Headache Pharmacology
Headache Pharmacology
What Do You Need to Know?
- CGRP pathway: released from trigeminal ganglion → meningeal vasodilation + neurogenic inflammation; 4 anti-CGRP mAbs plus 4 gepants are FDA-approved across acute and/or preventive migraine indications: ubrogepant, rimegepant, atogepant, and zavegepant
- Triptans: 5-HT1B/1D agonists — contraindicated in CAD, uncontrolled HTN, hemiplegic migraine / migraine with brainstem aura, stroke history; sumatriptan SC has fastest onset (~10 min)
- Gepants: CGRP receptor antagonists — non-vasoconstrictive option when triptans are contraindicated by CAD, stroke, PVD, or hemiplegic/brainstem aura migraine; do NOT describe as risk-free in uncontrolled HTN (monitor for new/worsening hypertension and Raynaud phenomenon per labeling); can be used acutely AND preventively; rimegepant is dual-approved
- Ditans: 5-HT1F agonist (lasmiditan) — no vasoconstriction, Schedule V controlled substance, 8-hour driving restriction
- Verapamil: first-line preventive for cluster headache — must monitor ECG with every dose increase (risk of PR prolongation and heart block)
- Indomethacin: diagnostic AND therapeutic for paroxysmal hemicrania, hemicrania continua, primary cough HA, and primary stabbing HA
- Pregnancy: ergots absolutely contraindicated (uterotonic); valproate and topiramate are teratogenic; acetaminophen is safest acute option
🚩 Don’t Miss — Test-Day Priorities
- Triptan contraindications: CAD, uncontrolled HTN, hemiplegic migraine / migraine with brainstem aura, recent stroke, PVD; ergot within 24 hr; MAOI within 14 d
- Sumatriptan SC 6 mg → fastest onset (~10 min) — first-line acute pharmacologic for BOTH migraine and cluster headache
- Rizatriptan + propranolol → reduce rizatriptan to 5 mg max (propranolol ↑ AUC ~70%); classic interaction question
- Frovatriptan T½ 26 hr → longest half-life triptan; perimenstrual prophylaxis (start 2 days before menses)
- Lasmiditan (ditan) → 5-HT1F agonist, NO vasoconstriction, Schedule V, mandatory 8-hour driving restriction
- Erenumab = only CGRP mAb targeting the receptor; the other 3 (fremanezumab, galcanezumab, eptinezumab) target the ligand
- Rimegepant = only gepant approved for BOTH acute (75 mg PRN) AND preventive (75 mg every-other-day)
- Galcanezumab = only CGRP mAb FDA-approved for episodic cluster headache (300 mg SC monthly)
- OnabotulinumtoxinA (PREEMPT): chronic migraine ONLY; 155–195 U across 31–39 sites in 7 muscle groups q12wk; NOT for episodic
- Verapamil for cluster prophylaxis (240–960 mg/d) → ECG before initiation and with every dose increase (PR prolongation, AV block)
- Pregnancy avoid: ergots (uterotonic — absolute), valproate (NTDs), topiramate (oral clefts); avoid NSAIDs at ≥20 wk gestation unless specifically indicated and supervised (oligohydramnios), especially at ≥30 wk (ductus closure); acetaminophen +/- metoclopramide is the usual first-line acute approach
- MOH thresholds: triptans/ergots/opioids/butalbital ≥10 d/mo; simple analgesics/NSAIDs ≥15 d/mo — AVOID opioids + butalbital for headache
🔍 Buzzwords & Pathognomonic FindingsMechanism · Adverse effects · Use / pregnancy
Mechanism of action
- Triptans → 5-HT1B/1D agonists — cranial vasoconstriction + inhibition of trigeminal CGRP/substance P release
- Ditans (lasmiditan) → selective 5-HT1F agonist — central pain modulation, NO vasoconstriction
- Gepants (ubrogepant, rimegepant, atogepant, zavegepant) → CGRP receptor antagonists (small molecule)
- Erenumab → mAb against the CGRP receptor (CLR/RAMP1 complex)
- Fremanezumab / galcanezumab / eptinezumab → mAbs against the CGRP ligand
- DHE / ergotamine → non-selective 5-HT1B/1D + multi-receptor (also α-adrenergic, dopaminergic)
- Topiramate → Na+ channel + GABA enhancement + AMPA/kainate inhibition + carbonic anhydrase inhibition
- Valproate → Na+ channel + GABA + glutamate modulation
- Amitriptyline → 5-HT / NE reuptake inhibition (+ anticholinergic, antihistaminic)
- Onabotulinumtoxin-A → cleaves SNAP-25 → blocks acetylcholine + peripheral CGRP release
Adverse effects / contraindications
- Chest tightness / paresthesias / dizziness → triptans (also avoid in CAD, uncontrolled HTN, hemiplegic migraine / migraine with brainstem aura)
- “Dopamax” cognitive slowing + word-finding difficulty + kidney stones + paresthesias + oligohidrosis + metabolic acidosis → topiramate
- Weight gain + tremor + alopecia + thrombocytopenia + hyperammonemia + hepatotoxicity → valproate
- Constipation + injection-site reaction + HTN → erenumab
- Sedation + dry mouth + urinary retention + QT prolongation + weight gain → amitriptyline (avoid in elderly)
- Acute dystonia / akathisia → metoclopramide, prochlorperazine (pre-treat with diphenhydramine)
- PR prolongation / AV block / bradycardia → verapamil — ECG with every dose increase
- Narrow therapeutic window + renal + thyroid monitoring → lithium (cluster: 0.4–0.8 mEq/L)
- Medication overuse headache + bounce-back / tolerance / dependence → opioids + butalbital (avoid)
- Mandatory 8-hour driving restriction + sedation → lasmiditan (Schedule V)
Use / pregnancy / pearls
- Fastest acute migraine + cluster abortive → sumatriptan SC 6 mg (~10 min onset)
- Menstrual migraine perimenstrual mini-prophylaxis → frovatriptan (longest T½ 26 hr; alt: naratriptan)
- Status migrainosus IV protocol → DHE (Raskin) + metoclopramide pre-treatment
- Non-vasoconstrictive acute migraine option when triptans are contraindicated (CAD, prior stroke, PVD, hemiplegic/brainstem aura migraine) → gepants or ditans; monitor for new/worsening HTN and Raynaud phenomenon per labeling — not risk-free in uncontrolled HTN
- Dual acute + preventive oral agent → rimegepant (75 mg PRN or every-other-day)
- Episodic cluster headache CGRP option → galcanezumab 300 mg SC monthly (only mAb with cluster FDA indication)
- Chronic migraine PREEMPT → onabotulinumtoxin-A q12wk (NOT for episodic)
- Cluster prophylaxis first-line → verapamil; bridge with brief prednisone taper ± GON block; lithium for chronic cluster
- Pregnancy first-line acute → acetaminophen + metoclopramide (magnesium also safe; GON block safe)
- Pregnancy absolute contraindication → ergotamine / DHE (uterotonic → uterine contractions / fetal distress)
- Pregnancy acceptable preventives → propranolol + amitriptyline (monitor neonatal β-blockade syndrome at delivery)
- CGRP mAbs + conception → discontinue ≥5 half-lives (~5 months) before planned pregnancy
CGRP Pathway & Mechanism
Calcitonin Gene-Related Peptide (CGRP)
- CGRP = 37-amino-acid neuropeptide; most potent endogenous vasodilator known
- α-CGRP — predominant in trigeminal ganglion and central nervous system (relevant to headache)
- β-CGRP — predominant in enteric nervous system
- Trigeminovascular activation → CGRP released from trigeminal ganglion → meningeal vasodilation, mast cell degranulation, plasma protein extravasation, neurogenic inflammation
- CGRP receptor: heterodimer of CLR (calcitonin receptor-like receptor) + RAMP1 (receptor activity-modifying protein 1)
- IV CGRP infusion triggers migraine-like attacks in susceptible individuals — proof-of-concept for CGRP as migraine mediator
💎 Board Pearl
- CGRP levels are elevated in jugular venous blood during migraine attacks and normalize with successful triptan treatment — this finding validated the CGRP pathway as a therapeutic target
- The CGRP receptor requires both CLR and RAMP1 for function — erenumab targets this receptor complex; the other 3 mAbs target the CGRP ligand itself
Acute Migraine Treatment — Master Table
Comprehensive Acute Treatment Overview
Stratified care (match treatment to attack severity) is superior to step care. Treat within 60 minutes of onset for best efficacy.
| Drug Class | Agent | Mechanism | Dose | Onset | Key Features | Contraindications |
|---|---|---|---|---|---|---|
| Triptans | Sumatriptan SC | 5-HT1B/1D agonist | 6 mg SC | ~10 min | Fastest onset of all triptans; widest formulations (SC, nasal, oral, patch) | CAD, uncontrolled HTN, hemiplegic migraine, migraine with brainstem aura, stroke, PVD, pregnancy (relative) |
| Sumatriptan nasal | 20 mg | ~15 min | Good for nausea/vomiting; bitter taste | |||
| Sumatriptan oral | 50–100 mg | ~30 min | Most commonly prescribed form | |||
| Zolmitriptan | 2.5–5 mg PO/nasal | ~15 min (nasal) | Nasal form effective for cluster HA; also available as ODT | |||
| Rizatriptan | 5–10 mg ODT | ~30 min | Fastest-onset oral triptan; reduce dose to 5 mg with propranolol | |||
| Eletriptan | 40–80 mg | ~30 min | Highest oral efficacy; CYP3A4 substrate — avoid with strong CYP3A4 inhibitors | |||
| Naratriptan | 2.5 mg | ~60 min | Gentle onset, fewer side effects; long T½ | |||
| Triptans (cont.) | Frovatriptan | 5-HT1B/1D agonist | 2.5 mg | ~60 min | Longest T½ (26 h) — best for menstrual migraine prophylaxis | Same as above |
| Almotriptan | 5-HT1B/1D agonist | 12.5 mg | ~30 min | Fewest side effects; best tolerability profile | Same as above | |
| Gepants | Ubrogepant (Ubrelvy) | CGRP receptor antagonist | 50–100 mg | ~60 min | Acute only; may repeat ×1 after ≥2 h; CYP3A4 substrate | No vasoconstrictive contraindication, but monitor for new/worsening HTN and Raynaud phenomenon per labeling; avoid strong CYP3A4 inhibitors |
| Rimegepant (Nurtec) | 75 mg ODT | ~60 min | Dual-approved: acute (75 mg PRN) + preventive (75 mg EOD) | |||
| Ditans | Lasmiditan (Reyvow) | 5-HT1F agonist | 50, 100, or 200 mg PO; max 1 dose per 24 h (do NOT repeat) | ~60 min | NO vasoconstriction; Schedule V — no driving for at least 8 hours after each dose; sedation, dizziness | No vasoconstriction, but monitor per labeling; caution with CNS depressants |
| NSAIDs | Ketorolac IV/IM | COX inhibition | 30–60 mg IV/IM | ~15–30 min | ER workhorse; no sedation; short course only | Renal disease, GI bleeding; avoid NSAIDs at ≥20 weeks gestation unless specifically indicated and supervised (FDA 2020), especially at ≥30 weeks (ductus closure) |
| Naproxen | 500–750 mg | ~30–60 min | Long-acting; good with triptan (SumaRT combination) | |||
| Ibuprofen | 400–800 mg | ~30 min | First-line for mild–moderate attacks | |||
| Ergots | DHE IV/nasal | 5-HT1B/1D + multi-receptor | DHE 0.5–1 mg IV q8h (status migrainosus, Raskin protocol); nasal Migranal 2 mg total per attack (1 spray each nostril, repeat in 15 min); nasal Trudhesa 1.45 mg | ~15–30 min (IV) | Status migrainosus (repetitive IV protocol); low headache recurrence | CAD, HTN, pregnancy, CYP3A4 inhibitors; separate triptan and ergot by ≥24 h (in either direction) |
| Anti-emetics | Metoclopramide | D2 antagonist | 10–20 mg IV | ~15 min | Prokinetic; enhances oral drug absorption; also effective as monotherapy | Dystonia, akathisia (pre-treat with diphenhydramine); QT risk with chlorpromazine |
| Prochlorperazine | 10 mg IV | ~15 min | Highly effective ER monotherapy for migraine; evidence rivals triptans | |||
| Chlorpromazine | 12.5–25 mg IV | ~15 min | Potent; risk of hypotension — give with IV fluids | |||
| Corticosteroid | Dexamethasone | Anti-inflammatory | 10 mg IV | Hours | Prevents headache recurrence (NNT ~6); does NOT abort the acute attack itself | Hyperglycemia; not for repeated use |
💎 Board Pearl
- Triptans are contraindicated in hemiplegic migraine and migraine with brainstem aura due to theoretical vasoconstriction risk — gepants and ditans are non-vasoconstrictive alternatives
- Dexamethasone in the ER prevents headache recurrence but does NOT abort the acute migraine — always give an abortive agent alongside
Status Migrainosus Management
- Definition: >72 h debilitating migraine
- IV fluids
- IV ketorolac
- IV metoclopramide or prochlorperazine + diphenhydramine (pretreat for dystonia/akathisia)
- IV magnesium 1–2 g
- IV dexamethasone 10–20 mg
- DHE Raskin protocol (0.5–1 mg IV q8h)
Triptans Deep Dive
Mechanism of Action
- 5-HT1B: vasoconstriction of meningeal arteries (the reason for cardiovascular contraindications)
- 5-HT1D: inhibits trigeminal neuropeptide release (CGRP, substance P) from peripheral and central terminals
- 5-HT1F: central pain-modulating effects (no vasoconstriction; the selective target of lasmiditan)
- Cannot combine with MAOIs (sumatriptan, rizatriptan, zolmitriptan are substrates of MAO-A) or DHE (24 h washout)
- Serotonin syndrome: FDA warning (2006) re: triptan + SSRI/SNRI; AAN/AHS 2010 position — actual risk very low, do not routinely withhold triptans
- MAO-A substrate distinction: Sumatriptan, rizatriptan, zolmitriptan ARE MAO-A substrates. Naratriptan, eletriptan, frovatriptan, almotriptan are NOT MAO-A substrates (safer with MAOIs/linezolid)
Triptan Comparison Table
| Triptan | Routes | T½ | Distinguishing Feature |
|---|---|---|---|
| Sumatriptan | SC, nasal, oral, patch | ~2 h | SC fastest onset (10 min); most formulations available; most pregnancy data |
| Zolmitriptan | Oral, ODT, nasal | ~3 h | Nasal onset ~15 min; effective for cluster headache (nasal form) |
| Rizatriptan | Oral, ODT | ~2–3 h | Fastest-onset oral triptan; propranolol increases rizatriptan AUC ~70% — reduce rizatriptan to 5 mg max, no more than 15 mg/24h, and separate by 2 hours |
| Eletriptan | Oral | ~4 h | Highest oral efficacy; CYP3A4 substrate — contraindicated with strong CYP3A4 inhibitors |
| Naratriptan | Oral | ~6 h | Gentle onset, fewer side effects; good for patients with triptan-related nausea; long T½ |
| Frovatriptan | Oral | ~26 h | Longest T½ of all triptans — best for menstrual migraine prophylaxis (perimenstrual dosing) |
| Almotriptan | Oral | ~3 h | Fewest side effects; best overall tolerability; FDA-approved for adolescents |
💎 Board Pearl
- Rizatriptan dose must be reduced to 5 mg when taken with propranolol — propranolol increases rizatriptan AUC ~70% (reduce to 5 mg max, no more than 15 mg/24h, separate doses by 2 hours)
- Frovatriptan has the longest half-life (26 h) of all triptans — use it for short-term perimenstrual prophylaxis (start 2 days before expected menses)
CGRP-Targeted Therapies
Monoclonal Antibodies (Preventive)
| Drug | Brand | Target | Dose & Route | Frequency | Key Distinction |
|---|---|---|---|---|---|
| Erenumab | Aimovig | CGRP receptor | 70–140 mg SC | Monthly | Only mAb targeting the receptor; side effects include constipation and HTN |
| Fremanezumab | Ajovy | CGRP ligand | 225 mg SC (monthly) or 675 mg SC (quarterly) | Monthly or quarterly | Quarterly dosing option (only SC mAb with this convenience) |
| Galcanezumab | Emgality | CGRP ligand | 240 mg loading → 120 mg SC monthly | Monthly | Also FDA-approved for episodic cluster headache (only CGRP mAb with cluster indication) |
| Eptinezumab | Vyepti | CGRP ligand | 100 or 300 mg IV q3 months | Quarterly | Only IV CGRP mAb; fastest onset of preventive effect (can work within days of first infusion) |
Gepants (Small Molecules)
| Drug | Brand | Indication | Dose | Key Features |
|---|---|---|---|---|
| Ubrogepant | Ubrelvy | Acute only | 50–100 mg; may repeat ×1 after ≥2 h | CYP3A4 substrate; dose adjustment with moderate CYP3A4 inhibitors; avoid strong inhibitors |
| Rimegepant | Nurtec ODT | Acute + Preventive | 75 mg PRN (acute) or 75 mg every other day (preventive) | Only gepant with dual approval; orally disintegrating tablet |
| Atogepant | Qulipta | Preventive only | 10–60 mg daily | Only oral daily preventive gepant; dose adjustment with CYP3A4 inhibitors/inducers |
| Zavegepant | Zavzpret | Acute migraine | Intranasal 10 mg | FDA-approved 2023; only intranasal gepant; onset within 15–30 min |
💎 Board Pearl
- Erenumab is the only mAb targeting the CGRP receptor; the other 3 (fremanezumab, galcanezumab, eptinezumab) target the CGRP ligand
- Rimegepant is the only gepant approved for BOTH acute and preventive use
- Galcanezumab is the only CGRP mAb with an FDA indication for episodic cluster headache (300 mg SC monthly)
Clinical Pearl
- Gepants are non-vasoconstrictive and are used when triptans are contraindicated by CAD, prior stroke, PVD, or hemiplegic/brainstem aura migraine — do NOT describe as risk-free in uncontrolled HTN; monitor for new/worsening hypertension and Raynaud phenomenon per labeling
- CGRP mAbs have minimal drug interactions (no CYP metabolism) and no hepatotoxicity monitoring — major advantage over oral preventives
- All CGRP mAbs have long half-lives (~28 days for SC; ~27 days for IV) — effects persist weeks after discontinuation
Preventive Medications — Master Table
Oral & Injectable Preventives
| Drug | Class | Dose Range | Key Side Effects | Evidence | Special Notes |
|---|---|---|---|---|---|
| Propranolol | Beta-blocker | 40–240 mg/day | Fatigue, bradycardia, depression, exercise intolerance | Level A | FDA-approved for migraine prevention; also treats essential tremor; avoid in asthma; check rizatriptan interaction |
| Timolol | Beta-blocker | 10–30 mg/day | Fatigue, bradycardia, depression, exercise intolerance | Level A | FDA-approved for migraine prevention |
| Metoprolol | Beta-blocker | 50–200 mg/day | Fatigue, bradycardia, depression, exercise intolerance | Level A | NOT FDA-approved for migraine prevention (off-label, Level A evidence) |
| Topiramate | Anticonvulsant | 50–200 mg/day | Weight loss, kidney stones, paresthesias, cognitive slowing, metabolic acidosis | Level A | Teratogen (cleft palate); also used for IIH; “Dopamax” = cognitive slowing / word-finding difficulty |
| Valproate | Anticonvulsant | 500–1500 mg/day | Weight gain, tremor, alopecia, hepatotoxicity, thrombocytopenia, pancreatitis | Level A | Major teratogen (NTDs, cognitive impairment); FDA contraindicated for migraine prevention in pregnancy (2013 boxed warning); avoid in women of childbearing potential without highly effective contraception (FDA replaced letter categories with PLLR in 2015) |
| Amitriptyline | TCA | 10–75 mg at bedtime | Sedation, weight gain, dry mouth, constipation, QT prolongation | Level B | Good for comorbid insomnia or tension-type HA overlap; avoid in elderly (anticholinergic) |
| Venlafaxine | SNRI | 150 mg/day | Nausea, HTN at high doses, discontinuation syndrome | Level B | Good for comorbid depression/anxiety |
| Candesartan | ARB | 16 mg/day | Hypotension, hyperkalemia | Level B | Well tolerated; option when beta-blockers contraindicated; teratogenic |
OnabotulinumtoxinA (Botox) — PREEMPT Protocol
- Indication: chronic migraine ONLY (≥15 headache days/month for ≥3 months, with ≥8 migraine features)
- Dose: minimum 155 units per session
- Injection sites: 31 fixed sites across 7 muscle groups — corrugator, procerus, frontalis, temporalis, occipitalis, cervical paraspinals, trapezius
- Frequency: every 12 weeks
- Optional “follow-the-pain” protocol allows up to 195 units across 39 sites (additional doses to temporalis, occipitalis, trapezius, cervical paraspinals)
- NOT indicated for episodic migraine or tension-type headache
- Side effects: injection site pain, neck weakness, ptosis
💎 Board Pearl
- Topiramate + valproate = both Level A evidence for migraine prevention, but both are teratogenic — avoid in women of childbearing age without reliable contraception
- OnabotulinumtoxinA is approved ONLY for chronic migraine — the PREEMPT protocol uses 31 fixed sites across 7 muscle groups every 12 weeks; it is NOT for episodic migraine
Cluster Headache Pharmacology
Acute Treatment
| Treatment | Dose / Route | Efficacy | Notes |
|---|---|---|---|
| High-flow O2 | 100% at 12–15 L/min via NRB mask, 15–20 min | ~78% at 15 min | First-line; no side effects; carry portable O2 unit |
| Sumatriptan SC | 6 mg subcutaneous | ~75% at 15 min | First-line pharmacologic; fastest onset among triptans |
| Zolmitriptan nasal | 5 mg intranasal | ~60% at 30 min | Alternative when SC sumatriptan not tolerated |
Transitional (Bridge) Therapy
- Prednisone: 60–80 mg/day, taper over 2–3 weeks — rapid relief while awaiting preventive onset
- Greater occipital nerve (GON) block: local anesthetic (lidocaine/bupivacaine) ± corticosteroid — provides days to weeks of relief
Preventive Treatment
| Drug | Dose | Type | Key Monitoring & Notes |
|---|---|---|---|
| Verapamil | 240–960 mg/day (divided) | First-line | ECG mandatory with each dose increase — risk of PR prolongation, AV block, bradycardia |
| Lithium | 600–1200 mg/day | Second-line (especially chronic cluster) | Monitor serum levels (0.4–0.8 mEq/L for cluster — lower than psychiatric target of 0.6–1.0), renal function, thyroid; narrow therapeutic window |
| Galcanezumab | 300 mg SC monthly (administered as 3 consecutive 100-mg SC injections; continue monthly while bout is active) | FDA-approved for episodic cluster | Only CGRP mAb with a cluster headache indication |
💎 Board Pearl
- Verapamil can cause heart block at high doses — ECG is mandatory before initiation AND with each dose increase; some patients require doses up to 960 mg/day
- Oral triptans are too slow for cluster attacks (15–180 min duration) — always use SC sumatriptan or intranasal zolmitriptan
Indomethacin-Responsive Headaches
Conditions with Absolute Indomethacin Response
| Headache | Key Features | Indomethacin Response |
|---|---|---|
| Paroxysmal hemicrania (PH) | Short attacks (2–30 min), severe unilateral, autonomic features, ≥5/day | Absolute — diagnostic criterion (ICHD-3) |
| Hemicrania continua (HC) | Continuous unilateral headache with autonomic features and migrainous exacerbations | Absolute — diagnostic criterion (ICHD-3) |
| Primary cough headache | Bilateral, seconds–minutes, triggered by cough/Valsalva (rule out Chiari first) | Excellent response |
| Primary stabbing headache | Ultrashort jabs (1–3 seconds), periorbital “ice-pick” pains | Good response |
| Primary exercise headache | Bilateral, pulsating, brought on by exertion (rule out SAH) | Variable response (some patients) |
Dosing & Practical Points
- Start: 25 mg TID, increase to 50–75 mg TID
- Response: usually within 1–2 days (often dramatic and complete)
- Always co-prescribe a PPI (omeprazole, pantoprazole) for GI protection
- Long-term use limited by GI, renal, and cardiovascular side effects
- If indomethacin is not tolerated: consider celecoxib (partial response in some), topiramate, or melatonin (hemicrania continua)
💎 Board Pearl
- “Indomethacin-responsive headache” on boards = think paroxysmal hemicrania or hemicrania continua
- PH mimics cluster headache but has shorter attacks, higher daily frequency, and absolute indomethacin response — cluster does NOT respond to indomethacin
Pregnancy & Headache Safety
Drug Safety in Pregnancy
| Category | Drug | Notes |
|---|---|---|
| Safe | Acetaminophen | First-line acute analgesic in pregnancy |
| Metoclopramide | Anti-emetic; also effective for migraine; safe across all trimesters | |
| Nerve blocks (lidocaine) | GON block safe; no systemic absorption concerns | |
| Magnesium | Oral (preventive) or IV (acute); also used for eclampsia | |
| Probably Safe | NSAIDs (1st–2nd trimester) | FDA 2020: avoid NSAIDs from 20 weeks (oligohydramnios) and especially from 30 weeks (premature ductus closure) |
| Prednisone (short course) | Brief courses acceptable; minimal fetal risk; avoid prolonged use (cleft palate risk in 1st trimester) | |
| Limited Data | Triptans | Sumatriptan has the most pregnancy data (registry: no major signal); not formally recommended |
| Propranolol | Can be used but monitor for fetal bradycardia, IUGR, neonatal hypoglycemia; neonatal beta-blockade syndrome at delivery (hypotension, hypoglycemia, respiratory depression) | |
| Avoid / Contraindicated | Ergotamine / DHE | Absolutely contraindicated — potent uterotonic → uterine contractions, fetal distress |
| Valproate | NTDs, reduced IQ, autism risk; FDA contraindicated for migraine prevention in pregnancy (2013 boxed warning); avoid in women of childbearing potential without highly effective contraception (FDA replaced letter categories with PLLR in 2015) | |
| Topiramate | Oral clefts (cleft lip/palate); 2–3× background risk | |
| CGRP mAbs | Insufficient human data; discontinue ≥5 half-lives before planned conception (~5 months) |
💎 Board Pearl
- Ergotamine is absolutely contraindicated in pregnancy — it is a potent uterotonic agent that causes uterine contractions and can precipitate miscarriage/fetal distress
- NSAIDs in pregnancy: FDA 2020 — avoid from 20 weeks (oligohydramnios) and especially from 30 weeks (premature ductus arteriosus closure)
Medication Overuse Headache (MOH)
ICHD-3 Overuse Thresholds
| Medication | Overuse Threshold |
|---|---|
| Triptans | ≥10 days/month |
| Ergotamine | ≥10 days/month |
| Opioids | ≥10 days/month |
| Combination analgesics (butalbital) | ≥10 days/month |
| Simple analgesics / NSAIDs | ≥15 days/month |
Management Strategy
- Withdraw the overused medication — abrupt (triptans, NSAIDs) or tapered (opioids, butalbital)
- Bridge therapy: naproxen, short prednisone taper, DHE IV protocol, or GON blocks
- Start preventive therapy simultaneously — CGRP mAbs and topiramate have the best evidence in MOH
- Withdrawal headache worsens for 2–10 days then improves — counsel patients
- Opioid and butalbital overuse have highest relapse rates
💎 Board Pearl
- Triptans, opioids, and combination analgesics cause MOH at ≥10 days/month; simple analgesics at ≥15 days/month
- Butalbital-containing compounds are particularly prone to MOH and dependence — avoid prescribing butalbital for headache
References
- Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78(17):1337-1345.
- Dodick DW, Turkel CC, DeGryse RE, et al. OnabotulinumtoxinA for chronic migraine: PREEMPT pooled results. Headache. 2010;50(6):921-936.
- Ashina M, Goadsby PJ, Reuter U, et al. Long-term efficacy and safety of erenumab in migraine prevention (STRIVE/ARISE). N Engl J Med. 2017;377(22):2123-2132.
- Goadsby PJ, Dodick DW, Leone M, et al. Galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141.
- Headache Classification Committee of the IHS. ICHD-3. Cephalalgia. 2018;38(1):1-211.
- Diener HC, Dodick D, Evers S, et al. Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol. 2019;18(9):891-902.
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