ANALGESICS — Aspirin and acetaminophen, used alone, together, or combination with caffeine, and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in relieving mild to moderate migraine pain.2-4 The NSAID diclofenac is available in a powder for oral solution (Cambia) for treatment of migraine; it has a rapid onset of action (~15 minutes).5

Products that contain butalbital or an opioid are not recommended for acute treatment of migraine. There is limited evidence that butalbital is effective in relieving migraine pain. Opioids can be effective, but they can cause serious adverse effects. Regular use of butalbital- or opioid-containing analgesics can lead to medication overuse headache, tolerance, dependence, and addiction.

Pregnancy – Occasional use of acetaminophen during pregnancy is generally considered safe.6 Use of NSAIDs during the third trimester may cause premature closure of the ductus arteriosus and persistent pulmonary hypertension in the neonate, but these effects appear to be uncommon if the drug is stopped 6-8 weeks before delivery.

TRIPTANS — The shorter-acting oral 5-HT_1B/1D receptor agonists (triptans) sumatriptan, almotriptan, eletriptan, rizatriptan, and zolmitriptan are similar in efficacy (placebo-corrected 2-hour headache response rates of ~30-50% with maximum initial doses). The longer-acting oral triptans naratriptan and frovatriptan are generally better tolerated than shorter-acting triptans, but they have a slower onset of action and lower initial response rates. Patients who do not respond to one triptan may respond to another. An oral fixed-dose combination of sumatriptan and naproxen (Treximet, and generics) has been more effective in relieving moderate or severe migraine than either of its components alone.7

Intranasal and injectable triptan formulations are faster-acting than oral tablets. Subcutaneously administered sumatriptan relieves pain faster and more effectively than oral triptan formulations, but it causes more adverse effects.8

Recurrence – Moderate to severe migraine recurs within 24 hours after treatment with a triptan in ~20-40% of cases. Early treatment of an attack reduces recurrence rates. Recurrences may respond to a second dose of the triptan.

Adverse Effects – Triptans can cause tingling, flushing, dizziness, drowsiness, fatigue, and a feeling of heaviness or tightness in the chest. Subcutaneous sumatriptan can cause injection-site discomfort. Intranasal triptan formulations can leave an unpleasant aftertaste. CNS symptoms such as somnolence and weakness are commonly reported following triptan therapy, but they may be part of the migraine attack, unmasked by the successful treatment of pain, rather than adverse effects of the drug. Use of triptans for ≥10 days per month can cause medication overuse headache. Sumatriptan and naratriptan are contraindicated for use in patients with severe hepatic impairment. Naratriptan is also contraindicated for use in patients with severe renal impairment.

Angina, myocardial infarction, cardiac arrhythmias, stroke, seizures, and death have occurred very rarely with use of triptans.9 All triptans are contraindicated for use in patients with ischemic or vasospastic coronary artery disease, Wolff-Parkinson-White syndrome, peripheral vascular disease, ischemic bowel disease, uncontrolled hypertension, or a history of stroke, transient ischemic attack, or hemiplegic or basilar migraine. They should be used with caution in patients with other significant risk factors for vascular disease, particularly diabetes.

Drug Interactions – Triptans should not be used within 24 hours of another triptan or an ergot because vasoconstriction could be additive. Concurrent use of monoamine oxidase (MAO) inhibitors and triptans can result in additive serotonergic effects. Use of sumatriptan, rizatriptan, or zolmitriptan within 2 weeks after an MAO-A inhibitor can result in increased triptan serum concentrations and is contraindicated. Propranolol increases serum concentrations of rizatriptan. Cimetidine increases serum concentrations of zolmitriptan. Inhibitors of CYP3A4 can increase serum concentrations of almotriptan and eletriptan; use of eletriptan is contraindicated within 72 hours after taking a strong CYP3A4 inhibitor.10 Serotonin syndrome has been reported with concurrent use of triptans and serotonin reuptake inhibitors, but data from large observational studies suggest that the risk is low.11

Pregnancy and Lactation – In a population study in Norway, there was no association between triptan use during pregnancy and birth defects.12 Levels of sumatriptan and eletriptan in breast milk are low and are not expected to cause adverse effects in most breastfed infants.13

View the Comparison Table: Triptans for Migraine

CGRP RECEPTOR ANTAGONISTS — Three smallmolecule calcitonin gene-related peptide (CGRP) receptor antagonists are FDA-approved for acute treatment of migraine in adults: rimegepant (Nurtec ODT) and ubrogepant (Ubrelvy) are taken orally,14,15 and zavegepant (Zavzpret) is available as a nasal spray.16 In clinical trials, about 10% more patients were free of headache 2 hours post-dose with these drugs compared to placebo.17-19

The onset of pain relief appears to occur sooner with zavegepant than with rimegepant or ubrogepant (~15 vs ~60 minutes). The half-life of rimegepant (~11 hours) is longer than that of ubrogepant (5-7 hours) or zavegepant (~6.5 hours). No trials directly comparing these drugs with each other or with triptans are available. CGRP receptor antagonists appear to be less effective than triptans, but they can be used in patients with vascular disease and do not cause medication overuse headache.20

Adverse Effects – Systemic adverse effects are uncommon with use of CGRP receptor antagonists. Nausea, somnolence, and (rarely) hypersensitivity reactions can occur. Zavegepant can cause dysgeusia, ageusia, and nasal discomfort.

Drug Interactions – Ubrogepant and rimegepant are substrates of CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Concurrent use of these drugs with strong inhibitors or inducers of CYP3A4 or with inhibitors of P-gp or BCRP should be avoided.10

Zavegepant is a substrate of organic anion transporting polypeptide 1B3 (OATP1B3) and sodium taurocholate cotransporting polypeptide (NTCP); its use with inhibitors or inducers of these transporters should be avoided. Intranasal decongestants can decrease zavegepant absorption; concurrent use should be avoided.

Pregnancy and Lactation – Rimegepant, ubrogepant, and zavegepant have not been adequately studied in pregnant women. Levels of rimegepant in breast milk are low; ubrogepant and zavegepant are also likely to be minimally secreted into breast milk because they are highly protein-bound.21,22

SELECTIVE 5-HT_1F RECEPTOR AGONIST — Lasmiditan (Reyvow) selectively binds to 5-HT_1F receptors expressed on trigeminal neurons, inhibiting pain pathways in the trigeminal system. In clinical trials, the rate of freedom from headache 2 hours post-dose was modestly higher with lasmiditan (~30%) than with placebo (15-20%).14,17 Lasmiditan appears to be less effective than triptans, but it can be used in patients with vascular disease.20

Adverse Effects – Lasmiditan can cause CNS adverse effects including dizziness, paresthesia, sedation, vertigo, incoordination, cognitive changes, and confusion. Fatigue, nausea and vomiting, muscle weakness, lethargy, palpitations, increases in blood pressure, decreases in heart rate, reactions consistent with serotonin syndrome, and hypersensitivity reactions, including angioedema and rash, have also been reported. Like triptans, lasmiditan can cause medication overuse headache.

Lasmiditan can decrease wakefulness and impair driving ability. The lasmiditan labeling warns against driving or operating machinery for at least 8 hours after taking the drug. Lasmiditan is classified as a schedule V controlled substance.

Drug Interactions – Use of lasmiditan with alcohol or other CNS depressants could result in additive effects. Coadministration of lasmiditan with serotonergic drugs may increase the risk of serotonin syndrome. Lasmiditan should be used with caution in patients who are taking other heart rate-lowering drugs. Lasmiditan inhibits P-gp and BCRP; coadministration with P-gp or BCRP substrates should be avoided.10

Pregnancy and Lactation – No data on the use of lasmiditan in pregnant or breastfeeding women are available. Lasmiditan and its metabolites have been detected in the milk of lactating rats.

ERGOTS — A fixed-dose combination of ergotamine tartrate, a nonspecific serotonin agonist and vasoconstrictor, and caffeine is available in tablets and suppositories for acute treatment of moderate to severe migraine. The combination is less effective than a triptan.23

Dihydroergotamine can be effective in some patients whose migraine headaches do not respond to triptans.17 It is available parenterally and as a nasal spray (Migranal, and generics; Trudhesa). In clinical trials, Migranal relieved migraine pain after 2 hours in ~30-60% of patients.24 Systemic bioavailability is greater with Trudhesa than with Migranal; it requires only one spray per nostril rather than two to deliver a full dose.25

Adverse Effects – Dihydroergotamine is a weaker arterial vasoconstrictor than ergotamine and causes fewer serious adverse effects. Nausea and vomiting are common with ergotamine, but pretreatment with or concurrent use of an antiemetic drug such as metoclopramide can reduce GI adverse effects. Serious adverse effects, such as vascular occlusion and gangrene, are rare and are usually associated with overdosage (>6 mg in 24 hours or >10 mg per week). Hepatic impairment or fever can accelerate development of severe vasoconstriction. Ergots are contraindicated for use in patients with arterial disease or uncontrolled hypertension.

Drug Interactions – Concurrent use of ergots and strong CYP3A4 inhibitors is contraindicated.10 The effects of ergots can also be potentiated by triptans, beta blockers, dopamine, and nicotine. Trudhesa is contraindicated for use with peripheral and central vasoconstrictors. Ergots and triptans should not be taken within 24 hours of each other. Rarely, reactions consistent with serotonin syndrome have been observed when 5-HT₁ agonists such as dihydroergotamine were coadministered with selective serotonin reuptake inhibitors.

Pregnancy and Lactation – Ergots can reduce placental blood flow and ergotamine is secreted into breast milk. Use of ergots in pregnant or breastfeeding women is contraindicated.

ANTIEMETICS — The dopamine receptor antagonists metoclopramide, prochlorperazine, chlorpromazine, and droperidol can reduce nausea and headache pain in patients with migraine.26 These drugs can cause extrapyramidal adverse effects and prolong the QT interval, increasing the risk of torsades de pointes.

MEDICATION OVERUSE HEADACHE — Overuse of drugs for acute treatment of migraine, especially butalbital and opioids but also triptans, lasmiditan, NSAIDs, and ergots, can lead to increased frequency and severity of headache with poor response to acute and preventive treatment. Treatment of medication overuse headache involves withdrawing the overused drug(s); abrupt withdrawal may require hospitalization and bridge therapy with other drugs. Preventive treatment for migraine should be considered, and some expert clinicians suggest limiting future acute migraine treatment to 2 days per week.27 CGRP receptor antagonists have not been associated with development of medication overuse headache.

DRUGS FOR PREVENTIVE TREATMENT

Indications for preventive treatment of migraine include frequent or severe attacks, a contraindication to or toxicity with acute treatments, and patient preference.1 Menstrual migraine can sometimes be prevented by taking an NSAID or a triptan (particularly frovatriptan) for several days before and after the onset of menstruation.28

BETA BLOCKERS — Propranolol and timolol are FDA-approved for preventive treatment of migraine, but metoprolol, atenolol, bisoprolol, and nadolol are also effective.

Adverse Effects – Beta blockers can worsen asthma symptoms and depression, and cause fatigue, exercise intolerance, sleep disorders, and orthostatic hypotension. They should not be used in patients with decompensated heart failure.

View the Comparison Table: Some Drugs for Migraine Prevention in Adults

ANTISEIZURE DRUGS — Valproate and topiramate are FDA-approved for migraine prevention. About 50% of patients achieve a ≥50% reduction in headache frequency with use of either drug.29 In double-blind trials, topiramate was at least as effective as propranolol for migraine prevention.30 Topiramate has reduced migraine frequency and symptoms in adults with ≥15 headache days/month for ≥3 months and in those with medication overuse headache.31

Adverse Effects – Valproate can cause nausea, fatigue, tremor, weight gain, and hair loss. Acute hepatic failure, pancreatitis, and hyperammonemia (in patients with urea cycle disorders) occur rarely. Polycystic ovary syndrome, hyperinsulinemia, lipid abnormalities, hirsutism, and menstrual disturbances have also been reported.

Topiramate commonly causes paresthesias; fatigue, language and cognitive impairment, taste perversion, weight loss, and nephrolithiasis can also occur. Topiramate can rarely cause narrow-angle glaucoma, oligohidrosis, and metabolic acidosis.

Pregnancy – Use of topiramate or (especially) valproate during pregnancy has been associated with congenital malformations.32,33

ANTIDEPRESSANTS — Amitriptyline is the only tricyclic antidepressant that has been shown to be effective (off-label) for preventive treatment of migraine,34 but it often causes sedation, dry mouth, and weight gain. Other tricyclics such as nortriptyline, which may have fewer adverse effects, are frequently used as alternatives.

The serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine may also be effective in preventing migraine.35,36 Adverse effects include nausea, vomiting, sweating, tachycardia, urinary retention, and blood pressure elevations.

CGRP ANTAGONISTS — The long-acting CGRP monoclonal antibodies erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti) and the oral CGRP receptor antagonists atogepant (Qulipta) and rimegepant (Nurtec ODT) have reduced the number of migraine days by about 1-2 per month compared to placebo in double-blind trials in patients with episodic or chronic migraine.37-41 CGRP monoclonal antibodies may be effective when other therapies have failed.42-45 No head-to-head comparisons of these drugs are available. Erenumab has been shown (off-label) to be effective for prevention of menstrual migraine.46

Adverse Effects – Injection-site reactions and constipation are the most common adverse effects of CGRP antibodies. Hypersensitivity reactions have been reported.47 Erenumab has been associated with hypertension and hair loss.48,49

Systemic adverse effects are uncommon with use of oral CGRP receptor antagonists. Nausea and somnolence can occur. Hypersensitivity reactions have been reported with use of rimegepant.

Pregnancy – No adequate data are available on use of CGRP antagonists in pregnant women. Fetal exposure to CGRP antibodies could occur for months after stopping them.

OTHER PREVENTIVE DRUGS — Pericranial intramuscular injections of onabotulinumtoxinA (Botox) are FDA-approved for preventive treatment of chronic migraine in adults with ≥15 days per month of headaches lasting ≥4 hours.50 Botulinum toxin is not recommended or FDA-approved for prevention of episodic migraine.

NSAIDs, such as naproxen and ibuprofen, have been used to prevent episodic migraine.51 The antihypertensive drugs lisinopril, candesartan, and verapamil have reduced migraine frequency in small studies.52-54

NONPHARMACOLOGIC ACUTE AND PREVENTIVE TREATMENT

DEVICES — Five neuromodulatory devices are FDA-cleared for acute treatment of migraine; four of these are also FDA-cleared for preventive treatment. Some can be used in adolescents as well as adults (see Table 4). These devices have decreased migraine frequency and/or severity compared to sham treatment or historical controls in clinical trials. No trials comparing them to each other or to pharmacologic treatments are available, and experience with their use in clinical practice is limited.1

OTHER INTERVENTIONS — Behavioral interventions, such as cognitive behavioral therapy and biofeedback, and acupuncture have been found to be effective for preventive treatment of migraine, but study quality is mixed.53-57

REFERENCES