1. Dermatol Clin 22 (2004) 167 – 175
Botulinum neurotoxin for the treatment of migraine and
other primary headache disorders
Andrew M. Blumenfeld, MDa,*, David W. Dodick, MD, FRCP(C), FACPb,c,
Stephen D. Silberstein, MD, FACPd
a
Department of Neurology, Kaiser Permanente, 4405 Vandever Avenue, San Diego, CA 92120, USA
b
Department of Neurology, Mayo Medical School, USA
c
Department of Neurology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
d
Jefferson Headache Center, Thomas Jefferson University Hospital, 111 South 11th Street, Suite 8130,
Philadelphia, PA 19107, USA
Migraine is a chronic neurovascular disorder that [6]. There is a significant need to develop more
afflicts 2% to 15% of the world’s population. In the effective therapies for migraine prevention because
United States there are an estimated 28 million mi- 35% of migraineurs suffer from two to three severe
graine sufferers, with women being affected three attacks per month, whereas 25% suffer from more than
times as often as men [1]. It is characterized by severe four attacks per month [6]. Furthermore, more than 4%
headaches and is often associated with nausea, vomit- of the United States population suffers from chronic
ing, and heightened sensitivity to sound and light at the daily headache [7].
peak of the attack. Migraine is considered to cause Patients with frequent, disabling, or refractory
more disability than epilepsy, and severe migraine has migraine should be considered for prophylactic treat-
been judged by the World Health Organization to be as ment. Current United States guidelines recommend
disabling as quadriplegia, psychosis, and dementia [2]. preventive therapy in one or more of the following
Most sufferers are in their most socially active and situations: (1) frequent headaches; (2) recurring mi-
productive years (25 to 55) [1]. Not only is migraine graines that significantly interfere with daily routine;
painful and disabling for the sufferer, but it exerts (3) failure of, a contraindication to, overuse of, or ad-
a significant economic burden on society. It causes verse events (AEs) with acute migraine therapies;
112 million bedridden days each year and costs (4) cost of acute and preventive therapies; (5) patient
$14 billion in reduced productivity and missed work- preference; and (6) the presence of uncommon mi-
days [3]. The economic burden of migraine is com- graine conditions, including hemiplegic migraine,
parable with that of diabetes [4] and higher than that basilar migraine, migraine with prolonged aura, or
of asthma [5]. migrainous infraction [8]. Although numerous thera-
Even among migraineurs who consult a physician, pies are currently available for the prevention and
many are not satisfied with their therapy and report that treatment of migraine, most of these agents have sig-
prescribed medications are not always optimal. Triptan nificant side effects.
medications, the most effective therapy for acute Commonly used agents for migraine prophy-
migraine attacks, are only effective in improving the laxis include b-adrenergic blockers, calcium channel
pain and associated migraine symptoms, such as blockers, tricyclic antidepressants, and anticonvul-
photophobia and nausea, in up to two thirds of patients sants (Table 1). Moderate to severe AEs are not un-
common with all available prophylactic medications.
b-Blockers are known to produce a wide array of
* Corresponding author. AEs, including drowsiness, fatigue, lethargy, sleep
E-mail address: Andrew.m.Blumenfeld@kp.org disorders, and depression. AEs typically associated
(A.M. Blumenfeld). with the calcium channel blockers include constipa-
0733-8635/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved.
doi:10.1016/S0733-8635(03)00105-0

2. 168 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175
Table 1 the treatment of glabellar lines [11]. Although not
Preventive therapeutics commonly prescribed for migraine currently indicated, it has also been safely used for
Quality of Scientific Clinical spasticity; hyperkinetic disorders, such as tremor;
Evidencea Effectb Impressionc autonomic disorders, such as hyperhidrosis; and cos-
Anticonvulsants metically troublesome hyperfunctional facial lines
Divalproex sodium A +++ +++ (crow’s feet, forehead lines) [12,13].
Topiramate A +++ +++ The analgesic effect of BoNT-A has long been
Gabapentin B ++ ++ observed in the treatment of dystonia and spasticity
Antidepressants [14,15]. This led to further investigation of the efficacy
Amitriptyline A +++ +++ of BoNT-A for other painful conditions, including
Fluoxetine B + + migraine and tension-type headaches. Because most
b-blockers
clinical experience with the use of BoNT for the
Propranolol A ++ +++
treatment of headache has been with BoNT-A, this
Metoprolol B ++ +++
Timolol A +++ ++ article describes the potential antinociceptive mecha-
Atenolol B ++ ++ nism of action of BoNT-A, summarizes the clinical
Calcium channel blockers evidence to date for BoNT-A as effective migraine
Verapamil B + + prophylactic therapy, and reviews the injection tech-
Nimodipine B + + nique and strategies used in treating headache and
a
A, Multiple well-designed randomized clinical trials, cervical myofascial pain.
directly relevant to the recommendation, yielded a consistent
pattern of findings; B, some evidence from randomized cli-
nical trials supported the recommendation, but scientific sup- Mechanism of action
port was not optimal.
b
+, Effect of medication is either statistically or not Botulinum toxins are exotoxins of the anaerobic
clinically significant; ++, effect of medication is statistically bacterium Clostridium botulinum. This bacterium has
significant and exceeds the minimally clinically significant
eight serotypes: A, B, C-alpha, C-beta, D, E, F, and G.
benefit; +++, effect is statistically significant and far exceeds
the minimally clinically significant benefit. Seven serologically separate exotoxins are produced.
c
+, Somewhat effective: few people get clinically sig- The intracellular targets of each of these toxins vary;
nificant improvement; ++, effective: some people get cli- however, their biologic activity at the neuromuscular
nically significant improvement; +++, very effective: most junction is similar [16].
people get clinically significant improvement. Injection of BoNT-A directly affects neuromuscu-
Adapted from Silberstein SD, Goadsby PJ. Migraine: lar signaling processes. On injection, the toxin enters
Preventive treatment. Cephalalgia 2002;22:491 – 512. the nerve terminals by endocytosis; interacts with
intracellular proteins (snare proteins); and inhibits
the vesicular release of the acetylcholine neurotrans-
tion, peripheral edema, and weight gain [9], whereas mitter at the neuromuscular junction. Inhibition of
the tricyclic antidepressants commonly are associated acetylcholine produces chemical denervation and
with a variety of AEs, including sedation, weight paralysis of the striated muscles. Paralysis usually
gain, dry mouth, constipation, dizziness, mental con- peaks 2 weeks postinjection. Because of molecular
fusion, palpitations, blurred vision, and urinary reten- turnover within the neuromuscular junction and neu-
tion. The AEs associated with antiepileptic drugs are ronal sprouting, neuronal activity begins to return at
unique to each medication, but the most common AEs 3 months, with complete function at approximately
include nausea, vomiting, and gastrointestinal distress 6 months [17].
[9]. Because of the AE profile and limited efficacy of Although neuromuscular activity inhibition may
currently available preventive therapies, there is a alleviate a portion of the pain associated with headache
need for novel and improved prophylactic therapies. disorders, it does not fully explain the pain relief
Recently, the potent neurotoxin botulinum toxin mechanisms mediated by BoNT-A. Intensive research
type-A (BoNT-A) has been under intensive clinical on BoNT-A has begun to suggest that this toxin may
investigation for the treatment of migraine and other interact with several other neuronal signaling path-
types of headache. Over the last 20 years, BoNT-A has ways, although the exact mechanisms remain elusive.
been used to treat a variety of disorders characterized Current data suggest that BoNT-A modifies the sen-
by inappropriate and involuntary muscle contraction sory feedback loop to the central nervous system by
[10]. BNT-A is currently approved for blepharospasm, blocking intrafusal fibers, resulting in decreased acti-
strabismus, cervical dystonia, and, more recently, for vation of muscle spindles. This effectively alters the

3. A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 169
sensory afferent system by reducing the traffic along Ia
spindle afferent fibers [18]. This toxin also seems to
inhibit the release of glutamate from primary afferent
nociceptive fibers, reduce the firing of wide dynamic
range neurons within the dorsal horn of the spinal cord,
and reduce the activity of central nociceptive neurons
as measured by a reduction in the expression of
immediate early genes (c-Fos) after nociceptor stimu-
lation [19]. A reduction in afferent sensory activity
coming from pericranial and cervical muscles, and
inhibition of peripheral and central trigeminal sensi-
tization, may represent the potential mechanisms by
which BoNT-A exerts its therapeutic effect in mi-
graine, tension-type headache, and other primary
headache disorders [20].
Clinical efficacy: retrospective reviews and open-
label trial
Historically, while conducting the initial clinical
trials of BoNT-A for the treatment of hyperfunctional Fig. 2. Injection site: temporalis and masseter muscles.
facial lines, Binder et al [21] noted a correlation
between pericranial BoNT-A injections and alleviation
of migraine headache symptoms. Based on these initial
findings, the authors conducted a combined, multicen-
ter, open-label trial that evaluated the efficacy of
Fig. 3. Injection site: occipital, suboccipital, and trapezius
Fig. 1. Injection sites: glabellar and frontal regions. muscles.

4. 170
Table 2
Retrospective/open-label and placebo-controlled trials of botulinum toxin A treatment for migraine
Study Design (N) and Patient Typea Dose Injection site Primary result reported
Retrospective Reviews/Prospective Open-label Trials
Binder et al (2000) Retrospective chart Mean dose 31 units Fixed injection sites 51% of migraine patients reported
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175
review (N=77) (range 5 – 110 units) Glabellar complete response
Frontal
Temporal
Mauskop and Basedo (2000) Retrospective chart 25 – 100 units Fixed injection sites 85% (23 of 27) of patients reported significant
review (N=27) (frontalis, glabellar, reduction in frequency and intensity
and temporalis)
Some patients received
a combination of fixed
injections and
‘‘follow-the-pain’’ injections
Mauskop (2002) Retrospective chart review (N=78) Varying dose from ‘‘Follow-the-pain’’ protocol Most patients reported partial to complete
Episodic migraine, N=32 25 – 200 units response (no percentage improvement given
Chronic migraine, N=46 in this study)
Miller and Denny (2002) Retrospective chart review (N=48) Varying dose from Fixed injection site 86% of patients treated with BTX-A reported
All patients were chronic headache 50 – 300 units (frontalis, corrugator, nominal benefit with 35% reporting good and
patients who had failed temporalis, splenius captis) 27% very good benefits
previous therapy with ‘‘follow-the-pain’’
as needed
Blumenfeld (2002) Retrospective chart Average dose 63.2 units Injection sites were 25% reduction in headache intensity ( P < .001)
review (N=271) either ‘‘fixed’’ or 56% reduction in headache days per month
Headache types includeb ‘‘follow-the-pain’’ ( P < .0001)
Chronic daily 85.6% of patients reported symptomatic improvement
Episodic-tension
Episodic-migraine
Mixed
Mathew et al (2002) Retrospective chart 50 – 100 units Combination of fixed Three months after third injection a significant
review (N=112) injection sites (frontal/ decrease in the number of headache days
All patients diagnosed with glabellar/ temporal/ ( P < .05) and a decrease in mean MIDAS scores
chronic migraine occipital/ suboccipital) ( P < .01) were observed
and ‘‘follow-the-pain’’

5. Smuts and Barnard (2000) Prospective, open-label 100 units Variable sites 68% (13 of 19) of migraine patients reported
(N=19) (no specific protocol positive response
mentioned in abstract)
Eross and Dodick (2002) Prospective, open-label 25 units Fixed injection sites Of patients who responded > 50% reported an
(N=73) If required based on Frontalis improvement in disability
Episodic migraine, N=12 pain, 25 – 75 additional Temporalis 61% of responders reported decrease in headache
Chronic migraine, N=36 units injected into Procerus frequency and 27% reported decrease in
cervical paraspinals Corrugator headache severity
Placebo-Controlled Trials
Barrientos and Chana (2002) Placebo-controlled (N=30) 50 units Fixed injection sites Significant reduction in frequency (P < .001),
Glabellar severity (P < .02), and adjunct medications
A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175
Frontal (P < .001) compared with placebo
Temporal
Procerus
Trapezius
Splenium capitis
Silberstein et al (2000) Placebo-controlled/ 25 units (low dose) Fixed injection sites 45% of patients in low-dose group (25 units)
double-blind (N=123) 75 units (high dose) Glabellar reported a >50% decrease in frequency
Frontal
Temporal
Brin et al (2000) Placebo-controlled/ Dose not given Fixed injection sites BTX-A was superior than placebo in reducing
double-blind (N=56) in study Frontal severity (P=.04)
Temporal
Ondo et al (2002) Placebo-controlled/ 200 units Individual injection 10% of patients reported a ‘‘dramatic’’ improvement
double-blind (N=60) choice using ‘‘follow- and 24% a ‘‘marked’’ improvement.
Chronic migraine, N=19 the-pain’’ protocol Significant reduction in the number of headache
Chronic tension headache, days (weeks 8 – 12) compared with placebo
N=22 (P < .05)
Features of both types of
headache, N=19
a
Unless specified, patient population consists of migraine headache.
b
Number of patients in each headache not specified.
171

6. 172 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175
BoNT-A for migraine management. Efficacy was poralis muscle. At the end of the 3-month follow-up
categorized as either complete response with total period postinjection, the low-dose BoNT-A group
symptom elimination, partial response with greater experienced a mean decrease of 1.88 moderate-to-
than 50% reduction in headache severity and fre- severe migraines compared with the placebo group
quency, or no beneficial response. In this study, 51% (P = .042). Furthermore, patients in the low-dose
of patients treated with BoNT-A as migraine pro- group had a significant reduction in the incidence of
phylaxis reported a complete response to localized migraine-associated vomiting compared with placebo
head and neck BoNT-A injections with a mean dura- (P = .012). The high-dose BoNT-A group, however,
tion of 4.1 months. An additional 38% reported par- did not have a significant effect on migraine pain and
tial improvement with a mean response period of associated symptoms. In fact, at the higher dose, there
2.7 months [21]. was an increase in AEs. The authors suggest that the
Since then, many researchers have reported their lack of BoNT-A activity at this higher concentration
experience with BoNT-A. Mauskop and Basedo [22] may actually be caused by a lower number of migraine
reviewed chart records of 27 patients treated with headaches at baseline compared with the low-dose
BoNT-A for migraine prophylaxis by injections in BoNT-A group [8]. In this trial, BoNT-A was well
the pericranium. A decrease in headache frequency tolerated with no AEs observed in the low-dose group
and severity was reported in 85% (N = 23) of patients. compared with placebo.
Rather than focusing solely on the end point of severity Barrientos and Chana [29] also conducted a ran-
and frequency of headache, Eross and Dodick [23] domized, placebo-controlled trial (no indication of
evaluated the effect of BoNT-A (25 to 100 units) on being double-blinded) that evaluated the efficacy and
reducing disability in 47 patients with either episodic tolerability of BoNT-A as prophylaxis for episodic
or chronic migraine. Using a well-validated tool to migraine. Thirty patients with a history of two to
assess migraine-related disability (the MIDAS ques- eight migraine attacks per month were enrolled and
tionnaire), 58% of all patients reported a decrease in randomized to receive placebo or 50 units of BoNT-A
migraine-associated disability. Episodic migraine injected in 15 pericranial muscle sites. During the
patients (N = 12) seemed to show the most benefit, 3-month study, when compared with baseline, patients
with 75% reporting a decrease in migraine frequency treated with BoNT-A experienced fewer attacks at
compared with 53% of chronic migraine patients [23]. day 30 (3.7 versus 5.8, P < .02); day 60 (3.2 versus
Other retrospective reviews [24 – 28] further sup- 5.8, P < .2); and day 90 (2.5 versus 5.8, P < .01). In
port the beneficial role of BoNT-A for the preventive comparison, no significant reduction from baseline
treatment of episodic migraine, chronic tension-type was observed in the placebo group. Severity and
headache, and treatment-refractory chronic migraine duration of migraine attacks also were significantly
headaches. Aside from the obvious limitation of a reduced in the BoNT-A group compared with placebo.
retrospective review or open-label design, the weak- At the end of the 3-month study, the BoNT-A – treated
nesses of many of these study reports include small group reported a significant decrease in the use of
patient number; poorly defined end points; and often nonsteroidal anti-inflammatory drugs and triptan
heterogeneous patient populations (episodic-chronic medications for acute headache treatment compared
migraine, tension-type or chronic headaches). with placebo. This supports the previous clinical data
that BoNT-A is effective and well tolerated for pre-
ventive migraine treatment.
Clinical efficacy: placebo-controlled trials A small, double-blind, placebo-controlled study of
BoNT-A conducted by Brin et al [30] further supports
Currently, few well-conducted clinical trials of the efficacy of BoNT-A in migraine. In this trial,
BoNT-A in migraine prevention exist. The first 56 subjects with a history of two to six migraines per
double-blind, placebo-controlled, randomized clinical month were randomized into four groups receiving (1)
trial was published by Silberstein et al [8]. In this study, BoNT-A in frontal-temporal regions, (2) BoNT-A in
123 patients who had experienced between two to frontal and placebo in temporal, (3) placebo in frontal
eight moderate-to-severe migraine headaches over a and BoNT-A in temporal, and (4) placebo in frontal-
3-month period were randomized to receive a single temporal regions. Migraine frequency was reduced by
injection of either placebo, low-dose (25 units), or a median of 1.8 headaches per month in BoNT-A –
high-dose (75 units) BoNT-A. This single dose was treated groups (groups 1 to 3) compared with a median
injected into multiple sites of pericranial muscles reduction of 0.2 headaches per month in the placebo
during the injection visit. Injections were performed group (group 4). This study is limited, however, by its
anteriorly, in the frontalis, glabellar region, and tem- small population size.

7. A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175 173
Recently, Ondo et al [31] conducted a randomized, For patients with only tension-type headaches, the
double-blind, placebo-controlled, parallel clinical trial follow-the-pain approach is used. Even in these cases,
that examined the effect of BoNT-A treatment on pa- cosmetic effects in the frontal region need to be
tients with chronic daily headache, including chronic obtained, but asymmetric injections can be given in
tension-type headache and chronic migraine. Sixty the temporalis, occipitalis, splenius capitus, cervical,
patients who experienced chronic headache more than and subcervical paraspinal muscles. The doses injected
15 days each month were enrolled and randomized to in the cervical-shoulder girdle muscles are low to pre-
receive, based on the ‘‘follow-the-pain’’ rationale, vent any possible weakness, which could cause head-
either 200 units of BoNT-A or matching placebo and ache. Patients need to be assessed carefully for
at 12 weeks, if patient consented, a second open-label associated cervical dystonia, which requires injection
BoNT-A injection. Following the first injection, of the dystonic muscles.
patients treated with BoNT-A had significantly fewer Current available data do not seem to indicate a
headache days from week 8 to 12 compared with dose response-benefit [8,21,23,24]. There is need for
placebo. In addition, 10% of patients treated with further randomized, placebo-controlled clinical trials
BoNT-A reported a dramatic improvement and 24% to identify the optimal dosing regimen and injection
reported a marked improvement compared with 3% sites for BoNT-A. Some data, however, report greater
and 7%, respectively, in the placebo-treated group. At efficacy with repeated dosing. In the Ondo et al [31]
week 24, patients who had received two BoNT-A trial, patients who received a repeat BoNT-A injection
injections had significantly fewer headache days over reported better improvement than patients who re-
the second 12-week period than those receiving one ceived only a single BoNT-A injection [31]; these data
injection (40 versus 19 days, P < .05). are also supported by results from retrospective chart
reviews [26,28]. Until results of large, well-conducted
trials are available, optimal method of BoNT-A deliv-
Use of botulinum toxin A: dosage and ery remains unresolved.
administration
The most common sites of injections include the Tolerability
glabellar (procerus and corrugators), frontal, temporal,
and sometimes the occipital regions (Figs. 1 – 3). The clinical dose of BoNT-A commonly used for
BoNT-A is administered either at fixed injection sites; migraine therapy is between 25 and 100 units, which is
at sites of pain or tenderness (‘‘follow the pain’’); or a 30 to 120 times below the toxic limit [17]. Most
combination of both. The total dosage of toxin, the published trials have reported minimal to no AEs. In
number of units per site of injection, dilution of toxin, a placebo-controlled, double-blind trial, Silberstein
and sites of injection varied widely, however, between et al [8] found that although no serious AEs occurred,
studies (Table 2). The total dosage ranged from 25 to some patients receiving BoNT-A injections experi-
300 units over several injection sites. enced transient minor AEs, including blepharoptosis,
The fixed-site approach consists of bilateral in- diplopia, and injection site weakness. The authors also
jections, even if the patient has strictly unilateral found that injection of high doses of BoNT-A
headaches. The muscles injected are the procerus, (75 units) resulted in a dose-dependent increase in
corrugators, frontalis, and temporalis. Follow-the-pain the side effect profile of BoNT-A. In an open-label
injection sites are identified by history (‘‘Where does it study, Binder et al [21] also reported only minimal and
hurt when you have a headache’’? and ’’ Show me with transient AEs, including brow ptosis, local injection
your hands where the pain is’’) and by examination of discomfort, and ecchymosis at the injection site. Over-
the cervical-shoulder girdle and temporomandibular all, clinical studies and retrospective reviews confirm
musculature. These sites include the frontalis, tempo- the tolerable side effect profile of BoNT-A and that
ralis, occipitalis, trapezius, splenius capitus, suboccipi- associated AEs are typically mild and transient.
tal, and cervical paraspinal muscles.
For patients with migraine or migrainous headache
features by history, treatment with a fixed-site ap- Summary
proach may be required for successful results. When
only a follow-the-pain approach is used in patients Clinical data and experience to date have demon-
with migraine or migrainous headache, two problems strated that BoNT-A is an effective and well-tolerated
arise: first, a poor cosmetic outcome; and second, the therapy for the prevention of migraine and other
headaches often shift to the previously unaffected side. headache disorders. It has a long duration of action

8. 174 A.M. Blumenfeld et al / Dermatol Clin 22 (2004) 167–175
that may last over 4 months with no systemic or serious Evidence-based medicine: botulinum toxin A in mi-
AEs. Several issues remain to be defined, however, graine and tension – type headache. J Neurol 2001;
including dosing, location, and number of injections; 248(suppl 1):34 – 8.
[11] Allergan Pharmaceuticals. BOTOX (botulinum toxin
optimal dilution of BoNT-A; specific headache types
type A) prescribing information. Irvine, CA: Aller-
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toxin type A (BOTOX) in a combination fixed-injec- pincott Williams & Wilkins; 2002. p. 233 – 50.
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num toxin type A (BOTOX) in the prophylactic treat- 21 – 23, 2002.