Headache Pharmacology
Headache Pharmacology
What Do You Need to Know?
- CGRP pathway: released from trigeminal ganglion → meningeal vasodilation + neurogenic inflammation; 4 anti-CGRP mAbs + 3 gepants approved for migraine
- Triptans: 5-HT1B/1D agonists — contraindicated in CAD, uncontrolled HTN, hemiplegic/basilar migraine, stroke history; sumatriptan SC has fastest onset (~10 min)
- Gepants: CGRP receptor antagonists with NO cardiovascular contraindication — 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
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, basilar migraine, 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 | None cardiovascular; 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 | 50–200 mg | ~60 min | NO vasoconstriction; Schedule V — 8 h driving restriction; sedation, dizziness | None cardiovascular; 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, 3rd trimester pregnancy |
| 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 | 1 mg IV; 4 mg nasal | ~15–30 min (IV) | Status migrainosus (repetitive IV protocol); low headache recurrence | CAD, HTN, pregnancy, CYP3A4 inhibitors; 24 h gap from triptans |
| 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 and basilar migraine due to theoretical vasoconstriction risk — gepants and ditans are safe alternatives
- Dexamethasone in the ER prevents headache recurrence but does NOT abort the acute migraine — always give an abortive agent alongside
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)
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; reduce to 5 mg with propranolol (MAO-A inhibition by propranolol increases levels) |
| 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 inhibits MAO-A, increasing rizatriptan plasma levels by ~70%
- 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 | 100–300 mg IV | 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 |
💎 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 have no cardiovascular contraindications — unlike triptans, they are safe in patients with CAD, prior stroke, and uncontrolled HTN
- 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 | Also treats essential tremor; avoid in asthma; check rizatriptan interaction |
| 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” = word-finding difficulty |
| Valproate | Anticonvulsant | 500–1500 mg/day | Weight gain, tremor, alopecia, hepatotoxicity, thrombocytopenia, pancreatitis | Level A | Major teratogen (NTDs, cognitive impairment); pregnancy category X; AVOID in women of childbearing age |
| 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
- 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 (0.6–1.0 mEq/L), renal function, thyroid; narrow therapeutic window |
| Galcanezumab | 300 mg SC monthly | 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) | Avoid 3rd trimester — risk of premature ductus arteriosus closure and oligohydramnios |
| 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 | |
| Avoid / Contraindicated | Ergotamine / DHE | Absolutely contraindicated — potent uterotonic → uterine contractions, fetal distress |
| Valproate | NTDs, reduced IQ, autism risk; pregnancy category X | |
| 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 are safe in the 1st and 2nd trimester but must be avoided after 30 weeks due to risk of 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.