Migraine Drugs: What Causes It and What Treats It

What Is Migraine and How Common Is It?

Migraine is a primary headache disorder characterized by recurrent attacks of moderate-to-severe unilateral throbbing pain, often accompanied by nausea, photophobia, and phonophobia. The Global Burden of Disease Study identified migraine as the second leading cause of disability worldwide and the leading neurological cause of disability in people under 50 [1].

Epidemiology by the Numbers

The worldwide prevalence sits at approximately 14 to 15% of the general adult population [1]. In the United States alone, the American Migraine Prevalence and Prevention (AMPP) study found that 17.1% of women and 5.6% of men experience migraine, equating to roughly 39 million Americans [2]. Attacks peak during the most economically productive years of life, ages 25 to 55, making migraine one of the costliest neurological conditions for both individuals and health systems.

The Neurobiology Behind an Attack

Migraine is not simply a vascular headache. Contemporary research points to cortical spreading depression (CSD) as the neural correlate of aura, followed by activation of the trigeminovascular system [3]. Calcitonin gene-related peptide (CGRP) is released from trigeminal nerve terminals during attacks and drives much of the pain and sensitization observed clinically. Plasma CGRP levels rise significantly during spontaneous migraine attacks compared with pain-free intervals, a finding confirmed across multiple controlled studies [3]. This pathway is now the primary target for the newest generation of preventive and acute therapies.

Drugs That Can Cause or Worsen Migraine

Several commonly prescribed and over-the-counter drugs are recognized migraine triggers or can worsen existing headache patterns. Recognizing these agents is the first step before layering on additional therapy.

Medication Overuse Headache (MOH)

The most clinically significant drug-related cause of worsening migraine is medication overuse headache, previously called rebound headache. The International Headache Society's ICHD-3 criteria define MOH as headache occurring on ≥15 days per month in a patient with a pre-existing headache disorder who has overused one or more acute or symptomatic headache medications for more than 3 months [4]. Overuse thresholds are:

• Simple analgesics (aspirin, acetaminophen, NSAIDs): ≥15 days per month
• Triptans, ergots, opioids, or combination analgesics: ≥10 days per month

A Cochrane review found that withdrawal of the offending analgesic results in meaningful headache improvement in approximately 50 to 70% of patients within 2 months [5].

Hormonal Medications

Estrogen-containing contraceptives can trigger migraine with aura or worsen existing aura frequency in susceptible women. A study published in the BMJ found that combined oral contraceptive use was associated with a small but measurable increase in ischemic stroke risk specifically in women with migraine with aura [6]. The American Headache Society recommends avoiding estrogen-containing contraceptives in women with migraine with aura, particularly those who smoke or have additional vascular risk factors [6].

Estrogen withdrawal during the pill-free interval of cyclical contraceptive regimens is itself a potent migraine trigger, driving attacks in up to 60% of women who experience menstrual migraine [7].

Vasodilators and Other Agents

Nitroglycerin (glyceryl trinitrate) reliably triggers migraine-like attacks within 4 to 6 hours of administration in people with migraine, a property exploited in human experimental models to study the condition [3]. Phosphodiesterase inhibitors such as sildenafil and tadalafil share a similar nitric oxide-mediated mechanism and are recognized triggers in clinical practice. Reserpine, hydralazine, and some calcium-channel blockers have also been reported to precipitate headache, though prospective data on these agents are more limited.

Acute Treatments for Migraine

Acute migraine therapy aims to stop an attack already in progress. The choice of agent depends on attack severity, the presence of nausea or vomiting, contraindications to vasoconstrictors, and patient preference.

Triptans: The Benchmark Acute Drug Class

Triptans are selective 5-HT1B/1D receptor agonists. Sumatriptan was the first approved in 1991 and remains the most studied. A landmark meta-analysis of 53 randomized controlled trials (N=24,089) published in The Lancet found that oral sumatriptan 100 mg achieved pain freedom at 2 hours in 29% of patients versus 8% for placebo, and pain relief (moderate-to-severe becoming mild or absent) in 57% versus 26% [8]. Seven triptans are available in the United States: sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, and eletriptan.

Key practical points for triptans:

• Rizatriptan 10 mg oral shows the highest 2-hour pain-free rate among oral triptans at approximately 40% [8].
• Sumatriptan 6 mg subcutaneous injection achieves 2-hour pain freedom in up to 70% of patients, useful when nausea prevents oral dosing [8].
• Triptans are contraindicated in patients with ischemic heart disease, uncontrolled hypertension, or history of stroke.

Gepants: CGRP Receptor Antagonists for Acute Use

Ubrogepant and rimegepant are small-molecule CGRP receptor antagonists approved for acute migraine treatment. Unlike triptans, gepants lack vasoconstrictive properties, making them an option for patients with cardiovascular contraindications to triptans.

The ACHIEVE I trial (N=1,327) demonstrated that ubrogepant 100 mg produced 2-hour pain freedom in 21.2% of patients versus 11.8% for placebo (P<0.001) [9]. Rimegepant 75 mg orally disintegrating tablet showed 2-hour pain freedom in 19.6% versus 12.0% for placebo in its key trial (N=1,466) [10].

Rimegepant has a secondary FDA approval for preventive use (every-other-day dosing), making it the only single molecule approved for both indications.

Lasmiditan: A Ditan for Cardiovascular-Risk Patients

Lasmiditan is a selective 5-HT1F receptor agonist with no vasoconstrictive activity. The SAMURAI trial (N=1,856) reported 2-hour pain freedom in 28.2% of patients receiving lasmiditan 200 mg versus 15.3% for placebo [11]. The drug carries a mandatory 8-hour no-driving restriction due to central nervous system effects including dizziness and somnolence.

NSAIDs and Combination Analgesics

For mild-to-moderate attacks, aspirin 900 to 1,000 mg plus metoclopramide 10 mg is a guideline-supported option endorsed by the European Federation of Neurological Societies. Ibuprofen 400 mg and naproxen sodium 500 to 550 mg have Level A evidence from multiple randomized controlled trials [12]. The combination product containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg (Excedrin Migraine) demonstrated superiority over placebo in a randomized trial but is subject to the medication overuse concerns noted above [12].

Preventive Treatments for Migraine

Prevention is indicated when attacks occur on 4 or more days per month, are severely disabling, or are poorly responsive to acute therapy. The goal is a ≥50% reduction in monthly migraine days.

Oral Preventives: First-Line Options

Topiramate and propranolol carry the strongest evidence base among oral preventives.

A randomized controlled trial published in JAMA (N=483) found topiramate 100 mg/day reduced monthly migraine frequency by 4.1 days versus 1.3 days for placebo over 26 weeks [13]. Common adverse effects include paresthesia, cognitive slowing, and weight loss. Topiramate is a recognized teratogen (oral clefts) and carries a boxed warning regarding use in pregnancy.

Propranolol at doses of 40 to 240 mg/day reduces migraine frequency by approximately 44% compared with placebo based on meta-analytic data [14]. It is contraindicated in asthma and decompensated heart failure. Metoprolol and timolol also carry FDA approval for migraine prevention and share a similar mechanism.

Amitriptyline 10 to 75 mg at night provides a second-line oral option with reasonable trial data, particularly useful when comorbid depression or insomnia is present. Valproate 500 to 1,500 mg/day has Level A evidence but is absolutely contraindicated in pregnancy due to teratogenicity.

CGRP Monoclonal Antibodies: The Preventive Standard-of-Care Shift

Four CGRP-pathway monoclonal antibodies are FDA-approved for migraine prevention: erenumab, fremanezumab, galcanezumab, and eptinezumab.

The STRIVE trial (N=955) evaluated erenumab (anti-CGRP receptor) 70 mg and 140 mg monthly versus placebo over 6 months [15]. At 6 months, erenumab 70 mg reduced monthly migraine days by 3.2 days versus 1.8 days for placebo, and 43.3% of patients achieved a ≥50% reduction in monthly migraine days [15]. Erenumab 140 mg showed 50.0% of patients reaching that threshold (P<0.001 for both doses).

The HALO CM trial (N=1,121) tested fremanezumab quarterly dosing in chronic migraine and found a reduction of 4.3 monthly headache days versus 2.5 for placebo [16]. Both quarterly and monthly fremanezumab dosing regimens were superior to placebo.

All four CGRP mAbs are administered subcutaneously (eptinezumab intravenously every 3 months) and are generally well tolerated. Constipation is the most commonly reported adverse effect with erenumab, occurring in up to 3% of patients [15].

OnabotulinumtoxinA for Chronic Migraine

OnabotulinumtoxinA (Botox) is FDA-approved specifically for chronic migraine, defined as ≥15 headache days per month with ≥8 migraine features. The PREEMPT program (two phase 3 trials, combined N=1,384) established a 31-site injection protocol of 155 units every 12 weeks, reducing monthly headache days by 8.4 versus 6.6 for placebo at week 24 [17]. The effect size is modest but clinically meaningful in patients who have failed oral preventives.

Special Populations: Menstrual Migraine, Pregnancy, and Older Adults

Menstrual Migraine

Menstrual migraine, occurring within 2 days before to 3 days after menstrual onset in at least 2 of 3 cycles, affects approximately 7 to 14% of women with migraine. Short-term prevention with frovatriptan 2.5 mg twice daily for 6 days perimenstrually reduced the incidence of menstrual migraine attacks by 52% versus placebo in a double-blind crossover trial (N=546) [18]. Frovatriptan's longer half-life of 26 hours makes it well suited for this indication.

Migraine in Pregnancy

Triptans, topiramate, and valproate should be avoided in pregnancy whenever possible. Acetaminophen remains the default acute analgesic. Magnesium 400 to 600 mg daily has modest preventive evidence and an acceptable safety profile in pregnancy, with one randomized controlled trial showing a 41.6% reduction in attack frequency versus placebo [19]. The American College of Obstetricians and Gynecologists supports magnesium supplementation discussion in this context [19].

Older Adults

CGRP mAbs have not been well studied in patients over 65. Triptans require caution given higher background rates of cardiovascular disease. Rimegepant and ubrogepant, given their lack of vasoconstrictive activity, may offer a safer acute option in older adults, though controlled data in this subgroup remain limited.

Diagnosing Migraine: ICHD-3 Criteria

Migraine without aura is diagnosed when a patient has had at least 5 attacks meeting all of the following ICHD-3 criteria [4]:

1. Attack duration of 4 to 72 hours (untreated or unsuccessfully treated).
2. At least two of: unilateral location, pulsating quality, moderate-to-severe pain intensity, aggravation by or avoidance of routine physical activity.
3. During the headache, at least one of: nausea or vomiting, or both photophobia and phonophobia.
4. Not better accounted for by another ICHD-3 diagnosis.

No imaging is required for straightforward migraine. MRI brain is indicated when headaches are of new onset, are progressive, occur in patients over 50, are associated with neurological signs, or meet any of the secondary headache red flags summarized below.

Red-Flag Features Requiring Urgent Evaluation

The mnemonic SNOOP4 captures the main secondary headache warning signs [20]:

• S Systemic symptoms (fever, weight loss) or secondary risk factors (HIV, malignancy)
• N Neurological symptoms or signs
• O Onset sudden (thunderclap headache, maximal at onset)
• O Older age (new headache over 50 years)
• P Progressive headache or change in headache pattern
• P Postural component
• P Papilledema
• P Precipitated by Valsalva

The American Headache Society states: "Patients with a thunderclap headache, defined as a severe headache reaching maximum intensity within 60 seconds, require immediate evaluation to exclude subarachnoid hemorrhage" [20].

Understanding Why Migraine Happens: Triggers vs. Causes

Migraine has a strong genetic basis. First-degree relatives of people with migraine have a 1.5- to 4-fold elevated risk, and twin studies show heritability estimates of 40 to 65% [21]. Genome-wide association studies have identified more than 40 susceptibility loci, with many in genes regulating glutamatergic and pain-signaling pathways [21].

Common Modifiable Triggers

Triggers do not cause migraine in the biological sense; they lower the threshold for an attack in a brain already predisposed. The most consistently reported triggers across epidemiological surveys include:

• Sleep disruption: both sleep deprivation and oversleeping
• Stress and stress letdown (the "let-down headache" of weekends)
• Hormonal fluctuation: estrogen drop in the late luteal phase
• Dietary factors: alcohol (particularly red wine and beer), caffeine withdrawal, prolonged fasting
• Sensory stimuli: bright light, strong odors, loud noise
• Weather changes: barometric pressure drops

A prospective diary study published in Neurology (N=200) found that 76% of patients identified at least one trigger, but fewer than 30% could reliably predict which trigger would produce an attack on a given day [22]. Trigger avoidance as a sole strategy has limited effectiveness and may inadvertently increase sensitization.

The Role of Sleep

Poor sleep quality is both a trigger and a consequence of migraine. Bidirectional associations between migraine and insomnia have been documented in population-based cohorts, with people who have insomnia carrying a hazard ratio of 1.40 (95% CI 1.19 to 1.64) for incident migraine compared with normal sleepers [23]. Addressing sleep hygiene is a low-cost adjunct to pharmacologic management.

Putting It Together: A Practical Drug-Selection Framework

When choosing between treatment options, a step-through approach based on attack frequency and disability score is the most evidence-consistent method.

Episodic migraine (1 to 3 attack days/month, low MIDAS score): Start with an NSAID (ibuprofen 400 mg or naproxen 500 mg). If inadequate, add a triptan. Track days of use carefully to stay under the MOH threshold.

Episodic migraine (4 to 14 attack days/month, moderate MIDAS score): Initiate acute therapy with a triptan plus consider starting an oral preventive (topiramate 25 mg titrated up over 8 weeks, or propranolol 40 mg twice daily). Re-evaluate response at 3 months.

Chronic migraine (≥15 headache days/month): A CGRP monoclonal antibody is now appropriate at this stage based on guidelines from the American Headache Society [20], particularly after one or two oral preventive failures. OnabotulinumtoxinA is an alternative or add-on.

Cardiovascular contraindications to triptans: Use rimegepant 75 mg or ubrogepant 50 to 100 mg for acute treatment. Both gepants are well tolerated and carry no vasoconstrictive risk.

Dr. Andrew Charles, director of the Goldberg Migraine Program at UCLA, has noted: "CGRP is not simply a biomarker of migraine. It is a mediator. Blocking it at the receptor or ligand level interrupts the attack cascade at a mechanistically validated point" [3].