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Excerpt: Hormones and Headaches
Dr. Larry Robbins
Excerpt from Dr. Robbins
"Management of Headache and Headache Medications"

In women migraineurs, the female sex hormones, progestins and estrogens, exert a profound influence on the number and severity of migraine headaches. Why this occurs and the mechanisms involved, remains unclear. Menstrual migraines generate an enormous amount of suffering because they tend to be more severe than non-menstrually related headaches. In addition, they are often resistant to the usual migraine medication strategies.  Headaches often decline in severity during pregnancy but when present they are difficult to treat, because of the limited number of safe medications available. During menopause, headaches may follow any pattern, and they often improve after this time.  When women require hormone replacement therapy, there are certain hormonal approaches that may help limit the headaches. Oral contraceptives may induce or exacerbate headache, or, less often, the headaches may improve. The majority of the time, the birth control pill does not influence migraine; however, it is important to be aware of the possibility of migraine exacerbation with the oral contraceptives.

Menstrual Migraine

Menstrually related migraine occurs prior, during, or after menstruation. Many women with menstrual migraine also experience an exacerbation with ovulation. Most often, the woman will also experience migraines that occur at other times of the cycle that are not hormonally influenced. Occasionally, women may suffer menstrual migraine alone, without other headaches.

In several studies, progestin and estrogen levels have been found to be increased premenstrually in women migraineurs. However, others have not discovered this difference.  Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, as well as testosterone levels, have been the same in migraineurs as in controls. Estrogen withdrawal may produce migraine headaches, but the exact mechanism of this is uncertain.

Estrogen and progesterone influence serotonin receptors. Estrogen withdrawal exerts a profound effect on hypothalamic control mechanisms. Prostaglandins have been found in increased concentrations in women experiencing menstrual migraine.

Prostaglandin synthesis is blocked by the nonsteroidal anti-inflammatory drugs (NSAIDs), which may help to explain the role of the NSAIDs in treating menstrual migraine. Opioid peptide levels may be altered during menstrual migraine. All of the above factors may play a role in menstrual migraine. For any of the following medications, patients need to be informed of the side effects, as listed in the PDR and package insert.

Treatment of Menstrual Migraine:  Menstrual migraine is often severe, refractory, and prolonged.  However, many women suffer only a mild or moderate one day migraine, easily managed with the first line abortive migraine medications (see Chapter 2), such as Excedrin or ibuprofen. At times, the standard migraine preventive medications help the menstrual migraines, such as propranolol or amitriptyline.  For those women who experience severe, prolonged menstrual migraines, the preventive approaches include the following:

  1. NSAIDs, such as naproxen, ibuprofen, or the COX-2 inhibitors (Vioxx, Celebrex) warrant consideration. The COX-2 may not be as effective; this has yet to be determined.<.LI>
  2. Ergotamine derivatives such as Ergomar, ergonovine, CHE, or methysergide.
  3. Hormonal approaches, such as tamoxifen, estrogen, or the birth control pill.
  4. Triptans, such as naratriptan (Amerge), sumatriptan (Imitrex), or rizatriptan (Maxalt).

Abortive Treatment:  Abortive treatment of menstrual migraine usually follows the abortive therapy of migraine, as outlined in Chapter 2. For severe menstrual migraines, cortisone is one of the more effective treatments, usually Decadron or Prednisone. These are discussed in Chapter 2. Decadron, 4 mg. tablets, or Prednisone, 20 mg. pills, are usually limited to 3 pills per month at most and are taken every 6 hours, as needed. The triptans are crucial in abortive therapy for menstrual migraines. Dexamethasone, 2 to 4 mg. every 6 hours PRN, or Prednisone, 20 mg. every 6 hours PRN, limited to three per month, are often helpful. The triptans, particularly SQ sumatriptan (Imitrex SQ), are also very effective. All three forms of sumatriptan, naratriptan (Amerge) or rizatriptan (Maxalt) may be used. IM Toradol, IM DHE, or Migranal nasal spray benefit some women. If these strategies fail, at times a strong narcotic, such as meperidine (Demerol) with a powerful antiemetic, such as chlorpromazine (Thorazine), helps to avoid emergency room visits. As a last resort, Stadol N.S. may be helpful. The intense severity of menstrual migraines necessitates stronger abortive measures in many women. These abortive migraine strategies are discussed extensively in Chapter 2.

Preventive Medications:

Nonsteroidal Anti-inflammatories: The anti-inflammatories remain the mainstay of menstrual migraine preventive therapy, not because they are extremely effective, but because the side effects are less than with the other medications that are used. The anti-inflammatory is usually begun 3 days prior to the expected onset of the headache; if the patient experiences migraine beginning on the first day of the period, the NSAID is instituted 3 days prior to the expected onset of menses. The medication is continued for several days past the point of the “expected” headache. When the menstrual periods are irregular, medication is usually started the first day of the period, or when the woman feels that the menses is about to begin. Women who tend to experience the headache prior to, during, or after the menses require a much longer period of preventive therapy than women with premenstrual migraines. The timing of preventive therapy for hormonal headaches is often extremely difficult.

Naproxen (Naprosyn, Anaprox, Naprelan, Aleve) has been the most widely studied medication for prevention of menstrual migraine. For a complete discussion of naproxen for headache, please see Chapters 2 and 3. The usual dose is approximately 1,000 mg/day, taken with food. GI side effects are common, but otherwise the naproxen is well tolerated. Fluid retention may occur. The naproxen may also be utilized as an abortive agent once the headache begins.

Ibuprofen (Motrin) is available over the counter, and is well tolerated. It is also very effective for many women’s menstrual cramps. The effective dose of ibuprofen varies widely, from as little as 400 mg. per day to 2,400 mg. per day, in divided doses. As with naproxen, GI side effects are common.  Ibuprofen may also be used as an abortive medication. Ibuprofen is also discussed in Chapter 2.

Flurbiprofen (Ansaid) is an effective and generally well tolerated anti-inflammatory. The usual dose is one 100 mg. pill twice per day, or, if tolerated, the 2 tablets may be taken at the same time. GI side effects are common, as with any anti-inflammatory. Flurbiprofen may be used abortively.

Many other NSAIDs have been utilized for menstrual migraine prophylaxis. These include ketoprofen (Orudis and Oruvail), meclofenamate sodium (Meclomen), mefenamic acid (Ponstel), and fenoprofen (Nalfon). These are all probably as effective as naproxen or flurbiprofen. Some women will tolerate or respond to one anti-inflammatory significantly better than to another. It is sometimes worthwhile to attempt treatment with several anti-inflammatories as preventive medications prior to abandoning this class. The Cox-2 inhibitors (Vioxx, etc.) eliminate the gastrointestinal (GI) side effects. These are useful with a history of reflex or ulcers.

Ergotamine Derivatives or Triptans: Ergotamine or triptans may be utilized for the prevention of menstrual migraine, with minimal risk for developing rebound headaches. These may also be used abortively for the acute headache. The forms that are employed are: (1) ergotamine tartrate, (2) ergonovine, (3) DHE, and Triptans (Imitrex, Amerge, Maxalt, and Zomig).

Ergotamine Tartrate: Although ergotamine is usually considered to be a migraine abortive, it is occasionally helpful as a preventive for certain forms of migraine or cluster headache. Ergomar sublingual pills are “pure” ergotamine tablets, to be taken sublingually or swallowed. Each tablet contains 2 mg. of ergotamine tartrate. One tablet should be swallowed each day, beginning one day prior to the expected onset of the migraine, and continued until the headache period has passed. If the woman usually experiences a migraine on the first day of the period, the Ergomar would be started 1 day earlier, and used for 3 or 4 days. The possibility of rebound headaches needs to be considered when utilizing ergots in this preventive fashion.

Frequent side effects of ergots are nausea or severe GI upset, nervousness, and leg cramps. Besides these common effects, the possibility always exists that daily use of these may actually exacerbate migraine headaches; they need to be discontinued if this occurs. The ergots are discussed extensively in Chapter 2.

Ergonovine: Ergonovine is generally a well tolerated ergotamine derivative. Ergonovine is occasionally effective for both cluster and migraine. Ergotrate is the brand name that is available, but is often available in pharmacies in only very limited quantities. Compounding pharmacists are easily able to formulate ergonovine from the powder in any desired strength. The primary use for ergonovine in medicine is to increase the frequency, duration, and strength of uterine contractions, thus treating and preventing postabortal and postpartum uterine hemorrhage.

The Ergotrate brand is available as 0.2 mg. tablets, and the usual dose is 0.2 mg 2 to 4 times per day. This would be started 1 day prior to the expected onset of the headache, and continued for 2 or 3 days after the headache period. Side effects are usually somewhat less than with the standard ergotamines, but nausea and GI upset are common. Leg cramps or anxiety also may occur, but are generally encountered less often than with other ergotamines.

DHE: DHE is primarily an abortive medication, but occasionally it is useful for the prevention of menstrual migraine. For menstrual migraine prophylaxis, DHE is given as a 1 mg. injection once a day, beginning 1 day prior to the expected onset of the headache and continued for 1 day after the headache period. Alternatively Migranal nasal spray may be used each day during the same period. Intravenous DHE is effective for menstrual migraine prophylaxis, but is not very practical for regular monthly use.

The usual side effects of DHE are nausea, throat or chest tightness, mild muscle contraction headache, leg cramps, and a “hot” feeling about the head. The nasal spray may cause nasal congestion. DHE is usually very well tolerated, and may be used during the menstrual time as both a preventive and abortive medication. DHE is discussed extensively in Chapters 2 and 3.

Triptans (Imitrex, Amerge, Maxalt, Zomig): For some women, triptans are the most effective abortive and preventive therapy. Ideally, the longer-acting ones (Amerge) may be best; however, Imitrex has been effective (preventively) for certain women. The usual dose would be one tablet twice per day, starting 1 day (or so) prior to the “usual” onset of the migraine. It would usually be continued for 3 to 5 days. Timing of the menstrual migraine is often difficult, however. Amerge (2.5 mg.) is very well tolerated, and is particularly suited to this use. Triptans do not have an indication for this use from the FDA as of yet. See Chapter 2 for a complete discussion on triptans.

Hormonal Approaches to Menstrual Migraine Prevention

If the above therapies have not been effective and the menstrual migraines are very severe and debilitating, it is justified to consider stronger approaches, such as the use of hormonal therapy. Prior to utilizing hormonal therapies, women need to be informed of associated risks, as listed in a major drug reference guide.

Tamoxifen (Nolvadex): Tamoxifen competes with estrogen in target tissues, and is primarily used as an adjuvant breast cancer therapy. Gynecomastia and mastalgia have also been treated with tamoxifen. In low doses, I use tamoxifen for the prevention of menstrual migraine. Tamoxifen is one of the more effective menstrual migraine prevention medications. In some women, tamoxifen has decreased migraines and daily headaches at other times of the month as well.

Tamoxifen is available as a 10 mg. pill. The usual dose is 10 mg. per day for 7 to 14 days, usually given just prior to the menstrual period. Starting the tamoxifen earlier in the cycle, such as 1 week after menses, may be more effective in some women. The dose may be lowered to 5 mg. or increased to 15 to 20 mg. per day. The usual dose for the treatment or prevention of breast cancer is 10 or 20 mg. per day, but this has been increased in some patients.

Adverse effects are usually absent or mild, and include nausea, hot flashes, and menstrual irregularities. Rashes, vaginal bleeding, and vaginal discharges may occur. Other side effects such as leukopenia, weight gain, edema, headache, shortness of breath, loss of appetite, pain in the legs, blurred vision, and dizziness may occur but are rare with the low doses utilized for headache. Malignant liver tumors have been reported in animal studies; however, the animal studies have, in general, been conducted with very large doses. The patient needs to be informed of the association of liver carcinomas, at least in laboratory studies, and the use of tamoxifen. Uterine CA has also been reported. Frequent Pap smears need to be considered in women on tamoxifen.

Estrogen: During the normal menstrual cycle, there is a decrease in levels of estrogen during the late luteal phase. This may be a prominent factor in triggering the headache. Estrogen alleviates the headache in some women and exacerbates the headache in others. Progesterone is generally not effective for menstrual migraine, and will often increase headaches. Percutaneous estradiol gel, used perimenstrually, has been effective in the prevention of menstrual migraine, but this preparation is not available in the United States. I primarily use oral estrogen, usually ethinyl estradiol (Estinyl), 0.05 mg., or micronized estradiol (Estrace), 1 or 2 mg. Premarin, which is a natural conjugated estrogen, has an irregular absorption, and the fluctuating estrogen levels may contribute to headache. In addition, Premarin has miscellaneous natural compounds, equine-derived, that may possibly trigger headache. The synthetic estrogen preparations are, in theory, better for headache patients. The estradiol transdermal system (Estraderm) gives very consistent absorption of estrogen, and is useful for menstrual migraine prophylaxis. Since the use of estrogens is contraindicated during pregnancy, this issue needs to be explained prior to initiating therapy.

The usual dose of estrogen is 0.05 mg. of ethinyl estradiol(Estinyl), one tablet each day for 5 days prior to menses; this may be continued for 2 days after the onset of menstrual flow. I will usually utilize estrogen for a 1 week period of time. Alternatively, Estrace may be used, usually 1 mg. per day. The estrogen transdermal patch, Estraderm, may be utilized, with the 0.05 mg. patches. The total estradiol content is 4 mg., and the release rate is 0.05 mg. per 24 hours. The patch is changed twice weekly, and utilized for a total of 7 days. The idea is to minimize the length of time on estrogen, but to use the medication for a long enough time for it to be effective. The women who are placed on estrogens, or any hormonal therapy, have very severe, prolonged migraines. The debilitating nature of these severe menstrual migraines justifies the use of stronger medication approaches.

Side effects of estrogens are many, and include: breakthrough bleeding, dysmenorrhea, amenorrhea, menstrual flow changes, endometrial hyperplasia, vaginal candidiasis, nausea, abdominal cramps, colitis or cholestatic jaundice, alopecia or hives, hirsutism, headache, dizziness, depression, decrease or increase in weight, edema, decreased libido, tenderness of the breasts, and chloasma. Estrogens may also increase the risk of endometrial carcinoma. Breast cancer may be influenced by estrogens. Estrogens are contraindicated during pregnancy or with a history of thrombophlebitis or thromboembolic disorders. Preexisting uterine leiomyomas may grow during estrogen therapy. Although small doses are utilized for limited periods of time, women on estrogens should be followed closely by their gynecologist.

Continuous Birth Control Pill: For some women with extremely severe, prolonged menstrual migraine, a low-dose continuous (noncycling) birth control pill may be effective. The birth control pill will be utilized for a number of months to decrease the devastating headaches for that period of time. This approach is relatively safe, and at times is the only effective therapy. While the birth control pill may help decrease headache, when it is used on a cyclical basis (in the usual manner), the menstrual migraines are often more severe. Women who smoke cigarettes should not be on the birth control pill.

Oophorectomy as a Therapy for Severe Menstrual Migraine: In very rare circumstances, in women past age 40 with prolonged, severe, refractive menstrual migraine, Lupron injections (to stop the menstrual cycle) have been given for a number of months. If the headaches are gone, even with added estrogens and progesterone, a few women have had an oophorectomy in order to stop the devastating headaches. It remains controversial whether this is ever indicated or appropriate.

Vitamins and Minerals: Magnesium oxide (250 to 500 mg. per day) has been helpful for some women with menstrual migraines. It is usually given daily, or for 1 week prior to and with menses. Long-term side effects, if any, are unknown. Calcium may be helpful as well (750 to 1500 mg. daily).

Quick Reference Guide: Treatment of Menstrual Migraine

The abortive therapy follows the general abortive therapy for migraine. Cortisone (Prednisone, Decadron) is very effective for many women; it is utilized in very limited amounts. The severe intensity of menstrual migraines often dictates stronger abortive measures. Triptans (particularly Imitrex SQ) are particularly useful.

Preventive Treatment:

... NSAIDs (Naproxen, etc.): Effective for many women and usually well tolerated. These are started 3 days prior to the expected onset of the headache. Many NSAIDs have been utilized, including naproxen, ibuprofen, flurbiprofen, meclofenamate sodium, etc. GI upset is common.

... Ergot derivatives or triptans: These are begun 1 day prior to the expected onset of the headache (if timing is possible). Ergotamine preparations may occasionally prevent menstrual migraine. Ergomar (2 mg. of pure ergotamine) or Ergonovine 0.2 mg. may be utilized. Dihydroergotamine (DHE) (Migranal nasal spray) or triptans (particularly Amerge, a long-acting triptan) are being utilized for prevention; these medications do not have Food and Drug Administration (FDA) approval for this purpose as yet.

... Hormonal approaches:
    a.  Tamoxifen (Nolvadex) competes with estrogen and may decrease
         headache in certain women. Tamoxifen (5 or 10 mg.) is usually
         given for 1 to 2 weeks prior to menses.
    b.  Estrogen (patches, tabs, or gel) given prior to menses is
         occasionally helpful.
    c.  Oral contraceptives on a continual daily basis without a break
         are effective in some women in alleviating hormonal headaches.
         This treatment is usually considered if other milder
         therapies have failed.

... Triptans: Amerge (naratriptan) is a long-acting, smooth, well tolerated triptan. Its utility in menstrual migraine is being investigated. The usual dose would be 2.5 mg. once or twice a day for three to five days around the time that the menstrual migraine would occur. Occasionally, sumatriptan, which is shorter acting than naratriptan, has been used for this purpose. Rizatriptan (Maxalt) may also be useful in this regard.

Headache During Pregnancy and Breastfeeding

Migraine often diminishes during pregnancy. However, the headaches may at times be increased during the pregnancy, or the onset of migraine may occur during pregnancy. Organic causes for headache need to be considered and excluded in pregnant women with severe headaches. Treatment of the migraine or CDH during pregnancy consists of utilization of the non-medication techniques, such as ice and relaxation therapy, and judicious use of small amounts of medication. The abortive medications are predominantly used, with preventive therapy reserved for only the most resistant headaches. Although we attempt to maintain a drug free pregnancy, severe headaches require therapy, and if the physician does not adequately treat the headaches, most women will resort to OTC preparations. Women need to be informed of any risks to the fetus, as listed in the PDR or “Drug Facts and Comparisons”.

Acetaminophen is the primary abortive medication during pregnancy. This may be combined with small amounts of caffeine, such as aspirin-free Excedrin. Ice packs, a dark room, and relaxation exercises are utilized in addition. Limited amounts of NSAIDs such as ibuprofen or naproxen are also utilized, particularly in combination with small amounts of caffeine. Narcotics, particularly meperidine, codeine, or morphine, are also utilized. Aspirin in small doses may be used, but acetaminophen is preferred. Limited amounts of steroids, particularly Prednisone, can be used for severe intractable headache. Prednisone is preferable to dexamethasone. We cannot use ergotamine or triptans. Antiemetics may be used, particularly the over-the-counter (OTC) vitamin B6 or Emetrol. For more moderate to severe nausea, metoclopramide (Reglan) or prochlorperazine (Compazine) may be used. Dramamine and Antivert are also considered relatively safe. For extremely severe prolonged attacks of migraine, intravenous fluids, intravenous prochlorperazine (Compazine), narcotics, and steroids may all need to be utilized.

Prophylactic medication is occasionally necessary if headaches are very frequent and severe during pregnancy. Depending on comorbidities, SSRIs such as Prozac and Zoloft and b-blockers such as propranolol are usually utilized. Calcium channel blockers have also been used. Recent preliminary studies on SSRIs have indicated that they appear to be relatively safe. b-blockers, particularly in the first trimester, have been reported to cause intrauterine growth retardation, but have been considered to be relatively safe during pregnancy. We usually discontinue medication 3 weeks prior to delivery. During the first trimester we attempt to minimize or avoid medication, if possible. Women need to be completely informed as to potential side effects of any medication, as listed in major sources such as the PDR, and risks need to be completely understood and discussed.

Treatment of Headache During Pregnancy

... Limit, minimize medication
... Ice Packs, relaxation therapy, diet
... Caffeine, acetaminophen prn, occasionally NSAIDs are used
... If above not effective, utilize small amounts of analgesics such as codeine or meperidine. Meperidine may be formulated as a suppository by compounding pharmacists.
... For frequent, severe, intractable headache, prophylactic medication may be utilized. Beta blockers, such as propranolol (Inderal), are most commonly used. These should be stopped during the last month of pregnancy. In addition, medication must be minimized during the first trimester. SSRIs have become increasingly popular.

Breastfeeding and Headache: As with pregnancy, we wish to minimize medication during breast-feeding. As needed, acetaminophen, caffeine and NSAIDs are primarily used. The narcotic painkillers, in addition, are compatible with breast-feeding. Because of sedation, barbiturates are used with caution. Antihistimines are not used. Prochlorperazine is the antinausea drug of choice. Ergots and triptans are best avoided. Preventively, beta-blockers, calcium channel blockers, and Depakote are all utilized. Steroids are used in limited situations for limited periods of time. Antidepressants are still utilized with caution, but SSRIs (Prozac, Zoloft) have been widely used during this period.

Headache During Menopause and Post-Hysterectomy

Migraine follows several different pathways during and after menopause. The headaches often increase in frequency or severity, but at times they may cease altogether. Many women do not experience any change in the migraine pattern. After hysterectomy or oophorectomy, there is also no consistent pattern to the headaches. They may greatly improve after the surgery, but more often the migraines increase.

The confusion surrounding menopausal headaches is increased by the fact that some women improve with estrogen replacement therapy and others experience more headaches. In women placed on estrogens and cyclic progestins, a moderate or severe increase in migraine should initiate a change in the hormone regimen. At times, it is necessary to discontinue the hormones completely. In women who have not had a hysterectomy, cyclic progestins are necessary, and these are the primary culprit in the exacerbation of the headaches. In addition, the withdrawal of estrogen for a number of days may trigger migraine. In women who have undergone hysterectomy, continuous estrogen therapy for the entire month, without a break, is often the best approach for the headaches.

When choosing an estrogen preparation the synthetic compounds seem to create less migraine than Premarin. The equine-derived conjugated estrogens (Premarin) are not absorbed at a steady rate, and contain many natural compounds that could possibly trigger headache. Ethinyl estradiol (Estinyl), micronized estradiol (Estrace), esterified estrogens (Estratab), and estropipate (Ogen) are commonly used oral preparations. Estraderm is a transdermal estradiol that delivers a consistent blood level of estrogen. Depo-Estradiol is estradiol cypionate that is injected once every month. Many women will experience less migraine with this once per month injection. The effect of estrogen dose on migraine varies, with some women improving with increased doses, and others experiencing more headaches.

Progestins are utilized primarily to prevent endometrial cancer, increase new bone formation, and prevent osteoporosis. The progestins may exacerbate headache, however. It is helpful to keep the dose to a minimum, and to utilize the progestins for the minimum number of days. However, some women have fewer migraines when on continuous low dose progestins throughout the month.

The addition of androgens (methyltestosterone) may help to alleviate certain symptoms of the menopause. Women often have improved libido, increased feelings of well-being, decreased depression, and improvement in headaches while on androgens. Methyltestosterone is occasionally helpful for menstrual and menopausal migraine. The androgens are utilized along with the estrogen, on the same days. Combination preparations are available, such as Estratest tablets, which consists of methyltestosterone (2.5 mg.), and esterified estrogens (1.25 mg). Injectable forms are also available. A typical regimen would include one tablet of Estratest from day 1 though 25, and a progestin added from day 13 through 25.

The above section, “Hormones and Headaches” is excerpted from Dr. Lawrence Robbins’ book, Management of Headache and Headache Medications. All references in the above text to specific chapter numbers refer to chapters in the book.