An overview of the efficacy of several triptan agents in menstrually related migraine (MM), as well as of other treatment modalities that are commonly used in the treatment of MM.
Steven D. Silberstein, MD, FACP
Practical Pain Management, May-June 2002
Many researchers have established a link between estrogen and progesterone — the female sex hormones — and migraine.[1-5] Migraine occurs more frequently in adult women (18%) than in men (6%),[2,6] and develops most frequently in the second decade, with the peak incidence occurring with adolescence.[1-4] Menstrually related migraine (MM) begins at menarche in 33% of affected women, occurring mainly at the time of menses in many migrainous women and exclusively with menses — true menstrual migraine (TMM) — in some. Its frequency has been reported to be as high as 60% to 70%; retrospective analysis suggests that its prevalence ranges from 26% to 60%, in headache clinic patients, although the prevalence appears to be lower in non-headache clinic patients.
Menstrual migraine can be associated w.ith other somatic complaints arising before and often persisting into menses, such as nausea, backache, breast tenderness and cramps, and, like these symptoms, appears to be the result of falling sex hormone levels.[5,6,8] Indeed, MM appears to occur at the time of greatest fluctuation in estrogen levels. In addition, premenstrual migraine (PMM), defined as attacks occurring 2 to 7 days before the onset of menses, can be associated with premenstrual syndrome (PMS), which is distinct from the physical symptoms of the perimenstrual period and is probably not directly driven by declining progesterone levels. Migraine occurring during (rather than prior to) menstruation is usually not associated with PMS. One group of researchers  has defined “true menstrual migraine” (TMM) as attacks that occur regularly on or between days -2 to +3 of the menstrual cycle and at no other time, and MM as attacks that occur at any time during the cycle with an increased frequency during menstruation. It now appears that migraine attacks occur more frequently with menstruation but are not longer in duration or clinically significantly more severe.
Treating Menstrually Related Migraine
Effective migraine treatment depends upon making an accurate diagnosis, teaching the patient to identify and avoid headache triggers and developing a treatment plan that reduces the impact of migraine on the individual patient, targeting the most disturbing symptoms. The use of a headache calendar will help establish a relationship between headache and the menstrual cycle and establish if headaches are menstrually triggered migraine (MM) or TMM. Women who have headache throughout their menstrual cycle should be treated with reassurance, education, and pharmacologic intervention.
There are two pharmacologic approaches to treatment. Acute (abortive) therapy is used to decrease the duration and intensity of an individual attack and the associated symptoms such as nausea and vomiting.[12,13] Preventive (prophylactic) treatment is used to decrease attack frequency and severity and should be considered when there are three or more attacks a month that are prolonged and unresponsive to abortive measures, or when abortive measures are contraindicated or produce significant side effects.
The Rationale for the Use of Triptans in Menstrually Related Migraine
The class of medications known as triptans are considered especially useful in MM because they can be used for both acute and preventive treatment. These agents are selective 5-HT1 agonists with activity at the 5-HT1D, 5-HT1B, and/or 5-HT1F receptor sites. In particular, zolmitriptan (Zomig®), sumatriptan (Imitrex®) and rizatriptan (Maxalt®) are as effective for menstrually associated migraine  as for migraine not associated with menses (non-MM) and, in addition, control the nausea and vomiting associated with attacks.[15,16]
The efficacy of zolmitriptan has been evaluated in three placebo-controlled (2.5 or 5mg) clinical trials involving almost 1000 women. Approximately 28% of the women had MM and 14% had migraines while using oral contraceptives (OCs). Zolmitriptan induced a similar two-hour headache response in the OC group (those using oral contraceptives).
The 2.5mg data from those three placebo-controlled trials were included in an analysis of prospectively recorded data from the zolmitriptan clinical trial program. Also included were data from two multiple-attack comparative trials with sumatriptan and two long-term open studies; all used zolmitriptan 2.5 or 5 mg, and data were combined where both dosages were used. A total of 4,345 menstruating patients were included in the analysis. Zolmitriptan 2.5mg was significantly more effective than placebo in the treatment of moderate to severe MM; two-hour headache response rates were 60% with zolmitriptan vs. 39% with placebo (p=0.0008). In the active comparator trials, zolmitriptan produced a two-hour headache response in 68% of MM attacks and 65% of non-MM attacks. In the two long-term studies, the two-hour response rates were 80% and 83% in MM vs. 81% and 82% in non-MM. Furthermore, within individual patients, response rates were similar in both types of attacks, irrespective of the percentage of attacks treated during menses.
A more recent study involving 579 women suggests that zolmitriptan exhibits efficacy as early as 30 minutes in MM. This study differs from others in that treatment was intensity based, with mild migraine headaches treated with one half of a zolmitriptan 2.5-mg tablet, moderate headache with 2.5mg, and severe headache with 5mg (two 2.5-mg tablets), or corresponding placebos. Additionally, patients were required to have MM in two of three prior menstrual cycles. Treatment with zolmitriptan was more effective than placebo in achieving early headache response for all MM as well as a subset excluding mild attacks.
Decrease in VAS (visual analog scale) of 50% or greater in headache response over a two-hour period was seen as early as 30 minutes.
In a retrospective analysis of data from two randomized, double-blind, placebo-controlled, parallel-group trials, 80% of women who treated MM with sumatriptan injection (6mg) reported headache relief one hour post-dose (p<0.001) compared with 19% of placebo-treated patients. Among women who treated non-MM with sumatriptan injection, 70% reported headache relief one hour post-dose (p< 0.001) compared with 20% of placebo-treated patients. Sumatriptan injection 6mg was also effective in the acute treatment of MM in a prospective, double-blind, placebo-controlled, parallel-group, two-attack study. Across the two attacks, 70% to 71% of patients treating MM with sumatriptan reported headache relief one hour post-dose, versus 22% to 24% of placebo-treated patients. Additionally, sumatriptan tablets (100 mg) were effective in the acute treatment of MM in a prospective, double-blind, placebo-controlled, cross-over study in women with a history of MM.
Sumatriptan injection and tablets were generally well tolerated as a treatment for acute MM in the studies described. Oral sumatriptan (25 mg) has also been evaluated as a preventive therapy in an open-label study of 20 women with MM,  in which therapy was started two to three days before the expected headache onset and continued for a total of five days. In 126 sumatriptan-treated cycles, headache was absent in 52.4% of patients and reduced in severity by 50% or greater in 42%. Breakthrough headaches were rare and significantly reduced in severity compared with baseline headache.
The efficacy of oral rizatriptan (10 mg and 5 mg) in MM was evaluated in two large, randomized, double-blind, placebo-controlled, incomplete-block, two-period, crossover-design clinical trials. Only data from the first attack in women with migraines who were treated with rizatriptan or placebo were included in the analysis. MM was defined as an attack that occurred within three days before or after the onset of the last menstrual period. At two hours after dosing, pain relief was reported by 68% of the 139 women who had MM and took the 10-mg dose of rizatriptan, and by 70% of the 115 women who had MM and took the 5-mg dose, compared with 44% of the 81 patients who took placebo (p<0.05). Results were similar in women taking rizatriptan for nonmenstrually associated attacks (n = 393): 69% of those taking the 10-mg dose and 66% of those taking the 5-mg dose reported pain relief two hours post-dose (test of menstrual association = nonsignificant).
The efficacy of oral naratriptan (1 mg and 2.5 mg) as short-term prophylactic treatment for MM was assessed in a randomized, double-blind, placebo-controlled, parallel-group study. MM was defined as migraines occurring on day -2 to +4 relative to onset of menses. Naratriptan 1 mg, 2.5 mg, or matching placebo tablets (1:1:1) were administered twice daily for five days, starting two days before the predicted onset of the MM, during four perimenstrual periods. Naratriptan 1 mg significantly reduced the number of MMs (2.0 MMs vs. 4.0 MMs, p=0.011) and MM days (4.0 days vs. 7.0 days, p=0.001) compared with placebo. More women treated with naratriptan 1 mg reported absence of MMs across all treated perimenstrual periods (23% vs. 8%, p<0.05) and had at least a 50%, reduction in MMs (61% versus 38%, p<0.05) compared with placebo-treated women. More women treated with naratriptan 2.5 mg had a reduced number of MMs and MM days, but the reductions were not significantly different than with placebo.
Other Treatment Modalities
Other treatments proven effective or commonly used for the acute treatment of menstrual migraine include nonsteroidal anti-inflammatory drugs (NSAlDs), dihydroergotamine, and the combination of aspirin, acetaminophen, and caffeine (AAC). The benefits of AAC were retrospectively examined in three double-blind, randomized, placebo-controlled, single-dose trials. Starting at 30 minutes post-dose with a maximum effect at six hours, pain relief (pain reduced to mild or none) was significantly (p<0.05) greater for AAC than placebo for both MM (AAC 76%; placebo 46%) and non-MM (AAC 77%; placebo 50%).
Prostaglandin production may be enhanced in menstrual migraine. The effectiveness of the NSAIDs [27,28] may be a result of blocking prostaglandin synthesis by inhibiting the enzyme cyclooxygenase. The meclofenamates, in addition, are prostaglandin receptor antagonists. One NSAID, ketoprofen, inhibits the formation of leukotrienes by inhibiting 5-lipooxygenase. NSAIDs must be used in adequate doses.[30,31] If the first NSAID fails, a different NSAID from another chemical class should be tried. NSAIDs can be used preventively one to two days before the expected onset of headache and continued for the duration of vulnerability.
Dihydroergotamine, a nonselective 5-HT1 agonist available in parenteral form and as a nasal spray, is effective for the treatment of MM.[32-34] Ergotamine and dihydroergotamine can be used prophylactically at the time of menses without significant risk of developing ergot dependence.[3,5,35,36] Ergotamine tartrate, at bedtime or twice a day, is an effective prophylactic agent. Dihydroergotamine nasal spray, given every eight hours for six days beginning three days before the expected onset of headache, produced a lower mean pain severity rating than placebo in two-thirds of patients evaluated in a double-blind, short-term trial for the treatment of MM.
Successful hormonal or hormonal modulation therapy of MM has been reported with estrogens  (alone or in combination with progesterone or testosterone), combined OCs,[39,40] synthetic androgens,[41,42] estrogen modulators and antagonists,[43,44] and medical oophorectomy with GnRH analog with or without addback therapy and prolactin release inhibitors.[45-47] The decrease in estrogen levels during the late luteal phase of the menstrual cycle is a trigger for migraine. Estrogen replacement prior to menstruation has been used to prevent migraine. Significant headache reduction has been reported in two double-blind trials of percutaneous estradiol gel.[15,50] Estradiol implants (available investigationally in the United States) and cyclic progesterones have also been found to be effective in MM.[38,51]
PMS sufferers who have had a hysterectomy without an oophorectomy continue to have cyclic mental and physical symptoms during the late luteal phase of the menstrual cycle, demonstrating that neither the presence of the uterus nor the occurrence of menstruation is necessary for the maintenance of PMS. Some physicians are again advocating the use of hysterectomy and oophorectomy in women with severe intractable PMS or MM who respond to medical ovariectomy.[53,54] There are no long-term follow-up or controlled studies to prove the effectiveness of this radical procedure. Until more conclusive data are available, oophorectomy should not be recommended for MM; instead, GnRH agonists should be used as a last resort, supplemented by estrogens, preferably in a patch or depo formulation, and low dose progestins.
Aids to Treatment Selection
Many migraineurs do not consult their physicians despite the severity of their attacks. In the case of MM, misperceptions about menses and a general lack of awareness of the link between headache and the female sex hormones may prevent many women from seeking treatment. A considerable number of migraineurs who do consult physicians are not accurately diagnosed. Those who receive an accurate diagnosis still may not receive the most appropriate therapy, despite the availability of effective treatment options. Consequently, many migraineurs lapse from care.
Experts have thus sought to encourage headache sufferers to consult their physicians as a means to increase the likelihood of accurate diagnosis and to develop effective medical care strategies. The Migraine Disability Assessment questionnaire (MIDAS)  was developed to match migraine treatment to migraine severity. The MIDAS questionnaire grades patients according to the level of disability caused by their migraines, with headache-related disability measured by counting the number of days of lost and limited activity due to migraine. According to its developers, the MIDAS may serve to enhance patient-physician communication about headache-related disability. Disability is both a target and a predictor of treatment needs, and so enhanced communication should lead to more effective management of migraine. The MIDAS can be used as an aid to treatment selection based on illness severity, as it is designed to increase patients’ chances of receiving the most suitable treatment the first time they consult their physicians.
The normal female life cycle is associated with a number of hormonal milestones: menarche, pregnancy, contraceptive use, menopause, and the use of replacement sex hormones. These events and interventions may cause a change in the prevalence or intensity of headache. Menarche marks the onset of menses and cyclic changes in hormone levels. The menstrual cycle is the result of a carefully orchestrated sequence of interactions between the hypothalamus, pituitary, ovary, and endometrium, with the sex hormones acting as modulators and effectors at each level. The primary trigger of MM appears to be the withdrawal of estrogen rather than the maintenance of sustained high or low estrogen levels. The selective 5-HT1 agonists known as the triptans have emerged as a valuable treatment approach because of their documented efficacy and utility in both acute and preventive treatment. Encouraging results have also been reported with hormonal therapy, NSAIDs and other types of analgesics. Treatment selection ultimately depends on accurate diagnosis and assessment of migraine severity. It is hoped that the wide utilization of treatment selection aids will facilitate appropriate matching of patients and treatments, thereby leading to enhanced patient adherence and more effective utilization of healthcare resources.
1. Epstein MT, Hockaday JM, Hockaday TDR. Migraine and reproductive hormones throughout the menstrual cycle. Lancet. 1975. 1:543-548.
2. Goldstein M, Chen TC. The epidemiology of disabling headache. In: Critchley M, ed. Advances in neurology. Volume 33 ed. New York: Raven Press. 1982. 377-390.
3. Raskin NH. Headache. 2nd ed. New York: Churchill-Livingstone. 1988.
4. Selby G, Lance JW. Observation on 500 cases of migraine and allied vascular headaches. J Neural Neurosurg Psychiatry. 1960. 23:23-32.
5. Silberstein SD, Merriam GR. Estrogens, progestins, and headache. Neurology. 1991. 41.775-793.
6. Waters WE, O’Connor PJ. Epidemiology of headache and migraine in women. J Neurol Neurosurg Psychiatry. 1971.34:148-153.
7. Johannes CB, Linet MS, Stewart WF, Celentano DD, Upton RB, Szklo M. Relationship of headache to phase of the menstrual cycle among young women: a daily diary study. Neurology. 1995. 45:1076-1082.
8. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. Fourth ed. Washington. 1994.
9. Mortola JF. Premenstrual syndrome-pathophysiologic considerations. N Engl J Med. 1998. 338:256-257.
10. MacGregor EA, Chia HVRC, Wilkinson M. Migraine and menstruation. Cephalalgia. 1990. 10:305-310.
11. Stewart WF, Upton RB, Chee E, Sawyer J, Silberstein SD. Menstrual cycle and headache in a population sample of migraineurs. Neurology. 2000. 55:1517-1523.
12. Saper JR, Silberstein SD, Lake AE, Winters ME. Double-blind trial of fluoxetine: Chronic daily headache and migraine. Headache. 1994. 34:497-502.
13. Silberstein SD, Saper JR. Migraine: Diagnosis and treatment. In: Dalessio DJ, Silberstein SD, eds. Wolff’s headache and other head pain. Sixth ed. New York: Oxford University Press. 1993.
14. Solbach MR Waymer RS. Treatment of menstruation-associated migraine headache with subcutaneous sumatriptan. Obstet Gynecol. 1993. 82:769-772.
15. DeLignieres B, Vincens M, Mauvais-Jarvis P, Mas JL, Touboul PJ, Bousser MG. Prevention of menstrual migraine by percutaneous estradiol. Br Med J Clin Hes. 1986. 293:1540.
16. Sheftel F, Silberstein SD, Rapoport A. Pharmacological treatment of chronic headache. Drug Therapy. 1992. 22:47-59.
17. Loder E, Silberstein SD. Clinical efficacy of 2.5 and 5mg Zolmitriptan (ZomigTM) in migraine associated with menses or in patients using nonprogestogen oral contraceptives. Neurology. 1998. 50:341.
18. Silberstein SD. Zolmitriptan is effective in the treatment of menstrually associated migraine attacks. Presented at the 10th Congress of the International Headache Society, NY, Jun 29-Jul 2, 2001. (abstract).
19. Loder E, Silberstein S, Giammarco R, et al. Oral zolmitriptan exhibits efficacy as early as 30 minutes in menstrually associated migraine: results of a large multicenter placebo-controlled study. To be presented at the 54th Annual Meeting of American Academy of Neurology, Denver, CO, Apr 13-20, 2002. (abstract).
20. Facchinetti F, Bonellie G, Kangasniemi P, Pascual J, Shuaib A. The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine. The Sumatriptan Menstrual Migraine Study Group. Obstet Gynecol. 1995. 86:911-916.
21. Silberstein SD, Watson C, O’Quinn S. Sumatriptan tablets and injection are effective in the treatment of menstrually associated migraine: a review. Neurology. 1998. 50:406.
22. Newman LC, Upton RB, Lay CL, Solomon S. A pilot study of oral sumatriptan as intermittent prophylaxis of menstruation-related migraine. Neurology. 1998.51:307-309.
23. Silberstein SD, Massiou H, leJeunne C, Pratt LJ, McCarroll KA, Lines CR. Rizatriptan in the treatment of menstrual migraine. Ob Gyn. 2000. 96:237-242.
24. Newman LC, Mannix LK, Landy SH, et al. Naratriptan as prophylaxis for menstrually associated migraine: a randomized, double-blind, placebo-controlled study. Neurology. 2000. 54:A14 (Abstract).
25. Silberstein SD, Armellino JJ, Hoffman HD, et al. Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen, aspirin, and caffeine: results from three randomized, placebo-controlled studies. Clin therapeutics. 1999. 21:475-491.
26. Silberstein SD, Armellino JJ, Hoffman HD, Battikha JP, Upton RB. Successful treatment of menstrual migraine with a nonprescription combination of aspirin, acetaminophen, and caffeine: results from three randomized, placebo-controlled studies. Neurology. 1998. 50:376 (Abstract).
27. Chan WY. Prostaglandins and nonsteroidal antiinflammatory drugs in dysmenorrhea. Ann Rev Pharmacol Toxicol. 1983. 23:131-149.
28. Vijayan N. Brief therapeutic report: papaverine prophylaxis of complicated migraine. Headache. 1977. 17:159-162.
29. Moncada S, Flower RJ, Vane JR. Prostaglandins, prostacyclin, thromboxane A2, and leukotrienes. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. The pharmacological basis of therapeutics. New York: MacMillan. 1985.
30. Sargent J, Solbach P, Damasio H, et al. A comparison of naproxen sodium to propranolol hydrochloride and a placebo control for the prophylaxis of migraine headache. Headache. 1985. 25:320-324.
31. Robinson K, Huntington KM, Wallace MG. Treatment of the premenstrual syndrome. Br J Obstet Gynecol. 1977. 84:784-788.
32. D’Alessandro R, Gamberini G, Lozito A, Sacquegna T. Menstrual migraine, intermittent prophylaxis with a timed-release pharmacological formulation of dihydroergotamine. Cephalalgia. 1983. 15:158.
33. Silberstein SD, Schulman EA, Hopkins MM. Repetitive intravenous DHE in the treatment of refractory headache. Headache. 1990 30:334-339.
34. Winner P, Sheftell F, Sadowsky C, Dalessio D, et al. A profile of menstrual migraine sufferers. Cephalalgia. 1993. 13:242.
35. Edelson RN. Menstrual migraine and other hormonal aspects of migraine. Headache. 1985. 25:376-379.
36. Silberstein SD. Treatment of headache in primary care practice. Am J Med. 1984. 77:65-72.
37. Silberstein SD. DHE-45 in the prophylaxis of menstrually related migraine. Cephalalgia. 1996. 16:371.
38. Magos AL, Brincat M, Studd JWW. Treatment of the premenstrual syndrome by subcutaneous estradiol implants and cyclical oral noresthisterone: placebo controlled study. Br Med J Clin Res. 1986. 292:1629-1633.
39. Kappius REK, Goolkasian P. Group and menstrual phase effect in reported headaches among college students. Headache. 1987. 27:491-494.
40. Sulak PJ, Cressman BE, Waldrop E, Holleman S, Kuehl TJ. Extending the duration of active oral contraceptive pills to manage hormone withdrawal symptoms. Obstet Gynecol. 1997. 89:179-183.
41. Calton GJ, Burnett JW. Danazol and migraine. N Eng J Med. 1984. 310:721-722.
42. Sarno AP, Miller EJ, Lundblad EG. Premenstrual syndrome: beneficial effects of periodic, low-dose danazol. Obstet Gynecol. 1987. 70:33-36.
43. O’Dea PK, Davis EH. Tamoxifen in the treatment of menstrual migraine. Neurology. 1990. 40:1471.
44. Powles TJ. Prevention of migrainous headaches by tamoxifen. Lancet. 1986. 2:1344.
45. Thomas EJ, Okuda KJ, Thomas NM. The combination of depot gonadotrophin releasing hormone agonist and cyclical hormone replacement therapy for dysfunctional uterine bleeding. Br J Obstet Gynecol. 1991.98:1155-1159.
46. Pickersgill A. GnRH agonists and add-back therapy: is there a perfect combination? Br J Obstet Gynecol. 1998. 105:475-485.
47. Murray SC, Muse KN. Effective treatment of severe menstrual migraine headaches with gonadotropin-releasing hormone agonist and “addback” therapy. Fertil Steril. 1997. 67:390-393 (Abstract).
48. Somerville BW. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology. 1975. 25:239-244.
49. Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol. 1984. 16:157-168.
50. Dennerstein L, Morse C, Burrows G, Oats J, Brown J, Smith M. Menstrual migraine: a double-blind trial of percutaneous estradiol. Gynecol Endocrinol. 1988.2:113-120.
51. Magos AL, Zilkha KJ. Treatment of menstrual migraine by estradiol implants. Gynecol Endocrinol. 1988.2:113-120.
52. Bakstromm CT, Boyle HBDT. Persistence of symptoms of premenstrual tension in hysterectomized women. Br J Obstet Gynecol. 1981. 88:530-536.
53. Casson P, Hahn PM, VanVugt DA, Reid RL. Lasting response to ovariectomy in severe intractable premenstrual syndrome. Obstet Gynecol. 1990. 162:99-105.
54. Casper RF, Hearn MT. The effect of hysterectomy and bilateral oophorectomy in women with severe premenstrual syndrome. Am J Obstet Gynecol. 1990 162:105-109.
56. Lipton RB, Goadsby PJ, Sawyer JPC, Blakeborough P, Stewart WF. Migraine: diagnosis and assessment of disability. Rev Contemp Pharmacother. 2000 11:63-73.