What it is:Migraine is a recurrent, moderate-to-severe primary headache driven by activation of the trigeminovascular system, usually unilateral and throbbing, with GI and sensory symptoms riding along. Tension-type headache is a different, milder animal: bilateral, band-like, nonpulsatile, and mostly a muscle/central sensitization problem rather than a vascular one.
The core problem:Once the trigeminal nerve fires, it dumps vasoactive neuropeptides (CGRP chief among them) onto meningeal blood vessels, causing dilation, plasma leakage, and an inflammatory soup that keeps hurting even after the trigger is gone. Every acute drug class either shuts that firing down, constricts the vessels back, or blocks CGRP from doing its job.
What you do about it:Match drug intensity to attack severity, treat early and with an adequate single dose, and never let acute-medication frequency creep past the medication-overuse threshold. If attacks are frequent or disabling, layer in daily prevention.
Think of migraine care as two completely separate prescriptions living in the same patient: an abortiveplan for when the attack hits, and a preventiveplan running quietly in the background. Mixing up which drugs belong to which job (or letting the abortive drugs get overused) is where most of the exam traps and most of the real-world harm live.
The International Classification of Headache Disorders splits headache into primary(the headache isthe disease: migraine, tension-type, cluster) and secondary(a symptom of something else). Get this distinction right before you reach for any drug table.
| Type | Pattern |
|---|---|
| Migraine | Unilateral, throbbing, moderate-severe, 4-72 hr, with nausea/vomiting or photophobia/phonophobia, with or without aura |
| Tension-type | Bilateral, band-like ("hatband"), nonpulsatile, mild-moderate, no aura, minimal GI symptoms |
| Cluster | Unilateral periorbital, excruciating, 15-180 min, clusters of attacks over weeks with remission periods; different disease, different drugs (high-flow O2 + triptan) |
| Secondary | Caused by infection, hemorrhage (thunderclap onset), tumor, post-concussion, substance withdrawal, or medication overuse itself |
New headache onset after age 50, a thunderclap onset, an abnormal neuro exam, or a headache pattern that doesn't fit the usual story all push toward neuroimaging to rule out mass lesion, cerebrovascular disease, or temporal arteritis before you commit to a migraine diagnosis.
This is a pure numbers question and a favorite on exams. Diagnosis hinges on counting two things every month: monthly migraine days (MMD)and monthly headache days (MHD).
Every acute and preventive migraine drug traces back to one anatomic story: the trigeminovascular system. Learn this once and the entire drug list stops being a memorization exercise.
Something (a trigger, or in migraine with aura, a wave of cortical spreading depression moving across the cortex at 2-6 mm/min) activates the trigeminal nerve. Its cell bodies sit in the trigeminal ganglion, and its fibers wrap around the meningeal blood vessels, which are richly innervated and pain-sensitive. Firing releases calcitonin gene-related peptide (CGRP), substance P, and neurokinin A from perivascular nerve endings. CGRP is the standout: it is an extremely potent vasodilator. The result is dilation and distention of meningeal vessels, plasma extravasation, and a local neurogenic inflammatory response. That inflamed, stretched vasculature is what actually hurts, and it keeps signaling pain back up through the trigeminal ganglion to the brainstem, thalamus, and cortex, which is why the pain often builds rather than spikes instantly.
Read the drug classes straight off that cascade. Triptans and ergotsconstrict the dilated vessels and block neuropeptide release via 5-HT1B/1D agonism. Gepants and CGRP monoclonal antibodiesblock CGRP or its receptor directly, without needing to constrict anything. Lasmiditanhits a serotonin receptor (5-HT1F) that dampens the pain pathway withouttouching vascular tone at all. NSAIDsblunt the neurogenic inflammation itself by inhibiting prostaglandin synthesis. Four different drug classes, one shared target.
The trigeminal nerve is unusual: it's a non-serotonergic nerve that still expresses presynaptic serotonin receptors. 5-HT1D and 5-HT1Freceptors on the nerve terminal inhibit further neuropeptide release, while 5-HT1Breceptors on the meningeal vessels themselves cause direct vasoconstriction. Triptans hit all of these fairly broadly (1B/1D, some 1F activity), which is exactly why they both stop the neurogenic firing andsqueeze the vessels back down, and also why cardiovascular risk (from 1B-mediated vasoconstriction elsewhere) rides along as a class liability.
Lasmiditan is selective for 5-HT1Fand essentially spares 5-HT1B. No 5-HT1B means no meaningful vasoconstriction, which is exactly why it carries no cardiovascular warnings and can be used in patients who are triptan-contraindicated for CV reasons. Same logic protects the gepants: they block the CGRP receptor itself rather than constricting anything, so they're also CV-safe.
Genetic susceptibility shapes both baseline risk and how a given patient responds to triggers (food, sleep disruption, hormonal shifts, stress, weather, sensory overload - see the trigger table under Diagnosis). A rare but testable example: familial hemiplegic migraineis a channelopathy from a mutation in the alpha subunit of the P/Q-type voltage-gated calcium channel (CACNA1A), producing a state of neuronal hyperexcitability that predisposes to cortical spreading depression.
A full migraine attack unfolds in four recognized phases, though not every patient experiences all four every time.
~77% of patients. Neurologic (photophobia, phonophobia, hyperosmia, poor concentration), psychological, autonomic, or constitutional symptoms.
~25% of patients. Visual (scintillations, fortification spectrum, scotoma), sensory (paresthesias), or speech/motor symptoms.
Unilateral, throbbing, moderate-severe. Nausea/vomiting almost invariable; photophobia, phonophobia, osmophobia common.
Exhaustion, malaise, irritability, scalp tenderness. Some patients instead feel refreshed or lightheaded.
Beyond the core throbbing pain, patients commonly report anorexia, constipation or diarrhea, abdominal cramping, nasal stuffiness, blurred vision, diaphoresis, facial pallor, and localized facial or scalp edema. Many instinctively seek out a dark, quiet room, which is itself a useful history clue.
Students mix these up constantly. Prodromeis vague, happens hours to days out, and is not itself a focal neurologic symptom. Aurais a discrete, reversible, focal neurologic event (usually visual) that evolves over minutes and directly precedes or accompanies the pain. Only about a quarter of migraineurs get aura at all.
| Category | Examples |
|---|---|
| Food/drink | Alcohol, caffeine or caffeine withdrawal, MSG, nitrates (processed meats), chocolate, aspartame/saccharin, aged/fermented foods, skipped meals |
| Environmental | Glare/flickering light, loud noise, strong smells, tobacco smoke, high altitude, weather changes |
| Behavioral/physiologic | Sleep excess or deficit, fatigue, stress or the letdown after stress, menstruation/menopause, sexual activity, strenuous exertion |
Migraine and tension-type headache are both clinical diagnoses; there's no lab test or imaging finding that confirms either one. The work is in the history.
New migraine-like headache starting after 50 is atypical enough that it should push you toward an organic cause: mass lesion, cerebrovascular disease, or temporal (giant cell) arteritis. Don't anchor on "it's just a migraine" in this age group.
Goals:fast, consistent relief with minimal side effects; minimize disability and emotional distress; get the patient back to normal activity without an ED trip. Nonpharmacologic care runs alongside drug therapy, not instead of it: ice to the head, rest in a dark quiet room, trigger avoidance, and behavioral approaches (relaxation therapy, biofeedback, cognitive therapy) for patients who prefer them or who don't tolerate medication.
DiPiro's algorithm is built on severity-based stratified care: mild-to-moderate attacks start with simple analgesics, NSAIDs, or combination analgesics (acetaminophen/aspirin/caffeine). Severe attacks, or attacks that failed the mild-tier drugs, go straight to a migraine-specific agent: a triptan first-line, or DHE/ergotamine as an alternative. If nausea or vomiting is prominent, pretreat with an antiemetic 15-30 minutes before the oral or nonoral migraine drug, and lean on rectal, intranasal, or parenteral formulations since gastroparesis during an attack tanks oral absorption.
Lecture take-home, and it matters clinically: treat early, and treat with an adequate dose the first time.A large single dose given right at attack onset outperforms chasing the pain with repeated small doses. Waiting it out or under-dosing is what pushes patients toward ED visits and toward escalating their own use into medication-overuse territory.
Metoclopramide, chlorpromazine, or prochlorperazine given 15-30 minutes before the migraine-specific drug is advisable whenever nausea/vomiting is significant. Metoclopramide has a second job here too: it reverses migraine-associated gastroparesis, which actually improves absorption of whatever oral drug follows it.
Frequent or excessive use of anyacute migraine drug class (simple analgesics, combination analgesics, opioids, ergotamine, triptans) paradoxically increases headache frequency. The overarching rule is to cap acute therapy at 15 days or fewer per month, but the granular, more clinically useful numbers from lecture are tighter for the migraine-specific drugs: triptans and ergotamine ≤10 days/month, and opioids/barbiturates ≤5 days/month. Simple NSAIDs get more runway (~15 days/month) than combination or migraine-specific agents.
| Drug | Dose | Max / Notes |
|---|---|---|
| Analgesics & NSAIDs (first-line, mild-moderate) | ||
| Acetaminophen | 500-1000 mg q4-6h PRN | Max 4 g/day |
| Acetaminophen/aspirin/caffeine (Excedrin Migraine) | 2 tabs q6h PRN | OTC combination |
| Aspirin | 500-1000 mg q4-6h PRN | Max 4 g/day |
| Ibuprofen | 400-800 mg q4-6h PRN | Max 3.2 g/day |
| Naproxen sodium | 220-550 mg q8-12h PRN | Avoid >1.375 g/day |
| Diclofenac potassium | 50-100 mg q8h PRN | Avoid >150 mg/day |
| Ketorolac (nasal, Sprix) | 31.5 mg (1 spray/nostril) q6-8h PRN | Max 126 mg/day × 5 days |
| Ketorolac IM | 30-60 mg q6h PRN | Max 120 mg/day × 5 days |
| Ergot alkaloids (moderate-severe) | ||
| Ergotamine/caffeine oral (Cafergot) | 2 mg at onset, repeat 1-2 mg q30min PRN | Max 6 mg/day or 10 mg/week |
| Ergotamine sublingual (Ergomar) | 2 mg at onset, repeat q30min PRN | Max 4 mg/day or 10 mg/week |
| DHE injection (IM/IV/SC) | 0.25-1 mg at onset, repeat hourly PRN | Max 3 mg/day or 6 mg/week |
| DHE nasal spray (Migranal) | 1 spray (0.5 mg) each nostril, may repeat once at 15 min | Max 3 mg/day or 6 mg/week |
| Triptans (first-line, mild-severe or as rescue) | ||
| Sumatriptan SC | 1-6 mg at onset, repeat after 1 hr PRN | Max 12 mg/day |
| Sumatriptan oral | 25-100 mg at onset, repeat after 2 hr PRN | Max 200 mg/day; combo w/ naproxen 85/500 mg exists |
| Sumatriptan nasal | 5-20 mg at onset, repeat after 2 hr PRN | Max 40 mg/day |
| Zolmitriptan oral/ODT | 1.25-5 mg at onset, repeat after 2 hr PRN | Max 10 mg/day; don't split the ODT |
| Naratriptan | 1-2.5 mg at onset, repeat after 4 hr PRN | Max 5 mg/day |
| Rizatriptan oral/ODT | 5-10 mg at onset, repeat after 2 hr PRN | Max 30 mg/day; use 5 mg (15 mg/day max) with propranolol |
| Almotriptan | 6.25-12.5 mg at onset, repeat after 2 hr PRN | Max 25 mg/day |
| Frovatriptan | 2.5-5 mg at onset, repeat after 2 hr PRN | Max 7.5 mg/day |
| Eletriptan | 20-40 mg at onset, repeat after 2 hr PRN | Max 80 mg/day |
| Ditans | ||
| Lasmiditan | 50-200 mg single dose at onset | Max 1 dose/24 hr; no driving x8 hr |
| CGRP antagonists (gepants) | ||
| Ubrogepant | 50-100 mg at onset, repeat after 2 hr PRN | Max 200 mg/day |
| Rimegepant | 75 mg at onset | Max 1 dose/24 hr; empty stomach |
| Antiemetics / miscellaneous | ||
| Metoclopramide | 10 mg q4-6h PRN | Max 40 mg/day |
| Metoclopramide + aspirin | 10 mg / 1000 mg q4-6h PRN | Similar efficacy to sumatriptan; option if triptan contraindicated |
| Prochlorperazine | 5-10 mg PO 3-4x/day, or 25 mg PR up to 2x/day | Max 40 mg PO or 50 mg PR per day |
| Promethazine | 25 mg PO/PR q4-6h PRN | Max 100 mg/day |
Simple analgesics and NSAIDs are first-line for mild-to-moderate attacks, and some severe attacks still respond. Aspirin, diclofenac, ibuprofen, naproxen sodium, and the acetaminophen/aspirin/caffeine combination all have solid evidence. Mechanistically, NSAIDs blunt the neurogenically driven inflammation in the trigeminovascular system by inhibiting prostaglandin synthesis, which is a different target than the vasoconstriction/CGRP-blocking approach of the migraine-specific drugs, and it's why NSAIDs still help even in patients who can't take vasoconstrictors.
Rectal formulationsare the go-to when nausea/vomiting makes oral dosing unreliable. The combination products deserve a second look: aspirin or acetaminophen combined with the short-acting barbiturate butalbital(Fiorinal, Fioricet, and their codeine-containing versions) works, but overuse risk is high and these should be used sparingly given MOH and dependence concerns.
Metoclopramide plus aspirin has efficacy comparable to sumatriptan, which makes it a genuinely useful substitute when a triptan is contraindicated (cardiovascular disease, pregnancy, MAOI use) rather than just a nausea add-on.
Ergotamine and dihydroergotamine (DHE) are nonselective 5-HT1 agonists with additional affinity for dopamine and alpha-adrenergic receptors, which is exactly why their side effect burden is heavier and messier than the triptans'. They constrict intracranial vessels and inhibit neurogenic inflammation, same target as triptans, blunter tool. Ergotamine is oral, sublingual, or rectal, always formulated with caffeine to boost GI absorption and add a stimulatory, vasoconstrictive assist. DHE can be self-administered IM or SC, or given IV in a hospital setting; the nasal spray formulation also works and is generally better tolerated than oral ergotamine.
Nausea and vomiting are near-universal (direct dopamine receptor effect, roughly 10% of oral patients get frank emesis), so pretreat with an antiemetic and titrate to a tolerable dose. Watch for ergotism: cold, numb, painful extremities, diminished pulses, claudication, and in severe cases gangrene, MI, hepatic necrosis, or bowel/brain ischemia. Contraindications: renal or hepatic failure, coronary/cerebral/peripheral vascular disease, uncontrolled hypertension, sepsis, pregnancy, and breastfeeding. Never give an ergot and a triptan within 24 hours of each other- additive vasoconstriction and serotonin syndrome risk.
DHE doesn't appear to cause rebound/MOH the way ergotamine can, but ergotamine's dosage limits (4-6 mg/day, 10 mg/week) need to be respected strictly to avoid it.
Triptans are appropriate first-line for mild-to-severe migraine, or as rescue when nonspecific drugs fail. They're selective 5-HT1B/1D agonists that work three ways: normalizing dilated intracranial arteries, inhibiting vasoactive peptide release, and blocking transmission through second-order neurons headed to the thalamus. Sumatriptan was first (developed through the 1980s, approved 1991) and remains the only agent available as a self-injectable autoinjector, which gives it the fastest onset of the class alongside the nasal spray.
All triptans perform similarly except frovatriptan and naratriptan, which are meaningfully slower onset because of their pharmacokinetics. Second-generation triptans (everything but sumatriptan) generally have higher oral bioavailability and longer half-lives, which is a plausible efficacy edge but hasn't been proven head-to-head in trials. Lack of response to one triptan does not predict failure of another - it's reasonable to try a second agent.
| Agent | Half-life | Tmax | Notes |
|---|---|---|---|
| Rizatriptan | 2-3 h | 1-1.2 h (oral) | Fastest onsetof the class |
| Sumatriptan SC | 2 h | 12-15 min | Fastest overall via injection |
| Eletriptan | 4-5 h | 1-2 h | CYP3A4 metabolized |
| Almotriptan | 3-4 h | 1.4-3.8 h | MAO-A, CYP3A4, CYP2D6 |
| Zolmitriptan | 3 h | 2 h (oral) | CYP1A2, MAO-A |
| Naratriptan | 5-6 h | 2-3 h | Slow onset, longer duration; menstrual migraine prophylaxis option |
| Frovatriptan | 25 h | 2-4 h | Slowest onset, longest half-life; least recurrence; menstrual migraine prophylaxis option |
Rizatriptan = fastest onset. Frovatriptan = longest half-life, slowest onset, least headache recurrence.Naratriptan is a slower second. That's exactly why frovatriptan and naratriptan double as short-course prophylaxisfor predictable menstrual migraine, while rizatriptan is the pick when you need speed.
Up to 25% of patients get chest tightness, pressure, or throat/neck discomfort from an unclear mechanism; true cardiac events (MI, coronary vasospasm) are rare but reported. Assess cardiovascular risk before the first dosein menopausal patients, men over 40, and anyone with uncontrolled risk factors, and consider giving the first dose under supervision. Contraindications:ischemic heart disease, uncontrolled hypertension, cerebrovascular disease, hemiplegic or basilar migraine, and pregnancy. Never combine with an ergot within 24 hours, and avoid within 2 weeks of an MAOI. Concomitant SSRIs/SNRIs carry a reported (if debated) serotonin syndrome risk - use with caution and counsel on the symptoms.
Drug interaction to catch on a med rec:rizatriptan is partly cleared by MAO-A, and propranolol raises rizatriptan levels, so patients on propranolol are capped at the 5 mg dose (15 mg/day maximum) instead of the usual 10 mg.
Lasmiditan is a first-in-class, CNS-penetrant, selective 5-HT1F agonist. Because it essentially spares 5-HT1B, it doesn't meaningfully constrict blood vessels, so it can be used in patients who are triptan-contraindicated for cardiovascular reasons - that's its entire clinical niche. It blocks neurogenic dural inflammation and dampens trigeminal nucleus caudalis signaling instead of squeezing vessels shut.
Significant CNS depressant effects: dizziness, paresthesia, somnolence, and in trials about 1% of patients reported hallucination-like or euphoric effects, which is why it's Schedule V. Labeling specifically warns against driving or operating heavy machinery for at least 8 hoursafter each dose. One dose per 24 hours; safety of treating more than 4 attacks in 30 days hasn't been established. No data in pregnancy or lactation.
Ubrogepant and rimegepant block the CGRP receptor directly, preventing vasodilation and dampening the mast-cell-mediated neurogenic inflammatory piece of the cascade, all without constricting anything. Their efficacy is roughly comparable to triptans and lasmiditan but they're generally better tolerated, and unlike the vasoconstrictors, a history of cardiovascular disease is nota contraindication. There's also encouraging (if still limited) evidence that gepants don't drive medication-overuse headache the way triptans and ergots do.
| Ubrogepant | Rimegepant | |
|---|---|---|
| Half-life | 5-7 h | 11 h |
| Repeat dosing | Yes, 2 hr after first dose | No - one dose per 24 hr |
| Common ADRs | Nausea, xerostomia, somnolence | Nausea |
| Also approved for prevention? | No | Yes- the first dual-indication drug (75 mg every other day) |
Both are substrates that get meaningfully affected by strong CYP3A4, P-glycoprotein, or BCRP inhibitors - avoid concomitant use. Avoid in severe renal or hepatic impairment as well.
Dopamine antagonists (metoclopramide, prochlorperazine, chlorpromazine) given parenterally aren't just for nausea control - they have genuine analgesic properties in migraine and, per DiPiro, provide pain relief comparable to triptans in some settings, particularly useful when triptans are contraindicated or when nausea dominates the picture.
Parenteral dopamine antagonists carry a real risk of extrapyramidal symptoms/dystonia- diphenhydramine is frequently co-administered to blunt this (the classic "migraine cocktail"). Chlorpromazine and prochlorperazine also cause postural hypotension (alpha blockade) and QTc prolongation; screen for bradycardia, hypokalemia/hypomagnesemia, and other QT-prolonging drugs before dosing.
The evidence for opioids and derivatives (meperidine, butorphanol, oxycodone, hydromorphone) in migraine is weak. Oral codeine or tramadol combined with acetaminophen are "probably effective," and butorphanol nasal spray has established efficacy, but none of these are preferred therapy. Reserve for moderate-to-severe, infrequent headaches where conventional therapy is contraindicated or has failed, used as true rescue medication under close supervision.
Barbiturate-containing combinations (butalbital products) carry the same last-line logic. Both classes carry high MOH riskand should be capped at roughly 5 days per monthof use.
Prophylaxis is daily therapy meant to reduce attack frequency, severity, and duration, and to make acute drugs work better when they're needed.
Start low, go slow.Efficacy across classes is roughly similar, so drug choice is driven by adverse effect profile and comorbidities, not superior efficacy of one class. Give any agent a genuine 2-3 month trialat an adequate dose before calling it a failure. Once headache frequency/severity has meaningfully improved, continue for 6-12 monthsbefore considering a gradual taper. Opioids and barbiturates have no role in prevention.
| Comorbidity | Preferred agent |
|---|---|
| Hypertension / atrial arrhythmia / CAD | Beta blocker or verapamil |
| Depression | Venlafaxine or amitriptyline |
| Epilepsy | Valproic acid or topiramate |
| Obesity | Topiramate (weight loss side effect works in your favor) |
| Raynaud phenomenon | Verapamil (avoid beta blockers, which worsen vasospasm) |
| Drug | Start | Usual Range |
|---|---|---|
| Beta-adrenergic antagonists (only propranolol & timolol are FDA-approved for this) | ||
| Propranolol | 40 mg/day divided | 40-160 mg/day divided FDA-approved |
| Timolol | 20 mg/day divided | 20-60 mg/day divided FDA-approved |
| Metoprolol | 25-100 mg/day divided | 100-200 mg/day divided |
| Atenolol | 25-50 mg/day | 50-200 mg/day |
| Nadolol | 40-80 mg/day | 80-240 mg/day |
| Antidepressants | ||
| Amitriptyline | 10 mg at bedtime | 20-50 mg at bedtime |
| Venlafaxine | 37.5 mg/day | 75-150 mg/day |
| Antiseizure medications (only divalproex & topiramate are FDA-approved) | ||
| Topiramate | 12.5-25 mg/day, up 12.5-25 mg/week | 50-200 mg/day divided or bedtime FDA-approved |
| Valproic acid/divalproex | 250-500 mg/day divided | 500-1500 mg/day FDA-approved |
| CGRP monoclonal antibodies all FDA-approved | ||
| Erenumab | 70 mg SC monthly | 70-140 mg SC monthly |
| Fremanezumab | 225 mg SC monthly | 225 mg monthly OR 675 mg SC q3mo |
| Galcanezumab | 240 mg SC loading dose | 120 mg SC monthly |
| Eptinezumab | 100 mg IV over 30 min q3mo | 100-300 mg IV q3mo |
| Gepants (oral, small molecule) | ||
| Atogepant | 10 mg/day | up to 60 mg/day |
| Rimegepant | 75 mg every other day | 75 mg every other day; no titration needed |
| Menstrual migraine only - intermittent, start ~1 week before vulnerability | ||
| Naproxen sodium | 550 mg/day divided | 550-1100 mg/day divided |
| Frovatriptan | 2.5-5 mg/day; start 6 days pre-menses | 5 mg/day divided |
| Naratriptan | 2 mg/day; start 6 days pre-menses | 2 mg/day divided |
| Miscellaneous / nutraceutical | ||
| Magnesium | 400 mg/day | 800 mg/day divided; may help migraine with aura |
| Riboflavin | 400 mg/day divided | Benefit only after ~3 months |
| Feverfew (MIG-99) | 10-100 mg/day divided | Withdrawal may rebound headaches |
Beta blockers(propranolol, timolol, metoprolol, and probably atenolol/nadolol) cut attack frequency roughly in half in over half of patients. Watch for drowsiness, fatigue, sleep disturbance, vivid dreams, depression, bradycardia, and hypotension; use cautiously with heart failure, PVD, AV conduction disease, asthma, depression, or diabetes.
TCAs and venlafaxinehelp independent of their antidepressant activity, likely via downregulating central 5-HT2 receptors and boosting synaptic norepinephrine. TCAs are dosed at bedtime because of sedation; watch for anticholinergic burden (especially in older adults or those with BPH/glaucoma), weight gain, and orthostatic hypotension. Venlafaxine is dose-dependently associated with rising blood pressure - check it as you titrate.
Topiramatecauses paresthesias in roughly half of patients and weight loss in 9-12% (which is a feature, not a bug, in an obese patient). Also watch for fatigue, anorexia, cognitive/language slowing, taste changes, and nausea; use cautiously or avoid with a history of kidney stones or cognitive impairment.
Valproic acid/divalproexcan cause nausea, tremor, sedation, weight gain, hair loss, and hepatotoxicity - get baseline LFTs. The extended-release divalproex is once-daily and better tolerated than the enteric-coated version. Contraindicated in pregnancyand in a history of pancreatitis or chronic liver disease; antiseizure agents broadly should be avoided in people of childbearing potential given teratogenicity concerns.
Four anti-CGRP monoclonal antibodies target the pathway two different ways: erenumabblocks the CGRP receptor; fremanezumab, galcanezumab, and eptinezumabbind the CGRP liganditself. All four reduce frequency of episodic and chronic migraine (with or without aura). Injection site reactions are the most common adverse effect across the subcutaneous agents; also watch for constipation, nasopharyngitis, and hypersensitivity (rare angioedema/anaphylaxis reported). They carry essentially no known drug-drug interactions, a real advantage in polypharmacy patients, but cost and access remain the limiting factor in practice - these are expensive, long-half-life biologics, and long-term safety data are still accumulating.
Rimegepant and atogepantare the oral small-molecule alternative. Rimegepant is unique for having dualacute-and-preventive approval, the first drug to earn that distinction. Atogepant is preventive-only. Both share the gepant interaction profile: avoid with strong CYP3A4/P-gp/BCRP inhibitors.
OnabotulinumtoxinAis FDA-approved specifically for chronic migraine: 15 or more headache days per month, each lasting 4 or more hours. It's given as multiple small IM injections (5 units per injection/muscle site) that cleave SNARE proteins and block acetylcholine release at the neuromuscular junction. A 6-week trial performs comparably to other second-line options.
Multiple RCTs found it ineffective for episodic migraine (fewer than 15 headache days/month), and the American Academy of Neurology specifically recommends againstusing it there. This is a clean distractor: "prevents migraines" does not mean "works for all migraine," only chronic migraine meets the bar.
Other options with evidence:the ACE inhibitor lisinopril and the ARB candesartan have shown effectiveness; verapamil is used fairly extensively clinically (and is the preferred CCB in Raynaud comorbidity); clonidine and guanfacine have possible efficacy but side effects limit use. NSAIDs and certain triptans (frovatriptan established, naratriptan/zolmitriptan probably effective) can be used intermittently, started about a week before an anticipated predictable trigger like menstruation, purely to cover that vulnerability window rather than as daily therapy.
Overusing anyacute headache drug (simple analgesics, combination products, triptans, ergotamine, opioids, all of them) can trigger a distinct rebound syndrome: a dull, throbbing ache that's often worst in the morning and present nearly every day. Caffeine can make it worse. The only fix is decreasing use of the offending medication, typically over 1-2 weeks, sometimes with a bridge strategy (steroid taper, or switching to a different drug class temporarily) to get through withdrawal. This is exactly why the day-per-month caps under Acute Therapy exist - they aren't arbitrary, they're the threshold above which rebound headache becomes likely.
Complex/atypical migrainepresents with unusual, severe, reversible neurologic symptoms (slurred speech, aphasia, sensory changes, limb weakness) preceding the headache by 20-60 minutes - it can look like a stroke, and ruling out an actual cerebrovascular event is the first job. Hemiplegic migraine(familial or sporadic) similarly mimics stroke, with temporary unilateral weakness that can precede or outlast the pain; the familial form is a channelopathy (CACNA1A mutation) and can respond to verapamil.
Because these variants already involve vascular spasm and stroke-mimicking neurology, triptans and ergot alkaloids are contraindicatedin complex and hemiplegic migraine - you don't want to add more vasoconstriction on top of a process that may already involve it. Combination analgesics (e.g., Fioricet) remain an option, and the newer CGRP-targeted therapies (gepants, mAbs) are considered safe here since they don't constrict vessels.
Acetaminophenis the preferred first-line acute agent. Triptans aren't teratogenic based on available registries, but safety data remain limited, so use is individualized. NSAIDs should be avoided in the third trimester. Valproic acid is contraindicated in pregnancy, and antiseizure agents generally should be avoided in patients of childbearing potential unless there's no reasonable alternative. Ergot alkaloids are contraindicated outright given their potent vasoconstrictive/oxytocic-like effects.
Older studies tied combined oral contraceptive (COC) use in migraineurs to roughly double the stroke risk, which drove broad discouragement of COCs in this population. Important nuance: those studies mostly used estrogen doses around 50 mcg, far higher than today's formulations. Current practice still leans conservative, especially in migraine with aura, where COCs are generally avoided. The safer default is progestin-only options: the minipill, depot progestin injections, progestin implants, or a hormonal IUD.
Attacks clustering tightly around menstruation can be managed with short-course, intermittent prophylaxis rather than daily dosing: an NSAID or a long-half-life triptan (frovatriptan or naratriptan) started about 6 days before expected onset and continued through the vulnerability window.
The most common primary headache overall, more frequent in women, and a fundamentally different mechanism from migraine: myofascial and central sensitizationrather than a vascular/neuropeptide cascade. Classified as episodic (infrequent or frequent) or chronic based on attack frequency and duration.
Pain likely originates from myofascial factors and peripheral sensitization of nociceptors, with central mechanisms contributing too. The trigger can be mental distress, abnormal motor/postural stress, or local release of myofascial irritants, alone or combined. This is a big reason muscle relaxants seem intuitive but actually lack evidence here - the pathology isn't primarily muscle spasm.
No premonitory symptoms and no aura, which is a fast way to distinguish it from migraine. Pain is mild-to-moderate, bilateralin a band-like "hatband" distribution, and nonpulsatile (as opposed to migraine's unilateral throb). Mild photophobia or phonophobia can occur (but not both together, unlike migraine), and pericranial or cervical muscles may be tender or show localized nodules on exam.
Migraine:unilateral, throbbing, moderate-severe, worsens with activity, GI symptoms nearly universal, aura possible. Tension-type:bilateral, band-like pressure, mild-moderate, not worsened much by routine activity, GI symptoms minimal, no aura. If you see both photophobia andphonophobia together, or GI symptoms, think migraine; isolated mild sensitivity to light or sound alone fits tension-type.
Simple analgesics (alone or with caffeine) and NSAIDs are the mainstay: acetaminophen, aspirin, diclofenac, ibuprofen, naproxen, ketoprofen, and ketorolac all work. Aspirin or acetaminophen combined with butalbital is effective, and codeine can help select patients, but butalbital/codeine combinations should be minimized given overuse risk. There is no evidence supporting muscle relaxantsdespite the intuitive appeal.
Cap butalbital-containing or combination analgesics at 10 days/month, and NSAIDs at 15 days/month, to prevent progression into chronic tension-type headache. Same underlying MOH mechanism as migraine, same fix.
Indicated when attacks exceed twice weekly, last longer than 3-4 hours, or cause substantial disability. TCAs are the most-used agent; venlafaxine, mirtazapine, gabapentin, topiramate, and tizanidine may also help. Trigger point lidocaine injections have limited supportive data, and evidence for botulinum toxin here is inconsistent (unlike its clear role in chronic migraine).
Nonpharmacologic carefor tension-type headache includes reassurance/counseling, stress management, relaxation training, and biofeedback; physical therapies (heat/cold, ultrasound, electrical nerve stimulation, massage, acupuncture, trigger point injections, occipital nerve blocks) have inconsistent evidence but are reasonable adjuncts.
| Parameter | When | Watching for |
|---|---|---|
| Headache diary(frequency, duration, severity, triggers) | Ongoing, every attack | Establishes need for prophylaxis and tracks response to it |
| Acute medication use frequency | Every visit | Approaching MOH thresholds (10-15 days/month depending on class) |
| Cardiovascular risk screen | Before first triptan/ergot dose in at-risk patients | Silent CAD, uncontrolled HTN, arrhythmia |
| Liver function tests | Baseline and periodically on valproate | Hepatotoxicity |
| Renal function | Baseline and periodically on topiramate, NSAIDs | Kidney stones (topiramate), renal impairment (NSAIDs) |
| Weight | Each visit on topiramate, TCA, or valproate | Unwanted weight loss (topiramate) or gain (TCA, valproate) |
| Blood pressure | Each visit on venlafaxine, each titration of a beta blocker or CCB | Dose-dependent rise (venlafaxine) or bradycardia/hypotension (beta blocker) |
| Cognitive/mood status | Each visit on topiramate | Word-finding difficulty, cognitive slowing, new/worsening depression |
| Response to prophylaxis | After a full 2-3 month trial | Target is ≥50% reduction in attack frequency before declaring success or failure |