Preventive Treatment of Migraine
Most migraineurs can be effectively treated with various acute headache medications and nonpharmacologic strategies including lifestyle regulation, stimulant reduction, and trigger avoidance. However, the following clinical presentations warrant the introduction of a pharmacologic agent to reduce the frequency, duration, and severity of migraine attacks:
- Headache frequency more than 2 days per week (or >8 days/month)
- Use of acute medications, successfully or unsuccessfully, more than 2 days per week
- Headache attacks that remain disabling despite aggressive acute intervention, as documented by lifestyle interference, ratings on disability scales, or use of rescue medications more than once a month
- Presence of prolonged aura (>1 hour), complex aura (basilar or hemiplegic), or migraine-induced stroke
- Contraindications to, failure of, overuse of, or adverse events with acute therapies
- Patient desire to reduce frequency of acute attacks
Women of childbearing age require particular attention. Be sure to inform these patients of all potential risks and to select medications that will have the least adverse effect on the fetus. For pregnant patients, migraine attacks must be severe and disabling, and accompanied by nausea, vomiting, and possibly dehydration, before preventive pharmacologic treatments can be considered.
The Treatment Process
Patients should be involved in the treatment process. Their preferences about cost, drug delivery, dosing schedule, and tolerability should be considered when choosing a course of action. In addition, educating patients about the goals, use, and appropriate expectations of migraine preventive therapies is crucial to maximizing the chance for therapeutic success. Patients must understand that these therapies may reduce the frequency or severity of attacks, may improve the efficacy of acute medications, and may assist with the management of comorbid conditions but that they rarely result in complete eradication of headaches. In fact, preventive medications are considered effective if the frequency of attacks is reduced by more than 50%.
A basic principle of preventive treatment is to start the drug at a low dose and increase the dose slowly. Migraine patients often require a dose of a preventive medication that is lower than would be used for other indications. The need for compliance with the program must be emphasized, as the drug dose is generally titrated up over a few weeks and then sustained for 4 to 8 weeks before potential benefit may be realized. Most clinicians recommend a 6 to 12-month maintenance phase once a greater than 50% reduction in headache frequency has been achieved, followed by a tapering phase. To ensure optimal benefit from the prophylactic drug, have patients track their progress with the use of a headache diary and encourage them to avoid using acute headache medications, analgesics, decongestants, and stimulants more than 2 days per week.
Treatment Strategies
Preventive treatment strategies fall into 3 basic categories: episodic, short-term, and chronic. Preventive episodic treatment should be considered if the headache trigger is known. For example, if exercise often leads to an attack, the patient can be instructed to treat prior to the activity. Short-term prevention is used when exposure to the trigger is time-limited, such as flying at high altitudes or menstruation. Treatment with daily medication just before and after exposure has been shown to be effective. For longer-term needs, chronic treatment can be used for months or years.
Pharmacologic Agents
The major classes of agents available for migraine prevention include beta-adrenergic blockers, antidepressants, anticonvulsants (now commonly called neurostabilizers), calcium antagonists, nonsteroidal agents, and serotonin receptor antagonists. The selection of a drug should be based first on efficacy, with consideration given to comorbid psychiatric or medical disease, patient preference, and patient compliance. The US Headache Consortium has published evidence-based medication guidelines following analysis of nearly 300 controlled trials of drugs used to prevent migraine (see the tables below). These guidelines assist clinicians in the selection of appropriate migraine preventive therapy by ranking drugs according to clinical efficacy, adverse events and safety, and clinical experience.
| US Headache Consortium Guidelines for Migraine Prophylaxis |
| Group 1
Medium to high efficacy, good strength of evidence, mild to moderate side effects
|
- Amitriptyline (10-150 mg/day)
- Divalproex sodium (125-200 mg/day)
- Timolol (10-30 mg/day)
- Propranolol (20-160 mg/day)
- Topiramate (50-150 mg/day)a
|
| Group 2
Lower efficacy, limited strength of evidence, mild to moderate side effects
|
- Aspirin (325 mg/day)
- Atenolol (25-100 mg/day)
- Fenoprofen (600 mg three times a day [tid])
- Flurbiprofen (1,000 mg bid-tid)
- Fluoxetine (10-80 mg/day)
- Gabapentin (300-2,400 mg/day)
- Ketoprofen (75 mg tid)
- Metoprolol (50-200 mg/day)
- Nadolol (20-120 mg/day)
- Naproxen (200-550 mg two times a day [bid])
- Nimodipine (30 mg tid)
- Verapamil (120-480 mg/day
- Botulinum toxin type A (25-100 units/3 months)a
|
| Group 3
No scientific evidence of efficacy, but clinically efficacious based on consensus of experience
- Low to moderate adverse events
- Frequent or severe adverse events (or safety concerns); complex management issues
|
- Cyproheptadine
- Antidepressants such as nortriptyline, paroxetine, venlafaxine, doxepin, sertraline, and phenelzine
- Methylergonovine
|
| Group 4
Medium to high efficacy, good strength of evidence, but side effect concerns
|
|
| Group 5
Evidence indicating no efficacy over placebo
|
- Acebutolol
- Pindolol
- Carbamazepine
- Nicardipine
- Nifedipine
- Indomethacin
|
| a Based on evidence not available at the time of Guideline publication
|
Guidelines for Selected Prophylactic Therapies in the Treatment of Migraine
(see Table 4.2 in the original guideline document for doses and clarifications) |
| MEDICATION |
US HEADACHE CONSORTIUM GUIDELINES |
| Beta-Blockers |
|
| Beta-blockers with partial agonist activity have not been shown to have efficacy in migraine prophylaxis |
|
| Atenolol |
Group 2 |
| Metoprolol |
Group 2 |
| Nadolol |
Group 2 |
| Propranolol |
Group 1 |
| Timolol |
Group 1 |
| Calcium Entry Blockers |
|
| Diltiazem |
Group 3a |
| Nimodipine |
Group 2 |
| Nicardipine |
No controlled clinical trials |
| Verapamil |
Group 2 |
| Neurostabilizers |
|
| Divalproex sodium |
Group 1 |
| Gabapentin |
Group 2 |
| Tiagabine |
Group 3a |
| Topiramate |
Meets Group 1 criteria based on evidence not available at time of publication of Guidelines |
| NSAIDs |
|
| Acetylsalicylic acid |
Group 2 |
| Celecoxib |
No controlled clinical trials |
| Fenoprofen |
Group 2 |
| Flurbiprofen |
Group 2 |
| Ketoprofen |
Group 2 |
| Nabumetone |
Group 5 |
| Naproxen |
Group 2 |
| Rofecoxib* |
No controlled clinical trials |
| Tricyclic Antidepressants |
|
| Some drugs in this category have not been studied in controlled clinical headache trials, although clinical experience shows good effect in selected patients. Cost and potential for side effects should be considered. |
|
| Nonsedating: Desipramine |
Group 3a |
| Nonsedating: Protriptyline |
Group 3a |
| Sedating: Amitriptyline |
Group 1 |
| Doxepin |
Group 3a |
| Imipramine |
Group 3a |
| Nortriptyline |
Group 3a |
| Serotonin Reuptake Inhibitors |
|
| Fluoxetine |
Group 2 |
| Fluvoxamine |
Group 3a |
| Paroxetine |
Group 3a |
| Sertraline |
Group 3a |
| Other Antidepressants |
|
| Bupropion |
Group 3a |
| Nefazodone |
No controlled clinical trials |
| Trazodone |
Group 3a |
| Venlafaxine |
Group 3a |
| Special-Use Therapies |
|
| Methylergonovine |
Group 3b |
| Phenobarbital 40 mg, ergotamine tartrate 0.6 mg, and belladonna alkaloids (bellafoline) 0.2 mg |
No controlled trials |
| Cyproheptadine |
Group 3a |
| Methysergide |
Group 4 |
| Monoamine oxidase inhibitor (MAOI): Phenelzine requires intensive patient education and cooperation |
Group 3b |
| Botulinum toxin type A |
|
| Feverfew |
Group 2 |
| Magnesium |
Group 2 |
| Petasites hybridus extract |
2 placebo controlled trials |
| Riboflavin (vitamin B2) |
Group 2 |
*On September 30, 2004, Vioxx (rofecoxib) was withdrawn from the U.S. and worldwide market due to safety concerns of an increased risk of cardiovascular events. See the
U.S. Food and Drug Administration (FDA) Web site for more information.
Beta-blockers
The beta-adrenergic blockers are the most thoroughly studied and most widely used of all the migraine preventive agents. Generally, beta-blockers are 60 to 80% effective in reducing the frequency of attacks by more than 50%. The evidence is best for propranolol and timolol, both approved by the Food and Drug Administration (FDA) for migraine prophylaxis. Agents with partial agonist activity have not been shown to be effective in migraine prevention. The choice of beta-blocker should be based on specific properties such as beta-1 selectivity, convenience of the drug formulation, and idiosyncratic drug effectiveness. Combined or alternate trials of beta-blockers should be considered before giving up on treatment. Common side effects include fatigue, light-headedness, insomnia, bradycardia or exercise intolerance, depression, and sexual dysfunction. Use of beta-blockers should be avoided in patients with depression, asthma, severe cardiovascular disease, insulin-dependent diabetes mellitus, and Raynaud's disease.
Antidepressants
Antidepressants are also widely prescribed for migraine, despite the absence of FDA approval for their use in this setting. The tricyclic antidepressants, particularly amitriptyline, have long been established as extremely efficacious agents. They are inexpensive, are generally dosed once daily at bedtime, and offer advantages for patients with coexistent depression, insomnia, tension-type headache, or fibromyalgia. Drowsiness, weight gain, and dry mouth may limit their use, and they should be avoided in patients with cardiac conduction deficits. Several of the tricyclic agents are more activating, compared with those that are more sedating, and they should be taken in the morning, if possible.
Nontricyclic antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) and venlafaxine and bupropion, have no established efficacy in migraine prevention. However, they are included among the agents found to be effective through clinical experience, and they can be particularly helpful in the presence of comorbid anxiety or mood disorders. Common adverse events include sedation or insomnia, nausea, and sexual dysfunction.
Monoamine oxidase inhibitors (MAOIs), such as phenelzine, may be effective in selected cases. A tyramine-reduced diet is essential when MAOIs are used, and drug interactions (with selective serotonin reuptake inhibitors, meperidine, and certain triptans) limit their utility.
Calcium Antagonists
Although calcium antagonists are relatively popular because of their limited adverse events, they do not possess the established efficacy of the aforementioned drug classes. Verapamil and nimodipine exhibit the best efficacy data. Dizziness or hypotension, constipation, flushing, and edema are among the most common side effects.
Neurostabilizers
Neurostabilizers are relatively new in migraine prophylaxis and are becoming increasingly popular. Divalproex sodium has the most established efficacy through controlled clinical trials. Accumulating evidence indicates that topiramate is in the same general range of efficacy and tolerability as divalproex sodium. As with the other drug classes in migraine prophylaxis, the neurostabilizers may be used at doses lower than would be prescribed for other clinical uses. Typical doses are between 500 and 1,500 mg. Neural tube defects have been reported with divalproex sodium, and it is contraindicated in pregnant women or women at risk of pregnancy. Many specialists recommend providing folic acid when prescribing valproate for women of childbearing potential, although there is no evidence that folic acid prevents neural tube defects.
More recently, topiramate has been approved as a prophylactic agent for migraine. Most headache specialists recommend starting with a low dose (15 to 25 mg) and increasing the dose by 25 mg at weekly intervals until a dose of 100 to 200 mg is achieved. Occasional patients require higher doses. Topiramate has been associated with weight loss, which makes it an attractive option for appropriately selected patients.
Numerous other antiepileptic drugs are currently being investigated for use in migraine prophylaxis. The adverse events and cautions associated with this class of drugs vary, and they will need to be clarified based on the characteristics of each individual product.
Nonsteroidal Agents
The nonsteroidal anti-inflammatory drugs (NSAIDs) have modest efficacy in migraine prevention. Gastrointestinal side effects (erosive gastritis, peptic ulcer disease) and concerns over renal adverse events have limited their use in migraine prevention. More recently, the selective cyclooxygenase-2 (COX-2) agents have garnered interest as potential alternatives.
Other Agents
Three alternative therapies have efficacy data that place them in Group 2 (medications with efficacy suggesting only "modest" improvement and mild to moderate adverse events) of agents ranked by the US Headache Consortium: feverfew, magnesium (400 to 800 mg/day), and riboflavin (vitamin B2, 400 mg/day). Novel anticonvulsants, leukotriene antagonists, and botulinum toxin have all been the focus of recent clinical research.
Combination Therapy
Combination therapy may exhibit clinical efficacy as indicated by experience or expert consensus, but no evidence is available to support polypharmacy for migraine prophylaxis. Nevertheless, certain patients seem to benefit from treatment with multiple agents, influencing migraine through varied mechanisms. The most commonly used combinations are beta-blockers with tricyclic antidepressants or anticonvulsants with antidepressants. Combining methylergonovine with a vasodilator, such as a calcium channel blocker, to decrease side effects has been advocated. Some clinicians cautiously use the combination of phenelzine and amitriptyline in patients with headache refractory to treatment. Patients whose headaches do not respond to single agents in the first tier of drugs from the US Headache Consortium guidelines should be considered for referral to a physician who specializes in headache.
Certain acute medications should be used with caution when prescribing preventive medications. Ergotamine, dihydroergotamine, and sumatriptan can potentially enhance vasospastic properties in the presence of methysergide or methylergonovine. Moreover, because MAOIs decrease the first-pass metabolism of triptans (other than almotriptan, eletriptan, frovatriptan and, naratriptan), increasing their half-lives, their use with triptans should be avoided. Similarly, meperidine, tramadol, dextromethorphan, and sympathomimetics can be potentially lethal when added to MAOIs and may result in serotonin syndrome or hypertensive crisis.
Comorbid Conditions
Comorbid diseases can present certain therapeutic opportunities. For example, when a patient presents with migraine and hypertension and/or angina, beta-blockers or calcium channel blockers may be an effective choice for all conditions. For patients with migraine and depression or anxiety, the use of antidepressants should be considered. Alternatively, for patients with migraine and epilepsy, anticonvulsants such as divalproex sodium offer unique advantages.
Conversely, in individuals with more than one disease, certain medications may be contraindicated. For example, beta-blockers should be used with care in depressed patients. Tricyclic antidepressants, neuroleptics, and sumatriptan may lower the seizure threshold and should be used with caution in patients with epilepsy.
