The Medical Letter on Drugs and Therapeutics
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1514
Drugs for Migraine
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TREATMENT OF MIGRAINE
 

An oral nonopioid analgesic may be sufficient for treatment of mild to moderate migraine without severe nausea or vomiting. A triptan is the drug of choice for treatment of moderate to severe migraine.1,2 Use of a triptan early in an attack when pain is still mild to moderate in intensity improves headache response and reduces recurrence rates.

ANALGESICS – Aspirin and acetaminophen, used alone or together in combination with caffeine (Excedrin Migraine, and others), and nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen sodium (Aleve, and others) and ibuprofen (Advil, Motrin, and generics) are effective in relieving mild to moderate migraine pain.3-5 The NSAID diclofenac is FDA-approved as a powder for oral solution (Cambia) for treatment of migraine; it has a rapid onset of action (about 15 minutes).6 Some patients may respond better to one NSAID than to another.

Products that combine butalbital and caffeine with aspirin (Fiorinal, and others) or acetaminophen (Fioricet, and others) are used for treatment of migraine despite evidence that butalbital is not effective in relieving migraine pain. Their frequent use can lead to tolerance, addiction, and medication overuse headache. Oral combinations of aspirin or acetaminophen with an opioid can be effective for relief of migraine pain, but they cause the usual opioid adverse effects (e.g., nausea, drowsiness, and constipation), and regular use can lead to dependence and addiction.

Pregnancy – Occasional use of acetaminophen for treatment of mild to moderate migraine during pregnancy is generally considered safe.

TRIPTANS – The short-acting oral serotonin (5-HT1B/1D) receptor agonists (triptans) sumatriptan (Imitrex, and others), almotriptan (Axert, and generics), eletriptan (Relpax), rizatriptan (Maxalt, and generics), and zolmitriptan (Zomig, and generics) are similar in efficacy.7 Onset of pain relief generally occurs 30-60 minutes after administration. The longer-acting oral triptans naratriptan (Amerge, and generics) and frovatriptan (Frova, and generics) have a slower onset of action and lower initial response rate than other triptans, but they are better tolerated.8 Patients with migraine who have nausea or vomiting may not be able to take an oral triptan.

An oral fixed-dose combination of sumatriptan and naproxen (Treximet) is more effective in relieving moderate or severe migraine pain than either of its components alone.9

View the online table: Comparison Chart of Triptans

Intranasal triptan formulations have a more rapid onset of action than oral tablets, but their efficacy is partially dependent on GI absorption of the portion of the dose that is swallowed. Use of sumatriptan nasal powder (Onzetra Xsail) results in a faster rise in sumatriptan plasma concentrations and higher peak concentrations than use of a similar dose of sumatriptan nasal spray, suggesting that a larger portion of the dose is absorbed intranasally with the powder.10

Subcutaneously administered sumatriptan relieves pain faster (in about 10 minutes) and more effectively than other triptan formulations, but it causes more adverse effects.

Recurrence – In patients with moderate to severe migraine, the rate of recurrence within 24 hours after treatment with a triptan is generally 20-40%. Early treatment of an attack reduces recurrence rates. Recurrences may respond to a second dose of the triptan.

Adverse Effects – Tingling, flushing, dizziness, drowsiness, fatigue, and a feeling of heaviness, tightness, or pressure in the chest can occur with all triptans, but most commonly with SC sumatriptan. A burning sensation at the injection site is also common with SC sumatriptan. Intranasal formulations of sumatriptan and zolmitriptan can have an unpleasant taste. CNS symptoms such as somnolence and asthenia following triptan therapy may be part of the migraine attack, unmasked by the successful treatment of pain, rather than adverse effects of the drugs. Sumatriptan is contraindicated for use in patients with severe hepatic impairment. Naratriptan is contraindicated in patients with severe renal or hepatic impairment.

Angina, myocardial infarction, cardiac arrhythmia, stroke, seizure, and death have occurred rarely with triptans.11 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, hemiplegic migraine, or migraine with brainstem aura. Triptans should be used with caution in patients with other significant risk factors for vascular disease, particularly diabetes.

Drug Interactions – The labels of all triptans state that a triptan should not be taken within 24 hours of another triptan or an ergot because vasoconstriction could be additive. MAO inhibitors increase serum concentrations of rizatriptan, sumatriptan, and zolmitriptan; they should not be used within 2 weeks of each other. Propranolol increases serum concentrations of eletriptan, frovatriptan, rizatriptan, and zolmitriptan. Cimetidine increases serum concentrations of zolmitriptan. Inhibitors of CYP3A4 can increase serum concentrations of almotriptan and eletriptan.12 Cases of serotonin syndrome have been reported with concurrent use of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), but data from large observational databases suggest that the risk is low.13,14

Pregnancy and Lactation – Based on available evidence, use of sumatriptan, or possibly rizatriptan, eletriptan, or zolmitriptan during pregnancy does not appear to be associated with an increased risk of birth defects.15,16 Levels of sumatriptan and eletriptan in breast milk are low and these drugs would not be expected to cause adverse effects in most breastfed infants17; avoiding breastfeeding for 8-12 hours after taking a short-acting triptan would reduce the infant's risk of exposure to the drug.

ERGOTS – A fixed-dose combination of ergotamine tartrate, a nonspecific serotonin agonist and vasoconstrictor, and caffeine is available as tablets (Cafergot) and suppositories (Migergot) for treatment of moderate to severe migraine. The combination is less effective than a triptan for acute treatment of migraine.18

Dihydroergotamine, which can be administered subcutane ously, intramuscularly, intravenously (D.H.E., and generics), or intranasally (Migranal), is effective for acute treatment of migraine. Dihydroergotamine nasal spray relieves migraine after 2 hours in about 50% of patients, with a 15% incidence of recurrence within 24 hours. It can be effective in some patients who do not respond to triptans.

Adverse Effects – Dihydroergotamine is a weaker arterial vasoconstrictor than ergotamine and causes fewer serious adverse effects. Nausea and vomiting are fairly common with ergotamine, but pretreatment with or concurrent use of an antiemetic such as metoclopramide (Reglan, and generics) can reduce GI effects. Serious adverse effects, such as vascular (including coronary) 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 in patients with arterial disease or uncontrolled hypertension.

Drug Interactions – The effects of ergots can be potentiated by triptans, beta blockers, dopamine, nicotine, or CYP3A4 inhibitors. Use of ergots is contraindicated with strong CYP3A4 inhibitors such as clarithromycin (Biaxin, and generics) or itraconazole (Sporanox, and generics).12 Ergots and triptans should not be taken within 24 hours of each other.

Pregnancy and Lactation – Ergots can reduce placental blood flow and are contraindicated for use during pregnancy. Ergotamine is excreted in human breast milk; women who take an ergot should avoid breastfeeding.

TRANSCRANIAL MAGNETIC STIMULATION — The FDA has approved the use of a transcranial magnetic stimulation device (SpringTMS – eNeura) for self-treatment of migraine with aura. In one trial, the pain-free response rate 2 hours after treatment of the first migraine attack was significantly higher with use of transcranial magnetic stimulation at the onset of aura than with sham stimulation (39% vs 22%).19

MEDICATION OVERUSE HEADACHE — Overuse of drugs for headache, particularly butalbital and opioids, can lead to chronic headache with structural and functional changes in the brain. 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. Future use of acute migraine treatments should be limited to ≤2 days per week.20,21

 
PREVENTION OF MIGRAINE
 

Patients with frequent or severe migraine headaches and those who cannot take vasoconstric tors or are refractory to acute treatment should receive preventive treatment.22,23 Menstrual migraine attacks may sometimes be prevented by a brief course of an NSAID or triptan, particularly frovatriptan or naratriptan, taken for several days before and after the onset of menstruation.24,25 Preventive therapy is generally not recommended during pregnancy.

View the online table: Comparison Chart of Drugs for Migraine Prevention

BETA BLOCKERS — Beta blockers are commonly used for prevention of migraine. Propranolol (Inderal LA, and others) and timolol are the only beta blockers approved by the FDA for this indication, but metoprolol (Lopressor, and others), nadolol (Corgard, and generics), and atenolol (Tenormin, and generics) are also effective in preventing migraine.23 All beta blockers can cause fatigue, exercise intolerance, and ortho static hypotension, and should not be used in patients with decompensated heart failure. All are relatively contraindicated in patients with asthma. Patients with migraine often have comorbid depression, which may be aggravated by beta blockers.

Pregnancy – Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported with use of propranolol during pregnancy. Atenolol has been associated with the birth of small for gestational age infants and, at high doses, with embryofetal resorptions in animals.

ANTIEPILEPTIC DRUGS — Valproate (Depakote, and others) and topiramate (Topamax, and generics) are similarly effective in decreasing migraine frequency and are FDA-approved for migraine prevention. About 50% of patients achieve a ≥50% reduction in headache frequency with these drugs.26 In randomized, double-blind trials, topiramate was at least as effective as propranolol for migraine prevention.27,28 Topiramate has reduced the number of migraine headache days per month and improved associated symptoms in patients with chronic migraine (≥15 headache days/month for ≥3 months) and medication overuse headache.29,30 In a trial in pediatric patients, however, topiramate was no better than placebo in preventing migraine.31

Adverse Effects – Adverse effects of valproate include nausea, fatigue, tremor, weight gain, and hair loss. Acute hepatic failure, pancreatitis, and hyperammonemia (in patients with urea cycle disorders) occur rarely. Other adverse effects include polycystic ovary syndrome, hyperinsulinemia, lipid abnormalities, hirsutism, and menstrual disturbances. Topiramate commonly causes paresthesias; fatigue, language and cognitive impairment, taste perversion, weight loss, and nephrolithiasis can also occur. Topiramate can rarely cause secondary narrow-angle glaucoma, oligohydrosis, and symptomatic metabolic acidosis.

Pregnancy – Use of topiramate or valproate during pregnancy has been associated with congenital malformations32,33; neither drug should be used for migraine prevention in pregnant women.

ANTIDEPRESSANTS — Amitriptyline is the only tricyclic antidepressant shown to be effective for migraine prevention in clinical trials,34 but it often causes sedation, dry mouth, and weight gain. Other tricyclics such as nortriptyline, which may have fewer adverse effects than amitriptyline, are frequently used for migraine prevention in adults. In a trial in pediatric patients, amitriptyline was no better than placebo in preventing migraine.31

The SNRIs venlafaxine (Effexor, and others) and duloxetine (Cymbalta, and generics) may also be effective in preventing migraine.22,35,36 They can cause nausea, vomiting, sweating, tachycardia, urinary retention, and increased blood pressure.

Pregnancy – Tricyclic antidepressant use during pregnancy has been associated with jitteriness and seizures in newborns. Fetal malformations are uncommon with SNRIs, but increased risks of neonatal behavioral syndrome and perinatal complications have been reported with use of SNRIs during pregnancy.37

OTHER PREVENTIVE TREATMENTS — NSAIDs, such as naproxen and ibuprofen, have been used for prevention of migraine and for aborting acute attacks.38

The angiotensin-converting enzyme (ACE) inhibitor lisinopril (Prinivil, and others) and the angiotensin receptor blocker (ARB) candesartan (Atacand, and generics) have reduced migraine frequency by about 30-35% in small, double-blind trials.39 In a randomized, placebo-controlled, crossover trial, candesartan was noninferior to propranolol for prevention of migraine.40

The calcium channel blocker verapamil (Calan, and others) was somewhat more effective than placebo in some small studies.41

The combination of simvastatin (Zocor, and others) and vitamin D was effective for migraine prevention in one small, randomized, placebo-controlled trial.42

The dietary supplement petasites (butterbur; Petadolex) 100-150 mg daily reduced migraine attack frequency by 36-60% in two randomized, placebo-controlled trials in about 300 patients,38 but it has been associated with hepatic toxicity.43 Melatonin, riboflavin, magnesium citrate, coenzyme Q10, and feverfew have also been effective in preventing migraine in small, randomized, placebo-controlled trials.38,43,44

Pericranial intramuscular injections of onabotulinumtoxinA (Botox) are FDA-approved for prevention of headaches in adults with chronic migraine (≥15 headaches/month).45 Botulinum toxin is not recommended for prevention of episodic migraine.

A transcutaneous electrical nerve stimulation device (Cefaly) that is worn on the forehead has been approved by the FDA for prevention of episodic migraine in adults. In one small study, daily 20-minute treatments for 3 months were modestly effective in reducing the number of migraine days per month.46

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