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{mosimage}CURRENT TRENDS IN THE TREATMENT OF MIGRAINE HEADACHE
TREATMENT OVERVIEW
Although pharmacotherapy has traditionally been and currently is the mainstay of migraine therapy, nonpharmacologic therapies should be considered as first-line choices or as adjuncts to pharmacotherapy. A specific form of nonpharmacologic therapy is behavioral therapy, which has been demonstrated to improve communication between the patient and the clinician as well as patient participation in the recommended treatment process. Another nonpharmacologic treatment has centered on lifestyle changes for the patient, encouraging him or her to identify and avoid migraine precipitators and to allow for appropriate rest when indicated. More recently, several clinically-oriented treatments, such as relaxation therapy, stress management, and biofeedback, have also gained credibility. Another clinically-oriented therapy, acupuncture, has also come into focus as a result of anecdotal success and has been validated in recent studies. The addition of a regular aerobic exercise program can have an additive effect to drug treatment. Chiropractic therapy and physical manipulation, in contradistinction to other therapies mentioned, have performed less favorably in controlled trials; these 2 techniques cannot be fully endorsed at this time.
Although no single nonpharmacologic therapy has been shown to be superior to another, a building body of evidence now shows the individual effectiveness of each of these treatments. The headache index (a composite score based on headache frequency, severity, duration, or a combination thereof) can be reduced 50% or more in 30-60% of patients; these results are comparable to the effects of commonly used prophylactic drugs. When considering nonpharmacologic treatments, clinicians must recognize patient-specific factors and the necessity of patient cooperation. Patients must be willing to practice the techniques at home and make the commitment to meet regularly with clinicians or trainers, as necessary.
ACUTE TREATMENT
The ultimate goal of acute treatment should be to restore the patient’s ability to function. This should be achieved with minimal adverse effects. Two common strategies are used when selecting a medication regimen for the acute treatment of migraine headaches. A stepped-care approach, in which patients are initially prescribed a nonspecific analgesic, regardless of headache index, is often used for treating migraine headaches in children and patients with unknown risk factors. A different strategy is a stratified-care approach, which selects initial pharmacologic treatments based on headache burden and medication potency, cost, and toxicity.2 The stratified-care approach requires that the physician spend more time assessing the patient’s migraine patterns; however, it has been found to more effectively reduce both disability time and total cost associated with treatment.3 Despite the demonstrated superiority of the stratified-care approach, many physicians continue to utilize the traditional stepped-care approach for many of their patients.
Among the choices for pharmacotherapy, a trial of a nonspecific analgesic such as acetylsalicylic acid or a nonsteroidal medication with or without the addition of an antiemetic (eg, metoclopramide, prochlorperazine) is a reasonable selection of first-line therapy for mild to moderate migraine headaches. If migraine episodes are not controlled with these initial medications within 40-60 minutes, migraine-specific agents should be added to the regimen.1
Currently, most migraine-specific agents that are prescribed work, at least in part, by exerting a vasoconstrictive effect. Combination products that contain a vasoconstrictor (isometheptene), an analgesic (acetaminophen), and a sedative (dichloralphenazone) may be considered. Examples of these products include Amidrine, Duradrin, and Midrin. Also, any one of the triptans may be considered. Triptans are a class of medications that bind to serotonin receptors in the cranial blood vessels, leading to cerebral vasoconstriction. Examples of triptans include almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig).
Triptans
Seven different medications in the triptan family are currently available in the United States, as listed above. Subcutaneous and intranasal formulations provide alternative modes of drug delivery to treat patients who cannot ingest medications effectively because of migraine-associated nausea and vomiting. These formulations may also provide more rapid palliation. Triptans differ from one another in tolerability and pharmacokinetics. They should not be used in an additive fashion; ie, a patient who takes the maximum dosage of one triptan cannot use another triptan or ergot derivative until the duration of effect has elapsed. One specific advantage of the more recently developed triptans, such as frovatriptan, is an extended half-life, which prevents the need for repetitive dosing to control pain.4
The adverse effects of triptans are mostly serotonergic and mild; only a small number of patients experience symptoms to a degree that necessitates discontinuation. Triptans can also lead, rarely, to the development of chest pain as a result of vasoconstriction of the coronary arteries. This class of drugs is currently contraindicated in patients with ischemic heart disease, uncontrolled hypertension, and cerebrovascular disease. However, some more recent studies cast doubt on the notion that triptans may actually lead to an increased relative risk of ischemic events in these high-risk patient populations, when the migraine headache itself may lead to an even greater increased risk of ischemic events.5 This warning, however, is evocative enough to prevent some physicians from offering triptans to their patients.
Ergot derivatives
Ergot derivatives were marketed as abortive treatments as early as the 1930s. These medications are now falling out of favor because of their relatively higher association with adverse effects, their association with overuse and withdrawal, and the availability of other agents that are more effective.6
Other treatments
Intravenous magnesium sulfate is increasingly used, especially in the in-patient setting, as an adjunct therapy for refractive headache.7 Systemic steroid tapers also have a possible niche in the treatment of chronic daily headache or analgesia-induced migraine. Short courses of prednisone by mouth have been used to help break episodes of prolonged migraine.
PROPHYLACTIC TREATMENT
The US Headache Consortium currently supports the use of prophylactic treatments in the following situations: migraines that cause 3 or more days of disability per month, abortive therapy used more than 2 times per week, hemiplegic or basilar migraine, failure of acute medications, and risk of acute medication overuse.8 Evidence is available that several classes of medications reduce the frequency of headaches. These medications include beta-blockers, calcium channel blockers, antidepressants, and antiepileptics. A trial of these medications often requires 3-4 weeks.
Beta-blockers
In the United States, the beta-adrenergic receptor blockers propranolol, metoprolol, and timolol are first-line prophylaxes and are doubly useful in treating patients who also have hypertension. Their use, however, is limited by their sedating effects and is not suggested for patients with depression. They are contraindicated in cases of congestive heart failure, asthma, and insulin-dependent diabetes. Prophylaxis appears to be a class effect of all beta-blockers, as those agents with selective activity at beta2-receptors or with membrane stabilizing effects are not more effective in clinical trials than other beta-blockers.9
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Calcium channel blockers
Among calcium channel blockers, verapamil is the most commonly prescribed medication. Verapamil has a vascular stabilizing effect and may reduce neurovascular inflammation and the spread of cortical depression. It has been shown to have a slight benefit in treating migraines with associated aura and hemiplegia. Flunarizine, another medication in the calcium channel blocker class, is designed to specifically target cerebral vessels and has performed well in clinical trials. Flunarizine is considered a first-line prophylactic in Europe but is not available in the United States.10
Antidepressants
Among the antidepressants, the tricyclic amitriptyline is the most studied. Its sedating effect can be advantageous for patients who have migraine with comorbid depression or sleep disturbances. Nortriptyline is a less sedating alternative. Although their efficacy is far less established, selective serotonin reuptake inhibitors (eg, fluoxetine, sertraline) and serotonin norepinephrine reuptake inhibitors are also used for migraine prophylaxis. In general, serotonergic-specific antidepressants have fewer adverse effects and lower chance for toxicity compared to the tricyclic antidepressants. The effectiveness of serotonergic-specific antidepressants for migraine prophylaxis has further substantiated the theories of serotonin and associated neurotransmitters as the underlying pathophysiology to migraine generation.8
Antiepileptics
Although the exact mechanism of most antiepileptics is not completely understood, their success in migraine prophylaxis is clear. The concept of the spread of cortical depression as a mechanism in the pathophysiology of migraine is supported by their effectiveness. Both migraine frequency and severity have been shown to respond positively to antiepileptics such as divalproex, gabapentin, and topiramate. Generally, these medications are prescribed in lower doses than when used to treat epilepsy. These medications can have additional benefits for patients who have migraines with comorbid anxiety and depressive disorders.6 Antiepileptic trials investigating levetiracetam and zonisamide to treat refractory migraine are currently under way.8
Other therapies
When standard prophylactic medications do not yield results, other therapies may be used. The injection of botulinum toxin type A (BOTOX®) into the forehead and cervical muscles is used by some practitioners to reduce the monthly migraine burden and migraine-associated vomiting. Early trials of ACE inhibitors such as lisinopril and the angiotensin receptor blocker candesartan have also yielded favorable results.
Still other treatments, which are somewhat less validated, include supplements like feverfew, vitamin B12, coenzyme Q10, and magnesium. To date, most literature stops short of endorsing these therapies because of the lack of large-scale trials and absence of standardized dosages.12
Research also continues to investigate the role of trigeminal ganglia in the pathophysiology of migraine. As a result of this research, specific receptors (eg, opioid receptor-like 1, vanilloid type 1 receptor) and neurotransmitters that modulate the trigeminal system have come under scrutiny.8
CONCLUSION
Abortive medications, which include nonspecific analgesics, triptans, and ergots, continue to be the mainstay of therapy during acute episodes. Despite the fact that no drugs specific to migraine prophylaxis were developed, an array of pharmaceutical agents that have proven their effectiveness are currently available. In addition to pharmacotherapy, behavioral techniques, lifestyle modifications, and other nonpharmacologic options should be considered and offered to patients.5 The pharmaceutical agents discussed in this newsletter are discussed in more detail in other articles of eMedicine’s Migraine Feature Series. Readers are encouraged to review these discussions, which are available here.
Some estimates put the percentage of patients who are diagnosed with migraine but do not consult regularly with their physicians at over 50%. This is certainly a result of many factors, but one possible reason is dissatisfaction with previous treatment experiences or the belief that effective treatments do not exist. Further research that focuses on empirical therapy and the pathophysiologic mechanisms and genetic factors that initiate and perpetuate migraine headaches will continue to advance and expand the effectiveness and choices available to both patients and their physicians in the coming years. Future treatment options will continue to be more effective in both aborting migraine headaches when they occur and reducing the frequency of episodes in both the general migraine headache population and specific patient subgroups.1
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REFERENCES
1. Linde M. Migraine: a review and future directions for treatment. Acta Neurol Scand. 2006;114:71-83.
2. Ninan M. Pro and con – Brief article. Fam Pract News. 2001;31(8):17.
3. Lipton RB, Stewart WF, Stone A, et al. Stratified care vs step care strategies for migraine: the disability in strategies of care (DISC) study – a randomized trial. JAMA. 2000;284(20):2599-605.
4. Goadsby PJ, Lipton RB, Ferrari MD. Medicine – current understanding and treatment. N Engl J Med. 2002;346(4):257-70.
5. Velentgas P, Alexander JC, Mo J, et al. Severe vascular events in migraine patients. Headache. 2004;44:642-51.
6. Lampl C, Buzath A, Yazdi K, Sandor PS. Ergot and triptan overuse in Austria – an evaluation of clinical data and cost. Cephalagia. 2002;22:807-11.
7. Corbo J, Esses D, Bijur PE, et al. Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache. Acad Emerg Med. 2001;38(6):621-7.
8. Rapaport AM, Bigal ME. Migraine prevention therapy: current and emerging treatment options. Neurol Sci. 2005;26:S111-20.
9. Limmroth V, Michel MC. The prevention of migraine: a critical review with special emphasis on beta-adrenoceptor blockers. Br J Clin Pharmacol. 2001;52:237-43.
10. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalagia. 2002;22:491-512.
11. Ben-Menachem E, Axelsen M, Johanson E, et al. Predictors of weight loss in adults with topiramate-treated epilepsy. Obes Res. 2003;11:556-62.
12. Silberstein, SD. Migraine. Lancet. 2004;363(9406):381-91.
