Pharmacotherapy Perspectives

by Sarah E. Bland, RPh

Column Editor: Lee Vermeulen, MS, RPh,
Director, Center for Drug Policy, University of Wisconsin Hospital and Clinics

Migraine Prophylaxis
Principles, goals and drug therapy

Introduction of males and 68% of females had never consulted a physician

Migraine headache is a chronic condition characterized by for their headaches.4 Of those who consulted with physicians,
repeated, debilitating attacks of severe, usually unilateral, 42% reported that they had not received a diagnosis of mi-
pulsatile headaches, often accompanied by nausea, vomiting, graine. Only 13.6% of female migraineurs and 10.4% of males
photophobia and a variety of other symptoms. Classical mi- consulted with a neurologist about their headaches; fewer still,
graine is associated with prodromal symptoms referred to as 1.6% of females and 4.7% males, consulted with a pain or
aura; common migraine usually lacks these prodromal symp- headache specialist.
toms. It is a disorder with a prevalence of 17.6% in American While the degree of disability experienced by migraineurs
females and 5.7% in American males.1 The prevalence of varies widely from patient to patient5, efforts have been made
migraine begins to increase starting at age 12, peaks at about to estimate the cost of the disability resulting from migraine.
age 38, and declines thereafter. It is approximately twice as A recently published study estimated that each year in the
common in boys as in girls at age 12, becomes 3.3 times as United States, 112 million workdays are missed and $13
common in women as men between the ages of 42-44 and billion are lost to employers due to absenteeism and reduced
decreases to 2.5 times as common in women by age 70.2 productivity.6 There are also losses experienced in the social
Although there is a common misperception that migraine is aspects of life that have no means of measurement.
more common in those who have the time and money to seek The recent studies of migraine have shown that it is a
treatment, the American Migraine Study has provided docu- common problem, afflicting over 10 million Americans at a
mentation that its incidence actually decreases with higher high social and economic cost. At the same time, it appears to
socioeconomic status.1 be a medical problem for which patients often do not seek help,
Among the respondents to the American Migraine Study, and when they do, the diagnosis is often missed and referrals
25% of the women had four or more severe attacks monthly, to specialists are infrequent. This is unfortunate, because there
35% had three severe attacks monthly and 40% had one severe are many effective, well-tolerated methods available for the
attack per month or less.1 The male respondents reported a prevention and treatment of migraine. This article will address
similar frequency of attacks. Over 80% of respondents re- the principles and goals of migraine prophylaxis. The primary
ported at least some degree of disability with their headaches, reference for the recommendations made here is the UW
including severe disability or the need for bed rest in one- Hospital and Clinics Migraine Assessment and Treatment
fourth of cases. Despite the degree of disability reported, 57% Guideline.7

Goals of treatment Non-pharmacologic measures

According to the University of Wisconsin Hospital and All prophylactic treatment plans should include some non-
Clinics Migraine Treatment Guideline, the goals of treatment pharmacologic treatment strategies intended to reduce the
are to reduce the frequency and severity of migraine attacks; a patient’s exposure to triggers that may cause a migraine attack
secondary goal may include improving the responsiveness of to start. Common triggers are missed meals; too little sleep;
attacks to abortive therapy.7 A good response may be defined excessive heat and humidity; certain foods such as chocolate,
as a 50% reduction in the frequency or severity of the attacks. hard cheeses, alcoholic beverages, citrus fruits, nuts, excessive
The lowest effective dose of medication should be used in caffeine, and caffeine withdrawal; medication such as oral
order to minimize side effects. Patients should not expect that contraceptives, overuse of analgesics, sympathomimetic street
they will become completely free of migraines; rather, they drugs; strong sensory stimuli such as bright lights, glare,
should expect that they will have less disability. Rescue flickering lights, odors, smoke and prolonged exposure to heat
medications should still be available to the patient. or cold. Patients should be encouraged to keep a headache diary
in an effort to identify triggers.

The information given and views expressed herein do not necessarily reflect the opinions of PSW, its Board or members.

20 Nov/Dec 2000 Journal of the Pharmacy Society of Wisconsin

 Pharmacotherapy Perspectives

Indications for pharmacologic prophylaxis required to effectively treat migraine are often lower
Any one of the following indications is sufficient to war- than the doses required to treat other conditions such as
rant a trial of prophylactic medications.7-9 Some published epilepsy, hypertension or depression.
guidelines may recommend a minimum threshold number of 6. While many patients may require combinations of drugs
attacks per month, but such thresholds are in fact arbitrary and for effective prophylaxis, it is important to add the drugs
any patient who wishes to reduce the number or intensity of one at a time in order to keep track of their respective
attacks should be considered as a candidate for prophylactic efficacies and to sort out side effect profiles.
therapy.
7. Consider comorbid conditions when choosing a prophy-
1. Occurrence of 2-3 attacks/month OR recurring attacks
lactic agent. For example, in a patient with hypertension,
that patients feel are interfering with their daily ac-
it may be possible to choose drugs like beta-blockers or
tivities even with acute treatment
verapamil that will control hypertension and also reduce
2. Attacks lasting 48 hours or more migraine recurrence. Choice of a multifunctional agent
3. Extreme headache severity or prolonged aura can decrease possible adverse effects, increase compli-
4. Presence of uncommon migraine conditions such as ance and improve cost-effectiveness of therapy. Avoid
hemiplegic migraine, basilar migraine, or migrainous medications that could compromise patient care, like
infarction beta-blockers in patients with asthma.
5. Inadequate relief from or overuse of acute therapies 8. Consider also the side effect profile of the prophylactic
drugs and whether some of the side effects might be
6. Contraindication to or intolerable adverse effects beneficial in some patients. For example, the drowsi-
from acute therapies ness caused by the tricyclic antidepressants might be a
7. Intolerable cost of acute therapies beneficial side effect in a patient who is also suffering
8. Patient demand from insomnia.

Guiding principles of drug therapy Migraine guidelines

There are a number of helpful principles that can be used to The University of Wisconsin Hospital and Clinics has
maximize the likelihood of successful results in migraine developed a Migraine Prophylaxis Guideline (on next page)
prophylaxis.7,8,10 Careful consideration of these principles can based on drugs that have proven efficacy for this indication.7
be useful in selecting the appropriate drug with which to begin The guideline is arranged by drug class, with drugs within that
a prophylactic trial. Additionally, it is important to explain the class listed in the second column. Minimum and maximum
principles relating to commitment, compliance, trial duration dosages are recommended, and contraindications and com-
and elimination of confounding medications to patients so they ments for each drug are included in the third column. The
are able to participate fully in the process. Their input is section immediately following the guideline outlines the clini-
essential to successful prophylaxis. cal evidence for efficacy of each agent listed in the guideline.
1. Recognize that a plan of prophylactic therapy requires a
Clinical evidence for efficacy
major commitment on the part of the patient and the
Propranolol has been demonstrated in a number of clinical
physician.
trials to be significantly more effective than placebo in reduc-
2. Educate patients about the importance of compliance. ing the number of migraine attacks. 11-14 In addition, it has been
Once an effective dose is determined, use of a long- reported as effective in case series.15,16 Typical doses range
acting, once-daily dosage form may encourage compli- from 80 mg/day up to 320 mg/day. Good results were obtained
ance. with the long-acting formulation which is convenient for
3. Give each medication an adequate trial of two to three patients, and the drug was well-tolerated by most patients.
months before evaluating its efficacy. Other beta-blockers have been studied for migraine pro-
4. Reduce or eliminate the use of medications that exacer- phylaxis. Metoprolol, in doses of 100-200 mg/day, was signifi-
bate migraine or interfere or interact with the prophylac- cantly better than placebo in reducing the number of attacks
tic drug. and number of migraine days, although its effect on pain
severity scores and analgesic tablet consumption was signifi-
5. Use the lowest effective dose. Start with a very low dose cant only at the higher dose.17,18 Metoprolol has been directly
of the selected medication and titrate upward until a compared to propranolol in double-blind, cross-over studies;
satisfactory benefit is obtained without side effects or 100-200 mg/day of metoprolol was found to be as effective as
until the dosage is limited by side effects. The doses 80 mg/day of propranolol in reducing headache frequency,

Journal of the Pharmacy Society of Wisconsin Nov/Dec 2000 21

 Pharmacotherapy Perspectives

UWHC Migraine Prophylaxis Recommendations

Drug Class Drug/Dose Contraindications/Comments

Beta Blockers • Propranolol 40-240 mg/day PO • Propranolol and nadolol are contraindicated in bronchial asthma or
• Atenolol 50-150 mg/day PO COPD
• Metoprolol 100-200 mg/day PO • All beta-blockers are contraindicated in overt cardiac failure, 2nd or 3rd
• Nadolol 20-60 mg/day PO degree AV block or severe sinus bradycardia
• Caution in CHF, diabetes mellitus, hyperthyroidism/thyrotoxicosis, pe-
ripheral vascular disease
• Do not withdraw abruptly; taper over 1-2 weeks

Calcium Channel • Verapamil 240-320 mg/day PO • Diltiazem and verapamil are contraindicated with atrial fibrillation or
Blockers • Diltiazem 90-360 mg/day PO flutter, accessory bypass tracts, short PR syndromes, hypotension (<90
• Nimodipine 120-360 mg/day PO mm Hg systolic), 2nd or 3rd degree AV block without functioning artificial
pacemaker, sick sinus syndrome, wide-complex ventricular tachycardia
(QRS>0.12)
• Verapamil is contraindicated in CHF, digital ischemia, ulceration or
gangrene, idiopathic hypertrophic cardiomyopathy, severe left ventricu-
lar dysfunction
• Diltiazem and verapamil are contraindicated with impaired renal function
• Avoid extended-release dosage forms of diltiazem and verapamil with GI
hypermotility or GI obstruction

Serotonin Receptor • Methysergide 2 mg every night, • Contraindicated in pregnancy, peripheral vascular or coronary artery
Antagonists gradually increased to TID (maximum disease, lower limb phlebitis, pulmonary disease, collagen diseases or
8 mg/day if needed); usual dose is 4-8 fibrotic disease, impaired liver or renal function or valvular disease;
mg/day · “drug holidays” of 3-4 weeks every 6 months are needed to prevent
serious drug toxicity

Tricyclic
Antidepressants
• Amitriptyline 10-150 mg every night • TCAs are contraindicated in the acute recovery phase following myo-
• Nortriptyline 10-150 mg every night cardial infarction, and with concomitant use of monamine oxidase
(start with 10 mg and increase as inhibitors (MAOIs)
tolerated until adequate response or • Use with caution in seizure disorders; history of urinary retention,
intolerable side effects) glaucoma or increased ocular pressure; hyperthyroidism; schizophre-
nia and cardiovascular disease
• Nortriptyline should not be used concomitantly with reserpine

Anti-epileptics • Divalproex 500-1500 mg/day • Valproic acid and divalproex are contraindicated in pregnancy or with
• Valproic acid 500-1500 mg/day liver disease
• Use with caution with drugs that affect platelet function, or with concomi-
tant use of other CNS depressants

migraine days, analgesic consumption and ergotamine con- prophylaxis is nadolol. In a study of 80 patients taking 0, 80,
sumption.19,20 In the Olsson study, 100 mg metoprolol/day was 160 or 240 mg/day, patients taking 160 or 240 mg/day had a
effective in reducing headache pain severity scores statisti- reduction in the frequency and severity of their migraines.22
cally significantly from baseline. Nadolol 80 and 160 mg/day have also been compared to
Atenolol was evaluated in a small trial of 24 patients in a propranolol 160 mg/day in migraine prophylaxis.23,24 In the
double-blind, cross-over, placebo-controlled study.21 Doses of Sudilovsky study, the higher dose of nadolol produced supe-
100 mg/day were significantly better than placebo in reducing rior results to propranolol in headache frequency, intensity,
migraine frequency and in its effect on headache overall. pain days and use of relief medications by the end of the first
Eleven of 20 patients included in the final analysis had a 50% month of treatment. In the Ryan study, the lower dose of
reduction in headache severity and two patients had no head- nadolol produced the greatest improvements but the difference
aches during the study period while on atenolol. between the groups was not statistically significant.
A fourth beta-blocker that has been studied for migraine Verapamil is a calcium channel blocker that has been used
22 Nov/Dec 2000 Journal of the Pharmacy Society of Wisconsin
 Pharmacotherapy Perspectives

prophylactically for migraine, although there has been little Amitriptyline has been used widely and effectively for
clinical study of it. A review of three double-blind clinical migraine prophylaxis, although there are not many clinical
trials indicates that verapamil, in doses of 240-320 mg/day, is trials available. A placebo-controlled trial in 100 patients
significantly more effective than placebo in preventing mi- found that amitriptyline in doses of up to 100 mg/day was more
graine, with the 320 mg dose being more effective than the 240 effective than placebo in preventing migraine.38 Over 55% of
mg dose.25 Forty-five percent of the 133 patients in the trials patients receiving amitriptyline had a 50% improvement in
reported greater than 50% improvement in migraine frequency. their headaches, compared to 34% of patients taking placebo.
Diltiazem has also been used successfully in migraine prophy- Amitriptyline was most effective in non-depressed patients
laxis, although it, too, has been little studied.26 with severe migraine and depressed patients with less severe
Nimodipine has been found to be superior to placebo in migraine; depressed patients with severe migraine did not
migraine prevention in a double-blind, cross-over trial of 33 respond as well. A second trial compared amitriptyline in
patients.27 Statistically significant improvements were attained doses of 50 to 150 mg/day to propranolol 80 to 240 mg/day.39
in headache frequency, duration and headache index (pain Both drugs were superior to placebo and there was no differ-
severity X migraine days/28 days). Studies comparing ence in efficacy between them. Amitriptyline has been com-
nimodipine to flunarizine and pizotifen as well as placebo pared to fluvoxamine for migraine prophylaxis in a study of 70
found nimodipine to be superior to placebo and equivalent in patients.40 Both drugs reduced the headache index to a statis-
efficacy to the comparator drugs.28,29 Two other studies have tically significant degree. Drowsiness was more common
shown a strong placebo response in addition to a good response among patients receiving amitriptyline; a larger number of
to nimodipine; a superior benefit from nimodipine could not be patients taking amitriptyline dropped out of the study (9
established in these studies.30,31 The usual dose of nimodipine compared with 2 for fluvoxamine). Nortriptyline is sometimes
administered in the studies was 40 mg three times daily. used as an alternative to amitriptyline. It is often better toler-
A fourth calcium channel blocker, nifedipine, was com- ated than amitriptyline and it appears to be effective, but
pared to propranolol for migraine prophylaxis.32 In this small, clinical trials demonstrating its efficacy are lacking.
open-label study, nifedipine was less effective than propra- Divalproex sodium was evaluated for migraine prophy-
nolol and had a much higher incidence of side effects; 45% of laxis in a placebo-controlled, dose-ranging study. 41 Patients
the 20 patients on nifedipine withdrew from the study within received either placebo, divalproex 500 mg/day, 1000 mg/day
two weeks. A second study found no difference between or 1500 mg/day. The three treatment groups had statistically
nifedipine and placebo in the frequency of headaches, although significant improvements in headache frequency and severity,
side effects were frequent among nifedipine users.33 Based on although there was no significant difference among the doses
the lack of significant benefit and the frequency of side effects, in degree of improvement. A second trial compared divalproex
nifedipine is generally not used for migraine prophylaxis. sodium to placebo in 107 patients.42 Headache frequency and
Methysergide is a serotonin receptor antagonist that has severity were significantly decreased while patients were
been used for migraine prophylaxis for many years. It has taking divalproex. Side effects, mainly nausea and drowsiness,
unique and serious toxicities, however, that limit its use to the were generally mild to moderate. There was no significant
most severe and refractory cases and require drug holidays of difference between the treatment and placebo groups in the
3-4 weeks every six months. Its efficacy has been demon- number of patients withdrawing due to intolerance. A review
strated in several clinical trials.34-37 In the Pedersen trial, 60 of of studies of sodium valproate and divalproex sodium for
102 patients completed the trial; 57% had a 50% response to migraine and chronic daily headache found that patients im-
methysergide and methysergide was superior to placebo.34 In proved on these drugs in 10 of 11 studies.43 Doses from 500 to
the Whewell trial, 50 of 74 patients completed the trial. 2000 mg/day were evaluated and were well-tolerated.
Patients achieved a small decrease in the number of attacks, a Divalproex has become one of the mainstays in the treatment
small decline in the duration of attacks and a larger decrease in of migraine, although its use is associated with the undesirable
the duration of severe headaches.35 Use of methysergide re- side effect of weight gain. Patients should be counseled about
sulted in a statistically significant decline in the number of this effect and monitored for weight gain during treatment.
attacks per week and in headache index in the Forssman trial;
decreases in duration and intensity were not statistically sig- Emerging treatments
nificant.36 In the Lance trial, methysergide produced the best There are a number of drugs that are currently being used
results among six different serotonin antagonists including for migraine prophylaxis that have scant published evidence
cyproheptadine and methdilazine; 64% of patients on for efficacy or only anecdotal evidence. For most of these
methysergide had a 50% or greater improvement in their drugs, there is not yet enough experience with them to offer
headaches.37 firm recommendations for dosing. However, their use may
prove beneficial in refractory patients and are mentioned here
Journal of the Pharmacy Society of Wisconsin Nov/Dec 2000 23
 Pharmacotherapy Perspectives

for informational purposes. in the number of attacks while on lamotrigine. A third study of
Fluoxetine and its s-enantiomer, s-fluoxetine, have been lamotrigine in patients with migraine with and without aura
studied for migraine prophylaxis with mixed results.44-46 A showed a tendency toward reductions in migraine days and
double-blind, placebo-controlled trial in 32 patients evaluated severity scores for the active treatment group, but no statisti-
fluoxetine over an 8-week period.44 Headache scores in the cally significant benefits were shown.49
active group decreased significantly beginning in the third and A recent case series on the use of gabapentin in centrally
fourth weeks of treatment; no change was observed in the and peripherally mediated pain, migraine and tremor reported
placebo group. No changes in depression scores were observed on 14 patients with migraine and cluster headache who were
in either group. A second trial evaluated fluoxetine vs. placebo treated with gabapentin in doses of 900-2700 mg/day. Ten of
in 122 patients with migraine or chronic daily headache.45 the 14 patients reported moderate to excellent reduction in
Fluoxetine was not significantly effective for migraine in this headache frequency, duration and severity.50
study but was moderately effective in reducing chronic daily Other agents currently in use or under investigation for
headache. S-fluoxetine was evaluated in a placebo-controlled migraine prevention are riboflavin 51 , magnesium 52 ,
trial in 53 patients.46 The active treatment resulted in a statis- montelukast53 and sumatriptan (taken intermittently for men-
tically significant decrease in the number of attacks, although strual migraine).54 The anticonvulsant topiramate has been
the decreases in secondary efficacy measures, such as mi- used successfully in refractory patients, although there is very
graine days, attack severity and medication use, did not reach little published data available. Anecdotal reports have indi-
statistical significance. cated excellent response rates with very little toxicity.
Lamotrigine is a newer anticonvulsant that has been ex-
plored for migraine prophylaxis. A study in 15 patients found Summary
that lamotrigine reduced the frequency and duration of aura While there are many apparently effective options avail-
symptoms to a statistically significant degree, but this study able for the preventive treatment of migraine headache, there
did not measure the effect on headaches.47 A second study is good supporting data for some and relatively little clinical
evaluated lamotrigine for prevention of migraine with aura in data supporting the use of others among these agents. Never-
18 patients.48 Doses of 100 mg/day decreased the number of theless, having a wide variety of drug classes to choose from
attacks per month significantly. This study also treated five affords more opportunities to find a drug that will be effective
patients who had migraine without aura; they had no reduction and well-tolerated in a given patient. It is unfortunate that so
many migraine sufferers are not receiving adequate medical
management of their condition, because substantial relief is
Costs: Estimated Average Wholesale Prices available with prophylactic treatment. Many of the treatments
for a One-Month Supply are very affordable — some costing less per month than a
single dose of the migraine abortive agent sumatriptan. Pa-
DRUG DOSE RANGE AWP/MONTH tients who are frequent users of abortive medications should be
encouraged to ask their physicians about prophylactic treat-
Amitriptyline 10-150 mg/day $2.72-14.64 ment, and if they are not seeing a physician with expertise in
Propranolol 40-240 mg/day $3.90-44.55 this area, they should be encouraged to seek a referral to one.
Nortriptyline 10-150 mg/day $10.26-35.55
The potential gains for patients in reduction of migraine
frequency, pain severity and disability are tremendous.
References available on request. n
Metoprolol 100-200 mg/day $18.63-37.27
Atenolol 50-150 mg/day $21.60-64.80
Nadolol 20-60 mg/day $25.64-76.94
Valproic acid 500-1500 mg/day $49.04-147.15
Diltiazem 90-360 mg/day $35.27-64.20
www.your.ehealthcenter.com
Verapamil 240-360 mg/day $36.30-66.60
Divalproex sodium 500-1500 mg/day $49.04-147.15 independent pharmanex medical rep
Lamotrigine 100 mg/day $65.60 Nathalie Knowles-Beck
Methysergide 2-8 mg/day $69.59-278.35
414-961-9162
Fluoxetine 20-40 mg $81.30-162.60
male, female, family preventative health care
Gabapentin 900-2700 mg/day $104.40-313.20
Topiramate 200 mg/day $177.19
Nimodipine 120-360 mg/day $803.00-2411.00

24 Nov/Dec 2000 Journal of the Pharmacy Society of Wisconsin