Prophylactic Treatment of Migraine:
Possibilities for Pharmacist Interventions
Brought to you by an
unrestricted educational grant from 
Kristen H. Schwetschenau, PharmD
Dr. Schwetschenau is an Assistant Professor of Pharmacy Practice and a Clinical Pharmacist in Ambulatory Care at Temple University School of Pharmacy
Migraine is a chronic headache disorder characterized by episodic attacks of head pain and associated features. Significant variation exits between attacks and between migraine sufferers. The majority of migraine sufferers has less than one attack per month. However, 15% of migraineurs report having two or more attacks per month. About 85% of patients report a severe headache, while 50% say they are disabled by the
attack.1 Many migraine patients fear that their headache is associated with a serious, underlying
disorder.2
In the United States, migraine afflicts more than 18 million women and 5 million men, with half of this 23 million being children and adolescents. The peak occurrence of migraine occurs between the ages of 35 to 45, when adults are the most productive and financially responsible. An annual medical cost of migraine approaches $17 billion. Although it is hard to elucidate an overall cost of migraine, the majority of its effect has been associated with disability and decreased functional status. Almost 6 billion days (2.8 days per 100 people) are lost annually from work or
school.3 This results in indirect costs to employers.4 Chronic headache has a profound negative effect on patients’ quality of
life.5
The following symptoms are associated with migraines: anorexia, nausea, vomiting, lightheadedness, photophobia, visual disturbances, scalp tenderness, and neurologic symptoms. The headache itself is usually unilateral and frontotemporal, with a gradual onset that is throbbing or dull. A family history may be
common.3,6
The underlying mechanisms for migraine are not fully understood. The hypothesized mechanism is believed to be located in the region of the dorsal raphe of the brain stem. This region is activated during an attack. This mechanism, however, does not account for the pain factor associated with migraine. Pain is produced by secondary activation of nociceptive fibers in the terminals of the trigeminal nerve. These terminals are found on both the extracranial and intracranial blood vessels, and their activation produces inflammation and vasodilation. Therefore, the migraine attack is triggered centrally, while the pain is transduced at the level of the blood vessels and nerve
endings.5
The clinical application of this hypothesized mechanism is that abortive medications act primarily at the peripheral level, whereas prophylactic medications act primarily at the central
level.5 This continuing education article reviews migraine prophylaxis options and highlights the importance of educating the patient about migraine management.
Migraine remains underrecognized and undertreated, in part because no biological markers exist to confirm the
diagnosis,7 and because of the underestimation of its effect on
society.4 In 1988, the International Headache Society (IHS) Classification Committee published operational diagnostic criteria for a broad range of headache disorders, including migraine. The Headache Classification Committee standardized nomenclature and created new terms. The subtypes of migraine were classified according to clinical features and concepts of pathophysiology. The criteria included the following:
(1) Migraines may be preceded by a prodrome. A prodrome occurs about 24 hours before the actual migraine, and its symptoms include sensory symptoms, such as photophobia or phonophobia. Approximately 55% to 80% of migraineurs experience a prodrome.
(2) Thirty minutes prior to a migraine, patients may experience an aura. During this phase, sensory symptoms may still be present. Abnormal sensations, such as numbness or “pins and needles” in the face or hands, may also occur during this time. Auras occur in only about 10% to 20% of migraine sufferers. Migraine with aura is associated with typical changes in regional cerebral blood flow and includes all forms of migraine that are preceded by neurologic symptoms. Migraine without aura is characterized by normal cerebral blood flow and the absence of neurologic symptoms. The operational diagnostic criteria for migraines with or without aura are provided in Table
1.8,9
Table 1. International Headache Society
Criteria for Migraine
Long-term strategies should be implemented for pain management to circumvent long-term problems associated with migraines. Management should focus on the type of migraine and the stage of life of the
patient.10 Rational treatment begins with incorporating the patient into the treatment scheme. Educating patients about the etiology of head pain and engaging them as active participants in their treatment are the cornerstones to appropriate
therapy.5 Developing an understanding of the patient’s medication usage and risk factors is essential. Pharmacists should obtain a list of all medications the patient has previously used and a detailed description of their dosages and duration of treatment. Patient assessment should include frequency of headache, degree of inconvenience or severity, medications used previously, medications currently used, trigger factors, and threshold
factors.11 It is equally important to ask patients how their headaches affect their work, family, and leisure time. Principal factors of increased cost of care incorporate missed or impaired
work.2 Medications are useful treatment modalities; however, patients often don’t find them helpful usually as a result of inappropriate use, too short of a treatment period, or too low of a
dose.11,12
Understanding of the triggers and thresholds that promote migraines is important in the treatment of this condition. Significant factors that can raise or lower thresholds are hormones, sleep disturbance, and mood. Common triggers include exercise, glare, noise, thirst, hunger, stressful situations, odors, tiredness, and some
foods.11 The most common foods that trigger a migraine are ones that contain nitrites, aspartame, monosodium glutamate, tyramine, tyrosine, and phenylalanine (Table
2).13,14 Some general principles for migraineurs include regular exercise and mealtimes, adequate sleep, and regular patterns of activity. Migraineurs do not adjust well to
change.10
Table 2. Specific Triggers for Migraines
The global treatment of migraine includes both pharmacologic and nonpharmacologic
modalities.5 A treatment approach should address the following aspects: (1) removing trigger factors, (2) raising the threshold, (3) treating the acute headache, and (4) prescribing long-term prophylactic
therapy.10,11 Additional nonpharmacologic treatments include relaxation, biofeedback, and
acupuncture.10,13
Although health care providers offer advice and education, patients must ultimately learn to manage their own condition. During attacks, patients must decide which medication to use and how. In between attacks, patients must make a conscious effort to change lifestyle habits to decrease their risk of attacks. Headache diaries, migraine diets, and behavioral interventions provide cost-effective tools for most patients. Empowering patients with a sense of control does much to improve their
outcomes.2
Drug therapy is indicated if the headaches threaten to disrupt the patient’s ability to function normally. As previously stated, migraine attacks vary in severity among sufferers and have variable effects on the functioning of each patient. During a mild attack, patients often can continue usual activities with only minimal disruption. With a moderate attack, patients tend to experience some interference with daily activities. Severe attacks result in patients being unable to continue their normal activities. In severe cases, there is prolonged inability to perform in any useful
capacity.7
The symptomatic treatment of migraine includes pharmacologic and nonpharmacologic modalities. Patients should be counseled to treat their migraine as soon as signs or symptoms occur, use simple drugs at adequate doses, treat dehydration or sleep deprivation, treat nausea and vomiting, give medication a sufficient trial, and be prepared to try several different
agents.11 Pharmacologic agents include simple analgesics, combination analgesics with or without opiate narcotics, nonsteroidal anti-inflammatory drugs (NSAIDs), ergotamine derivatives, and serotonin 5-HT1 receptor
agonists.5 Patients should be warned that frequent use of symptomatic treatments can lead to rebound (medication-induced) headaches and eventually to chronic daily headaches.
Although the first priority in controlling migraines is to optimize the abortive treatment, sometimes this is not sufficient. Prophylactic therapy is an option in such situations. Patients should have a realistic view of the outcome of therapy. They need to be educated that prophylactic therapy is not a cure. The desired outcome of prophylactic therapy is to decrease the number of migraine attacks. A 50% reduction in the frequency or severity of migraines can be categorized as a “good” response to prophylactic
treatment.7
It is important to note that prophylactic medications for migraine are ineffective in patients who often use analgesics or
ergotamines.15 Therefore, first determining if the migraine is being caused from “rebound” overuse of abortive medications is essential.
Raising the threshold for onset of a migraine often requires prophylactic medication and removal of triggers. Several circumstances warrant prophylactic treatment, such as two or more attacks per month resulting in 3 or more days of disability, contraindications or ineffectiveness of symptomatic medications, or use of abortive medication more than twice per
week.6,10,15
A detailed history of previous prophylactic use can help guide the current treatment scheme. Pharmacists should ascertain if optimal doses were used, what the duration of action was, which side effects the patient experienced, and if the prescribed prophylactic agents were used concomitantly with analgesics or ergotamines. When choosing an appropriate agent, comorbid conditions should be taken into account. Consideration also should be given to selecting a medication with the fewest side effects and using the least amount of such therapy to gain control over the symptoms. The chosen drug should be started at a low dose and titrated slowly to achieve a therapeutic effect. This titration usually occurs at 2- to 4-week intervals. Doses required to treat migraines are often lower than those needed for other indications. When selecting an appropriate medication for prophylaxis, a trial of 2 months on a particular medication is suggested before deeming the therapy a failure. The major pharmacologic groups of prophylaxis therapy include beta blockers, antidepressants, calcium channel blockers (CCBs), and
anticonvulsants.7,10,15 The efficacy of drug combinations has not been proven. Currently, avoiding drug combinations is preferable to decrease adverse effects associated with such
treatments.6
Beta blockers, antidepressants, CCBs, anticonvulsants, and NSAIDS have all been used as migraine prevention therapy. Only amitriptyline (an antidepressant), divalproex sodium (an anticonvulsant), and propranolol (a beta blocker) have proven their prophylactic action through clinical trials.
Beta blockers are widely used for the prevention of recurrent migraine; however, their mechanism of action for this purpose is poorly elucidated. Available data suggest that beta blockers reduce the frequency, duration, and intensity of migraine attacks. In one study, 60% to 80% of patients who took beta blockers responded well to therapy compared with 40% of patients who took
placebo.16 Patients who have been on beta-blocker therapy for more than 1 year should have a trial period without the drug. Therapy should be titrated down, because abruptly stopping treatment may cause rebound
headaches.7
Because several effective beta blockers are on the market and no evidence exists that one is more effective than another, choosing the right beta blocker to use for migraine prophylaxis is a challenge. For example, propranolol, metoprolol, atenolol, nadolol, and timolol have all been found effective for prophylaxis of migraine. In addition, because failure to one beta blocker does not constitute failure to the whole class, a patient who fails therapy with one beta blocker may be tried on
another.15,17
Both propranolol, a much-studied beta blocker, and timolol have an FDA indication for migraine
prophylaxis.18 The usual dosage for propranolol is 80 mg/day; it may be titrated up to 160 to 240 mg/day. The usual starting dose of timolol is 10 mg twice daily, with a maximum of 30 mg/day.
Patients should be counseled about side effects associated with beta blockers, such as fatigue, cold extremities, diarrhea, and depression. These side effects are often transient, therefore, the patient should be counseled not to immediately discontinue medication.
Because beta blockers are also antihypertensives and can decrease heart rate, patients taking this medication should have their pulse and blood pressure occasionally monitored. Beta blockers are contraindicated in patients with asthma, chronic obstructive pulmonary disease, brittle diabetes, cardiac arrhythmias, peripheral vascular disease, or depression (Table
3).5,7,15
Table 3. Comparisons of Commonly Used Prophylactic
Medications for Migraines
FOOTNOTES & ABBREVIATIONS *FDA approved for
migraine prevention; AV = atrioventricular; bid = twice daily; COPD =
chronic obsctructive pulmonary disease; MAOI = monoamine oxidase
inhibitors; PVD = peripheral vascular disease; SBP = systolic blood
pressure.
Source: References 1,5,7,10, 15-18 and 21.
The various types of antidepressants used for prophylaxis of migraines include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs).
Of the antidepressants, the TCA class has been studied the most for the prevention of migraines and has shown the best efficacy. The TCA amitriptyline is the only antidepressant that has been proven in clinical trials to be an effective prophylactic agent. Clinical trials with amitriptyline have shown that the antimigraine effects are independent of the antidepressant effect. The recommended starting dose of amitriptyline is 10 mg taken at night. It may be increased every 2 weeks, with a usual maintenance dose of 20 to 50
mg.15 Currently, amitriptyline is not FDA-approved for the prevention of migraine, nor are any other TCAs.
Common side effects of TCAs include dry mouth, constipation, urinary retention, blurred vision, and orthostatic hypotension. Contraindications to using TCAs include patients with bundle branch block, second-degree heart block, glaucoma, hypotension, uncontrolled seizures, and those taking MAOIs (Table
3).5,7
MAOIs are limited in use by the necessity to maintain a strict tyramine-free diet augmented by serious side effects secondary to interactions with other medications. MAOIs are contraindicated in patients with a history of hypertension, cardiac or cerebrovascular disease, advanced renal or hepatic disease, or
asthma.5
SSRIs have also been reported to be useful as prophylactic treatment for migraine sufferers. A review of the literature shows that fluoxetine is the only SSRI studied for migraine prophylaxis. Studies conducted using fluoxetine have reported conflicting results. One study demonstrated that fluoxetine was superior to placebo in preventing migraine; another study did not find similar
results,1 while a trial comparing fluoxetine to amitriptyline showed that fluoxetine reduced pain
intensity.19 The latter trial results should be viewed with caution because the study population was very small and the study was not blinded. Reports have shown that fluoxetine may cause restlessness, anxiety, agitation, insomnia, diarrhea, decreased libido, and
nausea.5 Similar side effects are associated with this drug when it is used as an antidepressant. Fluoxetine is not FDA-approved for migraine prophylaxis.
Inhibiting vasospasm in the cerebral arteries and a protective action against cerebral hypoxia are two hypothesized mechanisms that may explain how CCBs prevent migraines. Currently, no CCBs are FDA-approved for the prevention of migraines. In clinical practice, clinicians have prescribed verapamil, nifedipine, diltiazem, and nimodipine for migraine prophylaxis. However, few large-scale studies have proven that CCBs are effective therapy for migraine sufferers. The studies examining verapamil are small in nature, and therefore have not sufficiently proven this drug’s effectiveness in migraine
prevention.15,17 Although some studies with small numbers of patients have shown promise for patients using nifedipine, other study
data20 have suggested that nifedipine is not an optimal choice for the prophylaxis of migraine because of its frequent side effects. In clinical practice, some benefit from diltiazem and nimodipine as prophylaxis has been observed, but there are no clinical studies to support
this.17 Thus, caution in recommending CCBs for this indication is advised.
The onset of action of CCBs is gradual, and their maximum effect may not be seen for several months. The most significant side effects include weight gain, constipation, leg edema, and hypotension. CCBs are contraindicated in patients who are pregnant or who have ventricular dysfunction, sinoatrial or atrio ventricular node conduction disturbances, or systolic blood pressure less than 90 mm Hg (Table
3).5,7
Valproic acid has been shown to be effective in the prophylaxis of migraine headaches. It is suggested that valproic acid may decrease migraine attacks by acting on gamma-aminobutyric acid receptors or by reducing levels of excitatory amino acid glutamate in the central nervous
system.15 Before starting patients on valproic acid, clinicians should perform a baseline chemistry profile, complete blood count with differential, platelets and liver function tests, and evaluate prothrombin time and activated partial thromboplastin time.
Divalproex sodium is the only anticonvulsant that is FDA-approved for the prevention of migraine headaches. The usual starting dose is 250 mg twice daily. It may be titrated up to 1,000 mg/day if
necessary.21 Serum levels should be between 50 and 120 mg/L.15
Although carbamazepine may have been used in the past, there are no clinical trials indicating that it is a proven prophylaxis for
migraine.22
Data from several trials evaluating the use of valproic acid in prophylaxis treatment of migraines proved that divalproex sodium is efficacious in this
indication.23 Patients taking divalproex sodium had fewer days with migraines and used significantly less symptomatic medication for each migraine headache than patients receiving
placebo.22,23 In a 1997 study,24 divalproex sodium was found to be as effective as propranolol (a CCB) for the prophylaxis of migraine without aura. Both drugs significantly reduced the frequency and number of migraine attacks. It should be noted that this study evaluated a small study population, and patients were not blinded to treatment.
The side effects of valproic acid include drowsiness, nausea, slight hand tremor, weight gain, and alopecia. Hepatic failure has also occurred, but it is rare in patients older than age
10.21 Contraindications include hepatic disease and
thrombocytopenia.5,10 Women trying to conceive should not use valproic acid because this drug can increase the incidence of neural-tube defects in
infants.21
Methysergide, an antiserotonin drug, was the previous gold standard for migraine prophylaxis treatment. Although a very effective prophylactic agent, methysergide’s potentially serious side effects limit its use to only the most severe cases for which other prophylactic agents have not produced optimal results.
NSAIDs are primarily used as prophylaxis of menstrual-related migraines. They can be used for 1 week prior to and 1 week after menstruation. Patients should be aware, that although they are not taking an NSAID every day, they can still develop dyspepsia, peptic ulceration, diarrhea, and hematologic complications.
Patients’ complaints should be taken seriously. Along with headache relief, patients also want to know that their health care professional is dedicated to relieving their
distress.10 Verbal and written education about the pathophysiology and types of migraines will help alleviate patients’ fears.
Education on triggers and precipitating factors can help decrease frequency of migraines. Patients should be instructed to keep a migraine calendar to establish frequency, intensity, duration of headache, and presence of associated symptoms.
Prophylactic medication should be started at the lowest dose and titrated up depending on the side effects and the patient’s response. Patients should be given an adequate trial of the medication before a new modality is tried. When taking a prophylactic medication, patients should not be taking analgesics on a regular basis because they render the prophylactic medication ineffective and may be the etiology of the
migraine.7
Upon diagnosis of migraine, patients should be counseled that migraine is a multifactorial disorder that includes external and internal triggers as well as genetic factors. They should also be aware that a migraine is a temporary disruption of normal functions of the brain. Patients’ fears of cancer or tumors should be addressed. It is also important for patients to realize that migraines are not a psychosomatic disorder.
Psychological factors may trigger a migraine, but migraine is not of a neurotic origin. Currently, there is no cure for migraines, but there are abortive and prophylactic medications that can help alleviate or control
them.6
A key element in controlling migraine is patient education. Patients must take an active part in their therapy. Migraineurs should try to spread out their workload to avoid peaks and troughs that could occur throughout the day. They should maintain a normal sleep schedule, such as not “sleeping in” on weekends. Migraineurs should also eat regularly and avoid skipping meals. They should avoid foods that they know will trigger an attack. Caffeine-containing products should be limited because they can precipitate a rebound headache. Patients should keep a headache diary in which the date, the day of the week, and the time of day of the attack can be recorded. Precipitating and relieving factors should also be
included.7
Patients should be informed about the side effects, doses, and contraindications of the medication they are taking for relief of their migraines. For example, patients should know that regularly using analgesics may reduce the effectiveness of the prophylactic
agents.7 Patients should be aware that prophylactic treatments will not work immediately; results may not be seen for at least 2 months. In addition, they should understand that prophylactic treatment does not mean that they will never have another migraine, but that their migraines will decrease in severity and duration. For most patients, prophylactic treatment will not be life-long therapy. Thus, they should be made aware that their medication will be discontinued in the future to evaluate how well they function without it.
Migraine continues to be a debilitating disease that is undertreated and underdiagnosed. To address those issues, the IHS continues to update its guidelines for the diagnosis and treatment of migraine. New guidelines developed by the IHS, the American Academy of Neurology, and the American Headache Society will be announced in the next few
months.25 Among other areas in the treatment of migraine, these new guidelines will help with the decision tree for choosing the best prophylactic medication.
Pharmacists can play an important role in patient education by explaining what a migraine is, which triggers patients should avoid, and which medications can be used to prevent migraines. Side effects of the medications and monitoring parameters also should be discussed with patients. This interplay of discussion will enable the patient and pharmacist to work as a team to control migraines.
Questions in the quiz are based on the following case:
MM is a 35-year-old African-American woman. She explains that she has been having “killer headaches” that are associated with lightheadedness. She says she “can’t stand to be in bright lights” when her headaches occur. She also states that she has been having some diarrhea; this occurred 2 weeks ago. She states that no one else in her family has these headaches. The headaches are unilateral in nature, and they last about 6 to 7 hours. She states that they started a couple of years ago. She does not keep a headache diary and, therefore, does not know what her triggers are. Her medications include fluticasone propionate 220 mg 2 puffs bid, albuterol inhaler prn, famotidine prn (when she has stomach upset), and acetaminophen prn (for back pain).
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