Migraine and Other Primary Headache Disorders¶
Chapter 441 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 441
Key Clinical Points¶
- Migraine is the second most common cause of headache and the leading neurologic cause of disability globally.
- Migraine attacks typically progress through four phases: premonitory (prodrome), aura, headache, and postdrome.
- Pathophysiology involves trigeminovascular system activation, CGRP/PACAP release, and brainstem/hypothalamus dysfunction.
- Triptans are 5-HT1B/1D agonists; Ditans are 5-HT1F agonists (acting only on neural targets).
- CGRP receptor antagonists (gepants) and monoclonal antibodies provide both acute and preventive options.
- Medication-overuse headache (MOH) is a risk with frequent use of analgesics, especially opioids or barbiturates.
- Preventive treatment is indicated for ≥ 4 migraine days per month; effect lag is 2–12 weeks.
- Neuromodulation (sTMS, nVNS, REN, Cefaly, Relivion) is FDA-cleared for both acute and preventive use.
- Migraine is generally not associated with life-threatening illness except in women on specific hormonal medications.
- Opioids are suboptimal for recurring headaches and may reduce the efficacy of triptans.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 24e): Disorders in which headache and associated features occur in the absence of any exogenous cause.
• Migraine: Second most common cause of headache; most common neurologic cause of disability.
• Tension-Type Headache (TTH): Characterized as a featureless headache. Most patients with disabling headaches have migraine.
• Trigeminal Autonomic Cephalalgias (TACs): Includes conditions like cluster headache; full list in Table 441-1.
Primary Headache Disorders (Table 441-1)¶
• Migraine Categories: Includes migraine without aura, migraine with aura (typical, brainstem, hemiplegic, retinal), chronic migraine, and complications like status migrainosus or migrainous infarction. • TTH Categories: Infrequent episodic, frequent episodic, and chronic TTH. • TACs Categories: Cluster headache (episodic/chronic), paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks (SUNCT/SUNA). • Other Primary Disorders: Includes cough, exercise, sexual activity, thunderclap, cold-stimulus, external-pressure, stabbing, nummular, hypnic, and new daily persistent headache (NDPH).
EPIDEMIOLOGY¶
• Prevalence: Affects ~15% of women and 6% of men over a 1-year period. • Impact: Second most common cause of headache; leading neurologic cause of disability worldwide.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Sensory Sensitivity: Due to dysfunction of monoaminergic and other sensory control systems in the brainstem and hypothalamus. • Trigeminovascular System: Activation of trigeminal neurons → release of vasoactive neuropeptides (CGRP, PACAP) at vascular terminals and within the trigeminal nucleus. • Central Processing: Second-order trigeminal neurons cross midline → project to ventrobasal/posterior thalamic nuclei; also project to periaqueductal gray and hypothalamus. • Descending Modulation: rudium pathways from locus coeruleus, parabrachial nucleus, and rostroventromedial medulla provide antinociceptive effects._
Neurotransmitter Involvement¶
• 5-HT (Serotonin): Involved in migraine pathophysiology; triptans target 5-HT1B and 5-HT1D receptors to arrest nerve signaling and promote vasoconstriction. • Ditans: Target 5-HT1F receptor; act only at neural targets (no vasoconstriction). • Dopamine: Premonitory symptoms can be induced by dopaminergic stimulation; migraineurs show dopamine receptor hypersensitivity (e.g., yawning, nausea, vomiting). • Hypothalamus: Activation in the premonitory phase may explain the role of dopamine.
Genetic Factors¶
• Ion Channel Involvement: Mutations suggest altered membrane excitability predisposes to migraine. • FHM 1: CACNA1A gene (Ca2+ channel) mutation; accounts for ~50% of FHM cases. • FHM 2: ATP1A2 gene (Na+-K+ ATPase) mutation; accounts for ~20% of FHM cases. • FHM 3: SCN1A gene (Na+ channel) mutation.
CLINICAL FEATURES¶
• Triggers: Altered sleep, hunger, stress let-down, physical exertion, weather/barometric changes, hormonal fluctuations (menses), alcohol, and chemical stimulants (nitrates). • Patient Education: Migraine is an inherited tendency; it can be managed but not eradicated; generally not life-threatening except in specific cases involving estrogen/contraceptives.
Attack Phases (Table 441-2)¶
• Premonitory (Prodrome): Neck discomfort, higher center, cognitive impairment (brain fog), mood change, fatigue, yawning/sleepiness, polyuria/polydipsia, food cravings. • Aura: Neurologic disturbance; e.g., scintillating scotoma (20–25% of patients). • Headache Phase: Pain, nausea/vomiting, sensory sensitivity (photophobia, phonophobia, osmophobia), allodynia, vertigo. • Postdrome: Tiredness, weariness, concentration impairment.
DIFFERENTIAL DIAGNOSIS¶
• TTH vs. Migraine: TTH is featureless; migraine includes associated features (nausea, photophobia). • TACs: Includes cluster headache and paroxysmal hemicrania.
DIAGNOSTIC APPROACH¶
- Initial Assessment: Identify repeated attacks of headache lasting 4–72 h with a normal physical exam and no other reasonable cause.
- Migraine Criteria (Table 441-3): Must have ≥ 2 features: Unilateral pain, Throbbing pain, Aggravation by movement, or Moderate/severe intensity.
- Associated Features: Must have ≥ 1 feature: Nausea/vomiting OR Photophobia and phonophobia.
- Chronic Migraine Identification: Diagnosis if patient has migraine on ≥ 8 days per month AND ≥ 15 total headache days per month.
- Disability Assessment: Utilize MIDAS (Figure 6) to quantify impact on daily life.
MANAGEMENT & TREATMENT¶
• General Principles: Select treatment based on severity; use adequate dose as soon as possible. If symptoms persist/return within 60 min, increase initial dose or switch class. • Nonpharmacologic Management: Trigger avoidance, regular sleep/diet, exercise, and stress reduction (yoga, meditation, biofeedback).
-
Acute Attack Therapies (Table 441-4): Simple Analgesics: Acetaminophen, aspirin, caffeine (Excedrin Migraine: 2 tabs q6h, max 8/day). NSAIDs: Naproxen (220–550 mg PO bid), Ibuprofen (400 mg PO q3–4h), Tolfenamic acid (200 mg PO; repeat x1 after 1–2 h), Diclofenac K (50 mg PO). Triptans: Ergotamine/Caffeine (1mg/100mg, max 6/day, 10/week), Naratriptan (2.5 mg), Rizatriptan (5–10 mg), Sumatriptan (50–100 mg oral; 3–6 mg SC; 5–20 mg nasal), Frovatriptan (2.5 mg), Almotriptan (12.5 mg), Eletriptan (40 or 80 mg). Nasal Agents: Dihydroergotamine (Migranal/Trudhesa), Sumatriptan (Imitrex Nasal), Zolmitriptan (Zomig).* _Gepants: Rimegepant (75 mg ODT), Ubrogepant (50 or 100 mg), Zavegepant (10 mg nasal). Ditans: Lasmiditan (50, 100, or 200 mg). Dopamine Antagonists: Metoclopramide (5–10 mg/d), Prochlorperazine (1–25 mg/d), Chlorpromazine (0.1 mg/kg IV). Neuromodulation: sTMS, nVNS, REN, Cefaly, Relivion.
-
Clinical Stratification of Acute Treatment (Table 441-5): Failed NSAIDs → Triptans (Sumatriptan, Almotriptan, Rizatriptan, Eletriptan, Zolmitriptan) or Gepants/Ditans. Slower effect/better tolerability → Naratriptan (2.5 mg), Frovatriptan (2.5 mg). Headache recurrence → Ergotamine 2 mg (most effective PR) or Naratriptan, Almotriptan, Eletriptan, Rimegepant, Ubrogepant. Early vomiting → Zolmitriptan 5 mg nasal, Zavegepant 10 mg nasal, Sumatriptan 25 mg PR or 6 mg SC. Very rapidly developing symptoms → Zolmitriptan 5 mg nasal, Zavegepant 10 mg nasal, Sumatriptan 6 mg SC, Dihydroergotamine 1 mg IM.
-
Preventive Treatments (Table 441-6): Beta blockers: Propranolol (40–120 mg bid), Metoprolol (25–100 mg bid). Anticonvulsants: Topiramate (25–200 mg/d), Valproate (400–600 mg bid or 0.5–2 mg qd). CGRP Blockers: Eptinezumab (100-300 mg every 12 weeks), Erenumab (70-140 mg monthly), Fremanezumab (225mg/675mg), Galcanezumab (240mg load, 120mg monthly). Gepants: Rimegepant (75 mg every other day), Atogepant (10-60 mg daily). Neuromodulation: sTMS (4–24 pulses/day), nVNS (120s 2–3x daily), REN (45 min every other day), Cefaly (20 min daily).
Trigeminal Autonomic Cephalalgias Management (Table 441-7 & 8)¶
• Cluster Headache: Acute: Sumatriptan injection/nasal, Zolmitriptan nasal, Oxygen, nVNS. Prevention: Verapamil (160–960 mg/d), Galcanezumab (300 mg SC), Melatonin (9–12 mg/d), Topiramate (100–400 mg/d), Lithium (400–800 mg/d). • Paroxysmal Hemicrania: Acute: Indomethacin. Prevention: Indomethacind, nVNS. • SUNCT/SUNA: Prevention: Lamotrigine, Gabapentin.
COMPLICATIONS & PROGNOSIS¶
• Medication-Overuse Headache (MOH): Result of frequent use of acute analgesics; especially opioids or barbiturates. • Status Migrainosus: Defined in Table 441-1 as a complication. • Migrainous Infarction: Potential complication listed in Table 441-1.
SPECIAL POPULATIONS¶
• Women and Reproductive Years: Sensitivity to triggers is amplified during the menstrual cycle. Migraine is not associated with life-threatening illness except in women on oral estrogens or contraceptives.
KEY PEARLS & HIGH-YIELD POINTS¶
• Triptan vs Ditan: Triptans (5-HT1B/1D) cause vasoconstriction; Ditans (5-HT1F) do not. • Opioid Use: Opioids are suboptimal for recurring headache and may decrease response to triptans. • CGRP Blockers: Include both monoclonal antibodies (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab) and small molecules (Rimegepant, Atogepant). • Clinical Rule for Acute Treatment: If symptoms do not abate within 60 min, increase dose or switch class.
Reference Tables¶
TABLE 441-1 Primary Headache Disorders, Modified from International Classification of Headache Disorders-III (Headache…¶
Harrison's 22e, p.3463
| 1. Migraine | 1.1 Migraine without aura 1.2 Migraine with aura 1.2.1 Migraine with typical aura 1.2.1.1 Typical aura with headache 1.2.1.2 Typical aura without headache 1.2.2 Migraine with brainstem aura 1.2.3 Hemiplegic migraine 1.2.3.1 Familial hemiplegic migraine (FHM) 1.2.3.1.1 Familial hemiplegic migraine type 1 1.2.3.1.2 Familial hemiplegic migraine type 2 1.2.3.1.3 Familial hemiplegic migraine type 3 1.2.3.1.4 Familial hemiplegic migraine, other loci 1.2.3.2 Sporadic hemiplegic migraine 1.2.4 Retinal migraine 1.3 Chronic migraine 1.4 Complications of migraine 1.4.1 Status migrainosus 1.4.2 Persistent aura without infarction 1.4.3 Migrainous infarction 1.4.4 Migraine aura-triggered seizure 1.5 Probable migraine 1.5.1 Probable migraine without aura 1.5.2 Probable migraine with aura 1.6 Episodic syndromes that may be associated with migraine 1.6.1 Recurrent gastrointestinal disturbance 1.6.1.1 Cyclical vomiting syndrome 1.6.1.2 Abdominal migraine 1.6.2 Benign paroxysmal vertigo 1.6.3 Benign paroxysmal torticollis A 1.6.4 Infantile colic A 1.6.6 Vestibular migraine |
|---|---|
| 3. Trigeminal autonomic cephalalgias | 3.1 Cluster headache 3.1.1 Episodic cluster headache 3.1.2 Chronic cluster headache 3.2 Paroxysmal hemicrania 3.2.1 Episodic paroxysmal hemicrania 3.2.2 Chronic paroxysmal hemicrania 3.3 Short-lasting unilateral neuralgiform headache attacks 3.3.1 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) 3.3.1.1 Episodic SUNCT 3.3.1.2 Chronic SUNCT 3.3.2 Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) 3.3.2.1 Episodic SUNA 3.3.2.2 Chronic SUNA 3.4 Hemicrania continua 3.5 Probable trigeminal autonomic cephalalgia |
TABLE 441-2 Migraine Symptoms by Attack Phase Premonitory (prodromal) - Neck discomfort - Higher center • Cognitive…¶
Harrison's 22e, p.3464
- Premonitory (prodromal)
- Neck discomfort
- Higher center
• Cognitive impairment (brain “fog”)
• Mood change
• Fatigue
- Homeostatic
• Yawning/sleepiness
• Polyuria/polydipsia
• Food cravings
Aura
- Neurologic disturbance, such as scintillating scotoma
Headache phase
- Pain
- Nausea/vomiting
- Sensory sensitivity
• Photophobia
• Phonophobia
• Osmophobia
• Allodynia
• Vertigo
Postdrome
- Tiredness
- Weariness
- Concentration impairment
TABLE 441-3 Simplified Diagnostic Criteria for Migraine¶
Harrison's 22e, p.3466
| REPEATED ATTACKS OF HEADACHE LASTING 4–72 H IN PATIENTS WITH A NORMAL PHYSICAL EXAMINATION, NO OTHER REASONABLE CAUSE FOR THE HEADACHE, AND: |
|
|---|---|
| AT LEAST 2 OF THE FOLLOWING FEATURES: |
PLUS AT LEAST 1 OF THE FOLLOWING FEATURES: |
| Unilateral pain | Nausea/vomiting |
| Throbbing pain | Photophobia and phonophobia |
| Aggravation by movement | |
| Moderate or severe intensity |
TABLE 441-4 TREATMENT of Acute Migraine DRUG Simple Analgesics Acetaminophen, aspirin, caffeine NSAIDs Naproxen…¶
Harrison's 22e, p.3467
| DRUG | TRADE NAME | DOSAGE |
|---|---|---|
| Simple Analgesics | ||
| Acetaminophen, aspirin, caffeine | Excedrin Migraine | Two tablets or caplets q6h (max 8 per day) |
| NSAIDs | ||
| 5-HT Receptor Agonists—Triptans 1B/1D |
||
| Oral | ||
| Ergotamine 1 mg, caffeine 100 mg | Cafergot | One or two tablets at onset, then one tablet q½h (max 6 per day, 10 per week) |
| Naratriptan | Amerge | 2.5-mg tablet at onset |
| Rizatriptan | Maxalt | 5–10-mg tablet at onset |
| Maxalt-MLT | ||
| Sumatriptan | Imitrex | 50–100-mg tablet at onset |
| Frovatriptan | Frova | 2.5-mg tablet at onset |
| Almotriptan | Axert | 12.5-mg tablet at onset |
| Eletriptan | Relpax | 40 or 80 mg at onset |
| Zolmitriptan | Zomig | 2.5-mg tablet at onset |
| Zomig Rapimelt | ||
| Nasal | ||
| Dihydroergotamine | Migranal Nasal Spray Trudhesa Nasal Spray |
Prior to nasal spray, the pump must be primed 4 times; 1 spray (0.5 mg) is administered, followed in 15 min by a second spray One spray into each nostril |
| Sumatriptan | Imitrex Nasal Spray | 5–20 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg spray |
| Zolmitriptan | Zomig | 5 mg intranasal spray as one spray |
| Parenteral | ||
| Dihydroergotamine | DHE-45 | 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week) |
| Sumatriptan | Imitrex Injection Alsuma Sumavel DosePro |
3, 4, or 6 mg SC at onset (may repeat once after 1 h for max of 2 doses in 24 h) |
| CGRP Receptor Antagonists—Gepants | ||
| Oral Rimegepant Ubrogepant Nasal Zavegepant |
Nurtec Ubrelvy Zavzpret |
75 mg ODT PO 50 or 100 mg PO; a second dose may be taken 2 h after the first, if needed 10 mg intranasal, single spray to one nostril once in 24 h |
| 5-HT Receptor Agonist—Ditans 1F Oral Lasmiditan |
Reyvow | 50, 100, or 200 mg PO |
| Dopamine Receptor Antagonists | ||
| Reglan,a generica Compazine,a generica Generica Reglan,a generic Compazine,a generica |
||
| Other | ||
| Parenteral | ||
| Opioids Other Neuromodulation Single-pulse transcranial magnetic stimulation (sTMS) Noninvasive vagus nerve stimulation (nVNS) Remote electrical neuromodulation (REN) Transcutaneous supraorbital nerve stimulation External concurrent occipital and trigeminal neurostimulation (eCOT-NS) |
Generica Savi Dual gammaCore Nerivio Cefaly Relivion |
Multiple preparations and dosages; see Table 14-1 Two pulses at onset followed by two further pulses Two doses each of 120 s 30- to 45-min stimulation to the upper arm 60-min stimulation 30- to 60-min stimulation |
TABLE 441-5 Clinical Stratification of Acute Specific Migraine Treatments¶
Harrison's 22e, p.3468
| CLINICAL SITUATION | TREATMENT OPTIONS |
|---|---|
| Failed NSAIDs/ analgesics |
First tier |
| Sumatriptan 50 mg or 100 mg PO | |
| Almotriptan 12.5 mg PO | |
| Rizatriptan 10 mg PO | |
| Eletriptan 40 mg PO | |
| Zolmitriptan 2.5 mg PO Rimegepant 75 mg Ubrogepant 50 or 100 mg Lasmiditan 50, 100, or 200 mg |
|
| Slower effect/better tolerability | |
| Naratriptan 2.5 mg PO | |
| Frovatriptan 2.5 mg PO | |
| Infrequent headache | |
| Ergotamine/caffeine 1–2/100 mg PO | |
| Dihydroergotamine nasal spray 2 mg | |
| Headache recurrence | Ergotamine 2 mg (most effective PR/usually with caffeine) |
| Naratriptan 2.5 mg PO | |
| Almotriptan 12.5 mg PO | |
| Eletriptan 40 mg Rimegepant 75 mg Ubrogepant 50 or 100 mg |
|
| Early vomiting | Zolmitriptan 5 mg nasal spray Zavegepant 10 mg nasal spray |
| Sumatriptan 25 mg PR | |
| Sumatriptan 6 mg SC | |
| Very rapidly developing symptoms |
Zolmitriptan 5 mg nasal spray Zavegepant 10 mg nasal spray Sumatriptan 6 mg SC |
| Dihydroergotamine 1 mg IM |
TABLE 441-6 Preventive Treatments in Migraine a DRUG Beta blocker¶
Harrison's 22e, p.3470
| DRUG | DOSE | SELECTED SIDE EFFECTS |
|---|---|---|
| Beta blocker Propranolol Metoprolol |
40–120 mg bid 25–100 mg bid |
Reduced energy Tiredness Postural symptoms Contraindicated in asthma |
| 10–75 mg at night 25–75 mg at night 25–75 mg at night 75–150 mg/d |
||
| Anticonvulsants | ||
| Topiramate | 25–200 mg/d | Paresthesias |
| Cognitive symptoms | ||
| Weight loss | ||
| Glaucoma | ||
| Caution with nephrolithiasis | ||
| Valproate | 400–600 mg bid | Drowsiness |
| Weight gain | ||
| Tremor | ||
| Hair loss | ||
| Fetal abnormalities | ||
| Hematologic or liver abnormalities | ||
| 0.5–2 mg qd | ||
| CGRP pathway blockers Eptinezumab Erenumab Fremanezumab Galcanezumab |
100 or 300 mg IV every 12 weeks 70 or 140 mg SC monthly 225 mg monthly or 675 mg q3 months, SC 240 mg loading then 120 mg monthly, SC |
Nasopharyngitis Nasopharyngitis, constipation Injection site reactions Nasopharyngitis |
| Rimegepant Atogepant |
75 mg every other day 10, 30, or 60 mg once daily |
Nausea abdominal pain/dyspepsia Constipation, nausea |
| 5–15 mg qd 4–24 mg daily 5–20 mg daily 3–12 mg nightly |
||
| Neuromodulation Single-pulse transcranial magnetic stimulation (sTMS) Noninvasive vagus nerve stimulation (nVNS) Remote electrical neuromodulation (REN) Transcutaneous supraorbital nerve stimulation |
4–24 pulses per day 120-s treatments 2–3 times daily 45 min every other day 20 min daily |
Lightheadedness Tingling Tinnitus Site discomfort, irritation or pain Muscle twitching Well-tolerated; some local sensory symptoms Local paresthesia |
| 155 U |
TABLE 441-7 Clinical Features of the Trigeminal Autonomic Cephalalgias Gender Pain¶
Harrison's 22e, p.3471
| CLUSTER HEADACHE | PAROXYSMAL HEMICRANIA | SUNCT/SUNA | |
|---|---|---|---|
| Gender | M > F | F = M | F ~ M |
| Stabbing, boring Excruciating Orbit, temple |
Throbbing, boring, stabbing Excruciating Orbit, temple |
||
| Attack frequency | 1/alternate day–8/d | 1–20/d (>5/d for more than half the time) | 3–200/d |
| 15–180 min | 2–30 min | ||
| Autonomic features | Yes | Yes | Yes (prominent conjunctival injection and lacrimation)a |
| Yes | Yes | ||
| Alcohol trigger | Yes | No | No |
| No | No | ||
| Indomethacin effect | — | Yesc | — |
| Sumatriptan injection or nasal spray Zolmitriptan nasal spray Oxygen nVNSc |
No effective treatment | ||
| Preventive treatment | Verapamil Galcanezumab |
Indomethacind nVNS |
Lamotrigine |
| Topiramate Melatonin |
Topiramate | ||
| Lithium | Gabapentin |
TABLE 441-8 Preventive Management of Cluster Headache¶
Harrison's 22e, p.3472
| SHORT-TERM PREVENTION | LONG-TERM PREVENTION |
|---|---|
| EPISODIC CLUSTER HEADACHE | EPISODIC CLUSTER HEADACHE AND PROLONGED CHRONIC CLUSTER HEADACHE |
| Prednisone 1 mg/kg up to 60 mg qd, tapering over 21 days Verapamil 160–960 mg/d Galcanezumab 300 mg SC Greater occipital nerve injection (local anesthetic and corticosteroids) |
Verapamil 160–960 mg/d nVNS 6–24 stimulations/d Melatonina 9–12 mg/d Topiramatea 100–400 mg/d Lithium 400–800 mg/d |