Migraine Headaches

Description

Medications Used for Prevention

Many agents are being used or investigated for preventing migraines. To date, most standard agents still provide every modest protection.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) for Prevention

Standard NSAIDs. Nonsteroidal anti-inflammatory drugs (common pain relievers that are available over the counter or in prescription form). NSAIDs may be used for prevention of migraine under the following circumstances:

• Nonprescription NSAIDs. Regular, preventive use of low-dose aspirin (so-called baby aspirin), ibuprofen (Advil), and naproxen (Aleve) may reduce the occurrence of migraine headaches by about 20%. (Even with nonprescription NSAIDs, no one should take them regularly without consulting a physician.)
• Prescription-strength NSAIDs. Prescription-strength NSAIDs can reduce the frequency of attacks in over half of migraine sufferers. There are many prescription brands available. Mefenamic acid (Ponstel) and naproxen (Anaprox) are particularly useful for preventing migraines associated with menstruation.

Long-term use of these drugs can lead to ulcers and possibly gastrointestinal bleeding.

COX-2 Inhibitors. Celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra) are known as COX-2 (cyclooxygenase-2) inhibitors. These NSAIDs have specific actions that appear to reduce the risk for ulcers and bleeding while still relieving pain. Some early evidence suggests they may be useful for preventing migraines. There is some concern, however, about adverse effects on kidney function and a higher incidence of heart attacks in patients taking these agents.

Beta-Blockers

Beta-blockers are usually prescribed to reduce high blood pressure. Some, however, are also useful in reducing the frequency of migraine attacks and their severity when they occur. Propranolol (Inderal) and timolol (Blocadren) have been approved specifically for prevention of migraine. Others that may be effective include metoprolol (Lopressor, Toprol XL), and nadolol (Corgard).

Side Effects. Side effects may include the following:

• Fatigue and lethargy are common.
• Some people experience vivid dreams and nightmares, depression, and memory loss.
• Dizziness and lightheadedness may occur upon standing.
• Exercise capacity may be reduced.
• Other side effects may include cold extremities, asthma, decreased heart function, gastrointestinal problems, and sexual dysfunction.

If side effects occur, the patient should call a physician, but it is extremely important not to stop the drug abruptly. There is some suggestion that people with migraines who have had a stroke should avoid beta-blockers.

Anti-Seizure Drugs

Anti-seizure drugs, also called anti-epileptics or anticonvulsants, affect the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. GABA may also have a role in migraines. These agents are commonly used for epilepsy and bipolar disease. Anti-seizure agents are more expensive than other agents used, however. They also have significant side effects. Some experts, then, recommend them only as second-line prevention after older agents have failed.

Valproate and Divalproex Sodium. Valproate (Depakene) and a similar drug, divalproex sodium (Depakote), are the only drugs approved for preventing migraines. Studies report that valproate reduces migraine frequencies by 30% to 50% or greater by the end of one year, after which the benefits remain stable.

Gabapentin (Neurontin). The safety and efficacy of gabapentin also has been tested for migraine prevention. A 2001 multicenter study found that 2400 mg/day of gabapentin is an effective prophylactic agent for patients with migraine headaches. Side effects are similar to those of valproate and may include sleepiness, dizziness, fatigue and weight gain.

Topiramate (Topamax). Topiramate (Topamax) has been prescribed off-label for several years for prevention of migraines with considerable success. The FDA is expected to grant it specific approval for migraines in 2004. Weight loss is a side-effect. In clinical trials, patients lost an average of 3.8% of their body weigh.

Levetiracetam (Keppra). Levetiracetam significantly reduced the frequency and impact of headaches in patients with transformed migraine, according to study presented at the 56th annual meeting of the American Academy of Neurology in April 2004. Earlier studies have suggested that levetiracetam, when used alone and in combination with other treatments, provided pain relief to more than 90 percent of patients afflicted with migraine headaches to neck and back pain.

Other Anti-Seizure Agents Under Investigation. These include Felbamate (Felbator), Tiagabine (Gabitril), oxcarbazepine (Trileptal) and Zonisamide (Zonegran). Patients taking oxcarbazepine 300 mg/day for other medical conditions have reported a decrease in migraine frequency. Zonisamide has been shown to reduce migraine frequency in open label trials. Further study is warranted. Zonegran may also be associated with weight loss.

General Side Effects. The side effects given here are associated with valproate. Other anti-seizure agents have similar effects and some specific ones of their own. Most are usually minor, occurring early in therapy, and then subsiding. Those of valproate include the following:

• Gastrointestinal problems (nausea, vomiting, diarrhea, heartburn). (In some studies, such side effects occurred initially in half the patients taking valproate.)
• Headaches.
• Visual disturbances.
• Ringing in the ear.
• Temporary hair thinning and loss have occurred; taking zinc and selenium supplements may help reduce the effect.
• Weight gain (a significant problem with valproate). In one study 23% of valproate-treated patients gained weight. (Other anti-seizure agents, such as topiramate, may actually be helpful for reducing treatment-related weight gain.)
• Agitation.
• Drowsiness. (In one study, this was the most common side effect reported by patients taking gabapentin.)
• Specific adverse effects in women. Premenopausal women are at increased risk for menstrual irregularities and polycystic ovaries, due to elevated male hormones. The effects are reversible. There is a higher risk for birth defects when taken by pregnant women. (These side effects also appear in women using other anti-epileptic drugs, but the risk from valproate appears to be higher.)
• Symptoms of Parkinson's disease preceded by hearing loss in people who have taken it for more than a year, but they were reversible when the drug was withdrawn.

Toxic Side Effects

• Cases of pancreatitis, a serious and even life-threatening inflammation in the pancreas, have been reported in children and adults taking valproate.
• Valproate and divalproex sodium are not usually recommended for young children because of an unusual, but potentially fatal, toxic effect on the liver. Children with epilepsy who take valproic acid may eventually develop some problems in the kidney, although according to a 2001 study, they are generally not significant.

Tricyclic and Other Antidepressants

Certain antidepressants are quite effective in preventing all forms of headache, including migraine. The effects of any of these antidepressants on headaches are most likely due to their effects on serotonin, a chemical messenger in the brain that influences depression and migraine.

Tricyclics. Tricyclics are the most effective antidepressants for migraine prevention. They include amitriptyline (Elavil, Endep), nortriptyline (Pamelor, Aventyl), doxepin (Sinequan), and protriptyline (Vivactil). They are beneficial for migraine patients who also suffer from depression, may be particularly useful for patients who suffer from both migraines and tension headaches. Low doses may also help prevent cyclic vomiting in childhood migraine. They can have some significant side effects, including disturbances in heart rhythms. They can also be fatal in overdose.

Other Antidepressants. Serotonin-reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and fluvoxamine (Luvox). SSRIs are sometimes helpful in reducing migraines, although they in general their effects are disappointing.

Newer antidepressants target neurotransmitters, such as norepinephrine, alone or in addition to serotonin. Nefazodone (Serzone) and venlafaxine (Effexor) are such agents that are showing some promise in preventing migraines.

Calcium-Channel Blockers

Calcium-channel blockers have been prescribed for preventing both migraine and cluster headaches. They must be taken for weeks to months before any benefit is noticed. Certain calcium-channel blockers may be particularly beneficial for preventing migraines in migraine patients who have experienced stroke.

Verapamil (Calan) is most commonly used for prevention of migraines. Others used or being investigated for migraines include diltiazem (Cardizem), nimodipine (Nimotop), nifedipine (Procardia), amlodipine (Norvasc), felodipine (Plendil), and nisoldipine (Sular). Novel calcium blockers, such as dotarizine and flunarizine (Sibelium), are being investigated and show promise for migraines. Flunarizine, available overseas but not in the US, is effective and may help prevent migraines in children. (Other calcium-channel blockers are not useful for children.)

Side Effects. They vary among different preparations. They may cause the following:

• Fluid accumulation in the feet.
• Drop in blood pressure, with accompanying dizziness.
• In some people they cause headaches as severe as the migraines they are preventing.
• Constipation.
• Fatigue.
• Impotence.
• Gingivitis.
• Flushing, and allergic symptoms.

Note: Grapefruit boosts the effects of calcium-channel blocking drugs.

Other Agents Investigated for Preventing Migraines

Angiotensin Converting Enzyme (ACE) Inhibitors. Commonly used for treating high blood pressure, ACE inhibitors block the production of the protein angiotensin, which constricts blood vessels and may be involved in migraine. Studies using the ACE inhibitor lisinopril (Prinivil, Zestril) are reporting significant reduction in migraine attacks.

Angiotensin-Receptor Blockers (ARBs). Angiotensin-receptor blockers (ARBs) have actions similar to ACE inhibitors, but may have fewer side effects. In one study sponsored by the manufacturer, patients who took the ARB candesartan (Atacand) experienced significant reduction in the number of headaches compared to patients on a placebo ("sugar pill").

Botulinum. Botulinum toxin A (Botox) injections, a common wrinkle treatment, causes small muscles to relax. This approach is now being used with some success for treating disorders that involve over-excited muscle activity, including myofascial pain syndrome and migraine. One study, for example, reported complete migraine relief in more than half of patients being tested and improvement of more than 50% in another 35% of patients. Relief lasted three to four months with no adverse effects.

Leukotriene-Antagonists. Leukotriene-antagonists are anti-inflammatory agents that blocks leukotrienes, powerful immune system factors that are important in causing airway constriction. They include zileuton (Ziflo), zafirlukast (Accolate), montelukast (Singulair), and pranlukast (Ultair, Onon). These agents are being used in asthma and some physicians have observed a reduction in migraine frequency in asthmatic patients who also had these headaches. In one study that investigated their use for migraine prevention, more than half of patients experienced a reduction in frequency of severe attacks. In a controlled study, however, montelukast had no effect on migraines.

Dopamine Agonists. Alpha-dihydroergocryptine is a drug known as a dopamine agonist, which may be helpful in preventing common migraine (without aura).