Nervous System & Special Senses

CGRP antagonists for migraine prevention

Clinical Overview and When to Suspect Need for CGRP-Targeted Prevention

— Monoclonal antibodies (mAbs): erenumab (anti-receptor), fremanezumab, galcanezumab, eptinezumab (all anti-ligand). Monthly or quarterly SC injection (eptinezumab is IV q3 months).

— Small-molecule gepants used for prevention: atogepant (daily PO) and rimegepant (every-other-day PO, dual acute + preventive).

— ≥4 migraine days/month, or

— ≥2 days/month with significant disability (MIDAS ≥11), or

— Acute therapies contraindicated/ineffective/overused, or

— Hemiplegic migraine, migraine with brainstem aura, or prolonged auras.

— Failure or intolerance of ≥2 traditional preventives (β-blocker, topiramate, amitriptyline, valproate, candesartan) — most US payers require this.

— Medication-overuse headache where you need a non-overuseable preventive.

— Chronic migraine (≥15 headache days/month, ≥8 migrainous) — strong evidence base.

— Patients in whom topiramate (cognitive effects, kidney stones, pregnancy risk) or β-blockers (asthma, bradycardia, depression) are contraindicated.

Calcitonin gene-related peptide (CGRP) is a potent vasoactive neuropeptide released from trigeminal sensory neurons during migraine attacks; it drives neurogenic inflammation, vasodilation of meningeal vessels, and central pain sensitization.

CGRP-targeted preventives fall into two pharmacologic classes:

Who needs migraine prevention at all? Consider when patients have:

When to suspect a patient is a CGRP-class candidate specifically:

Step 3 management: Don't reflex to CGRP agents first-line on the exam. Start with a guideline-supported oral preventive matched to comorbidities (β-blocker if HTN, topiramate if obesity, amitriptyline if insomnia/depression, valproate if epilepsy — avoid in pregnancy). Document a ≥8-week trial at therapeutic dose before declaring failure.

Board pearl: CGRP mAbs have onset within 1 week for some patients — faster than the 2–3 months required for topiramate or amitriptyline titration, making them appealing in highly disabled patients once first-line options have failed.

Presentation Patterns and Key History

— Headache days per month and migraine days per month (these differ).

— Average severity (0–10), duration, photophobia/phonophobia, nausea, aura.

— Triggers: menstrual cycle, sleep deprivation, alcohol, skipped meals, weather.

— Acute medication use frequency — critical for diagnosing medication-overuse headache (MOH): triptans/combination analgesics ≥10 days/month, or simple analgesics ≥15 days/month.

— Chronic migraine (≥15 headache days/month for >3 months, ≥8 with migraine features).

— High-frequency episodic migraine (8–14 days/month) with disability.

— Migraine with prolonged or atypical aura, where triptans may be relatively avoided.

— Cardiovascular disease, uncontrolled HTN, Raynaud, prior stroke → use CGRP mAbs with caution (theoretical vasoconstriction; erenumab carries HTN warning).

— Constipation (especially erenumab — class warning).

— Depression/anxiety — gepants and mAbs are neutral; amitriptyline may help both.

— Pregnancy plans — see chunk 10.

The decision to start a CGRP-targeted preventive hinges on headache history, not on a single visit. Step 3 stems will give you a longitudinal picture.

Headache diary elements to elicit (and to ask the patient to track for 4 weeks before deciding):

Migraine subtypes that nudge toward CGRP therapy:

Prior preventive trials — document drug, maximum tolerated dose, duration (≥8 weeks), and reason for discontinuation (lack of efficacy vs adverse effect). Payors typically demand failure of two classes.

Comorbidities that influence choice:

Red flag (SNNOOP10) screen before labeling as primary migraine: systemic symptoms, neoplasm, neuro deficit, sudden onset, age >50 new headache, pattern change, positional, papilledema, precipitated by Valsalva, pregnancy, painful eye.

Board pearl: A 38-year-old woman with 18 headache days/month who has "failed" propranolol — ask about dose and duration. If she took 20 mg BID for 3 weeks, she hasn't truly failed it; optimize before escalating to a CGRP agent. Adequate trial = target dose × ≥8 weeks.

Physical Exam Findings and Baseline Assessment

— Vital signs, especially BP — erenumab has an FDA warning for new-onset or worsening HTN; document baseline. Recheck within weeks of starting.

— Cardiovascular exam — pulses, bruits, signs of peripheral vascular disease (theoretical vasoconstriction risk with CGRP blockade, though clinical events are rare).

— Full cranial nerve exam, fundoscopy (papilledema rules out IIH), gait, cerebellar testing.

— Skin exam at planned injection sites (abdomen, thigh, upper arm) — avoid active dermatitis, tattoos, scars.

— Papilledema, focal deficit, ataxia, asymmetric reflexes.

— New thunderclap headache (SAH, RCVS).

— Horner syndrome (dissection).

— Fever + meningismus, or immunocompromise with new headache.

— MIDAS (Migraine Disability Assessment): 0–5 little, 6–10 mild, 11–20 moderate, ≥21 severe.

— HIT-6 (Headache Impact Test): ≥60 = severe impact.

— MIDAS ≥11 or HIT-6 ≥60 generally justifies preventive therapy.

— Baseline BP, history of constipation, opioid use, prior bowel obstruction. Severe constipation requiring hospitalization has been reported.

Migraine is fundamentally a clinical diagnosis with a normal neurologic exam between attacks. Abnormal findings should prompt secondary headache workup before any preventive is started.

Required baseline exam before initiating a CGRP agent:

Findings that should halt the preventive plan and trigger imaging/workup:

Functional/disability assessment — quantify before treatment so response can be measured:

Hemodynamic and constipation screen specifically before erenumab:

Step 3 management: On the order screen for CCS, when starting a CGRP agent, order baseline BP, pregnancy test in reproductive-age women, and a brief targeted exam. Schedule a 4-week follow-up to reassess headache days and recheck BP. Don't order an MRI in classic migraine with normal exam — low yield and not cost-effective.

Board pearl: A perfectly normal interictal neurologic exam is the norm in migraine; any persistent deficit demands neuroimaging before preventive therapy.

Diagnostic Workup — Initial Evaluation and Pre-Treatment Labs

— Duration 4–72 hours untreated.

— ≥2 of: unilateral, pulsating, moderate–severe, aggravated by activity.

— ≥1 of: nausea/vomiting OR photophobia + phonophobia.

— Not better explained by another disorder.

— Any SNNOOP10 red flag.

— New headache after age 50.

— Aura that is always on the same side (consider AVM).

— Progressive headache pattern, postural headache, exertional/cough headache.

— Otherwise, routine neuroimaging in stable migraine with normal exam is not recommended (Choosing Wisely, AHS).

— CBC, BMP, TSH to screen for anemia, electrolytes, thyroid dysfunction contributing to headache.

— Pregnancy test in reproductive-age women.

— Lipid panel and HbA1c if cardiovascular risk factors — informs whether vasoactive concerns matter.

Migraine is diagnosed clinically by ICHD-3 criteria, not by labs or imaging. The pre-CGRP workup is therefore about (1) excluding secondary headache, (2) establishing safety baseline, and (3) satisfying payer requirements.

ICHD-3 migraine without aura — ≥5 attacks meeting:

Migraine with aura — ≥2 attacks with ≥1 fully reversible aura symptom (visual, sensory, speech, motor, brainstem, retinal) developing over ≥5 minutes, each symptom 5–60 minutes.

When to image (MRI brain preferred over CT for chronic headache):

Labs before CGRP therapy — no specific monitoring labs are required, but reasonable workup includes:

Headache diary for 4 weeks — the most cost-effective "test" you can order. Confirms frequency, identifies MOH, and provides the baseline against which response is measured.

Key distinction: Unlike topiramate (requires no specific labs but consider bicarbonate) or valproate (LFTs, CBC, pregnancy test mandatory), CGRP mAbs and gepants require no routine lab monitoring — a real practical advantage and a frequent test point.

Board pearl: A patient with stable migraine for 10 years, normal exam, and no red flags does not need an MRI before starting erenumab. Ordering one is low-value care.

Diagnostic Workup — Advanced and Confirmatory Studies

— Red flags as above.

— Suspected secondary headache: idiopathic intracranial hypertension (look for empty sella, posterior globe flattening, optic nerve tortuosity), Chiari I, pituitary lesion, demyelination, venous sinus thrombosis (add MRV).

— CT head only for acute settings (thunderclap, trauma) where SAH or hemorrhage is suspected; follow with LP if CT negative within 6 hours.

— Suspected cervical artery dissection (neck pain + Horner + headache).

— Suspected reversible cerebral vasoconstriction syndrome (RCVS) — recurrent thunderclap headaches in young women, often postpartum or with serotonergic drugs.

— Aneurysm screen if family history of SAH in ≥2 first-degree relatives or known polycystic kidney disease.

— Neurology referral before starting CGRP therapy is not universally required but is recommended for chronic migraine, status migrainosus, hemiplegic or brainstem aura, or diagnostic uncertainty.

— Cardiology clearance if recent MI, unstable CAD, severe PVD — though CGRP agents lack the absolute cardiovascular contraindications of triptans/ergots, caution is warranted.

— ICHD-3 diagnosis documented.

— ≥4 migraine days/month (episodic) or chronic migraine criteria.

— Documented failure/intolerance of ≥2 oral preventive classes at adequate dose and duration.

— Sometimes prior failure of onabotulinumtoxinA for chronic migraine.

Most patients heading to a CGRP-targeted preventive will not need advanced studies. Reserve them for atypical features or treatment-refractory cases.

MRI brain with and without contrast indications:

MRA/CTA:

Lumbar puncture with opening pressure — for suspected IIH (>25 cm H₂O in non-obese adults; >28 in obese), meningitis, or low-pressure headache (postural, after dural puncture).

Specialty consultation considerations:

Pre-authorization documentation — payers commonly require:

Step 3 management: When a stem asks "next best step" in a 32-year-old with classic migraine, normal exam, and no red flags, the answer is almost never advanced imaging — it's headache diary + start an evidence-based preventive.

Board pearl: Hemiplegic migraine and migraine with brainstem aura were historically triptan contraindications; CGRP antagonists are considered safe in these subtypes and are often preferred.

Risk Stratification and Treatment Selection Logic

— β-blockers (propranolol, metoprolol, timolol) — first-line; great if HTN, anxiety; avoid in asthma, bradycardia, depression.

— Topiramate — first-line; useful if obese; avoid in pregnancy (cleft palate, neural tube defects), kidney stones, glaucoma, depression.

— Amitriptyline/nortriptyline — useful if insomnia, depression, tension-type overlap; avoid in elderly (anticholinergic), prolonged QT.

— Valproate — avoid in pregnancy/reproductive-age women without contraception; helpful if comorbid epilepsy/bipolar.

— Candesartan — well tolerated alternative.

— Adequate trial = target dose × ≥8 weeks (some guidelines say 2–3 months).

— Inadequate response = <50% reduction in migraine days, or intolerable side effects.

— mAbs (erenumab, fremanezumab, galcanezumab, eptinezumab) — best for patients who prefer monthly/quarterly dosing or who have poor PO adherence.

— Gepants (atogepant, rimegepant) — daily/EOD oral; rimegepant doubles as acute therapy (unique value in patients with both needs).

Step 1 — Establish need for prevention: ≥4 migraine days/month with disability, or attacks not controlled by optimized acute therapy, or MOH risk.

Step 2 — Choose preventive class based on comorbidity matching (first-line oral options before CGRP per most US payers):

Step 3 — Define "failure" of an oral preventive:

Step 4 — Escalate to CGRP therapy when ≥2 classes have failed/are contraindicated:

OnabotulinumtoxinA (PREEMPT protocol, 155 units q12 weeks) — FDA-approved only for chronic migraine (≥15 headache days/month); often required before mAbs by payers in chronic migraine.

Combination therapy: CGRP mAb + gepant or + oral preventive is increasingly used in refractory chronic migraine, though evidence is emerging.

Step 3 management: Match the agent to the patient — chronic migraine with prior topiramate intolerance + obesity + needle phobia → atogepant PO daily. Chronic migraine in a patient who forgets daily pills → fremanezumab SC monthly or quarterly.

Board pearl: A ≥50% reduction in monthly migraine days at 3 months is the standard responder definition; if not achieved, consider switching CGRP agent or class.

Pharmacotherapy — CGRP Agents in Detail

— Erenumab (Aimovig): anti-CGRP receptor. 70 mg or 140 mg SC monthly. Warning: hypertension and constipation (most prominent of the class). Black box-level HTN warning added in 2020.

— Fremanezumab (Ajovy): anti-CGRP ligand. 225 mg SC monthly OR 675 mg SC quarterly — only quarterly option among mAbs that's SC.

— Galcanezumab (Emgality): anti-ligand. 240 mg SC loading dose, then 120 mg SC monthly. Also approved for episodic cluster headache (300 mg monthly).

— Eptinezumab (Vyepti): anti-ligand. 100 mg or 300 mg IV every 3 months — fastest onset (often within 24 hours); useful for high-frequency or chronic migraine and in clinic settings.

— Atogepant (Qulipta): 10, 30, or 60 mg PO daily. Approved for episodic and chronic migraine. Adjust for hepatic/renal impairment and CYP3A4 interactions.

— Rimegepant (Nurtec ODT): 75 mg ODT every other day for prevention; also 75 mg PRN for acute attacks (max 1/day, ≤18 doses/month). Unique dual indication.

— mAbs — minimal (cleared by reticuloendothelial proteolysis, not CYP).

— Gepants — avoid with strong CYP3A4 inhibitors (clarithromycin, itraconazole, ritonavir) and inducers (rifampin, phenytoin, carbamazepine, St. John's wort).

Anti-CGRP monoclonal antibodies — all are large molecules, do not cross the BBB significantly, are not hepatically metabolized, and require no dose adjustment for renal or hepatic impairment.

Gepants for prevention (small molecules, CGRP receptor antagonists, hepatically metabolized via CYP3A4):

Common adverse effects (class): injection-site reactions, constipation (especially erenumab), nasopharyngitis, fatigue, hypersensitivity reactions (rare anaphylaxis reported).

Drug interactions:

Step 3 management: When starting any CGRP agent, document baseline BP and headache frequency, set a 3-month reassessment, and counsel that benefit may appear within weeks but full effect takes 3 months. Continue acute therapy as needed.

Board pearl: Among CGRP mAbs, erenumab is the only receptor antagonist; the other three target the ligand. Erenumab also carries the most notable HTN and constipation signal.

Expanded Pharmacology — Sequencing, Switching, and Combination Strategies

— Optimize ≥2 oral preventives at therapeutic dose for ≥8 weeks each.

— In chronic migraine, consider onabotulinumtoxinA (PREEMPT: 155 units across 31 sites q12 weeks); responders show ≥30% reduction in headache days at 24 weeks.

— Add or switch to CGRP-targeted therapy. Many payers now allow CGRP agents earlier (after one oral failure).

— Lack of response to one mAb does not predict failure of another — switching, especially between anti-receptor (erenumab) and anti-ligand (the other three), can yield response in ~30–40%.

— Allow 3 months at adequate dose before declaring failure.

— When switching from mAb to gepant or vice versa, no washout required.

— CGRP mAb + atogepant — emerging evidence of additive benefit in refractory chronic migraine.

— CGRP mAb + onabotulinumtoxinA — studied; some additive benefit; payer coverage variable.

— CGRP mAb + traditional oral preventive — common; allows lower doses of poorly tolerated oral agents.

— Triptans remain first-line acute therapy in patients without CV contraindications.

— Ubrogepant or rimegepant (acute gepants) and lasmiditan are CV-safe acute options.

— Do not combine atogepant with rimegepant for prevention (redundant); rimegepant PRN for acute use during atogepant prevention is acceptable per practice patterns.

— Reassess at 3 months. If <50% reduction in migraine days, switch class.

— Consider drug holiday after 6–12 months of sustained benefit; many patients maintain improvement, others relapse and can restart.

Sequencing strategy for the chronic/refractory patient:

Switching within the CGRP class:

Combination therapy scenarios (specialist-level, increasingly supported):

Acute therapy alongside CGRP prevention:

Stopping CGRP therapy:

Cost considerations: CGRP agents are expensive ($600–$700/month list price); manufacturer copay cards and patient assistance programs are routinely used. Document medical necessity carefully.

Step 3 management: A chronic migraine patient with partial response to erenumab after 3 months — switch to an anti-ligand mAb (fremanezumab or galcanezumab) rather than abandon the class.

Board pearl: Rimegepant is uniquely both acute and preventive — a useful answer choice when the stem describes a patient who wants one drug for both purposes.

Special Populations — Elderly and Renal/Hepatic Impairment

— Pharmacokinetics largely unchanged with age; no dose adjustment.

— Watch BP more closely — erenumab-associated HTN may be clinically meaningful in patients with baseline HTN or CKD.

— Constipation — particularly important in elderly on opioids, anticholinergics, or with prior obstruction; erenumab carries the strongest signal.

— Cardiovascular caution — CGRP is a vasodilator and is upregulated in ischemia; theoretical concern about blunting protective vasodilation in patients with known CAD, PAD, or prior stroke. Trials excluded these patients. Use shared decision-making.

— mAbs: no dose adjustment in any stage of CKD including ESRD; not dialyzed (large molecules).

— Atogepant: avoid in severe renal impairment (CrCl <30 mL/min) and ESRD; for moderate impairment, 10 mg/day is the recommended dose.

— Rimegepant: avoid in ESRD/dialysis (CrCl <15); no adjustment for milder impairment.

— mAbs: no hepatic metabolism; no dose adjustment.

— Atogepant: avoid in severe hepatic impairment (Child-Pugh C); use with caution in moderate.

— Rimegepant: avoid in severe hepatic impairment; no adjustment for mild–moderate.

— Atogepant + strong CYP3A4 inhibitor (e.g., clarithromycin) → reduce atogepant dose.

— Atogepant + strong inducer (e.g., rifampin) → use 30 or 60 mg.

— Rimegepant — avoid with strong CYP3A4 inhibitors; avoid second dose within 48 hours if on moderate inhibitor.

Migraine in older adults is less common but exists; new headache after age 50 is a red flag that demands secondary workup (GCA, mass, subdural, cervicogenic, medication-induced) before labeling as migraine.

CGRP mAbs in elderly:

Renal impairment:

Hepatic impairment:

Polypharmacy and CYP3A4 interactions (especially relevant in elderly):

Step 3 management: A 72-year-old with chronic migraine, CKD stage 4, and HTN: mAbs are preferred over gepants (no renal dose adjustment); choose fremanezumab or galcanezumab over erenumab to minimize HTN risk.

Board pearl: CGRP mAbs are uniquely friendly to renal and hepatic impairment because they are cleared by proteolysis, not by kidney or liver.

Special Populations — Pregnancy, Lactation, Reproductive-Age Women

— All CGRP-targeted therapies are Category not formally assigned but pregnancy not recommended. Animal data show no clear teratogenicity, but human data are limited.

— CGRP is critical for uteroplacental blood flow and gestational vasodilation; chronic blockade has theoretical risk of preeclampsia, hypertension, growth restriction.

— Long half-life of mAbs (up to 5–6 months for some) means residual exposure persists after discontinuation — counsel women planning pregnancy to stop mAbs ≥5 months before conception when feasible.

— Gepants have short half-lives (atogepant ~11 h, rimegepant ~11 h) — easier to washout but still avoided.

— Lifestyle (sleep, hydration, regular meals), magnesium 400 mg/day, riboflavin 400 mg/day, CoQ10.

— Propranolol or metoprolol — generally considered safe (monitor for fetal growth restriction, neonatal bradycardia/hypoglycemia at term).

— Amitriptyline at low doses (some risk discussion).

— Avoid: valproate (neural tube defects, neurodevelopmental delay — contraindicated), topiramate (cleft palate, low birth weight), ACEi/ARBs.

Migraine peaks in women of reproductive age; ~60–70% improve during pregnancy (especially second/third trimesters) due to stable high estrogen, but a minority worsen.

CGRP agents in pregnancy — generally avoided:

Pregnancy-safe migraine prevention options:

Lactation: mAbs are large proteins with minimal oral bioavailability — likely safe but limited data; shared decision-making.

Contraception counseling — required before starting valproate or topiramate; advisable for CGRP agents until safety data mature.

Acute migraine in pregnancy: acetaminophen first-line; avoid NSAIDs in third trimester (premature ductus closure); triptans (sumatriptan most data) considered if needed; metoclopramide for nausea.

Pediatrics: CGRP mAbs are not yet FDA-approved in children; trials ongoing. Galcanezumab failed its pediatric efficacy trial. Pediatric migraine prevention rests on lifestyle, amitriptyline, topiramate, propranolol — though the CHAMP trial showed no difference vs placebo, raising the bar for evidence.

Step 3 management: A 28-year-old on erenumab who reports a positive pregnancy test — stop erenumab, transition acute therapy to acetaminophen ± sumatriptan, counsel about residual drug exposure, refer to maternal-fetal medicine if migraines worsen significantly.

Board pearl: Migraine with aura is an independent risk factor for ischemic stroke — avoid combined estrogen-containing contraception; use progestin-only or non-hormonal methods.

Complications and Adverse Outcomes

— Disability — among the top causes of years lived with disability worldwide.

— Migraine with aura → ~2× risk of ischemic stroke, higher with smoking and combined OCPs.

— Medication-overuse headache from frequent acute drug use.

— Status migrainosus (>72-hour debilitating attack) — may require IV therapy, steroids, hospitalization.

— Injection-site reactions — erythema, pain, pruritus; usually mild, self-limited.

— Constipation — most prominent with erenumab; severe cases with hospitalization and surgical evaluation reported. Counsel about fiber, hydration, prophylactic laxatives if predisposed.

— Hypertension — erenumab carries an FDA warning for new or worsening HTN; can occur within weeks; monitor BP at follow-ups.

— Hypersensitivity reactions — rare anaphylaxis; rash, urticaria, angioedema reported. Often delayed (days after injection).

— Raynaud phenomenon — class effect; new or worsening Raynaud has been described; rare digital ischemia reported.

— Alopecia, fatigue, muscle spasms — variable across agents.

— Hepatotoxicity was a concern with older gepants (telcagepant, withdrawn) — current gepants (atogepant, rimegepant, ubrogepant) have not shown clinically significant hepatotoxicity in trials, but caution in severe hepatic impairment remains.

— Nausea, fatigue, constipation.

— CGRP is upregulated as a protective vasodilator in ischemia; chronic blockade could theoretically blunt this. Trials excluded patients with significant CV disease, so real-world risk in high-CV-risk patients is incompletely characterized.

— No clear signal of MI or stroke in trials, but post-marketing surveillance ongoing.

Migraine itself carries morbidity:

Adverse effects of CGRP-targeted therapy:

Gepant-specific concerns:

Theoretical cardiovascular concerns:

Loss of efficacy / tachyphylaxis — uncommon but described; switching class can help.

Step 3 management: Patient on erenumab presents with worsening constipation and abdominal pain — order abdominal imaging if obstruction suspected, hold erenumab, manage with laxatives, and consider switching to an anti-ligand mAb or a gepant.

Board pearl: Migraine with aura + smoking + combined OCP is a triad that markedly elevates stroke risk — a classic exam combination demanding intervention.

When to Escalate — Consultation, Admission, and Specialty Referral

— Diagnostic uncertainty or atypical features.

— Chronic migraine (≥15 headache days/month) — especially if onabotulinumtoxinA candidate.

— Status migrainosus or recurrent ED visits.

— Hemiplegic migraine, migraine with brainstem aura, retinal migraine.

— Failure of ≥2 preventive classes including a CGRP agent.

— Suspected secondary headache.

— Thunderclap headache — emergent CT, LP if CT negative, consider SAH/RCVS/dissection.

— Focal neurologic deficit not consistent with prior aura — stroke workup.

— Fever + meningismus — LP, empiric antibiotics.

— Status migrainosus refractory to outpatient therapy — IV hydration, antiemetics (metoclopramide, prochlorperazine), ketorolac, IV magnesium, dihydroergotamine (Raskin protocol), dexamethasone to prevent recurrence.

— Severe persistent vomiting with dehydration.

Most migraine management, including CGRP initiation, can occur in primary care. Escalation is warranted in specific scenarios.

Neurology referral indications:

Headache specialist (subspecialty neurology) — refractory chronic migraine, complex MOH, candidates for nerve blocks, neuromodulation devices (sTMS, eTNS, REN, nVNS), or clinical trial enrollment.

Emergency department / inpatient escalation:

CCS pearl: For status migrainosus in the ED, sequential orders include: IV NS bolus, IV metoclopramide 10 mg + diphenhydramine 25 mg (prevent akathisia/dystonia), IV ketorolac 30 mg, IV magnesium sulfate 1–2 g, and IV dexamethasone 10 mg before discharge to reduce 72-hour recurrence. Counsel and arrange neurology follow-up within 1–2 weeks.

Cardiology consult before CGRP initiation if recent ACS, unstable angina, severe PAD, or recent stroke — though not absolute contraindications, shared decision-making is essential.

OB-GYN / MFM — pregnant patients with disabling migraine, or reproductive-age women requiring teratogenic preventives (valproate, topiramate) — contraception counseling.

Ophthalmology — visual aura that doesn't fit migraine pattern (e.g., monocular persistent loss); rule out retinal/optic causes.

Step 3 management: Frequent ED visits for migraine should trigger a systems-level intervention: schedule outpatient neurology, optimize preventive (CGRP if not already tried), establish MOH counseling, provide acute rescue plan, and coordinate care to break the cycle.

Key Differentials — Other Primary Headache Syndromes

— Bilateral, pressing/tightening (non-pulsating), mild–moderate, not aggravated by activity, no nausea, ≤1 of photophobia/phonophobia.

— Treat with NSAIDs/acetaminophen acutely; amitriptyline for prevention. CGRP agents not indicated.

— Severe unilateral orbital/temporal pain, 15–180 min, with ipsilateral autonomic features (conjunctival injection, lacrimation, nasal congestion, ptosis, miosis, eyelid edema), restlessness/agitation.

— Acute: 100% O₂ at 12 L/min via NRB, SC sumatriptan. Prevention: verapamil (titrate with ECG monitoring for AV block), prednisone bridge, lithium.

— Galcanezumab 300 mg SC monthly is FDA-approved for episodic cluster headache — only CGRP agent with this indication.

— Like cluster but shorter (2–30 min), more frequent (>5/day), and exquisitely responsive to indomethacin — diagnostic.

— Continuous unilateral headache with autonomic features; also indomethacin-responsive.

— Short-lasting unilateral neuralgiform attacks with autonomic features; treat with lamotrigine.

— Patient remembers the exact day headache started, daily ever since; difficult to treat.

— Brief electric-shock pains in V2/V3 territory; carbamazepine first-line.

Always confirm the diagnosis is migraine before committing to a CGRP-targeted preventive — these agents are FDA-approved for migraine (and galcanezumab for episodic cluster); they are not first-line for other primary headache disorders.

Tension-type headache (TTH):

Cluster headache:

Paroxysmal hemicrania:

Hemicrania continua:

SUNCT/SUNA:

New daily persistent headache (NDPH):

Trigeminal neuralgia:

Key distinction: Cluster = restless, autonomic, short attacks, indomethacin-non-responsive. Paroxysmal hemicrania = shorter, more frequent, indomethacin-responsive. Both have autonomic features and can mimic migraine but are managed entirely differently.

Board pearl: A patient with severe unilateral periorbital pain, lacrimation, and ptosis pacing the exam room is cluster, not migraine — give oxygen and SC sumatriptan, not a CGRP mAb (unless using galcanezumab for episodic cluster prevention).

Key Differentials — Secondary Headache Causes

— Thunderclap headache, "worst of life," peak within seconds. CT head non-contrast (sensitivity ~98% within 6 hours), LP if CT negative and suspicion remains (xanthochromia).

— Unilateral neck/face pain, partial Horner syndrome, sometimes preceding TIA/stroke. MRA or CTA neck.

— Recurrent thunderclap headaches over days–weeks, often postpartum or with serotonergics/sympathomimetics. MRA shows "string of beads"; resolves over weeks. Calcium channel blockers; avoid triptans/ergots/CGRP triggers.

— Headache + focal deficits/seizures, especially postpartum, OCP use, hypercoagulable states. MRV diagnostic. Anticoagulate.

— Obese young woman, daily headache, transient visual obscurations, papilledema, pulsatile tinnitus, diplopia from CN VI palsy. LP opening pressure >25 cm H₂O. Acetazolamide, weight loss.

— Age >50, new headache, jaw claudication, scalp tenderness, vision loss, polymyalgia symptoms. ESR/CRP elevated; start high-dose prednisone immediately then biopsy.

— Headache ≥15 days/month with regular overuse of acute meds (triptans/combination ≥10 days; simple analgesics ≥15 days). Withdraw overused med; bridge with steroids or naproxen scheduled; start preventive (CGRP agents are excellent here — they don't cause MOH).

— After concussion; often migraine-like. Limited CGRP data but increasingly used off-label.

Before committing to expensive long-term CGRP therapy, exclude secondary headache mimics — missing these is a high-stakes error.

Subarachnoid hemorrhage (SAH):

Cervical artery dissection:

Reversible cerebral vasoconstriction syndrome (RCVS):

Cerebral venous sinus thrombosis (CVST):

Idiopathic intracranial hypertension (IIH):

Giant cell arteritis:

Medication-overuse headache (MOH):

Mass lesions, hydrocephalus, sinusitis, CO poisoning, sleep apnea-related morning headache — context-dependent.

Post-traumatic headache:

Key distinction: A 45-year-old new daily headache + transient visual blurring + BMI 38 + papilledema = IIH, not migraine. Acetazolamide, weight loss, ophthalmology — not erenumab.

Step 3 management: When MOH is identified, discontinue the overused acute medication, educate the patient, and start a non-overuseable preventive — CGRP mAbs or atogepant are ideal because they don't perpetuate MOH and have rapid onset.

Secondary Prevention, Lifestyle, and Long-Term Plan

— Sleep — consistent 7–9 hours; treat OSA; avoid sleep debt and oversleeping.

— Exercise — aerobic 30 min ≥3×/week; comparable efficacy to topiramate in some studies.

— Eat — regular meals, avoid skipping; identify dietary triggers (variable: alcohol especially red wine, aged cheese, MSG, nitrates, aspartame).

— Diary — track headaches, triggers, medication use.

— Stress — CBT, mindfulness, biofeedback — evidence-based for migraine prevention.

— Magnesium 400–600 mg/day (diarrhea limits dose).

— Riboflavin (B2) 400 mg/day.

— CoQ10 100 mg TID.

— Butterbur — historically used but hepatotoxicity concerns — avoid unless PA-free preparations confirmed.

— Feverfew — modest evidence.

— Treat obesity (independent risk factor for chronic migraine).

— Treat OSA, depression, anxiety — all comorbid and bidirectionally worsen migraine.

— Smoking cessation, particularly with aura (stroke risk).

— Limit caffeine to <200 mg/day to avoid rebound.

— Reassess every 3–6 months.

— Consider a trial off therapy after 6–12 months of sustained ≥50% reduction; many patients tolerate discontinuation, others relapse and restart.

— First-line: triptan + NSAID at attack onset; antiemetic if nausea.

— CV-safe alternatives: ubrogepant, rimegepant, lasmiditan.

— Limit acute medication days to <10/month to prevent MOH.

CGRP therapy is one pillar of a comprehensive migraine prevention plan. Lifestyle modification remains essential and exam-friendly.

SEEDS mnemonic for lifestyle migraine prevention:

Nutraceuticals (Level B evidence):

Manage modifiable risk factors:

Vaccinations and routine care during CGRP therapy — no contraindications; standard adult immunization schedule.

Duration of CGRP therapy:

Acute rescue plan alongside prevention:

Step 3 management: At each follow-up, ask the 4 P's: pain frequency/severity, prevention adherence, PRN (acute) use frequency, and patient goals. Adjust therapy stepwise.

Board pearl: Stable patients on CGRP therapy with sustained response should still be counseled on lifestyle, MOH prevention, and acute rescue planning — the drug is one part of a multimodal strategy.

Follow-Up, Monitoring, and Patient Counseling

— 4 weeks: check BP (especially erenumab), assess tolerability, injection-site issues, constipation, early efficacy signal.

— 3 months: formal efficacy assessment using monthly migraine days (MMD), MIDAS, HIT-6.

— 6 and 12 months: continued reassessment; consider drug holiday discussion at 12 months if sustained response.

— ≥50% reduction in MMD is the standard responder threshold.

— Some patients are "super-responders" (≥75% or 100% reduction); document carefully.

— Non-responders at 3 months → switch class (anti-receptor ↔ anti-ligand, or mAb ↔ gepant).

— BP at every visit for erenumab; periodically for others.

— Bowel habits — proactive constipation counseling, especially erenumab.

— Mood, sleep, function — migraine improvement often improves these; track to demonstrate value.

— No routine lab monitoring required for any CGRP agent — a teaching point.

— Onset of benefit: days to weeks for some (especially eptinezumab IV); full effect at 3 months.

— Continue acute medications and oral preventives initially; don't stop other therapies abruptly.

— Injection technique training for SC agents (autoinjectors available).

— Report severe constipation, new HTN, allergic symptoms, Raynaud-like symptoms.

— Discuss pregnancy plans — stop ≥5 months before conception when possible.

— Communicate with PCP, neurologist, OB-GYN (for women of reproductive age), and pharmacy regarding refill cadence (mAbs are specialty pharmacy distributed).

— On hospital admission, confirm last dose date and resume on schedule when stable.

Follow-up cadence after initiating a CGRP agent:

Defining response:

Monitoring parameters:

Patient counseling at initiation:

Headache diary or app (Migraine Buddy, N1-Headache) — improves accuracy and engagement.

Transitions of care:

Cost and access counseling — copay assistance, prior authorization renewal annually; document response to support continuation.

Step 3 management: A patient at 3-month follow-up reports MMD dropped from 16 to 12 (25% reduction) on erenumab 70 mg — first escalate to erenumab 140 mg, then if no response at next 3-month mark, switch to an anti-ligand mAb.

Board pearl: Treatment continuation criteria typically require documented ≥50% reduction in MMD or substantial functional improvement at the 3-month mark — payers will audit.

Ethical, Legal, and Patient Safety Considerations

— Discuss the long half-life of mAbs (weeks to months) and inability to "stop" the drug quickly.

— Disclose pregnancy uncertainty and the recommendation to discontinue ≥5 months before conception — particularly important in reproductive-age women.

— Discuss cost, the chronic nature of therapy, and that benefit may not persist after discontinuation.

— Cardiovascular caveats in patients with CV disease — shared decision-making documentation.

— Pediatric use, post-traumatic headache, vestibular migraine, and chronic daily headache that doesn't strictly meet migraine criteria are off-label. Document rationale and informed consent.

— CGRP agents are expensive; PA processes can delay care for weeks. Document failed trials thoroughly to expedite approval and ensure equitable access. Patients from underserved backgrounds may face disproportionate barriers.

— Patients switching insurance may lose CGRP coverage mid-course — proactively check formulary, document medical necessity, and arrange continuity to avoid rebound migraine cycles.

— Hospitalization: confirm last dose and resume on schedule; missed doses can lead to attack rebound.

— Pregnancy diagnosis on an active mAb — counsel, stop drug, transition acute therapy, communicate with OB; document residual exposure risk.

— Patients should be educated that frequent acute drug use perpetuates the disease they're trying to treat. Provide written limits (acute meds <10 days/month).

— Aura with visual or motor symptoms — counsel patients not to drive during aura; document discussion. Some jurisdictions have reporting requirements for impaired drivers.

— Adverse events to FDA MedWatch — anaphylaxis, severe constipation requiring hospitalization, new severe HTN, possible CV events.

Informed consent for CGRP therapy — go beyond routine:

Off-label use considerations:

Prior authorization and access equity:

Transitions of care risk (high-yield Step 3 theme):

Medication-overuse counseling is an ethical duty:

Driving and occupational safety:

Mandatory reporting considerations:

Disability paperwork — provide accurate, evidence-based documentation for FMLA, accommodations; avoid both over- and under-statement.

Step 3 management: A 32-year-old woman on galcanezumab reports a positive pregnancy test — stop the drug today, document counseling about residual exposure (drug half-life ~27 days), notify OB, switch acute therapy to acetaminophen, and arrange MFM consult if migraines are disabling. Document the shared decision in the chart.

High-Yield Associations and Rapid-Fire Clinical Facts

Erenumab — only anti-CGRP receptor mAb; HTN and constipation warnings most prominent.

Fremanezumab — anti-ligand; only mAb with quarterly SC dosing option (675 mg q3 months).

Galcanezumab — anti-ligand; only CGRP agent approved for episodic cluster headache (300 mg monthly).

Eptinezumab — only IV CGRP mAb; q3 months; fastest onset (often within 24 hours).

Atogepant — daily oral gepant for prevention; renal/hepatic dose adjustment required.

Rimegepant — only agent FDA-approved for BOTH acute and preventive treatment of migraine.

Ubrogepant — acute only, not preventive.

Lasmiditan — 5-HT1F agonist, acute only; CV-safe; driving prohibited for 8 hours post-dose.

Migraine with aura + smoking + combined OCP = high stroke risk; switch to progestin-only or non-hormonal contraception.

MOH thresholds: triptans/combination/opioids/ergots ≥10 days/month; simple analgesics ≥15 days/month for ≥3 months.

Chronic migraine definition: ≥15 headache days/month for >3 months, with ≥8 having migraine features.

OnabotulinumtoxinA: FDA-approved only for chronic migraine; PREEMPT protocol, 155 units, q12 weeks.

Status migrainosus: attack >72 hours; treat with IV fluids, metoclopramide, ketorolac, magnesium, dexamethasone.

Indomethacin-responsive headaches: paroxysmal hemicrania, hemicrania continua — not migraine.

Cluster acute therapy: 100% O₂ 12 L/min + SC sumatriptan; verapamil is preventive mainstay.

CGRP mAbs: no CYP metabolism, no renal/hepatic dose adjustment, no routine lab monitoring.

Gepants are CYP3A4 substrates — beware interactions with macrolides, azoles, ritonavir, rifampin.

Pregnancy migraine prevention: lifestyle, magnesium, riboflavin, propranolol — avoid valproate, topiramate, ACEi/ARBs, CGRP agents.

Aura criteria: fully reversible, develops over ≥5 min, each symptom 5–60 min.

Responder definition: ≥50% reduction in monthly migraine days at 3 months.

Board pearl: When the stem hints at the patient wanting a single drug for both acute and preventive use, the answer is rimegepant.

Board Question Stem Patterns

— A 35-year-old with 10 migraine days/month, well-controlled HTN, normal exam, has tried propranolol (max dose, 3 months, no benefit) and topiramate (cognitive side effects). What next?

— Answer: A CGRP-targeted agent (mAb or atogepant). Two prior preventive failures justify escalation.

— Migraine + HTN → propranolol or candesartan first.

— Migraine + obesity → topiramate first.

— Migraine + depression/insomnia → amitriptyline first.

— Migraine + epilepsy → valproate (not in pregnancy) or topiramate.

— Answer: Hold erenumab, manage symptom, switch to an anti-ligand mAb (fremanezumab/galcanezumab) or to a gepant.

— "29-year-old on galcanezumab discovers she's 6 weeks pregnant. Next step?" → Stop drug, counsel, OB referral, switch acute therapy to acetaminophen.

— Patient using sumatriptan 15 days/month with worsening daily headache → diagnose MOH, withdraw overused agent, start non-overuseable preventive (CGRP agent ideal), bridge with naproxen or steroids.

— Unilateral periorbital pain, lacrimation, ptosis, restless patient → 100% O₂ + SC sumatriptan acutely; verapamil for prevention; galcanezumab if episodic cluster.

— Obese young woman with daily headache, papilledema, transient visual obscurations → IIH, not migraine; do not start CGRP; LP, acetazolamide, weight loss.

— Woman with migraine with aura on combined OCP, smoker → switch to progestin-only contraception; counsel smoking cessation; this is stroke prevention.

— No response to erenumab at 3 months → switch to anti-ligand mAb, not abandon class.

— Chronic migraine + CKD stage 4 → CGRP mAb preferred over gepant (no dose adjustment, no renal clearance issues).

Stem 1 — "Which preventive should you start?"

Stem 2 — Comorbidity-driven choice before CGRP:

Stem 3 — "Patient on erenumab develops severe constipation/HTN":

Stem 4 — Pregnancy on CGRP:

Stem 5 — Medication overuse:

Stem 6 — Cluster headache mimicking migraine:

Stem 7 — Secondary headache trap:

Stem 8 — Aura + contraception:

Stem 9 — Failure of one CGRP agent:

Stem 10 — Renal impairment:

Board pearl: Many CGRP stems test the prerequisite step — confirm migraine diagnosis, exclude red flags, optimize and document failure of standard preventives, then escalate. Don't skip steps.

One-Line Recap

CGRP-targeted therapies — anti-receptor mAb erenumab, anti-ligand mAbs fremanezumab/galcanezumab/eptinezumab, and gepants atogepant and rimegepant — are evidence-based migraine preventives indicated after failure or intolerance of ≥2 traditional oral preventive classes, with monitoring focused on BP (especially erenumab), constipation, and pregnancy planning rather than routine labs.

Rapid-fire high-yield recaps:

Indication threshold: ≥4 migraine days/month with disability, or chronic migraine, or MOH — typically after failure of ≥2 oral preventives at therapeutic dose for ≥8 weeks. Match initial oral preventive to comorbidities (β-blocker, topiramate, amitriptyline, valproate, candesartan).

Class differentiation: Erenumab targets the CGRP receptor; the other mAbs and gepants target the ligand/peptide. mAbs are clean for renal/hepatic impairment (no adjustment, no CYP metabolism); gepants are CYP3A4 substrates and need dose adjustment in moderate–severe organ dysfunction. Rimegepant uniquely treats both acute and preventive; galcanezumab uniquely treats episodic cluster.

Safety and special populations: Monitor BP for erenumab-related HTN; counsel about constipation, injection reactions, and rare Raynaud/hypersensitivity. Avoid CGRP agents in pregnancy and stop mAbs ≥5 months before planned conception due to long half-life. Migraine with aura + smoking + combined OCP is a stroke-risk combo demanding contraceptive change.

Follow-up and decision rules: Reassess at 3 months — ≥50% reduction in monthly migraine days = responder; if not, switch within class (anti-receptor ↔ anti-ligand) or between classes (mAb ↔ gepant). Always pair pharmacotherapy with SEEDS lifestyle counseling, MOH prevention (acute meds <10 days/month), and a written acute rescue plan, and consider a drug holiday after 6–12 months of sustained benefit.

Step 3 final pearl: Confirm the diagnosis, document failed trials, choose the agent by comorbidity and patient preference, monitor BP and bowels, and plan transitions of care — especially around pregnancy and insurance changes — to keep patients on therapy that works.