

Second-Line / Adjunct (Conventional)

CGRP-Pathway Biologics (Migraine-Specific)

OnabotulinumtoxinA (Botox)

• FDA-approved for chronic migraine only (≥ 15 headache days/month)
• 155–195 units injected across 31–39 sites on head/neck every 12 weeks
• Effective when oral agents have failed

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Stepwise Approach

Step 1: Identify candidates for prophylaxis
        (frequency, disability, overuse, patient preference)
            ↓
Step 2: Address modifiable triggers & lifestyle
        (sleep hygiene, hydration, regular meals, stress management,
         exercise, caffeine regulation)
            ↓
Step 3: Start first-line oral agent
        → Match to comorbidities:
          - HTN/anxiety → beta-blocker (propranolol)
          - Depression/insomnia → amitriptyline
          - Epilepsy/obesity → topiramate (weight loss SE)
          - Bipolar/mood disorder → valproate (avoid if childbearing)
          - Minimal comorbidities → any first-line agent
            ↓
Step 4: Assess at 2–3 months
        Goal: ≥50% reduction in MMDs
        If inadequate → optimize dose, address adherence,
        consider switching class
            ↓
Step 5: After failure of 2–3 conventional agents
        → CGRP monoclonal antibody (any of the 4 agents)
        → OnabotulinumtoxinA if chronic migraine
            ↓
Step 6: Refractory cases
        → Combination preventive therapy
        → Specialist referral
        → Neuromodulation devices (Cefaly, gammaCore, sTMS)

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General Principles

• Trial duration: Minimum 2–3 months at therapeutic dose before declaring failure (some guidelines suggest up to 6 months)
• Efficacy target: ≥ 50% reduction in monthly migraine days is the standard responder threshold
• Duration of therapy: Continue for 6–12 months after good response, then consider tapering — many patients can discontinue
• Comorbidity-driven selection: Choose agents that treat migraine AND a comorbid condition (e.g., propranolol for HTN, amitriptyline for depression, topiramate for epilepsy)
• Avoid in pregnancy: Topiramate, valproate (high teratogenic risk); CGRP mAbs not recommended (insufficient data); prefer propranolol or amitriptyline with caution
• Combination therapy: Reasonable when monotherapy is partially effective; evidence for specific combinations is limited

Drug Therapy for Migraine Prophylaxis: Doses & Duration

General Principles Before Starting

• Set a realistic goal: ≥ 50% reduction in monthly migraine days (MMDs) is the accepted responder threshold
• Allow adequate trial duration before declaring failure: conventionally 6–12 months at therapeutic dose, though there is debate — patient reviewers have noted this may be too long, especially with partial response or intolerable side effects (Integrating New Migraine Treatments Into Clinical Practice, p. 13)
• Require failure of 2 established preventives before stepping up to CGRP monoclonal antibodies in most guideline/payer frameworks (though this is disputed given the modest efficacy and poor tolerability of older agents)
• Match drug to comorbidities to maximize benefit and minimize harm
• Start low, titrate slowly — most agents require gradual up-titration to reduce side effects

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First-Line Conventional Agents

1. Beta-Blockers

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2. Antiepileptics

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3. Antidepressants

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4. Calcium Channel Blockers

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5. Angiotensin Agents

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6. Nutraceuticals (Adjuncts)

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CGRP-Pathway Agents (Migraine-Specific)

Monoclonal Antibodies

• Onset of benefit: 1–3 months
• Well tolerated; main SE: injection site reactions, constipation (erenumab)
• No drug interactions; no routine lab monitoring required
• Use after failure of 2+ conventional preventives (guideline/payer requirement in most settings)

Oral CGRP Receptor Antagonists (Gepants) — Emerging Preventive Role

• Do not cause medication overuse headache — an advantage over traditional acute agents
• Oral alternative to injectable CGRP mAbs

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OnabotulinumtoxinA (Botox)

• Indication: Chronic migraine only (≥ 15 headache days/month)
• Dose: 155–195 units across 31–39 fixed injection sites (head, neck, shoulders) — PREEMPT protocol
• Frequency: Every 12 weeks
• Onset: 4–6 weeks; full benefit after 2–3 treatment cycles
• SE: Neck pain, ptosis, injection site pain; generally well tolerated

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Duration of Therapy

• Premature discontinuation is the most common reason for perceived treatment failure
• A partial response at 3 months warrants dose optimization before switching
• CGRP mAbs: trials of ≥ 3 months are standard; some guidelines support longer trials given favorable safety profiles
• Topiramate and valproate: if effective, continue 6–12 months then reassess; avoid indefinite use given metabolic/teratogenic risks

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Drug Selection by Comorbidity

Drug Therapy for Migraine Prophylaxis + Rizatriptan

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Rizatriptan: Role in Migraine

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What Triptans Actually Do

Rizatriptan Specifically (Acute Use)

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The Exception: "Mini-Prophylaxis" with Triptans

• Rizatriptan and sumatriptan have been studied in this context but have less evidence than frovatriptan/naratriptan
• This is not continuous daily prophylaxis — it is short-cycle prevention tied to a predictable trigger

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Why Triptans Cannot Be Used as Continuous Prophylaxis

1. Medication overuse headache (MOH): Use of triptans ≥ 10 days/month leads to MOH (chronification of migraine) — the opposite of prevention
2. No evidence base for daily dosing in prevention
3. Cardiovascular contraindications (vasoconstrictive mechanism) preclude long-term daily use
4. Acute vs. preventive pharmacology: Triptans abort active attacks; they do not modify the underlying neurobiological threshold that makes migraines recur

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Established Prophylaxis — Doses & Duration (Summary)

Conventional First-Line Agents

Migraine-Specific Agents

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Key Duration Principles

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Bottom Line on Rizatriptan

Rizatriptan = acute abortive therapy only. It is taken at the time of an attack (10 mg orally; 5 mg if on propranolol). It does not prevent migraines and cannot be used as a prophylactic agent. Overuse (≥ 10 days/month) will cause medication overuse headache, worsening the overall migraine burden. If a patient requires frequent rizatriptan use, that is itself an indication to start prophylaxis with one of the established agents above.