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The following may be considered indications for prophylactic migraine therapy:

• Frequency of migraine attacks is greater than 2 per month
• Duration of individual attacks is longer than 24 hours
• The headaches cause major disruptions in the patient’s lifestyle, with significant disability that lasts 3 or more days
• Abortive therapy fails or is overused
• Symptomatic medications are contraindicated or ineffective
• Use of abortive medications more than twice a week
• Migraine variants such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurological injury^[65]

The goals of preventive therapy are as follows:

• Reduce attack frequency, severity, and/or duration
• Improve responsiveness to acute attacks
• Reduce disability

Currently, the major prophylactic medications for migraine work via one of the following mechanisms:

• 5-HT2 antagonism - Methysergide
• Regulation of voltage-gated ion channels - Calcium channel blockers
• Modulation of central neurotransmitters - Beta-blockers, tricyclic antidepressants
• Enhancing GABAergic inhibition - Valproic acid, gabapentin

Another notable mechanism is alteration of neuronal oxidative metabolism by riboflavin and reducing neuronal hyperexcitability by magnesium replacement.
As with abortive medications, the selection of a preventive medication must take into consideration comorbid conditions and side effect profile (see Table 2 and Table 3 below). Most preventive medications have modest efficacies and have therapeutic gains of less than 50% when compared to placebo. The latency between initiation of therapy and onset of positive treatment response can be quite prolonged. Furthermore, the scientific basis for using most of these medications is wanting.
Propranolol, timolol, methysergide, valproic acid, and topiramate (Topamax) have been approved by the FDA for migraine prophylaxis. However, a 2009 report suggested that long-term topiramate use in pediatric patients can cause metabolic acidosis and hypokalemia; the risk was deemed mild but statistically significant.^[66]
The nonsteroidal anti-inflammatory drug naproxen sodium has also been used for prophylaxis. In controlled clinical trials, naproxen sodium demonstrated better efficacy than placebo and efficacy similar to propranolol. Tolfenamic acid has also been tried for migraine prophylaxis, but the clinical efficacy is not as good as that of beta-blockers, valproate, or methysergide.
Table 2. Preventive Drugs (Open Table in a new window)

First line	High efficacy	Beta-blockers Tricyclic antidepressants Divalproex Topiramate
	Low efficacy	Verapamil NSAIDs SSRIs
Second line	High efficacy	Methysergide Flunarizine MAOIs
	Unproven efficacy	Cyproheptadine Gabapentin Lamotrigine

Table 3. Preventive Medication for Comorbid Conditions (Open Table in a new window)

Comorbid Condition	Medication
Hypertension	Beta-blockers
Angina	Beta-blockers
Stress	Beta-blockers
Depression	Tricyclic antidepressants, SSRIs
Underweight	Tricyclic antidepressants
Epilepsy	Valproic acid, Topiramate
Mania	Valproic acid

Of note, an open pilot study reports that quetiapine is effective for migraine prophylaxis in patients with migraine refractory to treatment with standard therapies (eg, atenolol, nortriptyline, flunarizine). The authors stated that controlled studies are necessary to confirm their observations.^[67]

Classes of prophylactic drugs

The 3 principal classes of medications that are effective for migraine prevention are antiepileptics, antidepressants, and antihypertensives.
Antiepileptics are generally well tolerated. The main adverse effects of topiramate are weight loss and dysesthesia.^[68] Valproic acid (Depakote) is useful as a first-line agent. It is a good mood stabilizer and can benefit patients with concomitant mood swings. However, it can cause weight gain, hair loss, and polycystic ovary disease; therefore, it may not be ideal for young female patients who have a tendency to gain weight.
Valproic acid also carries substantial risks in pregnancy; it may be best suited for women who have had tubal ligation and who cannot tolerate calcium channel blockers because of dizziness. Data for other antiepileptics (eg, gabapentin,^[69] lamotrigine, oxcarbazepine) are limited in migraine.
Tricyclic antidepressants are good second-line alternatives because of their adverse-effect profile and efficacy. Amitriptyline and nortriptyline are most effective. Although serotonin-selective reuptake inhibitors are widely used, data regarding their efficacy in migraine prevention are lacking.
Antihypertensives such as beta-blockers should be tailored if the patient is young and anxious. They may not be the ideal choice for elderly patients or patients with depression, thyroid problems, or diabetes. Calcium channel blockers are another possible choice of treatment. ACE inhibitors (eg, lisinopril) and angiotensin-receptor blockers (eg, candesartan)^[70] have also been shown to be effective for migraine prevention.^[71]
For any of these prophylactic agents, prophylaxis should not be considered a failure until it has been given at the maximum tolerable dose for at least 30 days.

Botulinum toxin

Botulinum toxin A (onabotulinumtoxinA; BOTOX®) may be beneficial in patients with intractable migraine headaches that fail to respond to at least 3 conventional preventive medication. The injections are administered to the scalp and temple. They may reduce the frequency and severity of migraine attacks after 2-3 months of injections.
The injections are expensive and must be administered every 2-3 months to maintain their effectiveness. The most appropriate duration of prophylactic therapy has not been determined. In most patients who are receiving prophylaxis, therapy must be continued for at least 3-6 months.
Multiple trials of onabotulinumtoxinA for migraine prevention have been conducted, with mixed results.^[72] A review by Schulte-Mattler and Martinez-Castrillo found no evidence for a beneficial effect of botulinum toxin. These authors do not recommend the widespread use of botulinum toxin therapy in headaches.^[73]
More recently, however, 2 multicenter, placebo-controlled trials included in the Phase 3 Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program found onabotulinumtoxinA to be effective for headache prophylaxis in adults with chronic migraine. Nearly 1400 patients were included in the results. Secondary benefits included significantly reduced headache-related disability and improved functioning, vitality, and overall health-related quality of life.^[74]

Migraine Treatments and drugs

A variety of drugs have been specifically designed to treat migraines. In addition, some drugs commonly used to treat other conditions also may help relieve or prevent migraines. Medications used to combat migraines fall into two broad categories:

• Pain-relieving medications. Also known as acute or abortive treatment, these types of drugs are taken during migraine attacks and are designed to stop symptoms that have already begun.
• Preventive medications. These types of drugs are taken regularly, often on a daily basis, to reduce the severity or frequency of migraines.

Choosing a strategy to manage your migraines depends on the frequency and severity of your headaches, the degree of disability your headaches cause, and your other medical conditions.
Some medications aren't recommended if you're pregnant or breast-feeding. Some aren't used for children. Your doctor can help find the right medication for you.
Pain-relieving medications
For best results, take pain-relieving drugs as soon as you experience signs or symptoms of a migraine. It may help if you rest or sleep in a dark room after taking them:

• Pain relievers. These medications, such as ibuprofen (Advil, Motrin, others) or acetaminophen (Tylenol, others) may help relieve mild migraines. Drugs marketed specifically for migraines, such as the combination of acetaminophen, aspirin and caffeine (Excedrin Migraine), also may ease moderate migraine pain but aren't effective alone for severe migraines. If taken too often or for long periods of time, these medications can lead to ulcers, gastrointestinal bleeding and rebound headaches. The prescription pain reliever indomethacin may help thwart a migraine headache and is available in suppository form, which may be helpful if you're nauseous.
• Triptans. For many people with migraine attacks, triptans are the drug of choice. They are effective in relieving the pain, nausea, and sensitivity to light and sound that are associated with migraines. Medications include sumatriptan (Imitrex), rizatriptan (Maxalt), almotriptan (Axert), naratriptan (Amerge), zolmitriptan (Zomig), frovatriptan (Frova) and eletriptan (Relpax). Side effects of triptans include nausea, dizziness and muscle weakness. They aren't recommended for people at risk for strokes and heart attacks. A single-tablet combination of sumatriptan and naproxen sodium (Treximet) has proved more effective in relieving migraine symptoms than either medication on its own.
• Ergot. Ergotamine and caffeine combination drugs (Migergot, Cafergot) are much less expensive, but also less effective, than triptans. They seem most effective in those whose pain lasts for more than 48 hours. Dihydroergotamine (D.H.E. 45, Migranal) is an ergot derivative that is more effective and has fewer side effects than ergotamine. It's also available as a nasal spray and in injection form.
• Anti-nausea medications. Because migraines are often accompanied by nausea, with or without vomiting, medication for nausea is appropriate and is usually combined with other medications. Frequently prescribed medications are metoclopramide (Reglan) or prochlorperazine (Compro).
• Opiates. Medications containing narcotics, particularly codeine, are sometimes used to treat migraine headache pain when people can't take triptans or ergot. Narcotics are habit-forming and are usually used only as a last resort.
• Dexamethasone. This corticosteroid may be used in conjunction with other medication to improve pain relief. Because of the risk of steroid toxicity, dexamethasone should not be used frequently.

Preventive medications
You may be a candidate for preventive therapy if you have two or more debilitating attacks a month, if pain-relieving medications aren't helping, or if your migraine signs and symptoms include a prolonged aura or numbness and weakness.
Preventive medications can reduce the frequency, severity and length of migraines and may increase the effectiveness of symptom-relieving medicines used during migraine attacks. Your doctor may recommend that you take preventive medications daily, or only when a predictable trigger, such as menstruation, is approaching.
In most cases, preventive medications don't eliminate headaches completely, and some cause serious side effects. If you have had good results from preventive medicine and have been migraine-free for six months to a year, your doctor may recommend tapering off the medication to see if your migraines return without it.
For best results, take these medications as your doctor recommends:

• Cardiovascular drugs. Beta blockers — commonly used to treat high blood pressure and coronary artery disease — can reduce the frequency and severity of migraines. The beta blocker propranolol (Inderal La, Innopran XL, others) has proved effective for preventing migraines. Calcium channel blockers, another class of cardiovascular drugs, especially verapamil (Calan, Verelan, others), also may be helpful in preventing migraines and relieving symptoms from aura. In addition, the antihypertensive medication lisinopril (Zestril) has been found useful in reducing the length and severity of migraines. Researchers don't understand exactly why these cardiovascular drugs prevent migraine attacks. Side effects can include dizziness, drowsiness or lightheadedness.
• Antidepressants. Certain antidepressants are good at helping to prevent some types of headaches, including migraines. Tricyclic antidepressants, such as amitriptyline, nortriptyline (Pamelor) and protriptyline (Vivactil) are often prescribed for migraine prevention. Tricyclic antidepressants may reduce migraine headaches by affecting the level of serotonin and other brain chemicals, though amitriptyline is the only one proved to be effective for migraine headaches. You don't have to have depression to benefit from these drugs. Other classes of antidepressants called selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) haven't been proved as effective for migraine headache prevention. However, preliminary research suggests that one SNRI, venlafaxine (Effexor, Venlafaxine HCL), may be helpful in preventing migraines.
• Anti-seizure drugs. Some anti-seizure drugs, such as valproate (Depacon), topiramate (Topamax) and gabapentin (Neurontin), seem to reduce the frequency of migraines. Lamotrigine (Lamictal) may be helpful if you have migraines with aura. In high doses, however, these anti-seizure drugs may cause side effects, such as nausea and vomiting, diarrhea, cramps, hair loss, and dizziness.
• Cyproheptadine. This antihistamine specifically affects serotonin activity. Doctors sometimes give it to children as a preventive measure.
• Botulinum toxin type A (Botox). The FDA has approved botulinum toxin type A for treatment of chronic migraine headaches in adults. During this procedure, injections are made in muscles of the forehead and neck. When this is effective, the treatment typically needs to be repeated every 12 weeks.