Headache Pharmacology
Headache Pharmacology
What Do You Need to Know?
- Acute migraine agents: triptans (5-HT1B/1D), gepants (CGRP antagonists), ditans (5-HT1F), DHE, and their contraindications
- Preventive migraine therapies: beta-blockers, topiramate, valproate, amitriptyline, CGRP monoclonal antibodies, onabotulinumtoxinA
- Indications for starting preventive therapy (≥4 migraine days/month, significant disability, medication overuse)
- Medication overuse headache thresholds and management (triptans >10 d/mo, analgesics >15 d/mo)
- Cluster headache acute (high-flow O2, sumatriptan SC) and preventive (verapamil, lithium) treatments
- Trigeminal neuralgia pharmacology: carbamazepine first-line, oxcarbazepine, surgical options
- Indomethacin-responsive headache syndromes (hemicrania continua, paroxysmal hemicrania, primary cough/exertional)
🚩 Don’t Miss — Test-Day Priorities
- Triptans (5HT1B/1D agonists): CONTRAINDICATED in CAD, uncontrolled HTN, hemiplegic migraine, basilar migraine, recent stroke/TIA, peripheral vascular disease, vasospastic angina, pregnancy (relative); SC sumatriptan is the fastest-onset triptan and the go-to for cluster headache; 24h gap required from DHE.
- Gepants (CGRP-receptor antagonists — ubrogepant, rimegepant, zavegepant, atogepant): NO vasoconstriction and no triptan-like CAD/stroke contraindication → useful when triptans are contraindicated; rimegepant and atogepant double as preventives; no serotonin syndrome risk. Use clinical caution in active/unstable vascular disease — pivotal trials often excluded unstable CV disease; long-term high-risk safety data remain limited.
- Ditans (lasmiditan, 5HT1F agonist): NO vasoconstriction and no triptan-like CAD/stroke contraindication; Schedule V; mandatory 8-hour driving restriction after each dose due to sedation/dizziness. Use clinical caution in active/unstable vascular disease (limited data).
- DHE and ergots: Non-selective ergot for status migrainosus (IV protocol); CONTRAINDICATED with triptans (24h gap), in pregnancy, CAD, uncontrolled HTN, and with CYP3A4 inhibitors. AVOID opioids and butalbital — high medication-overuse-headache (MOH) risk and inferior efficacy.
- ED/status migrainosus — MENU of options (not all-at-once): dopamine-antagonist antiemetic (metoclopramide or prochlorperazine; pretreat with diphenhydramine for akathisia/dystonia), NSAID (IV ketorolac), IV fluids when needed, IV magnesium in selected patients (aura/menstrual), IV valproate in selected non-pregnant patients (avoid in pregnancy and significant hepatic disease), DHE protocols, occipital nerve block. Antiemetics are effective MONOTHERAPY for acute migraine in the ER.
- Oral preventives: Propranolol/metoprolol (β-blockers); topiramate → cognitive slowing, kidney stones, weight loss, cleft lip/palate (AVOID in pregnancy); valproate → teratogen (neural tube defects, AVOID in pregnancy); amitriptyline (covers tension-type + migraine, anticholinergic + cardiac conduction risk); venlafaxine and nortriptyline as alternatives; candesartan (ARB); memantine off-label for chronic migraine.
- CGRP-targeting preventives (erenumab, fremanezumab, galcanezumab, eptinezumab; oral atogepant/rimegepant): FIRST-LINE options for migraine prevention per AHS 2024 position statement — do not require failure of oral preventives as a biologic rule (though insurance step therapy may lag). Erenumab → constipation and possible HTN; use caution in Raynaud’s; AVOID in pregnancy. OnabotulinumtoxinA (PREEMPT protocol, 155–195 U q12 weeks) is approved ONLY for CHRONIC migraine (≥15 headache days/month).
- Cluster headache: Acute = 100% O2 + SC sumatriptan; prophylaxis = verapamil HIGH-DOSE (baseline + serial ECGs for PR prolongation/AV block), galcanezumab (episodic cluster), GON block as bridge, lithium for chronic cluster.
- MOH (medication overuse headache): Triptans/ergots/opioids/combination analgesics >10 days/month OR simple analgesics >15 days/month for >3 months → management = withdraw offender, bridge therapy, start preventive.
- Pregnancy & pediatrics: Pregnancy acute migraine → acetaminophen ± metoclopramide first; sumatriptan may be considered with caution when needed (best pregnancy safety data among triptans); AVOID ergots, valproate, topiramate. Pediatric prevention = amitriptyline or topiramate (CHAMP trial — both not superior to placebo, but still used). AVOID serotonergic combos (triptan + MAOI; caution with SSRI/SNRI — serotonin syndrome risk small but recognized).
🔍 Buzzwords & Pathognomonic FindingsMechanism · Adverse effects · Use / pregnancy
Mechanism
- Triptans (sumatriptan, rizatriptan, eletriptan) → 5-HT1B/1D agonists → cranial vasoconstriction + inhibit trigeminal nociceptive transmission
- Gepants (ubrogepant, rimegepant, atogepant, zavegepant) → small-molecule CGRP RECEPTOR antagonists
- Ditans (lasmiditan) → selective 5-HT1F agonist — NO 5-HT1B activity → NO vasoconstriction
- CGRP mAbs (erenumab, fremanezumab, galcanezumab, eptinezumab) → monoclonal antibodies vs CGRP ligand (all except erenumab) or CGRP receptor (erenumab)
- DHE / ergots → non-selective 5-HT1B/1D + alpha-adrenergic + dopaminergic agonist
- OnabotulinumtoxinA (PREEMPT) → blocks SNAP-25 → inhibits release of acetylcholine and CGRP from peripheral trigeminal nociceptors
- Topiramate → Na+ channel block, AMPA/kainate antagonism, GABA potentiation, carbonic anhydrase inhibition
- Valproate → ↑ GABA, Na+ channel block, T-type Ca²+ inhibition
- Verapamil → non-dihydropyridine L-type Ca²+ channel blocker — cluster prophylaxis of choice
- Antiemetics (metoclopramide, prochlorperazine) → D2 dopamine receptor antagonists
Adverse effects / contraindications
- CAD, uncontrolled HTN, hemiplegic/basilar migraine, recent stroke → triptans and DHE CONTRAINDICATED (use gepant or ditan)
- Cognitive slowing + kidney stones + weight loss + metabolic acidosis + cleft lip/palate + oligohidrosis → topiramate
- Teratogen — neural tube defects, ↓ IQ, hepatotoxicity, pancreatitis, hyperammonemia, thrombocytopenia → valproate (AVOID in pregnancy)
- Anticholinergic effects + QT prolongation + orthostasis + weight gain → amitriptyline / TCAs
- Constipation + injection-site reaction + possible HTN + Raynaud’s caution → erenumab (CGRP-R mAb)
- Sedation, dizziness, 8-hour driving ban, Schedule V → lasmiditan (ditan)
- PR prolongation / AV block — ECG-monitored uptitration → high-dose verapamil (cluster)
- Tremor, polyuria, polydipsia, hypothyroidism, nephrogenic DI, narrow therapeutic index → lithium (chronic cluster)
- Akathisia and acute dystonia in ER → metoclopramide / prochlorperazine (pretreat with diphenhydramine)
- Serotonin syndrome (clonus, hyperreflexia, autonomic instability) → triptan or DHE + MAOI; caution with SSRI/SNRI
- Neck/jaw/chest tightness (“triptan sensations”) → triptans — usually benign
- MOH from butalbital, opioids, combination analgesics → AVOID in routine acute treatment
Use / pregnancy / pearls
- Fastest-onset triptan / cluster headache acute therapy → SC sumatriptan (with 100% O2)
- Longest-half-life triptan — menstrual migraine mini-prophylaxis → frovatriptan
- Acute migraine when triptans are contraindicated (CAD, recent stroke, etc.) → gepant or lasmiditan (no vasoconstriction, no triptan-like CV contraindication; still use caution in active/unstable vascular disease)
- Status migrainosus / ED — MENU (not all-at-once): dopamine-antagonist antiemetic (+ diphenhydramine), NSAID (ketorolac), IV fluids, magnesium (selected), IV valproate (selected non-pregnant; avoid in hepatic disease), DHE protocols, occipital nerve block
- Chronic migraine (≥15 headache days/month) prevention → onabotulinumtoxinA PREEMPT 155–195 U q12 weeks (NOT episodic)
- Cluster prophylaxis → high-dose verapamil (ECG monitoring), galcanezumab (episodic), GON block as bridge, lithium for chronic
- Acute migraine in pregnancy → acetaminophen ± metoclopramide first; sumatriptan may be considered with caution when needed (best pregnancy safety data); AVOID ergots, valproate, topiramate; NSAIDs avoid in 3rd trimester
- Migraine prevention in pregnancy → non-pharm first; if needed — propranolol or amitriptyline (lowest risk)
- Oral preventive that is also acute (dual-use gepant) → rimegepant (q-other-day prevention) and atogepant (daily prevention)
- MOH thresholds → triptans/ergots/opioids/combos >10 d/mo; simple analgesics >15 d/mo
- Pediatric migraine prevention → amitriptyline or topiramate (CHAMP trial — placebo non-inferior, but still used)
- CYP450 interactions → valproate inhibits glucuronidation (↑ lamotrigine); topiramate induces OCP metabolism; rizatriptan dose ↓ with propranolol
Acute Migraine Treatment
Goal: abort the attack early. Treat within 60 minutes of onset for best efficacy. Stratified care (match treatment to attack severity) is superior to step care.
| Drug Class | Mechanism | Key Agents | Board-Relevant Pearls |
|---|---|---|---|
| Triptans | 5-HT1B/1D agonists → cranial vasoconstriction + inhibit trigeminal nociceptive transmission | Sumatriptan (PO, SC, nasal), rizatriptan, eletriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan | Contraindicated: CAD, uncontrolled HTN, hemiplegic migraine, basilar migraine, prior stroke/TIA, peripheral vascular disease, vasospastic/Prinzmetal angina, pregnancy (relative). Cannot combine with DHE (24h gap). Rizatriptan dose ↓ with propranolol. Frovatriptan has longest half-life — useful for menstrual migraine. Triptan + SSRI/SNRI: FDA 2006 warning of serotonin syndrome; real-world incidence very low; AHS 2010 position found insufficient evidence to limit co-prescribing |
| Gepants | CGRP receptor antagonists (small molecules) | Ubrogepant, rimegepant, zavegepant (Zavzpret — intranasal, FDA March 2023), atogepant (Qulipta — prevention) | No vasoconstriction; no triptan-like CAD/stroke contraindication — useful when triptans are contraindicated. Use clinical caution in active/unstable vascular disease (pivotal trials often excluded unstable CV disease; long-term high-risk data limited). Rimegepant also approved for prevention (every other day dosing). Atogepant approved for preventive use. Zavegepant is the first intranasal gepant. No serotonin syndrome risk |
| Ditans | 5-HT1F agonist — NO vasoconstriction (does not activate 5-HT1B) | Lasmiditan | Schedule V — sedation, dizziness, driving restriction (8h). No vasoconstriction; no triptan-like CV contraindication; use clinical caution in active/unstable vascular disease (limited data) |
| NSAIDs | COX inhibition → prostaglandin reduction | Ibuprofen, naproxen, ketorolac IV | First-line for mild–moderate attacks. Ketorolac IV/IM useful in ER. Risk of MOH if used >15 days/month |
| Opioids | Mu-opioid agonism | (Generally avoided) | Avoid opioids — lower efficacy than triptans/gepants, high MOH risk, abuse potential. Not recommended for routine acute migraine management |
| IV adjuncts (status migrainosus / ED) | Various | Menu of options (not all-at-once): dopamine-antagonist antiemetic, NSAID (ketorolac), IV fluids, IV magnesium in selected (esp aura/menstrual), IV valproate in selected non-pregnant, DHE protocols, nerve blocks | IV magnesium 1–2 g particularly effective for migraine with aura and menstrual migraine. IV valproate useful for refractory status migrainosus — AVOID in pregnancy and significant hepatic disease |
| Antiemetics | Dopamine (D2) receptor antagonists | Metoclopramide, prochlorperazine, chlorpromazine | Effective as monotherapy in ER for migraine. Risk of akathisia and dystonia — pretreat with diphenhydramine. Prochlorperazine IV is highly effective |
| Dihydroergotamine (DHE) | 5-HT1B/1D agonist + multiple receptor activity | DHE IV, nasal spray, SC | Contraindicated with triptans — must wait 24 hours between. Contraindicated in pregnancy, CAD, uncontrolled HTN. Used for status migrainosus (IV protocol). Also contraindicated with CYP3A4 inhibitors |
💎 Board Pearl
Triptans are contraindicated in hemiplegic and basilar migraine due to theoretical risk of vasoconstriction worsening aura-related ischemia. Gepants and ditans have no vasoconstriction and no triptan-like CV contraindication, so they are useful alternatives when triptans are contraindicated — but use clinical caution in active/unstable vascular disease (pivotal trials excluded unstable CV disease; long-term data in high-risk populations remain limited).
Preventive Migraine Treatment
When to Start Prevention
- ≥4 migraine days per month
- Attacks cause significant disability despite acute treatment
- Contraindications to or failure of acute therapies
- Medication overuse or risk of overuse
- Patient preference (e.g., frequent auras, hemiplegic migraine)
| Drug | Class | Key Side Effects | Board Notes |
|---|---|---|---|
| Propranolol / Metoprolol | Beta-blockers | Fatigue, bradycardia, depression, exercise intolerance | First-line oral preventive. Avoid in asthma. Propranolol also treats essential tremor |
| Topiramate | Anticonvulsant (multiple mechanisms) | Weight loss, kidney stones, paresthesias, cognitive slowing (“dopamax”), metabolic acidosis, acute angle-closure glaucoma, oligohidrosis/hyperthermia (esp. pediatric) | Teratogen (cleft palate). Causes word-finding difficulty. Contraindicated with nephrolithiasis history. Counsel about visual symptoms (acute glaucoma) and decreased sweating/heat intolerance in children. Also used for IIH |
| Valproate | Anticonvulsant (GABA enhancer) | Weight gain, tremor, alopecia, hepatotoxicity, thrombocytopenia, pancreatitis | Contraindicated in pregnancy for migraine prevention (boxed warning); causes neural tube defects, reduced IQ, and increased autism spectrum risk (MONEAD/EURAP). AVOID in women of childbearing age |
| Atogepant (Qulipta) | Oral CGRP receptor antagonist (gepant) | Nausea, constipation, fatigue | Approved for prevention of episodic AND chronic migraine. Daily oral dosing. No vasoconstriction; no triptan-like CAD contraindication; use clinical caution in active/unstable vascular disease (limited high-risk data) |
| Amitriptyline | Tricyclic antidepressant | Sedation, weight gain, dry mouth, constipation, QT prolongation | Effective preventive (AAN Level B); preferred when comorbid tension-type, insomnia, or depression. Avoid in elderly (anticholinergic burden) |
| Venlafaxine | SNRI | Nausea, HTN at high doses, discontinuation syndrome | Good option for migraine + comorbid depression/anxiety |
| Erenumab | CGRP receptor mAb | Injection site reactions, constipation can be severe (FDA warning, rare hospitalization/surgery), HTN (warning added 2020, unique to erenumab) | Only CGRP mAb that targets the receptor (others target the CGRP ligand). Monthly SC injection |
| Fremanezumab | Anti-CGRP ligand mAb | Injection site reactions | Monthly or quarterly SC dosing option |
| Galcanezumab | Anti-CGRP ligand mAb | Injection site reactions | Monthly SC. Also approved for episodic cluster headache |
| Eptinezumab | Anti-CGRP ligand mAb | Nasopharyngitis, hypersensitivity | Only IV CGRP mAb — quarterly infusion. Fastest onset of all CGRP mAbs |
| OnabotulinumtoxinA | Botulinum toxin type A | Injection site pain, neck weakness, ptosis | Chronic migraine ONLY (≥15 headache days/month for ≥3 months, with ≥8 migraine features). PREEMPT protocol: 155 units minimum across 31 fixed sites in 7 muscle groups (optional “follow-the-pain” up to 195 U). Every 12 weeks. NOT for episodic migraine |
💎 Board Pearl
OnabotulinumtoxinA is approved ONLY for chronic migraine (≥15 days/month). The PREEMPT protocol uses 31 fixed injection sites across 7 head/neck muscle groups every 12 weeks. It is NOT indicated for episodic migraine or tension-type headache.
🧪 CGRP Monoclonal Antibodies — Board Distinctions
- Erenumab = targets the CGRP receptor; all others target the CGRP ligand
- Eptinezumab = the only IV formulation (quarterly infusion)
- Galcanezumab = also approved for episodic cluster headache
- All are well-tolerated with minimal drug interactions — major advantage over oral preventives
- No hepatotoxicity monitoring required (unlike valproate)
Medication Overuse Headache (MOH)
Headache present ≥15 days/month developing as a consequence of regular overuse of acute headache medication for >3 months. Requires a pre-existing primary headache disorder; triptans/ergots/opioids/combination analgesics >10 d/mo OR simple analgesics >15 d/mo.
Overuse Thresholds (ICHD-3 Criteria)
| Medication | Overuse Threshold |
|---|---|
| Triptans | ≥10 days/month |
| Ergotamine | ≥10 days/month |
| Opioids | ≥10 days/month |
| Combination analgesics (butalbital compounds) | ≥10 days/month |
| Simple analgesics / NSAIDs | ≥15 days/month |
Management
- Withdrawal of the overused medication — can be abrupt (triptans, NSAIDs) or tapered (opioids, butalbital)
- Bridge therapy during withdrawal: naproxen, prednisone taper, DHE protocol, or nerve blocks
- Start preventive therapy simultaneously — CGRP mAbs or topiramate most studied
- Withdrawal headache worsens for 2–10 days then improves — counsel patients
- Opioid and butalbital overuse are hardest to treat and have highest relapse rates
💎 Board Pearl
Triptans, opioids, and combination analgesics cause MOH at ≥10 days/month; simple analgesics at ≥15 days/month. Treatment = withdrawal + bridge + preventive. Butalbital-containing medications are particularly problematic and should be avoided in headache management.
Cluster Headache Treatment
Severe unilateral periorbital pain with autonomic features (lacrimation, conjunctival injection, ptosis, miosis, rhinorrhea, eyelid edema). Attacks last 15–180 minutes, up to 8/day during cluster periods.
| Setting | Treatment | Details |
|---|---|---|
| Acute | High-flow oxygen | 100% O2 at 12–15 L/min via non-rebreather mask for 15–20 min. First-line. ~78% effective. No side effects |
| Sumatriptan SC | 6 mg SC, max 2 injections/24 h — onset in 5–15 min. First-line pharmacologic. Intranasal zolmitriptan also effective | |
| Lidocaine intranasal | Ipsilateral nostril. Adjunctive agent | |
| Preventive | Verapamil | First-line preventive. Doses often >480 mg/day. Requires ECG monitoring — risk of PR prolongation and heart block. Repeat ECG with each dose escalation |
| Lithium | Second-line. Monitor levels, renal function, thyroid. More effective for chronic than episodic cluster | |
| Topiramate | Second-line preventive for cluster headache | |
| Galcanezumab | FDA-approved for episodic cluster headache (only CGRP mAb with this indication). 300 mg SC monthly during cluster cycle (vs 240 mg load + 120 mg monthly for migraine) | |
| Suboccipital steroid injection | Greater occipital nerve (GON) block with corticosteroid — used as bridge therapy while waiting for preventive to reach efficacy | |
| Short-term prednisone | Bridge therapy during cluster onset. Rapid effect but cannot use long-term |
💎 Board Pearl
Verapamil is first-line preventive for cluster headache — but requires ECG before initiation and with every dose increase due to risk of PR prolongation and AV block. High-flow 100% O2 (12–15 L/min) is first-line acute treatment.
Trigeminal Neuralgia Pharmacology
Sudden, severe, lancinating facial pain in V2/V3 distribution, lasting seconds. Triggered by chewing, talking, light touch. Must rule out secondary causes (MS, tumor, vascular compression).
| Treatment | Details |
|---|---|
| Carbamazepine | First-line. NNT ~2. Monitor for hyponatremia, aplastic anemia, agranulocytosis, SJS/TEN. HLA-B*1502 screening (Asian populations) and HLA-A*3101 (European/Japanese populations) for hypersensitivity reactions. Induces CYP3A4. Check CBC, LFTs, Na |
| Oxcarbazepine | Better tolerated alternative. Higher risk of hyponatremia than carbamazepine. Similar efficacy |
| Baclofen | Add-on therapy. GABA-B agonist. Useful when carbamazepine alone is insufficient |
| Lamotrigine | Second/third-line. Slow titration required (risk of SJS) |
| Gabapentin / Pregabalin | Adjunctive options for trigeminal neuralgia, particularly when carbamazepine/oxcarbazepine are not tolerated or are insufficient |
| Microvascular decompression (MVD) | Surgery for vascular compression (typically SCA on CN V). Highest long-term cure rate (~80%). Preferred for younger, medically fit patients |
| Percutaneous procedures | Radiofrequency thermocoagulation, balloon compression, glycerol rhizolysis — for poor surgical candidates |
| Stereotactic radiosurgery | Gamma knife to trigeminal root entry zone. Delayed onset of relief (weeks–months) |
🧪 Carbamazepine — Board Testing Points
- Screen for HLA-B*1502 in patients of Southeast Asian descent before starting — risk of SJS/TEN. Also HLA-A*3101 in European/Japanese populations for hypersensitivity reactions
- Potent CYP3A4 inducer — reduces efficacy of OCPs, warfarin, and many other drugs
- Monitor CBC (aplastic anemia risk), LFTs, and sodium levels
- Autoinduction: carbamazepine induces its own metabolism → levels drop after 2–4 weeks → may need dose increase
Indomethacin-Responsive Headaches
A distinct group of primary headache disorders that show an absolute and dramatic response to indomethacin — this response is diagnostic.
- Hemicrania continua: Continuous unilateral headache with autonomic features. Must respond to indomethacin (ICHD-3 diagnostic criterion). Typical dose 25–75 mg TID
- Paroxysmal hemicrania: Short attacks (2–30 min) of severe unilateral pain with autonomic features, ≥5/day. Distinguished from cluster by shorter duration, higher frequency, and indomethacin response
- Primary cough headache: Bilateral headache provoked by coughing/Valsalva. Rule out Chiari malformation first
- Primary exertional headache: Bilateral, pulsating, brought on by physical exercise. Rule out SAH
- Primary stabbing headache (“ice-pick headache”): Ultrashort jabs (seconds), often periorbital. May respond to indomethacin
Occipital Nerve Blocks
- Greater occipital nerve (GON) block: Local anesthetic ± corticosteroid injection at the GON (medial to occipital artery at superior nuchal line)
- Used for: cluster headache bridge therapy, occipital neuralgia, cervicogenic headache, migraine (adjunctive)
- Rapid onset; effects last days to weeks
💎 Board Pearl
Indomethacin response is a diagnostic criterion for hemicrania continua and paroxysmal hemicrania. If the headache does not respond to indomethacin, the diagnosis must be reconsidered. Paroxysmal hemicrania mimics cluster headache but has shorter attacks, higher frequency, and absolute indomethacin response.
SUNCT / SUNA (Trigeminal Autonomic Cephalalgias)
Short-lasting Unilateral Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT) and with cranial Autonomic symptoms (SUNA). Brief (seconds to minutes), severe unilateral pain in V1 distribution with prominent autonomic features, very high attack frequency.
| Treatment | Details |
|---|---|
| Lamotrigine | First-line preventive. Slow titration required (SJS risk) |
| Topiramate | Second-line |
| Gabapentin | Second-line |
| IV lidocaine | For severe refractory attacks (inpatient setting) |
💎 Board Pearl
SUNCT/SUNA is NOT indomethacin-responsive — a key distinction from paroxysmal hemicrania and hemicrania continua, which are. Lamotrigine is first-line preventive. SUNCT differs from trigeminal neuralgia by the presence of prominent autonomic features (lacrimation, conjunctival injection) and longer attack duration.
Idiopathic Intracranial Hypertension (IIH)
Elevated intracranial pressure without identifiable cause. Typically young, obese women of childbearing age. Headache, papilledema, vision loss, pulsatile tinnitus, transient visual obscurations. Diagnosis requires elevated opening pressure on LP with normal CSF composition and normal neuroimaging (or empty sella / transverse sinus stenosis).
| Treatment | Details |
|---|---|
| Acetazolamide | First-line medical therapy (IIHTT trial 2014 — Diamox + low-Na diet superior to diet alone for vision outcomes). Carbonic anhydrase inhibitor reduces CSF production. AEs: paresthesias, metallic taste, nephrolithiasis, metabolic acidosis |
| Topiramate | Carbonic anhydrase inhibitor activity + weight loss bonus. Useful alternative or adjunct |
| Weight loss | Single most effective intervention — 6–10% reduction in body weight can induce remission |
| Serial lumbar punctures | For symptom relief; not a long-term solution |
| Surgical: CSF shunt (LP or VP) | For fulminant IIH with rapidly progressive vision loss or medical failure |
| Optic nerve sheath fenestration | For vision-threatening papilledema |
| Venous sinus stenting | For documented transverse sinus stenosis with significant pressure gradient |
💎 Board Pearl
Acetazolamide is first-line medical therapy for IIH (IIHTT 2014). Weight loss is the single most effective long-term intervention. Topiramate is a useful alternative given its CA-inhibitor activity plus weight-loss effect. Urgent surgical intervention (shunt, ONSF) is required for fulminant IIH with progressive vision loss.
Quick Reference Table
| Headache Type | First-Line Acute | First-Line Preventive | Key Board Fact |
|---|---|---|---|
| Episodic migraine | Triptans, NSAIDs | Propranolol, topiramate, CGRP-targeting agents (mAbs & oral gepants) — first-line per AHS 2024 | Triptans contraindicated in CAD, hemiplegic/basilar migraine; CGRP biologics do NOT require oral preventive failure as biologic rule |
| Chronic migraine | Same as episodic | OnabotulinumtoxinA, CGRP-targeting agents (mAbs & oral gepants) — first-line per AHS 2024, topiramate | OnabotulinumtoxinA only for ≥15 days/month; CGRP biologics first-line, do not require oral preventive failure |
| Medication overuse | Withdraw offending agent | CGRP-targeting agents (first-line per AHS 2024), topiramate | Triptans ≥10 d/mo; analgesics ≥15 d/mo |
| Cluster headache | High-flow O2, sumatriptan SC | Verapamil | ECG monitoring for verapamil (PR prolongation) |
| Trigeminal neuralgia | Carbamazepine | Carbamazepine, oxcarbazepine | HLA-B*1502 screening; MVD for vascular compression |
| Hemicrania continua | Indomethacin | Indomethacin | Response is diagnostic (ICHD-3 criterion) |
| Paroxysmal hemicrania | Indomethacin | Indomethacin | Short attacks + high frequency + indomethacin response = PH |
| Tension-type | NSAIDs, acetaminophen | Amitriptyline | Amitriptyline is first-line preventive for chronic TTH |
🧪 Pregnancy & Headache Pharmacology
- Acetaminophen is safest acute option in pregnancy
- Valproate and topiramate are teratogenic — absolutely contraindicated
- Propranolol can be used but monitor for fetal bradycardia/growth restriction
- Triptans are NOT an absolute "avoid all" category in pregnancy. Sumatriptan has the best pregnancy safety data and may be considered with caution when needed, ideally in shared decision-making with obstetrics
- CGRP mAbs: Insufficient pregnancy data — discontinue before conception (long half-life)
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 treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 2010;50(6):921-936.
- Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241-254.
- Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine (STRIVE). N Engl J Med. 2017;377(22):2123-2132.
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38(1):1-211.
- May A, Leone M, Afra J, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. Eur J Neurol. 2006;13(10):1066-1077.
- Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol. 2008;15(10):1013-1028.
- Diener HC, Dodick D, Evers S, et al. Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol. 2019;18(9):891-902.
- Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132-141.
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