Migraine Headaches
Bernard R. Elhaj, PharmD, Julie Dopheide, PharmD,
and Mark A. Gill, PharmD
Dr. Elhaj is a Level IV Student at the University of Southern California School of Pharmacy.
Dr. Dopheide is an Assistant Professor of Clinical Pharmacy, Psychiatry, and the Behavioral Sciences at USC’s Schools of Pharmacy and Medicine.
Dr. Gill is Professor of Clinical Pharmacy at USC’s School of Pharmacy.
Headache
Lord, how my head aches,
What a head have I!
It beats as it would fall in
twenty pieces.
—William Shakespeare (1564–1616), English dramatist, poet. Juliet’s nurse, in
Romeo and Juliet, Part 2, act 5, sc. 48.1
After completing this continuing education article, the pharmacist should be able
to
:
1. Describe the prevalence and incidence of migraines.
2. List the chronology of a migraine.
3. Describe the diagnostic criteria of migraine with aura and migraine without aura.
4. Identify the triggers and etiologies of migraines.
5. Delineate the prophylactic and symptomatic drug regimens of
migraineurs.
6. Counsel a patient on migraine identification, prevention, and treatment.
Vincent van Gogh, Claude Monet, Julius Caesar, Napoleon, Ulysses S. Grant, Robert E. Lee, Lewis Carroll, Mary Todd Lincoln, and Elvis Presley all had migraine
headaches.2 Their remedies for this affliction varied. The earliest
recorded treatments focused on purging to draw away the “bilious humors.” In the 17th century, bloodletting was used
for migraines. While this may suggest an inkling of the vascular nature of migraines, in reality the proponents were
hoping to extract the humors associated with
migraine.3 The modern era of migraine treatment began in 1883 with
the earliest report in the medical literature of the use of ergot for the treatment of migraines. A. Eulenburg (Germany)
used injections of ergot extract in five cases of headache.
A migraine headache can be defined as a recurring, pulsating, unilateral, moderate-to-severe headache that is
usually accompanied by pain, nausea, vomiting, and light and sound
sensitivity.4 There are two classifications of
migraine headaches according to the International Headache Society: migraine headache with aura and migraine
headache without aura. Migraine headaches are one of the most common complaints reported by patients to their
physicians, and it is estimated that migraines account for approximately 18 million physician visits per year. Nevertheless, migraine headaches remain undertreated and underdiagnosed worldwide. In fact, studies have shown that up to 59% of women and 70% of men with migraines have never been
diagnosed.5 Treatment for this disorder has changed significantly in the past few years with the advent of new pharmacologic treatments and routes of administration. As such, health care practitioners have more treatment options at their disposal and are better able to prevent pain and suffering in their patients once properly diagnosed.
It is estimated that about 24 million Americans have experienced a migraine headache at some point in their lives. They are three times more common in women than in men, occurring in 18% of women and 6% of men. The usual age of onset is between the ages of 15 and 35, but migraines are more prevalent in 35- to 45-year-olds. The incidence of migraine headaches tends to decrease in both sexes after the age of
45.6 It has been It has been estimated that migraines occur in 5% to 10% of children less than 10 years old.
Of those, about 15% to 30% experience migraines with
aura.7 Prior to puberty, the incidence of migraine headache is the same in males and females; however, after puberty the incidence in females to males becomes 3 to
1.8 It has also been found that migraine headaches are more common in lower income households. This has been hypothesized to be caused by the differences in diet, stress, and environment between lower and higher income individuals. In addition, those with higher incomes usually have better access to health care, which may decrease the duration and frequency of migraine headaches and, therefore, decrease its prevalence. Also, in some cases, severe migraine headaches may inhibit one’s socioeconomic advancement, which would result in a lower
income.9
Migraine headaches have personal costs in terms of pain and suffering. In addition, though, they are responsible for economic losses as well. The cost of medical care and productivity loss attributed to migraines accounts for billions of dollars per year in direct and indirect costs. Indirect costs are measured in terms of lost earnings, lost production, decreased employee efficiency, and reduced worker output. Direct costs, on the other hand, include medical costs, such as physician visits, hospitalizations, and use of prescription and over-the-counter drugs. It also includes other expenses, such as cost of transportation to obtain care, cost of specialized training, and cost of medical
research.10 It is estimated that industries lose approximately $6 billion to $18 billion per year in direct and indirect medical
costs.6 In fact, some estimates are as high as $50 billion. One reason for this is that it is estimated that migraine sufferers miss more than 157 million days of work per year. Another factor contributing to the high cost of migraines is the exceedingly high cost of medications and medical
care.11
Migraine headaches usually last from 4 to 72 hours and typically progress through five distinct phases: prodrome, aura, headache, resolution, and
postdrome.12 The prodrome phase, which occurs about 24 hours before the headache, consists of changes in sensory perception including photophobia (fear of light), phonophobia (morbid fear of sounds), and osmophobia (morbid fear of odors). During this phase, the migraineur may also experience changes in mood, excessive yawning, food cravings, fluid retention, or speech or memory problems. Approximately 50% to 80% of migraineurs will go through the prodrome phase.
The next stage is the aura phase, in which some migraineurs experience visual disturbances, such as seeing flashing lights, shimmering and drifting zigzag lines, and blind spots. They may also have abnormal sensations including a feeling of numbness or pins and needles, typically around the lips or hand. Difficulty speaking and muscle weakness are also common manifestations of the aura phase. Aura occurs within an hour preceding the headache, lasts for about 20 to 30 minutes, and is experienced by only 10% to 20% of migraineurs. Most of the migraineurs who suffer from migraine with aura have also experienced migraines without aura. Although the aura does not dictate which drug to use, the aura may give the migraineur some warning of the impending headache.
The next phase in the chronology of a migraine headache is the actual headache itself. The headache usually begins as a dull ache and then escalates to a pulsating,
painful sensation that usually occurs on only one side of the head. In 40% of patients, however, the pain occurs on both sides of the head and alternates from side to side. The main site of pain is usually the temples, but any area of the face, head, or neck may also be involved. During the headache process, the migraineur can experience nausea, vomiting, photophobia, and/or phonophobia.
The next phase is the resolution phase, in which the headache resolves and the body regains normal homeostasis. This process occurs over several hours, usually during sleep or rest.
The final stage in the chronology of a headache is the postdrome phase, in which one feels drained, fatigued, and tired. The migraineur typically has aching muscles, low food tolerance, a slow thinking process, and volatile
emotions.13
Migraine headaches more commonly occur in the early morning hours of the day, usually upon awakening. Fox et al examined the circadian variation in the frequency of migraines. The study found that of a total of 3,582 migraine attacks, there was an average of 254 attacks per hour from 4 am to 9 am compared to 115 attacks per hour during the rest of the day
(Figure 1).14 The lowest frequency of migraines occurred between midnight and 1 am.
Figure 1 Circadian variation in the frequency of
migraines. Of a total of 3582 migraine attacks, the highest
frequency of migraine attacks occurred from 4AM to 9AM.
The International Headache Society has set forth specific criteria for the diagnosis of a migraine
headache.15 According to their guidelines, a positive diagnosis is based purely on a patient’s symptoms and medical history. Therefore, an experienced clinician and detailed patient description of symptoms are the best tools for migraine diagnosis. Patients should be encouraged to keep a “migraine diary” to record the timing, triggers, severity, and duration of symptoms for the clinician to review. Physical examination, neuroimaging, and laboratory results are not necessary for a diagnosis, but can be utilized to exclude other suspected etiologies, such as stroke, tumor, infection, head trauma, or substance
abuse.12
To fulfill the diagnostic criteria for migraine headache without aura, a patient must have experienced at least five attacks with certain characteristics. The untreated or unsuccessfully treated headache must last from 4 to 72 hours. The headache must also have at least two of the following four characteristics: unilateral pain, pulsatile pain, be of moderate-to-severe intensity, or be aggravated by routine physical activity, such as walking up stairs. A moderate-to-severe headache is defined as one that inhibits daily activities. During these headaches, a patient must experience nausea and/or vomiting, or photophobia or
phonophobia.16
The diagnostic criteria for migraine headache with aura require that the patient experience a migraine headache with at least three of four defining characteristics. First, the patient must experience one or more of the reversible aura symptoms. As previously discussed, these include visual disturbances, abnormal skin sensations, difficulty speaking, and muscle weakness. Another possible characteristic is that the patient experiences an aura that gradually develops over more than 4 minutes or two or more aura symptoms that develop in succession. A third characteristic is that no one aura symptom can last for more than 60 minutes, and, finally, the aura must precede the headache by no more than 60 minutes. In addition, as with the criteria for migraine without aura, a medical history, physical examination, and neurologic examination, when appropriate, must rule out any other possible
etiologies.16 It is important to distinguish migraine from other types of headaches since, for example, tension headaches may not require as aggressive or toxic treatment.
Migraine headaches are often triggered by environmental or physiological factors. Identifying these triggers is one of the first steps toward coping with, and avoiding, migraine headaches. Possible triggers that may be encountered in one’s environment include certain foods, drinks, spices, medications, and sensory stimuli. Typically, the foods that are most likely to induce a migraine are those that contain nitrates, aspartame, monosodium glutamate, tyramine, tyrosine, and phenylalanine. More specifically, these are foods such as chocolate, caffeine (withdrawal), cheese, alcohol, and cured meats, such as hot dogs
and bacon.17 Certain medications are also common triggers of migraine headaches. This is especially true of vasodilating medications, such as hydralazine, nitroglycerin, and reserpine. Other migraine-associated medications include cimetidine, danazol, diclofenac, indomethacin, nifedipine, nitrofurantoin, sildenafil, and estrogen-containing
oral
contraceptives.13,17 Certain sensory stimuli have been found to be potential triggering factors as well. Common offenders include glares, bright or flickering lights, loud noises, allergens, and certain offending odors. In addition, the weather may be a contributing factor, especially hot, humid weather or bright, partly cloudy
skies.12,13
Physiological influences will similarly play a role in triggering migraine headaches. One, for example, is a change in sleep pattern, such as sleep deprivation or excessive sleep. Other migraine inducers include fasting or missing a meal, physical exertion, and minor head trauma. Mental stress can also trigger a migraine headache, although the headache will not typically occur during the stressful period but will occur afterwards during a time of
relaxation.12
One of the most significant physiological triggers of migraine headaches in women is menstruation. This trigger is believed to be mainly responsible for the higher incidence of migraine headaches in females than in males. Typically, women tend to experience migraines either during or just prior to menses. Migraines that routinely occur during menses are termed “menstrual migraines,” while those that occur just prior to menses are termed “menstrually related migraines.” Menstrually related migraines are more common, occurring in 52% to 72% of female migraineurs, whereas menstrual migraines occur in 8% to 25%. Several studies have suggested that this phenomenon may be caused by changes in hormone levels. Migraines appear to be triggered by the late luteal phase drop in estrogen. Migraines are worsened by fluctuating estrogen levels and may improve with even estrogen levels; however, the relationship is unclear. It may be more of an indirect effect, in which the physiological and psychological stressors brought about by menses may be the main
cause.18
It has also been found that migraineurs have an inherited predisposition to getting migraine headaches. Studies in the past have found that the relative risk of getting migraines in subjects with a family history of migraines compared with control groups ranged from 1.5 to 19.3. The wide variation of relative risks between
studies
is attributable to methodological differences. Stewart et al19 found that the risk of getting migraines was 50% more likely in relatives with a family migraine history than those without. They also found that the relative risk was higher for those with migraines with aura than those suffering from migraines without aura.
Comorbid conditions may influence migraines. In a study by Guidetti et
al,20 migraineurs with anxiety disorder were more likely to experience persistent migraines than those without a psychiatric condition.
The earliest theories on the causes of migraines focused on the stomach. The rationale was that the nausea and vomiting began the series of events ending in the headache. More recently, vascular, muscular, and neurotransmitter theories have been espoused. Common to each is the concept of a triggering event
(Figure 2).21 The theories vary with the next step. The vascular theory follows. Exposure to a migraine trigger initiates a poorly understood response in the cerebral cortex, thalamus, hypothalamus, and the internal and external carotid arteries. The cerebral cortex appears to respond to emotion or stress; the thalamus responds to bright lights, noises, or smells; the hypothalamus responds to changes in the internal environment; and the carotid arteries respond to vasodilators. This, in turn, stimulates the locus ceruleus, which causes norepinephrine release from the adrenal medulla, resulting in the release of serotonin-releasing factor (SRF). SRF liberates serotonin from platelets and increases free serotonin concentrations in the
plasma.22 The increased level of serotonin results in arterial vasoconstriction. Vasoconstriction and the resulting drop in cranial blood flow cause an ischemic event, which may be the physiological cause of aura. This initial ischemic event eventually subsides and is then followed by a period of cerebral vasodilation, neurogenic inflammation, and pain. Some of the prophylactic treatments for migraine headaches attempt to prevent this initial event by antagonizing serotonin and preventing
vasoconstriction.6
Figure
2. Neurotransmitter theory of migraines. The headache of migraines is thought to be due to neurological stimulation of blood vessels that is mediated by the neurotransmitters, serotonin and norepinephrine. External stimuli cause brainstem stimulation, which causes dilatation or contraction of the blood vessels in the cerebrum and the scalp. Stimulation of the trigeminal nerve causes head pain through the thalamus and cerebral cortex. Another pathway via the chemoreceptor trigger zone (in the reticular formation) causes nausea and vomiting. Stimulation of the hypothalamus can lead to photophobia.
The pathophysiological cause of migraine pain is believed to be caused by a disruption in the trigeminovascular system. This system is composed of the meninges and the cerebral and cranial vessels, all of which are innervated by the trigeminal nerve. The trigeminal nerve branches into three divisions: the ophthalmic, the maxillary, and the mandibular nerves
(Figure 3).23 The ophthalmic nerve is thought to be responsible for the pain associated with migraines. This is because it innervates the frontal and parietal regions of the head, which are the sites in which migraine pain is typically felt. The trigeminal nerve is bipolar, having a termination on the cranial vessels on one end, and on the dorsal horn of the spinal cord and medulla at the other end. It is the latter termination that transmits signals to the brain stem, thalamus, and higher cortical areas for the processing and recognition of pain. The former termination innervates intracranial vessels, of which the major one is the superior sagittal sinus (SSS). The SSS runs between the meninges and is the primary vein draining the cranial vasculature
(Figure 3).23
Figure
3. Trigeminal innervation of cranial structures. The ophthalmic division of the trigeminal nerve innervates meningeal, cerebral, and cranial vessels. It is the ophthalmic nerve that is thought to be responsible for the pain associated with migraines. The superior sagittal sinus runs between the meninges and is the primary vein draining the cranial
vasculature.23
The trigeminal nerve terminals are believed to be mainly affected by two local transmitters, serotonin (5-HT) and calcitonin gene-related peptide (CGRP). During a migraine headache, the trigeminal nerve releases CGRP, which is a potent vasodilator. CGRP is released from the perivascular terminal bouton and is synthesized in the trigeminal ganglion cell body. Once released, CGRP then activates receptors on the trigeminal nerve and cranial vessels, resulting in vasodilation
(Figure 3).23 Release of the neuropeptides, substance P and neurokinin A, is also believed to help induce vasodilation. Vasodilation of these vessels results in plasma protein extravasation through their fenestrated endothelia. It is the leakage of these plasma proteins into the surrounding tissue of the dura mater that stimulates nerve endings and causes migraine
pain.24 Similarly, 5-HT also has receptors on the trigeminal nerve and cranial vessels. More specifically, the receptors are of the 5-HT1B/1D subtype. When these receptors are activated, however, trigeminal nerve activation is blocked, resulting in a reduction in CGRP release. This, in turn, blocks cranial vessel dilation, which inhibits migraine pain
(Figure 4).23 5-HT agonists and highly specific 5-HT1B/1D agonists are now being used effectively as symptomatic treatments for migraine
headaches.23
Figure
4.
Trigeminal nerve activity during migraine and with the addition of a serotonin agonist. During a migraine, the trigeminal nerve releases CGRP, substance P, and neurokinin A, which are vasodilators. The addition of a serotonin agonist inhibits the release of these neuropeptides, inhibiting vasodilation and migraine
pain.23
Prophylactic. Prophylactic treatment of migraine headaches is recommended in patients who experience three or more attacks per month, in patients who do not respond to symptomatic therapy, and in patients whose migraines are predictable in
occurrence.4,6 Such treatment should only be initiated after certain nonpharmacologic interventions have failed to yield migraine relief.
As a general rule, prophylactic medications should be started at low doses and titrated up slowly as needed and tolerated by the patient. It is recommended that prophylactic treatment be given for 3 months. After this period, the treatment regimen should be reassessed for efficacy and side effects. If the treatment plan is well tolerated and bringing about improvement in the patient, it should be continued for 6 months. After 6 months, if the frequency and severity of headaches have improved, the patient should be gradually titrated off the
medications.4
The initial line of prophylactic therapy is beta blockers
(Figure 5).13 If these medications are contraindicated or ineffective in a patient, then the next two options are tricyclic antidepressants (TCAs) or calcium channel
blockers. The decision between the two is based on the patient’s comorbid conditions and/or tolerance to side effects. The next step in the treatment algorithm is the use of valproate. If this medication is not effective or well tolerated, then a combination of any of the above medications can be considered. The last treatment option is methysergide, which is a last-resort drug because of its side-effect
profile.13
Figure
5. Algorithm for the symptomatic and prophylactic treatment of migraine headache (adapted from
Capobianco13).
Beta-Adrenergic Blocking Agents. Beta blockers are the most commonly used agents for the prophylaxis of migraine headaches. Propranolol (Inderal) and timolol (Blocadren) are the only ones that are FDA-approved for this purpose; however, acebutolol (Sectral), atenolol (Tenormin), bisoprolol (Zebeta), metoprolol (Lopressor), and nadolol (Corgard) are also considered
effective.25 For some reason, beta blockers with intrinsic sympathomimetic activity are ineffective in preventing migraine headaches. Beta blockers are especially useful in patients with stress-induced headaches. Their mechanism of action in preventing migraines is not exactly known but is theorized to involve the adrenergic and serotonergic
systems.4
Once initiated, it can take up to 4 weeks for beta blockers to take
effect.4 Patients should be started on the lowest dose indicated and reevaluated every 2 to 4 months. If the drug is well tolerated, then the dosage can be raised gradually. A beta blocker can be considered ineffective after the patient has been on the highest dose tolerated for 2 months with no improvement. The discontinuation of beta-blocker treatment must be a gradual process over at least 14 days. Tapering the drug is necessary to ensure that the patient does not experience the cardiovascular complications associated with sudden withdrawal. In addition, abrupt cessation of beta blockers may cause rebound headaches in
patients.26
Propranolol. Propranolol is considered the gold standard in migraine prophylaxis. Propranolol is typically initiated at 10 to 20 mg twice daily, and then gradually increased to the effective dosage range of 80 to 240 mg/day. Once an effective and well-tolerated dose is established for a patient, a switch can be made to the long-acting (LA)
formulation.25 Carroll et al compared propranolol LA 160 mg taken once daily with propranolol LA 80 mg taken twice daily.
Their study found that the higher once-daily dosing schedule was more effective at reducing migraine frequency than the lower twice-daily
dosing.27
Timolol. Timolol is another FDA-approved and effective alternative. It has been shown to reduce the frequency of headaches by as much as 22% to 49% compared with
placebo.4
Its daily dosage in the treatment of migraines ranges from 10 to 15 mg twice
daily.25 Timolol may be better suited for asthmatic patients, since it lacks the beta2-induced bronchoconstrictive effect of propranolol. Propranolol, however, has the advantage of once-daily
dosing.4 If a patient fails to respond to one beta blocker, that does not predict failure with all beta
blockers.28
Calcium Channel Blockers. Calcium channel blockers have been found to be effective in preventing migraines in some patients. However, their overall efficacy in controlled trials has not been overwhelming. Albers et al compared the effectiveness of nifedipine (Adalat, Procardia) 20 to 30 mg three times daily versus propranolol 40 to 60 mg three times daily for migraine prophylaxis. Their study found that nifedipine was less effective than
propranolol.29 Nifedipine has been found to be mainly effective in transforming a migraine headache into a dull, persistent one rather than eliminating it.
Verapamil (Calan, Covera-HS, Isoptin, Verelan) is the most commonly used medication in migraine prophylaxis. Other calcium channel blockers that are used in migraine prophylaxis are diltiazem and nimodipine
(Nimotop).13 None of the calcium channel blockers have been approved by the FDA for the prevention of migraine
headaches.25 The exact mechanism of action of calcium channel blockers in the prevention of headache is not known. It is theorized, however, that they act by decreasing the flux of calcium across the cells of arterial smooth muscles, which would inhibit the vasoconstriction that is initially seen with migraine
headaches.4
The usual dosage of verapamil in migraine prophylaxis is 80 mg three to four times daily (standard-release formulation), while the typical dose for nifedipine is 30 to 120 mg daily in divided doses. The standard dose for nimodipine is 40 mg three times daily, and that of diltiazem is 90 to 180
mg/day.6 Common side effects associated with calcium channel blockers include constipation, flushing, fluid retention, rash, dizziness, light-headedness, muscle fatigue, and bradycardia. This class of drug is contraindicated in those with heart block, ventricular tachycardia, sinus bradycardia, and hypotension. Calcium channel blockers interact with several hepatically metabolized medications. They decrease the effect of phenobarbital, hydantoins, vitamin D, sulfinpyrazone, and rifampin, and they increase the effect of quinidine. They may also increase cardiotoxicity when taken with amiodarone, cause bruising when taken with aspirin, cause hyperkalemia and myocardial depression when taken with dantrolene, and decrease atrioventricular conduction when taken with beta blockers. Calcium channel blockers can also increase the levels of carbamazepine, cyclosporine, digoxin, doxorubicin, theophylline, and vecuronium; whereas cimetidine can increase the bioavailability of calcium channel
blockers.30
Tricyclic Antidepressants. The TCAs have also been found to be effective in preventing migraine headaches. More specifically, the tertiary amines, amitriptyline (Elavil) and imipramine (Tofranil), are particularly effective because of their serotonin reuptake inhibition and central serotonin receptor
blocking.26 The secondary amines, nortriptyline (Pamelor) and desipramine (Norpramin), have less serotonin activity and are thus less
effective.6 As with most antimigraine drugs, though, the exact mechanism of action is not precisely known. None of the TCAs are FDA-approved for the prevention of migraines; however, they are widely used in other countries for this purpose. These drugs are considered the drugs of choice in migraines with coexisting depression or
insomnia.28
The most studied TCA in the prevention of migraine headaches is
amitriptyline.4 Couch et al compared the efficacy of amitriptyline and placebo in preventing migraine headaches. The study found that 55.3% of those taking amitriptyline and 34.0% of those taking placebo had a greater than 50% reduction in migraine
frequency.31 The investigators felt the antimigraine effect was independent of antidepressant activity. Ziegler et al compared the effectiveness of placebo, amitriptyline, and propranolol in reducing the severity, frequency, and duration of migraines. The study revealed that propranolol reduced the severity of attacks compared with placebo, whereas amitriptyline significantly reduced severity, frequency, and
duration.32 Amitriptyline was most likely to work in females and those with the highest headache frequency.
The usual dosage of amitriptyline in the prevention of migraines is about 50 to 200 mg/day taken nightly at bedtime. The patient should be started on 10 mg per night and titrated upwards by 10 mg every 1 to 2 weeks, depending on efficacy and toleration. The same dosing schedule applies to imipramine, nortriptyline, and desipramine. Upward titration is mainly limited by the TCA’s anticholinergic side-effect
profile.26
Valproate. Valproate (Depakote, Depakene) is an anticonvulsant that is also FDA-approved for, and has been shown to be quite effective in, reducing the frequency of migraine headaches in migraineurs. Its mechanism of action in preventing migraines is thought to be the result of its ability to reduce plasma extravasation by inhibiting substance P, by inhibiting the firing of serotonergic cells on the dorsal raphe nuclei, and by acting on voltage-dependent calcium and sodium channels. Valproate is thought to be the treatment of choice in migraineurs with mania, seizures, aggressive behavior, or an anxiety
disorder.4
Valproate is available in several dosage forms, including a soft gelatin capsule, an enteric coated tablet, a sprinkle, and a syrup. The enteric coated formulation helps to reduce gastrointestinal side effects, while the sprinkle formulation is made available so that the patient can open the capsule and mix it with food. The syrup is absorbed more rapidly than any of the solid
formulations.6
The dosage recommended by the manufacturer for the prevention of migraine headaches is 250 mg two to three times
daily.25 However, the average dose is about 1,200 mg/day. The dose can be increased as tolerated by the patient, and until the serum level approaches 100 µg/mL. Blood levels of valproate have not been shown to correlate with a reduction in the frequency of migraines; however, they should be monitored for
toxicity.13
Mathew et al compared the effectiveness of divalproex sodium and placebo in reducing migraine frequency. It was found that 48% of the patients who received divalproex sodium had a 50% or more reduction in migraine frequency compared with 14% to 18% of patients taking
placebo.33 Kaniecki et al studied 37 patients suffering from migraine without aura using divalproex sodium or propranolol. A 50% or more reduction in migraine frequency occurred in 66% of the patients taking divalproex sodium, 63% taking propranolol, and 19% taking placebo. The study concluded that valproate and propranolol are equally effective in reducing migraine
frequency.34 Unlike other prophylactic medications, however, valproate is also able to decrease the severity and duration of migraines when they do
occur.13
The most commonly reported side effects are gastrointestinal complaints, such as nausea, vomiting, anorexia, and weight gain.
These can be reduced by administering the enteric coated formulation or taking it with food. Other adverse effects associated with valproate include drowsiness, ataxia, tremor, hair loss, increased appetite, edema, and fatigue. Periodic liver function tests are recommended, especially within the first 4 months, because of possible hepatotoxicity. Hepatotoxicity is more common in children less than 2 years old, in mentally retarded individuals, and within the first few months of
therapy.35 Valproate has also been shown to cause hematological toxicity as well. Six percent to 40% of patients who have taken valproate have developed thrombocytopenia; however, this is reversible with a decrease in dose. Other blood dyscrasias that may occur are leukopenia, neutropenia, and erythroblastopenia. In addition, valproate is contraindicated in pregnant women because of the increased risk of congenital defects, such as neural tube
defects.4
Valproate interacts with other hepatically metabolized drugs (phenytoin, carbamazepine, lamotrigine) and highly protein-bound drugs (aspirin, chloral hydrate) leading to diminished efficacy or
toxicity.30
Methysergide. One of the oldest and most effective prophylactic medications for migraine headache is the ergot derivative methysergide (Sansert).4 The mechanism by which methysergide is believed to prevent migraine attacks is by antagonizing 5-HT2 receptors. However, other mechanisms are thought to be involved since other potent 5-HT2 receptor antagonists are ineffective in migraine
prophylaxis.28
Methysergide is typically utilized in severe migraine headaches that have not responded to other prophylactic treatments. It is used as a last resort because it has some potentially serious side effects. Long-term use can cause retroperitoneal, heart valve, and pleural fibrosis. Other more common side effects include postural hypotension, insomnia, nausea, vomiting, abdominal pain, diarrhea, peripheral edema, and heartburn. Methysergide is contraindicated in patients with peripheral vascular disease, severe atherosclerosis, severe hypertension, phlebitis, pregnancy, peptic ulcer disease, and disease of the lung, liver, or
kidney.28
The usual maintenance dose of methysergide in migraine prophylaxis is 3 to 6 mg/day divided into three times daily. It should be started at 1 mg/day and gradually increased by 1 mg every 3 days. Because of the risk of fibrosis with long-term use, it is recommended that methysergide be temporarily discontinued after 6 months to give the patient a 4- to 8-week medication-free interval before restarting therapy. Methysergide should be tapered off gradually over 1 week to prevent rebound migraine
headaches.28 If fibrosis is indeed detected, early recognition and discontinuation can reverse these
changes.6
The initial line of therapy for the symptomatic treatment of mild-to-moderate migraine headaches are simple analgesics, such as aspirin or acetaminophen, because they are over-the-counter and easily accessible
(Figure 5). The next treatment option for mild-to-moderate migraines and the initial treatment of choice for severe migraines are the nonsteroidal anti-inflammatory drugs (NSAIDs). If these medications are contraindicated or fail to provide relief, the next step in the treatment algorithm is the combination drugs that are available, which contain analgesics, barbiturates, opiates, mild tranquilizers, and/or vasoconstrictors. The next line of therapy is the serotonin agonists. If these medications are ineffective or contraindicated, then the next treatment option is to administer an ergot derivative. The last line of therapy is opiates, since they may result in physical
dependency.13
Simple Analgesics. Simple analgesics can be effective in patients with mild and infrequent migraines. These agents are most successful when administered early in the onset of a migraine. The standard dosage for aspirin and acetaminophen in migraine relief is 650 mg at the onset of headache, and this can be repeated every 4 hours as
needed.6 The effectiveness of these analgesics can be improved by coadministering metoclopramide (Reglan) 5 to 10 mg before taking the analgesic. This is because gastric stasis often occurs during migraines. Metoclopramide helps by increasing gastric emptying and improving
absorption.12
Nonsteroidal Anti-inflammatory Drugs. NSAIDs are the medications of choice for the acute treatment of mild-to-moderate migraine headaches. They are considered first-line therapy in treating migraines. Their mechanism of action appears to be to inhibit prostaglandin and leukotriene synthesis, preventing neurogenic inflammation in the trigeminovascular
system.4 The most widely used NSAID in acute migraine therapy is naproxen or naproxen sodium (Naprosyn, Anaprox). This is because of its proven efficacy and high tolerability by patients. Peak serum levels occur 1 hour after taking naproxen sodium and 2 hours after taking naproxen. Their half-life is approximately 12 to 15 hours, and so they are typically dosed twice
daily.12 Johnson et al compared the efficacy of naproxen versus placebo in their ability to relieve migraine
headaches. The study found that naproxen was able to effectively reduce the severity and duration of migraine
headaches.36 Pradalier et al compared naproxen sodium with ergotamine tartrate, and found naproxen to be more effective in reducing the severity of headache as well as nausea and vomiting. However, naproxen sodium was found to have a shorter duration of action than ergotamine
tartrate.37
The standard dose of naproxen is 750 mg at the onset of headache, and 250 mg as needed thereafter for a maximum of 1,375 mg/day. The dose for naproxen sodium is 550 to 750 mg at the onset of headache, which may be repeated again in 1 to 2
hours.6 Other NSAIDs that have shown efficacy in acute migraine treatment include oral ibuprofen (Motrin), flurbiprofen (Ansaid), and ketorolac
(Toradol).13 Ketorolac is also available in an intramuscular and intravenous injection, which can be useful in patients with severe nausea and
vomiting.6
NSAIDs have also been used prophylactically, but only on an intermittent basis since their adverse gastrointestinal effects limit continuous use. They can be used to prevent menstrual migraines, since their timing can be somewhat predicted. NSAIDs should be started 4 days before the typical time of menstrual migraines, and continued until the time of usual occurrence is over. The usual dose for naproxen sodium in such a treatment strategy is 275 mg three times daily after
meals.38
Combination Products. When simple analgesics and NSAIDs fail to provide relief, the administration of certain combination products can be attempted. The most frequently used are compounds that contain butalbital, such as Fiorinal (325 mg aspirin, 40 mg caffeine, and 50 mg butalbital), Fioricet or Esgic (325 mg acetaminophen, 40 mg caffeine, and 50 mg butalbital), and Phrenilin (325 mg acetaminophen and 50 mg
butalbital).38 The usual dosage of these medications is one to two tablets every 4 to 6 hours, with a maximum of six tablets per
day.6 These medications should also not be used more than twice a week, since frequent use can cause medication-induced or rebound
headache.13 Fioricet and Fiorinal are also available in combinations that contain 30 mg of codeine. Medications containing codeine may be effective in some patients, but should always be used as a last resort because they may become habit-forming. Other opiate and analgesic medications that are sometimes used are Percocet, Percodan, Darvon, Vicodin, Lortab, and
Hyrdrocet.38 However, Boureau et al compared acetaminophen 400 mg with codeine 25 mg versus aspirin 1,000 mg and versus placebo. The study found that acetaminophen with codeine did not have a higher response rate than aspirin
alone.39
Another combination medication used to treat migraine headaches is Midrin, which contains 325 mg acetaminophen, 100 mg dichloralphenazone, and 60 mg isometheptene mucate. Dichloralphenazone is a mild tranquilizer that reduces the emotional reaction to pain, while isometheptene mucate is a sympathomimetic amine that constricts cranial and cerebral blood
vessels.38 Midrin’s usual dosage is two capsules at the onset of headache, followed by one capsule every hour until the migraine is relieved. A maximum of five capsules may be taken within a 12-hour period, and it should not be used more than three times per
week.6,38
In January 1998, the FDA approved Excedrin Migraine‚ 250 mg of acetaminophen, 250 mg of aspirin, and 65 mg of caffeine per tablet. A two-tablet dose is recommended, taken at 6-hour intervals as needed. In clinical trials, at hour 2, 37% of the Excedrin Migraine subjects versus 14% of the placebo subjects had significant pain
relief.40 The product should not be used on a regular basis but only for periodic relief to avoid drug toxicity and the likelihood of drug rebound
headache.41
The serotonin agonists are the newest medications that are FDA-approved for the acute treatment of migraine headaches. Currently, there are four available in the United States: sumatriptan (Imitrex), zolmitriptan (Zomig), naratriptan (Amerge), and rizatriptan (Maxalt). All are agonists that are highly specific for 5-HT1B and 5-HT1D receptors, resulting in the
inhibition of CGRP release and inhibition of vasodilation.4 Common side effects associated with the serotonin agonists are drowsiness, dizziness, fatigue, hot flashes, chest tightness, tingling in the extremities, nausea, vomiting, and pain at the injection site.There have also been isolated reports of coronary vasospasms, myocardial infarctions, and ventricular fibrillation after using serotonin agonists. These reports and the fact that 3% to 5% of patients experience chest tightness resulted in an FDA mandate that these medications are contraindicated in patients with ischemic heart disease, angina pectoris, arrhythmias, previous myocardial infarctions, and uncontrolled
hypertension.42 In addition, serotonin agonists should be used with caution in patients with hypercholesterolemia, obesity, diabetes, smoking habits, or a family history of vascular disease, because they may have underlying coronary artery disease. If used in these patients, the first dose should be administered under medical supervision. Serotonin agonists should not be administered within 24 hours of taking an
ergot.13 An intriguing meta-analysis of the triptans compares the “therapeutic penalty” associated with each agent
(Figure 6).43 This parameter estimates the risk of side effects with each
agent
The triptans can transform episodic migraine into chronic daily headache. This may also be referred to as rebound migraine. Originally thought to be related to the short duration of action of sumatriptan, this rebound has also been reported with the longer-acting agents, zolmitriptan and
naratriptan.44 Management has been difficult since the options were to discontinue any triptan for a period of time or to be hospitalized and receive injectable ergots. Another approach examined is daily use of sumatriptan 25 mg TID until the headaches
remit.45
Sumatriptan (Imitrex Subcutaneous). The oldest and most studied serotonin agonist is sumatriptan. Sumatriptan is available in a 6-mg/0.5-mL subcutaneous injection, in 25- or 50-mg tablets, or in a 5- or 20-mg nasal spray. Subcutaneous sumatriptan is rapidly absorbed and has a 94% bioavailability, with a maximum serum concentration occurring after 10 minutes. The recommended dose is 6 mg at the onset of headache. This may be repeated once after at least 1 hour, for a maximum of two 6-mg injections in a 24-hour
period.4
Figure
6. Therapeutic penalty, which can be defined as the adverse event on active drug minus adverse event rate on placebo from all causality adverse event data plotted on the y-axis. Data are given as 95% Cls, and the horizontal dashed line provides the 95% Cl for sumatriptan 100 mg which, as the first and most widely used drug of the class, provides a
reference.43 Permission for use of this figure is granted from the
Journal of Neurology, Neurosurgery and Psychiatry for the BMJ Publishing Group.
Cady et al randomized 1,104 patients to either receive a 6-mg subcutaneous injection of sumatriptan or placebo. At 1 hour after the injection, 70% of those given sumatriptan had a reduction of their severe-to-moderate headache to mild or no pain compared with 22% of placebo patients. In addition, 49% had complete relief from the migraine compared with 9% of placebo patients. Those patients who were given sumatriptan and did not have relief from their migraine after 1 hour were either given a second dose of sumatriptan or a dose of placebo. The study found that there was no additional benefit of giving a second injection 1 hour later. The study also found that only 34% of the patients who received sumatriptan remained pain-free for 24 hours compared with 11% of placebo
patients.46 Headache recurrence is probably because of sumatriptan’s relatively short half-life of 2 hours or the drug’s reversible binding to serotonin
receptors.13,47 The median time to headache recurrence after subcutaneous injection is about 9 to 13
hours.47 Sumatriptan also significantly reduced the incidence of nausea, vomiting, and photophobia compared with placebo. The onset of effect occurred from 10 to 60 minutes after
injection.46
Touchon et al compared subcutaneous sumatriptan to intranasal dihydroergotamine (Migranal). The study found that sumatriptan was more effective in relieving migraine headaches and had a faster onset of action. It also found that sumatriptan was significantly better at relieving nausea, photophobia, and
phonophobia.48 Patients were more accepting of sumatriptan, although it produced more toxicity, because of the migraine relief. Winner et al compared subcutaneous sumatriptan with subcutaneous dihydroergotamine. Of 295 patients, 73.1% of patients taking sumatriptan and 85.3% of patients taking dihydroergotamine had migraine relief 2 hours after taking their medications. The study concluded that both medications were equally effective, but sumatriptan had a faster onset of action. The study also concluded that sumatriptan has a shorter duration, since 45% of those taking sumatriptan versus 17.7% of those taking dihydroergotamine experienced headache recurrence within 24
hours.49
Sumatriptan (Oral). Oral sumatriptan, on the other hand, is only 15% bioavailable
(Table 1),43,50,51 and this is because of extensive first-pass metabolism in the liver. Maximum serum concentration occurs about 1.5 hours after ingesting a 100-mg dose, and is 37% lower than after subcutaneous administration. The recommended oral dose of sumatriptan is 25 mg at the onset of headache, but a maximum of 100 mg can be given in a single dose. Additional tablets may be taken if headache returns at intervals of 2 hours or more. The maximum recommended daily dosage is 300 mg in a 24-hour period. As with subcutaneous administration, patients taking the oral formulation have a reduction of their severe-to-moderate headache to mild or no pain compared with placebo. Cutler et al evaluated 259 patients taking 25, 50, or 100 mg of oral sumatriptan or placebo. After 2 hours, 52% of those taking 25 mg, 50% of those taking 50 mg, and 56% of those taking 100 mg had migraine relief. This was compared with 26% of those who took placebo. This form of sumatriptan also significantly reduced the incidence of nausea and photophobia compared with
placebo.52
Oral sumatriptan was found to be more effective than the ergotamine and caffeine combination, Cafergot. A study by the Multinational Oral Sumatriptan and Cafergot Comparative Study Group found that 2 hours after administration, 66% of the patients taking sumatriptan experienced headache relief compared with 48% of those taking Cafergot. Sumatriptan was also more effective at relieving nausea, vomiting, photophobia, and phonophobia, and had a faster onset of action. However, 41% of those taking sumatriptan had a recurrence of headache within 48 hours compared with 30% of those who took
Cafergot.53
Sumatriptan (Intranasal). The intranasal formulation is a new and convenient route of administration that has proven to be effective. This formulation may be especially useful in those patients who shy away from self-injection and patients whose nausea and vomiting prevent them from oral administration. The standard dosage is 5, 10, or 20 mg sprayed into one nostril at the onset of headache. Additional doses may be administered 2 hours after the last dosage taken, for a maximum of 40 mg/day. Ryan et al conducted two clinical trials that compared the efficacy of 10- and 20-mg sumatriptan nasal spray and placebo. It was found that 2 hours after drug administration, 62% to 63% of those taking 20 mg, 43% to 54% of those taking 10 mg, and 29% to 35% of those taking placebo had their moderate-to-severe headache reduced to mild or none. Patients taking sumatriptan experienced significantly more relief from nausea, vomiting, photophobia, and phonophobia compared with placebo. Migraine relief occurred from 15 to 60 minutes postdose. The most commonly reported adverse effect with the sumatriptan nasal spray was a bitter or unpleasant
taste.54
Naratriptan (Amerge). Naratriptan shares similar characteristics with sumatriptan except that it shows significantly less headache recurrence, better oral bioavailability, and a prolonged duration of action. Patients may have less likelihood of headache recurrence with naratriptan since it has a longer duration of action than sumatriptan; however, if they require immediate pain relief, naratriptan may not be as promptly effective as sumatriptan. Naratriptan is available in 1- and 2.5-mg tablets; however, the 2.5-mg dose has been found to provide greater relief in patients. The standard dosing of naratriptan is one tablet at the onset of headache. The dose may be repeated in 4 hours if needed, but the patient should not exceed 5 mg in a 24-hour
period.30
Mathew et al examined the efficacy and tolerability of naratriptan 0.25, 1, and 2.5 mg versus placebo. The study found that naratriptan provided headache relief to 68% of those taking 2.5 mg, 57% of those taking 1 mg, and 39% of those taking 0.25 mg compared with 33% of those patients that received placebo. In addition, 48%, 36%, and 25% of those taking naratriptan 2.5, 1, and 0.25 mg, respectively, did not experience headache recurrence within 24 hours after taking it compared
with 19% of those taking placebo. Naratriptan was also effective in reducing the incidence of nausea, photophobia, and phonophobia, and showed comparable adverse events to placebo. The study concluded that all doses of naratriptan are effective in migraine relief, but the 2.5-mg dosage was
superior.55
Zolmitriptan (Zomig). Zolmitriptan is more rapidly absorbed than sumatriptan and has a higher oral bioavailability of approximately 40%. Zolmitriptan is available in 2.5- and 5-mg tablets. The n-desmethyl metabolite is active; in fact, it has two to six times the 5-HT1B/1D activity of the parent
compound.56 The initial recommended dose is 2.5 mg, which can be repeated after 2 hours. The patient should not exceed 10 mg in a 24-hour
period.30 Zolmitriptan should be used with caution in patients with liver disease because drug clearance is reduced and episodes of hypertension can occur.
A study by the International Zomig Long-term Study Group examined a total of 2,058 migraineurs and 31,579 migraine attacks. The study found that a 5-mg dose of zolmitriptan relieved 81% of the moderate-to-severe migraines 2 hours postdose, reducing the headaches to mild or none at all. A recurrence of headache occurred in 32% of the attacks that responded to the first dose, and these recurrences were treated with another 5-mg dose of zolmitriptan. The administration of a second dose resulted in a 90% response rate 2 hours after the second
dose.57
Rizatriptan (Maxalt). Rizatriptan is another serotonin agonist with better oral bioavailability and longer duration of action than sumatriptan. It is available in 5- and 10-mg regular tablets, and in 5- and 10-mg orally disintegrating tablets (Maxalt-MLT). The recommended dose is one 5- to 10-mg tablet at the onset of headache. Additional doses should be separated by 2 hours, with a maximum of 30 mg in a 24-hour period. Patients concomitantly taking propranolol should take 5 mg at the onset of headache with a maximum of 15 mg in a 24-hour
period.30 Rizatriptan should be used with caution in dialysis patients because there is a decrease in drug
clearance.42 It is not recommended in patients under 18 years of age. Rizatriptan should be used with caution in moderate hepatic insufficiency. It might appear that the Maxalt-MLT formulation taken under the tongue would produce a faster response than the standard oral formulation. However, the disintegrating tablet actually has a somewhat slower absorption
rate.51 The sublingual administration may be useful in those patients with nausea and vomiting.
Kramer et al examined the efficacy of rizatriptan 10 mg in treating multiple migraine attacks in 473 patients. The response rate 2 hours after the first migraine attack was 76.9% in those taking rizatriptan compared with 36.6% in those taking placebo. Migraine relief 2 hours after rizatriptan administration after the second, third, and fourth attacks was 78.4%, 79.9%, and 74.5% compared with 37.0%, 28.0%, and 54.4% with placebo,
respectively.58 Tfelt-Hansen et al50 studied rizatriptan 5 and 10 mg versus sumatriptan 100 mg in 1,268 patients. Rizatriptan 10 mg was more likely to lead to pain-free response than sumatriptan. As might be expected from the rapid absorption, rizatriptan 10 mg produced more rapid pain relief.
The triptans have been reported on rare occasions to produce weakness, hyperreflexia, and incoordination when given with selective serotonin reuptake inhibitors, such as fluoxetine, fluvoxamine, paroxetine, and sertraline. Rizatriptan, though, has been given to patients receiving paroxetine without negative
sequelae.42
Ergotamine Tartrate. Ergotamine tartrate was first introduced in the late 1920s and was the first drug used to treat acute migraine
attacks.4 In the United States, it is available by itself in sublingual tablets (Ergomar, Ergostat), with caffeine in a tablet form (Cafergot, Ercaf, Wigraine), or as a rectal suppository (Cafatine, Cafergot, Catetrate, Wigraine). The sublingual tablets contain 2 mg of ergotamine tartrate, whereas the regular tablets contain 1 mg of ergotamine tartrate and 100 mg of caffeine. The rectal suppositories contain 2 mg of ergotamine tartrate and 100 mg of caffeine. The suppository has better and more consistent absorption than the oral tablets. Ergotamine tartrate taken orally by itself is poorly absorbed, with an oral bioavailability of less than 5%.38 Therefore, caffeine is added to enhance its absorption and to possibly potentiate its vasoconstrictive
activity.12 The oral formulation is better suited for a slowly evolving migraine, whereas the rectal suppository is more appropriate for severe, rapid-onset migraine headaches. Peak plasma concentrations occur about 1 hour
after oral and rectal administration.4
Ergotamine tartrate is believed to have serotonin agonist activity. It has a moderate affinity for 5-HT1C, 5-HT2, and 5-HT3 receptors, and a high affinity for 5-HT1A and 5-HT1B receptors. It also has potent alpha1 and alpha2-adrenergic antagonist activity and moderate DA2
activity.4
The recommended dose of oral or sublingual ergotamine tartrate is 2 mg at the onset of headache. This can be followed by 1 to 2 mg at 30- to 60-minute intervals until the migraine is treated or until a total of 6 mg has been ingested. A patient should not exceed 6 mg of ergotamine tartrate in a 24-hour period or 10
mg/week,12 because excessive use can result in rebound headaches, coronary vasospasms, or ergotism (gangrene of the bowels and/or
limbs).38 Similarly, the standard dose of rectal ergotamine tartrate is one 2-mg suppository at the onset of headache, and this can be repeated at 30- to 60-minute intervals if needed. The maximum rectal dose is 4 mg per 24-hour period or 10
mg/week.12
The most common side effects associated with ergotamine tartrate are nausea, vomiting, abdominal pain, muscle aches, tremors, and tingling of the extremities. The nausea and vomiting can be prevented by administering antiemetics such as metoclopramide (Reglan), promethazine (Phenergan), or prochlorperazine (Compazine). Ergotamine tartrate is contraindicated in pregnancy, uncontrolled hypertension, coronary artery disease, peripheral vascular disease, sepsis, peptic ulcer disease, and liver or kidney disease. It interacts with erythromycin and potentially with other known 3A4 inhibitors (fluoxetine, nefazodone, and cimetidine) causing ergot
toxicity.38 There was also one case of severe vasoconstriction with pain and cyanosis when taken with
propranolol.30 If a patient who takes an ergotamine derivative for acute attacks is started on methysergide prophylaxis, then that patient should be advised to cut the effective ergotamine dose in half to prevent an extreme vasoconstricting
effect.28
Dihydroergotamine. Dihydroergotamine is a hydrogenated ergot preparation with the same mechanism of action, contraindications, and side-effect profile as ergotamine
tartrate.12 Unlike ergotamine, dihydroergotamine is a more potent alpha-adrenergic antagonist, and so is a weak arterial constrictor and a potent vasoconstrictor. In addition, it causes less nausea and
vomiting.25
Dihydroergotamine is available in the United States as an intramuscular and intravenous injection (D.H.E. 45) or as a nasal spray (Migranal).25 The standard dose for the intramuscular formulation is 0.5 to 1 mg at the onset of headache. If 0.5 mg is taken originally, it can be repeated in 1 hour if needed. An antiemetic is typically not necessary with intramuscular administration. The usual intravenous dose for dihydroergotamine is 0.25 to 0.5 mg by slow push over 5 to 10 minutes through a heparin lock. If the headache is not relieved, another 0.5 mg can be given after 30 minutes. Patients are usually premedicated with an antiemetic with intravenous administration. The nasal spray is calibrated to release 0.5 mg per spray. The standard dose is two sprays in each nostril, for a total of 2 mg. If this does not bring about relief, a total of 3 mg can be used. The nasal spray is more convenient and has fewer side effects than the intramuscular and intravenous formulations. The incidence of nausea and vomiting is low, so premedicating with an antiemetic is usually not necessary. Patients will occasionally develop nasal
stuffiness.4
Butorphanol. Butorphanol (Stadol, Stadol NS) is a synthetic opioid
agonist-antagonist.13 It stimulates the kappa opioid receptors rather than the mu receptors, so it theoretically does not cause euphoria and is not as addictive as other opiates, such as
morphine.38 However, this drug can be and has been reported to be
abused.26 Butorphanol should be used in patients with infrequent but severe migraines, in which all other
symptomatic medications have been ineffective or not well tolerated. It is available in intravenous, intramuscular, and intranasal
formulations.38 Hoffert et al examined the efficacy of the intranasal butorphanol compared with placebo. They found that butorphanol reduced migraine pain from severe to slight or absent in 33% of patients after 30 minutes, in 47% of patients after 1 hour, and in 71% of patients after 6 hours. This is
compared with 4%, 16%, and 30%, respectively, in patients taking placebo.59
Butorphanol’s onset of action is approximately 15 to 20 minutes. The recommended dose is one spray (1 mg) in one nostril at the onset of headache. If migraine pain relief is not achieved in 60 to 90 minutes, then the 1-mg dose may be repeated. If migraine recurrence occurs, this sequence can be repeated every 3 to 4 hours after the last
dose.38
The most common adverse effects associated with butorphanol are dizziness, nausea, vomiting, nasal congestion, and insomnia. Caution should be used in patients with hepatic and renal disease, head injury, respiratory impairment, myocardial infarction, ventricular dysfunction, coronary insufficiency, or severe hypertension. Increased central nervous system (CNS) effects can result with concomitant administration with CNS depressants, such as alcohol, barbiturates, tranquilizers, and
antihistamines.60
Controlled studies are needed to identify the best management strategies for migraine in children; however, acetaminophen is considered first-line symptomatic treatment for pediatric migraine. NSAIDs or aspirin are frequently effective when acetaminophen is
not.61 Midrin has been used with some success in children while butalbital combinations and opioids should be avoided because of negative effects on cognition. The triptans require further study in children but so far have not demonstrated significant efficacy. Cyproheptadine, an antihistamine with 5HT2 antagonist activity, is used with some success in migraine prevention in children. Nonpharmacologic interventions (relaxation, cognitive behavioral therapy, trigger avoidance) are useful adjuncts.
Nonpharmacologic interventions may be helpful in preventing or relieving migraine headaches in some patients. One nonpharmacologic method that should always be assayed before implementing pharmacologic therapy is the active avoidance of potential triggers. This includes certain foods, drinks, spices, medications, and sensory stimuli, as previously discussed. Another potentially helpful non-pharmacologic intervention is applying a cold compress to the painful areas on the head to relieve pain. Also, putting pressure on or firmly massaging the temporal arteries can relieve the throbbing pain, but the relief will usually only last as long as pressure is applied. In addition, resting or sleeping in a dark and quiet room will often bring about
relief.17
Some unconventional measures have also been effective in preventing migraines in patients. This includes such therapies as hypnosis, transcutaneous electrical stimulation, and acupuncture. Relaxation therapy is another unconventional approach involving breathing exercises, directed imagery, and muscular relaxation. Another prophylactic measure is biofeedback, in which various monitoring devices are used to measure physiological processes such as body heat or pulse. The patient then attempts to change them at will. This is thought by some to be as effective as relaxation therapy in preventing migraines. Cognitive-behavioral therapy is another method, and this involves identifying and modifying a patient’s response to migraine headaches, such as anxiety and distress. These responses can further aggravate a migraine, so the goal is to identify and remove these stressors. Patients learn to better adapt and react to migraines, usually through stress management training. Physical therapy, chiropractic, and osteopathy may also be helpful. These practices assume that spinal manipulations can reduce migraine frequency and severity. It is important to note that these
nonpharmacologic therapies have not been proven through valid, statistically significant clinical trials, but their effectiveness is based mainly on self-assessment by
patients.17
With the advent of more effective and convenient treatment options, migraine headaches can now, more than ever, be successfully prevented and controlled. Before this can occur, however, a greater effort must be put forth to better diagnose those who suffer from migraines. It is our responsibility, as pharmacists, to help identify migraineurs and to ensure that an effective and well-tolerated drug regimen is utilized.
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