The Medical Management of Migraine

Abstract

Migraine is a common, chronic neurologic disorder that affects 11% of the adult population in Western countries. In this article, we review the current approaches to the pharmacologic treatment of migraine. Once migraine is diagnosed, and illness severity has been assessed, clinicians and patients should work together to develop a treatment plan based on the patient needs and preferences. The goals of the treatment plan usually include reducing attack frequency, intensity, and duration; minimizing headache-related disability; improving health-related quality of life; and avoiding headache escalation and medication misuse. Medical treatments for migraine can be divided into preventive drugs, which are taken on a daily basis regardless of whether headache is present, and acute drugs taken to treat individual attacks as they arise. Acute treatments are further divided into nonspecific and migraine-specific treatments. The US Headache Consortium Guidelines recommend stratified care based on the level of disability to help physicians individualize treatment. Simple analgesics are appropriate as first-line acute treatments for less disabled patients; if simple analgesics are unsuccessful, treatment is escalated. For those with high disability levels, migraine-specific acute therapies, such as the triptans, are recommended as the initial treatment, with preventive drugs in selected patients. A variety of behavioral interventions are helpful. The clinicians have in their armamentariums an ever-expanding variety of medications. With experience, clinicians can match individual patient needs with the specific characteristics of a drug to optimize therapeutic benefit.

Full text

The Medical Management of Migraine
Marcelo E. Bigal,
1,3
* Richard B. Lipton,
1,2
and Abouch V. Krymchantowski
4,5
Migraine is a common, chronic neurologic disorder that affects 11% of the adult population in
Western countries. In this article, we review the current approaches to the pharmacologic treatment
of migraine. Once migraine is diagnosed, and illness severity has been assessed, clinicians and
patients should work together to develop a treatment plan based on the patient needs and prefer-
ences. The goals of the treatment plan usually include reducing attack frequency, intensity, and
duration; minimizing headache-related disability; improving health-related quality of life; and
avoiding headache escalation and medication misuse. Medical treatments for migraine can be
divided into preventive drugs, which are taken on a daily basis regardless of whether headache is
present, and acute drugs taken to treat individual attacks as they arise. Acute treatments are further
divided into nonspecific and migraine-specific treatments. The US Headache Consortium Guide-
lines recommend stratified care based on the level of disability to help physicians individualize
treatment. Simple analgesics are appropriate as first-line acute treatments for less disabled patients;
if simple analgesics are unsuccessful, treatment is escalated. For those with high disability levels,
migraine-specific acute therapies, such as the triptans, are recommended as the initial treatment,
with preventive drugs in selected patients. A variety of behavioral interventions are helpful. The
clinicians have in their armamentariums an ever-expanding variety of medications. With experi-
ence, clinicians can match individual patient needs with the specific characteristics of a drug to
optimize therapeutic benefit.
Keywords: migraine, treatment, medical management, preventive treatment, acute treatment
INTRODUCTION
Migraine is a chronic neurologic disorder character-
ized by episodic attacks of headache and associated
symptoms. In Western Countries, the condition affects
11% of the adult population.
1
Migraine is a heteroge-
neous condition that results in a range of symptom
profiles and various degrees of disability both within
and among different individuals.
2
The disability of
migraine can be severe and imposes a considerable
burden on the sufferer.
2–7
The past decade has pro-
duced a broad range of therapeutic advances. In this
article, we review the current understanding of the
treatment of migraine, beginning with a brief discus-
sion of clinical manifestations and diagnosis.
CLINICAL MANIFESTATIONS
AND DIAGNOSIS
Migraine is characterized by recurrent attacks of pain
and associated symptoms, typically lasting from 4 to
72 hours.
8
It has features in common with episodic
pain disorders, including the occurrence of self-
limited attacks of pain. It also has features in common
with chronic pain disorders in that sufferers have an
enduring predisposition to pain. It is therefore best
described as a chronic episodic disorder.
The migraine attack can be divided in four phases:
the premonitory phase (or prodrome), the aura, the
headache phase, and the resolution phase (the post-
drome). The presence or absence of aura distinguishes
the two major types of migraine, migraine with aura
and migraine without aura.
8
In migraine without aura,
1
Departments of Neurology,
2
Epidemiology and Social Medicine,
Albert Einstein College of Medicine, Bronx, New York;
3
The New
England Center for Headache, Stamford, Connecticut;
4
Depart-
ment of Neurology, Universidade Federal Fluminense, and
5
Insti-
tute of Neurology Deolindo Couto, Rio de Janeiro, Brazil.
*Address for correspondence: Department of Neurology, The Al-
bert Einstein College of Medicine, 1165 Morris Park Avenue,
Office 334A, Bronx, New York, 10461. E-mail: mbigal@aecom.
yu.edu
American Journal of Therapeutics 11, 130–140 (2004)
1075–2765 © 2004 Lippincott Williams & Wilkins

attacks usually last from 4 to 72 hours and are associ-
ated with variable combinations of associated symp-
toms such as nausea, vomiting, photophobia, and pho-
nophobia. Though a combination of features is re-
quired for the diagnosis,
8
not all features are present
in every attack or in every patient (Table 1). Since two
of four pain features are required, an attack with uni-
lateral throbbing pain or an attack with bilateral
severe pain aggravated by physical activity may
be migraine.
Migraine with aura is characterized by aura, a com-
plex of focal neurologic symptoms that most often pre-
cedes or accompanies the headache attack; auras may
occur in the absence of headache.
In addition to diagnosis, the US Headache Consor-
tium
9
recommends assessing the severity and disabil-
ity of migraine. The Migraine Disability Assessment
(MIDAS) (Table 2) questionnaire is a well validated,
five-item questionnaire that is easy to use in prac-
tice.
10–13
The questions evaluate activity limitations in
three domains: paid work, household work or chores,
as well as family, social, and leisure activities. Patients
record days of missed activity (ie, absence from work
due to headache), and days in which productivity was
reduced by at least at half. The MIDAS score is de-
rived as the sum of missed days of activity and days in
which productivity was reduced by at least half (sum
of responses to questions 1 through 5) over a 3-month
period. It is scored in units of lost days. Two addi-
tional questions on the MIDAS questionnaire, not in-
cluded in the score, assess frequency and intensity of
pain. The MIDAS questionnaire is used to assign pa-
tients to 1 of 4 grades as follows: grade I (scores rang-
ing from 0 to 5): little or no disability; grade II (scores
ranging from 6 to 10): mild disability; grade III (scores
ranging from 11 to 20): moderate disability; grade IV
(21 or greater): severe disability. As discussed below,
MIDAS grade predicts treatment needs.
PATHOPHYSIOLOGY
The pathophysiology of migraine has been reviewed
in detail elsewhere.
14
Briefly, migraine is best under-
stood as a primary disorder of the brain.
14
There is
abundant evidence that migraine is a familial disorder
with a clear genetic basis. For some uncommon forms
of migraine, such as familial hemiplegic migraine, spe-
cific pathogenic genes have been identified. The most
common mutation affects a gene on chromosome 19
that codes for a neuronal calcium channel.
14,15
This
observation suggests that other forms of migraine may
also be ion channelopathies.
14
During the migraine at-
tack, neural events result in the dilatation of menin-
geal blood vessels, which in turn results in pain, fur-
ther nerve activation, and inflammation.
15
Because
neural events are linked to vascular events, migraine
is considered a neurovascular headache disorder.
Table 1. International Headache Society revised criteria
for migraine
Diagnostic criteria
At least 5 attacks fulfilling the criteria listed below
Headache lasting 4 to 72 hours and occurring <15
days/month (untreated or unsuccessfully treated)
Headache has at least two of the following
characteristics:
Unilateral localization
Pulsating quality
Moderate or severe intensity (inhibits or prohibits
daily activities)
Aggravation by or causing avoidance of routine
physical activity (i.e., walking or climbing stairs)
During headache at least one of the following:
Nausea and/or vomiting
Photophobia and phonophobia
Not attributed to another disorder
Table 2. Migraine Disability Assessment
(MIDAS) questionnaire
MIDAS questionnaire Days
1. How many days in the last 3 months did
you miss work or school because of your
headaches?
2. How many days in the last 3 months was
your productivity at work or school reduced
by half or more because of headaches. (Do
not include days you counted in question 1
where you missed work or school.)
3. How many days in the last 3 months did
you NOT do housework because of your
headaches?
4. How many days in the last 3 months was
your productivity in household work
reduced by half or more because of your
headaches. (Do not include days you
counted in question 3 where you did not do
household work.)
5. How many days in the last 3 months did
you miss family, social, or leisure activities
because of your headaches?
MIDAS score: Add the total number of days
from questions 1–5.
A. How many days in the last 3 months did
you have headache? (If headache lasted
more than 1 day, count each day.)
B. On a scale of 0–10, on average how painful
were these headaches (0 = no pain and 10 =
pain as bad as it can be)?
Medical Management of Migraine 131
American Journal of Therapeutics (2004) 11(2)

Migraine probably results from dysfunction of
brainstem involved in the modulation of craniovascu-
lar afferents.
16
Brainstem activation may also lead to
activation of ascending and descending pathways,
with initiation of a perimeningeal vasodilatation and
neurogenic inflammation.
17–20
The pain is understood
as a combination of altered perception (due to periph-
eral or central sensitization) of stimuli that are usually
not painful,
21
as well as the activation of a feed-
forward neurovascular dilator mechanism in the first
(ophthalmic) division of the trigeminal nerve.
21
Corti-
cal spreading depression is the presumed substrate of
migraine aura; spreading depression also occurs in
migraine without aura.
THE TREATMENT OF MIGRAINE
Once a clinical diagnosis of migraine is made and dis-
ability and comorbidities have been assessed, the next
task is to develop an individualized treatment plan.
This plan usually has a number of goals that vary in
priority with the patient’s headache characteristics
and treatment preferences. The goals usually include
educating the patient about their illness and its man-
agement (eg, trigger avoidance and lifestyle changes);
reducing attack frequency, intensity, and duration;
minimizing disability, improving quality of life, and
avoiding headache escalation.
22
As with other chronic illnesses, several fundamental
management considerations are important for treat-
ment success in patients with migraine. Patients who
have suffering for years may be frustrated and may
not believe headache control is possible.
23
Pharmaco-
logic and nonpharmacologic (behavioral and some-
times physical) interventions may be necessary to pro-
duce a favorable outcome. Support programs and be-
havioral medicine techniques are an important part in
ensuring treatment plan success. The essential features
of an effective treatment regimen include the follow-
ing steps
24
:
1. Educate the patient: adequate instruction about
the biology of migraine and deleterious effects of
certain medications used in excessive quantities
and too frequent intervals
2. Establish expectations and a follow-up plan
3. Support the patient
4. Use nonpharmacologic therapies when necessary:
•Biofeedback and relaxation therapy
•Cognitive behavioral therapy
•Individual/family counseling as necessary
•Dietary instructions, chronobiologic therapy, and
sleep hygiene
•Daily exercise program
5. If medication overuse or rebound headaches are
present, potentially offending medications [in-
cluding both prescription and over-the-counter
(OTC) medications] and dietary caffeine should
be tapered
6. Institute a program of acute care and preventive
pharmacologic therapy
OVERVIEW OF DRUG THERAPY
Pharmacotherapy is usually divided into two catego-
ries: drugs that are taken whether or not headache is
present to reduce the frequency and severity of attacks
(preventive therapy) and drugs that are acutely taken
to treat attacks (acute treatment).
25,26
Acute treatment
is subdivided into nonspecific treatments, useful for a
range of pain disorders [ie, aspirin, acetaminophen,
nonsteroidal antiinflammatory drugs (NSAIDS), opi-
ates, and combination analgesics] and migraine-
specific treatments (ergotamine, dihydroergotamine,
and the triptans) The specific drugs are effective
for treating neurovascular headaches, such as mi-
graine and cluster headache, but not for treating other
types of pain, such as low back pain, painful neurop-
athy, etc.
27
While virtually every patient benefits from acute
treatment, preventive treatments are reserved for se-
lected migraine sufferers.
PREVENTIVE TREATMENT
The U.S. Headache Consortium Guidelines
9,28
suggest
that preventive treatment should be considered in the
following circumstances:
•Recurring migraine that significantly interferes
with the patient’s daily routine despite acute
treatment. (eg, two or more attacks a month that
produce disability that lasts ⱖ3 days or head-
ache attacks that are infrequent but produce pro-
found disability)
•Failure, contraindication to, or troublesome side
effects from acute medications
•Overuse of acute medications
•Special circumstances, such as hemiplegic mi-
graine or attacks with a risk of permanent neuro-
logic injury
•Very frequent headaches (more than two a week),
or a pattern of increasing attacks over time, with
the risk of developing rebound headache with
acute attack medicines
•Patient preference (ie, the desire to have as few
acute attacks as possible)
132 Bigal et al
American Journal of Therapeutics (2004) 11(2)

It is not clear how preventive therapy works, al-
though it seems likely that it modifies the sensitivity of
the brain that underlies migraine.
29
In addition, in a
patient with a concomitant illness that requires daily
treatment, one may be able to select a drug that treats
both migraine and the concomitant illness. For ex-
ample, a patient with migraine and epilepsy may ben-
efit if the epilepsy treatment is selected in part based
in its efficacy in migraine.
Many patients with migraine are reluctant to take a
preventive medication, particularly if they view mi-
graine as an episodic disorder and not as a chronic
episodic disorder. The decision to start preventive
therapy is best made collaboratively by clinician and
patient after considering the disability of the sufferer,
the frequency, duration, and severity of acute attacks,
as well as the preferences and priorities of the patient.
Some of the available options are listed in Table 3,
and the evidence regarding their use has been exten-
sively reviewed.
9,25,26,28,29
Once deciding to initiate
preventive pharmacotherapy, several general prin-
ciples of management may prove helpful
29
:
•Begin the preventive medications at a low dose
and gradually increase the dose over weeks or
months if necessary. For example, if no side ef-
fects emerge, if the desired clinical response has
not yet been achieved, and if the ceiling dose for
the drug had not been reached, the dose can
be escalated.
•Manage the patient’s expectations regarding the
time and extent of clinical benefit. Many preven-
tive medications take 3 to 4 weeks for a therapeu-
tic response at a particular dose; patients need to
be patient and compliant with the agreed-upon
treatment plan. Two thirds of the patients given
any of the drugs listed in Table 3 will have a 50%
reduction in the frequency of headaches. Break-
through headaches are inevitable and must be
managed with acute treatment. It is important to
explain the side effects of these drugs and engage
the patient in the decision-making process.
•Establish a comprehensive migraine management
plan that includes long-term goals, tips on when
the medication needs to be changed, a regular of-
fice visit schedule, and specific information on ad-
verse reactions that may warrant discontinuing
the medication, returning to the clinic, calling the
office, or even going to the hospital on an emer-
gency basis.
Evidence regarding the preventive drugs is most
common to the beta blockers, antidepressants, calcium
Table 3. Selected preventive therapies for migraine
Generic treatment Doses
Alpha
2
-agonists
Clonidine tablets 0.05–0.3 mg/day
Guanfacine tablets 1 mg
Anticonvulsants
Divalproex sodium tablets
1
500–1500 mg/day
Gabapentin tablets
1
300–3000 mg
Levetiracetam tablets 1500–4500 mg
Topiramate tablets
1
50–400 mg
Zonisamide capsules 100–400 mg
Antidepressants
MAOIs
Phenelzine tablets 30–90 mg/day
TCA
Amitriptyline tablets
1
30–150 mg
Nortriptyline tablets 30–100 mg
SSRIs Fluoxetine tablets 10–40 mg
Sertraline tablets 25–100 mg
Paroxetine tablets 10–30 mg
Venlafaxine tablets 37.5–225 mg
Mirtazapine tablets 15–45 mg
Beta-blockers
Atenolol tablets
1
25–100 mg
Metoprolol tablets 50–200 mg
Nadolol tablets 20–200 mg
Propranolol tablets
1
30–240 mg
Timolol tablets
1
10–30 mg
Calcium channel antagonists
Verapamil tablets
1
120–720 mg
Nimodipine tablets 40 mg tid
Diltiazem tablets 30–60 mg tid
Nisoldipine tablets 10–40 mg qd
Amlodipine tablets 2.5–10 mg qd
NSAIDs for prevention
Naproxen sodium tablets
1
500–1100 mg/day
Ketoprofen tablets tablets 150 mg/day
Mefanamic acid tablets 1500 mg/day
Flurbiprofen tablets 200 mg/day
Serotonergic agents
Methysergide tablets
1
2–12 mg
Cyproheptadine tablets 2–16 mg
Pizotifen tablets
1
1.5–3mg
Miscellaneous
Montelukast sodium tablets 5–20 mg
Lisinopril tablets 10–40 mg
Botulinum toxin A injection 25–100 units (IM)
Feverfew tablets 50–82 mg/day
Magnesium gluconate tablets 400–600 mg/day
Riboflavin tablets 400 mg/day
Petasites
1
75 mg bid
1
Evidence for moderate efficacy from at least two well designed,
placebo-controlled trials.
Medical Management of Migraine 133
American Journal of Therapeutics (2004) 11(2)

channel antagonists, and antiepileptic agents. We will
briefly discuss these classes of drugs below.
Beta Blockers
The Agency for Health Care Policy and Research
(AHCPR) technical report analyzed 74 controlled tri-
als of beta blockers for migraine prevention.
30
Pro-
pranolol. nadolol, atenolol, metoprolol, and timolol
have been shown to be effective. The beta blockers that
are partial agonists and have intrinsic sympathomi-
metic activity have not been found to be effective for
the prevention of migraine. As the relative efficacy of
the different beta blockers has not been clearly estab-
lished, decisions should be made based on beta selec-
tivity, convenience of drug formulation, side effects,
and the patient’s individual reaction.
29,30
Since beta
blockers can produce behavioral side effects such as
drowsiness, fatigue, lethargy, sleep disorders, night-
mares, depression, memory disturbance, and halluci-
nations, they are best avoided in patients with depres-
sion. Decreased exercise tolerance limits their use
by athletes. Less common side effects include impo-
tence, orthostatic hypotension, significant bradycar-
dia, and aggravation of intrinsic muscle disease.
Beta blockers are especially useful for patients with
comorbid angina or hypertension. They are relatively
contraindicated for patients with congestive heart
failure, asthma, Raynaud disease, and insulin-
dependent diabetes.
Antidepressants
The currently available antidepressants consist of a
number of different classes of drugs with different
mechanisms of action. The tricyclic antidepressants
(TCAs) most commonly used for migraine prophy-
laxis include amitriptyline, nortriptyline, doxepin, and
protriptyline. Amitriptyline is the only antidepressant
with fairly consistent support for its efficacy in mi-
graine prevention. Other agents have not been rigor-
ously evaluated; their use is based largely on clinical
experience and uncontrolled reports.
30
Many head-
ache experts use nortriptyline in preference to amitrip-
tyline because of its more favorable side effect profile.
TCAs are better used for patients who have sleep dis-
turbance or comorbid depression. Selective serotonin
reuptake inhibitors such as fluoxetine, paroxetine, and
sertraline can be used to treat coexistent depression
based on their favorable side effect profiles; their effi-
cacy as migraine preventives has not been established.
Side effects from TCAs are common. Most involve an-
timuscarinic effects, such as dry mouth and sedation.
The drugs also cause increased appetite and weight
gain; cardiac toxicity and orthostatic hypotension oc-
cur occasionally.
Calcium-channel blockers
The AHCPR Technical Report identified 45 controlled
trials of calcium antagonists.
30
A metaanalysis sup-
ports the clinical benefits of flunarizine (not available
in the US). Nimodipine had mixed results in placebo-
controlled trials. The evidence for nifedipine was dif-
ficult to interpret. Verapamil was more effective than
placebo in two of three trials, but both positive trials
had high dropout rates. Of the calcium channel block-
ers available in the US, verapamil is the most widely
used.
29
Verapamil is especially useful for patients with
comorbid hypertension or with contraindications,
such as asthma and Raynaud disease, to beta blockers.
Calcium channel blockers are also useful for patients
who have migraine with prolonged aura. Constipation
is verapamil’s most common side effect.
Antiepileptic drugs
Antiepileptic drugs (AEDs) are increasingly recom-
mended for migraine prevention because of placebo-
controlled, double-blind trials that prove them effec-
tive. Valproate or divalproex, topiramate, and gabap-
entin have demonstrated efficacy.
31
Many patients find divalproex sodium to be effec-
tive at a low dose (500–1000 mg/d). Side effects in-
clude sedation, hair loss, tremor, and changes in cog-
nitive performance. Nausea, vomiting, and indiges-
tion can occur, but these are self-limited side effects.
Hepatotoxicity is the most serious side effect, but ir-
reversible hepatic dysfunction is extremely rare in
adults. Pancreatitis has also been reported. Baseline
liver function studies should be obtained, but routine
follow-up studies are probably not routinely needed
in adults on monotherapy. Follow-up is necessary to
adjust the dose and monitor side effects. Silberstein
32
published practical recommendations and clinical
guidelines for using valproate for headache prophylaxis.
Gabapentin (1800–2400 mg) was found to be supe-
rior to placebo in reducing the frequency of migraine
attacks in a controlled, double-blind trial, supporting
the results of previous open trials. The responder rate
was 36% for gabapentin and 14% for placebo.
33
The
most common adverse events were dizziness and
drowsiness. Relatively high patient withdrawal rates
due to adverse events were reported in some trials.
Topiramate is a structurally unique anticonvulsant
with rapid and almost complete oral absorption. Topi-
ramate has been associated with weight loss, not
weight gain (a common reason to discontinue preven-
tive medication) with chronic use. Topiramate should
134 Bigal et al
American Journal of Therapeutics (2004) 11(2)

be started at a dose of 15 to 25 mg/d at bedtime and
increased weekly to 100 to 200 mg/d in divided doses.
Adverse events include weight loss, paresthesias, and
cognitive dysfunction (which is often prevented by
slow gradual dose escalation). Topiramate should be
used with caution in patients who have a history of
renal calculi. A recent double-blind, controlled study
showed that topiramate is superior than placebo in the
preventive treatment of migraine, supporting several
previous open label trials.
34
AEDs are especially useful when migraine occurs in
patients with comorbid epilepsy, anxiety disorder, or
manic-depressive illness. They can be safely adminis-
tered to patients with depression, Raynaud disease,
asthma, and diabetes, circumventing the contraindica-
tions to beta blockers. With the exception of valproic
acid and phenobarbital, many AEDs interfere with the
efficacy of oral contraceptives. Caution is therefore ad-
vised in women on AEDs and oral contraceptives.
SETTING PREVENTIVE
TREATMENT PRIORITIES
The choice of a preventive drug is made based on its
proven efficacy, the patient’s preferences and head-
ache profile, the drug’s side effects, and the presence
or absence of coexisting or comorbid disease (Table 4).
The clinician should select the drug with the best risk-
to-benefit ratio for the individual patient and mini-
mize the side effects that are most important to
the patient.
TREATMENT OF ACUTE ATTACKS
Virtually every patient benefits from acute treatment,
which can be subdivided into nonspecific treatments
(ie, aspirin, acetaminophen, NSAIDS, opiates, and
combination analgesics) and migraine-specific treat-
ments (ergotamine, dihydroergotamine, and the trip-
tans) (Table 5).
Analgesic and nonsteroidal antiinflammatory drugs
Many NSAIDs are more effective than placebo for the
acute treatment of migraine. Studies show that diclof-
enac (50–100 mg), flubiprofen (100–300 mg), ibuprofen
(200–800 mg) naproxen sodium (550 –1100 mg),
piroxicam (40 mg), and tolfenamic acid (200–400 mg)
are effective in the acute treatment migraine. Ibupro-
fen is approved for migraine as an OTC agent.
35
The
administration of antiemetic drugs or drugs that in-
crease gastric motility is likely to facilitate the absorption
Table 4. Choices of preventive treatment in migraine
Drug Efficacy
Adverse
events
Comorbid condition
Relative contraindication Relative indication
Beta blockers 4+ 2+ Asthma, depression, congestive heart
failure, Raynaud disease, diabetes
Hypertension, angina
Antiserotonin
Pizotifen 4+ 2+ Obesity
Methysergide 4+ 2+ Angina, vascular disease Orthostatic hypotension
Ca channel blockers
Verapamil 2+ 1+ Constipation, hypotension Aura, hypertension,
angina, asthma
Flunarizine 4+ 2+ Parkinson’s, depression Dizziness, vertigo
Antidepressants
TCAs 4+ 2+ Mania, Urinal retention, heart block Depression, anxiety,
insomnia, pain
SSRIs 2+ 1+ Mania Depression, OCD
MAOIs 4+ 4+ Unreliable patient Refractory depression
Anticonvulsants
Divalproex/Valproate 4+ 2+ Liver disease, bleeding disorders Mania, epilepsy, anxiety
Gabapentin 2+ 2+ Liver disease, bleeding disorders Mania, epilepsy, anxiety
Topiramate 4+ 2+ Kidney stones Mania, epilepsy, anxiety
NSAIDs 2+ 2+ Ulcer disease, gastritis Arthritis, other pain disorders
Ratings are on a scale from 1+ (lowest) to 4+ (highest) based on strength of evidence.
Data from Silberstein SD, et al.
30
Medical Management of Migraine 135
American Journal of Therapeutics (2004) 11(2)

of the primary drug and thus help to ameliorate the
attack.
36
Overuse of these drugs should be avoided,
and the intake should be restricted to no more than 2
or at most 3 days a week.
The same principles apply to combination analge-
sics. They seem to be most helpful in treating episodic
tension-type headaches and migraines in patients
who do not usually require bed rest with their head-
aches. The combination of aspirin, acetaminophen,
and caffeine has been approved as an OTC mi-
graine treatment.
37
As a rule, we avoid the use of butalbital or opiate
compounds. These drugs cause sedation and cognitive
side effects; they carry a risk of medication overuse
and rebound headache.
Ergotamine and dihydroergotamine
The ergot alkaloids were the first available migraine-
specific therapy. The main advantages of the ergota-
mine and dihydroergotamine ergot derivatives are
their low cost and the long experience with their use.
38
They also have a number of disadvantages. Ergota-
mine has a complex pharmacology, interacting with
many receptors. It has erratic oral absorption and vari-
able pharmacokinetics. It also has potent and sus-
tained generalized vasoconstrictor effects and is
Table 5. Selected acute therapies for migraine
Generic treatment Doses
Analgesics (monotherapy)
Aspirin tablets 325–650 mg
Acetaminophen tablets 325–1000 mg
Combination Analgesics
Aspirin plus acetaminophen plus caffeine tablets 250 mg plus 250 mg plus 65 mg
Isometheptene mucate plus acetaminophen plus
dichloralphenazone tablets
65 mg plus 325 mg plus 100 mg
Butalbital plus aspirin plus caffeine tablets 50 mg plus 325 mg plus 40 mg
Butalbital plus acetaminophen plus caffeine tablets 50 mg plus 325 mg plus 40 mg
Ergotamine Alkaloids
Erogotamine tartrate plus caffeine tablet 1 mg plus 100 mg
Ergotamine tartrate plus caffeine suppository 2 mg plus 100 mg
DHE nasal spray 0.5 mg/nostril (repeat in 15 min 1 ×for 2 mg total dose)
DHE IM or SC 1 mg
NSAIDs
Diclofenac K tablets 50–100 mg
Flurbiprophen tablets 100–300 mg
Ibuprophen tablets 200–1200 mg
Naproxen tablets 250–500 mg
Naproxen sodium tablets 550–1100 mg
Piroxicam tablets 40 mg
Tolfenamic acid tablets 200–400 mg
Diclofenac sodium IM 50 mg
Opiate Analgesics
Butorphanol nasal spray 1–2mg
Triptans
Almotriptan tablets 12.5 mg tablets
Naratriptan tablets 1 mg or 2.5 mg
Rizatriptan tablets 5 mg or 10 mg
Rizatriptan orally disintegrating tablets 5 mg or 10 mg
Sumatriptan tablets 25 mg, 50 mg or 100 mg
Sumatriptan nasal spray 5 mg or 20 mg
Sumatriptan sc self injection 6 mg
Zolmitriptan tablets 2.5 mg or 5 mg
Zolmitriptan orally disintegrating tablets 2.5 mg or 5 mg
Eletriptan tablets 40 mg
Frovatriptan tablets 2.5 mg
DHE, dihydroergotamine.
136 Bigal et al
American Journal of Therapeutics (2004) 11(2)

proven to cause medication overuse as well as re-
bound headaches.
38
Ergotamine is still widely used in some countries
for the treatment of severe migraine attacks. It is
generally regarded as a safe and useful drug when
prescribed in the correct dose.
39
In randomized clini-
cal trials, oral ergotamine was found superior to pla-
cebo but inferior to oral triptans. In contrast, rectal
ergotamine was found to have higher efficacy (73%
headache relief) than rectal sumatriptan (63% head-
ache relief). Dihydroergotamine is a less potent vaso-
constrictor then ergotamine and in useful in intrana-
sal, intramuscular, and intravenous treatment.
40–42
Combined with metoclopramide, it is widely used for
status migrainous and intractable chronic migraine.
The triptans
The migraine-specific triptans have revolutionized the
treatment of migraine. For patients who experience
temporary disability with their migraine, they are usu-
ally the drugs of choice to treat a migraine attack in
progress (Table 6). They have several advantages
when compared with the ergot derivatives, especially
regarding their selective pharmacology, simple and
consistent pharmacokinetics, evidence-based dose rec-
ommendations, and established efficacy based on
large, well designed, controlled trials. They are more
expensive then ergotamine compounds and, like ergot
derivatives, they are contraindicated in the presence of
cardiovascular disease.
Safety needs to be distinguished from tolerability.
Tolerability involves adverse events that cause short-
term but not long-term harm, such as nausea or diz-
ziness. Safety refers to medically significant adverse
events, such as myocardial infarction, stroke, or he-
patic toxicity.
The triptans as a class are both safe and well toler-
ated in appropriately selected patients. Less than half
of treated patients report adverse events. For the most
part, adverse events are mild and transient. Most of
the triptans show a modest increase in the incidence of
adverse events at higher doses.
43
The triptans as a class produce modest coronary
artery vasoconstriction.
44,45
Extensive use of triptans
over the past decade has provided substantial reassur-
ance that this physiologic effect carries minimal clini-
cal risk in appropriately selected patients. This is con-
sistent with pharmacologic data indicating that
5-HT
1B
receptors mediate less than 25% of the overall
vasoconstrictive potential of the coronary arteries.
45
Parenteral challenge with sumatriptan has been re-
ported to result in approximately 14% coronary vaso-
constriction.
44
It should be noted that the differential
vasoconstrictive selectivity of triptans is partly due to
the significantly higher density of 5-HT
1B
receptors in
the meningeal arteries compared with the coronary
arteries.
44–46
In patients with healthy coronary arter-
ies, this degree of vasoconstriction is hemodynami-
cally insignificant. All of the triptans are, however,
contraindicated in the presence of significant coronary
vascular disease.
47–48
In contrast with their similar safety profiles, the trip-
tans differ in tolerability. Overall, naratriptan, almo-
triptan, and frovatriptan appear to have the most fa-
vorable adverse event profiles.
44
It should be empha-
sized, though, that tolerability problems as a reason
for medication discontinuation are relatively low for
all triptans. Nonetheless, for a patient in whom avoid-
ing side effects is a priority, these agents may be bet-
ter choices.
A recent metaanalysis using data of 24,089 patients
in 53 controlled clinical trials of triptans compared the
oral triptans with 100 mg sumatriptan, and some re-
sults are summarized below.
46
The most important
conclusion of the metaanalysis is that all the triptans
are more effective than placebo in relieving the pain
TABLE 6. The triptans formulations
Generic Formulations Doses (mg) Maximum daily dose (mg)
Sumatriptan Oral tablet 25, 50, 100 200
Nasal spray 5, 20 40
Subcutaneous injection 6 12
Zolmitriptan Oral tablet 2.5, 5 10
Orally disintegrating tablet 2.5, 5 10
Rizatriptan Oral tablet 5, 10 30
Orally disintegrating tablet 5, 10 30
Naratriptan Tablet 1, 2.5 5
Almotriptan Tablet 12.5 25
Frovatriptan Tablet 2.5 7.5
Eletriptan Tablet 40 80
Medical Management of Migraine 137
American Journal of Therapeutics (2004) 11(2)

and associated symptoms of migraine. In the triptan
clinical trials, patients who had moderate or severe
pain were treated. The typical primary end point,
termed “2-hours headache response,”is defined as the
reduction in pain from moderate or severe at baseline
to mild or absent by 2 hours. 10 mg rizatriptan and 80
mg eletriptan were significantly more effective than
100 mg sumatriptan on this end point. Sumatriptan
was superior to 2.5 mg naratriptan, 20 mg eletriptan,
and 2.5 mg frovatriptan. The only triptans that pre-
sented lower rates of adverse events compared with
100 mg sumatriptan were 2.5 mg naratriptan and 12.5
mg almotriptan.
46
Route of administration may play an important role
in the onset of action and in the preference patterns of
triptans. Subcutaneous delivery of sumatriptan offers
the most rapid and complete pain relief of the triptans
beginning as early as 10 to 15 minutes, yet it also is
associated with a higher incidence of adverse events.
48
The second most rapid onset of action of the triptans
may be achieved through nasal spray deliveries.
48
Su-
matriptan nasal spray is not as effective as the subcu-
taneous delivery formulation. Zolmitriptan nasal
spray shows promise due to its rapid onset of action
and high response rates. All of the triptans are avail-
able as conventional tablets, and two (rizatriptan and
zolmitriptan) are also available in orally disintegrating
tablets. Orally disintegrating tablets are more conve-
nient to use and can be taken when the patient is
nauseated; their gastrointestinal absorption means
that they will not be absorbed if vomiting occurs soon
after ingestion, but they can be swallowed without
water.
48
SELECTING INITIAL TREATMENT
OF ACUTE ATTACKS
The US Headache Consortium Guidelines recommend
stratified care based on the level of disability to help
physicians target patients who require careful assess-
ment and treatment,
9
a concept also supported by the
DISC study.
49
There is therefore substantial clinical
evidence for using disability to guide the assessment
and treatment strategy.
Figure 1 provides a schematic view of how the MI-
DAS questionnaire might be used to provide appro-
priate treatment based on the patient’s level of head-
ache-related disability. All patients require a specific
diagnosis and education about their disorder and self-
management strategies. At the time of consultation
and diagnosis, the migraine patient completes a MI-
DAS questionnaire and is categorized into a MIDAS
grade (I–IV). A MIDAS score of 0–5 (MIDAS grade I)
or 6–10 (MIDAS grade II) indicates relatively low
medical need. Simple analgesics are appropriate for
first-line acute treatments for these patients. If simple
analgesics are unsuccessful, various combination
treatments (eg, aspirin plus metoclopramide) may be
needed. If these treatments fail, further escalation may
be necessary. A MIDAS score of 11 or higher (MIDAS
grade III/IV) indicates relatively high medical need.
Specific acute therapies, such as the triptans, may be
needed by these patients, together with prophylaxis,
when necessary. In patients with contraindications to
triptans, we prefer nonsteroidal antiinflammatory
agents alone or in combinations with a prokinetic such
as metoclopramide.
FIGURE 1. Potential utility of the
MIDAS questionnaire in relating
migraine severity to treatment
choice.
138 Bigal et al
American Journal of Therapeutics (2004) 11(2)

When patients report that treatment is not working,
it is important to understand the nature of the treat-
ment failure. The major categories include lack of ef-
ficacy (pain relief is slow, incomplete, or both), head-
ache recurrence (the pain is relieved but comes back
relatively quickly), or poor tolerability. For lack of ef-
ficacy, it may be useful to treat earlier in the attack,
while pain is still mild. Both post hoc analysis and
specifically designed clinical trials show that acute mi-
graine drugs work best when given early. Increasing
the dose can be useful, especially if there is a partial
response. Switching to a non-oral form (nasal spray or
injection) may help, especially if headaches are of
rapid onset, present on awakening, or associated with
prominent nausea or vomiting Anecdotally, switching
triptans or adding an NSAID or metoclopramide to
the triptan may help.
If recurrence is the problem, increasing the dose or
switching to a triptan with a favorable recurrence rate
is helpful. Examples of triptans with favorable recur-
rence rates include naratriptan, frovatriptan, and
eletriptan. Adding adjunctive medication to the trip-
tan may be helpful.
For problems with tolerability, naratriptan has ad-
vantages. In controlled clinical trials, it produces ad-
verse events at a rate similar to placebo.
For many patients, if one triptan fails, other may
well succeed. So, it is important to identify the nature
and reason for failure and manage as appropriate.
48
CONCLUSION
The selection of an antimigraine (acute or preventive)
drug for a patient depends upon the stratification of
the patient’s migraine attack by peak intensity, time to
peak intensity, level of associated symptoms such as
nausea and vomiting, time to associated symptoms,
comorbid diseases, and concomitant treatments that
might cause drug interactions. The clinicians have in
their armamentariums an ever-expanding variety of
medications, available in multiple formulations and
dosages, with good safety and tolerability profiles.
Continued clinical use will yield familiarity with the
various drugs, and it may become possible to match
individual patient needs with the specific characteris-
tics of a drug, optimizing the therapeutic benefits.
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