Migraine medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Andrea Tamayo Soto [2]

Migraine pharmacotherapy includes acute (abortive) treatment and preventive treatment. This microchapter covers analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), triptans, gepants, ditans, ergot derivatives, oral preventive medications, calcitonin gene-related peptide (CGRP)-targeted therapies, onabotulinumtoxinA, and pharmacologic management of medication-overuse headache. Neuromodulation devices, nerve blocks and other procedures, lifestyle interventions, and cost-effectiveness are addressed separately.

Acute therapy should generally be administered early in the headache phase. Goals include rapid pain freedom, restoration of function, sustained benefit, and avoidance of excessive acute medication use.^[1] Opioids and barbiturate-containing combinations should generally be avoided because of dependence, medication-overuse headache, and less favorable outcomes.^[2]

For nonpregnant adults with acute episodic migraine, the 2025 American College of Physicians (ACP) guideline recommends adding a triptan to an NSAID when an NSAID alone provides inadequate relief for moderate-to-severe attacks (strong recommendation; moderate-certainty evidence). When NSAIDs are contraindicated or not tolerated, adding a triptan to acetaminophen is a conditional recommendation based on low-certainty evidence.^[3]

The American Headache Society (AHS) recommends NSAIDs, acetaminophen, or appropriate combination analgesics for many mild-to-moderate attacks and migraine-specific agents for moderate-to-severe attacks or attacks responding inadequately to nonspecific therapy.^[4]

Selected evidence-supported adult doses for acute migraine include:^[2][1]

Aspirin plus acetaminophen plus caffeine is an effective over-the-counter combination.^[1] Metoclopramide may be added when nausea or vomiting limits oral treatment.

Triptans are 5-HT_1B/1D receptor agonists used for moderate-to-severe migraine or attacks responding inadequately to nonspecific therapy.^[4] A 2024 network meta-analysis of 137 randomized trials ranked eletriptan among the most effective oral acute treatments and highest among evaluated oral triptans for 2-hour pain freedom versus placebo.^[6]

A triptan should generally be assessed across approximately three attacks before being considered ineffective unless intolerance requires earlier discontinuation. Failure of one triptan does not establish class failure, and switching to another triptan may be beneficial.^[4]

For inadequate response to either agent alone, a triptan plus an NSAID may improve outcomes. The fixed combination of sumatriptan 85 mg plus naproxen sodium 500 mg has particularly favorable evidence for acute episodic migraine.^[3]

Triptans are generally contraindicated in patients with ischemic cardiovascular disease, prior stroke or transient ischemic attack, uncontrolled hypertension, or significant peripheral vascular disease. They are also generally avoided in hemiplegic migraine and migraine with brainstem aura. Product-specific contraindications and drug interactions should be reviewed before prescribing.^[2][1]

Gepants are small-molecule CGRP receptor antagonists that provide non-vasoconstrictive acute treatment and may be particularly useful when triptans are contraindicated, ineffective, or poorly tolerated.^[4][8]

Indirect comparative evidence generally favors several triptans over gepants for 2-hour pain freedom, although direct head-to-head evidence remains limited.^[3][6][9]

Lasmiditan, a selective 5-HT_1F receptor agonist, is non-vasoconstrictive but is associated with central nervous system adverse effects including dizziness and sedation and carries an 8-hour post-dose driving restriction.^[9] The FDA Orange Book listed both 50-mg and 100-mg Reyvow (lasmiditan) tablets as discontinued from marketing in June 2026; lasmiditan therefore should not be assumed to be commercially available in the United States.^[10]

Dihydroergotamine (DHE) has a limited but clinically useful role when other migraine-specific therapies are ineffective or unsuitable and may be used in refractory status migrainosus.^[4] Nasal and injectable formulations are available; dosing is formulation-specific.

For the traditional 1 mg/mL injectable DHE formulation, the FDA-labeled dose is 1 mg IV, IM, or SC and may be repeated at 1-hour intervals as needed. The maximum is 3 mg in 24 hours by the IM or SC route and 2 mg in 24 hours by the IV route; total weekly dosage should not exceed 6 mg.^[11]

Ergot derivatives are contraindicated in pregnancy and significant cardiovascular or peripheral vascular disease. DHE should not be administered within 24 hours of a triptan or another ergot-type medication, and concomitant strong CYP3A4 inhibitors are contraindicated because of the risk of serious ischemic complications.^[11]

The updated AHS evidence assessment of parenteral treatment for adults presenting to the emergency department recommends IV prochlorperazine as a Level A treatment that must be offered to eligible patients without contraindications. IV ketorolac and IV metoclopramide are Level B treatments that should be offered when appropriate; IV dexamethasone may be offered (Level C). IV hydromorphone must not be offered for acute migraine treatment (Level A).^[12]

Selected regimens include:

• Prochlorperazine 10–12.5 mg IV (Level A); this is the most strongly supported parenteral dopamine-receptor antagonist in the updated AHS guideline.^[12]
• Metoclopramide 10 mg IV (Level B); a reasonable dopamine-receptor antagonist when prochlorperazine is unavailable, contraindicated, or otherwise unsuitable.^[12]
• Ketorolac 30 mg IV (Level B).^[12]
• A single dose of IV dexamethasone may be used as an adjunct, particularly to reduce early headache recurrence after otherwise successful acute treatment.^[13] The optimal dose is uncertain; a Class I randomized trial found that 16 mg IV was not superior to 4 mg IV when added to metoclopramide 10 mg IV.^[14]

Dopamine-receptor antagonists such as prochlorperazine and metoclopramide can cause akathisia and other extrapyramidal adverse effects; individual risk should be considered when selecting and monitoring therapy.^[12]

Preventive therapy should be considered when one or more of the following are present:^[4]

• Approximately 4 or more migraine days per month.
• Significant disability despite optimized acute treatment.
• Frequent acute medication use, particularly more than approximately 2 days per week.
• Contraindication, intolerance, or inadequate response to acute therapies.
• Patient preference for preventive treatment.

Selection should incorporate migraine frequency and disability, prior treatment response, comorbidities, adverse-effect profile, pregnancy potential, and route or dosing preferences.

The 2025 ACP guideline recommends beginning episodic migraine prevention with selected traditional oral medications before CGRP-targeted therapy, whereas the AHS 2024 position statement considers CGRP-targeted therapy an appropriate first-line preventive option without requiring prior failure of conventional preventive medications.^[15][16]

The AHS 2024 position statement considers CGRP-targeted medications a first-line preventive option based on accumulated efficacy, tolerability, and safety evidence.^[16] ACP 2025 instead recommends CGRP-targeted therapy after inadequate response or intolerance to its preferred traditional oral agents.^[15] This represents an important current guideline difference rather than a single universally accepted treatment sequence.

Common adverse effects of CGRP monoclonal antibodies include injection-site reactions and, particularly with erenumab, constipation. Serious adverse events have been uncommon in available trials; long-term cardiovascular safety in selected high-risk populations continues to be studied.^[16][8]

OnabotulinumtoxinA is FDA-approved for prophylaxis of headache in adults with chronic migraine, defined in the labeling as at least 15 headache days per month with headache lasting 4 hours per day or longer. Safety and effectiveness have not been established for prophylaxis of episodic migraine.^[18]

• The FDA-labeled chronic migraine regimen is 155 units IM divided among 31 sites across 7 head and neck muscle areas every 12 weeks.^[18]
• The PREEMPT treatment paradigm permits 155–195 units across 31–39 sites every 12 weeks when additional follow-the-pain injections are used.^[19]
• Some patients who fail to respond after the first treatment cycle respond during the second or third cycle; efficacy should generally be assessed over 2–3 cycles when treatment is otherwise tolerated.^[20]

Medication-overuse headache should be identified and treated because ongoing overuse can perpetuate high-frequency headache and complicate migraine management.

The ICHD-3-based definition used in the available evidence is headache on at least 15 days/month in a patient with a pre-existing headache disorder who regularly overuses acute headache medication for more than 3 months. Overuse thresholds are at least 15 days/month for simple analgesics and at least 10 days/month for triptans, ergot derivatives, opioids, or combination analgesics.^[21][22]

Management includes:

1. Education regarding the relationship between frequent acute medication use and medication-overuse headache.
2. Withdrawal or reduction of the overused medication. Abrupt withdrawal is commonly used for triptans and many simple analgesics; opioids, barbiturates, and benzodiazepines generally require gradual tapering rather than abrupt cessation.^[23]
3. Initiation or optimization of preventive therapy. Preventive treatment may be started during medication withdrawal rather than waiting for withdrawal to be completed.^[24]
4. Short-term bridging treatment may be considered during withdrawal when clinically appropriate; evidence is heterogeneous and the optimal strategy is not established.^[23]

Withdrawal combined with preventive treatment produced consistent improvements in headache and medication-use outcomes in a randomized clinical trial, although treatment should be individualized.^[24] CGRP-targeted preventive therapy can also be effective in chronic migraine with medication overuse and does not invariably require successful withdrawal before initiation.^[25]

Treatment during pregnancy requires individualized assessment of maternal benefit and fetal risk.

• Acetaminophen is the preferred acute medication in the provided evidence.
• Sumatriptan has comparatively reassuring pregnancy experience but is not specifically approved for treatment of migraine during pregnancy.^[1]
• Valproate and topiramate should not be used for migraine prevention during pregnancy because of teratogenic risk.^[15][17]
• Propranolol and amitriptyline may be considered for prevention when clinically appropriate.^[1]
• CGRP-targeted therapies lack adequate pregnancy safety data and should generally be avoided during pregnancy.^[15]

Triptans and ergot derivatives are generally contraindicated in established ischemic cardiovascular or cerebrovascular disease. Gepants provide non-vasoconstrictive acute alternatives.^[2][8] CGRP-targeted preventive therapies have not demonstrated a major cardiovascular safety signal in available evidence, but long-term data in patients at high vascular risk remain limited.^[8]

Fremanezumab is FDA-approved for prevention of episodic migraine in pediatric patients aged 6–17 years who weigh at least 45 kg. The recommended pediatric dose is 225 mg subcutaneously monthly.^[26]

• Avoid routine opioid and barbiturate-containing treatment for migraine because of dependence and medication-overuse risk.^[2]
• IV hydromorphone should not be offered for acute migraine requiring parenteral treatment in the emergency department (AHS Level A: must not offer).^[12]
• Avoid triptans and ergot derivatives in patients with major cardiovascular or cerebrovascular contraindications.^[2]
• Avoid valproate and topiramate for migraine prevention during pregnancy.^[15][17]
• Limit excessive acute medication use and reassess patients approaching medication-overuse thresholds.^[22]