Migraine Medications Compared

Eletriptan has a longer half-life (~4 hours) than sumatriptan or rizatriptan, which may translate into a lower rate of headache recurrence — the return of migraine within 24 hours after initial response, a clinically common problem with shorter-acting triptans. Clinical trials have demonstrated high consistency of response and low rates of adverse events. Eletriptan is available in two tablet strengths and is metabolized by CYP3A4, meaning potent CYP3A4 inhibitors (such as clarithromycin, ketoconazole, and certain HIV protease inhibitors) can meaningfully increase eletriptan exposure and should be avoided within 72 hours of use.

Frovatriptan has by far the longest half-life of any triptan at approximately 26 hours — nearly ten times longer than sumatriptan. This extended half-life makes it particularly well-suited for menstrual migraine, where attacks are predictable and often prolonged. Short-term prophylaxis with frovatriptan during the perimenstrual window (typically starting 2 days before the expected onset of menstruation) is a clinical strategy supported by evidence for patients with reliably timed menstrual migraine. The long half-life also contributes to a very low rate of headache recurrence compared to shorter-acting triptans.

The trade-off is a slower onset of action compared to agents like rizatriptan or sumatriptan SC. For patients whose attacks escalate quickly and require rapid relief, frovatriptan is not the optimal choice. Standard triptan cardiovascular contraindications apply.

Naratriptan (Amerge) has a half-life of approximately 6 hours — longer than sumatriptan — and a relatively slow onset. This profile makes it better tolerated with a lower side-effect burden than some triptans, but less appropriate for attacks that require rapid relief. The 1mg and 2.5mg tablet strengths are available. Naratriptan is occasionally used as part of a short-term perimenstrual prophylaxis strategy, similar to frovatriptan.

Almotriptan (Axert) has a half-life of 3–4 hours and is notable for FDA approval in adolescents aged 12–17 with a history of migraine with aura — one of the few triptans with a pediatric indication. It has a favorable tolerability profile and is available in 6.25mg and 12.5mg tablets. Both agents carry standard triptan cardiovascular contraindications.

Ubrogepant (Ubrelvy) was the first oral CGRP receptor antagonist approved by the FDA for acute migraine treatment (December 2019). It is indicated for adults with or without aura and has no cardiovascular contraindications. A second dose may be taken at least 2 hours after the first dose if the migraine has not resolved. Clinical trial data demonstrated consistent pain freedom and freedom from the most bothersome symptom at 2 hours post-dose.

Ubrogepant is metabolized by CYP3A4. Potent CYP3A4 inhibitors (such as clarithromycin, ketoconazole, itraconazole) significantly increase ubrogepant exposure, and the dose should be adjusted accordingly. Potent CYP3A4 inducers (rifampin, carbamazepine) substantially reduce its effectiveness. Ubrogepant is manufactured by AbbVie and is currently available only as a branded product.

Rimegepant (Nurtec ODT) holds a uniquely dual FDA approval: it is indicated both for acute treatment of migraine (as-needed) and for preventive treatment (every other day on a scheduled basis). It is the only drug approved for both indications simultaneously in a single formulation. The orally disintegrating tablet dissolves in seconds and requires no water, making it practical in settings where nausea accompanies the attack.

FDA approved in February 2020 for acute treatment and in May 2021 for prevention, rimegepant belongs to the same gepant class and shares ubrogepant's freedom from cardiovascular contraindications. Like ubrogepant, it is a CYP3A4 substrate and moderate CYP3A4/P-gp inhibitor — drug interaction review is important before concurrent use with CYP3A4-sensitive medications. Rimegepant was originally developed by Biohaven and is now marketed by Pfizer.

Zavegepant (Zavzpret) is the first and only CGRP receptor antagonist delivered as a nasal spray. FDA-approved in March 2023, it is administered as a single-use nasal spray, making it the fastest-acting gepant on the market — nasal delivery allows absorption that partially bypasses the GI tract, which is advantageous during attacks when gastric stasis or nausea impairs oral drug absorption. Zavegepant is indicated for acute treatment of migraine in adults, with or without aura.

Like other gepants, zavegepant carries no cardiovascular contraindications. Its nasal route also makes it a practical option for patients who prefer not to use injections but need faster onset than oral therapies provide. Manufactured by Pfizer, zavegepant is available as a single-dose nasal spray device.

Lasmiditan (Reyvow) represents a distinct mechanistic class — it is a highly selective 5-HT1F receptor agonist, a target that is present on neurons but not on vascular smooth muscle. This selectivity means lasmiditan does not cause vasoconstriction, and therefore carries no cardiovascular contraindications — making it an option for patients with coronary artery disease, uncontrolled hypertension, or a history of stroke who cannot use triptans. FDA-approved in October 2019, it is indicated for acute treatment of migraine with or without aura in adults.

The primary safety concern with lasmiditan is central nervous system depression. It causes sedation, dizziness, and cognitive effects in a meaningful proportion of patients — likely due to its CNS penetration and 5-HT1F receptor activity in the brainstem and cortex. Due to these effects, patients must not drive or operate heavy machinery for at least 8 hours after taking lasmiditan, regardless of how they feel. For this reason, lasmiditan is classified as a Schedule V controlled substance by the DEA — the first and only migraine-specific prescription drug in this category. It is manufactured by Eli Lilly.

Ergotamine alkaloids were among the earliest effective migraine-specific treatments and remain in limited clinical use, though they have been largely supplanted by triptans and gepants for most patients. They work by constricting dilated cranial blood vessels through multiple receptor interactions including 5-HT, dopamine, and alpha-adrenergic receptors. This broad vasoconstrictive action is both the source of their efficacy and their primary toxicity risk.

Ergotamine/caffeine (Cafergot) is available as oral tablets and rectal suppositories (the 2mg rectal form is useful when vomiting prevents oral intake). Caffeine is included to enhance ergotamine absorption. Use should be limited to no more than 2 days per week to reduce the risk of ergotamine dependency and rebound headache. Ergotamine is contraindicated in cardiovascular disease, peripheral vascular disease, uncontrolled hypertension, pregnancy, and impaired hepatic or renal function.

Dihydroergotamine (DHE) has a cleaner tolerability profile than ergotamine with less nausea and vascular side effects. Migranal nasal spray provides ambulatory access to parenteral-speed onset without intravenous access. Trudhesa is a newer intranasal formulation using precision olfactory delivery (POD) technology designed to direct drug through the olfactory mucosa toward the brain, potentially improving speed and consistency of absorption compared to conventional nasal sprays. Intravenous and intramuscular DHE remains a mainstay of hospital-based treatment for refractory or status migrainosus attacks.

Propranolol (Inderal) and timolol (Blocadren) are the only beta-blockers with FDA approval for migraine prevention; metoprolol is commonly used off-label with good clinical evidence. The mechanism by which beta-blockers prevent migraine is incompletely understood but likely involves blockade of catecholamine-mediated arousal and modulation of serotonergic and noradrenergic systems that influence trigeminovascular pain pathways. Propranolol is available as immediate-release tablets and long-acting (LA) capsules; the LA formulation allows once-daily dosing and improved adherence.

Beta-blockers are particularly useful in patients with comorbid hypertension or anxiety. They should be avoided in patients with asthma, significant reactive airway disease, sinus bradycardia, heart block, decompensated heart failure, or insulin-dependent diabetes with hypoglycemia unawareness. Common side effects include fatigue, cold extremities, bradycardia, exercise intolerance, and, in some patients, depression or sleep disturbance. Metoprolol (cardioselective) is preferred over propranolol (non-selective) when there is a concern about bronchospasm.

Topiramate is one of the most widely used FDA-approved preventive treatments for migraine in adults and adolescents (≥12 years). Its anticonvulsant mechanisms — including sodium channel blockade, GABA enhancement, and glutamate receptor antagonism — are believed to contribute to migraine prevention by stabilizing neuronal excitability in the trigeminal system. It is available as immediate-release (Topamax) and extended-release formulations (Trokendi XR, Qudexy XR), with the ER versions providing smoother drug levels and potentially improved tolerability.

Two side effects are clinically prominent: cognitive effects (word-finding difficulty, memory and concentration problems — colloquially called "dopamax") and weight loss (which may be desirable in some patients but problematic in others). Paresthesias (pins and needles) in the extremities, kidney stone formation, and metabolic acidosis are also recognized adverse effects.

Critically, topiramate is teratogenic and is associated with an increased risk of cleft palate and other fetal malformations. In 2022, the FDA required a Risk Evaluation and Mitigation Strategy (REMS) program for topiramate: patients who can become pregnant must be counseled about this risk and must use effective contraception. Topiramate can also reduce the effectiveness of oral hormonal contraceptives by inducing their metabolism.

Divalproex sodium (Depakote) is FDA-approved for migraine prevention and is effective at reducing attack frequency. It is also used for epilepsy and bipolar disorder. Its mechanism in migraine prevention likely involves GABAergic effects that dampen cortical excitability and modulate trigeminovascular nociception. Divalproex is a prodrug of valproic acid; the delayed-release (DR) and extended-release (ER) formulations are designed to reduce GI side effects compared to immediate-release valproic acid.

Valproate is highly teratogenic — it is associated with a substantially increased risk of neural tube defects (spina bifida), other major congenital malformations, and adverse effects on neurodevelopment in children exposed in utero. Its use in women of childbearing potential requires careful counseling about reproductive risks and a strong clinical justification. Regular liver function monitoring is required during treatment due to rare but serious hepatotoxicity. Common adverse effects include weight gain, hair loss, nausea, and tremor.

Erenumab (Aimovig) was the first CGRP monoclonal antibody approved by the FDA for migraine prevention (May 2018), establishing an entirely new class of migraine therapy. Unlike the other CGRP mAbs which target the CGRP peptide (ligand), erenumab uniquely targets the CGRP receptor itself, blocking CGRP from binding. It is available as a self-injectable prefilled auto-injector given subcutaneously once monthly. Two available strengths allow prescribers to offer a higher monthly amount to patients who do not achieve adequate response at the lower strength.

The most common adverse effects include injection site reactions and constipation. Serious constipation — in some cases requiring hospitalization — has been reported, particularly at higher strengths, and is an important counseling point. Erenumab is developed by Amgen and co-marketed with Novartis.

Fremanezumab (Ajovy) targets the CGRP ligand itself (rather than the receptor) and is available in two dosing schedules: once monthly or once quarterly (three monthly amounts given together). The quarterly dosing option is clinically significant — it reduces injection frequency to four times per year, which many patients find more convenient and may improve long-term adherence. It is approved for both episodic and chronic migraine prevention. Manufactured by Teva, it is administered as a subcutaneous injection.

Galcanezumab (Emgality) targets the CGRP ligand and is approved for prevention of both migraine and episodic cluster headache — the only CGRP mAb with a cluster headache indication. It is administered as a subcutaneous injection using a prefilled auto-injector once monthly (with a loading amount in the first month for migraine prevention). For cluster headache, the treatment schedule differs from the migraine prevention protocol. Manufactured by Eli Lilly, it is available in both a prefilled pen and a prefilled syringe.

Eptinezumab (Vyepti) is unique among the CGRP monoclonal antibodies in being administered as an intravenous infusion every 3 months rather than as a subcutaneous injection. The IV route means drug delivery is complete in a single 30-minute clinic infusion, which completely eliminates concerns about subcutaneous injection technique or adherence between office visits. The quarterly schedule also means only four clinic visits per year for drug administration.

A clinically interesting feature of eptinezumab is its very rapid onset of preventive benefit — because the full amount is delivered intravenously in one infusion, meaningful effects on migraine frequency have been observed within days of the first infusion in clinical trials. Eptinezumab is manufactured by Lundbeck and targets the CGRP ligand.

Atogepant (Qulipta) was the first daily oral gepant approved by the FDA specifically for migraine prevention (September 2021). Unlike rimegepant, which is taken every other day for prevention, atogepant is taken daily and is not used as an acute treatment — it is formulated and approved solely as a preventive agent. Three available strengths provide flexibility for prescribers to tailor treatment to individual patients, including those with hepatic impairment or taking interacting medications.

Atogepant is metabolized primarily by CYP3A4. Potent CYP3A4 inhibitors (clarithromycin, ketoconazole) increase atogepant exposure; potent CYP3A4 inducers (rifampin) substantially reduce it. Like other gepants, it carries no cardiovascular contraindications and is an oral alternative to injectable CGRP mAbs for patients who prefer daily pills over injections. Common adverse effects include nausea, constipation, and fatigue. Atogepant is manufactured by AbbVie.

Amitriptyline has the largest evidence base among tricyclic antidepressants (TCAs) for migraine prevention. It modulates serotonin and norepinephrine reuptake, blocks histamine H1 receptors (contributing to sedation and weight gain), and has sodium channel stabilizing properties. It is typically initiated at a low strength and the sedating effect is often used advantageously by prescribing it at bedtime. Available in a wide range of tablet strengths (10 through 150mg), amitriptyline is particularly useful in patients who also have comorbid insomnia, depression, or neuropathic pain.

Nortriptyline is a metabolite of amitriptyline with a somewhat better tolerability profile — fewer anticholinergic effects (less dry mouth, constipation, urinary retention) and less sedation — while retaining preventive efficacy. It is available in 10, 25, 50, and 75mg capsules. Both TCAs should be used cautiously in elderly patients due to fall and cognitive risks, and both have QTc prolongation potential at higher amounts.

Venlafaxine (Effexor XR), an SNRI, has been studied for migraine prevention with a modest evidence base. It is particularly useful in patients with comorbid depression or generalized anxiety disorder, as it provides benefit for multiple conditions simultaneously. Available as extended-release capsules in 37.5, 75, and 150mg strengths. Discontinuation must be tapered to avoid discontinuation syndrome.