. . . REPORTS . . .
Migraine: Diagnosis, Management,
and New Treatment Options
R. Michael Gallagher, DO; and F. Michael Cutrer, MD
Abstract
Objective: The safety and tolerability of med-
ications used to treat acute migraine attacks are
summarized, the classification of headaches and
the causes of and diagnostic criteria for migraine
are reviewed, and the clinical tolerability profiles
and therapeutic benefits of second-generation trip-
tans are presented.
Background: Migraine is a paroxysmal disor-
der characterized by attacks of headache, nau-
sea, vomiting, photophobia, and phonophobia.
Drugs used to prevent migraine and those that
effectively treat acute migraine attacks are readily
available.
Methods: Mild or moderate migraines are often
treated with aspirin, acetaminophen, nonsteroidal
anti-inflammatory drugs, antiemetic drugs, or
isometheptene. Triptans (5-HT1 receptor agonists) are
used to treat moderate or severe migraine and when
nonspecific medications have been ineffective.
Because sumatriptan, the first triptan used, is effective
but can induce adverse events, second-generation
triptans (zolmitriptan, naratriptan, rizatriptan, and
almotriptan) were developed to increase the bene-
fit-to-risk ratio in migraine management.
Results: Important pharmacologic, pharmaco-
kinetic, and clinical differences exist among those
drugs, but the tolerability profile of the newer trip-
tans is very good, and they provide rapid relief
from headache and sustained duration of effect.
Conclusion: Primary care physicians must man-
age migraine patients with treatments that demon-
strate a balance between efficacy and tolerability.
(Am J Manag Care 2002;8:S58–S73)
igraine is a primary headache dis-
M order characterized by recurring
attacks of throbbing (often unilat-
eral) headache, photophobia, phonopho-
bia, nausea, and other symptoms. The
S58 THE AMERICAN JOURNAL OF MANAGED CARE
headache may be preceded by transient
focal neurologic symptoms known as aura.
Migraine is the most common primary
headache disorder for which patients
present to primary care physicians, yet
it remains underdiagnosed and under-
treated.1,2 Migraine sufferers are often the
most dissatisfied patients; less than 30% of
sufferers report that they are very satisfied
with their usual migraine treatment.3,4
Almost two thirds of migraine sufferers
experience unwanted side effects from
antimigraine treatment. Those patients
often delay taking medication, which
results in prolonged pain and disability.5
The prevalence of a family history of
migraine suggests that the disorder may
have a genetic component.6 An estimated
6% of men and 15% to 17% of women in the
United States experience migraine, but
only 3% to 5% of that population receive
preventive therapy.7 The prevalence of
migraine increased 60% (from 25.8 to 41
per 1000 population) from 1981 to 1989.8
In addition, 2 studies conducted many
years apart indicated that the incidence
of migraine in school children has
increased.9 Those data suggest that the
prevalence of migraine is increasing with
time; however, this increase could be the
result of increased awareness of the disor-
der among physicians and patients.
Pathophysiology of Migraine
The characteristics of migraine vary in
frequency, duration, and the extent of dis-
ability produced among sufferers and
between attacks. Some migraine patients
experience fewer than 1 attack per month,
and others suffer from 1 or more attacks
FEBRUARY 2002

per week.10 Some migraine patients are
disabled by their headaches; others are
not. Therefore, the care provided to those
who suffer from migraine must be strati-
fied by the frequency and severity of the
headache and by the resultant level of
disability.11
Abnormalities in blood vessels may be
important in the pathogenesis of migraine
and the excessive muscle contraction of
tension-type headaches, but current
research suggests that headaches are pro-
duced by abnormalities in the central nerv-
ous system (CNS) regulation of blood
vessels within pain-producing intracranial
meningeal structures.12,13 Evidence has
shown that changes in the level of serotonin
precede the changes in blood vessels and
muscle tone that occur during chronic
headaches.12 The influence of serotonin on
headache may also explain the effectiveness
of medications used to treat migraine.
The nature of the CNS dysfunction
produced in migraine patients is still
unclear and may involve spreading
depression-like phenomena and the acti-
vation of brain stem monoaminergic
nuclei that are part of the central auto-
nomic, vascular, and pain-control centers.
A proposed mechanism for the generation
of migraine is that of local vasodilation of
intracranial and extracerebral blood ves-
sels and a consequent stimulation of sur-
rounding trigeminal sensory nervous pain
pathways.13 This activation of the trigemi-
novascular system is thought to cause the
release of vasoactive sensory neuropep-
tides (substance P, calcitonin–gene-related
peptide, neurokinin A, and others) that
increase the pain response.13 The activated
trigeminal nerves convey nociceptive infor-
mation to central neurons in the brain stem
trigeminal sensory nuclei, which in turn
relay the pain signals to higher centers that
may become sensitized as a migraine
attack progresses.13
Diagnosis of Migraine
International Headache Society
Classification. The International Headache
Society (IHS) has developed the first clas-
sification system for migraine and other
types of headaches (Tables 1 and 2).14,15
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
Table 1. The International Headache
Society Classification of Migraine
■ Migraine without aura
■ Migraine with aura
Migraine with typical aura
Migraine with prolonged aura
Familial hemiplegic migraine
Basilar migraine
Migraine aura without headache
Migraine with acute onset aura
■ Ophthalmoplegic migraine
■ Retinal migraine
Childhood periodic syndromes that may be
precursors to or associated with migraine
Benign paroxysmal vertigo of childhood
Alternating hemiplegia of childhood
■ Complications of migraine
Status migrainous
Migrainous infarction
■ Migrainous disorder not fulfilling above criteria
Source: Headache Classification Committee of the
International Headache Society. Classification and
diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988;8
(suppl 7):1-96. Adapted with permission.
The IHS user-friendly classification con-
sists of 2 major categories: primary and
secondary headaches. Primary headaches
(headache disorders in which an identifi-
able pathologic factor is not present) con-
sist of migraine (with or without aura),
tension-type headaches (episodic or chron-
ic), cluster headaches, posttraumatic head-
aches, and rebound headaches caused by
drug use or withdrawal. Secondary head-
aches are symptoms of organic diseases
such as meningitis or cerebral tumors.
The IHS classification system provides
valuable information about the diagnosis
and treatment of headaches, but primary
care physicians and neurologists are ulti-
mately responsible for accurate diagnosis
and effective treatment. Migraine pro-
drome (phase 1 or preheadache period),
which may occur hours to days before the
onset of headache, consists of nonfocal
constitutional symptoms and can vary
widely among patients. Some feel euphor-
ic, and others may experience irritability
or extraordinary fatigue. Migraine post-
S59
REPORTS
Table 2. Diagnostic Criteria for Migraine Without Aura
A. At least 5 attacks fulfilling the criteria of B to D below
B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully
treated)
C. Headache with at least 2 of the following characteristics:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe intensity (inhibits or prohibits daily activities).
4. Intensified when patient walks up or down stairs or performs
a similar activity
D. During headache, at least 1 of the following must occur:
1. Nausea and/or vomiting
2. Photophobia or phonophobia
E. At least 1 of the following must apply:
1. History, physical, and neurologic examinations do not suggest
another disorder*
2. History and/or physical and/or neurologic examinations do suggest
such a disorder, but it is ruled out by appropriate investigations
3. Such a disorder is present, but migraine attacks do not occur for
the first time in close temporal relation to the disorder
*Other disorders that may cause headache include head trauma; vascular
and neurovascular disorders; substance use or withdrawal; noncephalic
infection; metabolic disorder; and disorders of the cranium, neck, eyes,
ears, nose, sinuses, teeth, mouth, or other facial or cranial structures.
Source: Headache Classification Committee of the International Headache
Society. Classification and diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988;8(suppl 7):1-96. Adapted with
permission.
drome appears as the pain wanes, after
which the patient feels tired and listless.
The clinical diagnosis of migraine with-
out aura requires that the patient experi-
ence at least 5 headaches with a duration of
4 to 72 hours. During migraine without
aura, unilateral pain of moderate-to-severe
intensity seems to pulsate, and patients
must experience at least 1 of the following
symptoms: nausea, vomiting, photophobia,
or phonophobia.14 Such headaches are
often exacerbated by routine physical activ-
ity. However, during a migraine, approxi-
mately 30% of migraine patients experience
an aura (usually visual) that precedes the
headache by 5 to 30 minutes, may reflect a
wide range of neural deficits, and fades with-
in 30 minutes. It may first be noticed near
the visual center as a small spot surround-
ed by bright, jagged lines. An aura that per-
sists for more than 1 hour may signal an
ischemic attack and should be evaluated.14
S60 THE AMERICAN JOURNAL OF MANAGED CARE
Medical History. Obtaining an accu-
rate medical history is the first step in an
evaluation for migraine. Information
obtained should include the patient’s age at
first migraine; the site or sites of pain; the
frequency, intensity, and duration of pain;
the presence of any associated symptom
(eg, aura, dizziness); aggravating, precipi-
tating, or ameliorating factors; prior med-
ication use; caffeine intake; prior head
trauma; results of neuroimaging studies;
and family history.16 The physician should
encourage the patient to keep a headache
“diary” in which the characteristics of each
headache and the response to treatment
are recorded. That type of diary is also valu-
able in helping the patient and physician
identify factors such as lifestyle, diet, men-
strual cycle, and the overuse of medication
or caffeine, all of which may precipitate
migraine.16
Physical Examination. After the
patient’s medical history has been obtained,
a physical examination should be performed
to evaluate (at the very least) blood pressure,
heart rate, extracranial structures (eg,
sinuses, scalp arteries, temporomandibular
joints), and the range of motion and pres-
ence of pain in the cervical spine.17 Addi-
tional laboratory tests and neuroimaging
studies should not be necessary unless the
physician observes the following danger sig-
nals: the sudden onset of a new type of
severe headache; headache onset during
exertion; first headache in a middle-aged
patient; headache accompanied by loss of
consciousness or systemic illness (fever, stiff
neck, rash); headache associated with
meningeal signs; an accelerating pattern of
headache; new onset of headache in
immunocompromised patients or those
with cancer; headache accompanied by
signs of disease or focal neurologic symp-
toms atypical for aura; and papilledema
(swelling of the optic disk).16 In those cases,
referral for diagnostic imaging or neurologic
testing is appropriate to rule out concomi-
tant illness that may cause headache.
Treatment
Two types of treatment are available for
headaches: abortive (treatment of the
FEBRUARY 2002

acute attack) and prophylactic (preven-
tion of headache by using medication
and/or nonpharmacologic measures to
lessen precipitating factors, such as stress
or lifestyle).
Nonpharmacologic Measures of
Preventing Migraine. The suggestions
below are recommended by a primary
care physician for the nonpharmacologic
management of migraine.18
• Maintain regular sleeping, eating, and
exercise habits.
• Avoid excessive stress-producing
activities.
• Practice relaxation techniques.
• Avoid potential triggers such as trauma,
caffeine, and certain foods (eg, choco-
late, aged cheeses, red wine, foods con-
taining sodium nitrate).
• Address possible underlying depression
or anxiety.
Pharmacologic Treatment. Early inter-
vention with appropriate medication can
completely abort a migraine so that the
patient can function normally and a
recurrence is prevented.19 Simple anal-
gesics and nonsteroidal anti-inflammato-
ry drugs (NSAIDs) may be used to treat
mild-to-moderate headache or migraine
that does not increase in intensity.
Triptans (5-HT1 receptor agonists) are the
preferred therapy for moderate-to-severe
headaches. In Table 3, therapies recom-
mended by primary care physicians for
patients with specific headache patterns
are presented.20,21
During prodrome, many interventions
can be effective. Over-the-counter (OTC)
or nonprescription products such as
NSAIDs, serotonin receptor agonists, aspirin,
acetaminophen, or a combination of aspirin
and acetaminophen may prevent the
headache.19 If prodromal warning signs do
not occur or intervention fails to abort the
migraine in its early stage, migraine-spe-
cific medications such as triptans are
indicated. Headache characterized by pho-
tophobia, phonophobia, and/or nausea and
vomiting suggests that the neurovascular
inflammatory process has begun, and trip-
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
tan drugs are highly effective when admin-
istered early in this phase of migraine.
When migraine evolves into an advanced
stage (late headache) and first- and second-
line treatments have failed, rescue therapy
must be considered. Intravenously admin-
istered phenothiazines are often effective
and can be combined with dihydroergota-
mine (DHE) or other serotonin agonists.
Opioid analgesics are also used to treat late
headache.
Selecting Pharmacologic Agents
Simple Analgesics and NSAIDs. Simple
analgesics, which may be used to treat
mild-to-moderate acute migraine, are most
effective as first-line treatments when
used before the pain becomes severe.22
Aspirin, which is both an analgesic and an
NSAID, inhibits prostaglandin and
leukotriene synthesis.23 Acetaminophen
can also be used to treat mild-to-moderate
acute migraine.24 Ibuprofen and OTC com-
bination products containing aspirin, aceta-
minophen, and caffeine have been approved
by the US Food and Drug Administration
(FDA) for the treatment of mild-to-moder-
ate migraine. Patients should be cautioned
that the overuse of all treatments for
migraine, including triptans and OTC anal-
gesics (especially combination products
containing caffeine) may cause rebound
headache.22
Prescription-strength NSAIDs such as
ibuprofen, naproxen sodium, and ketoro-
Table 3. Medications Prescribed for Headaches by Primary
Care Physicians
Headache Pattern Suggested Therapy
Mild-to-moderate migraine Nonspecific agents (eg, NSAIDs,
combination medications)
Moderate or severe migraine; or Migraine-specific agents
poor response to NSAIDs and (eg, triptans, dihydroergotamine)
combination medications
Migraine associated with severe Nonoral route of administration
nausea or vomiting
Severe migraine that fails to Self-administered rescue
respond to other treatments medication
NSAIDs = nonsteroidal anti-inflammatory drugs.
Source: Reference 27.
S61
REPORTS
lac are also effective treatments for mild-
to-moderate migraine.25 Diclofenac, a pre-
scription-strength NSAID, reduced the
intensity of migraine pain and ameliorated
associated symptoms such as photophobia
and phonophobia in a placebo-controlled,
double-blind, randomized clinical trial.26 If
a moderate dose of an NSAID adminis-
tered at the onset of migraine is not com-
pletely effective within 1 hour, a triptan
should be given.21 Cyclo-oxygenase-2
inhibitors may be useful adjuncts for the
treatment of migraine.27
Opioids. Opioids such as intramuscu-
larly or intravenously administered meperi-
dine or orally administered codeine are used
because of their analgesic potential but may
exacerbate nausea and vomiting and increase
the risk of drug addiction.25 A clinical trial
involving patients treated in an emergency
department for acute migraine indicated
that a combination of meperidine and
hydroxyzine reduced headache pain by
approximately 55%, ameliorated nausea,
and was not statistically significantly differ-
ent in effect (P < .05) from treatment with a
combination of DHE and hydroxyzine.28
Antiemetics. Antiemetic drugs may be
used to treat acute migraine. Orally or
intravenously administered metoclo-
pramide, a dopamine antagonist that
affects the 5-HT3 receptor, may provide
relief from pain and nausea or vomiting.29
Patients should be advised that antiemet-
ics often cause adverse events such as
diarrhea, drowsiness, or restlessness.
Ergot Compounds. Ergot compounds
such as ergotamine (ET) or DHE were the
first drugs used to treat migraine.25 Ergot
compounds are pharmacologically nonse-
lective but have been used successfully in
patients with moderate-to-severe migraine
since the turn of the century. Their clinical
efficacy is at least equal to that of NSAIDs.30
They have agonist affinity for several
different 5-HT receptors (5-HT1 A, B, D;
5-HT2 A, B, C), dopamine receptors (DA2),
and alpha-adrenergic receptors.31 The
great number of DHE-binding sites in the
dorsal raphe nuclei may precipitate
S62 THE AMERICAN JOURNAL OF MANAGED CARE
migraine.32 Suppression of the firing rate of
those serotonergic neurons and the subse-
quent stabilization of serotonergic neuro-
transmission is thought to be one of the
modes of action of ET compounds.32
ET was first introduced for the treat-
ment of migraine in the 1920s. However,
its bioavailability is poor and unpre-
dictable after oral administration.25 The
potent vasoconstrictor effect of ET, which
can last for up to 3 days, is undesirable.
When compared with ET, DHE is a more
potent α-adrenergic antagonist and is
therefore a potent vasoconstrictor. DHE is
a more potent antiemetic than ET, has
less effect on the uterus, and is not associ-
ated with rebound headache.25
Caffeine in combination with analgesics
or ET improves the absorption of the med-
ication and also potentiates pain relief, pos-
sibly as a result of its vasoconstrictor
effect.25 The combination of ET and caf-
feine, although effective in only 50% of
patients, is a treatment option for acute
migraine.25 The efficacy of ET is enhanced
by the addition of pentobarbital and the
levorotatory alkaloids of belladonna.
Although complete evidence regarding the
efficacy of DHE is unavailable, intravenous
administration can abort approximately
90% of attacks.33 In one study, DHE nasal
spray significantly reduced the severity of
headache.34 In another double-blind, pla-
cebo-controlled study of migraine patients,
those who used an intranasal formulation
of DHE as opposed to placebo experienced
statistically significant migraine resolution
(ie, mild or no pain) within 4 hours of tak-
ing the drug (70% versus 28%, P < .001).35
In that study, the most common adverse
events associated with intranasal DHE
were local, such as rhinitis (21% of
patients), nausea (4%), and taste perver-
sion (9%). Patients with ischemic heart dis-
ease, a history of myocardial infarction, or
clinical signs of coronary artery disease
should not take DHE.
Ergot compounds should not be pre-
scribed for pregnant patients or those with
peripheral vascular disease, hypertension,
coronary heart disease, or impaired renal
or hepatic function.25 The adverse events
produced by ergots include nausea, acro-
FEBRUARY 2002

paresthesia, ischemia, habituation, and
ergot-dependent headache. According to
some research, reports of serious adverse
events that occurred after recommended
doses of DHE were much fewer than
those associated with ET, and physical
dependence did not occur.36 The most
frequently noted adverse events with the
intravenous administration of DHE are
nausea, vomiting, and leg cramps. However,
after intramuscular or intranasal adminis-
tration, the incidence of nausea and vomit-
ing is low and concomitant administration
of an antiemetic is not warranted.
Newer Antimigraine Drugs
A new era in antimigraine drugs began in
1973 with efforts to synthesize a more
selective 5-HT1 agonist. Prior research had
indicated that serotonin 5-HT (a potent
vasoconstrictor and a pain modulator) was
a factor in the generation of migraine.37
Triptan antimigraine agents are serotoner-
gic agonists that act selectively. They cause
vasoconstriction by affecting serotonin (5-
HT1B) receptors in human intracranial
arteries and inhibit nociceptive transmis-
sion by their effect on 5-HT1D receptors on
peripheral trigeminal sensory nerve termi-
nals in the meninges and central terminal
in brain stem sensory nuclei. Those com-
plementary sites of action are the basis of
the clinical effectiveness of those 2 types of
agonists in treating migraine pain and its
associated symptoms.13
Sumatriptan. In 1991, sumatriptan, a
first-generation triptan, was introduced.
Sumatriptan produces agonist effects at 3
5-HT receptors (5-HT1B, 5-HT1D, and 5-
HT1F) and weaker effects at other 5-HT1
receptors.38 It is about 5-fold more potent
at 5-HT1D receptors than at 5-HT1A recep-
tors when compared with DHE, which is
about 10-fold more potent at 5-HT1A than
at 5-HT1D receptors.38 Sumatriptan
relieves migraine pain and associated
symptoms of nausea, vomiting, photopho-
bia, and phonophobia.39-41
Second-Generation Triptans. Nara-
triptan, zolmitriptan, and rizatriptan
entered the US market in late 1997 and
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
1998. Almotriptan became available in the
United States in 2001, frovatriptan has
been approved by the FDA, and FDA
approval of eletriptan is pending. It was
hoped that those second-generation trip-
tans would be superior in effect to suma-
triptan by providing a shorter onset of
action after oral administration, a longer
half-life, greater oral bioavailability, and
improved tolerability.42 However, current
clinical trial data pertaining to 2-hour pain
relief and pain-free endpoints suggest that
the differences among triptans are subtle
rather than dramatic. Some patients
found sumatriptan ineffective or difficult
to tolerate, especially when administered
subcutaneously. Many of those patients
benefit from treatment with a newer trip-
tan or with the oral form of sumatriptan.
The overall efficacy rates for all orally
administered triptans is approximately
65%.42 However, patients may prefer one
treatment as opposed to another.
Adverse events associated with triptans
include nausea, paresthesia, fatigue, som-
nolence, dizziness, pain, heaviness or
tightness in the chest or throat, warm or
cold sensations, and dry mouth. Triptans,
like ergot-containing drugs, are con-
traindicated or prescribed with caution for
those with uncontrolled blood pressure,
coronary artery disease, or peripheral vas-
cular disease.39
Naratriptan. Naratriptan is a second-
generation drug approved for marketing
as an oral formulation to abort migraine.
The pharmacologic profile of naratrip-
tan is superior to that of sumatriptan; its
bioavailability is about 60%, which
reduces the effective dose to 2.5 mg.42
The half-life of naratriptan is about 6
hours (2 to 3 times longer than that of
sumatriptan), which seems to slightly
lower the percentage of patients who
experience recurrent migraine.43 However,
clinical trials indicate that 2.5 mg of nara-
triptan is less effective than 100 mg of
sumatriptan but also produces fewer
adverse events. According to 1 study,
adverse events produced by naratriptan
included vomiting (7% of patients), nau-
sea (7%), and tingling (3%).41 Adverse
S63
REPORTS
events reported in other clinical trials
included dizziness, drowsiness, and
malaise or fatigue (4% to 7%); paresthesia
(2% to 4%); and pain and pressure sensa-
tion (2% to 4%). The side effect of chest
tightness is not mentioned on the product
label, which indicates that a low inci-
dence of chest pain or pressure and throat
or neck symptoms are associated with
naratriptan. It is important to note that
the decreased frequency of chest symp-
toms associated with that drug does not
diminish the importance of alerting
patients with active or potential coronary
artery disease or cardiac ischemia to their
potential occurrence.
Zolmitriptan. Zolmitriptan, the next
second-generation triptan to enter the
market, has an oral bioavailability of
approximately 50%, which exceeds that of
sumatriptan (14%).42 In addition, the half-
life of zolmitriptan (3 hours) provided a
more prolonged therapeutic plasma con-
centration than did sumatriptan. In a
recent study, zolmitriptan was effective in
relieving acute migraine 2 hours after
administration at an oral dose of 2.5 mg
(in 67% of the patients) or 5 mg (in 65%).44
Patients using zolmitriptan 2.5 mg or 5 mg
had a statistically significant 2-hour
response rate compared with that of
patients using sumatriptan 25 mg (P <
.001). When compared with sumatriptan
50 mg, zolmitriptan 2.5 mg also pro-
duced a statistically significant 2-hour
response (P = .017). The rate of headache
recurrence consistently associated with
zolmitriptan is about 30%.45 Adverse
events of zolmitriptan, including those
affecting the CNS, are similar to those of
oral sumatriptan, although zolmitriptan
can cross the blood-brain barrier.42 The
most common adverse events caused by
zolmitriptan 2.5 mg were nausea (in 8% to
11% of the patients), dizziness (8% to 9%),
paresthesia (6%), somnolence (5% to 7%),
chest tightness (5%), and vomiting
(2%).46,47 In clinical practice, zolmitriptan
2.5 mg is equivalent to sumatriptan 50 mg.
Rizatriptan. Rizatriptan, another sec-
ond-generation triptan, has an improved
S64 THE AMERICAN JOURNAL OF MANAGED CARE
pharmacologic profile and an oral bio-
availability of about 40%.40 Its half-life (2.5
to 3 hours) is only slightly longer than that
of sumatriptan. Rizatriptan has a more
rapid onset (tmax < 1 hour) than other trip-
tans currently on the market.40 In clinical
trials, rizatriptan produced pain relief 2
hours after administration at doses rang-
ing from 2.5 to 40 mg; a dose of 10 mg
produced the most benefit (52% of
patients experienced relief from headache
and few adverse events).40 Common adverse
events included dizziness (in 4% of the
patients), nausea (3%), somnolence (3%),
chest symptoms (2%), and fatigue (1%). As
with other triptans, the number of adverse
events caused by rizatriptan was dose
dependent.
Newer Triptans. Eletriptan has an oral
bioavailability of almost 50%; it is rapidly
absorbed (tmax < 1 hour) but has a half-life
of 5 hours.42 In 2 recent multicenter stud-
ies, the efficacy and tolerability of eletrip-
tan in acute migraine were examined. In
the first study, doses of oral eletriptan 5,
20, or 30 mg were studied in the treatment
of acute migraine in 365 patients.48 Two
hours after administration of the drug,
relief from headache was reported by 41%,
47%, and 49% of patients who had received
eletriptan 5, 20, or 30 mg, respectively.
Thirty-five percent of the patients had
received placebo. In the second trial, the
effect of oral eletriptan 20, 40, or 80 mg
was compared with that of sumatriptan
100 mg or placebo in 270 patients.48
Relief from headache 2 hours after drug
administration was reported by 44%, 67%,
80%, and 57% of the patients who had
received eletriptan 20, 40, or 80 mg or
sumatriptan 100 mg, respectively. In that
study, 25% of the patients had received
placebo. The adverse events produced by
eletriptan were similar to those of suma-
triptan. In another study, adverse events
from doses of eletriptan 20 or 40 mg were
less than those produced by sumatriptan
100 mg.49
Frovatriptan, another second-genera-
tion triptan, has a higher affinity for 5-
HT1B/1D receptors than does sumatriptan.
In higher doses, frovatriptan is an agonist
FEBRUARY 2002

of the 5-HT receptors that might cause
vasodilation on, for example, coronary
vessels.42 It is absorbed relatively slowly
and reaches its tmax 2 hours after adminis-
tration; its pharmacokinetic properties are
similar to those of naratriptan. Thus, 2
hours after receiving frovatriptan 2.5 or 5
mg, 38% and 37% of the patients, respec-
tively, reported headache relief. Four
hours after they received the drug, 68%
and 67% of patients, respectively, reported
headache relief.50 Frovatriptan has a long
half-life (> 10 hours); this may result in a
lower incidence of headache recurrence,
which was reported by 7% to 25% of
patients.51
Prophylaxis Against Migraine
The objective of prophylactic treatment
of migraine is to reduce the frequency,
severity, and/or duration of attacks while
keeping adverse events to a minimum.
No single prophylactic drug is superior
when potential adverse events are also
considered.25
Prophylactic therapy is indicated when
patients report that their acute migraines
are not adequately controlled or that
they often use medication to treat an
acute attack (Table 3). Prophylaxis should
be considered when nonpharmacologic
attempts have failed.25 Low doses of pro-
phylactic medication should be used at
first and slowly titrated upward.25 Treat-
ment can be administered for 3 months,
reassessed before being continued for an
additional 6 months or more, and then
gradually withdrawn after the frequency of
migraine attacks has been decreased.
Prophylaxis is also indicated after the
diagnosis of comorbid conditions (such as
depression) that can be treated with med-
ications effective in the treatment of
migraine.52 Patients with sleep distur-
bances or depression may benefit most
from treatment with a tricyclic antide-
pressant (eg, amitriptyline, doxepin, nor-
triptyline, imipramine, protriptyline,
desipramine). Those with agitation or
bipolar disorder or patients who have ter-
minated their drug therapy may benefit
from divalproate sodium. A beta-blocker
such as atenolol, nadolol, metoprolol, pro-
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
pranolol, or timolol may be the most effec-
tive initial therapy in patients who experi-
ence situational anxiety or “letdown”
migraine or in those with hypertension. A
calcium channel blocker may be appropri-
ate for patients with peripheral vascular
disease or hypertension. Doses of those
medications to prevent migraine often are
much lower than those used to treat a
comorbid disorder.
The amine ergot alkaloid methysergide
is an effective prophylactic agent in
migraine therapy.53 Although the drug is
devoid of α-adrenergic activity, long-term
use may result in pleural, pericardial, or
retroperitoneal fibrosis. However, those
problems can usually be avoided by close
medical monitoring and by advising the
patient to take a 1-month “drug holiday”
every 6 months.
Beta-blocking adrenergic drugs without
intrinsic sympathomimetic activity are
the only class of beta-blockers effective for
the prophylaxis of migraine.25 Their effect
is observed within 4 weeks and seems to
increase with time. That group of drugs is
particularly useful for treating patients
whose attacks are triggered by stress.
Propranolol and timolol have been studied
in numerous clinical trials and have also
been found to be effective.54 However, the
adverse events caused by beta-blocking
drugs must be considered before they are
prescribed. Propranolol is likely to pro-
duce adverse events on the CNS, which
may cause physicians to avoid prescribing
it. Metoprolol, which has been shown to
decrease the number of migraine attacks
by 22% to 49%, is a useful alternative to
propranolol. A lack of adequate, controlled
clinical trials prevents conclusions with
respect to the use of atenolol or nadolol as
alternatives to propranolol.25
Valproate, a gamma-aminobutyric acid
transaminase inhibitor and activator of
glutamic acid decarboxylase, was found to
be effective in double-blind, placebo-con-
trolled trials in reducing migraine fre-
quency in at least 48% to 65% of patients;
the placebo-treated patients experienced
a reduction of 14% to 18%. Unlike other
prophylactic agents, valproate reduced
the severity and duration of migraine
S65
REPORTS
attacks.55,56 Adverse events of valproate
include nausea, tremor, transient hair loss,
increase in appetite, and weight gain.
Hepatotoxicity was observed in patients
treated with valproate who were younger
than 2 years of age. Women of childbearing
age who consider treatment with valproate
must be cautioned about the potential
increased risk of spina bifida in the newborn.
The tricyclic antidepressant amitripty-
line may be effective because of its 5-HT2-
receptor-blocking and/or calcium-channel-
blocking effect on cerebral blood vessels
and its inhibitory effect on the dorsal raphe
nuclei.57 Amitriptyline, which reduces the
frequency and duration of migraine attacks,
is superior to placebo and more effective
than propranolol in decreasing the severity
of migraine attacks.58,59 However, amitripty-
line produces anticholinergic adverse
events and causes increased appetite and
weight gain. Other tricyclic antidepressants
with varying adverse-event profiles can
also be tried.
The use of calcium antagonists in
migraine prophylaxis has been disappoint-
ing.60 The dihydropyridine derivatives
nifedipine and nimodipine can actually
cause headache. Either verapamil or dil-
tiazem is usually used to prevent migraine
only after trials of the more effective beta-
blockers or amitriptyline have failed.
According to 1 review, verapamil was 19%
to 49% more effective than placebo in
decreasing the frequency of migraine
attacks.61 The most common adverse
events produced by verapamil are hyper-
tension and constipation. Despite wide-
spread use for treatment of migraine, the
results of clinical studies of diltiazem are
“underwhelming.”
Tolerability and Safety of
Migraine Treatment
Some adverse events (particularly nau-
sea) of drugs used to treat migraine can
mimic the signs or symptoms of the disor-
der. It is therefore critical to distinguish
drug-induced symptoms from those
caused by headache. Nausea, a common
symptom of migraine, occurs in 78% of
migraine sufferers. Because it is often
moderate to severe, nausea contributes to
S66 THE AMERICAN JOURNAL OF MANAGED CARE
the disability of the patient.62 It can also
interfere with the administration of oral
medication. Exacerbation of nausea after
the administration of oral medication can
indicate either the development of new
nausea or a disease-related worsening of
nausea, and alternative medications for
the treatment of migraine should be
explored.
Clinical Safety of Dihydroergota-
mine and Ergotamine. The clinical safe-
ty experience with DHE is based on 21
clinical studies; unfortunately, few of
those studies had clinical controls, many
were open label and unblinded, and most
did not compare DHE with placebo.63
Adverse events were often not document-
ed systematically because the focus of the
studies was the efficacy of the medication.
No clinical studies evaluated the effects or
efficacy of long-term intramuscular
administration of DHE, and only a few
evaluated the results of repetitive intra-
venous administration in hospital patients.
Although nausea was reported in a
number of trials after treatment of migraine
with DHE, critical quantitative observa-
tions demonstrated that the drug-induced
symptom was difficult to differentiate
from nausea caused by migraine. Open
trials reported few adverse events of
DHE. In summary, closed clinical trials
and open-label studies suggested that
serious adverse events occur very rarely
after a recommended dose of DHE has
been taken, regardless of the route of
administration.64
The clinical safety experience with ET
indicates that it is much more likely than
DHE to produce nausea and vomiting,
uterine effects, and rebound headache.63
Most of the adverse events produced by
ET were associated with excessive dosage
and/or long-term administration. The
peripheral vasoconstrictor effect of ET is
considerably stronger than that of DHE.
When primary care physicians prescribe
either DHE or ET, they must be aware that
both are safe in the treatment of migraine
with or without aura when used in recom-
mended doses and frequencies in adults
who have no contraindications to the
FEBRUARY 2002

medications. When compared with ET,
DHE causes less arterial constriction and
(according to indirect comparisons) less
frequent nausea and vomiting.63
The Quality Standards Subcommittee
of the American Academy of Neurology
appointed an advisory committee from
experts in its headache and facial pain
section to review the clinical literature on
the appropriate use of DHE and ET in the
treatment of migraine.65 On the basis of
that thorough literature review, practice
guidelines were formulated to define the
limits of ergot use. ET and DHE were
found to be safe and effective for the treat-
ment of migraine as long as recommended
dosages were not exceeded and high-risk
patients (those with uncontrolled hyper-
tension, coronary or peripheral artery dis-
ease, thyrotoxicosis, or sepsis) did not
receive those drugs. The committee also
recommended restricting the use of ET
in some instances, because its overuse
has been associated with physical and
psychological dependence. Drug-dependent
patients often experience predictable
recurrent and/or rebound headaches, and
subsequent medications are required to
alleviate the symptoms of withdrawal,
such as nausea. None of those symptoms
has been associated with DHE.
Clinical Safety of Triptans. First- and
second-generation triptans represent a
breakthrough treatment for patients with
acute migraine. However, those drugs cause
some degree of coronary vasoconstriction in
susceptible patients.66,67 At therapeutic doses,
triptans are unlikely to cause myocardial
ischemia in individuals with normal coronary
circulation.66 Although that effect is not
clinically significant for patients who do
not have coronary artery disease, triptans
are contraindicated in those who have or
are at risk for that disorder.66
Adverse-event databases compiled for
the triptans show that the risk of life-
threatening cardiovascular events pro-
duced by those medications is probably
less than 1 in 1 million.67 The level of risk
associated with triptans is actually similar
to (or perhaps even better than) that of
prescription NSAIDs.67 The patient’s level
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
of risk (rather than the number of risk fac-
tors) is the most important factor.67
“Therapeutic gain” refers to the propor-
tion of patients who respond to treatment
with a drug tested minus the proportion of
patients who respond to placebo. A review
of 30 clinical trials demonstrated that, 1
hour after administration, subcutaneous
sumatriptan 6 mg administered for the
acute treatment of migraine resulted in a
greater therapeutic gain than did 100 mg
of orally administered sumatriptan or 20
mg of intranasal sumatriptan 2 hours after
administration.68 Although 6 mg of subcu-
taneous sumatriptan is more effective
than the other doses and dosage forms
mentioned above, it causes more adverse
events than does 100 mg of oral sumatrip-
tan, which appears to have the better ben-
efit-to-risk ratio. However, most adverse
events produced by the subcutaneous
form of the drug were mild and short-last-
ing, and patients may find that the greater
efficacy and quicker onset of action of
subcutaneous sumatriptan outweigh the
higher incidence of adverse events.69
Placebo-controlled studies have report-
ed an incidence of chest-related adverse
events in up to 4% of patients treated with
second-generation triptans, compared
with an incidence ranging from less than
1% to 3% in placebo-treated patients.20 An
analysis of safety data indicates that
migraine patients seem to have a higher
level of risk for cardiovascular events
than does the general population; this
implies that such events may be associat-
ed with the underlying condition rather
than the treatment.70,71 However, those
agents should be used with caution in any
patient with vascular risk factors.
Clinical judgment is key when the deci-
sion to use triptans is made. If a patient
has ischemic heart disease and uncon-
trolled high blood pressure, the primary
care physician or specialist should not pre-
scribe a triptan.70 A patient with a family
history of heart disease and a high choles-
terol level should first receive other med-
ications for migraine treatment before
treatment with a triptan is initiated.
Safety is indeed a viable concern in the
selection of appropriate migraine treat-
S67
REPORTS
ment for a patient; however, it is important
to recognize that whether the patient can
tolerate the drug is also an important (yet
separate) issue. It is crucial to approach
those 2 distinct characteristics as separate
factors in treatment choice. The safety of
a drug is of primary importance to ensure
that a patient is least likely to experience
any serious life-threatening outcomes
from treatment. After the safety of treat-
ment has been established, the tolerabil-
ity of the treatment (ie, the point at
which adverse events are sufficiently
reduced so that a patient is most likely to
continue treatment) becomes an added
consideration.
Almotriptan—Pharmacology, Efficacy,
and Tolerability
Almotriptan, the most recent 5-HT1B/1D
agonist agent, demonstrates selective and
equipotent nanomolar affinity for 5-HT1B
and 5-HT1D receptors; this mechanism of
action is similar to that of sumatriptan.72
Functional affinity assays indicate that
almotriptan has a lower potency than
does sumatriptan at the 5-HT1D receptor
and that its potency at the 5-HT1B recep-
tor is similar to that of rizatriptan and
sumatriptan.72 Almotriptan exhibits 25
times the vasoconstrictor activity of
sumatriptan in the human meningeal
artery.72 The oral formulation of almotrip-
tan has the highest bioavailability (70%)
among the second-generation triptans; its
half-life, however, is 3.0 to 3.7 hours.
Almotriptan is rapidly absorbed after an
oral dose and reaches a peak plasma con-
centration of 66.2 ng/mL at 1.38 hours
after administration.73 The plasma elimi-
nation half-life of almotriptan is 3.9 hours
in healthy volunteers. This may have clin-
ical relevance, especially when compared
with sumatriptan’s half-life of about 2
hours (regardless of the route of adminis-
tration).71 Sumatriptan’s shorter half-life
may explain its association with recurring
headache, which has affected 21% to
57% of patients in trials of both oral and
subcutaneous formulations of the drug.71
Oral almotriptan has a bioavailability of
70%. In contrast, zolmitriptan has an
absolute bioavailability of 49%, and
S68 THE AMERICAN JOURNAL OF MANAGED CARE
sumatriptan has an absolute bioavailabili-
ty of only 14%.73-75
Of the approximately 45% of almotrip-
tan that is metabolized, about 27% is
metabolized by monoamine oxidase A and
12% by the cytochrome P-450 isozymes
CYP 3A4 and 2D6. As a result, almotriptan
has no substantial effect on the pharmaco-
kinetics of fluoxetine, which is metabo-
lized by CYP 2D6, or other commonly used
drugs such as verapamil or propranolol.76-78
Moclobemide, a reversible monoamine
oxidase-A (MAO-A) inhibitor, modestly
decreased the clearance of almotriptan.
Thus the lowest available dose of almotrip-
tan should be used in patients treated with
MAO-A inhibitors.79 MAO-A inhibitors dra-
matically reduce the metabolism of suma-
triptan and zolmitriptan; thus concurrent
administration of MAO-A inhibitors or the
use of sumatriptan or zolmitriptan within 2
weeks of the discontinuation of MAO-A
inhibitor therapy is contraindicated.
The efficacy of almotriptan was estab-
lished in 3 multicenter, randomized, dou-
ble-blind, placebo-controlled trials.80-82 In
those studies, a significantly higher per-
centage of patients who received either
almotriptan 6.25 or 12.5 mg as opposed to
placebo experienced pain relief (mild or no
pain) 2 hours after treatment. A higher
percentage of patients in all 3 studies
reported pain relief after treatment with
the 12.5-mg dose as opposed to the 6.25-
mg dose. In 2 of those studies, oral
almotriptan (as opposed to placebo) pro-
duced statistically significant 2-hour pain
relief rates (59% versus 34% and 65% ver-
sus 33%, respectively), and 1 hour after
administration, significant pain relief was
also experienced by patients given oral
almotriptan as opposed to placebo (36%
versus 19%, P = .007; and 34% versus 21%,
P = .001).80,81 In Table 4, the 2-hour pain-
relief rates after oral almotriptan adminis-
tration during an initial migraine are
summarized.
When compared with the results of
placebo, oral almotriptan 12.5 mg provid-
ed consistent pain relief over the course of
3 consecutive migraine attacks in another
double-blind, placebo-controlled study.82
Although oral almotriptan 12.5 mg also
FEBRUARY 2002

produced pain relief rates similar to those
of oral sumatriptan 100 mg in a random-
ized, double-blind, placebo-controlled
clinical study, almotriptan 12.5 mg was
associated with a significantly lower inci-
dence of treatment-related adverse events
(P < .05).81 In addition, almotriptan 12.5
mg and sumatriptan 50 mg were com-
pared in a randomized, double-blind
trial.83 Pain relief occurred 2 hours after
administration in 58% of patients treated
with almotriptan and in 57% of those
treated with sumatriptan. However, signif-
icantly fewer patients in the almotriptan
group (P < .05) experienced treatment-
related adverse events (9.1% versus 15.5%)
and chest symptoms in particular (0.3%
versus 2.2%).
The tolerability of almotriptan was in
most instances similar to that of placebo.
In controlled clinical trials, nausea in 2%
of the patients was the only adverse event
recorded in 2% or more of those treated
with almotriptan.84 Headache was fre-
quently noted when oral almotriptan 6.25
to 25 mg was administered. Infrequent
adverse events, all of which were mild and
transient in nature, included abdominal
cramps, vasodilation, palpitations, tachy-
cardia, dry mouth, diarrhea, vomiting, and
dyspepsia. In those trials, the adverse
events were similar to those attributed to
placebo.84 Patients who experienced migraine-
associated photophobia, phonophobia, nau-
sea, or vomiting at baseline had a decreased
incidence of those symptoms after the
administration of almotriptan as opposed to
placebo.
In controlled clinical studies, a total of
2809 patients were treated with almotrip-
tan (527 with 6.25 mg, 1313 with 12.5 mg,
and 387 with 25 mg) or sumatriptan (582
with 50 mg).84 The overall adverse event
rates in those studies were 12.4% (those
who received placebo), 14% (almotriptan
6.25 mg), 15.4% (almotriptan 12.5 mg),
20.4% (almotriptan 25 mg), and 19.4%
(sumatriptan 50 mg). The most common
adverse events associated with almotrip-
tan use (at a rate of at least 1%—a rate
greater than that of placebo) in the con-
trolled studies at the recommended doses
of 6.25 or 12.5 mg were headache, dry
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
mouth, nausea, paresthesia, and somno-
lence. No adverse events in the groups
who received the 6.25 or 12.5-mg dose
occurred at a rate of 1 or more percentage
points higher than that of the placebo
group. Dry mouth, paresthesia, and som-
nolence are adverse events produced by
triptans, and nausea and headache are
often observed in migraine patients. Other
adverse events associated with triptan use,
such as asthenia, chest pain, localized
pain, palpitation, vasodilation, and dizzi-
ness, were not associated with almotriptan
administered at recommended doses. For
both doses, the only adverse event that
occurred in 2% or more of the patients was
nausea (2% in those who received
almotriptan 12.5 mg).
The adverse-event profile for sumatrip-
tan in the studies cited above is consis-
tent with data from other studies of that
drug.85,86 Although the types of adverse
events in the almotriptan-treated groups
were similar to those observed in the
groups treated with sumatriptan, almotrip-
tan 6.25 and 12.5 mg produced lower rates
of chest pain and nausea than did suma-
triptan 50 mg. Vomiting occurred at a
higher rate in the placebo-treated group
(1.6%) than in any of the other main treat-
ment groups (all > 1%). Adverse-event
rates (particularly for chest pain, nausea,
Table 4. Clinical Studies of Oral Almotriptan Demonstrating
Pain Relief* in the Treatment of Acute Migraine
Placebo Almotriptan Almotriptan
Study Author(s) (%) 6.25 mg (%) 12.5 mg (%)
Dahlöf et al80 33.8 56.3† 58.5‡
(n = 80) (n = 166) (n = 164)
Dowson81 42.4 — 56.8§
(n = 99) (n = 183)
Pascual et al82 33.0 55.6‡ 64.9‡
(n =176) (n = 374) (n = 370)
*Pain relief was noted at 2 hours after administration of the drug for initial
headache.
†P = .002 in comparison with placebo.
‡P ≤ .001 in comparison with placebo.
§P = .025 in comparison with placebo.
S69
REPORTS
dizziness, or somnolence) in the groups
treated with higher doses of almotriptan
(25, 100, or 150 mg) were usually higher
than those in the patients who received
lower doses of the drug.
Conclusions
Migraine is an underdiagnosed and
undertreated disorder that is experienced
most often during peak productive years
(25 to 55 years of age). The recently devel-
oped IHS criteria for headache classifica-
tion have provided a uniform case
definition that has facilitated epidemiolog-
ic research on headaches. The disability
caused by headaches has a great effect on
individuals and on society, and health
interventions are critical to the manage-
ment of those disorders. Physicians must
be aware of the diagnostic criteria for
headaches and must be able to prescribe
effective therapy in accordance with the
patient’s possible intolerance of various
medications.
Primary care physicians are concerned
with 2 critical aspects in treating migraine
patients. The first is the efficacy of an
agent in rapidly relieving headache and
preventing recurrence. The second is the
knowledge that the agent does not produce
harmful adverse events. Therefore, at this
stage in the development of triptans used
to treat acute migraine, the tolerability and
safety of the drug are very important con-
siderations, especially when several agents
are now available to relieve headache. In
most patients, triptans alleviate migraine
pain in 2 hours, regardless of the time of
onset. However, the adverse events pro-
duced by triptans must be considered by
the primary care physician before he or
she prescribes a particular drug.
Although similar adverse events are
produced by triptans as a class, a benefit-
to-risk ratio must always be considered for
each drug in that class. This implies that a
particular oral dose of a triptan can pro-
duce an excellent therapeutic effect as
well as minimal adverse events. As newer,
more effective oral triptans are developed,
it is hoped that an improved benefit-to-
risk ratio will also be achieved. Naratriptan
appears to produce fewer adverse events
S70 THE AMERICAN JOURNAL OF MANAGED CARE
than do the other marketed triptans.
However, when compared with other
triptans, its delayed onset of action is a
disadvantage.
Almotriptan is characterized by a rapid
onset of action, effectiveness over 24
hours with a low recurrence rate of
migraine, and few adverse events. It is not
contraindicated in patients with severe
renal or hepatic impairment. However,
because of the potential of 5-HT1B/1D recep-
tor agonists to cause coronary vasospasm,
almotriptan should not be given to
patients with documented ischemic or
vasospastic coronary artery disease,
ischemic heart disease, or uncontrolled
hypertension. Low tolerability is not syn-
onymous with improved safety.
Almotriptan is well tolerated. Controlled
clinical trials of that drug indicate that at
therapeutic doses, it causes a lower inci-
dence of chest pain than does sumatrip-
tan, that it produces no dose-related
clinically relevant effects on electrocardio-
graphic results, and that (when compared
with placebo) it produces a low incidence
of somnolence and other CNS effects and
has a similar tolerability profile. In clinical
trials in which 20,000 migraine attacks
occurred in nearly 4000 patients, the
dropout rate of almotriptan-treated indi-
viduals was very low, and those patients
experienced no unanticipated adverse
events. Almotriptan should expand the
armamentarium of antimigraine drugs
available to physicians and patients.
. . . REFERENCES . . .
1. Bartelson JD. Treatment of migraine headaches.
Mayo Clin Proc 1999;74:702-708.
2. Lipton RB, Stewart WF, von Korff M. Migraine
impact and functional disability. Cephalalgia
1995;15(suppl 15):4-9.
3. Hu XH, Markson LE, Lipton RB, Stewart WF,
Berger ML. Burden of migraine in the United States:
Disability and economic costs. Arch Intern Med
1999;159:813-818.
4. Lipton RB, Stewart WF, Simon D. Medical consul-
tation for migraine: Results from the American
Migraine Study. Headache 1998;38:87-96.
5. Gallagher RM, Kunkel R. Migraine patient con-
cerns affecting compliance: Results from the NHF sur-
vey. Headache. 2002. In press.
6. Goadsby PJ. Current concepts of the pathophysiol-
ogy of migraine. Neurol Clin 1997;15:27-42.
FEBRUARY 2002

7. Stewart WF, Shechter A, Rasmussen BK. Migraine
prevalence. A review of population-based studies.
Neurology 1994;44(suppl 4):S17-S23.
8. Prevalence of chronic migraine headaches—United
States, 1980-1989. MMWR Morb Mortal Wkly Rep
1991;40:331-338.
9. Sillanpaa M. Headache in children. In: Olesen J,
ed. Headache Classification and Epidemiology. New
York, NY: Raven Press; 1994:273-281.
10. Rasmussen BK. Epidemiology of headache.
Cephalalgia 1995;15:45-68.
11. Lipton RB. Disability assessment as a basis for
stratified care. Cephalalgia 1998;18(suppl 22):40-46.
12. Marcus DA. Serotonin and its role in headache
pathogenesis and treatment. Clin J Pain 1993;9:159-
167.
13. Hargreaves RJ, Shepheard SL. Pathophysiology
of migraine—new insights. Can J Neurol Sci 1999;
26(suppl 3):S12-S19.
14. Headache Classification Committee of the
International Headache Society. Classification and
diagnostic criteria for headache disorders, cranial
neuralgias and facial pain. Cephalalgia 1988;8(suppl
7):1-96.
15. Olesen J, Lipton RB. Migraine classification and
diagnosis. International Headache Society criteria.
Neurology 1994;44(suppl 4):S6-S10.
16. Capobianco DJ, Cheshire WP, Campbell JK. An
overview of the diagnosis and pharmacologic treatment
of migraine. Mayo Clin Proc 1996;71:1055-1066.
17. Pryse-Phillips WE, Dodick DW, Edmeads JG.
Guidelines for the diagnosis and management of
migraine in clinical practice. CMAJ 1997;156:1273-
1287.
18. Diamond S. Diagnosing and Managing Headache.
2nd ed. Caddo, OK: Professional Communications,
Inc; 1998.
19. Cady RK, Sheftell F, Lipton RB, et al. Effect of
early intervention with sumatriptan on migraine pain:
Retrospective analyses of data from three clinical tri-
als. Clin Ther 2000;22:1035-1048.
20. Deleu D, Hanssens Y. Current and emerging sec-
ond-generation triptans in acute migraine therapy: A
comparative review. J Clin Pharmacol 2000;40:687-
700.
21. Silberstein SD. Practice parameter: Evidence-
based guidelines for migraine headache (an evidence-
based review): Report of the Quality Standards
Subcommittee of the American Academy of
Neurology. Neurology 2000;55:754-762.
22. Lobo BL, Cooke SC, Landy SH. Symptomatic
pharmacotherapy of migraine. Clin Ther
1999;21:1118-1130.
23. Buzzi MG, Sakas DE, Moskowitz MA.
Indomethacin and acetylsalicylic acid block neuro-
genic plasma protein extravasation in rat dura matter.
Eur J Pharmacol 1989;165:251-258.
24. Peatfield RC, Petty RG, Rose FC. Double blind
comparisons of mefenamic acid and acetaminophen
(paracetamol) in migraine. Cephalalgia 1983;3:
129-134.
25. Deleu D, Hanssens Y, Worthing EA. Symptomatic
and prophylactic treatment of migraine: A critical
reappraisal. Clin Neuropharmacol 1998;21:267-
279.
26. Massiou H, Serrurier D, Lasserre O, Bousser
MG. Effectiveness of oral diclofenac in the acute
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
treatment of common migraine attacks: A double-
blind study versus placebo. Cephalalgia 1991;11:59-
63.
27. Silberstein DS, Lipton RB, Dalessio DJ, eds.
Wolff's Headache and Other Head Pain. 7th ed. New
York, NY: Oxford University Press; 2001.
28. Carleton SC, Shesser RF, Pietzrak MP, et al.
Double-blind, multicenter trial to compare the
efficacy of intramuscular dihydroergotamine plus
hydroxyzine versus intramuscular meperidine plus
hydroxyzine for the emergency department treatment
of acute migraine headache. Ann Emerg Med
1998;32:129-138.
29. Ellis GL, Delaney J, DeHart DA, Owens A. The
efficacy of metoclopramide in the treatment of
migraine headache. Ann Emerg Med 1993;22:191-
195.
30. Ferrari MD. Migraine. Lancet 1998;351:1043-
1051.
31. Silberstein SD. The pharmacology of ergotamine
and dihydroergotamine. Headache 1997;37(suppl
1):S15-S25.
32. Goadsby PJ, Gundlach AL. Localization of 3H-
dihydroxyergotamine-binding sites in the cat central
nervous system: Relevance to migraine. Ann Neurol
1991;29:91-94.
33. Saadah HA. Abortive headache therapy in the
office with intravenous dihydroergotamine plus
prochlorperazine. Headache 1992;32:143-146.
34. Dihydroergotamine Nasal Spray Multicenter
Investigators. Efficacy, safety, and tolerability of dihy-
droergotamine nasal spray as monotherapy in the
treatment of acute migraine. Headache 1995;35:177-
184.
35. Gallagher RM, the Dihydroergotamine Working
Group. Acute treatment of migraine with dihydroer-
gotamine nasal spray. Arch Neurol 1996;53:1285-
1291.
36. Raskin NH. Repetitive intravenous dihydroergota-
mine as therapy for intractable migraine. Neurology
1986;36:995-997.
37. Goadsby PJ. Serotonin 5-HT1B/1D receptor ago-
nists in migraine. Comparative pharmacology and its
therapeutic implications. CNS Drugs 1998;10:271-
286.
38. Peroutka SJ. 5-Hydroxytryptamine receptor sub-
types. Pharmacol Toxicol 1990;67:373-383.
39. Weiss J. Assessment and management of the
client with headaches. Nurse Pract 1993;18:44-54.
40. Diener HC, Limmroth V. Acute management of
migraine: Triptans and beyond. Curr Opin Neurol
1999;12:261-267.
41. Diener HC, Kaube H, Limmroth V. Antimigraine
drugs. J Neurol 1999;246:515-519.
42. Limmroth V, Diener HC. New anti-migraine
drugs: Present and beyond the millennium. Int J Clin
Pract 1998;52:566-570.
43. Klassen A, Elkind A, Asgharnejad M, Webster C,
Laurenza A. Naratriptan is effective and well tolerated
in the acute treatment of migraine. Results of a dou-
ble-blind, placebo-controlled, parallel-group study.
Naratriptan S2WA3001 Study Group. Headache
1997;37:640-645.
44. Gallagher RM, Dennish G, Spierings EL, Chitra
R. A comparative trial of zolmitriptan and sumatriptan
for the acute oral treatment of migraine. Headache
2000;40:119-128.
S71
REPORTS
45. Ferrari MD. 311C90: Increasing the options for
therapy with effective acute antimigraine 5HT1B/1D
receptor agonists. Neurology 1997;48(suppl 3):S21-S24.
46. Rapoport AM, Ramadan NM, Adelman JU, et al.
Optimizing the dose of zolmitriptan (Zomig, 311C90)
for the acute treatment of migraine. A multicenter,
double-blind, placebo-controlled, dose range-finding
study. The 017 Clinical Trial Study Group. Neurology
1997;49:1210-1218.
47. Solomon GD, Cady RK, Klapper JA, Earl NL,
Saper JR, Ramadan NM. Clinical efficacy and tolera-
bility of 2.5 mg zolmitriptan for the acute treatment
of migraine. The 042 Clinical Trial Study Group.
Neurology 1997;49:1219-1225.
48. Farkkhila M, Diener HC, Dahlöf C, Steiner TJ,
on behalf of the Eletriptan Steering Committee. A
dose-finding study of eletriptan (5-30 mg) for the
acute treatment of migraine [abstract]. Cephalalgia
1996;16:387.
49. Jackson NC, for the Eletriptan Steering
Committee. A comparison of oral eletriptan (20-80
mg) and oral sumatriptan (100 mg) in the acute treat-
ment of migraine [abstract]. Cephalalgia 1996;16:368.
50. Goldstein J, Keywood C. A low-dose range find-
ing study of frovatriptan, a potent selective 5-HT1B/1D
agonist for the treatment of migraine. Funct Neurol
1998;13:178.
51. Migraine, frovatriptan. Available at http://www.
vernalis.com/r_d_portfolio/content1/content.htm
Accessed April 30, 2001.
52. Tomkins GE, Jackson JE, O’Malley PG, Balden E,
Santero JE. Treatment of chronic headache with anti-
depressants: A meta-analysis. Am J Med 2001;111:
54-63.
53. Steardo L, Marano E, Barone P, Denman DW,
Monteleone P, Cardone G. Prophylaxis of migraine
attacks with a calcium-channel blocker: Flunarizine
versus methysergide. J Clin Pharmacol 1986;26:524-
528.
54. Massiou H, Bousser MG. Beta-blocqants et
migraine. Pathol Biol (Paris). 1992;40:373-380.
55. Jensen R, Brink T, Olesen J. Sodium valproate
has a prophylactic effect in migraine without aura: A
triple-blind, placebo-controlled crossover study.
Neurology 1994;44:647-651.
56. Mathew NT, Saper JR, Silberstein SD, et al.
Migraine prophylaxis with divalproex. Arch Neurol
1995;52:281-286.
57. Peroutka SJ. 5-Hydroxytryptamine receptor sub-
types and the pharmacology of migraine. Neurology
1993;43:S34-S38.
58. Couch JR, Hassanein RS. Amitriptyline in
migraine prophylaxis. Arch Neurol 1979;36:695-699.
59. Ziegler DK, Hurwitz A, Preskorn S, Hassanein
RS, Siem J. Propranolol and amitriptyline in prophy-
laxis of migraine. Pharmacokinetic and therapeutic
effects. Arch Neurol 1993;50:825-830.
60. Andersson KE, Vinge E. Beta-adrenoceptor block-
ers and calcium antagonists in the prophylaxis and
treatment of migraine. Drugs 1990;39:355-373.
61. Ramadan NM, Schultz LL, Gilkey SJ. Migraine
prophylactic drugs: Proof of efficacy, utilization and
cost. Cephalalgia 1997;17:73-80.
62. Lipton RB, Solomon S, Newman LC, Sheftell FD.
Gastrointestinal symptoms in migraine: Results from
the AASH-Gallup survey [abstract]. Headache
1995;45:563.
S72 THE AMERICAN JOURNAL OF MANAGED CARE
63. Lipton RB. Ergotamine tartrate and dihydroergota-
mine mesylate: Safety profiles. Headache 1997;37
(suppl 1):S33-S41.
64. Silberstein SD. Migraine symptoms: Results of a
survey of self-reported migraineurs. Headache
1995;35:387-396.
65. Young WB. Appropriate use of ergotamine tartrate
and dihydroergotamine in the treatment of migraine:
Current perspectives. Headache 1997;37(suppl 1):
S42-S45.
66. MaassenVanDenBrink A, Reekers M, Bax WA,
Ferrari MD, Saxena PR. Coronary side-effect potential
of current and prospective antimigraine drugs.
Circulation 1998;98:25-30.
67. MacIntyre PD, Bhargava B, Hogg KJ, Gemmill
JD, Hillis WS. Effect of subcutaneous sumatriptan, a
selective 5HT1 agonist, on the systemic, pulmonary,
and coronary circulation. Circulation 1993;87:401-
405.
68. Tfelt-Hansen P. Efficacy and adverse events of
subcutaneous, oral, and intranasal sumatriptan used
for migraine treatment: A systematic review based on
number needed to treat. Cephalalgia 1998;18:532-538.
69. Simmons VE, Blakebourough P. The safety profile
of sumatriptan. Rev Contemp Pharmacother
1994;5:319-328.
70. O'Quinn S, Davis RL, Gutterman DL, Part GD,
Fox AW. Prospective large-scale study of the tolera-
bility of subcutaneous sumatriptan injection for acute
treatment of migraine. Cephalalgia 1999;19:223-231.
71. Perry CM, Markham A. Sumatriptan. An updated
review of its use in migraine. Drugs 1998;55:889-922.
72. Bou J, Domenech T, Puig J, et al. Pharmacological
characterization of almotriptan: An indolic 5-HT
receptor agonist for the treatment of migraine. Eur J
Pharmacol 2000;410:33-41.
73. Cabarrocas X, Salva M. Pharmacokinetic and
metabolic data on almotriptan, a new antimigraine
drug. Cephalalgia 1997;17:421.
74. Fowler PA, Lacey LF, Thomas M, Keene ON,
Tanner RJ, Baber NS. The clinical pharmacology,
pharmacokinetics and metabolism of sumatriptan.
Eur Neurol 1991;31:291-294.
75. Seaber E, On N, Dixon RM, et al. The absolute
bioavailability and metabolic disposition of the novel
antimigraine compound zolmitriptan (311C90). Br J
Clin Pharmacol 1997;43:579-587.
76. Fleishaker JC, Ryan KK, Carel BJ, Azie NE.
Evaluation of the potential pharmacokinetic interac-
tion between almotriptan and fluoxetine in healthy
volunteers. J Clin Pharmacol 2001;41:217-223.
77. Fleishaker JC, Sisson TA, Carel BJ, Azie NE. Lack
of pharmacokinetic interaction between the antimi-
graine compound, almotriptan, and propranolol in
healthy volunteers. Cephalalgia 2001;21:61-65.
78. Fleishaker JC, Sisson TA, Carel BJ, Azie NE.
Pharmacokinetic interaction between verapamil and
almotriptan in healthy volunteers. Clin Pharmacol
Ther 2000;67:498-503.
79. Fleishaker JC, Ryan KK, Carel BJ, Azie NE. Effect
of MAO-A inhibition on the pharmacokinetics of a
novel antimigraine agent, almotriptan, in humans. Paper
presented at: Annual Meeting of the American Academy
of Neurology; April 17-24, 1999; Toronto, Ontario.
80. Dahlöf C, Tfelt-Hansen P, Massiou H, Fazekas A,
for the Almotriptan Study Group. Dose finding,
placebo-controlled study of oral almotriptan in the
FEBRUARY 2002

acute treatment of migraine. Neurology 2001;57:
1811-1817.
81. Dowson A. Almotriptan is an effective and well-
tolerated treatment for migraine pain: Results of a ran-
domised, double-blind, placebo-controlled clinical
trial. Cephalalgia 2002. In press.
82. Pascual J, Falk RM, Piessens F, et al. Consistent
efficacy and tolerability of almotriptan in the acute
treatment of multiple migraine attacks: Results of a
large, randomized, double-blind, placebo-controlled
study. Cephalalgia 2000;20:588-596.
83. Spierings EL, Gomez-Mancilla B, Grosz DE,
Rowland CR, Whaley FS, Jirgens KJ. Oral almotriptan
vs. oral sumatriptan in the abortive treatment of
migraine: A double-blind, randomized, parallel-
VOL. 8, NO. 3, SUP. THE AMERICAN JOURNAL OF MANAGED CARE
Migraine: Diagnosis, Management, and New Treatment Options
group, optimum-dose comparison. Arch Neurol
2001;58:944-950.
84. Dodick DW. Oral almotriptan in the treatment of
migraine: Safety and tolerability. Headache 2001;41:
449-455.
85. Pfaffenrath V, Cunin G, Sjonell G, Prendergast S.
Efficacy and safety of sumatriptan tablets (25 mg, 50
mg, and 100 mg) in the acute treatment of migraine:
Defining the optimum doses of oral sumatriptan.
Headache 1998;38:184-190.
86. Multinational Oral Sumatriptan and Cafergot
Comparative Study Group. A randomized, double-
blind comparison of sumatriptan and cafergot in the
acute treatment of migraine. Eur Neurol 1991;
31:314-322.
S73