7.4 Migraine Prevention, Acute Treatment & Headache Disorders
Key Takeaways
- Migraine diagnosis without aura requires ≥5 attacks lasting 4–72 hours featuring ≥2 pain characteristics (unilateral, pulsating, moderate/severe, aggravated by physical activity) plus nausea/vomiting or photophobia/phonophobia; migraine with aura involves reversible focal neurological symptoms preceding headache by 5–60 minutes.
- Acute abortive therapy utilizes a stratified care approach: NSAIDs/caffeine combinations for mild-to-moderate attacks; 5-HT1B/1D triptans (sumatriptan, rizatriptan, eletriptan) for moderate-to-severe attacks, strictly contraindicated in coronary artery disease, uncontrolled HTN, stroke/TIA, or PVD.
- Calcitonin Gene-Related Peptide (CGRP) receptor antagonists (rimegepant, ubrogepant, zavegepant) and the 5-HT1F agonist lasmiditan (Reyvow) provide acute abortive efficacy without vasoconstriction (safe in cardiovascular disease); lasmiditan carries an 8-hour driving restriction.
- Medication Overuse Headache (MOH) is prevented by restricting triptans, combination analgesics, and opioids to <10 days/month, and simple NSAIDs/acetaminophen to <15 days/month; prophylactic therapy is indicated for ≥4 migraine days/month or severe disability.
- Preventive therapies include Level A oral agents (propranolol, metoprolol, topiramate, divalproex, amitriptyline), targeted CGRP monoclonal antibodies (erenumab [targets CGRP receptor; severe constipation warning], galcanezumab, fremanezumab, eptinezumab [target CGRP ligand]), oral gepants (rimegepant QOD, atogepant daily), and onabotulinumtoxinA (Botox 155 units across 31 sites every 12 weeks for chronic migraine ≥15 days/month only).
Migraine Prevention, Acute Treatment & Headache Disorders
Executive Summary: Migraine is a complex, neurovascular disorder affecting over 1 billion people worldwide, characterized by recurrent episodes of severe headache, sensory hypersensitivity, and autonomic dysfunction. For the Board Certified Ambulatory Care Pharmacist (BCACP), optimal clinical management requires applying the International Classification of Headache Disorders (ICHD-3) criteria, implementing a stratified acute abortive algorithm that balances 5-HT1B/1D triptans against vascular contraindications, integrating novel non-vasoconstricting CGRP receptor antagonists (gepants) and 5-HT1F agonists (ditans), rigorously preventing Medication Overuse Headache (MOH), and customizing evidence-based preventive regimens (beta-blockers, antiepileptics, targeted CGRP monoclonal antibodies, onabotulinumtoxinA) to patient-specific comorbidities.
1. ICHD-3 Diagnostic Criteria & Medication Overuse Headache (MOH)
Under the International Classification of Headache Disorders, 3rd Edition (ICHD-3), primary migraine is classified based on the presence or absence of an aura.
Migraine Without Aura Diagnostic Criteria
Must fulfill all of the following:
- At least 5 attacks fulfilling criteria 2 through 4.
- Headache attacks lasting 4 to 72 hours (when untreated or unsuccessfully treated).
- Headache has at least 2 of the following 4 characteristics:
- Unilateral location (typically frontotemporal; can be bilateral in children/adolescents).
- Pulsating / Throbbing quality.
- Moderate or severe pain intensity (inhibits or prohibits daily activities).
- Aggravation by or causing avoidance of routine physical activity (e.g., walking, climbing stairs).
- During headache, at least 1 of the following accompanying symptoms:
- Nausea and/or vomiting.
- Photophobia AND Phonophobia (hypersensitivity to both light and sound).
- Not better accounted for by another ICHD-3 diagnosis.
Migraine With Aura Diagnostic Criteria
- Aura Definition: Recurrent attacks of fully reversible focal neurological symptoms that develop gradually over ≥ 5 minutes and last between 5 and 60 minutes, typically followed within 60 minutes by a migraine headache.
- Aura Modalities: Visual (scintillating scotoma, flashing lights, jagged lines; most common >90%), sensory (unilateral paresthesias/numbness), speech/language (aphasia, dysarthria), motor (hemiplegic), brainstem (vertigo, diplopia, ataxia), or retinal.
Medication Overuse Headache (MOH / "Rebound Headache")
Medication Overuse Headache is a secondary chronic headache disorder resulting from the excessive, frequent use of acute abortive medications in patients with an underlying primary headache disorder.
+---------------------------------------------------------------------------------------+
| MEDICATION OVERUSE HEADACHE (MOH) DIAGNOSTIC THRESHOLDS |
+------------------------------------+--------------------------------------------------+
| Acute Medication Class | Overuse Threshold Mandating Deprescribing |
+------------------------------------+--------------------------------------------------+
| **Triptans, Ergotamines, Opioids, | Use on **≥ 10 days per month** for > 3 months |
| & Combination Analgesics** | *(e.g., Sumatriptan, Butalbital/APAP/Caffeine, |
| | Excedrin Migraine [APAP/ASA/Caffeine], Tramadol)*|
+------------------------------------+--------------------------------------------------+
| **Simple Analgesics** | Use on **≥ 15 days per month** for > 3 months |
| | *(e.g., Ibuprofen, Naproxen, Acetaminophen)* |
+------------------------------------+--------------------------------------------------+
- Clinical Presentation: Progressive increase in headache frequency, transitioning into a daily or near-daily dull, diffuse, holocranial headache present upon awakening that temporarily responds to acute analgesics only to return as the drug wears off.
- Ambulatory Management Strategy: Educate the patient on the paradoxical cycle of rebound headaches; abruptly or gradually withdraw the overused acute medication; initiate or optimize guideline-directed preventive pharmacotherapy; provide transitional bridge therapy (e.g., short course oral prednisone taper, long-acting NSAIDs, or peripheral nerve blocks) during acute withdrawal.
2. Acute Abortive Pharmacotherapy: Stratified Care & Triptans
Clinical guidelines recommend a Stratified Care Approach, where acute therapy is matched directly to attack severity and disability at the time of onset, rather than a stepped-care model (which delays effective relief).
STRATIFIED ACUTE ABORTIVE ALGORITHM
┌──────────────────────────────────────────────┴──────────────────────────────────────────────┐
▼ ▼
[Mild to Moderate Attack / Low Disability] [Moderate to Severe Attack / High Disability]
│ │
├──> Simple NSAIDs: Ibuprofen 400-800mg, Naproxen 500-550mg ├──> 1st-Line: Selective 5-HT1B/1D Triptan
├──> Fast-Acting NSAID: Diclofenac K+ Powder (Cambia 50mg) │ (Oral, ODT, Nasal Spray/Powder, or SC)
├──> Combination: Acetaminophen/Aspirin/Caffeine (Excedrin) │
└──> Add Antiemetic: Metoclopramide 10mg or Prochlorperazine 10mg ├──> If CVD Contraindication to Triptans:
(Enhances GI motility and treats nausea) │ Oral/Nasal CGRP Antagonist (Gepant) OR
│ 5-HT1F Agonist Lasmiditan (Reyvow)
│
└──> Refractory Emergency: IV Ketorolac +
IV Prochlorperazine + IV Dihydroergotamine
Triptans (Selective 5-HT1B / 5-HT1D Receptor Agonists)
Triptans bind selectively to vascular 5-HT1B receptors (inducing cranial vasoconstriction) and presynaptic neuronal 5-HT1D receptors (inhibiting the release of vasoactive neuropeptides like CGRP and substance P from trigeminal afferents and blocking central pain transmission).
| Triptan & Route | Dosing & Frequency | Onset of Action | Unique Clinical Pearls & Drug Interactions |
|---|---|---|---|
| Sumatriptan (Imitrex)<br/>SC Injection, Oral, Nasal | SC: 4–6 mg (max 12 mg/day)<br/>Oral: 50–100 mg (max 200 mg/day)<br/>Nasal: 5–20 mg spray; 11mg powder | SC: 10–15 min (Fastest)<br/>Nasal: 15–30 min<br/>Oral: 30–60 min | Gold Standard SC Formulation: Fastest abortive onset available; ideal for waking with severe nausea/vomiting. Nasal powder (Onzetra Xsail) uses breath-powered delivery. |
| Rizatriptan (Maxalt)<br/>Oral tablet, ODT (MLT) | 5–10 mg oral/ODT;<br/>Repeat in 2h (max 30 mg/day;<br/>Max 15 mg/day if on propranolol) | Oral/ODT: 30 min | Propranolol Interaction: Propranolol increases rizatriptan AUC by 70%. Dose must be capped at 5 mg per dose (max 15 mg/day) in patients taking propranolol. |
| Zolmitriptan (Zomig)<br/>Oral tablet, ODT, Nasal | 2.5–5 mg oral/ODT/Nasal;<br/>Repeat in 2h (max 10 mg/day) | Nasal: 15 min<br/>Oral: 45 min | Nasal spray provides rapid needle-free non-oral delivery. ODT contains phenylalanine (caution in PKU). |
| Eletriptan (Relpax)<br/>Oral tablet | 20–40 mg oral;<br/>Repeat in 2h (max 80 mg/day) | Oral: 30–45 min | High lipophilicity; metabolized primarily by CYP3A4. Contraindicated within 72 hours of potent CYP3A4 inhibitors (ketoconazole, clarithromycin). |
| Frovatriptan (Frova)<br/>Naratriptan (Amerge) | Frova: 2.5 mg (max 5 mg/day)<br/>Naratriptan: 1–2.5 mg (max 5 mg/day) | Slow Onset (2–4h);<br/>Ultra-Long Half-Life<br/>(Frova t1/2: ~26 hours) | Long-Duration Migraine & Menstrual Prophylaxis: Lowest headache recurrence rates; ideal for menstrual migraine mini-prophylaxis (start 2 days prior to menses for 5–7 days). |
Strict Cardiovascular Contraindications to Triptans: Because 5-HT1B receptors mediate vasoconstriction in coronary, cerebral, and peripheral vascular beds, triptans are absolutely contraindicated in patients with: (1) Established Coronary Artery Disease (CAD), angina, or history of Myocardial Infarction, (2) Uncontrolled Hypertension, (3) History of Stroke or Transient Ischemic Attack (TIA), (4) Peripheral Vascular Disease (PVD) or ischemic bowel disease, (5) Wolff-Parkinson-White syndrome or accessory conduction pathways, (6) Severe hepatic impairment, and (7) Concurrent use within 24 hours of another triptan or ergotamine derivative (ergotamine, DHE).
3. Non-Vasoconstricting Acute Therapies: Gepants & Ditans
For decades, patients with cardiovascular disease, uncontrolled hypertension, or prior stroke were excluded from migraine-specific abortive therapies. The development of small-molecule CGRP antagonists ("gepants") and 5-HT1F receptor agonists ("ditans") has eliminated this therapeutic barrier because neither class causes vasoconstriction.
Small-Molecule CGRP Receptor Antagonists (Gepants)
Gepants competitively block the Calcitonin Gene-Related Peptide (CGRP) receptor, terminating neurogenic inflammation and trigeminovascular pain signaling without altering coronary or cerebral vascular diameter.
+---------------------------------------------------------------------------------------------------------+
| ORAL & NASAL GEPANTS FOR ACUTE MIGRAINE |
+------------------+-----------------------+------------------------+-------------------------------------+
| Drug Name & Brand| Dosing & Administration| Metabolism & Kinetics | Clinical Pearls & Advantages |
+------------------+-----------------------+------------------------+-------------------------------------+
| **Ubrogepant** | 50 mg or 100 mg oral; | Major CYP3A4 substrate;| **Cardiovascular Safety:** Safe in |
| (Ubrelvy) | may repeat dose once | avoid strong CYP3A4 | patients with CAD, prior MI, stroke,|
| | after 2 hours (max 200| inhibitors (reduce dose| or uncontrolled HTN. Does not cause |
| | mg/24 hours) | with moderate CYP3A4i) | medication overuse headache. |
+------------------+-----------------------+------------------------+-------------------------------------+
| **Rimegepant** | 75 mg orally dissolving| Substrate of CYP3A4 & | **Dual Indication Molecule:** |
| (Nurtec ODT) | tablet (ODT); max 75 | P-gp; half-life ~11h | FDA approved for BOTH **acute |
| | mg per 24 hours | | treatment (75 mg PRN)** AND |
| | | | **preventive therapy (75 mg QOD)**. |
+------------------+-----------------------+------------------------+-------------------------------------+
| **Zavegepant** | 10 mg single nasal | Elimination primarily | **Fastest Non-Oral Gepant:** Nasal |
| (Zavzpret) | spray in one nostril; | non-CYP (biliary/renal)| formulation provides pain relief in |
| | max 10 mg per 24 hours| half-life ~6.5 hours | 15–30 minutes; ideal for severe |
| | | | nausea, vomiting, or gastroparesis. |
+------------------+-----------------------+------------------------+-------------------------------------+
Selective Serotonin 5-HT1F Receptor Agonist: Lasmiditan (Reyvow)
- Mechanism: High-affinity, selective agonist at the neuronal 5-HT1F receptor, which is expressed on trigeminal neurons but completely absent from vascular smooth muscle. Inhibits trigeminal neuropeptide release without inducing vasoconstriction.
- Dosing: 50 mg, 100 mg, or 200 mg orally once; maximum 1 dose in 24 hours (a second dose for the same attack has not been shown to be effective).
- Central Nervous System Safety & Mandatory Driving Restriction:
- Highly lipophilic and crosses the blood-brain barrier, causing profound dizziness, sedation, paresthesias, and visual disturbances.
- FDA Mandated Black Box Driving Restriction: Patients MUST NOT drive a motor vehicle or operate heavy machinery for AT LEAST 8 HOURS after taking each dose of lasmiditan.
- Classified as a Schedule V Controlled Substance due to low-level abuse potential.
4. Targeted CGRP Biologics, Oral Preventive Gepants & OnabotulinumtoxinA
Targeted Calcitonin Gene-Related Peptide (CGRP) therapies represent the first disease-specific mechanism developed specifically for migraine prevention. CGRP is a potent vasodilatory neuropeptide released from trigeminal perivascular nerves that mediates neurogenic inflammation, vasodilation, and central sensitization.
CGRP Monoclonal Antibodies (mAbs)
Large humanized or fully human IgG monoclonal antibodies that do not cross the blood-brain barrier, eliminating central cognitive/sedating adverse effects and avoiding hepatic CYP450 interactions.
| Monoclonal Antibody & Target | Dosing & Delivery Route | Half-Life & Administration | Key Adverse Effects & Clinical Warnings |
|---|---|---|---|
| Erenumab (Aimovig)<br/>Targets CGRP RECEPTOR | 70 mg or 140 mg SC once monthly | ~28 days<br/>Autoinjector | FDA Warning for Severe Constipation: Potent receptor blockade inhibits intestinal motility, leading to severe constipation, fecal impaction, bowel obstruction, and hospitalization. Also causes new-onset or worsening severe hypertension. |
| Galcanezumab (Emgality)<br/>Targets CGRP LIGAND | Loading dose 240 mg SC (two 120mg injections), then 120 mg SC once monthly | ~27 days<br/>Autoinjector | Injection site reactions (erythema, pain, pruritus), hypersensitivity. Also FDA approved for Episodic Cluster Headache (300 mg at onset of cluster period). |
| Fremanezumab (Ajovy)<br/>Targets CGRP LIGAND | 225 mg SC once monthly OR 675 mg SC once every 3 months (quarterly) | ~30 days<br/>Autoinjector / Prefilled syringe | Flexible monthly or quarterly dosing schedules; injection site reactions. |
| Eptinezumab (Vyepti)<br/>Targets CGRP LIGAND | 100 mg or 300 mg IV infusion over 30 minutes once every 3 months | ~27 days<br/>IV infusion | 100% Rapid Bioavailability: Immediate therapeutic drug levels within hours of infusion; hypersensitivity, nasopharyngitis. |
Oral Small-Molecule Gepants for Prevention
- Atogepant (Qulipta: 10, 30, or 60 mg orally once daily): Highly selective oral CGRP receptor antagonist FDA approved for the preventive treatment of both Episodic Migraine (<15 days/month) and Chronic Migraine (≥15 days/month). Adverse effects: Nausea, constipation, fatigue, decreased appetite/weight loss. Substrate of CYP3A4 and OATP1B1/1B3.
- Rimegepant (Nurtec ODT: 75 mg orally every other day [QOD]): Provides dual acute abortive and chronic preventive coverage with a single prescription.
OnabotulinumtoxinA (Botox) in Chronic Migraine
- Strict FDA Indication: Indicated ONLY for the prophylaxis of Chronic Migraine (defined as headaches occurring ≥ 15 days per month for at least 3 months, with at least 8 of those days meeting criteria for migraine). Controlled clinical trials (PREEMPT 1 & 2) proved that Botox is ineffective for episodic migraine (<15 days/month).
- Mechanism of Action: Cleaves SNAP-25, blocking the presynaptic vesicular release of acetylcholine at the neuromuscular junction (muscle relaxation) and inhibiting the exocytosis of pain neuropeptides (CGRP, substance P, glutamate) from primary nociceptive neurons.
- Standardized Dosing & Anatomical Protocol: Administered as 155 units divided across 31 standardized intramuscular injection sites into 7 specific head and neck muscle groups (Frontalis, Corrugator, Procerus, Occipitalis, Temporalis, Trapezius, and Cervical Paraspinal muscles) every 12 weeks.
A 52-year-old female with a past medical history of ST-elevation myocardial infarction (STEMI) treated with a drug-eluting stent 2 years ago, uncontrolled hypertension (clinic BP 158/96 mmHg), and episodic migraine without aura presents for an acute headache consultation. She reports experiencing 2 to 3 severe, throbbing unilateral migraines per month that cause disabling nausea and force her to miss work. Over-the-counter NSAIDs and acetaminophen provide zero relief. Which of the following acute abortive medications represents the most appropriate, guideline-directed therapy for this patient?
A 36-year-old male with a 10-year history of episodic migraine presents with worsening daily, diffuse, dull headaches present immediately upon awakening. Over the past 5 months, he has been taking an over-the-counter combination analgesic containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg (Excedrin Migraine) 2 to 3 times daily on approximately 20 days per month. He notes that the tablets provide transient relief for 3 to 4 hours, after which a rebound headache emerges. Which of the following is the most accurate clinical diagnosis and recommended initial management plan?
A 44-year-old female with chronic migraine (18 headache days per month) has experienced treatment failure or intolerable adverse effects with propranolol, topiramate, and amitriptyline. Her neurologist prescribes erenumab (Aimovig) 70 mg subcutaneously once monthly. As the ambulatory care pharmacist conducting the clinical injection teaching and safety counseling, which of the following unique adverse reactions and mechanisms must be specifically emphasized?