low-dose aspirin for migraine prophylaxis in women

Low-dose aspirin for migraine prophylaxis in women

IM BensenÄ or1, NR Cook1, I-M Lee1,2, MJ Chown1, CH Hennekens3 & JE Buring1,2,4

1Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 2Department of

Epidemiology, Harvard School of Public Health, Boston, 3Departments of Medicine, and Epidemiology and Public Health, University of Miami School of

Medicine, Miami and 4Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, USA

BensenÄ or IM, Cook NR, Lee I-M, Chown MJ, Hennekens CH & Buring JE. Low-dose

aspirin for migraine prophylaxis in women. Cephalalgia 2001; 21:175±183. London.

ISSN 0333-1024

Although migraine is more common among women than men, the only two large,

randomized trials of low-dose aspirin for migraine prophylaxis have been conducted in

men. As part of the Women's Health Study, an ongoing randomized trial of low-dose

aspirin and vitamin E among 39 876 female health professionals aged 45 and older, 1001

women with frequent migraine attacks were assigned to 100 mg of aspirin every other

day (n=525) or aspirin placebo (n=476). Migraine frequency, as well as severity,

duration, and degree of incapacitation, were assessed by self-report on questionnaires

12 months and 36 months after randomization, and also by monthly diaries kept before

and after randomization. Women assigned to aspirin reported small and consistent

decreases in migraine frequency (59.6% vs. 56.4% assigned to placebo reporting

improvement at 36 months; odds ratio 1.13, 95% con®dence interval, 0.86±1.48), as well

as decreases in severity, duration, and migraine-related incapacitation. These reductions

were not, however, statistically signi®cant. These data are compatible with a small

treatment effect of low-dose aspirin in the prophylaxis of migraine among middle-aged

women. u Aspirin, migraine, prophylaxis, treatment, women

J. E. Buring, Division of Preventive Medicine, Brigham and Women's Hospital, 900

Commonwealth Avenue East, Boston, MA 02215-1204, USA. Tel. +1 617 732 4965,

fax +1 617 731 3843, e-mail [email protected] Received 16 December 1999,

accepted 13 March 2001

Introduction

Migraine is a common medical problem. In a mail survey

conducted in the United States, 17.6% of females and

5.7% of males reported having one or more migraine

attacks per year (1). The prevalence varied with age

as well as gender, peaking between the ages of 35 and 45

(1, 2).

One medication that has been assessed as a possible

preventive agent for migraine is aspirin. Results from

small trials have been inconsistent (3±13). In two large-

scale trials of aspirin in the primary prevention of

cardiovascular disease, the British Doctors' Trial and the

Physicians' Health Study, the effect of low-dose aspirin

on migraine prophylaxis in men was evaluated in

secondary analyses comparing the numbers self-report-

ing subsequent migraine in the two treatment groups

(14, 15). Both found statistically signi®cant reductions in

migraine associated with aspirin use. It must be noted,

however, that randomization was not done according

to headache diagnosis. No similar large-scale trial has

evaluated low-dose aspirin for prophylaxis against

migraine among women, even though migraine is

much more frequent in women than men. Further, the

two large trials in men and many of the smaller trials that

have been conducted did not provide details regarding

migraine severity, duration, and degree of incapacita-

tion, nor did they attempt to verify self-reported

information on migraine using established standardized

criteria (16).

Many of the medications currently indicated for

migraine prophylaxis, which include beta-blockers,

calcium-channel blockers, anticonvulsants, serotonin

inhibitors, and tricyclic antidepressants, have signi®cant

side-effects while aspirin has a good and well-de®ned

safety pro®le. Furthermore, low-dose aspirin is being

increasingly used in the secondary prevention of

cardiovascular disease (17), as well as in the primary

prevention of myocardial infarction in men (18). Because

it is widely used, safe, and inexpensive, low-dose aspirin

# Blackwell Science Ltd Cephalalgia, 2001, 21, 175±183 175

would be an attractive agent to consider for prophylaxis

against migraine.

The pathophysiology underlying migraine is not yet

clearly understood, nor is it clear by what mechanism

aspirin can act on migraine prophylaxis. Changes in

serotonin concentrations have been implicated as a

possible trigger for migraine (19), and aspirin may

diminish serotonin-mediated ®ring of neurones in

the hypothalamus and brain stem (20). The ®nding of

activated platelets in migraine sufferers, while not

consistently demonstrated (21±23), raises the possibility

that regular use of a platelet antagonist such as aspirin

may help limit or prevent migraine (20). Aspirin's effects

on the central nervous system (24, 25) may also be

involved in migraine prophylaxis.

To examine the association between use of low-dose

aspirin and migraine in women, we initiated the

migraine substudy of the Women's Health Study

(WHS), an ongoing randomized, double-blind, placebo-

controlled trial testing the balance of bene®ts and risks

of low-dose aspirin and vitamin E in the prevention

of cardiovascular disease and cancer among healthy

women. The substudy was designed primarily to evalu-

ate the effect of low-dose aspirin on the frequency of

migraine among women reporting frequent headaches

at baseline, as well as to explore the effects of aspirin on

their severity, duration and degree of incapacitation.

Subjects and methods

The subjects and methods of the Women's Health Study

have been described in detail elsewhere (26). Brie¯y, a

total of 453 787 female health professionals responded to

a mailed invitation to participate in the WHS. Of these,

39 876 women who met the main eligibility criteria for

the study, i.e. no prior history of cardiovascular disease

or cancer other than nonmelanoma skin cancer and who

demonstrated good compliance during the trial's run-in

phase, were randomized using a two-by-two factorial

design to low-dose aspirin (100 mg every other day) or

aspirin placebo as well as to vitamin E (600 IU every

other day) or vitamin E placebo. Of the randomized

women, 1279 who had reported having at least one

migraine per month on the WHS baseline questionnaire

were sent an invitation to participate in the migraine

substudy along with a migraine substudy questionnaire.

A total of 1101 women responded and provided detailed

information on the written questionnaire about their

migraines. Of these, 1001 reported they had migraine

attacks at least monthly and were thus eligible for the

study ± 525 were allocated to active aspirin and 476 to

aspirin placebo. These 1001 women were asked to

complete monthly migraine diaries to more accurately

classify migraine occurrence and symptoms.

To examine the association between use of low-dose

aspirin and migraine, we collected three sets of data:

reports of migraine collected from all 39 876 women in

the WHS on follow-up questionnaires; responses to

detailed questionnaires from the 1001 participants in the

migraine substudy collected at baseline and 12 and

36 months after randomization; and monthly diaries

kept by the 1001 participants in the migraine substudy.

Analysis of entire randomized group

On the 12-month follow-up questionnaire sent to all

39 876 women randomized in the WHS, we collected

information about the occurrence of migraine in the

prior year. We calculated using logistic regression the

odds ratio (OR) and 95% con®dence interval (CI) of

reporting migraine on the 12-month questionnaire for

women allocated to aspirin compared with women

allocated to aspirin placebo. In addition, we categorized

all randomized women at baseline according to occur-

rence of menopause (yes or no) and current use of

hormone replacement therapy (yes or no). We repeated

the analysis for each of these four groups (premeno-

pausal without hormone replacement therapy, pre-

menopausal with hormone replacement therapy,

postmenopausal without hormone replacement therapy,

and postmenopausal with hormone replacement

therapy), adjusted for age and allocation to vitamin E.

Analysis of the migraine substudy group usingquestionnaires

On the baseline questionnaire for the migraine substudy,

women were asked to answer detailed questions about

migraine frequency, severity, duration, functional lim-

itation, and location and characteristics of pain. They

were also asked about the frequency and severity of

symptoms including aura, visual disturbances or other

visual phenomena, nausea and/or vomiting, sensitivity

to light, sensitivity to sound, behavioural or personality

changes, food cravings, bloating or ¯uid retention,

dizziness or vertigo, sensory symptoms such as numb-

ness or tingling, and unilateral weakness in the face,

arms, or legs. This questionnaire information was

compared with the International Headache Society

(IHS) criteria for categorizing migraine (16). We did

not ascertain the number of migraine attacks each

woman experienced prior to joining the Women's

Health Study, and thus could not establish the additional

IHS requirement of at least 5 attacks of migraine without

aura and 2 attacks of migraine with aura during one's

lifetime. However, since the women in our study

reported having migraine at least monthly, they were

likely to ful®l the IHS criteria for lifetime frequency.

176 IM BensenÄor et al.

# Blackwell Science Ltd Cephalalgia, 2001, 21, 175±183

At 12 months after randomization, the 1001 women in

the migraine substudy were sent follow-up migraine

questionnaires that asked about migraine frequency

(During the past year, do you believe that you had more, fewer,

or the same number of migraine headaches than previously?),

migraine severity (During the past year, do you believe that

your migraine headaches were more severe, less severe, or of

similar severity than previously?), migraine duration

(During the past year, do you believe that your migraine

headaches were longer, shorter, or the same duration than

previously?), and degree of incapacitation from migraines

(During the past year, do you believe that you were

incapacitated due to headaches for more, fewer, or the same

number of days than previously?). At 36 months after

randomization, the migraine substudy participants were

sent a nearly identical follow-up questionnaire asking

about changes during the three years since randomiza-

tion. We de®ned improvement at 12 and 36 months as

any response indicating fewer migraines, less severity,

shorter duration, and less incapacitation compared with

baseline; we determined no improvement as any

response indicating the same number or more migraines,

the same or greater severity, the same or longer duration,

and the same or more incapacitation.

Using responses to the follow-up migraine substudy

questionnaires, we compared migraine frequency,

severity, duration, and degree of incapacitation among

women allocated to aspirin with those allocated to

placebo. We used logistic regression analyses to calculate

the odds ratios of improvement in migraine symptoms

associated with aspirin vs. placebo. Analyses were

carried out according to intention to treat and were

adjusted for age (single years) and vitamin E assignment.

For each odds ratio, we calculated the 95% con®dence

interval (27).

Migraine substudy diaries

Participants in the migraine substudy received monthly

diaries with grids that allowed them to report for each

day whether a headache had occurred, its severity (mild,

moderate, or severe), and duration (less than 4 h, 4±12 h,

or 13±24 h). The daily grids also contained checklists for

symptoms associated with each headache, including

aura, nausea, sensitivity to light, and others. In analysing

data from the diaries, we classi®ed as migraines any

headaches of moderate or severe intensity accompanied

by one or more of the following symptoms: aura,

sensitivity to light, or nausea.

Participants kept diaries during the run-in phase

of the WHS trial (pre-randomization phase) and

after randomization (post-randomization phase). We

excluded information from the ®rst calendar month of

each woman's pre-randomization diary because women

frequently received the diary after the start of the month

and thus the data for that month were incomplete.

In analysing the diaries, we determined the number of

headaches reported on each monthly diary, standard-

ized to a 30-day month. For descriptive purposes, we

calculated the average number of headaches of any type

per month for each woman during the pre-randomiza-

tion period and the post-randomization period, as well

as the average number of migraines. Using a t-statistic,

we compared the mean number of headaches and the

mean number of migraines per month averaged over

all women in the pre- and post-randomization periods,

as well the changes in these means from the pre-

randomization to the post-randomization period among

those randomized to aspirin and to aspirin placebo.

In addition, we used the general estimating equation

(GEE) approach to allow for the varying number of

diaries and the correlation among diaries for each

woman. Poisson regression using PROC GENMOD of

SAS was used to model the number of headaches

of any type and migraines per month as a function of

randomization period, aspirin assignment, and the

interaction between them. The interaction term was

used to estimate the change in the log number of

headaches from the pre-randomization period to the

post-randomization period in the aspirin group vs. the

placebo group. The exponent function of this term is an

estimate of the ratio of number of headaches in the

aspirin vs. the placebo group in the post-randomization

period, adjusted for the baseline number.

We classi®ed all migraines reported in the diaries as

either severe or moderate in intensity, and lasting either

13 h or more or 12 h or less. We used a GEE model to

compare intensity and duration of migraine, and

modelled the proportions of migraines that were

severe or of longer duration using a binomial distribu-

tion with a logit link. To estimate the relative odds of

having more serious migraine attacks in the post-

randomization period than in the pre-randomization

period in the aspirin group vs. the placebo group, the

intensity and duration of migraine attacks were mod-

elled as a function of randomization period, aspirin

assignment, and the interaction between them. We again

used the exponent function of the interaction term to

estimate the odds ratio for migraines of greater intensity

or longer duration in the aspirin vs. placebo groups.

Results

Analysis of entire randomized group

For all 39 876 women randomized in the Women's

Health Study, 2418 self-reported occurrence of one or

more migraine attacks during the ®rst 12 months of the

Aspirin for migraine prophylaxis 177


trial ± 1177 among those assigned to aspirin and 1241

among those assigned to aspirin placebo. The odds ratio

for migraine among women randomized to aspirin

compared with women randomized to aspirin placebo

was 0.95 (95% CI, 0.87±1.03) after 12 months of treatment

(Table 1). When we analysed the four subgroups of

women de®ned by their menopausal status and current

use of hormone replacement therapy, there were no

signi®cant differences in the odds ratios between women

allocated to aspirin and women allocated to aspirin

placebo in any of the subgroups.

Analysis of the migraine substudy group usingquestionnaires

Table 2 presents the baseline characteristics of the 1001

women in the aspirin and placebo groups of the

migraine substudy. The two groups were similar with

respect to age; body mass index; history of hypertension,

diabetes, and parental myocardial infarction before

age 60; smoking; alcohol intake; menopausal status;

use of hormone replacement therapy; and randomiza-

tion to vitamin E. However, women allocated to aspirin

were more likely to report high cholesterol levels and

exercise than women allocated to aspirin placebo.

Of the 1001 women in the migraine substudy, 705

(70.4%) returned the 12-month migraine substudy

questionnaire while 893 (89.2%) returned the 36-month

migraine substudy questionnaire. Because women

entered the WHS in a staggered fashion, 100% of the

subjects had reached their 12 month follow-up when this

analysis was undertaken, while 96% had attained

36 months of follow-up.

Table 1 Odds ratio and 95% con®dence interval (CI) of self-reported migraine on the 12-month follow-up questionnaire amongall 39 876 women in the Women's Health Study, according to menopause status and current use of hormone replacementtherapy*

Number (%) reporting migraine on 12-month questionnaire

Aspirin (ASA)

(n=19 934)

Placebo

(n=19 942)

Odds ratio

(95% CI)

All randomized women 1177 1241 0.95

(5.9%) (6.2%) (0.87 to 1.03)

Hormonal status

Pre-menopausal without hormone replacement 296 323 0.93

therapy (ASA 4626/Placebo 4703)

Pre-menopausal with hormone replacement

(6.4%)

43

(6.9%)

35

(0.79 to 1.09),

1.10

therapy (ASA 530/Placebo 481) (8.1%) (7.3%) (0.69 to 1.79)

Post-menopausal without hormone replacement 109 100 1.09

therapy (ASA 3,261/Placebo 3264) (3.3%) (3.1%) (0.83 to 1.44)

Post-menopausal with hormone replacement 366 387 0.92

therapy (ASA 6,091/Placebo 5957) (6.0%) (6.5%) (0.79 to 1.06),

*Menopausal status and use of hormone replacement therapy could be accurately classi®ed in 28 913 women.

Table 2 Characteristics of the 1001 women in the migrainesubstudy of the Women's Health Study according to treatmentallocation

Aspirin

(n=525)

Placebo

(n=476) P-value

Age, years 51.5¡5.4 51.3¡4.9 0.20

Body mass index (kg/m2)* 26.1¡5.0 25.7¡4.8 0.21

History of hypertension (%){ 24.3 23.6 0.79

History of high cholesterol (%){ 31.3 25.1 0.03

History of diabetes (%) 1.5 0.8 0.48

History of parental myocardial

infarction before age 60 (%) 16.8 14.3 0.29

Smoking (%)

Never 60.6 58.2

Past 30.5 32.8 0.72

Current 9.0 9.0

Alcohol intake (%)

Rarely 53.9 54.0

Monthly 13.9 13.5 0.75

Weekly 28.0 26.7

Daily 4.2 5.9

Exercise at least weekly (%) 44.0 36.6 0.02

Post-menopausal (%) 41.0 39.2 0.75

Use of hormone replacement therapy (%)

Never 45.7 45.5

Past 7.2 9.1 0.82

Current 47.1 45.5

Randomized to active vitamin E 51.6 51.5 0.83

*Mean¡standard deviation. {De®ned as hypertension diag-nosed by physician, or self-reported systolic blood pressurei140 mmHg, diastolic blood pressure i90 mmHg or higher, ortreatment for hypertension. {De®ned as self-reported physician'sdiagnosis of elevated cholesterol or treatment for high cholesterol.



The follow-up questionnaires assessed improvement

in features of migraine. Overall, about half of women

reported a lower frequency of migraine at 12 months

and about 58% at 36 months compared with baseline. On

the 12-month follow-up questionnaire, after adjusting

for differences in age and randomized assignment to

vitamin E, 16% more women allocated to aspirin self-

reported less frequent migraine (OR, 1.16; 95% CI, 0.86±

1.57), 24% more women reported less severe migraine

(OR, 1.24; 95% CI, 0.92±1.68), 20% more women reported

shorter migraine attacks (OR, 1.20; 95% CI, 0.88±1.62),

and 23% more women reported less migraine-related

incapacitation (OR, 1.23; 95% CI, 0.91±1.66) than women

allocated to placebo. (Table 3). These differences,

however, were not statistically signi®cant.

Similar results were seen at the 36-month follow-up.

Women allocated to aspirin were more likely to report

less frequent migraine (OR, 1.13; 95% CI, 0.86±1.48), less

severe migraine (OR, 1.06; 95% CI, 0.81±1.39), shorter

duration of migraine attacks (OR, 1.11; 95% CI, 0.85±

1.45), and less migraine-related incapacitation (OR, 1.12;

95% CI, 0.86±1.47) than women allocated to aspirin

placebo. Again, these differences were not statistically

signi®cant.

To ascertain the validity of self-reported migraine, we

compared women's self-reports of migraine and their

descriptions of migraine characteristics with modi®ed

IHS criteria that omitted the lifetime frequency require-

ment, since we did not collect this information. We

de®ned agreement as ful®lling all of the modi®ed IHS

criteria (IHS codes 1.1, migraine without aura, and 1.2,

migraine with aura), and likely agreement as ful®lling all

but one of the modi®ed IHS criteria (IHS code 1.7,

migrainous disorder) (13). Among the 1001 participants

in the WHS migraine substudy, the self reports of

migraine agreed with modi®ed IHS criteria for 589

(58.9%) of women (including migraine with and without

aura). In addition, we found a likely agreement in 271

(27.1%) women. When we restricted our analyses to the

860 (85.9%) women who ful®lled the modi®ed IHS

criteria for migraine or likely migraine, the 12-month

and 36-month ®ndings were unchanged except for a

signi®cant difference in incapacitation at 12 months

(OR, 1.45; 95% CI, 1.04±2.02) and severity at 12 months

(OR, 1.45; 95% CI, 1.04±2.01). The results were also not

signi®cantly different for those whose headaches were

classi®ed as with or without aura.

Migraine substudy diaries

Diaries were returned by 864 women in the pre-

randomization phase and 790 women in the post-

randomization phase, with 750 women returning diaries

in both phases. We excluded information from the ®rst

monthly pre-randomization diary for all women because

some women received their ®rst diary after the begin-

ning of the month and thus these ®rst-month data were

incomplete. After these exclusions, 724 women returned

diaries with complete information in both phases. The

median number of pre-randomization diaries was 3 per

Table 3 Odds ratio and 95% con®dence interval (CI) for improvement in migraine characteristics, ascertained from questionnaires,among 1001 women in the migraine substudy of the Women's Health Study*

Migraine

characteristic

Time of

follow-up

Number of women reporting improvementOdds ratio{(95% CI)Aspirin Placebo

Lower frequency 12 months 189 172 1.16

(53.5%) (50.3%) (0.86 to 1.57)

36 months 271 235 1.13

(59.6%) (56.4%) (0.86 to 1.48)

Less severity 12 months 177 154 1.24

(50.4%) (44.9%) (0.92 to 1.68)

36 months 240 212 1.06

Shorter duration 12 months (52.5%)

156

(50.5%)

136

(0.81 to 1.39)

1.20

(44.4%) (40.0%) (0.88 to 1.62)

36 months 216 186 1.11

(47.7%) (44.8%) (0.85 to 1.45)

Less incapacitation 12 months 191 169 1.23

(54.9%) (49.9%) (0.91 to 1.66)

36 months 254 223 1.12

(56.8%) (53.7%) (0.86 to 1.47)

*705 women(70.4%) returned the 12-month migraine substudy questionnaire and 893 women(89.2%) returned the 36-monthquestionnaire. {adjusted for age and assignment to vitamin E.



participant, with a range of 1±21; the median number of

post-randomization diaries was 12 per participant, with

a range of 1±31.

In the diaries, women reported 54 409 headaches. In

the pre-randomization phase, the mean number of

monthly headaches was 5.2¡4.6 for women ultimately

randomized to aspirin and 5.3¡4.6 for women random-

ized to aspirin placebo. In the post-randomization

phase, the mean number of monthly headaches was

4.3¡4.4 for women randomized to aspirin and 4.8¡4.6

for women randomized to aspirin placebo. Change

(which is represented by the mean number of monthly

headaches in the post-randomization phase minus the

mean number in the pre-randomization phase) was

x0.80 for women randomized to aspirin and x0.41 for

women randomized to aspirin placebo (Pj0.03).

Of the 54 409 separate headaches reported in the

diaries, 16 384 (30.1%) were classi®ed as migraine

related (i.e. headaches of moderate or severe intensity

accompanied by one or more of the following symptoms:

aura, light sensitivity, or nausea). Among completed

diaries, the mean number of migraine-related headaches

was 1.5 per month.

Table 4 compares changes in the frequency of diary-

reported migraine-related headaches among women

assigned to aspirin compared with women assigned to

aspirin placebo in the pre-randomization and the post-

randomization phases of the study, as well as changes in

the percentage of severe and long-duration (lasting

13±24 h) migraine. The mean number of migraine-

related headaches was lower in women randomized to

aspirin compared with women randomized to aspirin

placebo in both the pre- and post-randomization phases.

The percentage of migraines reported as severe and the

percentage reported as lasting 13±24 h are also lower in

women randomized to aspirin compared with women

randomized to aspirin placebo in the pre- and post-

randomization phases. However, changes between the

two periods (represented by post-randomization data

minus pre-randomization data) were not statistically

signi®cant for the mean number of migraine-related

headaches, percentage of severe migraines, and percent-

age of migraines lasting 13±24 h. In addition, the GEE

analyses we performed to account for the correlation

among diaries indicated no differences in the number of

migraine-related headaches per month or the severity or

duration of migraines.

Discussion

In the migraine substudy of the Women's Health Study,

middle-aged women assigned to 100 mg of aspirin every

other day reported on follow-up questionnaires at 12

and 36 months after randomization that they had fewer

migraines than women assigned to aspirin placebo.

These migraine were also less severe and shorter, and

were associated with less incapacitation. Although the

trends in the results of the study were always favourable

to aspirin, the differences did not achieve statistical

signi®cance. However, the con®dence intervals were

wide, so the data are compatible with a small bene®t of

Table 4 Mean number and features of migraine in the pre-randomization and post-randomization phases among 1001 women{ inthe migraine substudy of the Women's Health Study

Aspirin Placebo

T-test

P-value

Ratio measure

(95% CI)

No. of

women{ Mean¡SD

No. of

women{ Mean¡SD

Mean number of migraines

Pre-randomization data 414 1.57¡1.66 396 1.80¡2.09 0.09 0.971

Post-randomization data

Change{403

364

1.30¡2.07

x0.19¡1.68

387

360

1.53¡1.94

x0.21¡1.43

0.11

0.91

(0.86 to 1.09),

Percent of migraines reported as severe

Pre-randomization data 396 34.6¡32.2 362 35.3¡32.7 0.76 0.88"


Change{348

304

33.1¡28.7

x1.4¡34.3

342

300

34.3¡27.5

x2.5¡34.7

0.58

0.71

(0.74 to 1.06),

Percent of migraines reported as lasting 13±24 h

Pre-randomization data


Change{

394

344

301

43.0¡36.5

43.2¡32.7

0.74¡37.7

359

340

296

49.1¡36.1

46.4¡31.2

x2.40¡33.9

0.02

0.19

0.29

1.03"

(0.85 to 1.24),

{Women in aspirin and placebo groups may not total 1001 because of missing data. {Change=mean number of migraines orpercentage in post-randomization period minus mean number of migraines or percent in pre-randomization periods. 1 Ratio of numberof migraines per month in the aspirin vs. placebo groups estimated using Poisson regression with generalized estimation equation (GEE)analysis. "Odds ratio for more severe or longer duration migraines in the aspirin vs. placebo groups estimated using logistic regressionamong migraines with GEE analysis.



low-dose aspirin in migraine prophylaxis. Analyses of

information recorded in participants' diaries also

showed small but statistically nonsigni®cant reductions

in the severity of migraine between the pre- and post-

randomization periods.

Other studies have also evaluated whether aspirin is

an effective prophylactic agent for migraine. Most of

these have been small studies of less than 50 subjects

(3±13) testing aspirin at daily dosages ranging from

80 mg to 1.5 g, either alone or in combination with

dipyridamol (4, 5), propranolol (7), ¯unarizine (11),

dihydroergotamine (13), or metoprolol (12). Results from

these trials have been inconsistent, with some showing a

clear reduction in migraine frequency associated with

aspirin use (3, 4, 7, 9, 11±13) and others showing no

signi®cant bene®t of aspirin therapy (5, 6, 8, 10). In

addition, some studies of lower-dose aspirin observed a

clear bene®t (3, 4, 9, 10) while others using higher-dose

aspirin did not (5, 6).

Two large, randomized trials in men have also

evaluated low-dose aspirin for migraine prophylaxis.

The British Doctors' Trial tested 500 mg of aspirin daily

in 5139 healthy male physicians between the ages of 50

and 75; two thirds of the group was allocated to aspirin

and one third was asked to avoid aspirin over the 6-year

trial. Among those allocated to aspirin there was a

statistically signi®cant 29% reduction in the number of

self-reported migraine attacks for which medical atten-

tion was sought compared with the aspirin avoidance

group (15). The Physicians' Health Study was a

randomized, double-blind, placebo-controlled trial of

325 mg of aspirin every other day in 22 071 healthy male

physicians between the ages of 40 and 84. This study

showed a statistically signi®cant 20% decrease (relative

risk, 0.80; 95% CI, 0.72±0.88; P=0.00001) in the number

of physicians self-reporting migraine on one or more

follow-up questionnaires (at 6, 12, 24, 36, 48, and

60 months after randomization) among those assigned

to aspirin compared with those assigned to placebo (14).

In neither the British Doctors' Trial or the Physicians'

Health Study was randomization done within the

headache diagnosis category.

There were a number of differences in the designs of

the present study and the two comparable studies in

male physicians. Our substudy of 1001 women was

smaller than the two studies in men (5139 participants in

the British Doctors' Trial and 22 071 in the Physicians'

Health Study) and included only women with frequent

migraine, while the two trials in men included those

with and without a history of migraine. However, in our

analyses of all 39 876 women randomized in the WHS,

we also observed no statistically signi®cant effect. In the

British Doctors' Trial, physicians in the control group

were not given placebo but were merely asked to refrain

from using aspirin or aspirin-containing medications,

possibly leading to bias in the self-reporting of migraine.

In both the Women's Health Study and the Physicians'

Health Study, control groups received aspirin placebo.

In all three studies, information on migraine was

provided by self-report on questionnaires that provided

no instructions on how to de®ne migraine. Self-reports of

migraine by female health professionals in our study

were quite valid, with 88.5% meeting modi®ed IHS

criteria for migraine and likely migraine. Restricting our

analyses to those participants for whom self-reported

migraine diagnosis was con®rmed by modi®ed IHS

criteria did not materially change the results. It is likely

that the physicians in the two trials in men were at least

as accurate in their self reports. It is also unlikely that

differences in compliance could explain the discrepancy

between our results and those of the prospective trials in

men, given that treatment compliance was high in all

three trials ± 87% of the group assigned to active

treatment in the WHS migraine substudy reported

taking at least two-thirds of the study capsules after

two years of follow-up, while compliance was 70% in the

British Doctors' Trial and 86% in the Physicians' Health

Study at the end of each trial.

It is possible that gender differences could account for

the variance between our results and those of the two

trials in men. Our study was conducted among women

45 years of age or older (mean age, 51 years), who were

either postmenopausal or with no intention to become

pregnant. This means that the results of the study may

not be generalizable to younger women. However, while

rates of migraine change with age and menopausal

status, this occurred in both the active agent and placebo

groups, thus not affecting in any way the validity of the

estimates of effect of aspirin on migraine. To investigate

possible gender differences, we examined the associa-

tion between menopausal status, use of hormone

replacement therapy, and prevalence of migraine

12 months after randomization among all participants

in the Women's Health Study (Table 2). The odds ratio of

migraine observed for postmenopausal women not

using hormone replacement therapy (in theory, those

who could be considered closest to men of that age in

their reproductive hormonal milieu) was no different

among women allocated to aspirin than among women

allocated to placebo. These data provide some indirect

evidence that gender differences may not play a large

role in the null ®ndings of the present study.

The aspirin dose used in the present study (100 mg

every other day) is substantially lower than the doses

used in the two trials in men (500 mg daily in the British

Doctors' Trial and 325 mg every other day in the

Physicians' Health Study). If platelet activation plays

a key role in triggering or maintaining migraine, then



low doses of aspirin such as those used in the Women's

Health Study could potentially prevent or limit migraine

attacks, as aspirin-related platelet inhibition occurs even

at doses of 100 mg every other day (28). If, however,

migraine prophylaxis is more dependent upon control-

ling the body's response to serotonin or upon some other

as-yet unknown mechanism, then low-dose aspirin may

not be effective against migraines. For example, it has

been demonstrated that aspirin diminishes the seroto-

nin-mediated ®ring of neurones in the hypothalamus

and brain stem (20). It is possible that the aspirin dose

used in the Women's Health Study (100 mg every other

day), while suf®cient to inhibit platelet activation and

while postulated to be effective against cardiovascular

disease, may not be suf®cient to counter serotonergic or

other mechanisms involved in initiating or sustaining

migraine, effects that may have been possible with the

higher aspirin doses used in the two trials in men.

There are a number of limitations that must be

recognized in this study, including the self-reported

migraine information, the older age range of the popula-

tion, and the inability to obtain treatment information.

However, with regard to studies of migraine prophy-

laxis among women, the present study is the largest to

date and the ®rst to gather information on migraine

severity, duration, and degree of incapacitation. In

addition, as an a priori substudy of a large, randomized,

placebo-controlled trial, the results are less prone to bias

and confounding. As it is unlikely that a large-scale

randomized trial would ever be mounted to evaluate

speci®cally the role of aspirin in the prophylaxis of

migraine, it is important to utilize opportunities to

evaluate this question as part of an ongoing trial. In

addition, a meta-analysis of all available trials would

be helpful in assessing aspirin's possible role in migraine

prophylaxis.

In conclusion, results from this large substudy of

a randomized, placebo-controlled trial are compatible

with a small but statistically nonsigni®cant effect of

100 mg of aspirin every other day in the prophylaxis

of migraine in middle-aged women.

Acknowledgements

We are grateful to the 39 876 dedicated and conscientious healthprofessionals who are participating in this study. We would like

to acknowledge the contributions of Dr Patricia Hebert, Ms. AnnKitross and Ms. Georgina Friedenberg, as well as the expert

editorial assistance of Mr P.J. Skerrett.Supported by grants CA-47988, HL-43851, and NS-34108 from

the National Institutes of Health. Dr BensenÄor is the recipient of afellowship from FAPESP (FundacËaÄo de Amparo a Pesquisa do

Estado de SaÄo Paulo), SaÄo Paulo, Brazil (97/4223±0).

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