27.1 Primary Acute Headaches: Migraine, Tension & Cluster

Primary Acute Headaches: Clinical Spectrum & Secondary Headache Red Flags

Headaches represent one of the most common chief complaints in ambulatory family medicine, accounting for millions of clinic visits annually. The primary care physician's first objective is to differentiate benign primary headache disorders—primarily migraine, tension-type headache (TTH), and cluster headache / trigeminal autonomic cephalgias—from life-threatening secondary headaches requiring emergent neuroimaging, lumbar puncture, or surgical intervention.

The SNOOP4 Secondary Headache Red Flag Criteria

The presence of any "red flag" symptom demands immediate escalation, emergent non-contrast head CT, or emergency department transfer to rule out conditions such as aneurysmal subarachnoid hemorrhage, bacterial meningitis, intracranial mass lesion, acute angle-closure glaucoma, or temporal (giant cell) arteritis.

                  THE SNOOP4 RED FLAG SYSTEM

  S - Systemic symptoms: Fever, night sweats, unexplained weight loss, 
      immunocompromised status (HIV, active chemotherapy), or history of cancer
  N - Neurologic signs/symptoms: Focal motor or sensory deficits, papilledema,
      altered mental status, cognitive decline, seizures, or neck stiffness
  O - Onset sudden / "Thunderclap": Pain reaching peak excruciating intensity 
      in < 1 minute (hallmark of subarachnoid hemorrhage, RCVS, or CVST)
  O - Older age at onset: New or progressive headache beginning at age ≥ 50 years
      (high suspicion for Giant Cell Arteritis or intracranial neoplasm)
  P1 - Pattern change or Progressive: Escalating frequency, change in attack 
       morphology, or "worst headache of life"
  P2 - Positional triggers: Pain substantially worsening upon standing upright 
       (low CSF pressure / leak) or lying flat (elevated ICP / mass / IIH)
  P3 - Precipitated by Valsalva: Headache provoked by coughing, sneezing, bending,
       or strenuous exertion (raises concern for posterior fossa lesion/Chiari)
  P4 - Papilledema: Optic disc swelling on fundoscopy indicating elevated ICP

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Migraine Headache: Pathophysiology, Clinical Features & Diagnostic Criteria

Migraine is a chronic, neurovascular pain disorder characterized by recurrent episodic attacks of moderate-to-severe headache accompanied by neurological, autonomic, and gastrointestinal symptoms.

Neurobiology & Pathophysiology

1. Trigeminovascular System Activation: The core generator of migraine pain involves activation of pseudo-unipolar primary sensory neurons located within the trigeminal ganglion. These neurons innervate the pain-sensitive intracranial meninges and dural blood vessels.
2. Neurogenic Inflammation: Antidromic stimulation of these sensory fibers leads to the local release of potent vasoactive neuropeptides, most notably Calcitonin Gene-Related Peptide (CGRP), substance P, and neurokinin A. CGRP binds to receptors on dural mast cells and vascular smooth muscle, causing mast cell degranulation, sterile neurogenic plasma extravasation, marked vasodilation, and sustained nociceptive sensitization of trigeminal caudate neurons in the brainstem.
3. Cortical Spreading Depression (CSD): The neurobiological substrate of the migraine aura. CSD is a slowly propagating wave (2 to 6 mm/minute) of intense neuronal and glial depolarization across the cerebral cortex, primarily originating in the occipital visual cortex. This depolarizing wave is accompanied by transient hyperperfusion followed by prolonged oligemia (reduced cortical blood flow) and prolonged neuronal suppression, activating meningeal nociceptors and opening the blood-brain barrier.

Clinical Diagnostic Criteria (ICHD-3) & The POUND Mnemonic

According to the International Classification of Headache Disorders (ICHD-3), a diagnosis of migraine without aura requires at least 5 attacks meeting the following parameters:

• Attack duration lasting 4 to 72 hours (untreated or unsuccessfully treated);
• At least two of the following four pain characteristics:
  • Unilateral location;
  • Pulsating / throbbing quality;
  • Moderate to severe pain intensity (inhibits or prohibits daily activities);
  • Aggravation by or causing avoidance of routine physical activity (e.g., walking, climbing stairs);
• At least one of the following associated symptoms during the attack:
  • Nausea and/or vomiting;
  • Both photophobia (light sensitivity) and phonophobia (sound sensitivity).

To rapidly identify migraine in the clinic, the validated POUND mnemonic is widely utilized:

• P - Pulsatile / throbbing quality
• O - One-day duration (typically 4 to 72 hours)
• U - Unilateral location
• N - Nausea or vomiting
• D - Disabling intensity (disrupts daily activities)

Diagnostic Accuracy: The presence of 4 or 5 POUND features provides a positive likelihood ratio (+LR) of 24, virtually confirming migraine. The presence of 3 features yields a +LR of 3.2, whereas ≤2 features has a -LR of 0.41, arguing against migraine.

Migraine with Aura vs. Without Aura

• Approximately 25% to 30% of patients experience migraine with aura.
• Aura Characteristics: Neurological symptoms that are completely reversible, develop gradually over ≥5 minutes, and typically last 5 to 60 minutes (rarely up to 4 hours), immediately preceding or accompanying the headache phase.
• Aura Modalities:
  • Visual Aura (>90% of auras): The classic scintillating scotoma (a luminous, flickering, jagged zigzag pattern resembling a fortified city wall [fortification spectrum or teichopsia]) that gradually expands across the visual field, leaving a central or paracentral blind spot (scotoma).
  • Sensory Aura: Unilateral paresthesias ("pins and needles") typically marching slowly from the fingers up the arm to the face and tongue, followed by numbness.
  • Speech / Language Aura: Transient expressive dysphasia, paraphasias, or word-finding difficulties.
• Differentiating Aura from Transient Ischemic Attack (TIA): A critical clinical distinction. Migraine aura characteristically displays a gradual evolutionary "march" over 5 to 20 minutes characterized by "positive" phenomena (flashing lights, shimmering lines, tingling paresthesias). In contrast, a TIA produces an abrupt, sudden-onset deficit reaching maximal intensity in seconds characterized by "negative" loss-of-function phenomena (sudden blindness, complete loss of sensation, dense motor paralysis).

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Stepwise Acute Abortive Pharmacotherapy for Migraine

Modern migraine management uses a stratified care approach: matching the initial treatment to attack severity and disability rather than utilizing a rigid step-up approach that forces severely disabled patients through ineffective low-tier medications.

                  STRATIFIED ACUTE MIGRAINE PHARMACOTHERAPY

  MILD TO MODERATE ATTACKS
  ┌─────────────────────────────────────────────────────────────┐
  │ • Oral NSAIDs: Ibuprofen 400-800 mg, Naproxen 500-550 mg    │
  │ • Acetaminophen 1,000 mg (alone or with Caffeine/Aspirin)   │
  │ • Limit use to <15 days/month to avoid medication overuse    │
  └──────────────────────────────┬──────────────────────────────┘
                                 ▼
  MODERATE TO SEVERE ATTACKS
  ┌─────────────────────────────────────────────────────────────┐
  │ 1. FIRST-LINE: Triptans (5-HT1B/1D Agonists)                │
  │    • Sumatriptan (50-100 mg PO, 6 mg SC, 20 mg Nasal)       │
  │    • Zolmitriptan, Rizatriptan (cap 5 mg if on propranolol) │
  │    • CONTRAINDICATED in CAD, stroke/TIA, uncontrolled HTN   │
  ├─────────────────────────────────────────────────────────────┤
  │ 2. VASCULAR CONTRAINDICATIONS OR TRIPTAN NON-RESPONDERS:    │
  │    • CGRP Antagonists (Gepants): Rimegepant, Ubrogepant     │
  │      *No vasoconstriction; safe in cardiovascular disease*  │
  │    • 5-HT1F Agonist (Ditan): Lasmiditan 50-100 mg           │
  │      *No vasoconstriction; mandatory 8-hour driving ban*    │
  ├─────────────────────────────────────────────────────────────┤
  │ 3. EMERGENCY / URGENT CARE RESCUE:                          │
  │    • IV Metoclopramide 10 mg OR Prochlorperazine 10 mg      │
  │      PLUS Diphenhydramine 25-50 mg (prevents akathisia)     │
  │    • IV Ketorolac 30 mg + IV Dexamethasone 10 mg (prevents  │
  │      headache recurrence over next 72 hours)                │
  └─────────────────────────────────────────────────────────────┘

1. Triptans (5-HT1B / 5-HT1D Receptor Agonists)

• Mechanism of Action:
  • Selective agonists at 5-HT1B receptors located on cranial and meningeal vascular smooth muscle, causing selective cranial vasoconstriction;
  • Selective agonists at presynaptic 5-HT1D receptors on trigeminal sensory nerve terminals, inhibiting the release of pro-inflammatory neuropeptides (CGRP, substance P);
  • Central inhibition of second-order nociceptive transmission within the trigeminal nucleus caudalis.
• Formulations & Routes:
  • Sumatriptan: 50-100 mg PO; 6 mg Subcutaneous (onset within 10-15 minutes; gold standard for rapid rescue or severe early vomiting); 5-20 mg nasal spray;
  • Zolmitriptan: 2.5-5 mg PO/ODT; 5 mg nasal spray;
  • Rizatriptan: 5-10 mg PO/ODT (fastest oral onset; Clinical Pearl: If co-administered with propranolol, the dose of rizatriptan must be capped at 5 mg because propranolol inhibits rizatriptan metabolism, increasing serum concentrations by 70%);
  • Eletriptan: 20-40 mg PO (highest bioavailability and receptor affinity).
• STRICT CONTRAINDICATIONS (HIGH-YIELD BOARD PEARL): Because 5-HT1B activation produces coronary and peripheral arterial vasoconstriction, triptans are strictly contraindicated in:
  1. Ischemic Heart Disease: Coronary artery disease, history of myocardial infarction, coronary artery bypass grafting, or coronary stent placement;
  2. Coronary Vasospasm: Prinzmetal (variant) angina;
  3. Cerebrovascular Disease: Prior ischemic stroke or transient ischemic attack (TIA);
  4. Uncontrolled Hypertension: Blood pressure ≥140/90 mmHg or history of labile malignant hypertension;
  5. Peripheral Vascular Disease (PVD) or ischemic bowel disease;
  6. Hemiplegic Migraine or Migraine with Brainstem Aura (basilar-type migraine), due to theoretical risk of ischemic stroke;
  7. Severe Hepatic Impairment;
  8. Concurrent use of Ergotamines or another triptan within 24 hours;
  9. Concurrent use of MAO Inhibitors within 14 days (specifically for sumatriptan, rizatriptan, and zolmitriptan);
  10. Pregnancy: Relative/strict contraindication due to potential uteroplacental vasoconstriction.

2. CGRP Receptor Antagonists (Gepants)

• Agents: Rimegepant (75 mg ODT), Ubrogepant (50-100 mg PO), Zavegepant (10 mg nasal spray).
• Mechanism: Small-molecule competitive antagonists that directly block the CGRP receptor on trigeminal neurons and meningeal vessels, interrupting neurogenic inflammation.
• Critical Cardiovascular Safety Profile: Gepants DO NOT cause vasoconstriction of coronary, cerebral, or peripheral vascular beds. Consequently, gepants are the first-line choice for acute migraine abortive therapy in patients with coronary artery disease, history of stroke/TIA, uncontrolled hypertension, or peripheral vascular disease.
• Dual Utility: Rimegepant is uniquely FDA-approved for both acute abortive therapy (75 mg PRN) and alternate-day preventive therapy (75 mg every other day).

3. Selective 5-HT1F Receptor Agonists (Ditans)

• Agent: Lasmiditan (50 mg or 100 mg PO).
• Mechanism: Highly selective agonist at the 5-HT1F receptor, inhibiting trigeminovascular nociceptive transmission without activating 5-HT1B receptors. Because it lacks 5-HT1B affinity, it produces zero vasoconstriction and can be used safely in patients with cardiovascular disease.
• CNS Adverse Effects & Mandatory Driving Restriction: Lasmiditan crosses the blood-brain barrier readily, frequently causing dizziness, sedation, vertigo, and paresthesias. FDA Black Box Warning: Patients must NOT drive or operate heavy machinery for at least 8 hours following each dose.

4. Antiemetic Dopamine Antagonists & Emergency Cocktail

• In the emergency department or urgent care setting, intravenous dopamine D2 receptor antagonists are highly effective abortive agents that also relieve nausea and overcome gastroparesis:
  • Metoclopramide 10 mg IV or Prochlorperazine 10 mg IV/IM.
• Mandatory Co-Administration of Diphenhydramine: IV dopamine receptor blockade frequently provokes distressing extrapyramidal symptoms, particularly akathisia (severe motor restlessness and urge to pace) and acute dystonic reactions. Co-administering Diphenhydramine 25 to 50 mg IV/IM provides anticholinergic protection, preventing akathisia.
• Preventing Migraine Recurrence: Adding Dexamethasone 10 mg IV does not immediately relieve pain but significantly reduces the rate of migraine recurrence over the subsequent 48 to 72 hours by ~30%.

5. Classes to AVOID in Acute Migraine

• Opioids (codeine, oxycodone, hydromorphone) and Butalbital-containing combinations (Fioricet, Fiorinal) should be strictly avoided. They cause rapid tolerance, high rates of dependence, cognitive blunting, and are the most potent triggers for medication overuse headache and migraine chronification.

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Medication Overuse Headache (MOH / Rebound Headache)

Medication Overuse Headache is a secondary headache disorder caused by the frequent, repetitive use of acute symptomatic headache medications in a patient with a pre-existing primary headache disorder.

Diagnostic Criteria (ICHD-3)

1. Headache occurring on ≥15 days per month in a patient with a pre-existing headache disorder;
2. Regular overuse of acute symptomatic headache medication for >3 months, defined as:
   • ≥10 days per month for triptans, ergotamines, opioids, or combination analgesics (e.g., butalbital-acetaminophen-caffeine);
   • ≥15 days per month for simple analgesics (acetaminophen, aspirin, NSAIDs) or any combination of simple analgesics.

Clinical Presentation & Vicious Cycle

Patients present with a chronic, daily or near-daily, dull-to-throbbing, holocephalic headache that is characteristically present upon awakening in the morning. When the patient consumes their overused medication, the headache temporarily subsides, only to rebound as the drug level falls hours later. This compels the patient to take another dose, establishing a self-sustaining vicious cycle.

Management Strategy for MOH

• Patient Education: Explain the paradox that the medicine taken to relieve the headache has become the primary cause of daily pain.
• Abrupt Discontinuation vs. Taper:
  • NSAIDs, acetaminophen, and triptans can be discontinued abruptly;
  • Butalbital combinations and opioids require a gradual outpatient taper to prevent severe withdrawal symptoms, rebound autonomic hyperactivity, or withdrawal seizures.
• Transitional "Bridge" Therapy: During the 1- to 2-week withdrawal period, withdrawal headaches can be severe. Bridge options include:
  • Oral Prednisone taper (e.g., 60 mg daily for 3 days, tapered by 20 mg every 3 days over 9-10 days);
  • Scheduled long-acting NSAID (Naproxen sodium 500 mg BID for 10-14 days);
  • Greater Occipital Nerve (GON) blocks with 1% lidocaine and bupivacaine.
• Early Initiation of Preventive Therapy: Start evidence-based preventive medications (Topiramate, Propranolol, Amitriptyline, or CGRP monoclonal antibodies [erenumab, fremanezumab, galcanezumab]) immediately upon initiating the withdrawal protocol.

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Tension-Type Headache (TTH)

Tension-Type Headache is the most prevalent primary headache disorder, affecting over 40% of the population worldwide.

Clinical Characteristics & Diagnostic Criteria (ICHD-3)

• Pain Quality: Non-pulsatile, dull, aching, band-like or vise-like tightness or pressure around the head, frequently involving the forehead, temples, and suboccipital neck muscles.
• Location: Characteristically bilateral (diffuse or circumferential).
• Intensity: Mild to moderate (does not completely disable the patient; patients can continue work or routine tasks).
• Aggravation: NOT aggravated by routine physical activity (walking, climbing stairs).
• Associated Symptoms: Absence of nausea and vomiting. Photophobia or phonophobia may be present, but never both simultaneously (if both are present, reclassify as migraine).
• Classification: Infrequent episodic (<1 day/month), Frequent episodic (1 to 14 days/month), or Chronic (≥15 days/month for >3 months).

Treatment of Tension-Type Headache

• Acute Abortive Therapy:
  • Simple NSAIDs: Ibuprofen 400 to 800 mg PO, Naproxen sodium 500 mg PO;
  • Acetaminophen 1,000 mg PO (preferred in pregnancy and renal impairment);
  • Combination analgesics: Acetaminophen + Aspirin + Caffeine.
  • Avoid: Triptans (ineffective in pure TTH), muscle relaxants (no proven superiority, high sedation), and opioids/butalbital (high MOH risk).
• Prophylaxis (for Chronic or Frequent Episodic TTH):
  • Indicated if headaches occur ≥2 days per week or significantly impair quality of life;
  • First-Line Prophylaxis: Amitriptyline (tricyclic antidepressant), initiated at 10 to 25 mg at bedtime and titrated up to 50 to 75 mg nightly. Mirtazapine or venlafaxine are second-line alternatives.

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Cluster Headache: Trigeminal Autonomic Cephalgias (TACs)

Cluster headache is an excruciating, disabling primary headache disorder belonging to the family of Trigeminal Autonomic Cephalgias (TACs). It is colloquially termed the "suicide headache" due to the agonizing intensity of individual attacks.

Epidemiology & Clinical Presentation

• Demographics: Strong male predominance (male-to-female ratio ~3:1), with typical onset between ages 20 and 40 years. Heavily associated with a history of heavy cigarette smoking (>80% of patients).
• Pain Profile:
  • Severity: Excruciating, boring, piercing, sharp, non-throbbing pain centered strictly unilaterally in the periorbital, retro-orbital, or temporal region (often described as "a hot poker being driven into the eye");
  • Duration: Untreated attacks last 15 to 180 minutes;
  • Frequency: Attacks occur from once every other day up to 8 times per day;
  • Episodic Clustering: Attacks cluster in episodic bouts lasting 6 to 12 weeks, separated by temporary remission periods lasting months to years. Chronobiological periodicity is striking: attacks recur at identical clockwork times each day, most commonly awakening the patient 1 to 2 hours after falling asleep (coinciding with REM sleep).
• Ipsilateral Cranial Autonomic Features: Driven by central trigeminal-parasympathetic reflex activation:
  • Conjunctival injection (red eye) and lacrimation (tearing);
  • Nasal congestion and/or rhinorrhea (runny nose);
  • Eyelid edema;
  • Forehead and facial diaphoresis (sweating);
  • Partial Horner Syndrome: Miosis (constricted pupil) and ptosis (drooping eyelid) on the side of the pain.
• Behavioral Hallmark: Unlike migraine patients who lie perfectly still in a dark, quiet room, cluster headache patients display profound motor restlessness and agitation, pacing the floor, rocking back and forth, banging their head, or crying out in agony.

Acute Abortive Treatment for Cluster Headache

Because cluster attacks peak within seconds to minutes and last <180 minutes, oral analgesics and oral triptans are completely ineffective due to slow gastrointestinal absorption.

1. 100% High-Flow Oxygen (First-Line Gold Standard):
   • Administration: Administer 100% oxygen at 12 to 15 L/minute via a non-rebreather face mask (with a well-sealed reservoir bag) for 15 minutes with the patient seated upright leaning forward;
   • Efficacy: Produces complete pain relief in >75% of patients within 15 minutes by inducing profound cerebral vasoconstriction and suppressing trigeminal sensory output;
   • Safety: Safe, highly effective, zero drug-drug interactions, and fully safe in patients with coronary artery disease or hypertension.
2. Subcutaneous Sumatriptan 6 mg:
   • The fastest and most effective pharmacologic abortive agent, achieving relief in 75% of attacks within 10 to 15 minutes (maximum dose: 12 mg in 24 hours, separated by at least 1 hour);
   • Alternative: Intranasal Zolmitriptan (5 to 10 mg nasal spray administered contralateral to the pain to bypass congested nasal mucosa).

Prophylactic Pharmacotherapy for Cluster Headache

Prophylaxis must be initiated immediately upon onset of a cluster period to suppress the cycle:

1. First-Line Maintenance Prophylaxis: Verapamil:
   • Calcium channel blocker; standard maintenance dose is 240 mg to 720 mg daily in divided doses;
   • MANDATORY ECG MONITORING (HIGH-YIELD BOARD PEARL): Verapamil suppresses cardiac atrioventricular conduction. A baseline 12-lead ECG is mandatory, and follow-up ECGs must be obtained 10 to 14 days after every dose titration to screen for PR interval prolongation, second-degree or third-degree AV block, and severe bradycardia.
2. Transitional "Bridge" Therapy:
   • Because verapamil requires 1 to 2 weeks to reach therapeutic steady-state, bridge therapy is started simultaneously:
   • Oral Prednisone taper: 60 to 80 mg daily for 5 days, tapered down by 10-20 mg every 3 days over 2 to 3 weeks; OR
   • Suboccipital Corticosteroid Injection: Greater occipital nerve block with triamcinolone and bupivacaine, providing rapid temporary attack suppression.
3. CGRP Monoclonal Antibody: Galcanezumab:
   • Galcanezumab (300 mg subcutaneous loading dose administered as three 100 mg injections at cluster onset) is FDA-approved for episodic cluster headache, significantly reducing weekly attack frequency.

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Summary Comparison of Primary Acute Headaches

| Feature | Migraine | Tension-Type Headache (TTH) | Cluster Headache | | :--- | :--- | :--- | :--- | :--- | | Sex Distribution | Female > Male (3:1) | Female ≥ Male (1.2:1) | Male > Female (3:1) | | Pain Location | Unilateral (60-70%) or bilateral | Bilateral (band-like / circumferential) | Strictly Unilateral (periorbital / temporal) | | Pain Quality | Pulsating, throbbing | Non-pulsatile, dull ache, pressure | Piercing, boring, stabbing ("hot poker") | | Pain Severity | Moderate to severe (disabling) | Mild to moderate (non-disabling) | Excruciating, agonizing ("suicide pain") | | Attack Duration | 4 to 72 hours | 30 minutes to 7 days | 15 to 180 minutes | | Aggravation by Activity | Yes (prefers dark, quiet room) | No (can continue daily activities) | No; patient is severely restless / pacing | | Associated Signs | Nausea, vomiting, photophobia, phonophobia | None; or only one of photophobia/phonophobia | Ipsilateral autonomic (tearing, rhinorrhea, Horner) | | First-Line Abortive | Triptans, Gepants, NSAIDs | NSAIDs, Acetaminophen | 100% High-Flow O2 (12-15 L/min), SC Sumatriptan | | First-Line Prophylaxis| Propranolol, Topiramate, Amitriptyline, CGRP mAbs | Amitriptyline (10-75 mg PO QHS) | Verapamil (240-720 mg/day) with serial ECGs |