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Treatment Options
in the Management of Migraine:
Beyond
Traditional Therapies
C. LeAnn Causey,
Pharm.D., Primary Care Resident
Deborah S. King,
Pharm.D., Assistant Professor of Pharmacy Practice
University
of
Mississippi
Medical
Center
School of
Pharmacy
Jackson
,
MS
Needs Statement: In the United States, approximately 18% of women and 7% of men experience migraines. More than half of these sufferers experience moderate to severe disability from this disease, losing an average of 4 to 6 workdays per year. Pharmacotherapeutic advances, most notably the “triptans”, have made a tremendous impact on the management of migraine. Despite these advances, more than 70% of migraine sufferers are dissatisfied with their treatment. After reviewing traditional treatment strategies, this lesson will focus on non-traditional and novel approaches for migraine management. These approaches offer additional options for those who are unresponsive to or intolerant of traditional treatment modalities, and those with contraindications to their use. In order to contribute to the care of migraine sufferers, pharmacists must be familiar with all therapeutic options.
Intended Audience: Pharmacists who care for patients with migraine headaches, or dispenses medications for migraine headaches
Goal: To provide an update for pharmacists on the roles of different treatment options in the management of migraine headache.
Objectives:
Upon completion of this
article, the pharmacist should be able to:
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Introduction
Pharmacists are asked to
recommend therapy for headaches more frequently than any other
treatment
category.
Migraine, a potentially
debilitating neurovascular disorder, remains underdiagnosed
with therapeutic treatment options remarkably
underutilized.
Pharmacists can
contribute to migraine management by being familiar with
symptoms, understanding appropriate pharmacological therapy,
and providing up-to-date disease and medication
education.
Pathophysiology
Although the exact
pathophysiology of migraine remains unclear, previous vascular
and neural theories of migraine development have merged into a
combined theory of neurovascular
mechanisms.
In
migraine, dysfunction occurs in brain-stem
pathways.
This dysfunction
involves cranial blood vessels, the trigeminal innervation of
these vessels, and the reflex connections of the trigeminal
system with cranial parasympathetic
outflow.
Neural events, including
the release of endogenous peptides substance P and calcitonin
gene-related peptide (CGRP), are mediated through the
trigeminovascular
system.
External or internal
stimuli such as stress, hormonal changes, climate changes, and
flickering lights trigger these neurochemical
changes.
Excessive peptide release leads to vasodilation. Activity within the trigeminovascular system may be regulated in part by noradrenergic, and most notably, serotonergic neurons within the brainstem. All of these factors contribute to the pulsatile pain characteristic of migraine. Some novel pharmacotherapeutic approaches block the innervations stimulating specific areas of this system that can result in altered cerebral perfusion.
Presentation
Symptoms of migraine
headache vary among patients but are characterized by episodes
of throbbing, frequently unilateral head pain that may last 4
to 72 hours if untreated or unsuccessfully
treated.
During the episode, the
migraine sufferer may experience other symptoms including
nausea, vomiting, photophobia, phonophobia, and sensitivity to
movement.
Approximately 20% of
migraine patients will have transient neurological symptoms,
known as an
aura.
These symptoms most
commonly involve visual changes, but may also consist of
auditory and olfactory alterations as well as facial
numbness.
The
aura may precede or accompany an attack typically evolving
over 5 to 20 minutes and lasting less than 60
minutes.
The
International Headache Society (IHS) provides criteria for
classification of migraine headaches based on clinical
presentation and
features.
Migraine without aura,
formerly called common migraine, and migraine with aura,
formerly called classical migraine, are the most common types
of
migraine.
Migraine can progress from episodic attacks to chronic daily headache. This progression usually occurs over 10 to 12 years and may be associated with neurologic baseline changes between headaches. Historical treatment of migraine in which patients were advised to treat attacks infrequently and only after pain became severe may have contributed to this process. Prolonged or frequent episodes of pain alter neurological processing and lower the migraine threshold for future attacks, a result or process known as kindling. Patients may have or develop symptoms or comorbid disease states such as anxiety, depression, sleep disturbances, panic disorder, irritable bowel disease, or asthma.
Diagnosis
Migraine must be
distinguished from other types of headache or causes of head
pain.
Headaches may be
classified as primary or
secondary.
Primary headaches
include tension, migraine, cluster and chronic daily
headache.
Secondary headaches are
head pain due to some other medical condition such as
glaucoma, intracranial hemorrhage, meningitis, pseudotumor
cerebri, stroke, or brain
tumor.
The
diagnosis of migraine is made based on the presence of
multiple characteristic features and the exclusion of other
primary forms of headache or causes of head
pain.
Though a combination of
features is required for diagnosis, features may vary among
patients and between attacks within a given patient. Modified
IHS diagnostic criteria for migraine without aura are listed
in Table 1. Additional information regarding migraine
diagnosis and management is available at
www.aan.com
and
www.guidelines.gov
.
Pharmacological
Treatment of Migraines
Pharmacological
treatment of migraine headaches includes management of acute
attacks and preventive
therapy.
Acute or abortive
therapy alone is sufficient for migraine sufferers with
infrequent headaches (< 4 per month) and/or of short
duration (< 12
hours).
If
migraines occur more frequently, have a longer duration, or
cause substantial disability to the patient, then a
combination of preventive and abortive therapy may be
required.
Acute Therapy: Acute therapy is used to halt or significantly reduce an attack and is typically more efficacious if initiated early in the course of the headache. A wide range of pharmacologically distinct medications are used for acute migraine therapy. Examples of these and selected adverse effects are listed in Table 2. Acute therapy should not be routinely used more than two days per week. Overuse leads to medication-induced or rebound headache over time.
Analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, naproxen, and ibuprofen, are commonly used to relieve mild to moderate migraine pain. Indomethacin is available in a suppository dosage form useful for patients with nausea. Though ketorolac is available for injection, has a rapid onset of action and a low incidence of rebound headache, use should be limited because of its adverse effect profile. Acetaminophen alone is not effective for migraine pain but has been beneficial when used in combination with other agents.
In general, the use of opiates should be avoided especially as initial therapy. Opiates do not alter any underlying pathophysiological process of migraine and cause substantial cognitive impairment. Chronic use is also associated with a high rate of rebound headaches and the potential development of dependency and tolerance.
Ergotamine-containing agents are among the oldest agents used for acute treatment of migraine. Today ergotamines are used less often due to the potential for significant side effects, including valvular heart disease, vascular occlusion, and rebound headaches. Ergots should be avoided in many comorbid conditions such as coronary heart disease, peripheral vascular disease, hypertension, and hepatic or renal disease.
The limitations of earlier therapies led to the development of the serotonin 5-HT1B/1D receptor agonists or triptans. Despite higher costs associated with triptans, they are extensively used in migraines due to the magnitude of data documenting their safety and efficacy. To date, there are seven available triptans with frovatriptan and eletriptan being the two most recently approved. An eighth triptan, donitriptan is in preclinical development. There is no clearly superior triptan. All are effective but individual patient characteristics and preferences influence response and tolerability of the different agents. Selection of a particular triptan should be tailored to the needs of the patient. Lack of response to one triptan does not predict response to other triptans and is not a reason to exclude a trial with another in the class. Sumatriptan 100mg is the standard of comparison for all other triptans. Common primary endpoints used in most trials with triptans include headache response at two hours, freedom from pain, and sustained freedom from pain at 2 hours. Figure 1 highlights the conclusions of a triptan meta-analysis published in 2001 by Ferrari and colleagues using data from over 24,000 patients in 53 controlled trials.
Triptans differ in the availability of dosage forms, the onset and duration of action, rates of headache recurrence, and potential drug interactions. Sumatriptan offers the most drug delivery options (subcutaneous, intranasal, oral). Alternative dosage forms may benefit patients with nausea, vomiting, or impaired gastric motility. Naratriptan is associated with the least headache recurrence rate but this benefit is somewhat negated by the slow onset of action. Rizatriptan has the fastest onset but requires dosage adjustments with concomitant propranolol use. Almotriptan showed fewer side effects than sumatriptan in one head-to-head comparison although discontinuation rates at one year were similar for the two agents.
Potential adverse effects common to all triptans are listed in Table 2. Because triptans work through vasoconstriction, patients may experience symptoms similar to angina pectoris and in extreme circumstances, myocardial infarction. Due to the potential for serious complications, triptans are contraindicated in ischemic heart disease, uncontrolled hypertension, and cerebrovascular disease. All patients should receive cardiovascular assessment prior to therapy with triptans.
Oral dosage forms are somewhat limited with all acute therapies because of the decrease in gastric mobility and absorption that is associated with migraine attacks. Adjunctive therapy with antiemetics or agents such as metoclopramide that increase gastric motility may be useful in ameliorating attacks.
Preventive Therapy: Migraine sufferers experiencing frequent attacks may require prophylactic or preventive therapy. Preventive therapy should be initiated with low doses and gradually titrated to either a desired response or a reasonable dose for the particular agent. The dose used should balance headache frequency with a low incidence of adverse effects. Four to six weeks at the titrated dose are needed before the full effect is realized. Because of this interval, an adequate trial of at least one to two months should be allowed before changing to an alternative agent.
Classes of agents commonly used as preventive therapy include beta blockers, calcium channel blockers (CCBs), antidepressants, and anticonvulsants. Table 3 lists these agents along with their most common adverse effects. NSAIDs may also be used for migraine prophylaxis. Other agents used less frequently in migraine prophylaxis include cyproheptadine, methysergide, and phenelzine. Clinical trials in migraine prevention are also emerging employing angiotensin converting enzyme inhibitors and angiotensin receptor blockers.
Numerous studies support the use of beta blockers in reducing both frequency and severity of migraines. Effective agents in this class include propranolol, timolol, atenolol, metoprolol, and nadolol. Like many of the agents used for migraine prevention, the maximum benefit of beta blockers may not be realized for several months.
CCBs are routinely used in migraine prophylaxis, although clinical data is limited. Of the CCBs, verapamil is most commonly used. Others, including nicardipine, nifedipine, and nimodipine, have also been studied for migraine prophylaxis. In some patients, a potential advantage of CCBs is their ability to relieve the symptoms commonly associated with auras. On the other hand, CCBs have been associated with the development of tolerance that may occur after treatment periods of eight weeks.
Antidepressants used for migraine prophylaxis include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and other serotonergic agents. Antidepressants have been used in both those patients with and without depression. The TCAs, such as amitriptyline and nortriptyline, have been the primary antidepressant class used because of their strong evidence of effectiveness. In general, TCAs are used in lower doses compared to those used in the treatment of depression.
SSRIs used in migraine prevention include sertraline, fluoxetine, paroxetine, and citalopram. Scientific evidence supporting the use of SSRIs is not as strong as with the TCAs though many patients find these agents easier to tolerate because of fewer adverse effects. In contrast with the TCAs, migraine prophylactic doses of SSRIs are comparable to those used for the treatment of depression. Other agents with serotonergic effects used in migraine prophylaxis include bupropion, mirtazapine, nefazodone, trazodone, and venlafaxine.
Several of the anticonvulsants represent the newest agents routinely prescribed for migraine prophylaxis. The mechanism of action of anticonvulsants is not fully understood, but all share a common role in enhancing or potentiating the actions of gamma-aminobutyric acid (GABA). Valproic acid and divalproex sodium (a 1:1 molar combination of valproate sodium and valproic acid) have the greatest amount of documented efficacy in reducing headache frequency. Therapeutic effects are seen relatively quickly with these agents, within the first few weeks of therapy, with many migraine sufferers having at least a 50% reduction in headache frequency. Divalproex sodium is the only antiepileptic drug actually FDA approved for migraine prevention. Valproic acid and divalproex sodium are contraindicated in pregnancy and in patients with liver dysfunction.
The use of newer anticonvulsants, particularly gabapentin and topiramate, is growing though these have less documented efficacy in migraine prevention and treatment. For both of these agents, clinical trial data is emerging. The antinociceptive or analgesic effects of gabapentin are much more widely recognized. Topiramate is quickly evolving as a viable prophylactic treatment modality and is a promising option for reducing migraine frequency. Tiagabine, levetiracetam, zonisamide, and lamotrigine may all be useful, but additional study is needed to confirm their efficacy.
With the wide range of options, the choice of an agent should take into account any coexisting conditions. Concomitant depression may benefit from use of TCAs or SSRIs. Migraine sufferers with anxiety may benefit from beta blockers or SSRIs. Understandably, patients with seizure disorders may be most appropriately treated with an anticonvulsant agent. Additionally, anticonvulsants are good treatment options in patients with bipolar or mood disorders. Patients with sleep disturbances or fibromyalgia may also benefit from the use of TCAs. The most appropriate preventive therapy in migraine sufferers with concomitant hypertension may be with beta blockers or CCBs. Likewise, it is also important to consider coexisting disorders that may deteriorate with a particular treatment. For example, beta blockers may exacerbate depression, TCAs may lower seizure threshold and precipitate mania in bipolar disorder, and divalproex sodium can worsen obesity.
Novel Treatment
Options
Botulinum
Neurotoxin:
Botulinum neurotoxin has
been studied as a potential preventative treatment for various
headache disorders. Botulinum neurotoxin is a substance
produced by the gram-positive anaerobic bacteria
Clostridium
botulinum.
Seven different and
distinct neurotoxins are produced of which four (Type A, B, E,
and F) affect
humans.
Of
those affecting humans, types A and B are the most toxic and
are resistant to digestion by gastric
enzymes.
Ingestion of spoiled
food containing the neurotoxin will block the release of
acetylcholine causing paralysis of the autonomic nervous
system.
Botulinum toxin cleaves
the membrane protein SNAP 25, blocking the calcium-activated
release of acetylcholine from
neurons.
Due
to its pathophysiological mechanism, botulinum toxin has
developed a role in the treatment of many medical conditions
including strabismus, blepharospasm, achalasia, spasmodic
torticollis, hemifacial spasm, wrinkles, and
headache.
Several theories exist to explain the observed therapeutic benefit of botulinum toxin in the treatment of migraine headache: When injected into muscle, botulinum toxin causes flaccid paralysis. This translates into relaxation of the cerebral vasculature and migraine relief through this mechanism. It is also theorized that botulinum toxin decreases acetylcholine release in the muscle spindle, an area where acetylcholine release may be excessive. By “re-normalization” of the muscle spindle activity, less neurological input is received in the central nervous system. Lastly, the efficacy of botulinum toxin may be as an anti-inflammatory because it inhibits the release of central nervous system substance P and thus modifies the transmission of pain.
Botulinum toxin type A (BTA) and type B (BTB) have been investigated in a variety of clinical trials. In a small number of migraine studies, low dose BTA was concluded to decrease the frequency of migraine with fewer side effects than seen with higher doses. Other outcomes found were decreased migraine severity and medication utilization.
BTB, the neurotoxin produced by a different strain of Clostridium, is slightly different from BTA in potency or activity. Approximatly 100 units of BTA are therapeutically comparable to 5000 units of BTB, though no exact equivalence exists. BTB is generally more stable than BTA, with both strains demonstrating similar safety and efficacy in low doses for treatment of migraine. BTA is superior to BTB in degree of administration discomfort. BTA is available in the product Botox® and BTB is available as Myobloc®.
At therapeutic doses, intramuscular injection of low doses of BTA or BTB should not result in detectable systemic levels of the toxin or systemic symptoms. Optimal injection site(s) for the intramuscular injection has not been established, although many have been studied. Specific sites include glabellar, frontalis, temporalis, posterior and suboccipital sites. Larger doses may be required for injection into posterior muscles whereas low doses in frontal and temporal sites have shown sufficient efficacy. Complete resolution of migraine pain has been associated mostly with glabellar injections and multiple site injections.
The use of botulinum toxin in the general population is limited by the high cost associated with therapy and the lack of coverage by health insurance plans. Additionally, this agent has not been FDA approved for the treatment of migraine and requires administration by a trained professional. There is still a paucity of well controlled clinical trials with this agent.
Use of BTA or BTB should be reserved for patients whose migraines are severe and unresponsive to traditional acute and preventive treatment.
Magnesium: Low cerebral levels of magnesium may be correlated with the cascade of events that trigger migraine. The administration of intravenous magnesium has been an adjunctive therapeutic option for the status treatment of migraines in many emergency departments. The role of oral magnesium dietary supplementation for migraine prophylaxis is evolving.
Identification of deficient magnesium levels in migraine sufferers has led to the investigation of supplementation as a treatment for these patients. Dietary supplementation of magnesium for prophylactic migraine therapy has been studied in four clinical trials with all but one showing positive results. In these trials, supplementation with 600 mg of elemental magnesium daily was associated with a decrease in migraine duration, intensity, and frequency.
Magnesium is available in many different salt formulations with the oxide, diglycinate, and slow-release chloride salts showing the greatest absorption and tolerability. Other salts have been associated with poor absorption, decreased efficacy, and a greater incidence of diarrhea. Prophylactic doses that have been used in migraine are between 400 and 800 mg of elemental magnesium daily. Although more clinical data is needed to further define the role of magnesium in migraine prophylaxis, it may offer a readily accessible alternative with little financial cost to the patient.
Feverfew: headache and migraine are two of the most frequent indications treated with herbal remedies. Tanacetum parthenium, more commonly known as feverfew, is an herbal frequently touted for its ability to prevent migraine attacks. Although the exact active ingredient is unknown, the sesquiterpene lactone parthenolide component appears to play a major role in inhibiting serotonin release. Another potential active ingredient is chrysanthenyl acetate, an essential oil constituent of feverfew that exerts an analgesic effect through inhibition of prostaglandin synthesis. Melatonin found in feverfew is a third constituent that possibly contributes to the overall efficacy of the herbal.
Feverfew has been studied in several trials evaluating migraine treatment. Not all trials have demonstrated efficacy, but some have shown positive benefits in reducing the number of migraine attacks, decreasing migraine severity, and decreasing migraine-associated nausea and vomiting.
The clinical efficacy of feverfew products seems closely linked to product formulation. Available formulations of feverfew include dried leaves, capsules, teas, and alcoholic tinctures. Of these, the lowest efficacy has been seen with tea and tincture preparations. Extremely poor results have been found with alcoholic tincture formulations, while dried feverfew preparations have showed the greatest benefits in migraine prevention. Capsule formulations should be standardized to 0.2% of the active parthenolide component. Usual daily doses range from 200 to 250 mg daily.
Studies demonstrate an acceptable tolerability profile with feverfew. Adverse effects, including oral cavity ulceration and gastrointestinal symptoms, were found to be mild and reversible. Other potential adverse effects include glossitis, contact dermatitis, and taste alterations. Abrupt withdrawal of feverfew after a prolonged treatment period has been associated with “post-feverfew syndrome”. This syndrome involves symptoms characteristic of migraine, anxiety, sleep disturbances, and muscle or joint stiffness.
Because of possible harm to the fetus, feverfew should never be used in pregnancy. Feverfew should be used with caution in patients allergic to chamomile, ragweed, yarrow or other plants in the Compositae (Asteraceae) family. Concomitant use with NSAIDS may lower the efficacy of feverfew by interfering with feverfew inhibition of prostaglandin synthesis. Feverfew may inhibit platelet activity and lead to prolonged bleeding time, complicating therapy in patients treated with anticoagulants such as warfarin.
As with all herbal remedies, potential concerns exist when considering use of feverfew for migraine management. These arise from uncertain product standardization, FDA regulation, and the paucity of clinical evidence. Patients should be aware of these considerations and if a trial of feverfew is elected, be carefully guided in appropriate product selection.
Riboflavin: Riboflavin, or vitamin B2 , is a water-soluble B-complex vitamin found in many food sources including meats, dairy products, and vegetables. Riboflavin may have benefits in migraine prophylaxis by increasing energy production within the mitochondria of cerebral blood vessels. Multiple studies of high dose riboflavin show a reduction in headache symptoms, number of headaches, duration of headaches, and number of days experiencing headaches. In these studies, a dose of 400 mg per day was used. This compares to the FDA recommended daily allowance of approximately 1.5 mg. Treatment periods studied ranged from three-months to one-year.
Adverse effects with riboflavin are infrequent and in the studies mentioned, there was only one report of discontinuation. This discontinuation was related to intolerable diarrhea. Patients should be warned that urine may be bright yellow and this is harmless. There are no known reports of riboflavin toxicity since excessive quantities are easily excreted through the kidneys.
Riboflavin is available over-the-counter as 50 and 100 mg tablets. Patients should be given an adequate trial of therapy because therapeutic effects may not be seen for two to three months. Compliance may be a problem in migraine prophylaxis because of the high doses required and large pill burden each day. Despite this drawback, riboflavin supplementation offers a favorable safety profile and low-cost alternative in migraine prophylaxis.
Lidocaine: intranasal lidocaine, a local anesthetic, offers another novel approach for acute migraine treatment. Multiple studies report rapid symptomatic relief of migraine using a 4% solution of intranasal lidocaine. migraine pain relief occurs within 10 to 15 minutes, with an accompanying reduction in symptoms of nausea, vomiting, and photophobia. Unfortunately, studies also report high relapse rates, usually within one hour of migraine response. The potential of lidocaine for acute relief has also been demonstrated in patients suffering from cluster headaches. Adverse effects with intranasal lidocaine are generally limited to local irritation of the nose, numbness of the throat, bitter taste, and possibly, dizziness and anxiety.
Intranasal lidocaine administration requires a rather involved regimen. The head should be placed specifically in a 45-degree hyperextended position and then rotated 30-degrees toward the side of head pain. The dose of intranasal lidocaine 4% is 0.5 ml or four sprays initially followed by a single repeat dose of two sprays 15 minutes later. For bilateral head pain, the regimen should be performed independently for each side.
The availability of efficacy data with intranasal lidocaine remains limited due to insufficient population size, lack of placebo-controlled trials, and lack of comparison to conventional medications. Intranasal lidociane is not FDA approved for use in acute migraine. More extensive data is needed before intranasal lidocaine is accepted as a routine treatment for acute migraine.
CONCLUSION
Migraine remains
severely underdiagnosed and
undertreated.
Traditional therapeutic
options have drastically reduced the burden of migraine
sufferers and improved quality of
life.
this is particularly
associated with the introduction of the
triptans.
These highly effective
agents free approximately 70% of patients from many symptoms
of
migraine.
For
those 30% who do not achieve adequate relief, other
alternatives and novel approaches may be
considered.
Botulinum toxin, magnesium, feverfew, riboflavin, or lidocaine may offer viable options for these refractory patients. For the majority of patients, additional clinical evidence is needed to define the most appropriate role for these agents in the management of migraine.
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