Botox para tratamiento profilactico migrana, estudio doble ciego. Clinica MAYO. 15 feb

8/7/2019 Botox para tratamiento profilactico migrana, estudio doble ciego. Clinica MAYO. 15 feb

1/12

Mayo Clin Proc. September 2005;80(9):1126-1137 www.mayoclinicproceedings.com1126

BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHEORIGINAL ARTICLE

From the Jefferson Headache Center, Thomas Jefferson University, Philadel-phia, Pa (S.D.S.); The Neurology & Headache Treatment Center, Alexandria,Va (S.R.S.); Department of Neurology, University of Washington MedicalCenter, Seattle (S.M.L.); Ottawa Headache Centre, Ottawa, Ontario (S.N.C.);and Allergan, Inc, Irvine, Calif (R.E.D., C.C.T.). A complete list of participantsin the BoNTA-039 Study Group appears at the end of this article.

Dr Silberstein is on the advisory panel and speakers bureau and receivesresearch support from Allergan, Inc; he is on the advisory panel or speakersbureau or serves as a consultant for Abbott Laboratories, AstraZenecaPharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson &Johnson, Merck & Co, Inc, Metis, NPS Pharmaceuticals, Ortho-McNeil Phar-maceutical, Inc, Pfizer Inc, Pozen, Inc, UCB Pharma, and X-Cel Pharmaceuti-cals; and he receives research support from Abbott Laboratories, Astra-Zeneca Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKline, Johnson &Johnson, Medtronics, Inc, Merck & Co, Inc, NPS Pharmaceuticals, Pfizer Inc,Pozen, Inc, UCB Pharma, and X-Cel Pharmaceuticals . Dr Stark has served as aprincipal investigator and subinvestigator for Allergan, Inc, for the past 4years. Dr Lucas is a consultant for Allergan, Inc, AstraZeneca Pharmaceuti-cals, Biogen Idec, GlaxoSmithKline, Merck & Co, Inc, Ortho-McNeil Pharma-ceutical, Inc, Pfizer Inc, and Serono Pharmaceuticals Ltd. Dr Christie hasreceived a research grant, consultancy fees, and honoraria from Allergan, Inc.Dr Turkel and Mr DeGryse are employed by and own stock in Allergan, Inc.

This study was sponsored by Allergan, Inc, Irvine, Calif.

Address reprint requests and correspondence to Stephen D. Silberstein, MD,Jefferson Headache Center, Thomas Jefferson University Hospital, 111 S11th St, Suite 8130, Philadelphia, PA 19107 (e-mail: [email protected]).

2005 Mayo Foundation for Medical Education and Research

For edit orialcomment, see

page 1119

Botulinum Toxin Type A for the Prophylactic Treatment

of Chronic Daily Headache:

A Randomized, Double-Blind, Placebo-Controlled Trial

STEPHEN D. SILBERSTEIN, MD; STUART R. STARK, MD; SYLVIA M. LUCAS, MD, PHD; SUZANNE N. CHRISTIE, MD;

RONALD E. DEGRYSE, MS, MA; AND CATHERINE C. TURKEL, PHARMD, FORTHE BONTA-039 STUDY GROUP

OBJECTIVES: To identify a treatment-responsive population forbotulinum toxin type A (BoNTA) and to evaluate the safety andefficacy of 3 different doses of BoNTA as prophylactic treatmentof chronic daily headache (CDH).

PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study of BoNTA in patients with CDH was conductedfrom July 6, 2001, through November 7, 2003, at 28 NorthAmerican study centers. Eligible patients were injected withBoNTA at 225 U, 150 U, 75 U, or placebo and returned foradditional masked treatments at day 90 and day 180. Patients

were assessed every 30 days for 9 months. The primary efficacyend point was the mean change from baseline in the frequency ofheadache-free days at day 180 for the placebo nonrespondergroup.

RESULTS: For this study, 702 patients were enrolled and random-ized. The primary efficacy end point was not met. Mean improve-ments from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 head-ache-free days per month were observed in the placebononresponder group treated with BoNTA at 225 U, 150 U, 75 U, orplacebo, respectively (P=.44). An a prioridefined analysis ofheadache frequency revealed that BoNTA at 225 U or 150 U hadsignificantly greater least squares mean changes from baselinethan placebo at day 240 (8.4, 8.6, and 6.4, respectively; P=.03analysis of covariance). Only 27 of 702 patients (3.8%) withdrewfrom the study because of adverse events, which generally weret ransient and mild t o moderate.

CONCLUSIONS: Although the primary efficacy end point was notmet, all groups responded to treatment. The 225 U and 150 Ugroups experienced a greater decrease in headache frequencythan the placebo group at day 240. The placebo response washigher than expected. BoNTA was safe and well tolerated. Furtherstudy of BoNTA prophylactic t reatment of CDH appears warranted.

Mayo Clin Proc. 2005;80(9) :1126-1137

ANCOVA = analysis of covariance; BoNTA = botulinum toxin type A;CDH = chronic daily headache; ICHD = International Classification ofHeadache Disorders; MIDAS = Migraine Disabilit y Assessment

Chronic daily headache (CDH) describes a heteroge-neous group of headache disorders that occur morethan 15 days per month in the absence of structural orsystemic disease and often are associated with considerable

disability.1-4 In population-based surveys, CDH affects ap-

proximately 4% to 5% of the general population,2,5,6 with

0.5% experiencing severe headaches daily.7 Chronic daily

headache is encountered frequently at major tertiary head-

ache centers, where it is responsible for headaches in up to

40% of patients.4,8 Analgesic overuse is a common risk

factor for CDH.1,8,9

More than 70% of patients with CDH previously had

experienced intermittent migraine that progressed eventu-

ally to headaches that occurred more frequently and/or

lasted longer,1,10-12 ie, transformed migraine. This shift from

episodic to chronic headache may involve progressive

changes to the central nociceptive sys-

tem,3 and preliminary evidence sug-

gests that repeated migraine may result

in recurrent damage and structural al-teration, leading to a decreased thresh-

old for further migraine attacks in this population.13 Pre-

ventive treatments for patients with chronic disabling mi-

graines are needed to reduce the frequency and/or severity

of headaches, slow disease progression, decrease the need

for medication for acute headache and for health care ser-

vices, and reduce the potentialfor medication overuse.14,15

Very few well-designed studies have evaluated prophylactic

headache treatment in patients with CDH.1,16-18

To date, no drug has received regulatory approval for

the prevention of headaches in patients with migraine and

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.


2/12


BOTULINUM TOXIN TYPE A AND CHRONIC DAILY HEADACHE

CDH. Numerous agents, encompassing various classes, are

used for prophylactic treatment of migraine (episodic

migraine and CDH). These classes include -blockers, cal-cium channel blockers, serotonin antagonists, antidepres-

sants, nonsteroidal anti-inflammatories, and antiepilep-

tics.19,20 Viewed collectively, they offer limited effectivenessand poor tolerability due to adverse events.19-22

Botulinum toxin type A (BoNTA) (BOTOX, Allergan,

Inc, Irvine, Calif), a focally administered neurotoxin, in-

hibits the release of acetylcholine at the neuromuscular

junction and is used therapeutically in disorders character-

ized by muscle hyperactivity.23 In preclinical models,

BoNTA has been shown to inhibit the release of nocicep-

tive mediators, such as glutamate, substance P, and calcito-

nin gene-related peptide, from nociceptive fibers.24-26 Re-

sults from several clinical trials suggest that BoNTA may

be an effective and safe preventive headache medication

for migraine and CDH.27-29

The objectives of this exploratory phase 2 trial were to

(1) identify a treatment-responsive population for BoNTA,

(2) evaluate the safety and efficacy of 3 different BoNTA

doses compared with placebo with use of a fixed injection-

site protocol, and (3) evaluate any BoNTA dose response in

the prophylactic treatment of CDH in a severely disabled

population of patients.

PATIENTS AND METHODS

STUDY DESIGNA randomized, double-blind, placebo-controlled, parallel-

group clinical study of 3 fixed-dose treatments of BoNTAcompared with placebo in the treatment of patients with

CDH was conducted from July 6, 2001, through November

7, 2003. The study was conducted at 28 North American

study centers. Before study initiation, the investigators re-

ceived appropriate institutional review board approval.

This study was conducted in compliance with the ethical

principles that originated in the Declaration of Helsinki

regarding biomedical research on human subjects and in-

formed consent regulations.

PARTICIPANT CHARACTERISTICS

Inclusion Criteria. Patients were men and women aged

18 to 65 years who experienced headaches on more than 15days during a 30-day baseline screening period. Headaches

could include any combination of migraines: those with or

without aura, migrainous headache, probable migraine,

and/or episodic or chronic tension-type headaches (as de-

fined by the International Headache Societys 1988 Inter-

national Classification of Headache Disorders [ICHD]-I).30

Patients had to be medically stable and willing and able to

give written informed consent. Patients taking long-term

medication (including long-term prophylactic headache

medications) had to be stable (no change in dose or dosing

regimen) for at least 3 months immediately before the

baseline period. Acute headache pain medication to relieve

headaches could be taken as needed. Patients had to be

willing to continue taking current medications during thecourse of the study, complete the entire course of the study,

and comply with study instructions including the daily use

of an electronic diary for data collection.

Exclusion Criteria. Patients were excluded from the

study if they had any medical condition (eg, neuromuscular

disorders) or used any agent that might expose them to risk

if they received BoNTA, had an infection or skin problem

at any of the injection sites, or had a known allergy or

sensitivity to the study medication or to its components.

Patients also were excluded if they had cluster headache or

chronic paroxysmal hemicrania, analgesic rebound head-

ache (as per the investigators discretion, since at the time

the study was conducted, no agreed-upon definition was

available), headache secondary to head trauma or whiplash

injury, a history of complicated migraine (eg, migrainous

infarction, hemiplegic migraine, ophthalmoplegic mi-

graine, or basilar migraine), a Beck Depression Inventory

score greater than 24, previous therapy with botulinum

toxin of any serotype, an injection of anesthetics or corti-

costeroids into the study-targeted muscles during the 30

days immediately before the baseline period, or if they

overused or abused symptomatic medication, alcohol, or

drugs in the investigators opinion. Concurrent or long-

term use of muscle relaxants (eg, cyclobenzaprine, cariso-

prodol, or benzodiazepines) during the 3 months before thescreening period was prohibited. Women who were preg-

nant or nursing or were unable or unwilling to use a reliable

form of contraception during the study were excluded.

TREATMENT SCHEDULEAND PROTOCOLThe overall duration of the study for each patient was 11

months. This included a 30-day screening (baseline) pe-

riod, followed by a 30-day placebo run-in period and a

9-month treatment period divided into 3 double-blind

treatment cycles each of 3 months duration. During the

baseline period, patients were screened for eligibility and

recorded data about specified headache characteristics in a

validated electronic headache diary using a telephone inter-active voice capture system daily (Phase Forward, Waltham,

Mass). Calls to the electronic diary system were to be com-

pleted daily throughout the study; the criterion for diary

compliance at baseline was 80% on a weekly basis. The

timing and duration of headache episodes, headache medica-

tion use, and other associated headache characteristics were

evaluated after the baseline period. Patients who continued

to meet inclusion/exclusion criteria were enrolled and re-



3/12



TABLE 1. BoNTA Dose or Placebo Inject ed per Muscle*

225 150 75 Placebo

Frontalis (4 sites) 30 20 10 0Corrugator (2 sites) 15 10 5 0

Temporalis (4 sites) 30 20 10 0Splenius capitis (2 sites) 30 20 10 0Trapezius (4 sites) 60 40 20 0Semispinalis capitis (2 sites) 30 20 10 0Suboccipital region (2 sites) 30 20 10 0

*Botulinum toxin type A (BoNTA) or placebo was injected bilaterallyinto the identified pericranial muscle groups at the indicated dose.

The dilution factor for the BoNTA 225 U group was 7.5 U/0.1 mL.The dilution factor for the BoNTA 150 U group was 5.0 U/0.1 mL.The dilution factor for the BoNTA 75 U group was 2.4 U/0.1 mL.

BoNTA (U)

Muscle area

ceived a single-blind placebo injection into 20 sites encom-

passing 7 muscle areas, including the frontalis, corrugator,

temporalis, splenius capitis, trapezius, semispinalis capitis,

and the suboccipital region (Table 1). The injection proto-

col used was a fixed-site approach, similar to that de-

scribed by Blumenfeld et al.31 Specified characteristics of

patients headaches were recorded again for 30 days using

electronic diaries. Patients were not informed about whether

they were injected with BoNTA or placebo. At the end of the

placebo run-in period, patients were classified as a placebo

responderif their number of headache days had changed

from 16 or more to less than 16 or if their number of

headache days decreased 30% or more from baseline. All

other patients were considered placebo nonresponders.

After the placebo run-in period, patients within the 2

groups (responders, nonresponders) were randomized atday 0 and received the first of 3 masked BoNTA treatments

(at 225 U, 150 U, or 75 U) or placebo. Patients returned for

2 additional masked treatments at day 90 and at day 180.

Patients were assessed subsequently at 30-day intervals

after each treatment through day 270. Patients were in-

jected with BoNTA or placebo using the same injection

protocol as used during the placebo run-in period. The

same volumes of study medication or placebo were in-

jected into the same muscles and muscle sites. If a patient

exited the study at any visit before day 270, all exit proce-

dures and evaluations were completed at that visit.

INTERVENTIONEach vial of BoNTA contained 100 U ofClostridium botu-

linum toxin type A, 0.5 mg of albumin (human), and 0.9 mg

of sodium chloride in a sterile, vacuum-dried form with

no preservative. Each vial of placebo contained 0.9 mg

of sodium chloride in a sterile, vacuum-dried form with

no preservative. All vials were reconstituted with 0.9%

sterile, preservative-free saline. The vials were reconsti-

tuted by using the volume of diluent assigned to each

specific randomization number to attain specific BoNTA

doses of 225 U, 150 U, or 75 U (1.33 mL, 2.0 mL, or 4.0 mL,

respectively).

BLINDINGAND RANDOMIZATION

The placebo run-in was a single-masked treatment where-by the investigator, but not the patient, knew that the treat-

ment administered was a placebo. This was a double-blind

study; therefore, neither the investigator nor the patient

knew which treatment was given at day 0, day 90, and day

180. On the basis of their baseline telephone diary data,

patients were randomized electronically within each group

(placebo nonresponder or placebo responder) to receive

BoNTA at 225 U, 150 U, or 75 U, or placebo in a ratio of

1:1:1:1 in blocks of 8.

To maintain the blinding, an individual with no other

study responsibilities reconstituted the study medication

and drew the study drug into the syringes for use. This

person diluted 3 vials of study medication and drew the

study drug into 7 syringes (1 for each muscle) for use. The

syringes then were given to the investigator for injection.

BoNTA injections and evaluations were performed by

the same investigator throughout the study whenever pos-

sible. If it was impossible for the same investigator to

monitor a given patient, then injections and evaluations

were to overlap between the investigators for at least 1 visit

when possible.

PRIORAND CONCOMITANT THERAPYThe use of any concurrent medication (eg, prescription

[including prophylactic medications] or over-the-counter[including herbal remedies]) was recorded along with the

reason that a medication was taken. Also, patients recorded

medications they had taken for treatment of each headache

by using their telephone diary as part of their daily call to

the integrated voice response system.

EFFICACY END POINTSBaseline data comprised the diary data collected daily dur-

ing the 30 days preceding the placebo run-in period (ie,

days 60 to 30). Each headache episode was characterized

by the recording in the diary of the headache start and stop

time, characteristics, symptoms, and medications taken. A

headache day was defined as the occurrence of a headacheepisode of any type or length in the 24-hour period from

midnight (inclusive) at the start of the day to midnight (not

inclusive) at the end of the day. A headache-free day was

defined as a complete day during which no headache was

recorded. The primary efficacy end point was the mean

change from baseline in the frequency of headache-free

days for the 30-day period ending on day 180 for the

placebo nonresponder group.



4/12



A secondary efficacy end point was the proportion of

patients with a decrease from baseline of 50% or more in

the frequency of headache days (per 30-day period) at day

180 for the placebo nonresponder group. Other variables

evaluated per 30-day period included the frequency of any

type of headaches, the proportion of patients with a de-crease from baseline of 50% or more headaches, the fre-

quency of migraine headaches of any severity, the propor-

tion of patients with a decrease from baseline of 50% or

more in migraine headaches, the proportion of patients

with a decrease from baseline of 2 or more migraine head-

aches, and the frequency of moderate to severe migraine

headaches.

For this analysis, the definition ofheadache frequency

was determined by several a prioridefined parameters. A

headache episode was determined by a diary entry of the

headache start and/or stop times and/or headache charac-

teristics, headache symptoms, and/or medications taken for

headaches. If the headache stopped 3 days after starting, it

was counted as 1 headache and 3 headache days. If a

patient recorded multiple headaches during the course of 1

day, the day was counted as 1 headache day, and the

frequency was recorded in relation to the number of head-

aches as defined by viable start and stop times. If the

headache was a migraine, it had to meet ICHD 1.1 or 1.2

criteria. For any 2 consecutive migraines, if the period of

time between the stop time of the first headache and the

start time of the second was less than 24 hours, they were

considered 1 continuous migraine headache. If the head-

ache met the criteria for probable migraine, the 24-hour

rule was not used and it counted as 2 headaches.Also evaluated was the number of days that medication

for acute headache was used during the study. Quality-of-

life questionnaires were distributed; patients were to com-

plete the Migraine Disability Assessment (MIDAS) at days

60, 90, 180, and 270, and the Headache Pain-Specific

Quality of Life Questionnaire was to be completed at days

60, 0, 90, 180, and 270.

SAFETY MEASURESAt each visit after treatment at day 0, adverse event infor-

mation was recorded, indicating the date of onset, resolu-

tion date (if applicable), severity (mild, moderate, or se-

vere), duration, frequency, relationship to study treatment,action taken regarding study treatment, treatment re-

quired (if any), and outcome. The relationship between an

adverse event and the study treatment was assessed by

the investigator as none, possible, probable, or definite.

Safety was assessed by reports of adverse events, physical

and neurologic examinations, and clinical laboratory tests

for the pooled population (placebo nonresponders and

placebo responders).

STATISTICAL ANALYSESThe as-treated population for both the safety and efficacy

analyses included all patients treated with the second injec-

tion at day 0 (randomization), regardless of subsequent

injections. They were analyzed in the responder or non-

responder group indicated by baseline and placebo run-indata, regardless of which group they were assigned to

during randomization. Data recorded in the patients dia-

ries were used in the analysis of outcome measurements.

Multiple comparison adjustments were made by using the

OBrien-Fleming group sequential method to set the sig-

nificance level at .048 for the primary analysis at day 180.

All other hypothesis tests used a type I error of=.05 to

determine statistical significance, except that treatment-by-

subgroup interactions were examined at the .10 level.

For the frequency of headache-free days at baseline and

its change from baseline in the nonresponder group, com-

parisons among all treatment groups were done with the

Kruskal-Wallis test, and pairwise comparisons between

treatment groups were done with the Wilcoxon rank sum

test.32 If there were significant baseline differences among

treatments in the primary variable, the baseline value of the

variable was included as a covariate in an analysis of

covariance (ANCOVA) of the variable.

An analysis of variance (with type III sums of squares)

modeling response was used for treatment-by-subgroup

interactions for several factors (eg, age, sex, race, time

since disease onset, chronic headache subtype, base-

line MIDAS total days score, and baseline prophylactic

treatment).

The proportion of patients with a decrease from baselineof 50% or more headache days per 30-day period was

analyzed by using the observed data with Pearson 2 orFisher exact tests. Additional secondary end points in-

cluded the changes from the baseline period to time points

other than day 180 (days 30, 60, 90, 120, 150, 210, 240, and

270). For the secondary efficacy variable, as for the pri-

mary variable, supplemental analyses using imputed data

for missing values were performed.

The primary analysis used observed data. When the

data reported were incomplete, certain a prioridefined

rules were applied. For example, if a patient recorded

diary data for at least 10 days but for less than 30 days in a

30-day study period, the number of headache-free daysfor the 30-day period was prorated and rounded to a

whole number.

RESULTS

PATIENT DEMOGRAPHICSAND BASELINE CHARACTERISTICSAmong 1200 screened patients, 702 (mean age, 43.4 years;

582/702 [82.9%] female) were enrolled, entered into the



5/12



TABLE 2. Baseline Characteristics (All Enrolled Patients)*

225 150 75 PlaceboBaseline characteristic (n=182) (n=168) (n=174) ( n=178) P value

Age (y)

Mean 42.4 43.7 43.7 43.7 .61Range 18-65 21-65 20-64 18-64

Mean (SD) years since onset 13.6 (11.9) 12.7 (10.8) 14.2 (13.2) 14.2 (12.9) .96Mean (SD) No. of headaches during

30-day baseline period 14.1 (8.5) 13.2 (8.8) 13.9 (7.4) 13.8 (9.6) .61Mean (SD) No. of migraines or probable

migraines per 30-day period at baseline 10.8 (7.5) 10.0 (7.4) 10.5 (6.6) 10.5 (8.5) .61No. (%) of patients using prophylactic

headache medications 93 (51.1) 85 (50.6) 84 (48.3) 86 (48.3) .93No. (%) of patients overusing pain

medication for acute headache 78 (42.9) 67 (39.9) 74 (42.5) 77 (43.3) .92Mean (SD) MIDAS score 56.0 (50.8) 52.0 (45.8) 50.7 (49.2) 59.9 (57.5) .63

*BoNTA = botulinum toxin type A; MIDAS = Migraine Disability Assessment.

BoNTA (U)

placebo run-in period, and subsequently randomized to

active treatment or placebo at day 0. At the end of the

baseline period, 498 patients were no longer enrolled for

the following reasons: 15 or fewer headache days (26%),

withdrew consent (20%), not enough diary calls (17%),

Beck Depression Inventory score greater than 24 (7%), lost

to follow-up (7%), personal reasons (4%), unstable chronic

medications (3%), taking exclusionary medications (2%),

medication overuse (1%), screen failure due to abnormal

laboratory results (1%), and other (12%).

At the end of the placebo run-in period, of 702 patients,

538 (76.6%) were classified as placebo nonresponders and

164 (23.4%) as placebo responders. Subsequently, patients

within each group were randomized to receive BoNTA at225 U (n=182), 150 U (n=168), 75 U (n=174), or placebo

(n=178). No statistically significant differences in demo-

graphic and other baseline characteristics were found

among the 4 treatment groups (Table 2).

Patient Disposition. A total of 71.9% (387/538) of the

placebo nonresponders and 75.6% (124/164) of the placebo

responders completed the study. Of the patients who dis-

continued (27.2% [191/702]), 10.5% (74/702) did so for

lack of efficacy, 7.4% (52/702) for administrative reasons,

3.8% (27/702) for adverse events, 0.4% (3/702) for proto-

col violation, and 4.3% (30/702) for other reasons; 5

patients (0.7%) discontinued the study because they were

administered incorrect doses of BoNTA. The placebogroup alone accounted for 43% (32/74) of the patients who

discontinued for lack of efficacy.

Type and Severity of Headaches. Each headache was

classified as migraine (ICHD-II level 1) or nonmigraine

(ICHD-II level 2; eg, tension-type headache). Patients in

the BoNTA 225 U, 150 U, 75 U, and placebo groups

experienced mean headache days per 30-day period at

baseline of 23.6, 23.6, 24.0, and 24.1, respectively (pooled

placebo nonresponder and placebo responder group). The

mean age at onset of CDH was 29.1 years, and the mean

time since onset was 13.7 years. The CDH diagnosis sub-

type, based on a clinical interview and assigned by the

investigator, was not recorded for approximately 30.9%

(217/702) of patients because this was part of a protocol

amendment that was initiated midway through the study.

Among the 485 of 702 patients (69.1%) who had their CDH

subtype classified, 77.3% (375) were classified as having

transformed migraine, followed by 18.4% (89) with

chronic tension-type headache, 3.3% (16) with new daily

persistent headache, and 1% (5) with other. No patients

were diagnosed as having hemicrania continua. All but 5

patients experienced at least 1 migraine or probable mi-graine during the baseline period, suggesting that the pa-

tients were migraineurs, even though this diagnosis was not

recognized by the investigator for all patients. A history of

migraine was recorded for almost half of all patients

(48.9%). The mean number of headaches experienced dur-

ing the 30-day baseline period was 14.1, 13.2, 13.9, and

13.8 for the 225 U, 150 U, 75 U, and placebo groups,

respectively. The mean number of migraine or probable

migraine headaches experienced during the (30-day)

baseline period was approximately 10.5 headaches for all

treatment groups. The mean baseline MIDAS score for all

patients (54.7) indicated that most patients experienced

moderate to severe disability.Medication Use at Baseline. Almost half the patients

(49.6% [348/702]) used prophylactic headache medica-

tions, yet met the inclusion criteria of 16 days or more of

headaches per 30-day period: 262 of 524 (50%) of all

patients receiving BoNTA and 86 of 178 (48.3%) of pa-

tients receiving placebo (Table 2). At baseline, 95.1%,

97.6%, 96.0%, and 96.1% of patients in the BoNTA 225 U,

150 U, 75 U, and placebo groups, respectively, were using



6/12



FIGURE 1. Mean change from baseline in the number of headache-free days per 30-day

period in placebo nonresponders. BoNTA = botulinum toxin type A.

0Day

30

Day

60

Day

90

Day

120

Day

150

Day

180

Day

210

Day

240

Day

270

1

2

3

4

5

6

No.ofheadache-freed

ays

(meanchangefrombas

eline)

7

8

9

10

BoNTA 225 U BoNTA 150 U BoNTA 75 U Placebo

medication for acute headache (eg, pain and antinausea

medications; P=.66). The mean number of days with medi-

cation for acute headache pain (eg, ergotamines, triptans,

simple analgesics, opioids, and combination medications

[ICHD-II section 8.2.1-8.2.5]) was 13.5, 12.6, 13.4, and

13.7 for the BoNTA 225 U, 150 U, 75 U, and placebo

groups, respectively (P=.49). According to the most re-

cently proposed definition ofmedication overuse (use for

15 days and 2 d/wk), about 42% of patients in all treat-

ment groups were overusing medication for acute headache

pain (ICHD-II, 2004), with no significant between-groupdifference (P=.92; Table 2).

ANALYSESOF EFFICACYMean Change From Baseline in the Frequency of

Headache-Free Days. In both the placebo nonresponders

and placebo responders, all treatment groups experienced

mean improvements from baseline in the number of head-

ache-free days per 30-day period.

At day 180, the primary end point, placebo nonre-

sponders treated with BoNTA at 225 U, 150 U, and 75 U

experienced mean changes from baseline of 6.0 (7.1), 7.9

(8.4), and 7.9 (7.8) headache-free days per 30-day pe-

riod, respectively, compared with a mean change frombaseline of 8.0 (8.8) headache-free days for placebo

patients treated in the same group (Figure 1). The among-

group difference was not statistically significant (P=.44);

therefore, the primary end point was not met. At day 30 in

the placebo nonresponder group, there was a mean in-

crease in the number of headache-free days from base-

line that was significantly greater for patients receiving

BoNTA at 75 U (5.06.5 headache-free days) compared

with the BoNTA 225 U, 150 U, and placebo groups

(3.16.0, 3.06.2, and 2.95.2 days, respectively; P=.01

for all).

In the placebo responder group, patients treated with

BoNTA at 225 U, 150 U, and 75 U experienced mean

changes from baseline at day 180 of 13.17.8, 11.47.5,

and 14.06.1 headache-free days, respectively, compared

with a mean change from baseline of 10.87.2 head-

ache-free days for placebo patients treated in the same

group. The among-group difference was not statistically

significant.Secondary Efficacy End Points. In the placebo non-

responder group at day 180, the percentages of patients

with a decrease from baseline of at least 50% in the

number of headache days per 30-day period were 25.4%,

35.1%, 30.9%, and 31.7% for the BoNTA 225 U, 150 U,

75 U, and placebo groups, respectively. The among-group

difference was not statistically significant. In contrast, in

the placebo responder group at day 60, a significantly

higher percentage of patients treated with BoNTA at 225

U (69.6% [32/46]) had at least a 50% decrease from

baseline in the number of headache days per 30-day pe-

riod compared with patients treated with BoNTA at 150 U

(44.4% [16/36]; P=.02) and placebo (37.1% [13/35];P=.004).

POOLED POPULATIONBecause of the nonstatistically significant treatment-by-

responder interaction, the placebo nonresponder and pla-

cebo responder groups were pooled and a post hoc analysis

was completed to compare BoNTA with placebo (pooled

population) for additional efficacy variables.



7/12



78

9

10

6

5

4

3

2

1

0

No

.ofheadaches(meandecreasefrombasel

ine)

*

Day30

Day60

Day90

Day120

Day150

Day180

Day210

Day240

Day270


FIGURE 2. Mean decrease from baseline in the number of headaches per 30-dayperiod. BoNTA = botulinum toxin type A.* P=.04, BoNTA at 225 U and at 75 U vs 150 U.P=.03, BoNTA at 225 U and at 150 U vs placebo.

In the following sections, analyses are presented only

for the pooled population.Number of Headaches. After correcting for differences

in the baseline frequency of headaches, an analysis of

results showed a statistically significant between-group

difference in the frequency of headaches favoring BoNTA

over placebo at multiple time points (Figure 1). Statisti-

cally significant differences existed overall among the

treatment groups in the least squares mean changes from

baseline in the number of headaches per 30-day period at

days 30 and 240 (P=.04 and P=.03, respectively) (Figure

2). At day 30, the least squares mean change was signifi-

cantly greater for the BoNTA 225 U group (4.5; P=.02

ANCOVA) and BoNTA 75 U group (4.5; P=.01

ANCOVA) compared with the BoNTA 150 U group(3.3). At day 240, the least squares mean changes were

significantly greater for the BoNTA 225 U group (8.4;

P=.04) and 150 U group (8.6; P=.02 ANCOVA) com-

pared with placebo (6.4). Although the among-group P

values were not statistically significant at day 210 (P=.08)

and day 270 (P=.08), there were some trends observed

regarding the BoNTA 225 U group and 150 U group vs

placebo. At day 210, the least squares mean change was

significantly greater for the BoNTA 225 U group vs pla-

cebo (P=.03). On day 270, the least squares mean changewas significantly greater for the BoNTA 150 U group vs

placebo (P=.03).

Number of Migraines or Probable Migraine Head-

aches. The mean number of migraines or probable mi-

graines during baseline for each treatment group was 10.8,

10.0, 10.5, and 10.5 for the BoNTA 225 U, 150 U, 75 U,

and placebo groups, respectively. A covariate analysis of

variance was performed with baseline as the covariate.

Statistically significant among-group differences were ob-

served for the mean changefrom baseline in the number of

migraine or probable migraine headaches (per 30-day pe-

riod) compared with placebo at days 30, 90, and 150

(P=.02; P=.02; P=.03 ANCOVA, respectively) (Figure 3).At day 30, the least squares mean change in the number of

migraines or probable migraines was 3.9 in the BoNTA

225 U group compared with 2.7 in the BoNTA 150 U

group (P=.01 ANCOVA) and 2.8 in the placebo group

(P=.02 ANCOVA). At day 90, the least squares mean

change from baseline was 4.8 in the BoNTA 75 U group

compared with 3.5 in the BoNTA 150 U group and 3.4 in

the placebo group (P.01 ANCOVA). At day 150, the least



8/12



7

6

5

4

3

2

1

0

Day30

Day60

Day90

Day120

Day150

Day180

Day210

Day240

Day270


No.ofmigrainesorprobablemigrain

es

(meandecreasefrombaseline)

*

FIGURE 3. Mean decrease from baseline in the number of migraine or probablemigraine headaches per 30-day period. BoNTA = botulinum toxin type A.* P=.02 for BoNTA at 225 U vs BoNTA at 150 U and placebo.P=.02 for BoNTA at 75 U vs BoNTA at 150 U and placebo.P=.03 for BoNTA at 75 U vs placebo.P=.003 for BoNTA at 225 U and at 75 U vs placebo.P=.006 for BoNTA at 225 U, at 150 U, and at 75 U vs placebo.P=.01 for BoNTA at 150 U and at 75 U vs placebo.

squares mean change from baseline was 5.8 in the 75 U

group compared with 3.8 in the placebo group(P=.002ANCOVA).

Percentage of Patients Using and Overusing Acute

Headache Pain Medications. At day 30, acute headache

pain medications were used by a significantly lower per-

centage of patients in the BoNTA 225 U group (83.2%)

compared with the BoNTA 150 U group (93.4%; P=.003)

and placebo group (91.0%; P=.03). At day 90, pain medi-

cations for acute headache were used by a significantly

lower percentage of patients in the BoNTA 225 U group

(79.1%) compared with the BoNTA 150 U group (90.3%;

P=.006).

Although no statistically significant among-group dif-

ferences were observed from day 120 to day 270 (exceptfor the day 180 visit), a greater percentage of placebo

patients were using pain medication for acute head-

ache compared with all 3 of the BoNTA groups. Simi-

larly, for medication overuse, from day 30 to day 270,

a greater percentage of patients in the placebo group

were overusing pain medication for acute headache com-

pared with all 3 of the BoNTA groups (except at days 60

and 90 in the 225 U group) (Figure 4). A statistically sig-

nificant among-group difference was observed at day 210

(P=.05).

HEALTH OUTCOME MEASURESOccasional statistically significant improvements were ob-

served in headache-related disability, primarily in the pla-

cebo responder group, as measured by MIDAS. Further

exploration of treatment group differences with the SF-36

Health Survey may be worthwhile in future studies because

many of the domains in the pooled population exhibited

greater improvement with BoNTA treatment compared

with placebo including bodily pain, general health, vitality,

social functioning, and health transition (data not shown).

SAFETYAND TOLERABILITYOne or more adverse events, regardless of causality, were

reported for 80.2% of patients (146/182) treated with

BoNTA at 225 U, 79.2% (133/168) treated with BoNTA at

150 U, 81.6% (142/174) treated with BoNTA at 75 U, and

68.0% (121/178) treated with placebo.The overall inci-

dence of adverse events was greater in each BoNTA group

than in the placebo group (P.02).Most of the adverse

events were transient and mild or moderate in severity.



9/12



TABLE 3. Treatment-Related Adverse Events Reported by at Least 3% of Patientsin any Treatment Group (Pooled Population)*

BoNTA (U)225 150 75 Placebo

Adverse event (n=182) (n=168) (n=174) (n=178) P value

Any 119 (65.4) 92 (54.8) 97 (55.7) 38 (21.3)


10/12



Only 27 of 702 patients (3.8%) discontinued the study

due to adverse events (9 receiving BoNTA at 225 U, 13

receiving BoNTA at 150 U, 3 receiving BoNTA at 75 U,

and 2 placebo patients). Thirty-four patients experienced

39 serious adverse events, all of which the investigator

considered to be unrelated to study treatment.

DISCUSSION

Most patients with CDH who seek treatment in headache

clinics have transformed migraine. These patients head-

aches tend to be severe and disabling.2,12,33 The dominant

population enrolled in this study included patients with

moderate to severe transformed migraine, many of whom

were overusing pain medications for acute headache. These

patients had an average of more than 20 days of headaches

per month and severe disability at baseline. There is clearly

an unmet therapeutic need in this patient population for

effective and tolerable preventive headache treatment.

In this study, the response in the placebo group was

greater than expected. A high placebo response has been

reported to be a confounder in evaluating treatment of

painful conditions, including headache.34 According to

Linde et al,35 the more uneven the randomization, the

greater the placebo response. An additional and perhaps

more influential confounding factor was the use of pain

medication for acute headache. For ethical reasons, pa-

tients were allowed to take pain medications for acute

headache on an as-needed basis. This could have con-

founded the data in this study in 2 ways. First, the charac-

teristics of the headaches may have been modified. Forexample, without medication, patients would have experi-

enced all the symptoms necessary to classify a headache as

a migraine that meets the criteria of the International Head-

ache Society for migraine 1.1. However, because of short-

term medication use, the headaches did not meet the crite-

ria for even a probable migraine. Therefore, for future

studies, headache frequency may be a more appropriate

variable of interest rather than the frequency of headache-

free days. Second, a trend was observed in which a larger

percentage of patients in the placebo group were using (and

overusing) pain medications for acute headache compared

with all the BoNTA groups. This could be an important

confounding factor because to be significantly different,the BoNTA group needed to show efficacy statistically

greater than the placebo group in which more patients were

using (and overusing) acute headache pain medications to

treat their headaches.

Although the primary efficacy outcome was not met in

this trial, the results indicate that BoNTA, injected for up to

3 treatment cycles (at fixed total doses of 225 U, 150 U, or

75 U) and placebo profoundly increased the frequency of

headache-free days at all post-placebo run-in time points.

A statistically significant among-group difference was ob-

served at day 30. In the placebo nonresponder group, the

mean increase in the number of headache-free days from

baseline was significantly greater for the BoNTA 75 U

group compared with the other treatment groups. In the apriori analysis of pooled data (placebo responders and pla-

cebo nonresponders), those receiving BoNTA at 225 U or

150 U had statistically significant mean reductions from

baseline in headache frequency in a 30-day period com-

pared with placebo at day 240.

For other variables, in both the placebo nonresponders

and placebo responders group efficacy analyses, there

were some differences among treatment groups that

reached significance. These differences always favored

BoNTA, but no specific BoNTA group was consistently

better than placebo. On the basis of data for headache-free

days and the reduction of migraine and probable migraine

headaches in the pooled population, BoNTA revealed an

initial onset of action within 30 days of the first active

treatment.

Results were published recently from a large random-

ized, placebo-controlled trial, conducted by Mathew et al,29

of multiple treatments of BoNTA as prophylactic treatment

of CDH by using a modified follow-the-pain dosing

regimen. In that trial, patients who received a mean

BoNTA dose of 190 U had statistically significant reduc-

tions in headache frequency, 40% had at least a 50% reduc-

tion in headache days, and there was at least a 50% reduc-

tion in the mean number of headaches in a 30-day period.

These results suggest that an effective BoNTA dosagerange may be 150 to 225 U.

This study adopted a fixed-site approach, whereby the

injection sites and doses delivered to these sites were un-

changed by pain location reported by individual patients.

This approach was designed to cover a broad distribution

of the trigeminal nerve affecting sensory nerves innervat-

ing the trigeminal nerve receptive fields, as well as the

receptive fields innervated by the upper cervical sensory

afferent nerves. Similar approaches have yielded some

clinically important and statistically significant effects of

BoNTA treatment in patients with migraine.14,28 More re-

cently, follow-the-pain approaches, in which injection sites

and dose distribution are dictated by pain distribution, havebeen advocated.36 The study conducted by Mathew et al29

cited previously identified significant treatment responses

in a similar patient population using a follow-the-pain ap-

proach. The results from this trial do not necessarily sup-

port abandonment of the fixed-site approach. Patients in all

treatment groups had a robust response to treatment, but the

outcome appears to have been confounded by the greater

use of acute headache pain medications in the placebo



11/12



REFERENCES1. Silberstein SD, Lipton RB. Chronic daily headache. Curr Opin Neurol.

2000;13:277-283.

2. Castillo J, Muoz P, Guitera V, Pascual J. Epidemiology of chronic daily

headache in the general population. Headache. 1999;39:190-196.

3. Welch KM, Goadsby PJ. Chronic daily headache: nosology and patho-

physiology. Curr Opin Neurol. 2002;15:287-295.

4. Pascual J, Colas R, Castillo J. Epidemiology of chronic daily headache.

Curr Pain Headache Rep. 2001;5:529-536.

5. Wang SJ, Fuh JL, Lu SR, et al. Chronic daily headache in Chinese

elderly: prevalence, risk factors, and biannual follow-up. Neurology. 2000;

54:314-319.6. Scher AI, Lipton RB, Stewart W. Risk factors for chronic daily head-

ache. Curr Pain Headache Rep. 2002;6:486-491.

7. Newman LC, Lipton RB, Solomon S, Stewart WF. Daily headaches in a

population sample: results from the American Migraine Study [abstract].

Headache. 1994;34:295. Abstract 6.

8. Mathew NT. Chronic refractory headache. Neurology. 1993;43(6, suppl

3):S26-S33.

9. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features

of medication overuse headache following overuse of different acute headache

drugs. Neurology. 2002;59:1011-1014.

10. Silberstein SD, Lipton RB, Sliwinski M. Classification of daily and near-

daily headaches: field trial of revised IHS criteria. Neurology. 1996;47:871-

875.

11. Mathew NT, Reuveni U, Perez F. Transformed or evolutive migraine.

Headache. 1987;27:102-106.

12. Bigal ME, Sheftell FD, Rapoport AM, Tepper SJ, Lipton RB. Chronic

daily headache: identification of factors associated with induction and transfor-mation. Headache. 2004;42:575-581.

13. Welch KMA, Nagesh V, Aurora SK, Gelman N. Periaqueductal gray

matter dysfunction in migraine: cause or the burden of illness? Headache.

2001;41:629-637.

14. Silberstein SD, US Headache Consortium. Practice parameter: evidence-

based guidelines for migraine headache (an evidence-based review): report of

the Quality Standards Subcommittee of the American Academy of Neurology

[published correction appears in Neurology. 2000;56:142]. Neurology. 2000;

55:754-762.

15. Silberstein SD, Winner PK, Chmiel JJ. Migraine preventive medication

reduces resource utilization. Headache. 2003;43:171-178.

group. Further study of how BoNTA acts on pain pathways

and affects the generation of migraine is needed to stimu-

late informed discussion about the dose-response relation-

ship and the optimal injection paradigm.

The results of this trial showed that BoNTA treat-

ment was safe and well tolerated at doses up to 225 U over3 treatment cycles. Most of the adverse events reported

were transient and mild to moderate in severity, were

similar to those reported previously with BoNTA us-

age for other conditions, and do not pose a serious safety

risk.

Dosing and results reported in this study are specific to

the formulation of botulinum toxin type A manufactured by

Allergan, Inc (Irvine, Calif). The Allergan, Inc, formula-

tion is not interchangeable with other botulinum toxin

products and cannot be converted by using a dose ratio.

CONCLUSIONSAlthough the primary efficacy end point was not met,

BoNTA treatment in this trial showed a significant differ-

ence from placebo in some analyses. At day 240, the de-

crease in headache frequency was significantly greater for

the BoNTA 225 U and 150 U groups compared with pla-

cebo; however, the placebo response was higher than ex-

pected. A greater percentage of patients in the placebo

group used pain medications for acute headache through-

out the study, thereby confounding the results. BoNTA

treatment was safe and well tolerated over multiple treat-

ment cycles. Thus, we believe that BoNTA prophylactic

treatment of migraine should be evaluated further in ran-domized, placebo-controlled trials with fewer treatment

arms to reduce the possibility of a placebo effect obscuring

genuine clinical phenomena. This approach may shed fur-

ther light on the appropriate treatment paradigm in the use

of BoNTA in migraine treatment.

Participants of theBoNTA-039 Study Group. Jeffrey Adel-

glass, MD (Skintastic, Dallas, Tex); Zahid H. Bajwa, MD (Beth

Israel Deaconess Medical Center, Boston, Mass); Peter J.

Barbour, MD (Lehigh Valley Hospital, Allentown, Pa); Werner

Becker, MD (Foothills Medical Center, Calgary, Alberta); David

Biondi, DO (Spaulding Rehabilitation Hospital, Boston, Mass);

Suzanne N. Christie, MD (Ottawa Headache Centre, Ottawa,

Ontario); David Dodick, MD (Mayo Clinic, Scottsdale, Ariz);

Ronald E. DeGryse, MS, MA (Allergan, Inc, Irvine, Calif);

Michael Elliott, MD (Virginia Mason Medical Center, Seattle,

Wash); Frederick Freitag, DO (Diamond Headache Clinic, Chi-

cago, Ill); Mark Forrest Gordon, MD (Long Island Jewish Med-

ical Center, New Hyde Park, NY); Matthews Gwynn, MD

(Neurotrials Research, Inc, Atlanta, Ga); Pan-Yu Lai, PhD

(Allergan, Inc, Irvine, Calif); Paul Later, MD (Fort Wayne Neuro-

logical Center, Fort Wayne, Ind); Kenneth A. Levin, MD (Neu-

rology Group of Bergen County, Ridgewood, NJ); Sylvia M.

Lucas, MD, PhD (University of Washington Medical Center,

Seattle); Joseph Nicolas, MD (University Neurology Inc, Cincin-

nati, Ohio); C. Phillip OCarroll, MD (Newport Beach Neurolo-

gists, Newport Beach, Calif); James Patton, MD (Mountain Neu-

rological Center, PA, Asheville, NC); Joel Saper, MD (MichiganHead Pain and Neurology Institute, Ann Arbor); Fred Sheftell,

MD (The New England Center for Headache, PC, Stamford,

Conn); Stephen D. Silberstein, MD (Jefferson Headache Center,

Philadelphia, Pa); Richard Singer, MD (Neurology Clinical Re-

search, Inc, Plantation, Fla); Robin Smith, RN, BSN (Allergan,

Inc, Irvine, Calif); Timothy Smith, MD (Mercy Health Research,

St Louis, Mo); Egilius Spierings, MD (MedTrial Boston Inc,

Wellesley, Mass); Stuart R. Stark, MD (The Neurology & Head-

ache Treatment Center, Alexandria, Va); Gabriel Tatarian, DO

(Jefferson Medical College of Thomas Jefferson University,

Philadelphia, Pa); Catherine C. Turkel (Allergan, Inc, Irvine,

Calif); Amanda M. VanDenburgh, PhD (Allergan, Inc, Irvine,

Calif); Thomas Ward, MD (Dartmouth Hitchcock Medical Cen-ter, Lebanon, NH); Kerri Wilks, MD (Baumel-Eisner Neuromed

Institute, Ft Lauderdale, Md).



12/12



16. Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali

L. Topiramate in the treatment of chronic migraine. Cephalalgia.2003;23:820-

824.

17. Saper JR, Lake AE III, Cantrell DT, Winner PK, White JR. Chronic daily

headache prophylaxis with tizanidine: a double-blind, placebo-controlled,

multicenter outcome study. Headache. 2002;42:470-482.

18. Spira PJ, Beran RG, Australian Gabapentin Chronic Daily Headache

Group. Gabapentin in the prophylaxis of chronic daily headache: a random-

ized, placebo-controlled study. Neurology. 2003;61:1753-1759.

19. Silberstein SD, Goadsby PJ. Migraine: preventive treatment. Cephalal-

gia. 2002;22:491-512.

20. Redillas C, Solomon S. Prophylactic pharmacological treatment of

chronic daily headache. Headache. 2000;40:83-102.

21. Brandes JL, Saper JR, Diamond M, et al, MIGR-002 Study Group.

Topiramate for migraine prevention: a randomized controlled trial. JAMA.

2004;291:965-973.

22. Silberstein SD, Neto W, Schmitt J, Jacobs D, MIGR-001 Study Group.

Topiramate in migraine prevention: results of a large controlled trial. Arch

Neurol. 2004;61:490-495.

23. Dolly O. Synaptic transmission: inhibition of neurotransmitter release by

botulinum toxins. Headache. 2003;43(suppl 1):S16-S24.

24. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type

A in pain management. Headache. 2003;43(suppl 1):S9-S15.

25. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of

botulinum toxin A reduces formalin-induced pain. Pain. 2004;107:125-133.

26. Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related

peptide secretion from trigeminal nerve cells by botulinum toxin type A:

implications for migraine therapy. Headache. 2004;44:35-42.

27. Silberstein S, Mathew N, Saper J, Jenkins S, BOTOX Migraine Clinical

Research Group. Botulinum toxin type A as a migraine preventive treatment.

Headache. 2000;40:445-450.

28. Barrientos N, Chana P. Botulinum toxin type A in prophylactic treatment

of migraine headaches: a preliminary study. J Headache Pain. 2003;4:146-

151.

29. Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C,

BOTOX CDH Study Group. Botulinum toxin type A (BOTOX) for the

prophylactic treatment of chronic daily headache: a randomized, double-blind,

placebo-controlled trial. Headache. 2005;45:293-307.

30. Headache Classification Committee of the International Headache Soci-

ety. Classification and diagnostic criteria for headache disorders, cranial neu-

ralgias and facial pain. Cephalalgia. 1988;8(suppl 7):1-96.

31. Blumenfeld AM, Binder W, Silberstein SD, Blitzer A. Procedures for

administering botulinum toxin type A for migraine and tension-type headache.

Headache. 2003;43:884-891.

32. Siegel S. Nonparametric Statistics for the Behavioral Sciences. New

York, NY: McGraw-Hill; 1956:116-127.

33. Sanin LC, Mathew NT, Bellmeyer LR, Ali S. The International Head-

ache Society (IHS) headache classification as applied to a headache clinic

population. Cephalalgia. 1994;14:443-446.

34. Couch JR Jr. Placebo effect and clinical trials in migraine therapy.

Neuroepidemiology. 1987;6:178-185.

35. Linde M, May A, Limmroth V, Dahlof C, Headache Masters

Programme. Ethical aspects of placebo in migraine research. Cephalalgia.

2003;23:491-495.

36. Blumenfeld A. Botulinum toxin type A as an effective prophylactic

treatment in primary headache disorders. Headache. 2003;43:853-860.


Documents

Botox para tratamiento profilactico migrana, estudio doble ciego. Clinica MAYO. 15 feb