1. Migraine and Women Dr Manuela Fontebasso General Practitioner, York and GPwSI in Headache, Headache Clinic, York Hospital

2. Are hormones important in migraine ? Prevalence equal in boys and girls before puberty In adults migraine is 3 times more common in women than men Studies have shown that the natural fall in oestrogen is a trigger for migraine Prostaglandin levels rise during menstrual migraine and have been shown to trigger migraine like headache Bille B Migraine in school children Acta Paediatr Scand 1962; 51 suppl 136: 1 - 151 Somerville BW, Neurology 1972; 22:355 - 365 and 1972; 22: 824 - 828 Fettes I. PostGrad Med 1997; 101: 67 - 77

3. Pure Menstrual Migraine without Aura Defined as Attacks that occur Day 1 +/- 2 days of each cycle And at no other time Most commonly migraine without aura Affects 10% of all women Diagnosis is made with diary cards monitor for 3 cycles Review and evaluate attack pattern Headache classification Subcommittee of the International Headache Society The International Classification of Headache Disorders 2 nd edition Cephalalgia 2004 24 Suppl 1 1 - 60

4. Menstrually Related Migraine without Aura Defined as Attacks that occur Day 1 +/- 2 days of each cycle And at other times in the cycle Diagnosis is made with diary cards monitor for 3 cycles Review and evaluate attack pattern Headache classification Subcommittee of the International Headache Society The International Classification of Headache Disorders 2 nd edition Cephalalgia 2004 24 Suppl 1 1 - 60

5. Migraine and Premenstrual Syndrome Defined as attacks that occur in the luteal phase following ovulation associated with other PMS symptoms Diagnosis is made with diary cards monitor for 3 months PMS symptoms must clear as menstruation starts Women with PMS may have severe headache not fulfilling IHS criteria for migraine

6. Pregnancy - 1 Migraine may occur for the first time in pregnancy especially migraine with aura 60 - 70% may experience a reduction in frequency especially migraine without aura more likely in women with menstrual migraine during the second and third trimester Marie- Germaine Bousser & Helene Massiou : Migraine in the reproductive cycle. Chapter 58.The Headaches. Silberstein SD. Migraine in Women. Post Grad Medicine; 97 (4) 147 - 153. Michel Aube. Migraine in Pregnancy. Neurology 1999; 53 (suppl 1):S26 - S28 PJ Goadsby J Goldberg SD Silberstein BMJ 2008; 336: 1502 – 1504 MacGregor EA, Migraine in pregnancy and lactation: a clinical review. J Fam Plann Reprod Health Care 2007:33 (2) 83 to 93

7. Pregnancy - 2 4 - 8% experience a worsening of symptoms especially those with migraine with aura Up to 25% may remain the same May experience rebound effect after delivery 40% resumed usual pre pregnancy rate in first post partum week breast feeding is associated with less migraine Marie- Germaine Bousser & Helene Massiou : Migraine in the reproductive cycle. Chapter 58.The Headaches. Silberstein SD. Migraine in Women. Post Grad Medicine; 97 (4) 147 - 153. Michel Aube. Migraine in Pregnancy. Neurology 1999; 53 (suppl 1):S26 - S28 PJ Goadsby J Goldberg SD Silberstein BMJ 2008; 336: 1502 - 1504 MacGregor EA, Migraine in pregnancy and lactation: a clinical review. J Fam Plann Reprod Health Care 2007:33 (2) 83 to 93

8. Migraine and the risk of stroke Migraine with aura increases the risk of ischaemic stroke two fold (1) Migraine without aura is not associated with an increase ischaemic stroke risk There are no studies to show that there is an increased risk of stroke in migraine sufferers over the age of 45 years (2) Annual incidence of stroke in Europe is 1 to 3 per 100,000 women under 35 years 10 per 100,000 women over 35 years (3) 1.Gudmundsson LA, Scher AI, Aspelund T et al Migraine with aura and risk of cardiovsacular and all cause mortality in men and women/BMJ 2010 341 c 3966 2. The IHS Task Force. Cephalalgia, 2000; 20: 155 – 6 3. MacGregor EA. Hormonal Contraception and migraine. Faculty of Family Planning Fact Sheet. Review no. 2001/01

9. The combined hormonal contraceptives (CHC), migraine and the risk of stroke CHC’s are an established risk factor for ischaemic stroke RR is 16 if you have migraine Smoking increases the risk of stroke RR is 10 if you have migraine Risk is additive RR is 34.4 is you take CHC’s and smoke (Tzourio et al BMJ 310: 830 - 833 and Chang et al BMJ 318: 13 - 18)

10. In the UK: Migraine and Combined Hormonal Contraceptives (CHC) You can use CHC’s if There is no aura and no additional risk factors You can use CHC’s with caution if There is no aura and one additional risk factor CHC’s are contraindicated if There is aura There is no aura BUT more than one risk factor There are severe and prolonged attacks There is concurrent use of ergot (WHO Improving Access to Quality Care in Family Planning. Medical Eligibility Criteria for Use. Second edition. WHO/RHR/00.02.) (MacGregor EA, Guillebaud J. Recommendations for clinical practice. Br J Fam Planning 1998; 24: 53 - 60) (Bousser M-G, Kittner SJ. Oral contraceptives and stroke. Cephalalgia 2000; 20: 183 - 189) (EA MacGregor Migraine and use of combined hormonal contraceptives: a clinical review J Fam Plann Reprod Health Care 2007; 33 (3): 159 – 169 )

11. Migraine in the Peri and Post Menopause Migraine prevalence increases in the peri menopause decreases in the post menopause Women who had a spontaneous menopause Had a migraine prevalence of 7% Women who had a surgical menopause Had a migraine prevalence of 27% + PMS had a migraine prevalence of 44% (Wang SJ, Headache 2003; 43: 470 - 478)

12. Migraine in the Peri and Post Menopause In any individual it May get better May get worse May stay the same Pattern of symptoms may change Aura without headache

13. Assessment and Investigations Careful history to exclude red flag symptoms Careful examination of patient to exclude focal neurological signs Is it aura or TIA? New onset symptoms or change in symptom profile Diagnostic tests only needed if a secondary headache is suspected MRI or MRA scan

14. The acute treatment of the menstrual migraine attack Menstrual migraine often harder to treat than attacks that occur at other times of the cycle Menstrual migraine associated with greater degree of disability Have to find the most effective combination for the individual may mean using a NSAID and an anti emetic and a triptan may need to use maximal dose of triptan EA MacGregor Managing Menstrual migraine: A clinical review J Fam Plann Reprod Health Care 2007; 33 (1): 36 - 47

15. Acute migraine treatment in pregnancy: 1 Paracetamol, drug of choice for mild to moderate pain Aspirin, safe in first and second trimester, caution at term NSAID, ibuprofen, not exceeding 600mg daily no evidence to show increased risk of malformation or spontaneous miscarriage caution or avoid after 30 weeks, risk of premature closure of ductus arteriosus and oligohydramnios Anti-emetics Buclizine, chlorpromazine, cyclizine, domperidone, metoclopramide and prochlorperazine, no reported adverse effects MacGregor EA, Migraine in pregnancy and lactation: a clinical review. J Fam Plann Reprod Health Care 2007:33 (2) 83 to 93

16. Acute migraine treatment in pregnancy: 2 Ergots, Contraindicated as cause uterine hypertonicity and vascular disruption increase risk of miscarriage Triptans, Safety in pregnancy yet to be confirmed Women who have used triptans in early pregnancy can be reassured, exposure has not been associated with adverse outcomes Triptan use during pregnancy is only recommended if no other treatment is effective Sumatriptan safety data base: 4.3% risk first trimester birth defects 3 to 5% risk in general population Rizatriptan safety data base: similar results but small numbers MacGregor EA, Migraine in pregnancy and lactation: a clinical review. J Fam Plann Reprod Health Care 2007:33 (2) 83 to 93

17. Acute migraine treatment while breastfeeding Paracetamol, drug of choice Aspirin, Avoid, risk of Reyes syndrome NSAID, Concentration in breast milk very low Anti-emetics Domperidone, pro-kinetic, stimulates prolactin, does not cross blood brain barrier, concentration in breast milk are low Ergots avoid, may inhibit lactation MacGregor EA, Migraine in pregnancy and lactation: a clinical review. J Fam Plann Reprod Health Care 2007:33 (2) 83 to 93 Preferred to metoclopramide

18. Triptan use while breastfeeding Consider bioavailability amount of medication in breast milk limited data available Summary of product characteristics usually suggest caution avoid breast feeding for 12 to 24 hours after treatment Sumatriptan Most extensive data base Low level of excretion in breast milk (0.5% of oral dose) Eletriptan One study, 80mg dose, 0.02% of dose in breast milk MacGregor EA, Migraine in pregnancy and lactation: a clinical review. J Fam Plann Reprod Health Care 2007:33 (2) 83 to 93

19. Pure Menstrual Migraine without Aura – Use of NSAID or Percutaneous/Transdermal oestrogen Use any NSAID Naproxen 500mg up to bd or mefenamic acid 500mg up to qds Use any oestrogen patch or gel transdermal oestrogen 100mcg or oestradiol gel 1.5mg Start 2 - 3 days before expected onset of attack and use for 7 days Can extend NSAID into period if the patient has dysmenorrheoa Need to have regular periods EA MacGregor Managing Menstrual migraine: A clinical review J Fam Plann Reprod Health Care 2007; 33 (1): 36 - 47

20. Pure Menstrual Migraine without Aura Migraine in pill free week Use oestrogen dominant pill Marvelon or Dianette Tricycle the COCP Take three packs consecutively Use NSAID daily in pill free week Use top up oestrogen in pill free week EA MacGregor Managing Menstrual migraine: A clinical review J Fam Plann Reprod Health Care 2007; 33 (1): 36 - 47

21. Migraine, HRT and the peri-menopausal women Ideally use patch or gel If she has NOT had a hysterectomy Cyclical HRT Oestrogen and progestogen preparation, with progestogen for 14 days in each cycle If she HAS had a hysterectomy Can use oestrogen alone

22. Migraine and HRT and the post-menopausal women Ideally use patch or gel If she has NOT had a hysterectomy and it is more than 12 months since her last period Continuous combined HRT Combined oestrogen and progestogen If she HAS had a hysterectomy Can use oestrogen alone

23. Migraine and HRT - 1 When using patch or gel Start at lowest possible dose Matrix patch offers most dose flexibility because you can cut it up Titrate the dose up slowly Oestrogen patch 25mcg Could start with a quarter patch By a quarter patch weekly or monthly

24. Migraine and HRT - 2 If unable to tolerate standard preparation could use oestrogen patch and dydrogesterone or medroxyprogesterone for 14 days in each cycle Could use Levonorgestrel releasing IUS as progestogen source to give period free HRT in the peri or post menopausal woman BUT what about the risks?

25. Migraine, HRT and breast cancer risk Background incidence per 1000 women not using HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using oestrogen only HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using combined HRT 50 to 59 yrs 60 to 69 yrs 10 over 5 yrs20 over 10 yrs 15 over 5 yrs30 over 10 yrs 2 for 5 yrs use 3 for 5 yrs use 6 for 10 yrs use 9 for 10yrs use 6 for 5 yrs use 9 for 5 yrs use 24 for 10 yrs use 36 for 10 yrs use Additional cases Adapted from BNF 58 September 2009

26. Migraine, HRT and endometrial cancer risk Background incidence per 1000 women not using HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using oestrogen only HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using combined HRT 50 to 59 yrs 60 to 69 yrs 2 over 5 yrs4 over 10 yrs 3 over 5 yrs6 over 10 yrs 4 for 5 yrs use 6 for 5 yrs use 32 for 10 yrs use 48 for 10yrs use 0 for 5 yrs use 0 for 10 yrs use Additional cases Adapted from BNF 58 September 2009

27. Migraine, HRT and ovarian cancer risk Background incidence per 1000 women not using HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using oestrogen only HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using combined HRT 50 to 59 yrs 60 to 69 yrs 2 over 5 yrs4 over 10 yrs 3 over 5 yrs6 over 10 yrs <1 for 5 yrs use 1 for 10 yrs use 2 for 10yrs use <1 for 5 yrs use 1 for 10 yrs use 2 for 10 yrs use Additional cases Adapted from BNF 58 September 2009

28. Migraine, HRT and VTE risk Background incidence per 1000 women not using HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using oestrogen only HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using combined HRT 50 to 59 yrs 60 to 69 yrs 4 over 5 yrs 5 over 5 yrs 2 for 5 yrs use 7 for 5 yrs use 10 for 5 yrs use Additional cases Adapted from BNF 58 September 2009 Especially in first year of use

29. Migraine, HRT and stroke risk Background incidence per 1000 women not using HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using oestrogen only HRT 50 to 59 yrs 60 to 69 yrs Additional cases per 1000 women using combined HRT 50 to 59 yrs 60 to 69 yrs 4 over 5 yrs 9 over 5 yrs 1 for 5 yrs use 3 for 5 yrs use 1 for 5 yrs use 3 for 5 yrs use Additional cases Adapted from BNF 58 September 2009 1 EA MacGregor Migraine, the menopause and hormone replacement therapy: a clinical review J Fam Plann Reprod Health Care 2007; 33 (4): 245 - 249 HRT initiated in the perimenopause is not associated with an increased stroke risk 1

30. Migraine, HRT and coronary heart disease Background incidence per 1000 women not using HRT 70 - 79 yrs Additional cases per 1000 women using combined HRT 70 – 79 yrs 29 - 44 over 5 yrs 15 for 5 yrs use Additional cases in women who start HRT more than 10 yrs after the menopause HRT initiated in the perimenopause is not associated with an increased cardiovascular risk 1 Adapted from BNF 58 September 2009 1 EA MacGregor Migraine, the menopause and hormone replacement therapy: a clinical review J Fam Plann Reprod Health Care 2007; 33 (4): 245 - 249

31. Conclusion In any patient with migraine the principles of management should be to adopt a holistic approach to care involve the patient in the decision making process find the most effective acute treatment option consider standard prophylaxis options remember that hormonal or similar targeted options do not suit everybody may not be a first line choice