Curt

Practice

Sumatriptan is effective in the treatment of menstrual migraine: a review of prospective studies and retrospective analyses
R Salonen, J Saiers Nctrrdogy Psych&y7herapeutic and DevelopmentGroup, Glaxo Wellcume,North Carolina, USA
!&&menR, Saiers J. Sumatriptan is effective in the treatment of menstrual migraine: a review of prospective studies and Hxqxctive ana@es. Cephalalgia 199!$19:1&9. Oslo. ISSN 0333-1024 migraine may be debilitating, long-lasting and refractory to treatment. because the efficacy and tolerability of abortive and prophylactic treatment options for menstrual migraine have generally not been evahrated in controlled clinical trials, treatment choices are often made on the basis of personal experience and anecdotal reports. This article reviews evidence from retrospective analyses and prospective studies showing that sumatriptan injection and tablets are effective and well tolerated in menstrual migraine. (1) Sumatriptan injection 6 mg was as effective in the treatment of menstrual migraine attacks as it was for nonmenstrual attacks in a retrospective analysis of data from two randomized, double-blind, placebocontrolled, parallel-group trials (n 51104). In the menstrual migraine group, 80% of women treated with sumatriptan injection 6 mg compared with 19% of placebo-treated patients reported headache relief 1 h postdose (pt0.001). (2) Sumatriptan injection 6 mg was effective in the acute treatment of menstrual migraine attacks in a prospective, double-blind, placebocontrolled, parallel-group, two-attack study (n = 226). Across the two attacks, 70 - 71% of patients treating menstrual migraine attacks with sumatriptan injec&n 6 mg compared with 22-24% of placebo-treated patients reported headache relief 1 h postdose @<0.001). (3) s umatriptan tablets 100 mg were effective in the acute treatment of menstrual migraine attacks in a prospective, double-blind, placebocontrolled, crossover study in women diagnosed with menstrual migraine (n = 115). For menstrual migraine attacks, headache relief 4 h postdose was reported by 67% of sumatriptan-treated patients compared with 33% of placebo-treated patients. Sumatriptan injection and tablets were genemlly well tolerated in these studies, in which adverse events were characteristic of those typically observed in sumatriptan acute migraine clinical trials. These data demonstrate that sumatriptan injection and tablets are effective and well tolerated in the treatment of menstrual migraine. 0 Menstrual migraine, migraine, sumatripfizn
Menstrual

Reijo Salonen, Glaxo Wellcome,5 Moore Drive, Research Triangle Park, NC!27709, USA. Tel. + 1 919 483 8119, &IX. + 1 919 483 0645. Received7 July 1998, ac+& 16 December 1998

Jktween W% and 70% of female migraine sufferers experience changes in migraine frequency related to their menstrual cycle (1 - 3). The minority (approximately 10%) of female migraine sufferers experience migraine attacks during the perimenstrual period, but not at other times of the month (3). Migraine attacks occurring or increasing in frequency during the perimenstrual period (2-3 days before onset of menses through the 2nd to 5th day of menstruation) are typically classified as menstrual migraines. However, menstrual migraine, which is not included in the International Headache Society criteria as a distinct migraine subtype, is variably defined in both clinical practice and clinical studies (1, 4, 5). For example, some clinicians do not diagnose menstrual migraine unless women suffer migraine attacks ady during the perimenstrual period and not at other times of the month, whereas others may diagnose menstrual migraine in a woman suffering migraines both during and outside the perimenstrual period. In the latter case, only those migraines occurring during the perimenstrual period are classed as menstrual migraines.

Menstrual migraines are commonly described in the medical literature as particularly debilitating, long-lasting (up to 3 days), and refractory to treatment (1,4-7). (These observations derive from clinical practice; no clinical studies to date have been conducted delineating the characteristics of nonmenstrual migraine attacks compared with menstrual migraine attacks.) Symptoms are similar to those reported with nonmenstrual migraines, in which moderate-to-severe, pulsating headaches are accompanied by nausea/vomiting, photophobia, and phonophobia. The pathophysiology of menstrual migraine has not been defmitively elucidated, but has been hypothesized to differ from that of nonmenstrual migraines and probably involves abnormal neurotransmitter responses (for example, of the opioid and/or serotonergic systems) to cyclical fluctuations in ovarian hormones (4, 5, 8, 9). Decreases in estrogen levels during the late luteal phase of the cycle have been hypothesized to trigger menstrual migraine attacks. Possibly, low estrogen states are associated with a loss of estrogens protective

cEPHALALaA19

(1999)

Sumatnjdan and mt3drual migraine

17

benefits, such as stabilization of serotonin function. The occurrence of menstrual migraine attacks coincides with the fall of estrogen during the menstrual cycle, and premenstrual administration of estrogen has been shown to delay the occurrence of migraine. There is also evidence that abnormal release of and/or biochemical responses to other hormones and neurotransmitters such as p-endorphin, prostaglandin Fz~ and El, dopamine, and melatonin are involved in the pathophysiology of menstrual migraine. (For more detailed information on the pathophysiology of menstrual migraine, see References 4, 5, 8 and 9.) Although the pathophysiology of menstrual migraine and nonmenstrual migraine may differ, treatments typically recommended for menstrual migraine are the same as those for nonmenstrual migraine. In their recent review (lo), Granella and colleagues advocate, based on their clinical experience, a sequential approach to treatment, in which acute attack medications such as sumatriptan are t&d first, accompanied or followed, if necessary, by intermittent prophylaxis, estrogen gel or patches, and anti-estrogen medications. Abortive therapeutic options for menstrual migraine include nonsteroidal anti-inflammatory drugs, ergot derivatives, and 5HTr agonists. Prophylactic treatments, the use of which is often prompted by the severity of attacks and their predictability, include beta-blockers and antidepressants. Estrogen has been used in both acute and prophylactic treatment of menstrual migraine. With the exception of sumatriptan (see below), these acute and prophylactic treatment options have not been evaluated in controlled, prospective chnical trials (1, 10). Evaluation of medications for menstrual migraine in controlled clinical trials may be particularly important given the strong possibility that the pathophysiology of migraine and of menstrual migraine differ. In this case, medications (e.g., the 5HTr agonist triptans) effective in nonmenstrual migraine would not necessarily be expected to be effective in menstrual migraine. A retrospective attempt to gauge the effects of the new 5HTr agonist zolmitriptan (2.5 mg to 10 mg) in menstrual migraine was made using a subset of data from 672 menstruant women from a doubleblind, randomized, placebo-controlled, parallelgroup study (11). Headache relief (moderate or severe predose pain reduced to mild or no pain) 2 h postdose in the active treatment groups was w by 69 -73% of women treating 118 menstrually associated migraines and by 64-71% of women treating 315 nonmenstrually associated migraines. Menstrual migraine was defined as occurring from 2 days before to 3 days after the onset of menstruation. Though these data suggest

that zolmitriptan may be effective in the treatment of menstrual migrame attacks, they lack corroboration in controlled, prospective studies.

Sumatriptan

in menstrual migraine

Sumatriptan is the most thoroughly studied acute migraine therapy in patients with menstrual migraine and menstruation-associated migraine. It is the only triptan to be evaluated for efficacy and tolerability in menstrual migraine in controlled, prospective studies as well as retrospective analyses.

Retrospective analysis
Solbach and colleagues (12) retrospectively assessed the efficacy of sumatriptan injection 6 mg in the treatment of menstrual migraine using data from Glaxo Wellcome studies S2B305 and S2B306. These studies were randomized, double-blind, placebo-controlled, parallel-group trials originally conducted to compare the efficacy and tolerability of sumatriptan injection 6 mg with those of placebo. Of the 1104 patients in the two studies, 157 women were retrospectively determined to have treated a menstrual migraine (defined as beginning 1 day before to 4 days after the onset of menstruation), and 512 women were determined to have treated a nonmenstrual migraine. Data from the remaining patients were excluded from the retrospective analyses because patients were male (n =123), women who had been hysterectomized (n =260), or women with missing data (n =52). The results demonstrate that sumatriptan injection was as effective in the treatment of menstrual migraine attacks as it was in nonmenstrual attacks. In the menstrual migraine group, 80% of women treated with sumatriptan injection 6 mg compared with 19% of placebo-treated patients reported headache relief (moderate or severe pain reduced to mild or no pain) 2 h postdose (p <O.OOl; Fig. 1). Similarly, in the nonmenstrual migraine group, 70%
n
I Sumatriptan injection6 mg Placebo

Menstrual migraine

Fig. 1. Percentage of women reporting relief of menstrual or

nonmenstrual migraine 2 h.postdose (retrospective anlysis).

18

R Salonen, J Saks

CEPHALALGIA 19 (1999)

of women treated with sumatriptan injection 6 mg compared with 20% of placebo-treated patients reported headache relief 2 h postdose (p <O.OOl; Fig. 1). Sumatriptan injection provided sustained duration of relief of menstrual migraines in this study. In the menstrual migraine group, 68% of women treated with sumatriptan injection 6 mg compared with 15% of placebo-treated patients maintained headache relief for at least 24 h after dosing (p<O.OOl). In the nonmenstrual migraine group, 60% of .women treated with sumatriptan injection 6 mg compared with 23% of placebo-treated patients maintained headache relief for at least 24 h after dosing (p <O.OOl). Sumatriptan injection was similarly well tolerated in the menstrual group compared with the nonmenstrual group. The most common adverse events (incidence not reported) were injection site reaction, dizziness, tingling, and nausea and/or vomiting. These events do not differ from those reported in typical sumatriptan injection clinical trials (13, 14). Prospective studies Facchinetti and colleagues (15) reported the results of a double-blind, placebo-controlled, parallel-group, two-attack study designed to assess the efficacy and tolerability of sumatriptan injection 6 mg in the treatment of menstrual migraine (defined as oc curring between 3 days before and 5 days after the first day of menstruation). Twohundred-and-twenty-six (226) patients treated at least one menstrual or nonmenstrual attack with sumatriptan or placebo. Efficacy analyses on patients treating a menstrual migraine with sumatriptan injection or placebo were conducted separately for attacks 1 (n= 179) and 2 (n = 139). The results demonstrate that sumatriptan injection was effective in the acute treatment of menstrual migraine attacks. For attack 1, 71% of patients treating menstrual migraine attacks with sumatriptan injection 6 mg compared with 22% of
n
Sumatriptan in-on 6 mg

placebo-treated patients reported headache relief (moderate or severe pain reduced to mild or no pain) 1 h postdose (p <O.OOl; Fig. 2). Seventy-three percent (73%) of sumatriptan-treated patients compared with 31% of placebo-treated patients reported headache relief 2 h postdose (p <O.OOl; Fig. 2). For attack 2, 70% of sumatriptan-treated patients compared with 24% of placebo-treated patients reported headache relief 1 h postdose @ <O.OOl; Fig. 2). Eighty-one percent (81%) of sumatriptantreated patients compared with 29% of placebotreated patients reported headache relief 2 h postdose (p <O.OOl; Fig. 2). Sumatriptan was also effective compared with placebo in alleviating nausea and photophobia/phonophobia associated with menstrual migraine attacks 1 and 2. Sumatriptan injection was generally well tolerated, with an adverse event profile typical of that observed in other sumatriptan injection studies. Like sumatriptan injection, sumatriptan tablets have been assessed in a prospective trial of menstrual migraine. Gross and colleagues (16) reported the results of a double-blind, placebocontrolled, crossover study designed to assess the efficacy and tolerability of sumatriptan tablets 100 mg compared with placebo in the treatment of all migraine attacks over four menstrual cycles in women diagnosed with menstrual migraine (retrospectively diagnosed if 380% of all attacks in the 6 months prior to the study occurred between 3 days before and 5 days after the onset of menstruation). One-hundred-and-fifteen (115) patients enrolled in the study, and 97 completed it. The results demonstrate that sumatriptan tablets were similarly effective for attacks occurring inside the menstrual window (defined as the 8 days commencing 3 days prior to the onset of menstruation; n =39 attacks) and attacks occurring outside the menstrual window (n=41 attacks). For attacks occurring inside the menstrual window, headache relief 4 h postdose was reported by 67% of sumatriptan-treated patients compared with 33% of placebo-treated patients (Fig. 3). For attacks occurring outside the menstrual window, headache relief 4 h postdose was reported by 79% of sumatriptan-treated patients compared with 31% of placebo-treated patients (Fig. 3). Adverse events were characteristic of those typically observed in sumatriptan tablet clinical trials. Study treatment was rated as good or excellent by 64% of patients on sumatriptan injection 6 mg compared with 21% of patients on placebo.

lhpostdose

2hAttack 1

lhpostdosfi

2hpostdose

Attack2

Conclusions
Considered togethei, the results of the retrospective and prospective studies demonstrate that suma-

Fig. 2. Percentage of women reporting relief of menstrual mipinelhand2 h postdose @ospective study).

CEPHALALGIA 19 (1999)

Sumatriptanand menstrual migraine

19

Sumatriptan tablets 100 mg

Insids menstrual window*

Outside menstrual window

.
7. 8. 9. 10.

Fig. 3. Percentage of women reporting relief of migraines inside

and outside the menstrual window 4 h postdose (prospective study). *De&ted as the 8 days commencing 3 days prior to the onset of menstruation. TDefined as days excluding the 8 days commencing 3 days prior to the onset of menstruation.

triptan injection and tablets are effective and well tolerated in the acute treatment of menstrual migraine. Sumatriptan also remains the only triptan which has been rigorously assessed in this migraine subtype. The therapeutic gain with sumatriptan over placebo is as large among patients treating menstrual migraine as it is among patients treating rrorunenstrual migraine. Sumatriptan tablets or inj&ion may provide a useful treatment option for women suffering from this debilitating, refractory migraine subtype.

11.

12
*
13.

14 .
15.

References
1. Bousser MG, Massiou H. Migraine in the reproductive cycle. In: Gksen J, Tfelt-Hansen P, Welch KMA, editors. The headaches. New York: Raven Press, 1993:413-g 2. Johannes CR, Linet MS, Stewart WF, Celentano DD, Lipton TB, Szklo M. Relationship of headache to phase of the 16.

menstrual cycle among young women: a daily diary study. Neurology 1995;45: 1076 - 82 Granella F, Sances G, Zanferrari C, Costa A, Marlignoni E, Manzoni GC. Migraine without aura and reproductive life events: a clinical epidemiological study in 1300 women. Headache 1993;33385 - 9 Fettes 1. Menstrual migraine: methods of prevention and control. Postgrad Med 1997;101:67 - 75 Kornstein SG, Parker AJ. Menstrual migraines: etiology, treatment, and relationship to premenstrual syndrome. Curr Opin Obstet Gynecol1997,9:154-9 Robbins L. Menstrual migraine with features of cluster headache. A report of 10 cases. Headache 1996%:X6-7 Silberstein SD. Migraine and women: the link between headache and hormones. Postgrad Med 1995;97:147-53 Welch KMA. Migraine and ovarian steroid hormones. Cephalalgia 1997;17 Suppl20:12-6 Benedetto C, Allais G, Ciochetto D, De Lorenzo C. Pathophysiological aspects of menstrual migraine. Cephalalgia 1997;17 Suppl20:32-4 Granella F, Sances G, Messa G, de Marinis M, Manzoni GC. Treatment of menstrual migraine. Cephalalgia 1997;17 Suppl 20:35 - 8 Dalessio DJ, Brown DL, Solbach P, Adelman JR, Elkind AH, Stark SR Oral 311C90 is effective in treatment of menstrual migraine. Cephalalgia 1996;16:400- 1 Solbach MP, Waymer RS. Treatment of menstruationassociated migraine headache with subcutaneous sumatriptan. Obstet Gynecol 1993;82:769 -72 The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med 1991;325:316-21 Cady RR, Wendt JR, Kirchner JF, Sargent JD, Rothrock JF, Skaggs H. Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;2652831-5 Fac&inetti F, Bonellie G, Kangasniemi P, et al. The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine. Obstet Gynecol 1995;86: 911-6 Gross MLP, Barrie M, Bates D, Dowson A, Ehington G. The efficacy of oral sumatriptan in menstrual migraine-a prospective study. Poster presented at the 7th International Headache Congress, 16-20 September, 1995, Toronto, Canada.