1. Menstrual Migraine Anne MacGregor www.migraineclinic.org.uk anne.macgregor@migraineclinic.org.uk

2. Role of hormones Migraine affects 1 in 5 women compared to 1 in 13 men

3. Rate of change of migraine prevalence over age continuum in females accelerating 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

4. Role of hormones 50% of women with migraine report an association between migraine and menstruation

5. 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 -1days +1 to +3 days 4+ Hazard Ratio *P < 0.01 **P < 0.001 ** P < 0.00001 1.50 *** 1.83 *** 1.21 * Headache Migraine Population based

6. 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 -1days -2 to -1days +1 to +3days +1 to +6 Relative Risk [95% CI] *P < 0.001 ** P < 0.0001 Clinic based

7. Menstrual vs non-menstrual attacks More severe Longer duration Less responsive to acute treatment Greater relapse Greater 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

8. Diagnosis Prospective diary for at least three consecutive cycles Attacks on or between days -2 to +3 in 2/3 cycles ICHD (2 nd edition). Cephalalgia 2004;24(suppl 1):1–160

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

11. Symptomatic treatment Standard prophylaxis Perimenstrual prophylaxis Continuous hormonal contraception Management

12. Pathophysiology No consistent biochemical or hormonal abnormalities have been identified in patients Increased sensitivity to NORMAL hormonal changes

13. 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

14. oestrogen progesterone 0 10 20 30 40 50 0 10 20 30 40 day of cycle -15-10-5151015 % days with reported migraine hormone metabolite concn ng/ml E1G and µg/ml PdG Inverse relationship between oestrogen and migraine MacGregor EA et al. Neurology 2006; 67: 2154-8

15. MacGregor et al. Neurology 2006;67:2159-63 Bridging luteal phase oestrogen

16. 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

17. MacGregor et al. Neurology 2006;67:2159-63 Relative Risk of migraine: estradiol vs placebo n=35 RR [95%CI]P During gel0.78 [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 gel1.04 [0.67 to 1.62]NS

18. 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 gel0.78 [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 gel1.04 [0.67 to 1.62]NS

19. 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

20. 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?

21. 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

22. Short-term prevention with frovatriptan: no evidence of delayed headache Silberstein et al. Neurology 2004;63:261-9 95 % of Patients Without Migraine 100 60 40 20 0 80 Treatment Day (Last Day of Treatment = 6) 1273184116210 Frovatriptan 2.5 mg qd Frovatriptan 2.5 mg bid Placebo

23. Short-term prevention with naratriptan: evidence of delayed headache Mannix et al. Headache 2007;47:1037-49 Study 1Study 2 15 0 60 100 40 20 90 80 50 30 10 70 Treatment Day (Last Day of Treatment = 6) 251520100 0 60 100 40 20 90 80 50 30 10 70 Treatment Day (Last Day of Treatment = 6) % of Patients Without Attack 525152010 Naratriptan Placebo n=290 Naratriptan Placebo n=365 % of Patients Without Attack

24. Uterine prostaglandin release  x3 over the menstrual cycle max release during first 48hrs menstruation HEADACHE NAUSEA & VOMITING MENSTRUAL CRAMPS Prostaglandin inhibitors provide relief

25. 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

26. 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

27. Contraceptive options Maintain stable oestrogen levels –Continuous combined contraception –Transdermal oestrogens + Mirena IUS Inhibit prostaglandin release –Mirena IUS

28. 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

29. ??????????? ??????????? ??????????? ??????????? ???????????