Menstrual Migraine

Anne MacGregor

www.migraineclinic.org.uk

anne.macgregor@migraineclinic.org.uk

Role of hormones

• Migraine affects 1 in 5 women compared to 1 in 13 men

Rate of change of migraine prevalence over age continuum in females

1.horizontal line at 0 on the y-axis indicates no change in the rate. 2.during childhood and early adolescence, the rate is accelerating quickly.

3. rate begins to slow its acceleration. 4. Rate is decelerating

Victor et al. Cephalalgia 2010;30(9):1065–72

2

1

3

4

Role of hormones

• 50% of women with migraine report an association between migraine and menstruation

Wöber et al. Cephalalgia 2007;27:304-314

Hazard ratios: headache & migraine:menstrual vs non-menstrual attacks

1.43**

1.96***

0

1

2

3

days -2 to -1 days +1 to +3 days 4+

Haz

ard

Rat

io

*P < 0.01**P < 0.001

** P < 0.00001

1.50***1.83***1.21*

HeadacheMigraine

Population based

MacGregor EA, Hackshaw A. Neurology 2004;63:351-3

Relative risk of migraine:menstrual vs non-menstrual attacks

2.19**2.5**

1.71**

1.25*

0

1

2

3

days -5 to -1 days -2 to -1 days +1 to +3 days +1 to +6

Rel

ativ

e R

isk

[95%

CI]

*P < 0.001** P < 0.0001

Clinic based

Menstrual vs non-menstrual attacks

More severeLonger duration Less responsive to

acute treatmentGreater relapseGreater disability

Couturier et al. Cephalalgia 2003;23:302-308 MacGregor EA, Hackshaw A. Neurology 2004;63:351-3

Granella et al. Cephalalgia 2004;24:707-16 Dowson et al. Headache 2005;45:274-82

Diagnosis

• Prospective diary for at least three consecutive cycles

• Attacks on or between days -2 to +3 in 2/3 cycles

ICHD (2nd edition). Cephalalgia 2004;24(suppl 1):1–160

Migraine and menstruation

MacGregor EA et al Headache Quarterly 1997;8:126-136MacGregor EA et al Cephalalgia 1990;10(6):305-10

• Symptomatic treatment• Standard prophylaxis• Perimenstrual

prophylaxis• Continuous hormonal

contraception

Management

Pathophysiology

• No consistent biochemical or hormonal abnormalities have been identified in patients

• Increased sensitivity to NORMAL hormonal changes

Oestrogen ‘withdrawal’

• Migraine associated with – Hormone-free interval of combined hormonal

contraceptives

– Late-luteal decline in oestrogen

– Decline in oestrogen levels following oestrogen challenge in postmenopausal women

Occurs in the absence of ovulation

Occurs in the absence of progesterone

oestrogen

progesterone

0

10

20

30

40

50

0

10

20

30

40

day of cycle-15 -10 -5 1 5 10 15

% d

ays

with

rep

orte

d m

igra

ine

hormone m

etabolite concn ng/ml E

1G and µ

g/ml P

dG

Inverse relationship between oestrogen

and migraine

MacGregor EA et al. Neurology 2006; 67: 2154-8

Day +2minimum oestrogen level

MacGregor et al. Neurology 2006;67:2159-63

Bridging luteal phase oestrogen

Evidence-based treatment of menstrual migraine: perimenstrual oestrogen

• Transcutaneous estrogen 1.5mg daily– de Lignières et al, 1986 (day -2 to day +5)

– Dennerstein et al, 1988 (7 days perimenstrually)

– MacGregor et al, 2006 (day -5 to day +2)

Pringsheim et al. Neurology 2008;70:1555-63

Recommendation B “We recommend that clinicians routinely offer estradiol gel 1.5 mg perimenstrually to women with PMM or MRM for the prevention of

migraine. We found fair evidence that transdermal estradiol applied perimenstrually provides substantial reduction in the occurrence of

PMM and moderate reduction in the occurrence of MRM.”

Not licensed for short-term prevention of menstrual migraine

MacGregor et al. Neurology 2006;67:2159-63

Relative Risk of migraine: estradiol vs placebo n=35

RR [95%CI] P

During gel 0.78 [0.62 to 0.99] <0.05

Days 1-5 post gel* 1.40 [1.03 to 1.92] <0.05

Days 6-10 post gel 1.04 [0.67 to 1.62] NS

Relative Risk of migraine: estradiol vs placebo n=35

*peak increase day 3 post gel

MacGregor et al. Neurology 2006;67:2159-63

RR [95%CI] P

During gel 0.78 [0.62 to 0.99] <0.05

Days 1-5 post gel* 1.40 [1.03 to 1.92] <0.05

Days 6-10 post gel 1.04 [0.67 to 1.62] NS

Practical guidance: perimenstrual oestrogen

• Need plasma levels >70 pg/ml

• 100mcg patches/1.5 mg gel

• Start 2-5 days before onset of period

• Continue to 5th day of period

• Taper off 6th/7th day• Try for 3 cycles

Oestrogen and serotonin

• Oestrogen ‘withdrawal’ associated with– Decreased serotonin production

– Increased serotonin reuptake

– Increased serotonin elimination

• Can specific serotonin agonists, i.e. triptans prevent menstrual migraine?

Evidence-based treatment of menstrual migraine: perimenstrual triptans

• Frovatriptan 2.5mg daily– 2 days before expected migraine for 6 days

• Naratriptan 1mg daily– 2 days before expected migraine for 5 days

Pringsheim et al. Neurology 2008;70:1555-63

Recommendation B “We recommend that clinicians routinely offer estradiol gel 1.5 mg perimenstrually to women with PMM or MRM for the prevention of

migraine. We found fair evidence that transdermal estradiol applied perimenstrually provides substantial reduction in the occurrence of

PMM and moderate reduction in the occurrence of MRM.”

Not licensed for short-term prevention of menstrual migraine

Short-term prevention with frovatriptan:no evidence of delayed headache

Silberstein et al. Neurology 2004;63:261-9

95

% o

f P

atie

nts

Wit

ho

ut

Mig

rain

e

100

60

40

20

0

80

Treatment Day (Last Day of Treatment = 6)

12731 84 1162 10

Frovatriptan 2.5 mg qd

Frovatriptan 2.5 mg bid

Placebo

Short-term prevention with naratriptan:evidence of delayed headache

Mannix et al. Headache 2007;47:1037-49

Study 1 Study 2

1 50

60

100

40

20

90

80

50

30

10

70

Treatment Day(Last Day of Treatment = 6)

2515 2010 00

60

100

40

20

90

80

50

30

10

70

Treatment Day(Last Day of Treatment = 6)

% o

f P

atie

nts

Wit

ho

ut

Att

ack

5 2515 2010

Naratriptan

Placebo

n=290

Naratriptan

Placebo

n=365

% o

f P

atie

nts

Wit

ho

ut

Att

ack

Uterine prostaglandin release

max release during first 48hrs menstruation

HEADACHE

NAUSEA & VOMITING

MENSTRUAL CRAMPS

Prostaglandin inhibitors provide relief

Short-term prevention with naproxen sodium

• Double-blind placebo-controlled study (n=40)– 550mg or placebo 12 hrly– Day -7 to day +6 (start of menses = day 1)– Reduced headache intensity, duration, and number

of headache days– 33% were headache free (none with placebo)

• Open-label study (n=25) – Day -7 to days +7 or day -5 to day +5– Reduced number of attacks, intensity, and duration

Sances et al. Headache 1990;30:705-9; Allais et al. Neurol Sci 2007;28(suppl):S225-8

Evidence-based treatment of menstrual migraine: perimenstrual naproxen

• Evidence is insufficient to recommend for or against routinely offering naproxen to patients with menstrual migraine as short-term preventive therapy

• Balance of benefits and harms cannot be determined

Pringsheim et al. Neurology 2008;70:1555-63

Contraceptive options

• Maintain stable oestrogen levels– Continuous combined contraception

– Transdermal oestrogens + Mirena IUS

• Inhibit prostaglandin release– Mirena IUS

Conclusions

• Many women report migraine associated with menstruation

• Menstrual attacks are more disabling than non-menstrual attacks

• Correct diagnosis is important to enable optimal management

• Diary cards confirm the diagnosis• Tailor treatment to individual patient needs

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