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)
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. Cannot combine with DHE (24h gap). Rizatriptan dose ↓ with propranolol. Frovatriptan has longest half-life — useful for menstrual migraine |
| Gepants | CGRP receptor antagonists (small molecules) | Ubrogepant, rimegepant | Can use in vascular disease (no vasoconstriction). Rimegepant also approved for prevention (every other day dosing). No serotonin syndrome risk |
| Ditans | 5-HT1F agonist — NO vasoconstriction (does not activate 5-HT1B) | Lasmiditan | Schedule V — sedation, dizziness, driving restriction (8h). Safe in vascular disease. No triptan-like CV contraindications |
| 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 |
| 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 are safe alternatives in these patients and in those with cardiovascular disease.
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 | Teratogen (cleft palate). Causes word-finding difficulty. Contraindicated with nephrolithiasis history. Also used for IIH |
| Valproate | Anticonvulsant (GABA enhancer) | Weight gain, tremor, alopecia, hepatotoxicity, thrombocytopenia, pancreatitis | Major teratogen (neural tube defects) — AVOID in women of childbearing age. Pregnancy category X |
| Amitriptyline | Tricyclic antidepressant | Sedation, weight gain, dry mouth, constipation, QT prolongation | First-line for migraine + tension-type headache overlap. Also useful for migraine + insomnia. 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, HTN (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). 31 injection sites, fixed paradigm (PREEMPT protocol). 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.
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 subcutaneous injection — 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 | |
| Galcanezumab | FDA-approved for episodic cluster headache (only CGRP mAb with this indication) | |
| 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 in Asian populations). 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) |
| 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
- 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.
Quick Reference Table
| Headache Type | First-Line Acute | First-Line Preventive | Key Board Fact |
|---|---|---|---|
| Episodic migraine | Triptans, NSAIDs | Propranolol, topiramate, CGRP mAbs | Triptans contraindicated in CAD, hemiplegic/basilar migraine |
| Chronic migraine | Same as episodic | OnabotulinumtoxinA, CGRP mAbs, topiramate | OnabotulinumtoxinA only for ≥15 days/month |
| Medication overuse | Withdraw offending agent | CGRP mAbs, 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: sumatriptan has most safety data in pregnancy (pregnancy registry data) but not formally recommended
- 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.