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MEDICATIONS FOR MIGRAINE HEADACHE: A REVIEW OF ADVERSE EFFECT PROFILE AND SAFETY

Over the last 2 decades, tremendous progress has been made in the pharmacologic therapy of migraine headaches. Safe and effective treatment options are now available for acute abortive treatment as well as the prevention of headaches.

The first migraine-specific acute abortive treatment with ergot extract was described by Eulenberg in Germany in 1883. However, controlled studies on ergot were not done in the United States until 1934. Ergotamine belongs to a class of drugs that are nonspecific agonists of the 5-HT receptors. Humphrey discovered sumatriptan in the late 1980s, heralding a new class of drugs, called triptans, for acute migraine therapy. These so-called designer drugs were more specific than ergots in that their action on the 5-HT receptors was specific to HT-1 sites. Sumatriptan subcutaneous injection treatment for migraine headache received approval from the United States Food and Drug Administration (FDA) in 1992. Seven triptans are currently available in the United States.

All the medications used for migraine prevention were discovered accidentally. While being used to treat other diseases, these medications were found to be also effective for migraine prevention. As such, no preventive medications for migraine are used solely for migraine headaches. Patients may be familiar with their prescribed migraine medication as treatment for another condition; this can be a source of confusion for patients.

ACUTE ABORTIVE TREATMENT

Serotonin agonists

Triptans are vasoconstrictors, and the listed risks and precautions include ischemic or vasospastic coronary, cerebral, and peripheral vascular disease. Serious vascular adverse effects due to triptans are uncommon but include myocardial infarction, arrhythmia, death, subarachnoid hemorrhage, stroke, transient ischemic attacks, and peripheral ischemia. Post-marketing surveillance in patients has shown rare instances of myocardial ischemia due to triptan use; in most cases, this has occurred in patients who had undiagnosed myocardial ischemic disease. A recent study shows that for individuals with migraine, even those who have a relatively high risk of CAD, performing cardiac testing or avoiding triptans is not beneficial.

The adverse effects most commonly reported with use of triptans include somnolence, dizziness, asthenia or fatigue, nausea, chest pain, abdominal pain, and vomiting. The severity of adverse effects is usually dose-related (eg, 5-mg dose of rizatriptan causes less asthenia than a 10-mg dose).

Patients commonly experience what have been called triptan sensations, which can be dramatic but benign. Patients report burning, tingling, or tightness in body areas such as the face, limbs, or chest. The chest symptoms can include chest tightness, heaviness, pain, or pressure. Placebo-controlled trials show these symptoms in 1-7% of patients taking triptan tablets. The symptoms were always mild and transient and were not associated with ECG or enzymatic evidence of myocardial ischemia. Chest symptoms in patients without cardiovascular disease are not ischemic in nature and are not serious. The mechanism of this adverse effect is not known.

Triptans are generally contraindicated in cases of hemiplegic or complicated migraine because of their vasoconstrictive properties, since they can potentially worsen ischemia.

The tolerability profiles among triptans are generally similar. However, the incidence of treatment-emergent adverse events appears to occur less frequently with naratriptan (2.5 mg) and almotriptan (12.5 mg). Tolerability of almotriptan 2.5 mg is very good, and the rate of adverse events is equal to that of placebo. Adverse effects of frovatriptan include dizziness (8% of patients), gastrointestinal symptoms such as nausea and dry mouth (6%), fatigue (5%), somnolence (4%), and flushing (4%). Overall, 36% of patients taking frovatriptan 2.5 mg reported adverse effects as opposed to 43% of patients who took sumatriptan 100 mg.

The risk of serotonin syndrome is increased when triptans are used concurrently with selective serotonin reuptake inhibitors (SSRIs). In reality, this issue is minimized if patients are taking triptans less frequently than on a daily basis, and the potential for this complication should not deter physicians from using SSRIs to treat depression concomitantly with triptans; depression is a common condition among patients with migraine. Triptans have been designated pregnancy category C. Caution is advised by the American Academy of Neurology for breastfeeding while taking triptans; the American Academy of Pediatrics considers it acceptable. For a summary of the metabolic interactions of triptans, please see Table 1 below.

Table 1. Metabolic Interactions of Triptans*

*Data from European Short Product Communications and Dahlöf et al, 2002. Table adapted from Dahlöf, 2002.
†Modification may be required to use.
‡Contraindicated in the presence of severe renal or hepatic impairment.
§Contraindicated.

Ergotamines are 5-HT nonspecific receptor agonists and have safety profiles similar to those of triptans. However, ergotamine is not tolerated as well as triptans are because of the adverse effect of nausea; ergotamine needs to be administered with an antiemetic. A derivative of ergotamine called dihydroergotamine (DHE) is better tolerated because it causes less nausea, vomiting, and leg cramps. The relative contraindications to this class of drugs are similar to those of triptans and include coronary, peripheral, or cerebral vascular disease; uncontrolled hypertension; hepatic failure; renal failure; and sepsis. Rebound headaches are rare, and lower headache recurrence is reported with the use of DHE than with short-acting triptans. This may be because of the longer half-life of DHE. Ergots are contraindicated with concomitant use of potent CYP3A4 inhibitors (eg, macrolides, protease inhibitors, azole antifungals) because of the risk of life-threatening peripheral ischemia. Ergots can also cause life-threatening fibrotic complications. This class of medications is also generally contraindicated in cases of hemiplegic or complicated migraine because of their vasoconstrictive properties, since they can potentially worsen ischemia. Ergots have been designated pregnancy category X and should not be used in patients who are pregnant or who may become pregnant.

Nonspecific migraine treatment

The first over-the-counter medicine to be approved by the FDA for migraine treatment is the combination of acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg per tablet in 1998. Nonsteroidal anti-inflammatory drugs (NSAIDs) are, perhaps, the most commonly used medications for the treatment of migraine. NSAIDs are cyclooxygenase inhibitors and, because of their action on gastric mucosa, can cause gastric upset, gastric ulcers, bleeding, abdominal pain, constipation, diarrhea, and nausea. Other adverse effects include lightheadedness, dizziness, somnolence, tinnitus, and fluid retention. Caffeine can cause rebound analgesic headaches and irritability. Rebound analgesic headaches are adverse effects seen when abortive migraine therapy (including triptan) is used very frequently or on a daily basis.

Midrin is an older agent used to treat acute migraine headaches. Relative contraindications for its use include glaucoma, severe renal disease, heart disease, hepatic disease, and concurrent use of monoamine oxidase inhibitors (MAOIs). Caution is advised in patients with hypertension, peripheral vascular disease, or recent myocardial infarction. Midrin has been designated pregnancy category D.

Antiemetics

Antiemetics can be used to treat migraine and accompanying symptoms in 2 ways. First, nausea and vomiting often accompany migraines and can be incapacitating. Secondly, some evidence indicates that antiemetics may also relieve the headache of migraine. Promethazine, prochlorperazine, chlorpromazine, and droperidol have been studied most often and are generally safe and effective. Adverse effects include asthenia, anxiety, akathisia, and somnolence.

PREVENTIVE TREATMENT

Five medications are currently FDA-approved for migraine prevention (see Table 2 below). Other medications may be used by individual practitioners on an off-label basis for the treatment and prevention of refractory migraines. Note that methysergide is no longer available in the United States because of adverse effects.

Table 2. Migraine Prevention Medications With FDA Approval

Anticonvulsants

Two anticonvulsants have been FDA-approved for the preventive treatment of migraine: topiramate and divalproex. Other antiepileptics are also used on an off-label basis to treat migraine. Adverse effects related to topiramate treatment include the following: paresthesia (8%), fatigue (9.8%), diarrhea (3.3%), hypoesthesia (3.3%), difficulty with memory (3%), confusion (4%), taste perversion (11-13%), and anorexia (9-17%). Weight loss can be seen in 8% of patients and is usually reported at about 3% of total body weight. Weight loss is dose-related; eg, 50 mg causes an approximate loss of 2.2% of total body weight, 100 mg causes a 3.3% loss, and 200 mg causes a 4.6% loss. In one trial, kidney stones were seen in 3 out of 200 patients. Rare instances of angle-closure glaucoma and acute myopia have been reported with the use of topiramate. Kidney stones and angle-closure glaucoma are relative contraindications for topiramate, and the medication has been designated pregnancy category C.

Divalproex (sodium valproate and valproic acid) is very effective in migraine preventive treatment and should be considered for use in patients with migraine headaches. However, because of a black box warning related to the development of fatal hepatic failure in certain patient subgroups, patients’ liver enzymes should be checked at periodic intervals for the first 6 months after initiating treatment. The medication is contraindicated in the presence of hepatic dysfunction and urea cycle disorders and is relatively contraindicated in the presence of bleeding disorders. Divalproex has been designated pregnancy category D. Other adverse effects and complications, such as hyperammonemia, gastric irritation, and thrombocytopenia, have also been reported. Valproic acid has drug interactions with many antiepileptics and other drugs. Life-threatening cases of pancreatitis have been reported; this complication should be considered when patients report abdominal pain, nausea, vomiting, and anorexia.

Antidepressants

The data that support the use of SSRIs for migraine prevention are weak. Nevertheless, SSRIs are still commonly used for the anticipated goal of preventing migraine headache, perhaps with the intent to treat concomitant depression. Adverse effects include worsening depression or increased risk of suicidality, especially for adolescents (see: http://www.fda.gov/cder/drug/antidepressants/default.htm for more information from the FDA on this topic). Patients should be monitored for emergence of mania, anxiety, agitation, panic attacks, hostility, and impulsivity. Relative contraindications for prescribing SSRIs include mania and agitation. For patients who are using triptans on a daily basis, the risk of drug interaction with the SSRIs, resulting in serotonin syndrome, is increased. SSRIs have been designated pregnancy category C. Their use during the third trimester of pregnancy is associated with neonatal complications that include respiratory, gastrointestinal, and feeding problems; seizures; and withdrawal symptoms.

Much stronger evidence supports the use of tricyclic antidepressants (TCAs) such as amitriptyline and nortriptyline for migraine prevention. Because the treatment of migraine with TCAs requires a much lower dose than treatment of depression, patients taking TCAs for migraine experience fewer adverse effects. Common adverse effects include sedation, dry mouth, irritability, and agitation. Adverse effects at higher doses include arrhythmias, orthostatic hypotension, and anticholinergic effects. Relative contraindications for TCA use include mania, urinary retention, and heart block.

Antihypertensives

The beta-blockers propranolol and timolol have been FDA-approved for the prevention of migraine. However, tolerability is an issue with these medications, especially in the elderly population. Both of these medications have been designated pregnancy category C. Relative contraindications for propranolol include asthma and depression; for timolol, they include Raynaud disease and diabetes.

In migraine trials, the angiotensin receptor blocker candesartan (16 mg/d) was well tolerated. Only minor adverse effects, like dizziness, were reported. Dizziness and fatigue are relative contraindications to candesartan, which has been designated pregnancy category C for the first trimester and category D for the second and third trimesters.

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor. It has been well tolerated in patients in migraine trials, and adverse events reported were those known to be associated with ACE inhibitors. Maximum dosing used for treatment of migraine was 20 mg. Symptoms associated with hypotension (eg, dizziness, tendency to faint) were reported. Cough, which is not dose-related, can be a reason for discontinuation in some patients and is a relative contraindication. This class of drugs has been designated category C during the first trimester of pregnancy (for organogenesis). It has been designated category D for the second and third trimesters of pregnancy because it can cause fetal and neonatal morbidity and mortality during this time. ACE inhibitors should be used only with caution in women of childbearing age.

Complementary medicine

Riboflavin is used to prevent migraine headaches because it affects mitochondrial dysfunction. It is considered safe and well tolerated for the prevention of migraine headaches. Rarely, riboflavin can cause diarrhea, abdominal cramps, or polyuria.

Petasites hybridus root (also known as butterbur) is an herb used for migraine prevention. The most commonly reported adverse events due to P hybridus are gastrointestinal disorders (eg, burping). In one study, 22-25% of patients taking P hybridus reported such symptoms versus 6.7% of patients taking placebo.

Feverfew is also an herb used for migraine prevention. It is well tolerated, and adverse effects are generally mild and reversible. Adverse effects are mostly related to gastrointestinal disturbance and include mouth ulceration, indigestion, heartburn, diarrhea, bloating, flatulence, and constipation.

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