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MIGRAINE PROPHYLACTIC DRUGS: EFFICACY, USE, AND PRESCRIBING TRENDS

Summary of the state of affairs

Migraine is a common primary paroxysmal headache disorder characterized by attacks of intractable headaches in combination with various autonomic and gastrointestinal symptoms; less commonly, acephalic migraine may occur. Migraine is a disabling disorder that affects nearly 30 million people in the United States alone, and it carries major social and economic burdens on patients and the health care system.¹ Despite a high 1-year prevalence of 10%, migraine is often misdiagnosed and undertreated.^2,3

Treatment is targeted at identifying and avoiding triggers, acute intervention, and preventive strategies, including both pharmacologic and nonpharmacologic approaches. Preventive therapies should be considered in patients who have frequent attacks (ie, >3/mo), debilitating headaches, migraine with unusual presentations, or migraine variants, or who are unable to tolerate abortive therapies. Effective migraine preventive therapy is aimed at reducing the frequency, intensity, and duration of migraine attacks; improving responsiveness to acute therapies; improving patient function; reducing disability and improving quality of life; and decreasing the cost of migraine management.^4,5

Despite the hugely unmet need, novel therapeutic targets for migraine prevention are lacking. Only a handful of agents are approved for the specific indication of migraine prevention in adults. The mechanism of currently available preventive agents remains unclear. Suggested mechanisms include modulation of neuronal excitability, inhibition of cortical spreading depression, enhancement of antinociception, and inhibition of peripheral and central sensitization. Prophylactic agents have been relatively under-studied in patients with migraine who are aged 18 years or younger; therefore, their use in this population is not the focus of this review.⁶

Current preventive therapies

Various pharmacological classes have been used in migraine prevention, and they have a broad spectrum of adverse effect profiles. Beta-blockers (eg, propranolol, timolol), tricyclic antidepressants (TCAs; eg, amitriptyline), anticonvulsants (eg, topiramate, divalproex), and calcium channel blockers (eg, flunarizine) have the best evidence-based efficacy, supported by years of clinical experience.^7,8

Propranolol has been extensively studied and proven effective in migraine prophylaxis and is usually used as first-line therapy. The use of a long-acting formulation may improve compliance. Beneficial response is usually achieved at dosages of 60-240 mg/d. Adverse effects include hypotension, bradycardia, impotence, and weight gain. Propranolol should be avoided in patients with depression, Raynaud disease, acute congestive heart failure, and asthma.

Amitriptyline is the most effective TCA in migraine prophylaxis. The effective therapeutic dose in migraine prevention is usually 50-100 mg/d. Adverse effects include weight gain, fatigue, constipation, dry mouth, drowsiness, and orthostatic hypotension. Rarely, cardiac dysrhythmias may occur. Other TCAs, such as protriptyline, nortriptyline, and imipramine, are also commonly used, and response with these agents is variable.

Divalproex sodium is proven effective for migraine prevention at doses of 500-1000 mg/d. Its use is limited by its adverse effect profile, which predominantly includes weight gain, alopecia, gastrointestinal symptoms, tremor, and thrombocytopenia. Liver toxicity and pancreatitis may occur.

Despite its numerous and frequent adverse effects and its high cost, topiramate, a third-generation antiepileptic drug, has become a popular migraine preventive therapy because of its potentially appealing weight reduction effect. Topiramate was proven an effective treatment for migraine at a dosage of 100-200 mg/d. Adverse effects include paresthesias, poor concentration, fatigue, acute angle closure glaucoma, and nephrolithiasis.

Flunarizine is a calcium channel blocker that is proven efficacious in migraine prevention. Therapeutic response is achieved at a dose of 10 mg/d. Adverse effects include bradyarrhythmias, lower extremity edema, and weight gain. Flunarizine is not available on the US market. Other calcium channel blockers, such as verapamil, are less effective.

Methysergide (in 2-8 mg doses) has long been proven effective in migraine prevention, but its use has been limited by its rare but potentially serious complications, which include retroperitoneal, endocardial, and pulmonary fibrosis.

Future preventive therapies

Some pharmaceuticals that are approved for indications other than migraine have also been used to treat migraine; limited evidence is available to support the use of these agents. Examples of these pharmaceuticals include serotonin receptor agonists, metoprolol, nadolol, cyproheptadine, levetiracetam, gabapentin, zonisamide, memantine, lithium, candesartan, and lisinopril. Nonsteroidal anti-inflammatory drugs (NSAIDs), mainly naproxen, and triptans have been evaluated and proven beneficial for the prevention of menstrual migraine.^4,5

Nonpharmacologic treatment has been used for migraine prophylaxis with conflicting results or limited evidence. Magnesium (400-600 mg), riboflavin (400 mg), vitamin B-12 (1 mg), coenzyme Q10 (150 mg), feverfew (6.25 mg 3 times daily), and petasites extract (75 mg twice daily) have been used. Alternative therapies, such as hypnosis and acupuncture, have also been explored.

Recently, botulinum toxin type A has been studied in migraine prevention, with mixed results. A few select studies have shown that botulinum toxin can reduce the intensity and frequency of migraines when injected in the glabellar, frontalis, and temporalis muscles. Patients whose migraines respond positively to botulinum toxin may require repeated injections every 3 months because the effect may wane with time. Until the results of currently ongoing randomized clinical trials are available, botulinum toxin should only be considered for the subset of patients who have refractory headaches that do not respond to all other conventional preventive strategies or who cannot tolerate those strategies.⁴

Novel migraine preventive pharmacological therapies that likely target the migraine mechanisms of neuronal excitability are currently being investigated.²

Guidelines for preventive management

Accurate diagnosis and institution of adequate migraine management are the keys to successful implementation of migraine management. Multiple factors are considered when selecting the appropriate preventive agent, including comorbidities, drug interactions, and patient preference.^4,9

• The goal is for monotherapy, at an effective dose, with the lowest levels of adverse effects.
• Medications with proven best evidence-based efficacy (eg, propranolol, divalproex sodium, topiramate, amitriptyline) should be used as first-line agents.
• Physicians should assess for comorbid conditions and consider agents with dual benefit (ie, agents whose adverse effects may help treat a comorbid condition).
• Medications should be started at lower doses and be gradually increased to achieve maximum clinical efficacy.
• Unwanted drug interactions and undesirable adverse effects should be avoided.
• Because benefits may not be seen until 6-8 weeks after reaching a target therapeutic dose, certain agents should not be discontinued before a fair therapeutic trial of at least 3 months at a maximum tolerated dose is achieved.
• Patients should be encouraged to maintain a headache diary to help determine response to therapy.
• Adverse effects and drug interaction are indications for discontinuation of a particular agent.
• Women of childbearing age should be aware of the teratogenic effects of preventive agents and should use effective contraceptive measures while taking migraine preventive treatments.
• Once an appropriate migraine control is achieved, patients should be maintained on an effective drug for approximately 6 months and then be reevaluated for possible discontinuation of therapy.

References

1. Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache. 2005;45 Suppl 1:S3-S13.

2. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257-70.

3. Lipton RB, Stewart WF, Diamond S, et al. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-57.

4. Silberstein SD. Migraine. Lancet. 2004;363(9406):381-91.

5. Loder E, Biondi D. General principles of migraine management: the changing role of prevention. Headache. 2005;45 Suppl 1:S33-47.

6. Ramadan NM. Prophylactic migraine therapy: mechanisms and evidence. Curr Pain Headache Rep. 2004;8(2):91-5.

7. Buchanan TM, Ramadan NM. Prophylactic pharmacotherapy for migraine headaches. Semin Neurol. 2006;26(2):188-98.

8. D’Amico D, Lanteri-Minet M. Migraine preventive therapy: selection of appropriate patients and general principles of management. Expert Rev Neurother. 2006;6(8):1147-57.