- Email: [email protected]
The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine
The Efficacy and Safety of Subcutaneous Sumatriptan in the Acute Treatment of Menstrual Migraine F. FACCHINETTI,
MD, G. BONELLIE,
FCOG(SA),
P. KANGASNIEMI,
1. PASCUAL, MD, AND A. SHUAIB, MD, FOR THE SUMATRIPTAN MIGRAINE STUDY GROUP” Objective: To compare the efficacy and safety of subcutaneous sumatriptan with placebo in the treatment of menstrual migraine. Methods: A double-blind, placebo-controlled, parallel group study was conducted to assess the efficacy and safety of subcutaneous sumatriptan in the treatment of menstrual migraine over two attacks. A total of 179 subjects received sumatriptan or placebo to treat at least one menstrual migraine attack. Results: The efficacy results were consistent for attacks one and two. Two hours after treatment in attacks one and two, 53 (73%) and 51 (81%;) of the sumatriptan-treated subjects, respectively, reported headache relief (reduction of a severe or moderately severe headache to a mild or no headache), compared with 27 (31%) and 18 (29%) of the placebo-treated subjects (P < .OOl). Within 24 hours of treatment in attack one, 28 (53%) and 14 (52%) of the initial responders to
sumatriptan
and placebo, respectively, experienced headThe incidence and nature of adverse events in this study were similar to that seen in previous studies. Conclusion: Subcutaneous sumatriptan is an effective and well-tolerated acute treatment for menstrual migraine. (01~ stet Gynecol 1995;86911-6) ache recurrence.
MD, MENSTRUAL
and the hormonal fluctuations concurrent with puberty, menses, pregnancy, and menopause suggested the involvement of such changes in the appearance of menstrual migraine, although a direct causal relationship has not been established. Several approaches to the treatment of menstrual migraine include acute treatment, cyclical prophylaxis, chronic prophylaxis, and hormonal therapy.8-‘0 Sumatriptan is a serotonin agonist at the vascular receptor subtype that is well-tolerated and effective in the acute a retrospective treatment of migraine. ‘l-i4 Through subanalysis of previously published data, the treatment of menstrual migraine with subcutaneous sumatriptan was found to be superior to placebo as assessed in 157 subjects.‘” In addition, an open-design study of the acute treatment of menstrual migraine with subcutaneous sumatriptan, reported in abstract form only (European Federation of Neurological Sciences [Berlin] 1993, abstract M-25), indicated that sumatriptan was effective in this situation. This study was undertaken to assess prospectively the efficacy and safety of subcutaneous sumatriptan in menstrual migraine.
Mnterials and Methods This multinational study was conducted at 40 centers in six countries (Canada,
Financial
on outpatients Finland, Italy,
Disclosure
This research was supported by Glaxo Research ment, Ltd. (Greenford, United Kingdom), which sumatriptan. The support included payment investigators directly or to their institutions momtoring, assessing, and following-up subjects.
SSDI
and Developmanufactures to individual for recruiting,
0029-7844/95/$9.50 0029-7844(95)00288-X
911
South Africa, Spain, and Sweden). Appropriate regulatory and ethics approvals were obtained. The study was conducted in accordance with the Declaration of Helsinki, and informed consent, written or oral, was obtained from all participating subjects. We recruited female subjects age 18-50 years, who had at least a 6-month history of migraine without aura (according to the International Headache Society classification16) occurring -3 to +5 days relative to the first day of menstruation and a history of regular menstrual cycles (24-32 days). In addition, subjects had to be able to distinguish migraine from other headaches. Exclusion criteria were as follows: pregnancy or breastfeeding, history or evidence of ischemic heart disease, supine diastolic blood pressure exceeding 95 mmHg, ergotamine or drug or alcohol abuse, and any other medical condition that would otherwise have contraindicated participation in the study. All subjects underwent a physical and neurologic examination. They were given a diary card to record details of their next menstrual migraine, any medication used, response to treatment, and adverse events. This was the practice attack. A maximum of 6 weeks later, subjects returned for a second clinic visit. At their second visit, if subjects had treated a menstrual migraine in the previous 6 weeks, they were randomized to study medication as the first treatment for their next two migraine attacks. Each patient received study medication (sumatriptan 6 mg or matching placebo-filled syringes) according to a computergenerated randomization scheme, supplied to each center in blocks of four. The study medication was administered using an auto-injector device. The device delivered the contents of a 0.5-mL pre-filled syringe as a subcutaneous injection. Two to 24 hours after the first treatment, subjects had the option of taking a second injection (of sumatriptan) if they experienced headache recurrence within 2 hours after the first injection. If relief was inadequate 2 hours after the first injection, rescue medication (not ergotamine-containing preparations or sumatriptan) could be taken.
Evaluation
of Efficacy, Safety, and Tolerability
Headache severity was used as the primary means of evaluating treatment efficacy. Subjects graded headache severity on a four-point scale: 0 = no pain, 1 = mild pain, 2 = moderately severe pain, and 3 = severe pain. The primary efficacy index, headache relief at 1 and 2 hours after the first dose, was defined as the number of subjects whose headache severity was reduced from severe or moderately severe pain (grade 3 or 2) to no or mild pain (grade 0 or 1).
912 Facchinetti et al
Sumntriptm
Ci Mrnstrunl
Migruiw
Subjects recorded the presence or absence of symptoms of nausea, vomiting, and photophobia and/or phonophobia before treatment and at 1 and 2 hours after each treatment. On the diary card, subjects recorded details of headache recurrence (headache relief within 2 hours followed by a worsening headache 2-24 hours after the first dose) or the use of rescue medication at 2 hours after the first dose. In addition, the time to the start of headache improvement and the time to complete resolution of headache were also recorded. Subjects graded their level of clinical disability at pretreatment and 1 and 2 hours after the first dose in both attacks on a four-point scale: 0 = able to work/function normally, 1 = working ability mildly impaired, 2 = working ability severely impaired, and 3 = requiring bed rest. Safety was assessed by the recording of adverse events, which were defined as any untoward clinical happening to the patient, including laboratory abnormalities and death, even if the event was unlikely to be causally related to the treatment. In the event of a patient experiencing symptoms in the chest after treatment, or at the investigators’ discretion, an electrocardiogram (ECG) was taken for analysis.
Statistical
Methods
The primary objective of this study was to compare sumatriptan and placebo with respect to headache relief at 1 and 2 hours. Assuming that 70% of subjects on sumatriptan and 30% of subjects on placebo would obtain headache relief at 2 hours, 50 subjects in each group would be required to detect this difference at the 5% level of significance with 80% power. All tests of significance were two-sided and used the 5% level of significance. There was no adjustment of P values to account for multiplicity of testing with respect to treatment comparisons. The percentage calculations in the text exclude missing or unrecorded data. The number of subjects who reported headache relief in 1 and 2 hours were compared between sumatriptan and placebo using the Mantel-Haenszel 2 test without continuity correction.‘7 Each of the secondary efficacy assessments-headache recurrence within 24 hours after the first dose; the need for rescue medication 2 hours after the first dose; the presence of nausea, vomiting, and photophobia and/or phonophobia at 1 and 2 hours after the first dose; the time to start of headache improvement; and the time to complete resolution of headache-were compared by Mantel-Haenszel ,$ test without continuity correction. If rescue medication was taken less than 2 hours after the first dose, this was considered as a treatment failure (grade 3, severe pain)
Obstetrics
6 Gynecology
Table
1. Demographic Population
Characteristics
of the Intent-to-Treat Sumatriptan
Placebo
115 37
111 38
No. of subjects Mean age (Range) Mean weight (kg) (Range) Mean height (cm)
(20 -53) 61
(40-100) 163 (140-180)
(Range)
(19p50) 61 (36-100) 164 (148-185)
10 10 Median duration of menstrual migraine history (y) Frequency of menstrual migraine attacks” 78 1 attack/m0 78 25 2 attacks/ma 27 5 7 3 attacks/ma 5 1 ~3 attacks/ma *Subjects may have more than one attack during the same menstrual cycle.
from the point of taking the rescue medication. All analyses were repeated using the Mantel-Haenszel ,$ test stratified by country. Data from all subjectswho used the study medication were included in the safety analyses. The intent-to-treat population was identical to the safety population. However, the efficacy analyses used data from a per protocol population that excluded all data from migraine attacks treated outside the period -3 to +5 days relative to the first day of menstruation. In addition, during the study, 3-6% of subjectswere diagnosed as having experienced a migraine with aura (according to the International Headache Society criteria’? that occurred -3 days to +5 days relative to the first dav of menstruation. It was decided that data from these patients should be included in the per protocol analyses becausethe relevant migraine
diagnoses
were based purely
on patient
iden-
tification of aura symptoms, which may have erroneously included prodromes and/or photophobia. In addition, all subjects had to have satisfied the relevant study inclusion criteria and have had a history of
Table
migraine without aura -3 to +5 days relative to the first day of menstruation.
Results Three hundred subjects were recruited into the study, of whom 260 were randomized, and 226 of these subjects (111 taking placebo and 115 taking sumatriptan) treated at least one menstrual or nonmenstrual migraine attack with sumatriptan or placebo (intent-totreat population). Forty-seven subjects (15 placebo and 32 sumatriptan) from the intent-to-treat population treated migraine attacks outside the period -3 to +5 days relative to the first day of menstruation and were therefore treated asprotocol violators. Efficacy analyses (per protocol analyses) were therefore carried out on the remaining 179 subjects (96 taking placebo and 83 taking sumatriptan) who treated a menstrual migraine as attack one with study medication. In addition, 139 subjects (69 taking placebo and 70 taking sumatriptan) treated a menstrual migraine as attack two with study medication. Demographic characteristics of subjects treating at least one menstrual or nonmenstrual migraine with study medication (intent-to-treat population) are presented in Table 1. No significant demographic differences were identified between the treatment groups.
All assessmentsof treatment efficacy showed a high degree of consistency between attack one and attack two. At 1 and 2 hours after treatment in attack one, significantly more subjects (54 [71%] and 53 [73%], respectively) treating a menstrual migraine reported headache relief (headache severity reduced from grade 3 or 2 to grade 0 or 1) with sumatriptan than with placebo (20 [22%] and 27 subjects [31%], respectively; P < .OOl) (Table 2). Sumatriptan was also significantly better than placebo in providing relief at 1 and 2 hours after treatment in attack two (Table 2). At 1 and 2 hours after treatment in attack one, more subjects(25 [33%1and 40 [55%1,respectively) treating a menstrual migraine with sumatriptan were pain-free
2. Headache Relief 1 and 2 Hours After Treatment Attack 1
Attack 2
Sumatriptan Placebo No. treating a menstrual migramr No. treating grade 2 or ? headache Subjects with relief at 1 h Subjects with relief at 2 II
VOL.
86,
NO.
6, DECEMBER
1YYS
(6 mgi
Sumatriptan Placebo
P
(6mg)
46
83
69
70
42
77
63
63
20 (22% )
54 (71’d 1 53 (73% )
15 (24%)
44 (70%)
18 (29%)
51 (81%)
27 (31 ‘A 1
c.001 c.001
Facchinetti
et al
Stunatriptnn
& Menstrual
P
c.001 c.001
Migraine
913
Table
3. Adverse
Adverse
Events
Reported Sumatriptan
events
Dizziness/vertigo Nausea/vomiting Paresthesia Tingling Warm/hot sensations Injection-site reaction Throat symptoms Neck pain/stiffness Sweating Pressure sensation * Proportions
12 10 10 8 8 7 7 s 5 2
compared
using
(10% 1 (9’4 1 (9%) (7’4) (7’4 ) (6’; ) (6’4) (4’.4 ) (4’1 ) (2’i)
two-sided
Most
Frequently Placebo
P* ,129 .084 II84 ,216 036 ,769 .Ohh .44h .Ohfl ,274
5 (5'::) 3 U'X) 3 UC%) 3 (3'4)
1 (
(headache severity from grade 3 or 2 to grade 0) than with placebo (nine [lo%] and 12 subjects [14%], respectively). Results were similar for attack two. The time to onset of headache improvement and the time to complete resolution of the headache were significantly shorter for the sumatriptan group than for the placebo group in both attacks. Within 60 minutes of treatment in attack one, 47 subjects (62Yc) who received sumatriptan began to feel an improvement in their headache, as did 14 subjects (16%) treated with placebo (P < ,001). Forty-nine subjects (70%) who recorded the time to complete resolution of their headache and who received sumatriptan had a completely resolved menstrual migraine attack within 6 hours of treatment in attack one, compared with 26 subjects (34YL) treated with placebo. Within 24 hours after treatment in attack one, 28 subjects (534) who reported initial headache relief after sumatriptan experienced headache recurrence, compared with 14 subjects (52%) who initially responded to placebo. A reduced incidence of headache recurrence was reported in both treatment groups (33% on sumatriptan, 39% on placebo1 after treatment of attack two. Eighteen subjects (24%) in the sumatriptan group who treated a menstrual migraine required rescue medication at 2 hours in attack one, compared with 52 subjects (57%) in the placebo group (P < ,001). Results were similar for attack two. The pre-treatment incidence of nausea and photophobia and/or phonophobia (54 [65%] and 58 subjects [72%], respectively) in the sumatriptan group was similar to that reported in the placebo group (65 [69%,1 and 74 subjects [78%], respectively). At 2 hours after treatment, 17 subjects (22%) who received sumatriptan reported nausea, compared with 48 subjects (52%) who received placebo (P < ,001). Also at 2 hours after dosing, 16 subjects (22%) who received sumatriptan reported photophobia and/or phonophobia, compared with 51 subjects (55%) who received placebo (P < ,001).
914
Facchinetti
et al
Sumafrfpfntz
G Memtrud
Mipirw
Similar differences between sumatriptan and placebo were observed in attack two. A low incidence of vomiting (14-15%) was reported before treatment in both groups, making statistical comparison difficult. Safety data were collected for all subjects who treated at least one menstrual or nonmenstrual migraine attack with study medication. Sumatriptan was generally well tolerated, and the profile of adverse events was similar to that seen in previous studies. Adverse events were reported during treatment by 54 subjects (47%) who received sumatriptan and by 34 subjects (31%) who received placebo. Most adverse events were assessed as drug related. Fifty-three subjects (46%) with sumatriptan and 28 subjects (25%) with placebo reported drug-related events. Two subjects (2%) assigned to placebo and three subjects (3%) assigned to sumatriptan withdrew from the study because of adverse events. The reported events for the three subjects who withdrew after sumatriptan were erythema at the injection site and neck and mouth paresthesias; choking sensation, flushing, and pallor; and headache exacerbation and nausea, respectively. All these adverse events resolved with no sequelae. The ten most frequently reported adverse events during treatment are summarized in Table 3. Only the incidence of warm or hot sensations was significantly higher in the sumatriptan group relative to placebo. In addition, two subjects (2%) in each treatment group reported “chest symptoms” and three subjects had ECG tracings taken after treatment with sumatriptan. The latter subjects had reported chest discomfort, choking sensation and pallor, and pressure sensations, respectively, after receiving sumatriptan. All post-treatment ECGs were assessed as normal.
Discussion This study represents the first prospective, doubleblind, placebo-controlled investigation of the efficacy and tolerability of sumatriptan in the treatment of menstrual migraine. Sumatriptan was significantly better than placebo at reducing headache severity to none or mild in two menstrual migraine attacks. These efficacy results are consistent with the clinical profile of subcutaneous sumatriptan in the treatment of migraine with and without aura described in previous studSumatriptan was also significantly better than ies. “-” placebo at resolving the symptoms commonly associated with migraine, such as nausea, photophobia, and phonophobia. These results are similar to those from a recent retrospective study’” and an open-design study of sumatriptan in menstrual migraine, which represent the
Obstetrics
G Gyn~ology
only two publications on the use of this drug for this migraine subtype. The retrospective study reported that 80% of the sumatriptan-treated subjects had headache relief 1 hour after dosing, compared with 19% of subjects receiving placebo.” In the open study (European Federation of Neurological Sciences [Berlin] 1993, abstract M-25), the authors concluded that the efficacy of sumatriptan in the treatment of menstrual migraine was comparable to that observed previously in nonmenstrual migraine. Comparisons of the relative efficacy of sumatriptan between this and the other two studies is complicated. Two of the studies are prospective and the other is retrospective in nature. In addition, different definitions of menstrual migraine are used in each of the three studies. In this study, the diagnostic criteria for menstrual migraine that was used f-3 to +5 days relative to the first day of menstruation) did not comply with the recommendation put forward by the International Headache SocietyI (90% of attacks between -2 days and last day of menses) because of the known variability of the duration of menses. Because the proportion of nonmenstrual migraine attacks experienced previously by subjects did not influence inclusion in the study, a larger group of migraine subjects were eligible for this study and had the opportunity to have their menstrually related attacks evaluated and treated. Overall, from this study and others, it is apparent that sumatriptan exhibits a high level of efficacy when used to treat menstrual migraine, irrespective of the definitions of menstrual migraine used. Headache recurrence within 24 hours of treatment was reported by a similar proportion of the subjects who initially responded to sumatriptan or placebo. Previously, 30-40% of initial responders have reported headache recurrence after subcutaneous sumatriptan, with a lower incidence of recurrence after oral sumatriptan. r1,i2 Headache recurrence after sumatriptan dosing could be due to the fact that the average duration of a migraine attack typically lasts 4-72 hours,” whereas the plasma half-life of sumatriptan is only 2 hours.lX Therefore, because the potential duration of headache lasts far beyond this half-life, recurrence could occur as a result of decreasing sumatriptan plasma levels beyond 2 hours after dosing.‘” However, a second subcutaneous dose of sumatriptan can be used to treat headache recurrence 2-24 hours after the initial dose. All subjects taking a second dose of medication for headache recurrence in this study received sumatriptan. The response rates to sumatriptan when used as a treatment for recurrence were not recorded. However, in an abstract (Cephalalgia 1993; supplement 13:157) reporting subjects who experienced headache recurrence after successful treatment of an initial attack, the
VOL.
86, NO.
6, DECEMBER
1995
response rate after subsequent treatment with subcutaneous sumatriptan was 84%‘. A response rate of 70% with a second oral dose of sumatriptan for headache recurrence also has been reported.” Before the first administration of subcutaneous sumatriptan in clinical practice, it is recommended that subjects at risk for coronary artery disease are evaluated carefully. In this study, sumatriptan was generally well tolerated in attacks of menstrual migraine, with most adverse events being of short duration and resolving spontaneously. The incidence and nature of reported adverse events were consistent with previous experience with subcutaneously administered sumatriptan.”
References 1. Linet .MS, Stewart WF, Celentano epidemiologic study of headache adults. JAMA 1989;261:2211-6.
DD, Ziegler D, Sprecher among adolescent and
M. An young
2. Henry P, Michel l’, Brochet B, Dartigues JF, Tison S, Salamon R. A nationwide survey of migraine in France: Prevalence and clinical features in adults. Cephalalgia 1992;12:229-37. 3. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology headache in a general population; A prevalence study. Eptdemiol 4. McGregor
1991;44:1147-57. EA, Chia H, Vohrah
RC,
Wilkinson
of J Clin
M. Migraine
menstruation: A pilot study. Cephalalgia 1990;10:305-10. 5. Epstein MT, Hockaday TD. Migraine and reproductive throughout the menstrual cycle. Lancet 1975;i:543-8.
and
hormones
6. Nattero G. Menstrual headache. Adv Neurol 1982;33:215-26. 7. Martignoni E, Sances G, Nappi G. Significance of hormonal changes in migraine and cluster headache. Gynecol Endocrinol 1987;1:295-319. 8. Digre K, Damasio evaluation 9. Silberstein Neurology
H. Menstrual
migraine:
and treatment. Clin Obstet SD, Merriam GM. Estrogens, 1991;41:786-93.
10. Hering RH. 1992;3:27-31.
Clifford-Rose
11. The Subcutaneous ment of migraine 325:316-21.
FS. Menstrual
Sumatriptan attacks with
Differential
diagnosis,
Gynecol 1987;30:417-30. progestins and headaches. migraine.
International sumatriptan.
Headache
Q
Study Group. TreatN Engl J Med 1991;
12. Cady RK, Wendt JK, Kirchner JR, Sargent JD, Rothrock JF, Skaggs H. Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265:2831-5. 13
14.
The Sumatriptan acute migraine
Auto-Injector with subcutaneous
injector device. Eur Neurol The Oral Sumatriptan
trtptan-An 15. Solbach migraine
Group. sumatriptan
1991;31:323-31. Dose-Defining
oral dose-defining study. MP, Waymer RS. Treatment headache with subcutaneous
necol 1993;82:768-72. 16. Headache Classification Society. Classification ders, cranial 7):1-96.
neuralgias
17. Mantel N, Haenszel from retrospective 719-48.
Facchinetti
Study
et
al
Committee and diagnostic and
facial
Study
Self-treatment using an Group.
Suma-
Eur Neurol 1991;31:300-5. of menstruation-associated sumatriptan. Obstet
Gy-
of the International Headache criteria for headache disorpain.
Cephalalgia
1988;8(suppl
W. Statistical aspects of the analysis studies of disease. J Nat1 Cancer Inst
Sumatriptan
of auto-
ti Menstrual Migraine
of data 1959;22:
915
18. Fowler PA, Lacey LF, Thomas M, Keene ON, Tanner RJN, Baber N. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. Eur Neural lYY1;31:291-4. 19. Ferrari MD, James MH, Bates D, et al. Oral sumatriptan: Effect of a second dose, and incidence and treatment of headache recurrence. Cephalalgia 1994;14:330-8. I’. The safety profile of sumatriptan. 20. Simmons VE, Blakeborough Rev Contemp Pharmacother 1994;5:77Y-28. Address
reprint
requests
Address
correspondence
to:
Dr. Fabio Facckinetti, MD lstituto di Clinica Ostetrica e Ginecologica Uniuersita’ De,@ Studi di Modena Via de1 Pozzo 71-41100 Modem lfaly
to:
Dr. P. Blakeborough c/o Regina Wfltts Glnxo Wellcome Inc. Five Moore Drive Box 13398 Research Triangle Pork, NC 27309
Rcceivrd April 12, 1995. Rccciucd irk woked ,for~r~ {uly 21, 1995. Accepted Augirst 12, 1995. Copyright 0 1995 by The C;ynecologists.
OFFICE AND CAREER MANAGEMENT
FORTHE
American
College
of Obstetricians
and
OB-GYN
OF THE ’90s February 22-24, 1996 The American College of Obstetricians and Gynecologists is sponsoring a course on office and career management, to be held at the Hilton Palacio de1Rio, San Antonio, Texas. This course hasbeen approved for 16 cognate hours (Formal Learning) by The American College of Obstetricians and Gynecologists. For further information, contact the Registrar, The American College of Obstetricians and Gynecologists, 409 12th Street SW, Washington, DC 20024-2188; (202) 863-2541.
916
Facchinetti
et al
%mtviptm
ci Menstrual Migraine
Obstetrics & Gynecology
MD, G. BONELLIE,
FCOG(SA),
P. KANGASNIEMI,
1. PASCUAL, MD, AND A. SHUAIB, MD, FOR THE SUMATRIPTAN MIGRAINE STUDY GROUP” Objective: To compare the efficacy and safety of subcutaneous sumatriptan with placebo in the treatment of menstrual migraine. Methods: A double-blind, placebo-controlled, parallel group study was conducted to assess the efficacy and safety of subcutaneous sumatriptan in the treatment of menstrual migraine over two attacks. A total of 179 subjects received sumatriptan or placebo to treat at least one menstrual migraine attack. Results: The efficacy results were consistent for attacks one and two. Two hours after treatment in attacks one and two, 53 (73%) and 51 (81%;) of the sumatriptan-treated subjects, respectively, reported headache relief (reduction of a severe or moderately severe headache to a mild or no headache), compared with 27 (31%) and 18 (29%) of the placebo-treated subjects (P < .OOl). Within 24 hours of treatment in attack one, 28 (53%) and 14 (52%) of the initial responders to
sumatriptan
and placebo, respectively, experienced headThe incidence and nature of adverse events in this study were similar to that seen in previous studies. Conclusion: Subcutaneous sumatriptan is an effective and well-tolerated acute treatment for menstrual migraine. (01~ stet Gynecol 1995;86911-6) ache recurrence.
MD, MENSTRUAL
and the hormonal fluctuations concurrent with puberty, menses, pregnancy, and menopause suggested the involvement of such changes in the appearance of menstrual migraine, although a direct causal relationship has not been established. Several approaches to the treatment of menstrual migraine include acute treatment, cyclical prophylaxis, chronic prophylaxis, and hormonal therapy.8-‘0 Sumatriptan is a serotonin agonist at the vascular receptor subtype that is well-tolerated and effective in the acute a retrospective treatment of migraine. ‘l-i4 Through subanalysis of previously published data, the treatment of menstrual migraine with subcutaneous sumatriptan was found to be superior to placebo as assessed in 157 subjects.‘” In addition, an open-design study of the acute treatment of menstrual migraine with subcutaneous sumatriptan, reported in abstract form only (European Federation of Neurological Sciences [Berlin] 1993, abstract M-25), indicated that sumatriptan was effective in this situation. This study was undertaken to assess prospectively the efficacy and safety of subcutaneous sumatriptan in menstrual migraine.
Mnterials and Methods This multinational study was conducted at 40 centers in six countries (Canada,
Financial
on outpatients Finland, Italy,
Disclosure
This research was supported by Glaxo Research ment, Ltd. (Greenford, United Kingdom), which sumatriptan. The support included payment investigators directly or to their institutions momtoring, assessing, and following-up subjects.
SSDI
and Developmanufactures to individual for recruiting,
0029-7844/95/$9.50 0029-7844(95)00288-X
911
South Africa, Spain, and Sweden). Appropriate regulatory and ethics approvals were obtained. The study was conducted in accordance with the Declaration of Helsinki, and informed consent, written or oral, was obtained from all participating subjects. We recruited female subjects age 18-50 years, who had at least a 6-month history of migraine without aura (according to the International Headache Society classification16) occurring -3 to +5 days relative to the first day of menstruation and a history of regular menstrual cycles (24-32 days). In addition, subjects had to be able to distinguish migraine from other headaches. Exclusion criteria were as follows: pregnancy or breastfeeding, history or evidence of ischemic heart disease, supine diastolic blood pressure exceeding 95 mmHg, ergotamine or drug or alcohol abuse, and any other medical condition that would otherwise have contraindicated participation in the study. All subjects underwent a physical and neurologic examination. They were given a diary card to record details of their next menstrual migraine, any medication used, response to treatment, and adverse events. This was the practice attack. A maximum of 6 weeks later, subjects returned for a second clinic visit. At their second visit, if subjects had treated a menstrual migraine in the previous 6 weeks, they were randomized to study medication as the first treatment for their next two migraine attacks. Each patient received study medication (sumatriptan 6 mg or matching placebo-filled syringes) according to a computergenerated randomization scheme, supplied to each center in blocks of four. The study medication was administered using an auto-injector device. The device delivered the contents of a 0.5-mL pre-filled syringe as a subcutaneous injection. Two to 24 hours after the first treatment, subjects had the option of taking a second injection (of sumatriptan) if they experienced headache recurrence within 2 hours after the first injection. If relief was inadequate 2 hours after the first injection, rescue medication (not ergotamine-containing preparations or sumatriptan) could be taken.
Evaluation
of Efficacy, Safety, and Tolerability
Headache severity was used as the primary means of evaluating treatment efficacy. Subjects graded headache severity on a four-point scale: 0 = no pain, 1 = mild pain, 2 = moderately severe pain, and 3 = severe pain. The primary efficacy index, headache relief at 1 and 2 hours after the first dose, was defined as the number of subjects whose headache severity was reduced from severe or moderately severe pain (grade 3 or 2) to no or mild pain (grade 0 or 1).
912 Facchinetti et al
Sumntriptm
Ci Mrnstrunl
Migruiw
Subjects recorded the presence or absence of symptoms of nausea, vomiting, and photophobia and/or phonophobia before treatment and at 1 and 2 hours after each treatment. On the diary card, subjects recorded details of headache recurrence (headache relief within 2 hours followed by a worsening headache 2-24 hours after the first dose) or the use of rescue medication at 2 hours after the first dose. In addition, the time to the start of headache improvement and the time to complete resolution of headache were also recorded. Subjects graded their level of clinical disability at pretreatment and 1 and 2 hours after the first dose in both attacks on a four-point scale: 0 = able to work/function normally, 1 = working ability mildly impaired, 2 = working ability severely impaired, and 3 = requiring bed rest. Safety was assessed by the recording of adverse events, which were defined as any untoward clinical happening to the patient, including laboratory abnormalities and death, even if the event was unlikely to be causally related to the treatment. In the event of a patient experiencing symptoms in the chest after treatment, or at the investigators’ discretion, an electrocardiogram (ECG) was taken for analysis.
Statistical
Methods
The primary objective of this study was to compare sumatriptan and placebo with respect to headache relief at 1 and 2 hours. Assuming that 70% of subjects on sumatriptan and 30% of subjects on placebo would obtain headache relief at 2 hours, 50 subjects in each group would be required to detect this difference at the 5% level of significance with 80% power. All tests of significance were two-sided and used the 5% level of significance. There was no adjustment of P values to account for multiplicity of testing with respect to treatment comparisons. The percentage calculations in the text exclude missing or unrecorded data. The number of subjects who reported headache relief in 1 and 2 hours were compared between sumatriptan and placebo using the Mantel-Haenszel 2 test without continuity correction.‘7 Each of the secondary efficacy assessments-headache recurrence within 24 hours after the first dose; the need for rescue medication 2 hours after the first dose; the presence of nausea, vomiting, and photophobia and/or phonophobia at 1 and 2 hours after the first dose; the time to start of headache improvement; and the time to complete resolution of headache-were compared by Mantel-Haenszel ,$ test without continuity correction. If rescue medication was taken less than 2 hours after the first dose, this was considered as a treatment failure (grade 3, severe pain)
Obstetrics
6 Gynecology
Table
1. Demographic Population
Characteristics
of the Intent-to-Treat Sumatriptan
Placebo
115 37
111 38
No. of subjects Mean age (Range) Mean weight (kg) (Range) Mean height (cm)
(20 -53) 61
(40-100) 163 (140-180)
(Range)
(19p50) 61 (36-100) 164 (148-185)
10 10 Median duration of menstrual migraine history (y) Frequency of menstrual migraine attacks” 78 1 attack/m0 78 25 2 attacks/ma 27 5 7 3 attacks/ma 5 1 ~3 attacks/ma *Subjects may have more than one attack during the same menstrual cycle.
from the point of taking the rescue medication. All analyses were repeated using the Mantel-Haenszel ,$ test stratified by country. Data from all subjectswho used the study medication were included in the safety analyses. The intent-to-treat population was identical to the safety population. However, the efficacy analyses used data from a per protocol population that excluded all data from migraine attacks treated outside the period -3 to +5 days relative to the first day of menstruation. In addition, during the study, 3-6% of subjectswere diagnosed as having experienced a migraine with aura (according to the International Headache Society criteria’? that occurred -3 days to +5 days relative to the first dav of menstruation. It was decided that data from these patients should be included in the per protocol analyses becausethe relevant migraine
diagnoses
were based purely
on patient
iden-
tification of aura symptoms, which may have erroneously included prodromes and/or photophobia. In addition, all subjects had to have satisfied the relevant study inclusion criteria and have had a history of
Table
migraine without aura -3 to +5 days relative to the first day of menstruation.
Results Three hundred subjects were recruited into the study, of whom 260 were randomized, and 226 of these subjects (111 taking placebo and 115 taking sumatriptan) treated at least one menstrual or nonmenstrual migraine attack with sumatriptan or placebo (intent-totreat population). Forty-seven subjects (15 placebo and 32 sumatriptan) from the intent-to-treat population treated migraine attacks outside the period -3 to +5 days relative to the first day of menstruation and were therefore treated asprotocol violators. Efficacy analyses (per protocol analyses) were therefore carried out on the remaining 179 subjects (96 taking placebo and 83 taking sumatriptan) who treated a menstrual migraine as attack one with study medication. In addition, 139 subjects (69 taking placebo and 70 taking sumatriptan) treated a menstrual migraine as attack two with study medication. Demographic characteristics of subjects treating at least one menstrual or nonmenstrual migraine with study medication (intent-to-treat population) are presented in Table 1. No significant demographic differences were identified between the treatment groups.
All assessmentsof treatment efficacy showed a high degree of consistency between attack one and attack two. At 1 and 2 hours after treatment in attack one, significantly more subjects (54 [71%] and 53 [73%], respectively) treating a menstrual migraine reported headache relief (headache severity reduced from grade 3 or 2 to grade 0 or 1) with sumatriptan than with placebo (20 [22%] and 27 subjects [31%], respectively; P < .OOl) (Table 2). Sumatriptan was also significantly better than placebo in providing relief at 1 and 2 hours after treatment in attack two (Table 2). At 1 and 2 hours after treatment in attack one, more subjects(25 [33%1and 40 [55%1,respectively) treating a menstrual migraine with sumatriptan were pain-free
2. Headache Relief 1 and 2 Hours After Treatment Attack 1
Attack 2
Sumatriptan Placebo No. treating a menstrual migramr No. treating grade 2 or ? headache Subjects with relief at 1 h Subjects with relief at 2 II
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1YYS
(6 mgi
Sumatriptan Placebo
P
(6mg)
46
83
69
70
42
77
63
63
20 (22% )
54 (71’d 1 53 (73% )
15 (24%)
44 (70%)
18 (29%)
51 (81%)
27 (31 ‘A 1
c.001 c.001
Facchinetti
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Stunatriptnn
& Menstrual
P
c.001 c.001
Migraine
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Table
3. Adverse
Adverse
Events
Reported Sumatriptan
events
Dizziness/vertigo Nausea/vomiting Paresthesia Tingling Warm/hot sensations Injection-site reaction Throat symptoms Neck pain/stiffness Sweating Pressure sensation * Proportions
12 10 10 8 8 7 7 s 5 2
compared
using
(10% 1 (9’4 1 (9%) (7’4) (7’4 ) (6’; ) (6’4) (4’.4 ) (4’1 ) (2’i)
two-sided
Most
Frequently Placebo
P* ,129 .084 II84 ,216 036 ,769 .Ohh .44h .Ohfl ,274
5 (5'::) 3 U'X) 3 UC%) 3 (3'4)
1 (
(headache severity from grade 3 or 2 to grade 0) than with placebo (nine [lo%] and 12 subjects [14%], respectively). Results were similar for attack two. The time to onset of headache improvement and the time to complete resolution of the headache were significantly shorter for the sumatriptan group than for the placebo group in both attacks. Within 60 minutes of treatment in attack one, 47 subjects (62Yc) who received sumatriptan began to feel an improvement in their headache, as did 14 subjects (16%) treated with placebo (P < ,001). Forty-nine subjects (70%) who recorded the time to complete resolution of their headache and who received sumatriptan had a completely resolved menstrual migraine attack within 6 hours of treatment in attack one, compared with 26 subjects (34YL) treated with placebo. Within 24 hours after treatment in attack one, 28 subjects (534) who reported initial headache relief after sumatriptan experienced headache recurrence, compared with 14 subjects (52%) who initially responded to placebo. A reduced incidence of headache recurrence was reported in both treatment groups (33% on sumatriptan, 39% on placebo1 after treatment of attack two. Eighteen subjects (24%) in the sumatriptan group who treated a menstrual migraine required rescue medication at 2 hours in attack one, compared with 52 subjects (57%) in the placebo group (P < ,001). Results were similar for attack two. The pre-treatment incidence of nausea and photophobia and/or phonophobia (54 [65%] and 58 subjects [72%], respectively) in the sumatriptan group was similar to that reported in the placebo group (65 [69%,1 and 74 subjects [78%], respectively). At 2 hours after treatment, 17 subjects (22%) who received sumatriptan reported nausea, compared with 48 subjects (52%) who received placebo (P < ,001). Also at 2 hours after dosing, 16 subjects (22%) who received sumatriptan reported photophobia and/or phonophobia, compared with 51 subjects (55%) who received placebo (P < ,001).
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Similar differences between sumatriptan and placebo were observed in attack two. A low incidence of vomiting (14-15%) was reported before treatment in both groups, making statistical comparison difficult. Safety data were collected for all subjects who treated at least one menstrual or nonmenstrual migraine attack with study medication. Sumatriptan was generally well tolerated, and the profile of adverse events was similar to that seen in previous studies. Adverse events were reported during treatment by 54 subjects (47%) who received sumatriptan and by 34 subjects (31%) who received placebo. Most adverse events were assessed as drug related. Fifty-three subjects (46%) with sumatriptan and 28 subjects (25%) with placebo reported drug-related events. Two subjects (2%) assigned to placebo and three subjects (3%) assigned to sumatriptan withdrew from the study because of adverse events. The reported events for the three subjects who withdrew after sumatriptan were erythema at the injection site and neck and mouth paresthesias; choking sensation, flushing, and pallor; and headache exacerbation and nausea, respectively. All these adverse events resolved with no sequelae. The ten most frequently reported adverse events during treatment are summarized in Table 3. Only the incidence of warm or hot sensations was significantly higher in the sumatriptan group relative to placebo. In addition, two subjects (2%) in each treatment group reported “chest symptoms” and three subjects had ECG tracings taken after treatment with sumatriptan. The latter subjects had reported chest discomfort, choking sensation and pallor, and pressure sensations, respectively, after receiving sumatriptan. All post-treatment ECGs were assessed as normal.
Discussion This study represents the first prospective, doubleblind, placebo-controlled investigation of the efficacy and tolerability of sumatriptan in the treatment of menstrual migraine. Sumatriptan was significantly better than placebo at reducing headache severity to none or mild in two menstrual migraine attacks. These efficacy results are consistent with the clinical profile of subcutaneous sumatriptan in the treatment of migraine with and without aura described in previous studSumatriptan was also significantly better than ies. “-” placebo at resolving the symptoms commonly associated with migraine, such as nausea, photophobia, and phonophobia. These results are similar to those from a recent retrospective study’” and an open-design study of sumatriptan in menstrual migraine, which represent the
Obstetrics
G Gyn~ology
only two publications on the use of this drug for this migraine subtype. The retrospective study reported that 80% of the sumatriptan-treated subjects had headache relief 1 hour after dosing, compared with 19% of subjects receiving placebo.” In the open study (European Federation of Neurological Sciences [Berlin] 1993, abstract M-25), the authors concluded that the efficacy of sumatriptan in the treatment of menstrual migraine was comparable to that observed previously in nonmenstrual migraine. Comparisons of the relative efficacy of sumatriptan between this and the other two studies is complicated. Two of the studies are prospective and the other is retrospective in nature. In addition, different definitions of menstrual migraine are used in each of the three studies. In this study, the diagnostic criteria for menstrual migraine that was used f-3 to +5 days relative to the first day of menstruation) did not comply with the recommendation put forward by the International Headache SocietyI (90% of attacks between -2 days and last day of menses) because of the known variability of the duration of menses. Because the proportion of nonmenstrual migraine attacks experienced previously by subjects did not influence inclusion in the study, a larger group of migraine subjects were eligible for this study and had the opportunity to have their menstrually related attacks evaluated and treated. Overall, from this study and others, it is apparent that sumatriptan exhibits a high level of efficacy when used to treat menstrual migraine, irrespective of the definitions of menstrual migraine used. Headache recurrence within 24 hours of treatment was reported by a similar proportion of the subjects who initially responded to sumatriptan or placebo. Previously, 30-40% of initial responders have reported headache recurrence after subcutaneous sumatriptan, with a lower incidence of recurrence after oral sumatriptan. r1,i2 Headache recurrence after sumatriptan dosing could be due to the fact that the average duration of a migraine attack typically lasts 4-72 hours,” whereas the plasma half-life of sumatriptan is only 2 hours.lX Therefore, because the potential duration of headache lasts far beyond this half-life, recurrence could occur as a result of decreasing sumatriptan plasma levels beyond 2 hours after dosing.‘” However, a second subcutaneous dose of sumatriptan can be used to treat headache recurrence 2-24 hours after the initial dose. All subjects taking a second dose of medication for headache recurrence in this study received sumatriptan. The response rates to sumatriptan when used as a treatment for recurrence were not recorded. However, in an abstract (Cephalalgia 1993; supplement 13:157) reporting subjects who experienced headache recurrence after successful treatment of an initial attack, the
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response rate after subsequent treatment with subcutaneous sumatriptan was 84%‘. A response rate of 70% with a second oral dose of sumatriptan for headache recurrence also has been reported.” Before the first administration of subcutaneous sumatriptan in clinical practice, it is recommended that subjects at risk for coronary artery disease are evaluated carefully. In this study, sumatriptan was generally well tolerated in attacks of menstrual migraine, with most adverse events being of short duration and resolving spontaneously. The incidence and nature of reported adverse events were consistent with previous experience with subcutaneously administered sumatriptan.”
References 1. Linet .MS, Stewart WF, Celentano epidemiologic study of headache adults. JAMA 1989;261:2211-6.
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2. Henry P, Michel l’, Brochet B, Dartigues JF, Tison S, Salamon R. A nationwide survey of migraine in France: Prevalence and clinical features in adults. Cephalalgia 1992;12:229-37. 3. Rasmussen BK, Jensen R, Schroll M, Olesen J. Epidemiology headache in a general population; A prevalence study. Eptdemiol 4. McGregor
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6. Nattero G. Menstrual headache. Adv Neurol 1982;33:215-26. 7. Martignoni E, Sances G, Nappi G. Significance of hormonal changes in migraine and cluster headache. Gynecol Endocrinol 1987;1:295-319. 8. Digre K, Damasio evaluation 9. Silberstein Neurology
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The Sumatriptan acute migraine
Auto-Injector with subcutaneous
injector device. Eur Neurol The Oral Sumatriptan
trtptan-An 15. Solbach migraine
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oral dose-defining study. MP, Waymer RS. Treatment headache with subcutaneous
necol 1993;82:768-72. 16. Headache Classification Society. Classification ders, cranial 7):1-96.
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Study
et
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Eur Neurol 1991;31:300-5. of menstruation-associated sumatriptan. Obstet
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W. Statistical aspects of the analysis studies of disease. J Nat1 Cancer Inst
Sumatriptan
of auto-
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915
18. Fowler PA, Lacey LF, Thomas M, Keene ON, Tanner RJN, Baber N. The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan. Eur Neural lYY1;31:291-4. 19. Ferrari MD, James MH, Bates D, et al. Oral sumatriptan: Effect of a second dose, and incidence and treatment of headache recurrence. Cephalalgia 1994;14:330-8. I’. The safety profile of sumatriptan. 20. Simmons VE, Blakeborough Rev Contemp Pharmacother 1994;5:77Y-28. Address
reprint
requests
Address
correspondence
to:
Dr. Fabio Facckinetti, MD lstituto di Clinica Ostetrica e Ginecologica Uniuersita’ De,@ Studi di Modena Via de1 Pozzo 71-41100 Modem lfaly
to:
Dr. P. Blakeborough c/o Regina Wfltts Glnxo Wellcome Inc. Five Moore Drive Box 13398 Research Triangle Pork, NC 27309
Rcceivrd April 12, 1995. Rccciucd irk woked ,for~r~ {uly 21, 1995. Accepted Augirst 12, 1995. Copyright 0 1995 by The C;ynecologists.
OFFICE AND CAREER MANAGEMENT
FORTHE
American
College
of Obstetricians
and
OB-GYN
OF THE ’90s February 22-24, 1996 The American College of Obstetricians and Gynecologists is sponsoring a course on office and career management, to be held at the Hilton Palacio de1Rio, San Antonio, Texas. This course hasbeen approved for 16 cognate hours (Formal Learning) by The American College of Obstetricians and Gynecologists. For further information, contact the Registrar, The American College of Obstetricians and Gynecologists, 409 12th Street SW, Washington, DC 20024-2188; (202) 863-2541.
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Obstetrics & Gynecology