C ?2007 by American Headache Society
Published by Blackwell Publishing
Botulinum Toxin Type A Prophylactic Treatment of Episodic
Migraine: A Randomized, Double-Blind, Placebo-Controlled
Sheena K. Aurora, MD; Marek Gawel, MB, BCh, FRCPC; Jan L. Brandes, MD; Suriani Pokta, PhD;
Amanda M. VanDenburgh, PhD; for the BOTOX North American Episodic Migraine Study Group
Objective.—This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin
type A (BoNTA; BOTOX?, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine
Patients were screened during a 30-day baseline period, and eligible patients with 4 or more migraine episodes
and ≤15 headache days entered a single-blind 30-day placebo run-in period. Patients were classified as placebo
nonresponders (PNR) if they had at least 4 moderate-to-severe migraine episodes and did not experience at least
a 50% decrease from baseline in the frequency of migraine episodes following their placebo treatment. All other
subjects were classified as placebo responders (PR). Patients were randomized within each stratum (PNR, PR)
to 3 treatments with BoNTA (110 to 260 U of BoNTA per treatment cycle) or placebo at 90-day intervals using a
modified follow-the-pain treatment paradigm. The primary efficacy outcome measure was the mean change from
measures included the proportion of patients with a decrease from baseline of 50% or more migraine episodes per
30-day period. Patients were allowed to take concomitant acute and prophylactic headache medications. Adverse
events were reported.
Results.—A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20
to 65 years) entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean
total dose of BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint
was not met. Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the
PNR stratum treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the
end of the study (day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50%
or more migraine episodes per 30-day period. However, in the group of patients with ≥12 headache days at baseline
day 180 compared with −1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related
adverse events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due
to adverse events (6 BoNTA, 1 placebo).
From Swedish Pain Center, Seattle, WA, USA (Dr. Aurora); Sunnybrook Women’s College Health Sciences Centre, Toronto, ON,
Canada (Dr. Gawel); Nashville Neuroscience Group, PC, Nashville, TN, USA (Dr. Brandes); and Allergan, Inc., Irvine, CA, USA
(Drs. Pokta and VanDenburgh).
Address all correspondence to Dr. Sheena K. Aurora, Swedish Pain Center, 1101 Madison, Suite 200, Seattle, WA 98104, USA.
Accepted for publication August 11, 2006.
Conclusion.—There were no statistically significant between-group differences in the mean change from base-
the course of the study in all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated
over an active treatment period lasting 9 months.
Key words: botulinum toxin type A, prophylactic, episodic migraine headache, double-blind, placebo-
Abbreviations: BoNTA botulinum toxin type A, CD cervical dystonia,
CDH chronic daily headache, IHS International Headache Society, ICHD International
Classification of Headache Disorders, PNR placebo nonresponders, PR placebo responders,
U units, MIDAS Migraine Disability Assessment, ANCOVA analysis of covariance
icans (approximately 18% of women and 7% of
stantial utilization of healthcare resources.1,2,5,6Mi-
bid with depression7and worsen patients’ perceptions
of their quality of life.5Billions of dollars annually in
marily due to oral pharmacotherapy, physician visits,
emergency department visits, and loss of productiv-
Migraineurs may be at risk of developing a clini-
study reported that approximately 14% of episodic
migraineurs developed chronic (≥15 days/month) mi-
graine headaches over a 1-year period.16
Prophylactic treatment of migraine may reduce
the frequency of migraine episodes and healthcare re-
source utilization.17,18However, the approved and/or
available treatments for migraine are associated with
As a result, gaps exist for current pharmaceutical pro-
phylactic treatment options for migraine.19-22
Botulinum toxin type A (BoNTA; BOTOX
blocks the release of acetylcholine from presynaptic
neurons, resulting in the inhibition of muscle contrac-
tions.23,24Focal administration of BoNTA has been
used therapeutically as treatment of disorders char-
acterized by muscle overactivity such as cervical dys-
resulted in improvement in pain in some patients with
CD25and post-stroke spasticity,26,27an effect initially
attributed to relaxation of excessive muscle activity.
However, reports of pain reduction prior to muscu-
has antinociceptive effects.28
Preclinical in vitro and in vivo data have shown
that BoNTA also blocks the release of nociceptive
mediators such as substance P, glutamate, and calci-
tonin gene-related peptide, suggesting that BoNTA
tem from the periphery.28-30The results of several
randomized double-blind, placebo-controlled clini-
cal trials demonstrated that BoNTA significantly re-
duced the frequency of headache episodes in the pro-
phylactic treatment of migraine and chronic daily
headache (CDH).31-33BoNTA treatment of headache
has been demonstrated to be safe with minimal side
effects and low discontinuation rates due to adverse
The current study was a phase 2 clinical trial that
vestigate the safety and therapeutic effect of BoNTA
as prophylactic treatment for various headache dis-
orders. Specific goals were to identify a responsive
patient population, a safe and efficacious dose, and
a well-defined treatment regimen.
Objective.—The objective of this study was to eval-
uate the safety and efficacy of multiple treatments of
BoNTA compared with placebo for the prophylactic
treatment of migraine headaches in a population of
patients suffering from episodic migraine.
Study Design.—This was a randomized, double-
blind, placebo-controlled, parallel-group, multicen-
ter, clinical study of repetitive treatments of BoNTA
BOTOX 037 Study Group: Richard Kaplan, MD
(California); Jan Lewis Brandes, MD (Tennessee);
Keith R. Edwards, MD (Vermont); Arthur Elkind,
MD (New York); Brian Freund, MD, DDS (Ontario);
Marvin Schwartz, DDS (Ontario); Benjamin Frish-
berg, MD (California); Marek Gawel, MD (Ontario);
Jack Klapper, MD (Colorado); Alexander Mauskop,
MD (New York); Peter McAllister, MD (Connecti-
cut); B. Todd Troost, MD (North Carolina); Bradley
V. Daniel Kassicieh, DO (Florida); Joel Saper, MD
Pokta, PhD (California); Amanda M. VanDenburgh,
Acknowledgment: This study was sponsored by Al-
lergan, Inc., Irvine, CA, USA.
Conflict of Interest:
Amanda M. VanDenburgh, PhD, are employed by Aller-
gan, Inc., and own stock in the company.
Suriani Pokta, PhD, and
1. 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.
2. Lipton RB, Scher AI, Kolodner K, Liberman J,
Steiner TJ, Stewart WF. Migraine in the United
States: Epidemiology and patterns of health care use.
3. Silberstein SD. Migraine. Lancet. 2004;363:381-391.
4. World Health Organization. Headache disorders
and public health: Education and management
implications. Available at http://www.migraines.org/
new/pdfs/who.pdf. Accessed April 5, 2006.
5. Lipton RB, Scher AI, Steiner TJ, et al. Patterns
of health care utilization for migraine in England
and in the United States. Neurology. 2003;60:441-
6. BadiaX,MagazS,Guti´ errezL,Galv´ anJ.Theburden
of migraine in Spain: Beyond direct costs. Pharma-
7. Lipton RB, Hamelsky SW, Kolodner KB, Steiner TJ,
A population-based case-control study. Neurology.
8. Ferrari MD. The economic burden of migraine to so-
ciety. Pharmacoeconomics. 1998;13:667-676.
9. Hu XH, Markson LE, Lipton RB, Stewart WF,
Berger ML. Burden of migraine in the United States:
Disability and economic costs. Arch Intern Med.
10. Stang P, Cady R, Batenhorst A, Hoffman L. Work-
and its treatment. Pharmacoeconomics. 2001;19:231-
11. Lipton RB, Pan J. Is migraine a progressive brain
disease? JAMA. 2004;29:493-494.
12. Lipton RB, Bigal ME. Migraine: Epidemiology, im-
pact, and risk factors for progression. Headache.
13. Welch KM, Goadsby PJ. Chronic daily headache:
Nosology and pathophysiology. Curr Opin Neurol.
14. Kruit MC, van Buchem MA, Hofman PA, et al. Mi-
graine as a risk factor for subclinical brain lesions.
15. Welch KM, Nagesh V, Aurora SK, Gelman N.
Periaqueductal gray matter dysfunction in mi-
graine: Cause or the burden of illness? Headache.
and predictors for chronicity of headache in patients
with episodic migraine. Neurology. 2004;62:788-
17. Silberstein SD. Migraine: Preventive treatment. Curr
Med Res Opin. 2001;17(suppl 1):s87-s93.
18. Silberstein SD, Winner PK, Chmiel JJ. Migraine
preventive medication reduces resource utilization.
19. Silberstein SD, Goadsby PJ. Migraine: Preventive
treatment. Cephalalgia. 2002;22:491-512.
20. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—
current understanding and treatment. N Engl J Med.
21. Brandes JL, Saper JR, Diamond M, et al, for the
MIGR-002 Study Group. Topiramate for migraine
prevention: A randomized controlled trial. JAMA.
22. Silberstein SD, Neto W, Schmitt J, Jacobs D, for
the MIGR-001 Study Group. Topiramate in migraine
prevention: Results of a large controlled trial. Arch
24. Dolly O. Synaptic transmission: Inhibition of neuro-
transmitter release by botulinum toxins. Headache.
25. Naumann M, Yakovleff A, Durif F, for the BOTOX?
Cervical Dystonia Prospective Study Group. A ran-
domized, double-masked, crossover comparison of
bulk toxin source for the treatment of cervical dysto-
nia. J Neurol. 2002;249:57-63.
Post-Stroke Spasticity Study Group. Intramuscular
and finger spasticity after a stroke. N Engl J Med.
27. Gordon MF, Brashear A, Elovic E, et al, for the
BOTOX Poststroke Spasticity Study Group. Re-
peated dosing of botulinum toxin type A for up-
per limb spasticity following stroke. Neurology.
29. Cui M, Khanijou S, Rubino J, Aoki KR. Subcuta-
neous administration of botulinum toxin A reduces
formalin-induced pain. Pain. 2004;107:125-133.
30. Durham PL, Cady R, Cady R. Regulation of calci-
tonin gene-related peptide secretion from trigeminal
nerve cells by botulinum toxin type A: Implications
for migraine therapy. Headache. 2004;44:35-43.
31. Silberstein S, Mathew N, Saper J, Jenkins S, for the
BOTOX?Migraine Clinical Research Group. Bo-
tulinum toxin type A as a migraine preventive treat-
ment. Headache. 2000;40:445-450.
32. Mathew NT, Frishberg BM, Gawel M, Dimitrova R,
Gibson J, Turkel C, and the BOTOX CDH Study
Group. Botulinum toxin type A (BOTOX?) for the
prophylactic treatment of chronic daily headache: A
randomized, double-blind, placebo-controlled trial.
33. Silberstein SD, Stark SR, Lucas SM, Christie SN,
DeGryse RE, Turkel CC, for the BoNTA-039 Study
Group. Botulinum toxin type A for the prophylac-
tic treatment of chronic daily headache: A random-
ized, double-blind, placebo-controlled trial. Mayo
Clin Proc. 2005;80:1126-1137.
34. Headache Classification Subcommittee of the Inter-
national Headache Society. The International Classi-
fication of Headache Disorders: 2nd edition. Cepha-
lalgia. 2004;24(suppl 1):9-160.
for migraine and tension-type headache. Headache.
36. Siegel S. Nonparametric Statistics for the Behavioral
Sciences. New York: McGraw-Hill; 1956:116-127.
37. Dodick DW, Mauskop A, Elkind AH, DeGryse R,
Brin MF, Silberstein SD, and the BOTOX CDH
Study Group. Botulinum toxin type A for the pro-
phylaxis of chronic daily headache: Subgroup anal-
ysis of patients not receiving other prophylactic
medications: A randomized double-blind, placebo-
controlled study. Headache. 2005;45:315-324.
38. Freitag FG, Collins SD, Carlson HA, et al, for the
Depakote ER Migraine Study Group. A randomized
migraine prophylaxis. Neurology. 2002;58:1652-1659.
39. Mathew NT, Rapoport A, Saper J, et al. Efficacy
of gabapentin in migraine prophylaxis. Headache.
40. Couch JR Jr. Placebo effect and clinical trials in mi-
graine therapy. Neuroepidemiology. 1987;6:178-185.
41. Zubieta JK, Bueller JA, Jackson LR, et al. Placebo
effects mediated by endogenous opioid activity on µ-
opioid receptors. J Neurosci. 2005;25:7754-7762.
42. Zubieta JK, Yau WY, Scott DJ, Stohler CS. Belief
or need? Accounting for individual variations in the
neurochemistry of the placebo effect. Brain Behav
effect. J Neurosci. 2005;25:10390-10402.
44. Bendtsen L, Mattsson P, Zwart JA, Lipton RB.
gesics in migraine. Cephalalgia. 2003;23:487-490.
45. Loder E, Goldstein R, Biondi D. Placebo effects in
oral triptan trials: The scientific and ethical rationale
for continued use of placebo controls. Cephalalgia.
46. Tfelt-Hansen P, Block G, Dahlof C, et al. Guidelines
for controlled trials of drugs in migraine: Second edi-
tion. Cephalagia. 2000;20:765-786.
47. European Agency for the Evaluation of Medicinal
vestigation of Medicinal Products for the Treatment
uation of Medicinal Products (EMEA); December