Place · Level 3 · Condition
Migraine
CGRP 现代模型 · 不只是头痛· 三剑客 B2 / Mg / CoQ10 + 现代单抗 · 触发因素 + 急救分层
Story path
Chapter 1
Migraine · not just a headache
Migraine · not just a headache
Migraine is the world's second leading cause of disability (GBD 2019), yet it is routinely underestimated or misdiagnosed as "tension headache" / "just tired" / "poor sleep."
Epidemiology:
Global prevalence 14-15% (women 17% / men 8%)China ~ 9% (~ 130 million patients)Disability: ranks 2nd in global years lived with disability (YLDs), behind only low-back painHighly heritable: if one parent has migraine, child's risk ≈ 50%; both parents, ≈ 75%
ICHD-3 criteria (migraine without aura, MO):
5+ attacksLasting 4-72 hours untreatedAt least 2 of: unilateral / pulsating / moderate-to-severe / aggravated by routine activityAt least 1 of: nausea / vomiting / photophobia + phonophobiaNot better explained by another disorder
Migraine with aura (MA) = the above + visual / sensory / speech aura (zigzag lights / hemianopia / numbness / aphasia) lasting 5-60 minutes
Migraine mimics (must be excluded):
Tension-type headache (TTH): bilateral / pressing / mild-to-moderate / no nauseaCluster headache: male predominance + unilateral orbital + excruciating + lacrimation / rhinorrhea / ipsilateral pupil changeSecondary: intracranial tumor / pressure changes / temporal arteritis / subarachnoid hemorrhage (thunderclap headache — emergency)
Red flags (immediate care):
"This is the worst headache of my life" (subarachnoid hemorrhage)Thunderclap (peaks in seconds-minutes)With fever + neck stiffness (meningitis)Progressive worsening (days / weeks)New-onset headache + 50+ y/o (rule out temporal arteritis)Persistent neurological signs (weakness / diplopia / speech / consciousness)Pregnancy + new severe headache
Common misconceptions (this island aims to break):
"Just push through it" → wrong: early treatment works best; the longer you delay, the harder to abort"Men don't get migraines" → wrong, 8% of men have it"Children don't get migraines" → wrong, 7-8% of children, often presents as "abdominal pain""Migraine = just being tired" → wrong, it is a distinct neurological disorder with a genetic basis"The more painkillers the better" → wrong, medication-overuse headache (MOH) is a common worsening pathway
Economic cost:
Annual workday loss + healthcare cost in China is on the order of 100 billion CNYPatients face long-term care barriers: scarce neurology appointments + cumbersome diagnosis / titrationThis island's promise: a complete pathway, not "just endure it"
Epidemiology:
Global prevalence 14-15% (women 17% / men 8%)China ~ 9% (~ 130 million patients)Disability: ranks 2nd in global years lived with disability (YLDs), behind only low-back painHighly heritable: if one parent has migraine, child's risk ≈ 50%; both parents, ≈ 75%
ICHD-3 criteria (migraine without aura, MO):
5+ attacksLasting 4-72 hours untreatedAt least 2 of: unilateral / pulsating / moderate-to-severe / aggravated by routine activityAt least 1 of: nausea / vomiting / photophobia + phonophobiaNot better explained by another disorder
Migraine with aura (MA) = the above + visual / sensory / speech aura (zigzag lights / hemianopia / numbness / aphasia) lasting 5-60 minutes
Migraine mimics (must be excluded):
Tension-type headache (TTH): bilateral / pressing / mild-to-moderate / no nauseaCluster headache: male predominance + unilateral orbital + excruciating + lacrimation / rhinorrhea / ipsilateral pupil changeSecondary: intracranial tumor / pressure changes / temporal arteritis / subarachnoid hemorrhage (thunderclap headache — emergency)
Red flags (immediate care):
"This is the worst headache of my life" (subarachnoid hemorrhage)Thunderclap (peaks in seconds-minutes)With fever + neck stiffness (meningitis)Progressive worsening (days / weeks)New-onset headache + 50+ y/o (rule out temporal arteritis)Persistent neurological signs (weakness / diplopia / speech / consciousness)Pregnancy + new severe headache
Common misconceptions (this island aims to break):
"Just push through it" → wrong: early treatment works best; the longer you delay, the harder to abort"Men don't get migraines" → wrong, 8% of men have it"Children don't get migraines" → wrong, 7-8% of children, often presents as "abdominal pain""Migraine = just being tired" → wrong, it is a distinct neurological disorder with a genetic basis"The more painkillers the better" → wrong, medication-overuse headache (MOH) is a common worsening pathway
Economic cost:
Annual workday loss + healthcare cost in China is on the order of 100 billion CNYPatients face long-term care barriers: scarce neurology appointments + cumbersome diagnosis / titrationThis island's promise: a complete pathway, not "just endure it"
Chapter 2
CGRP modern model
CGRP modern model
The biggest shift in migraine understanding (2010s-2020s): from the "vascular theory" to a "neurovascular + CGRP-dominant" model.
Old (vascular) model (1940s-1990s):
"Aura = cerebral vasoconstriction; headache = rebound vasodilation"Later evidence refuted this — blood-flow changes are a consequence, not the cause
Modern neurovascular + CGRP model:
Step 1: Cortical spreading depression (CSD):
A depolarisation wave in neurons and glia propagating at 3-5 mm/minThis is the neural basis of aura (zigzag lights correspond to visual-cortex CSD)Trigger activation: stress / hormonal swings / sleep deprivation / food / bright light
Step 2: Trigeminal-vascular activation:
CSD → activates trigeminal sensory fibers innervating the meningesThese fibers release CGRP (calcitonin gene-related peptide) + Substance P + neurokinin ACGRP is one of the most potent vasodilators known + drives neurogenic inflammation
Step 3: Pain transmission + central sensitisation:
CGRP → meningeal vasodilation + mast-cell degranulation + neurogenic inflammationTrigeminal nucleus → thalamus → cortex → pain perceptionLong-term recurrence → central sensitisation: lower thresholds → "trivial triggers cause attacks"
Why CGRP is revolutionary:
Experimentally infused CGRP can induce migraine attacksPlasma CGRP is markedly elevated during attacksSince 2018, anti-CGRP monoclonal antibodies (erenumab / fremanezumab / galcanezumab / eptinezumab) entered the clinic — the first class of mechanism-targeted migraine preventionFollowed by Gepants (oral small-molecule CGRP receptor antagonists, rimegepant / ubrogepant) — dual acute + prophylactic indication
Connections to other systems:
Hormonal / menstrual migraine: estrogen drop (premenstrual) → altered 5-HT receptor sensitivity + ↑ CGRP expressionFood triggers: some contain vasoactive amines (tyramine, phenylethylamine) or metabolic by-productsSleep + stress: hypothalamic–pituitary–adrenal axis: The body's stress-response chain (hypothalamus → pituitary → adrenal) that releases cortisol. activation → lowered trigger threshold5-HT system: some preventives (β-blockers, TCAs, certain antiepileptics) act on 5-HT pathways
This is why the classic nutritional interventions (B2, Mg, CoQ10) work:
Improving mitochondrial function → adequate adenosine triphosphate: The cell's universal energy currency — almost everything that costs energy spends it. in cerebral neurons → raises CSD threshold → fewer attacksDetailed in the next scene
Old (vascular) model (1940s-1990s):
"Aura = cerebral vasoconstriction; headache = rebound vasodilation"Later evidence refuted this — blood-flow changes are a consequence, not the cause
Modern neurovascular + CGRP model:
Step 1: Cortical spreading depression (CSD):
A depolarisation wave in neurons and glia propagating at 3-5 mm/minThis is the neural basis of aura (zigzag lights correspond to visual-cortex CSD)Trigger activation: stress / hormonal swings / sleep deprivation / food / bright light
Step 2: Trigeminal-vascular activation:
CSD → activates trigeminal sensory fibers innervating the meningesThese fibers release CGRP (calcitonin gene-related peptide) + Substance P + neurokinin ACGRP is one of the most potent vasodilators known + drives neurogenic inflammation
Step 3: Pain transmission + central sensitisation:
CGRP → meningeal vasodilation + mast-cell degranulation + neurogenic inflammationTrigeminal nucleus → thalamus → cortex → pain perceptionLong-term recurrence → central sensitisation: lower thresholds → "trivial triggers cause attacks"
Why CGRP is revolutionary:
Experimentally infused CGRP can induce migraine attacksPlasma CGRP is markedly elevated during attacksSince 2018, anti-CGRP monoclonal antibodies (erenumab / fremanezumab / galcanezumab / eptinezumab) entered the clinic — the first class of mechanism-targeted migraine preventionFollowed by Gepants (oral small-molecule CGRP receptor antagonists, rimegepant / ubrogepant) — dual acute + prophylactic indication
Connections to other systems:
Hormonal / menstrual migraine: estrogen drop (premenstrual) → altered 5-HT receptor sensitivity + ↑ CGRP expressionFood triggers: some contain vasoactive amines (tyramine, phenylethylamine) or metabolic by-productsSleep + stress: hypothalamic–pituitary–adrenal axis: The body's stress-response chain (hypothalamus → pituitary → adrenal) that releases cortisol. activation → lowered trigger threshold5-HT system: some preventives (β-blockers, TCAs, certain antiepileptics) act on 5-HT pathways
This is why the classic nutritional interventions (B2, Mg, CoQ10) work:
Improving mitochondrial function → adequate adenosine triphosphate: The cell's universal energy currency — almost everything that costs energy spends it. in cerebral neurons → raises CSD threshold → fewer attacksDetailed in the next scene
4 mAbs head-to-head + RCT
Since 2018, four anti-CGRP monoclonal antibodies have launched in sequence — the most recent example on the atlas of a "mechanism → drug" 30-year closure.Head-to-head comparison:
| Drug | Brand | Target | Form + frequency | US annual price | China launch |
|---|---|---|---|---|---|
| Erenumab | Aimovig | CGRP receptor | 70-140 mg SC / month | $7,000 | 2023 (Amgen) |
| Fremanezumab | Ajovy | CGRP ligand | 225 mg monthly or 675 mg quarterly | $7,000 | 2024 |
| Galcanezumab | Emgality | CGRP ligand | 120 mg / month + 240 mg loading | $7,000 | pending |
| Eptinezumab | Vyepti | CGRP ligand | 100-300 mg IV / quarter | $14,000 | pending |
Key differences:
Target: erenumab targets the receptor; the other three target the ligand (CGRP itself)Theory: ligand mAbs leave CGRP free to use the calcitonin receptor (a related pathway); receptor mAbs fully blockIn practice: clinical efficacy is similar across all four; no clear head-to-head winnerForm: erenumab/frem/galca are self-injected SC (like an insulin pen); eptinezumab requires in-clinic IV
RCT endpoints (approximate):
Reduction in monthly migraine days (MMD): -1.5 to -2.5 days/month vs placebo across all four50% responder rate: ~ 50-60% vs placebo ~ 30-40%30% responder rate: ~ 70%Refractory migraine (3 drugs failed): still ~ 30-40% responseSide effects: injection-site reactions / constipation (erenumab) / rare hypersensitivity
vs traditional preventives:
Efficacy comparable to topiramate / amitriptyline, but faster onset (1-3 months vs 3-6) + very few side effects + once-monthly improves adherenceDownsides: expensive + long-term (10+ years) data still accumulating
Indications (general principles):
Failure of 2-3 traditional preventives (adequate dose + ≥ 3 months)Disabling migraine (MIDAS Grade III-IV)Chronic migraine (≥ 15 days/month headache, ≥ 8 migraine days, ≥ 3 months)
Gepants + China access + future
Oral Gepants for prevention (since 2021):Rimegepant (Nurtec ODT): 75 mg every other day — dual acute + prophylactic indicationAtogepant (Qulipta): 10-60 mg/day, prophylactic-onlySlightly weaker than mAbs but oral + cheaperAdvantage: occasional acute + long-term prevention with the same drug (rimegepant)
China access (2024-2025 reality):
Erenumab (Anshining): launched 2023, ¥3,000-5,000/month, partial provincial reimbursement for some doses since 2024The other three: in regulatory reviewGepants: accessible via the Boao Lecheng pilot zoneBarriers: price + reimbursement + low clinician familiarity + strict indication approval
Practice:
Refractory / chronic migraine + ability to pay: discuss with neurology + headache specialistFirst confirm: trio (B2/Mg/CoQ10) + 2-3 traditional preventives + rule out MOH + lifestyle — only then consider mAbNot "first-line", but "third-line" — though for the truly refractory it is life-changingPregnancy / breastfeeding: data lacking, avoid for now
Future (2025+):
Anti-PACAP (Lu AG09222, Pituitary Adenylate Cyclase-Activating Polypeptide) — different neuropeptide pathway, similar mechanismCGRP + PACAP dual-target: theoretically synergistic, awaiting Phase IIIGenotype-guided therapy: which patient responds to which drug (not yet clinical)
Chapter 3
Trio · B2 / Mg / CoQ10
Trio · B2 / Mg / CoQ10
The "nutritional trio" for migraine prevention — one of the atlas's most systematic nutrition-neuropsychiatry stories:
① Riboflavin (vitamin B2) 400 mg/day:
Schoenen 1998 Neurology RCT (N = 55):400 mg/day × 3 months vs placeboMigraine frequency ↓ 56% vs ↓ 19% (p = 0.005)NNT = 3 (1 benefits per 3 treated)Mechanism: B2 → FAD → mitochondrial Complex II (atlas riboflavin-b2/flavins L4)Safety: very high (yellow urine, harmless)AHS / EHF guidelines: Level B evidence
② Magnesium 400-600 mg/day (elemental):
Peikert 1996 + Mauskop 2012 + Holland 2012 (AAN guideline):Multiple RCTs show Mg reduces migraine frequencyLevel B evidence (AAN migraine prevention guideline)Migraine patients have significantly lower plasma + RBC + brain Mg than non-patientsMechanism: NMDA receptor blockade (atlas magnesium/relax L4) + suppresses CSD + smooth-muscle relaxation + 5-HT modulationForms: Mg glycinate / citrate (well-absorbed); Mg oxide (cheap but laxative); Mg threonate (crosses blood–brain barrier: The 'security gate' on brain vessels that blocks most substances in blood from entering the brain., but expensive)Side effects: diarrhea at high dose; caution in CKD
③ Coenzyme Q10 100-300 mg/day:
Sándor 2005 Neurology RCT (N = 42): 100 mg × 3/day × 3 monthsFrequency ↓ 47% vs placebo ↓ 14%Severity also reducedSlater 2011 pediatric RCT replicated thisAHS / EHF Level B evidenceMechanism: cofactor for mitochondrial electron-transport chain (Complex I-III)The 2024 Hazen erythritol controversy (atlas sweeteners) does not affect CoQ10 recommendations — different metabolic pathwayForms: ubiquinone (oxidised, standard) vs ubiquinol (reduced, some studies show better absorption); the latter is more expensive
Combined trio:
Some headache specialists routinely prescribe B2 + Mg + CoQ10 together — individual variation is large, but at least one works for most patientsVery safe + moderate cost + should be mentioned in every migraine-prevention discussion
Why the atlas emphasises these three:
They are among the few nutritional interventions with real RCT evidenceCompared with prescription drugs, safer + cheaper + no adherence problemsNo conflicts with prescription preventivesEspecially suitable for: those unwilling to take prescription drugs / pregnancy planners (B2 + Mg are standard in pregnancy) / side-effect-sensitive patients
"Slow onset" warning:
The trio takes 2-3 months to show effect — not immediateDon't quit after 2 weeks of "feeling no effect"Keep a headache diary (frequency + severity + medications) in parallel for objective assessment
Other nutritional interventions (weak-to-moderate evidence):
Feverfew: some positive studies, Level B-CButterbur: Level B, but some products contain hepatotoxic pyrrolizidine alkaloids — only PA-free preparationsOmega-3: weak evidence, anti-inflammatoryVitamin D: signal in the deficient; weak evidence for universal supplementation5-HTP: interactions with SSRIs / prescription migraine drugs, use cautiously
① Riboflavin (vitamin B2) 400 mg/day:
Schoenen 1998 Neurology RCT (N = 55):400 mg/day × 3 months vs placeboMigraine frequency ↓ 56% vs ↓ 19% (p = 0.005)NNT = 3 (1 benefits per 3 treated)Mechanism: B2 → FAD → mitochondrial Complex II (atlas riboflavin-b2/flavins L4)Safety: very high (yellow urine, harmless)AHS / EHF guidelines: Level B evidence
② Magnesium 400-600 mg/day (elemental):
Peikert 1996 + Mauskop 2012 + Holland 2012 (AAN guideline):Multiple RCTs show Mg reduces migraine frequencyLevel B evidence (AAN migraine prevention guideline)Migraine patients have significantly lower plasma + RBC + brain Mg than non-patientsMechanism: NMDA receptor blockade (atlas magnesium/relax L4) + suppresses CSD + smooth-muscle relaxation + 5-HT modulationForms: Mg glycinate / citrate (well-absorbed); Mg oxide (cheap but laxative); Mg threonate (crosses blood–brain barrier: The 'security gate' on brain vessels that blocks most substances in blood from entering the brain., but expensive)Side effects: diarrhea at high dose; caution in CKD
③ Coenzyme Q10 100-300 mg/day:
Sándor 2005 Neurology RCT (N = 42): 100 mg × 3/day × 3 monthsFrequency ↓ 47% vs placebo ↓ 14%Severity also reducedSlater 2011 pediatric RCT replicated thisAHS / EHF Level B evidenceMechanism: cofactor for mitochondrial electron-transport chain (Complex I-III)The 2024 Hazen erythritol controversy (atlas sweeteners) does not affect CoQ10 recommendations — different metabolic pathwayForms: ubiquinone (oxidised, standard) vs ubiquinol (reduced, some studies show better absorption); the latter is more expensive
Combined trio:
Some headache specialists routinely prescribe B2 + Mg + CoQ10 together — individual variation is large, but at least one works for most patientsVery safe + moderate cost + should be mentioned in every migraine-prevention discussion
Why the atlas emphasises these three:
They are among the few nutritional interventions with real RCT evidenceCompared with prescription drugs, safer + cheaper + no adherence problemsNo conflicts with prescription preventivesEspecially suitable for: those unwilling to take prescription drugs / pregnancy planners (B2 + Mg are standard in pregnancy) / side-effect-sensitive patients
"Slow onset" warning:
The trio takes 2-3 months to show effect — not immediateDon't quit after 2 weeks of "feeling no effect"Keep a headache diary (frequency + severity + medications) in parallel for objective assessment
Other nutritional interventions (weak-to-moderate evidence):
Feverfew: some positive studies, Level B-CButterbur: Level B, but some products contain hepatotoxic pyrrolizidine alkaloids — only PA-free preparationsOmega-3: weak evidence, anti-inflammatoryVitamin D: signal in the deficient; weak evidence for universal supplementation5-HTP: interactions with SSRIs / prescription migraine drugs, use cautiously
Chapter 4
Triggers + meds
Triggers + meds
Migraine triggers (highly individual — use a headache diary to find your own):
Hormonal: premenstrual (premenstrual / menstrual migraine) / ovulation / perimenopauseSleep: too little + too much + irregular + jet lag + shift workStress + post-stress relaxation ("weekend headache": work-week tension → weekend release → attack)Food:Tyramine: aged cheese (Cheddar / Parmesan) / red wine / cured meatPhenylethylamine: chocolate (but often misattributed — really a prodromal sugar craving)MSG: rarely triggers; most people are fineNitrites: ham / sausageAlcohol: red wine / brandy are major triggers (tyramine + histamine + direct vascular effect)Caffeine withdrawal: heavy weekday + skipping on weekends → attackFasting + skipped meals + hypoglycemiaArtificial sweeteners (aspartame triggers in some, see atlas sweeteners)Environment: bright / flickering light / noise / strong smells (perfume / smoke / paint)Weather: pressure changes / heat / wind / seasonal transitionsHormonal medications: estrogen-containing contraceptives (in migraine-with-aura patients, stroke risk — switch to progestin-only)
Acute treatment (use early):
Mild-to-moderate:
NSAID: ibuprofen 600-800 mg / naproxen 500-1000 mg / diclofenacCombination: aspirin + acetaminophen + caffeine (Excedrin Migraine)
Moderate-to-severe (classic drugs):
Triptans: sumatriptan / zolmitriptan / rizatriptan / naratriptan / eletriptanSelective 5-HT1B/1D agonistsEarly use beats late use — take at aura onset, don't wait for full headacheSide effects: chest tightness / neck stiffness / contraindicated in cardiovascular diseaseMonthly total-dose limit (to avoid rebound)
New acute drugs (2020s):
Gepants (rimegepant 75 mg, ubrogepant 50-100 mg): CGRP receptor antagonists, good cardiovascular safetyDitans (lasmiditan 50-200 mg): 5-HT1F agonists, no vasoconstriction — suited to coronary disease history
The next page covers preventives (classic β-blocker / tricarboxylic acid (Krebs) cycle: The mitochondrial hub cycle that fully oxidizes fuel and harvests electrons for energy. / antiepileptic + breakthrough anti-CGRP mAbs), the medication-overuse headache (MOH) warning, and the special presentation of pediatric migraine.
Hormonal: premenstrual (premenstrual / menstrual migraine) / ovulation / perimenopauseSleep: too little + too much + irregular + jet lag + shift workStress + post-stress relaxation ("weekend headache": work-week tension → weekend release → attack)Food:Tyramine: aged cheese (Cheddar / Parmesan) / red wine / cured meatPhenylethylamine: chocolate (but often misattributed — really a prodromal sugar craving)MSG: rarely triggers; most people are fineNitrites: ham / sausageAlcohol: red wine / brandy are major triggers (tyramine + histamine + direct vascular effect)Caffeine withdrawal: heavy weekday + skipping on weekends → attackFasting + skipped meals + hypoglycemiaArtificial sweeteners (aspartame triggers in some, see atlas sweeteners)Environment: bright / flickering light / noise / strong smells (perfume / smoke / paint)Weather: pressure changes / heat / wind / seasonal transitionsHormonal medications: estrogen-containing contraceptives (in migraine-with-aura patients, stroke risk — switch to progestin-only)
Acute treatment (use early):
Mild-to-moderate:
NSAID: ibuprofen 600-800 mg / naproxen 500-1000 mg / diclofenacCombination: aspirin + acetaminophen + caffeine (Excedrin Migraine)
Moderate-to-severe (classic drugs):
Triptans: sumatriptan / zolmitriptan / rizatriptan / naratriptan / eletriptanSelective 5-HT1B/1D agonistsEarly use beats late use — take at aura onset, don't wait for full headacheSide effects: chest tightness / neck stiffness / contraindicated in cardiovascular diseaseMonthly total-dose limit (to avoid rebound)
New acute drugs (2020s):
Gepants (rimegepant 75 mg, ubrogepant 50-100 mg): CGRP receptor antagonists, good cardiovascular safetyDitans (lasmiditan 50-200 mg): 5-HT1F agonists, no vasoconstriction — suited to coronary disease history
The next page covers preventives (classic β-blocker / tricarboxylic acid (Krebs) cycle: The mitochondrial hub cycle that fully oxidizes fuel and harvests electrons for energy. / antiepileptic + breakthrough anti-CGRP mAbs), the medication-overuse headache (MOH) warning, and the special presentation of pediatric migraine.
Preventives + MOH + pediatric
Preventives (frequency ≥ 4/month or severely disabling):Classic (Level B-A):
β-blockers: propranolol 80-240 mg / metoprololtricarboxylic acid (Krebs) cycle: The mitochondrial hub cycle that fully oxidizes fuel and harvests electrons for energy.: amitriptyline 25-100 mg (lower than depression doses)Antiepileptics: topiramate 25-100 mg / valproateCCB: flunarizine (commonly used in China)ARB: candesartan 16 mg (recent evidence)
New drugs (breakthrough, since 2018):
Anti-CGRP mAbs (monthly or quarterly injection):Erenumab (Aimovig) / Fremanezumab (Ajovy) / Galcanezumab (Emgality) / Eptinezumab (Vyepti)50-70% response in refractory migraineExcellent safety profileLaunched in China since 2023, price still high (¥3000-5000/month), partial reimbursementOral gepants for prevention: rimegepant (75 mg every other day) / atogepant (10-60 mg/day)
Most important warning: medication-overuse headache (MOH):
Acute medication ≥ 10-15 days/month for 3 months → worsening headache + a "rebound" cycleSolution: discontinue overused medication (under professional guidance) + start a preventive"The more I take, the less it works, the more I want it" → immediate red flag
Pediatric migraine:
May present as abdominal pain (cyclical vomiting syndrome / abdominal migraine)Treatment similar to adults but with conservative drug choice (avoid long-acting triptans; cautious low-dose amitriptyline)Trio + CBT has good pediatric evidence
Menstrual migraine · E2 withdrawal
Menstrual migraine (MM) is the most common female-reproductive-age subtype, with a management logic completely different from ordinary attacks.Two subtypes (ICHD-3):
Pure menstrual migraine (PMM): attacks only in the menstrual window (2 days before through day 3), never otherwise — rare (~ 7%)Menstrually-related migraine (MRM): attacks during the menstrual window plus other times — common (~ 50% of female migraine)
Mechanism:
Estrogen (E2) withdrawal = main driver (confirmed by Somerville 1972 classic study)Late-cycle E2 ↓ → ↑ 5-HT receptor sensitivity + ↑ CGRP expression + Mg-related changes → migraine threshold fallsOvulatory E2 peak can also trigger (mechanism may be "E2 fluctuation" rather than "absolute level")
Clinical features:
More severe + longer (~ 72 h vs 24-48 h) + harder to stop with NSAIDs + higher recurrenceAura is rare (classic-aura patients trigger less during menses — possibly E2-receptor heterogeneity)
Short-term prevention (start 2 days before menstruation × 5-7 days):
NSAID: naproxen 550 mg × 2/day (classic)Naratriptan 1-2.5 mg × 2/day (long-acting triptan, t½ 6 h)Zolmitriptan 2.5 mg × 2-3/dayFrovatriptan 2.5 mg × 2/day — FDA-approved for menstrual migraine preventionMg 600 mg/day from 2 weeks before menstruation through to end — some positive studies
Hormonal strategy:
Continuous low-dose estradiol patch (0.1 mg) from 7 days before menstruation through period — keeps E2 stable, avoids withdrawalExtended-cycle contraception (e.g., 84 active + 7 inactive days): reduces frequencyAvoid estrogen-containing oral contraceptives (COCs) in migraine-with-aura patients — stroke risk ↑ 8-fold
Red flag: aura + E2-containing COC:
WHO + ACOG: migraine with aura + smoking + COC = stroke risk ↑ 30+ foldSwitch to: progestin-only or copper IUD or LNG-IUD
Pregnancy + postpartum · safe meds
Pregnancy migraineEpidemiology:
Most migraine sufferers improve during pregnancy (60-70%) — stably high estrogenA minority worsen or develop new-onset migraineFirst few weeks postpartum: relapse — rapid E2 drop
Safe acute medications (FDA pregnancy Category B + clinical judgment):
First-line:
Acetaminophen (Tylenol) 500-1000 mg — safe, though high-dose long-term use in late pregnancy has controversial associations with childhood ADHD/autismIce + dark room + rest non-pharmacologicAdequate hydration + no skipping meals
Use with caution:
NSAID: occasional short use in the 2nd trimester (14-30 weeks) is acceptable; contraindicated in late pregnancy (30+ weeks) (premature ductus arteriosus closure)Triptans: subcutaneous sumatriptan 6 mg as a single rescue has the most data (~ 4000 exposures, no clear malformation / prematurity signal)Metoclopramide for nausea + headache: short-term OK
Contraindicated:
Ergots: strictly contraindicated (uterine contraction + placental ischemia)Valproate: neural-tube defects + developmental impact — avoid generally in women of childbearing ageTopiramate: cleft-lip/palate risk ↑ — avoid in pregnancy
Prevention (pregnancy):
B2 400 mg/day: safe, recommendedMg 400 mg/day: safe, recommendedCoQ10: limited data, discuss with obstetricsβ-blocker (propranolol): can be continued in pregnancy, but slightly elevated risk of fetal growth restriction in late pregnancyAnti-CGRP mAbs / Gepants: insufficient data, not recommended
Postpartum:
Migraines often worsen in the first 1-2 weeks postpartum (E2 plunge + sleep deprivation)Breastfeeding: sumatriptan is relatively safe (minimal milk excretion)CGRP mAbs not recommended during lactationPostpartum depression + migraine: common comorbidity, manage in parallel
Atlas connections: perimenopause (E2 withdrawal + worsening migraines around menopause) + menstrual-cycle (the cycle + hormones in full) + reproductive (pregnancy & postpartum) + hormonal contraceptive choice.
Chapter 5
Decision tree
Decision tree
"I have frequent headaches" — action pathway:
Step 1 · Headache diary (4 weeks):
Date / time / duration / severity (0-10) / location / characterMenstrual cycleSleep / stress / diet / weatherWhat medication / how muchTools: apps (Migraine Buddy / 头痛通、妈妈帮) or a simple spreadsheet
Step 2 · Is it migraine?
Check against ICHD-3 (above)"Unilateral + pulsating + moderate-to-severe + nausea / vomiting / photo-phonophobia" = highly suggestiveSee neurology / headache specialist for diagnosis
Step 3 · Stratify acute treatment:
< 4 attacks/month: acute medication only (NSAID or triptan)≥ 4 attacks/month or severely disabling: add a preventiveAny month with ≥ 10 days of acute medication × 3 months: suspect MOH, reassess
The next page covers Step 4 prevention (lifestyle + nutritional trio + prescription ladder), Step 5 menstrual-migraine specifics, Step 6 long-term psychological adjustment, plus red flags + debunked misconceptions + atlas cross-links.
Step 1 · Headache diary (4 weeks):
Date / time / duration / severity (0-10) / location / characterMenstrual cycleSleep / stress / diet / weatherWhat medication / how muchTools: apps (Migraine Buddy / 头痛通、妈妈帮) or a simple spreadsheet
Step 2 · Is it migraine?
Check against ICHD-3 (above)"Unilateral + pulsating + moderate-to-severe + nausea / vomiting / photo-phonophobia" = highly suggestiveSee neurology / headache specialist for diagnosis
Step 3 · Stratify acute treatment:
< 4 attacks/month: acute medication only (NSAID or triptan)≥ 4 attacks/month or severely disabling: add a preventiveAny month with ≥ 10 days of acute medication × 3 months: suspect MOH, reassess
The next page covers Step 4 prevention (lifestyle + nutritional trio + prescription ladder), Step 5 menstrual-migraine specifics, Step 6 long-term psychological adjustment, plus red flags + debunked misconceptions + atlas cross-links.
Steps 4-6 + red flags + connections
Step 4 · Choosing a prevention plan:Lifestyle first:
Regular sleep (7-9 h, consistent timing including weekends)No skipped meals (hypoglycemia is a common trigger)Adequate hydrationExercise: 150 min/week moderate aerobic (sudden intense exercise can trigger)Limit alcohol + cut red wine (high tyramine)Stress management: mindfulness / CBT / yogaEnvironment: avoid bright light / strong smells / personal triggers
Nutritional trio (Level B evidence):
B2 400 mg/day (one pill, safe and cheap)Mg 400-600 mg elemental (Mg glycinate recommended)CoQ10 100-300 mg/dayTrial for 3 months (slow onset — don't give up early)
Prescription prevention (with a neurologist):
First-line: propranolol / topiramate / amitriptyline (by comorbidity)Second-line: valproate / flunarizine / ARBThird-line (refractory): anti-CGRP mAb / gepant prevention
Step 5 · Special handling for menstrual migraine:
Short-course NSAID (naproxen 500 × 2/day) or naratriptan starting 2 days pre-menstrualEstrogen-containing contraceptives (in aura patients, strictly contraindicated due to stroke risk) → switch to progestin-only / IUD
Step 6 · Long-term psychological adjustment:
Migraine is a chronic disease, not a "willpower" problemAccept + plan + optimise is more sustainable than "fighting"Find your personal trigger pattern + avoid + treat early
Red flags (immediate care):
Worst of lifeThunderclapFever + neck stiffnessProgressive worseningNew-onset + 50+ y/oPersistent neurological symptoms
Common misconceptions (debunked on the atlas):
"Endure without medication": wrong, early treatment works best"Migraine = just tired": wrong, it is a neurological disorder"Men and women are the same": wrong, women have 2× rates, estrogen-linked"Children don't get migraine": wrong, often presents as abdominal pain"All headaches are migraine": wrong, distinguish tension / cluster / secondary"More painkillers = better": wrong, MOH is a real problem
Atlas connections:
riboflavin-b2/flavins L4 (B2 mechanism)magnesium/atp + relax L4 (Mg mechanism)niacin-b3/nad + alpha-lipoic-acid (mitochondrial cofactors collectively)hashimoto + perimenopause + insomnia (comorbidities / triggers)sleep-apnea + shift-work-circadian (sleep drivers)alcohol-metabolism + UPF + sweeteners (dietary triggers)
Atlas position: migraine is not just "a headache" — it is a treatable disorder with a genetic and neurobiological basis. Trio + prescription + lifestyle + modern mAbs — most patients improve substantially over 6-12 months. If you or someone in your family has lived with migraine without systematic care, the atlas hopes you will revisit it.