Recognition of Migraine
Advances in Migraine
Treatment
George R. Nissan, DO
Merle L. Diamond, MD
Migraine is a common, incapacitating disorder that is underdiagnosed in clinical practice. Early and correct diagnosis of migraine is essential and can lead
to significant improvements in a patient’s quality of life. In the clinical practice
setting, a screening tool can be used that can help differentiate migraine from
other headache disorders. New research into the development of central sensitization and cutaneous allodynia in chronic migraine sufferers has led to an
early treatment approach with triptans and other agents for acute migraine
episodes. This approach results in greater 2-hour headache pain-free results. The
use of botulinum toxin type A in the prophylaxis of migraine and mixedheadache types offers an alternative treatment in patients who may not have
responded to other currently available migraine prophylactic agents.
M
igraine is one of the most prevalent disorders seen in clinical
practice today, affecting nearly 28 million Americans. Migraine is also a major
Dr Nissan is a staff physician at the Diamond
Headache Clinic, and Dr Diamond is associate
director of the Diamond Headache Clinic in Chicago,
Ill. Dr Diamond is also a clinical assistant professor
in the Department of Medicine at The Chicago
Medical School at Rosalind Franklin University of
Medicine and Science, in North Chicago, Ill.
Dr Nissan has served as a consultant to and/or
conducted research with Ortho-McNeil Pharmaceutical, Inc. Dr Diamond has served as a speaker
for AstraZeneca; GlaxoSmithKline; Merck & Co,
Inc; Ortho-McNeil Pharmaceutical, Inc; and Pfizer
Inc. She has served as a consultant for GlaxoSmithKline and Merck & Co, Inc; and she has conducted research for Abbott Laboratories;
AstraZeneca; GlaxoSmithKline; Merck & Co, Inc;
Ortho-McNeil McNeil Pharmaceutical, Inc; Pfizer
Inc; Pozen, Inc; and Winston Laboratories.
Address correspondence to George R. Nissan,
DO, Diamond Headache Clinic, 467 W Deming Pl,
Suite 500, Chicago, IL 60614-2970.
E-mail: [email protected]
cause of disability in the workplace,
leading to indirect costs to society
greater than 13 billion dollars a year.1
The prevalence of migraine is highest
during the years of peak productivity, ie,
between the ages of 25 and 55 years.
More than half of all patients
meeting the International Headache
Society (IHS) criteria for migraine,2(pp24-25)
have migraine that remains undiagnosed. 3 Several new advances in
migraine management have been made
in regard to the recognition of the disease, the pathogenesis of migraine, and
the phenomenon of central sensitization,
the emphasis on the early treatment of
patients with acute migraine and prevention modes of therapy, and the use of
botulinum toxin type A as a prophylactic
agent for chronic migraine.
Nissan and Diamond • Advances in Migraine Treatment
The American Migraine Study II revealed
the number of patients who meet the
IHS criteria (Table 1) for migraine, yet
had their headache diagnosed as sinus
headache, tension-type headache,
headache due to temporomandibular
joint dysfunction (TMJ), and other
headache types.4 The study observed
that of the patients who met the IHS criteria for migraine, 32% reported a physician’s diagnosis of tension-type headache.
Among the difficulties in differentiating
tension-type headache from migraine is
that at least 10% of patients with migraine
have bilateral pain and up to 82% have
neck pain,5 symptoms that are commonly
associated with tension-type headache.
Additionally, up to 50% of the patients
who met IHS criteria for migraine
reported nonpulsating pain, and up to
84% identified stress or tension as a precipitant of their headache.
The importance of early recognition
of migraine can lead to significant
improvement in the patient’s quality of
life. It is important to remember that by
the time patients present with the complaint of headache, they have likely been
suffering for many years. Prompt clinical recognition of migraine can prevent
unnecessary procedures and tests such as
lumbar puncture, electroencephalography (EEG), and repeated computed
tomography (CT) scans of the sinuses.
Months and even years can be wasted
in pursuing inappropriate treatment
when patients meeting the clinical criteria for migraine have their headaches
diagnosed as “sinus headache” or
headache due to “stress,” depression, or
anxiety.
Because migraine is believed to be a
chronic and progressive disease,6 delay in
appropriate treatment may lose crucial
time in halting progression of the disease and may hasten the development
of central sensitization within and
between attacks. Although this situation
has not been fully investigated scientifically, poor migraine hygiene is widely
believed to lower the threshold for
This continuing medical education publication supported by
an unrestricted educational grant from Merck & Co, Inc
JAOA • Supplement 2 • Vol 105 • No 4 • April 2005 • S9
attacks and, for patients at risk, potentiate the development of chronic
migraine. This progression from episodic
migraine to chronic migraine occurs in
approximately 5% of the population.6
Many clinicians do not screen for
migraine as they find it time-consuming
and another problem to add to “the list”;
yet, early and effective intervention
allows episodic migraine to be successfully managed.
When patients present to a primary
care physician’s office with a complaint
of headache, it is essential that the physician obtain a thorough history. The interview should include questions about
family history as well as the location, frequency, and severity of the headaches.
The history should reveal the presence of
premonitory symptoms (prodrome), an
aura, associated symptoms, and whether
the headache is exacerbated by exertion.
Neck pain, though not a part of the IHS
diagnostic criteria,2(pp24-25) is frequently
present and contributes to the misdiagnosis as tension-type headache.7
The presence of bilateral nasal
drainage with the headache is often mistakenly labeled as “sinus headache.” The
presence of autonomic symptoms,
including lacrimation and rhinorrhea, is
important in the migraine history.
Patients with frequent migraine, multiple comorbidities, or analgesic overuse
(or a combination of these situations),
underscore the importance of a detailed
history.
In a busy primary care practice, easy
screening devices are vital tools, and several are currently available. ID Migraine
is a validated tool useful in migraine
screening. Impact-based questions can
also help differentiate the patients with
migraine from that small percentage of
patients presenting to a primary care
office with organic disorders.8 This test
includes three screening questions that
can help identify candidates who are
likely migraine sufferers:
Do you have recurrent headaches that
interfere with work, family, or social
functions?
Do your headaches last at least
4 hours?
Have you had new or different
headaches in the past 6 months?
A migraine diagnosis is established if
Table 1
2004 International Headache Society Criteria
for Migraine Without Aura
1.1 Migraine Without Aura
Diagnostic criteria
A. At least five attacks fulfilling criteria B through D
B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated)
C. Headache has at least two of the following characteristics:
1) Unilateral location
2) Pulsatile quality
3) Moderate or severe pain intensity
4) Aggravated by or causing avoidance of routine physical activity
(eg, walking or climbing stairs)
D. During headache at least one of the following:
1) Nausea and/or vomiting
2) Photophobia and phonophobia
E. Not attributed to another disorder
Source: The International Classification of Headache Disorders, 2nd edition.
Cephalalgia. 2004;24(Suppl 1):9-160.
patients reply “Yes” to the first two questions and “No” to the third question.
Other tools are impact based. If the
clinical history is strongly suggestive of
migraine, it is important to establish the
diagnosis and initiate treatment early
with therapy for acute attacks and
lifestyle education (diet, relaxation exercises, and coping methods). Preventive
treatment (-blockers, anticonvulsants,
tricyclic antidepressants, etc) should be
started if patients have one of the following alone or in combination: a high
frequency of migraine attacks, their
abortive medications are not reliably
effective, or they have a high level of disability.
Pathogenesis of Migraine/Central
Sensitization
The theories of migraine pathophysiology have traditionally fallen into two
categories: vasogenic and neurogenic.
For many years, the vascular theory of
migraine was supported by the following
observations:
Visual auras transiently resolved with
cerebral vasodilation using amyl nitrate
or by inhalation of a gas mixture of 10%
carbon dioxide and 90% oxygen.
The superficial temporal artery
increased in pulse amplitude with an
increased throbbing quality of pain.
S10 • JAOA • Supplement 2 • Vol 105 • No 4 • April 2005
Ergotamine, which is a vasoconstrictor, relieved the pulsations of the
superficial temporal artery and the pain.9
Based on these observations, it was
hypothesized that intracranial vasoconstriction was responsible for the migraine
aura and that head pain resulted from
reactive vasodilation.
The neurogenic theory of migraine
offers the hypothesis that migraine originates from neuronal dysfunction. Based
on the concept of the cortical spreading
depression of Leao,10 the aura is characterized by a wave of reduced cerebral
blood flow (oligemia) that passes across
the cerebral cortex at a rate of 2 mm to
6 mm per minute. Oligemia is a response
to depressed neuronal function and is
present even when the headache begins.
Recent research focusing on the
physiologic causes of migraine has
revealed a neurovascular etiology, which
includes neurochemical imbalances, the
trigeminal system, and meningeal blood
vessels. The neurovascular theory proposes that migraine attacks are generated in the brain rather than in the vasculature. The threshold for the initiation
of cortical excitation is lowered because
of neuronal hyperexcitability. Migraine
aura is thought to occur when normally
nonnoxious stimuli trigger spontaneous
depolarization. Neuronal function is sub-
Nissan and Diamond • Advances in Migraine Treatment
Table 2
Medications Used to Treat Patients With Acute Migraine Attacks
According to Evidence of Scientific Effect
as Harmful or Ineffective and as Not Statistically or Clinically Significant*
Scientific Effect
and Medication
Adverse Effects
Use (by Consensus)
Effect Harmful or Ineffective
NSAIDs and
Nonopiate Analgesics
Acetaminophen
Infrequent
Pregnant migraineur
Frequent
Consider for selected patients
with moderate to severe migraine
Infrequent to
occasional
Adjunct therapy; may
be choice for acute attacks
of migraine
Infrequent
Consider in
emergency department
First-line for moderate
to severe migraine
Effect Not Statistically
or Clinically Significant
Ergot Alkaloids and
Derivatives
Ergotamine
Ergotamine plus caffeine
Antiemetics
Metoclopramide IM
NSAIDs and
Nonopiate Analgesics
Ketorolac IM
Oral NSAIDs
— flubiprofen
— naproxen
—
—
—
Other Medications
Corticosteroids
IV plus antiemetics
dexamethasone
hydrocortisone
Isometheptene compound
Occasional
Infrequent
Rescue therapy
in status migrainosus
Infrequent
Mild to moderate headache
*IM
indicates intramuscular; IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs.
Source: Adapted from Silberstein SD, for the US Headache Consortium. Practice parameter:
Evidence-based guidelines for migraine headache (An evidence-based review). American Academy
of Neurology; 2004. Available at: http://www.neurology.org/cgi/reprint/55/6/754.pdf. Accessed
April 19, 2005.
sequently suppressed, and this suppression spreads across the cortex.
The phenomenon of central sensitization is an important component in the
pathogenesis of migraine. This mechanism proposes that changes in neural
physiology lead to increased sensitivity
to normal sensations that occur during
migraine. These sensations occur when
performing activities such as combing
the hair, bending, and wearing tight
clothing. Over time, it is believed that
cranial nociceptors are sensitized by multiple migraine attacks. Neuropeptides
such as substance P and calcitonin generelated peptide (cGRP) are released
during the migrainous state and produce
perivascular neurogenic inflammation.
The inflammatory state likely sensitizes
cranial nociceptors and subsequently
lowers their threshold for activation and
expands their receptive field.11 Secondand third-order neurons are then activated. 12 Exposure to repeated pain
episodes ultimately results in increased
hyperalgesia (lowered pain threshold)
and cutaneous allodynia at both the
painful and remote body regions.
Nissan and Diamond • Advances in Migraine Treatment
Cutaneous allodynia refers to the
generation of a painful response by normally innocuous stimuli.13 In a recent
study of 42 patients with migraine,
mechanical and thermal pain thresholds
were repeatedly measured in the periorbital and forearm skin during and
between acute headache attacks. Nearly
79% of the subjects exhibited cutaneous
allodynia.14 It is important to emphasize
the need to treat acute migraine attacks
early to prevent the occurrence of cutaneous allodynia.
In a study of 100 patients with neck
pain during migraine, the subjects were
stratified into 50 with neck pain prior to
head pain and 50 with head pain prior to
neck pain.7 Each subject was then treated
with sumatriptan succinate, 100 mg, at
the first sign of neck pain. The primary
endpoint was headache-free at 2 hours.
The secondary endpoints were neck
pain-free at 2 hours—a clinical marker
for allodynia (neck muscle soreness)—
and incidence of triptan sensations. The
results were highly significant statistically. For those subjects who initially had
neck pain, both 2-hour pain-free
(headache and neck pain) results were
tremendous (89.4% and 82.9%, respectively). For those subjects who had neck
pain after head pain, only 7.3% achieved
headache-free results at 2 hours and only
4.9% had neck-pain–free results.
What does this mean for practicing
physicians in the approach to early intervention of acute migraine attacks? The
marker for triptan responsiveness in this
case is early neck pain prior to the development of headache. If the neck pain
occurs after the headache, then allodynia
has already developed and central sensitization has occurred. This situation
renders the triptans more likely to be
ineffective in treating patients for the
pain of headache. Physicians should
encourage patients with migraine to use
the triptan early in the course of the
headache prior to the development of
allodynia.
The triptans, which are administered
in injectable, oral, and nasal formulations, achieve significant 2-hour
headache-free results when used early
in the pre-allodynia stage. It is also important to emphasize to patients that they
should not use a triptan to treat an acute
JAOA • Supplement 2 • Vol 105 • No 4 • April 2005 • S11
migraine more frequently than 2 days a
week to decrease the possible development of rebound headaches.
Table 3
Medications Used to Treat Patients With Acute Migraine Attacks
According to Evidence of Scientific Effect as Statistically Significant
and Exceeding Minimally Clinically Significant Benefit
Preventive Intervention
The decision to undertake preventive
treatment in patients with migraine
remains significantly controversial. Issues
in preventive treatment include:
when to initiate therapy and for how
long,
which agents to use,
whether a patient who requires preventive therapy will always require preventive therapy, and
number of migraines per month that
indicate the need for preventive therapy.
For many of these issues, definitive
answers are still pending. What is known
is that few patients with migraine receive
preventive treatment, and no consensus
has been established as to when to initiate
treatment. With the advent of triptan
therapy and the limited efficacy of some
preventive agents, we have experienced
a decade of more hesitancy in committing patients to preventive therapy. Definite guidelines, such as those published
by the Headache Consortium,27 may be
used as a reference (Tables 2, 3, and 4).
Patients who have a high frequency
of migraine attacks are typically good
candidates for preventive treatment as
are those individuals with infrequent,
yet prolonged, attacks. Attacks that are
poorly controlled with appropriately
used modes of therapy for acute attacks
may indicate that the patient is a likely
candidate for preventive treatment.
Patients with multiple comorbidities in
addition to migraine seem to be at risk for
more frequent attacks15 and should be
considered for preventive treatment.
As the population with migraine
ages, some patients will achieve a reduction in the frequency and severity of
attacks; however, some modes of therapy
for acute attacks may be contraindicated
because of cardiovascular risk factors as
seen with the triptans and ergotamine, or
gastrointestinal and renal issues with
nonsteroidal anti-inflammatory drugs
(NSAIDs). For these older patients who
are having frequent and severe migraine
episodes, preventive treatment may be
necessary. Some patients prefer to prevent attacks and would like to avoid
Medication
Adverse Effects
Use (by Consensus)
Oral Triptans
Naratriptan
Infrequent
Moderate to severe migraine†
Ergot Alkaloids and
Derivatives
Dihydroergotamine IV
Dihydroergotamine IM
Dihydroergotamine nasal spray
Frequent
Occasional
Occasional
Low recurrence
Moderate to severe migraine†
Moderate to severe migraine†
Mild to
moderate
Adjunct therapy; may be
choice for acute attacks
Occasional
First-line for mild
to moderate migraine
Antiemetics
Chlorpromazine IM/IV
Metoclopramide PR/IV
NSAIDs and
Nonopiate Analgesics
Oral NSAIDs
— aspirin
— diclofenac potassium
— ibuprofen
— naproxen sodium
Barbiturate Hypnotics
Butalbital, ASA, caffeine, codeine
Opiate Analgesics
Opiates—oral combinations
— acetaminophen,
codeine combinations
Opiates—parenteral department
— butorphanol IM
Occasional use for moderate
to severe migraine; limit use
Occasional
Moderate to severe migraine;
rescue therapy; limit use
Frequent
Reserved for emergency
department use or rescue
medication; limit use
Frequent
Uncertain
— meperidine IM/IV
— methadone IM
Other Medications
Lidocaine IN
*ASA
indicates acetylsalicylic acid; IM, intramuscular; IN, intranasal; IV, intravenous;
NSAIDs, nonsteroidal anti-inflammatory drugs; PR, per rectum; SC, subcutaneous.
†Less severe migraine when nonopiate medications fail.
Source: Adapted from Silberstein SD, for the US Headache Consortium. Practice parameter:
Evidence-based guidelines for migraine headache (An evidence-based review). American Academy of
Neurology; 2004. Available at: http://www.neurology.org/cgi/reprint/55/6/754.pdf. Accessed April 19, 2005.
therapy for acute episodes. Other patients
may be successful with using therapy
for acute attacks but have intermittent
episodes in which prevention is warranted. It is important to remember
migraine escalates during the late thirties and into the forties, especially in
women.16
A thorough assessment of risk factors for exacerbation of migraine is useful
S12 • JAOA • Supplement 2 • Vol 105 • No 4 • April 2005
before considering migraine prevention.
A careful evaluation of analgesic and caffeine use is also helpful. Maintaining regular sleep and eating patterns, as well as
exercising, may improve the patient’s
overall outcome. Reviewing headache
diaries or calendars are useful for both
the patient and physician to determine
any progress. These headache calendars
can often facilitate monitoring of patient
Nissan and Diamond • Advances in Migraine Treatment
Table 4
Medications Used to Treat Patients With Acute Migraine Attacks
According to Evidence of Scientific Effect as Statistically Significant and
Far Exceeding Minimally Clinically Significant Benefit*
Medication
Adverse Effects
Use (by Consensus)
Triptans
Sumatriptan nasal spray
Occasional
Moderate to severe migraine;
useful when nonoral route is needed†
—
—
—
Occasional
Occasional
Occasional
Occasional
Moderate to severe migraine†
Frequent
Moderate to severe migraine;
useful when nonoral route is needed†
Dihydroergotamine SC
Occasional
Moderate to severe migraine
Dihydroergotamine IV
plus antiemetics
Frequent
Status migrainosus; therapy
of choice in emergency department
Antiemetics
Prochlorperazine IM
Occasional
Prochlorperazine IV
Frequent
Adjunct first-line therapy in
emergency department or office;
consider as adjunct (all 3 forms)
Prochlorperazine PR
Occasional
Oral triptans
rizatriptan
sumatriptan
zolmitriptan
Sumatriptan SC
Ergot Alkaloids
and Derivatives
Topiramate
†
Combination Analgesics
Acetaminophen,
aspirin, caffeine
Opiate Analgesics
Butorphenol nasal spray
channel blockers, and muscle relaxants.
None of these alternative agents has
either applied for, or received, FDA
approval. To evaluate their efficacy, the
Headache Consortium again evaluated
the quality of the evidence regarding
these medications and has rated them in
terms of evidence and efficacy. Adding
the patient presentation to the evidencebased information can be a highly useful
tool in selecting potential medications
for tolerability and appropriate indication. Recognizing comorbidity may also
be a useful tool in determining therapeutic options. Other important factors
are dosing and adequate trials to assess
the benefits of the medication.
Infrequent
First-line for migraine
Frequent
Moderate to severe migraine;
rescue therapy; limit use
*Less
severe migraine when nonopiate medications fail.
IM, intramuscular; IV, intravenous; PR, per rectum; SC, subcutaneous.
†Less severe migraine when nonopiate medications fail.
Source: Adapted from Silberstein SD, for the US Headache Consortium. Practice parameter:
Evidence-based guidelines for migraine headache (An evidence-based review). American Academy of
Neurology; 2004. Available at: http://www.neurology.org/cgi/reprint/55/6/754.pdf. Accessed April 19, 2005.
compliance with early intervention and
determining migraine triggers, as well
as yielding information about timing of
attacks. For example, patients with early
morning migraine, 17 may require
injectable medications to successfully
abort and manage their attacks. A significant feature to be considered is that
about 25% of female migraineurs may
become pregnant during their headache
course. Therefore, the safety of the
mother and the fetus must be given special consideration.
Currently, five agents are approved
by the US Food and Drug Administration (FDA) for migraine prophylaxis, and
include divalproex sodium, propranolol
hydrochloride, timolol maleate, topiramate, and methysergide (which is no
longer available in the United States).
Over the years, many other medications
have been used to prevent migraine with
varying success. Since the 1960s, the tricyclic antidepressants have been used in
migraine prophylaxis. Other agents used
for migraine prevention include other
antiepileptic drugs, NSAIDs, selective
serotonin-reuptake inhibitors, calcium
Nissan and Diamond • Advances in Migraine Treatment
The newest prophylactic agent approved
by the FDA is topiramate, which garnered approval during 2004. This
antiepileptic drug has been available for
a few years but was used off-label for
migraine prevention. In clinical trials,18,19
the drug decreased migraine attacks by
50% and was well tolerated. The experience from the clinical trials with topiramate showed efficacy at doses between
100 mg and 200 mg. Most patients tolerated the medication well and were able
to remain in the study.
Clinically, some important teaching
points are necessary for patients using
this medication. Patients should be cognizant that some tiredness or cognitive
dysfunction can occur but are usually
transient and mild. Topiramate therapy
should be started at a dose of 25 mg and
increased by 25-mg increments every
week to 10 days as tolerated. Some
patients will not require 100-mg doses
to achieve a significant response. Typical side effects include transient peripheral paresthesias and a distaste for carbonated beverages. Acute glaucoma has
rarely occurred with initiation of this
agent. Symptoms of renal colic may exacerbate with topiramate. Topiramate is a
category C drug in pregnancy and, at
doses of 200 mg/d or greater, it can
decrease the efficacy of oral contraceptives.
Patients have found excellent results
with this agent, and unlike many other
migraine preventive medications, it is
often weight neutral. Also, some patients
JAOA • Supplement 2 • Vol 105 • No 4 • April 2005 • S13
can lose weight during topiramate
therapy, though it is usually a modest
loss. This agent should be used cautiously in patients with a history of eating
disorders.
Botulinum Toxin Type A
and Chronic Migraine
With botulinum toxin type A, pain relief
has been reported frequently in the treatment of cervical dystonia and spasticity.20,21 The results of the initial studies
revealed significant benefits to the quality
of life of patients with cervical dystonia
and spasticity,22 benefits that could
extend to patients with chronic migraine
and chronic daily headache. It is also currently FDA-approved for the treatment of
blepharospasm, strabismus, and severe
primary hyperhydrosis that is inadequately managed with topical agents.
Botulinum toxin type A is a novel prophylactic headache treatment that,
through its actions on the neuromuscular
junction, has muscular actions without
vascular or systemic effects.
The number of clinical trials has
increased in the evaluation of the efficacy of botulinum toxin type A in the
prophylactic treatment of migraine. In a
study of 123 patients who met the IHS
criteria for migraine,2(pp24-25) the patients
were randomly assigned to receive either
0 U, 25 U, or 75 U of botulinum toxin
type A.23 Each sample was injected symmetrically into the glabellar, frontalis,
and temporalis muscles. While patients
assessed both active treatments favorably compared with placebo, only the
25-U treatment group fared significantly
better than placebo in several endpoints,
including reduction in mean frequency of
moderate to severe migraine attacks
during days 31 to 60 (P .008) and then
days 61 to 90 (P .04) postinjection.
Patients receiving 25 U also had a
reduced number of days using acute
migraine medications at month 2
(P .03). No serious treatment-related
adverse events were reported.
A 3-year retrospective study was
conducted in 271 patients who had
headache diagnosed according to IHS
criteria2(pp24-25) as either chronic daily
headache (headache for more than 15
days per month), episodic tension-type
headache, episodic migraine, or “mixed”
headache (headache less than 15 days
per month, a combination of migraine
and tension-type headaches).24 The main
reasons given for patients seeking
botulinum toxin type A treatment were
a refractory response to oral medications
(77%) and overuse of medication for
acute episodes (48%).
Depression, which is commonly
observed in patients with “refractory”
migraine, was a frequent comorbidity in
the patient population (34%). The mean
total treatment period was 8.6 months,
during which time patients received an
average of 3.4 treatments of botulinum
toxin type A. All patients were treated
at least twice, approximately 3 months
between treatments. The results of the
study revealed that botulinum toxin type
A treatment significantly reduced
headache frequency regardless of
headache type (all, P .001). The
number of headache days per month
decreased from 18.9 at baseline to 8.3 at
last treatment, a 56% reduction (P .001).
Headache intensity decreased significantly from 2.4 points at baseline to 1.8
points at last treatment (P .001), and
was highly significant in patients with
episodic migraine, chronic daily
headache, and mixed headache. Approximately 95% of the patients reported no
adverse events.24
Although results such as these are
encouraging, more placebo-controlled
studies will need to demonstrate consistent efficacy data. Additionally, the high
placebo response rate will need to be
evaluated further. The precise mechanism by which head pain is reduced by
this treatment modality is unclear. A possible hypothesis is that treatment with
botulinum toxin type A may reduce the
local release of nociceptive neuropeptides.25 Also, it is postulated that the
nerves may be stimulated by the strong
contraction of the corrugator supercilii
and the temporalis muscles.26
The question that most physicians
ask is, what type of patient who has
headaches is a suitable candidate for preventive treatment with botulinum toxin
type A? If the patient has localized pain
in the neck associated with the headache,
or if the headaches persist despite adequate headache preventive treatment (or
both), then treatment with botulinum
S14 • JAOA • Supplement 2 • Vol 105 • No 4 • April 2005
toxin type A may be considered. Patients
may have rebound headaches if excessive
amounts of prescription and over-thecounter analgesics, including acetaminophen, ibuprofen, naproxen, and
aspirin, are used. This type of patient
may also benefit from a trial of botulinum
toxin type A to decrease the use of these
medications.
Serious adverse reactions to
botulinum toxin type A include anaphylaxis, severe dysphagia, focal facial
paralysis, and dysphonia (very rare).
More common reactions include irritation and pain at the injection sites, neck
pain, flulike symptoms, and ptosis. Caution is advised with concomitant use of
neuromuscular blockers, succinylcholine,
quinidine, parenteral aminoglycosides,
and clindamycin hydrochloride as each
of these agents may potentiate the neuromuscular effect of the botulinum toxin.
Also, concomitant use of chloroquine
phosphate and hydroxychloroquine sulfate should be monitored as these drugs
may interfere with the activity of
botulinum toxin type A because of an
unknown mechanism.
Comment
Migraine is a commonly seen medical
disorder in primary care practice that
can be incapacitating and is a major cause
of workplace disability in the United
States. Early and accurate diagnosis of
migraine is important, because patients
who are given incorrect diagnoses of
sinus headache or tension-type headache
tend to have long delays in receiving
appropriate prophylaxis and treatment of
acute migraine attacks. A screening tool
can be used in the office setting to help
distinguish between migraine and other
headache disorders. Current research has
revealed the necessity to treat acute
migraine attacks early and to use a
triptan prior to the development of central sensitization and cutaneous allodynia.
Migraine prophylaxis should be
considered in patients who have at least
three moderate to severe headache days
per month, or in patients who have renal
or cardiovascular risk factors alone or in
combination with other comorbidities
that contraindicate the use of triptans or
other agents for acute migraine.
Nissan and Diamond • Advances in Migraine Treatment
Botulinum toxin type A treatment can
be considered in patients with neck pain
associated with migraine or those with
mixed headache disorders. Further
research into migraine pathogenesis and
treatment continues to evolve and will
provide greater insight into the selection
of patients with migraine for treatment
with botulinum toxin type A.
References
1. 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.
2. The International Classification of Headache
Disorders, 2nd edition. Cephalalgia. 2004;24(Suppl
1):9-160.
3. Lipton RB, Stewart WF, Diamond S, Diamond ML,
Reed M. Prevalence and burden of migraine in
the United States: data from the American
Migraine Study II. Headache. 2001; 41:646-657.
4. Lipton RB, Diamond S, Reed M, Diamond ML,
Stewart WF. Migraine diagnosis and treatment:
results from the American Migraine Study II.
Headache. 2001;41:638-645.
5. Kaniecki RG. Diagnostic challenges in headache:
migraine as the wolf disguised in sheep’s clothing.
Introduction. Neurology. 2002; 58:S1-S2.
6. Lipton RB, Pan J. Is migraine a progressive brain
disease? JAMA. 2004;291:493-494.
7. Kaniecki RG. Migraine and tension-type
headache: an assessment of challenges in diagnosis. Neurology. 2002;58(Suppl 6):S15-S20.
8. Cady RK, Borchert LD, Spalding W, Hart CC,
Sheftell FD. Simple and efficient recognition of
migraine with 3-question headache screen.
Headache. 2004;44:323-327.
9. Wolff HG. Headache and Other Pain. 2nd ed.
New York, NY: Oxford University Press; 1963.
prevention: results of a large controlled trial. Arch
Neurol. 2004;61:490-495.
10. Leao AA. Spreading depression of activity in the
cerebral cortex. J Neurophysiol. 1944;8:379-390.
20. Greene P, Kang U, Fahn S, Brin M, Moskowitz
C, Flaster E. Double-blind, placebo-controlled trial
of botulinum toxin injections for the treatment of
spasmodic torticollis. Neurology. 1990;40:12131218.
11. Burstein R, Yamamura H, Malick A, Strassman
AM. Chemical stimulation of the intracranial dura
induces enhanced responses to facial stimulation in
brain stem trigeminal neurons. J Neurophysiol.
1998;79:964-982.
12. Yamamura H, Malick A, Chamberlin NL,
Burstein R. Cardiovascular and neuronal responses
to head stimulation reflect central sensitization
and cutaneous allodynia in a rat model of migraine.
J Neurophysiol. 1999; 81:479-493.
13. Cutrer FM. Pain-sensitive cranial structures:
chemical anatomy. In: Silberstein SD, Lipton RB,
Dalessio DJ, eds. Wolff’s Headache and Other Head
Pain. 7th ed. New York, NY: Oxford University
Press; 2001:50-56.
14. Burstein R, Yarnitsky D, Goor-Aryeh, Ransil BJ,
Bajwa ZH. An association between migraine and
cutaneous allodynia. Ann Neurol. 2000;47:614-624.
15. Scher AI, Lipton RB, Stewart W. Risk factors
for chronic daily headache. Curr Pain Headache
Rep. 2002;6:486-491.
16. Lipton RB, Scher AI, Kolodner K, Liberman J,
Steiner TJ, Stewart WF. Migraine in the United
States: epidemiology and patterns of health care
use. Neurology. 2002;58:885-894.
17. Giffin NJ, Ruggiero L, Lipton RB, Silberstein
SD, Tvedskov JF, Olesen J, et al. Premonitory symptoms in migraine: An electronic diary study. Neurology. 2003;60:935-940.
18. Brandes JL, Saper JR, Diamond M, Couch JR,
Lewis DW, Schmitt J, et al. Topiramate for migraine
prevention: a randomized controlled trial. JAMA.
2004;291:965-973.
21. Jankovic J, Schwartz K. Botulinum toxin injections for cervical dystonia. Neurology. 1990;40:277280.
22. Jankovic J, Esquenazi A, Fehlings D, Freitag F,
Lang AM, Naumann M. Evidence-based review of
patient-reported outcomes with botulinum toxin
type A. Clin Neuropharmacol. 2004;27:234-244.
23. Silberstein S, Mathew N, Saper J, Jenkins S.
Botulinum toxin type A as a migraine preventive
treatment. For the BOTOX Migraine Clinical
Research Group. Headache. 2000;40:445-450.
24. Blumenfeld A. Botulinum toxin type A as an
effective prophylactic treatment in primary
headache disorders. Headache. 2003;43:853-860.
25. Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K,
Aoki S, Mukuno K, et al. Presynaptic effects of
botulinum toxin type A on the neuronally evoked
response of albino and pigmented rabbit iris
sphincter and dilator muscles. Jpn J Ophthalmol.
2000;44:106-109.
26. Guyuron B, Varghai A, Michelow BJ, Thomas T,
Davis J. Corrugator supercilii muscle resection and
migraine headaches. Plast Reconstr Surg.
2000;106:429-434.
27. Silberstein SD, for the US Headache Consortium. Practice parameter: Evidence-based guidelines for migraine headache (An evidence-based
review). American Academy of Neurology; 2004.
Available at: http://www.neurology.org/cgi/
reprint/55/6/754.pdf. Accessed March 4, 2005.
19. Silberstein SD, Neto W, Schmitt J, Jacobs D;
MIGR-001 Study Group. Topiramate in migraine
Nissan and Diamond • Advances in Migraine Treatment
JAOA • Supplement 2 • Vol 105 • No 4 • April 2005 • S15