Understanding Migraine: Strategies for Prevention

The authors explain the possible use of prophylactics ranging from antidepressants to botulinum toxin to limit the number, intensity, and duration of attacks. Also discussed are management of hormonally triggered migraine and special considerations for care of the pregnant migraineur.

By Jeff Unger, MD, Roger K. Cady, MD, and Kathleen Farmer-Cady, PsyD

One of the most important contributions primary care can make in managing migraine is to prevent the evolution of the episodic syndrome of migraine into the biopsychosocial disease of chronic migraine. As with acute therapy, early interventions with education, lifestyle changes, and medications can prevent significant disability for this population of patients and decrease the impact of migraine on the health care system and society in general. Thus, migraine prevention is a critical component of care for the migraine patient.

Migraine prevention can lessen the number, intensity, and duration of attacks. In addition, the efficacy of symptomatic medications is often enhanced when prophylactic drugs are employed. The indications for using migraine preventive therapy are listed in the table above and the specific prophylactic drugs that are helpful in limiting migraine attacks are listed in the table below.

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PROPHYLACTIC MEDICATIONS

The choice of prophylactic medications depends largely on the presence of coexisting disorders. For example, consider a selective serotonin reuptake inhibitor (SSRI) or tricyclic antidepressant (TCA) in depressed patients. Atypical antipsychotics or an antiepileptic medication may be useful for patients with migraine and bipolar depression. Patients with sleep disturbances and those who frequently awaken with migraine should do well with a TCA. If a patient has hypertension, calcium channel blockers or beta blockers are helpful. Patients who prefer to take nonprescription medications can be placed on melatonin, magnesium, feverfew, or riboflavin.

Antiepileptic drugs. These drugs have become popular choices recently for migraine prophylaxis. Antiepileptic drugs decrease migraine frequency, intensity, and duration at much lower doses than those used to treat seizure disorders. Side effects are not uncommon, however, and should be discussed with patients before the drugs are prescribed. Common adverse effects associated with divalproate sodium include weight gain, hair loss, gastric reflux, tremor, and potential neural tube defects if the drug is used during the first 15 weeks of pregnancy. Adverse effects associated with topiramate include paresthesias, memory impairment, language disturbances, and, rarely, visual disturbances (including glaucoma), and kidney stone formation. Topiramate can cause weight loss rather than weight gain and may be the drug of choice for obese patients with migraine. Topiramate should be prescribed at a low starting dose (25 mg) and titrated slowly to a dose of 100 to 200 mg. The effective dose for divalproate sodium is 500 to 1000 mg daily.

Tricyclic antidepressants. When taken in low doses two hours before bedtime, TCAs may be helpful in treating migraineurs who have sleep disturbances, anxiety, and depression. Side effects, such as dizziness, weight gain, blurred vision, and sexual dysfunction, become more problematic as the dose increases.

Selective serotonin reuptake inhibitors. While SSRIs have not been shown to be beneficial in migraine prophylaxis, patients with coexisting anxiety and depression are often placed successfully on these drugs and may note improvement in their migraine management. Side effects include difficulty with ejaculation, anorgasmia, tremor, and gastrointestinal distress. Patients taking triptans can safely use SSRIs concomitantly.

Beta blockers and calcium channel blockers. Beta blockers are well tolerated and effective in migraine prevention. Side effects include fatigue, cold hands, and, in patients with asthma, shortness of breath. Nadolol is preferred by many clinicians because dose titration is not usually necessary. Although calcium channel blockers have been used for migraine prevention, evidence-based studies suggest they may have greater efficacy in cluster headache patients than in migraineurs.

Magnesium. This over-the-counter drug is helpful in decreasing many types of pain syndromes. It should be used in doses of 250 to 750 mg. Side effects may include diarrhea. Plain magnesium should be used. Combinations of magnesium with calcium and zinc are not helpful.

Melatonin. This drug has recently been advocated for use in patients who awaken from sleep with various headache disorders, especially cluster headaches. We have been using melatonin at a dose of 10 to 15 mg taken at bedtime to prevent migraine headaches that awaken patients from sleep. Although no published data is available on melatonin use for migraine, the drug is safe and appears to eliminate up to 60% of nocturnal migraine. The most common side effect with melatonin appears to be bad dreams and difficulty sleeping for the first two or three nights of use.

Aspirin. At a dose of 325 mg, aspirin has been shown to reduce the incidence of migraine in male patients. It should be prescribed prophylactically to patients having migraine with aura. For patients who are obese, smoke cigarettes, have migraine with aura, or take birth control pills, the risk of migrainous stroke is quadrupled. Aspirin is also helpful in preventing retinal migraine, a form of migraine that occurs in older women who experience an aura but no migraine pain.

Riboflavin. This drug may be used in patients who prefer taking an alternative medication. The recommended dose is 200 to 400 mg daily. No side effects have been reported, but the drug may take two to five months to take effect.

Unlike abortive medications for migraine, prophylactic drugs may take several days or weeks to become effective. Low doses are usually very successful in limiting migraine attacks and side effects. Prophylactic drugs should be taken consistently at the same time each day. Once a patient responds well to prophylactic intervention, the drug should be continued for at least six months. The patient and physician can then discuss whether or not to taper off the medication or continue it, possibly at a lower dose.

Botulinum toxin A (Botox). This is a new therapeutic option for the preventive treatment of migraine and chronic daily headache, especially headaches that are refractory to other treatments. The drug is injected into the muscles of the face, head, and neck in doses of up to 100 units every three to four months. Botox has been shown to reduce the need for multiple preventive medications, to reduce the frequency of triptan use, and to minimize the frequency of headache-related emergency department and office visits. Side effects of Botox include mild pain and bleeding at the injection sites, possible worsening of the headache condition, drooping eyelid, and dry mouth. Some patients may experience aching in the injected muscles.

Physicians who have used Botox since 2000 report a success rate of 75% in patients for whom conventional forms of treatment have failed. Success is defined as a 50% reduction in the frequency, duration, and intensity of headaches.

The exact mechanism of action of Botox is unknown. The neurotoxin may reduce the release of neuropeptides within the trigeminal vascular system. These neuropeptides are known to potentiate the migraine process.

Patients are injected with Botox in muscles of the eye area, nose area, forehead, sides of the head, and neck. Many migraineurs report tenderness in these muscles during an acute migraine attack. Physical examination may reveal tender, knotted muscle tissue in these areas. Each muscle is injected with between 2.5 and 5 units of the neurotoxin, resulting in a total of 18 to 24 separate injections.

Two different injection strategies are used. In the so-called fixed-site pattern, the muscles in the face and sides of the head receive the neurotoxin. If the patient experiences frequent neck pain in association with the headaches, a "follow the pain" approach can be used and additional neck injections are performed. Often a combination of the two injection techniques is employed. After the injections, most patients notice improvement in their headaches within three to seven days. The effects of the neurotoxin will last for three to five months, after which the headaches commonly recur. As more injections are administered, however, the efficacy of the drug often improves. Patients should receive injections every three months unless their headaches stop completely. The table below lists the indications for use of Botox injections.

MIGRAINE AND HORMONAL TRIGGERS

Migraine is one of the most common disabling medical conditions in females. Approximately 18% of women suffer from migraine during their reproductive years. The predominance of migraine in females, with its associated social and economic burdens, makes headache disorders a critical issue in women's health.

Among female migraineurs, 60% report an exacerbation of headaches around the time of menstruation. Of these women, 10% have true menstrual migraine that occurs exclusively with menstruation. Falling estrogen levels around the time of menstruation may trigger migraine in headache-prone individuals. As estrogen levels drop, production of serotonin, which stabilizes pain receptors in the brain, falls and its rate of elimination is accelerated. At the same time, endogenous opioid activity and endorphin levels decrease.

Treatment for menstrual migraine involves behavioral strategies, preventive care, and acute therapies. Behavioral strategies include relaxation training, biofeedback, and avoidance of known environmental triggers. Lifestyle interventions should be strictly observed.

Preventive treatments should be considered when the migraines are frequent and disabling or if the patient is unable to avoid headache triggers. In general, monophasic oral contraceptives are preferred over triphasic formulations. Patients using oral contraceptives may have headaches during the seven days when they take a placebo. These patients can be instructed to take the oral contraceptive for 21 days and then start a new pack without using the placebos. After three months, they should cycle off the contraceptives for seven days, which may trigger a series of severe headaches. Patients may be given naratriptan 1 mg twice daily or 2.5 mg taken at 4 a.m. daily for seven days. An additional dose of naratriptan may be taken once within a 24-hour period for a breakthrough headache.

Patients who are not taking contraceptives may also use a transdermal patch (beta-estradiol 0.5 mg), applied three days prior to the onset of menstruation and replaced once after three days. The patch is helpful in preventing the critical drop in serum estrogen levels that may trigger migraine. The estrogen patch will not delay menstruation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used on a short-term basis beginning two or three days before the onset of menstruation. They should be continued until menstruation is over. Magnesium 250 mg daily taken at bedtime may be useful in preventing menstrual migraine, or it may be used in combination with an NSAID around the time of menstruation.

Postmenopausal women should avoid cycling their estrogen and progesterone tablets. Both should be taken together daily. In addition, use of a pure estrogen drug (estradiol, estrace, or the estradiol patch) is preferable to conjugated estrogens, which can trigger migraine in some women.

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HEADACHE DURING PREGNANCY

Migraine can occur for the first time during pregnancy. The course of pre-existing migraine during pregnancy is variable. In some patients, the headaches worsen, especially during the first trimester, but in about 65% of migraineurs, the headaches are not as bad during pregnancy.

Headaches are most likely to worsen in women who have pre-existing migraine with aura; they improve among women with true menstrual migraine. In some migraineurs, headaches completely remit during pregnancy. In general, headache frequency, intensity, and duration tend to improve over the course of a pregnancy. However, patients who report headaches at the end of their first trimester usually continue to experience headaches throughout pregnancy and during the postpartum period.

Pregnancy-related adverse outcomes, such as spontaneous abortions or stillbirths, are not increased in migraineurs. However, these women have a greater potential for developing toxemia than do nonmigraineurs.

Most patients who experience headaches during pregnancy have primary disorders, such as migraine and episodic tension type headaches. However, secondary headache disorders, such as acute sinusitis, meningitis, idiopathic intracranial hypertension (pseudotumor cerebri), and subarachnoid hemorrhage, may develop during pregnancy. If this occurs, neuroimaging or a spinal tap may be required for diagnosis. If neuroimaging is necessary, the study that provides the most information with the least fetal risk is the best choice.

Early in the embryonic stage, the most likely effect of radiation (at a threshold of 5 rads or more) is death of the conceptus. Radiation exposure at that level at any time during the first trimester may result in developmental anomalies or intrauterine growth retardation. A dose of 15 rads or more is necessary to produce deformities that might warrant termination of the pregnancy. A standard computed tomography (CT) scan of the head exposes the fetus to no more than 1 mrad. Head CT is relatively safe during pregnancy and is the study of choice for head trauma and subarachnoid hemorrhage.

The potential risk of magnetic resonance imaging (MRI) in pregnancy remains controversial. The MRI magnets induce an electric field that raises the body's core temperature by less than 1°C. This rise in temperature may be enough, however, to increase the incidence of neural tube defects. Nevertheless, MRI may be necessary to investigate pathology.

Gadolinium crosses the placental barrier and is excreted through the fetal kidneys. Although no ill effects have been demonstrated with gadolinium, MRI and CT contrast studies should be avoided during pregnancy.
 

TREATMENT OF PREGNANT PATIENTS

Treating pregnant migraineurs can be challenging. Because of the risk of injury to the fetus, medication use should be limited. Fortunately, most migraineurs improve enough by the second trimester that nonpharmacologic measures may be sufficient. Behavioral intervention is critical before and during pregnancy. Headaches should be treated whenever possible with ice packs, reassurance, and relaxation. Nonpharmacologic treatment significantly improves headache symptoms in 79% of pregnant patients. For moderate to severe headaches, NSAIDs, acetaminophen (alone or with codeine), or narcotics (meperidine suppositories, for example) may be used. Patients who experience severe headaches associated with nausea, vomiting, and dehydration may require inpatient care. Dehydration and electrolyte imbalance may pose a greater risk to the fetus than the risk posed by analgesics.

Patients who experience severe nausea with an acute migraine can be treated with injections or suppositories. Trimethobenzamide, chlorpromazine, prochlorperazine, and promethazine are available orally and parenterally and in suppository form. All can be used safely in pregnancy.

Some women develop new daily persistent headache during pregnancy. These intense headaches are associated with migraine symptoms. Pregnant patients with these headaches may obtain significant relief from occipital nerve blocks.

Another safe and effective treatment for acute migraine during pregnancy is the use of intravenous (IV) magnesium sulfate, a drug that is also helpful in managing patients with toxemia. One gram of magnesium sulfate can be given IV push over one to three minutes in patients with severe headache. Patients often experience a significant "hot flash" lasting 30 to 45 seconds during the injection. However, nearly 87% of patients achieve complete and rapid headache relief, as well as dissipation of their migraine-associated symptoms. A maximum of three weekly IV injections of magnesium sulfate may be given to patients who experience frequent disabling headaches during pregnancy.

Since migraine frequently affects women of child-bearing age, it is likely that acute migraine medications, such as triptans, may be taken by women before they know they are pregnant. In the United States, sumatriptan is currently labeled pregnancy category C (risk to humans has not been ruled out). Recent pregnancy registries have suggested that there is no evidence for any specific effect of sumatriptan on pregnancy outcome, although the sample size is insufficient to make definitive claims for events that occur at a frequency of less than 1 per 1000. Patients inadvertently exposed to sumatriptan during an early stage of pregnancy can be reassured and the pregnancy registered so that further data collection can be obtained. It is important to register patients in the triptan registries so that an accurate assessment of risk can be made at some point in the future.

The estimated teratogenic risk and congenital fetal malformations in women who inadvertently use sumatriptan during pregnancy has been calculated to be 2.7%, compared with a general population risk of 3.6%. Current information is not sufficient to rule out slight increases in the risk of birth defects with inadvertent sumatriptan exposure during pregnancy. For this reason, caution should be exercised in making a positive recommendation regarding the use of sumatriptan during pregnancy. The risk may or may not be similar for other triptans with a different chemical structure.

An increase in the frequency, intensity, or duration of migraine, as well as the presence of debilitating migraine-associated symptoms, may require the use of preventive medications during pregnancy. Migraine prophylaxis drugs should be used as a last resort after their risks and benefits have been fully disclosed to the patient. Preventive medications should be considered when a patient experiences three or four disabling headaches a month, has headaches that result in dehydration and possible fetal distress, or has headaches that do not improve with the use of acute drug therapy. The table below lists drugs that may be useful in migraine prevention, with dosing ranges and risk categories established by the Food and Drug Administration.

Headache patients who are breast-feeding may safely use acetaminophen, NSAIDs, or narcotics. Triptans should be used with caution; those with a short half-life are preferred, and mothers should avoid breast-feeding and should pump their breasts for four to six hours after using a triptan before they resume breast-feeding. In the interim, stored breast milk may be used. Ergotamines are contraindicated during lactation. In general, patients should be cautioned against using acute migraine drugs during lactation unless the benefits significantly outweigh the risks.
 

PATIENT'S ROLE IN HEADACHE MANAGEMENT

Physicians can help the migraineur live a more pain-free and disability-free life, but the patient must play the primary role. Patients must comply with the behavioral modifications discussed in this series. They should receive headache information from a reliable source. Advice from well-intentioned family members, friends, nutrition advocates, and talk show hosts, on the other hand, should be taken with a grain of salt. Encouraging the patient to keep a headache diary can help the physician plan future strategies for headache management.

The goals for patients and physicians may be different. Patients may want to be pain-free, a goal that may not always be attainable. Physicians want patients to be able to decrease the frequency, intensity, and duration of their headache attacks by at least 50%, while significantly improving their quality of life. Today, we are able to treat headache successfully in more than 90% of our patients. With the availability of new and improved migraine medications, there is no reason for patients to continue to suffer.

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