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ORIGINAL RESEARCH |
From the Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; Merck & Co. Inc., West Point, Pennsylvania; the Department of Neurology, Hôpital Lariboisière, Paris, France; and the Internal Medicine Department, Hôpital Laennec, Paris, France.
Address reprint requests to: Christopher R. Lines, PhD BL 1-12 10 Sentry Parkway Blue Bell, PA 19422 E-mail: chris_lines{at}merck.com
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Methods: Data from two large clinical trials with identical designs were included in a retrospective analysis. The studies were randomized, double-masked, placebo-controlled, incomplete block, two-period, crossover designs. Women with migraines were randomly assigned to one of five treatment sequences for the treatment of two migraine attacks. Only data from the first attack in women with migraines who were treated with rizatriptan or placebo were included in the analysis. A menstrually associated attack was defined as one that occurred within 3 days before or after the onset of the last menstrual period.
Results: In the subgroup of 335 women with menstrually associated migraine, rizatriptan was effective compared with placebo. At 2 hours after dosing, 68% of 139 women taking rizatriptan 10 mg and 70% of 115 women taking rizatriptan 5 mg with a menstrually associated migraine had pain relief compared with 44% of 81 patients taking placebo (P < .05). In all women, rizatriptan was as effective in treating menstrual as well as nonmenstrual migraine: 68% of 139 patients taking rizatriptan 10 mg with a menstrually associated migraine had pain relief at 2 hours after dosing compared with 69% of 393 patients with nonmenstrually associated attacks (test of menstrual association = nonsignificant; the analysis had 80% power to detect a difference of six percentage points between groups). Similar results were found for rizatriptan 5 mg (menstrual = 70%, nonmenstrual = 66%; not statistically significant).
Conclusion: Rizatriptan is effective in the treatment of menstrually associated migraine attacks.
Migraine is a common and debilitating neurologic disorder that affects women (13–18%) more than men (3–6%).1 The prevalence of migraine in women increases up to age 40 years and declines thereafter.1 Many women with migraines experience a change in migraine frequency associated with their menstrual cycle,2,3 but less than 10% only have migraines around the time of menstruation,3–5 sometimes referred to as true menstrual migraine.4
Menstrually associated migraine attacks are often stated to be more severe and more difficult to treat than migraine attacks not associated with menstruation6,7; these assertions are based on clinical experience and have not been demonstrated in controlled trials. However, differences in treatment efficacy might be postulated as a consequence of possible modification or exacerbation of the usual migraine pathophysiologic processes during a menstrually associated attack. For example, it has been suggested that the fluctuating estrogen levels that occur around the time of menstruation could result in destabilization of serotonin (5-HT) function4,8 and lead to changes in other hormones and neurotransmitters implicated in the pathophysiologic process.4,9–12
Many of the treatments approved specifically for treating migraines act through serotoninergic mechanisms.13 These include the traditional ergotamine-based medications14 and the newer 5-HT1B/1D receptor agonist (triptan) treatments that selectively target particular serotonin-receptor subtypes.15 In light of the possible differences in underlying pathophysiology between menstrually and nonmenstrually associated migraine attacks, it is important to establish that these new treatments are effective in treating menstrually associated migraine attacks.
Previous studies have suggested that sumatriptan, the first marketed 5-HT1B/1D receptor agonist, is effective in the treatment of menstrually associated migraine.16 In this paper we report the results of a retrospective analysis designed to evaluate the efficacy of rizatriptan, a recently-approved 5-HT1B/1D receptor agonist,17 for the treatment of menstrually associated migraine attacks. Rizatriptan is available in two oral dosage strengths of 10 mg and 5 mg, with the more effective 10-mg dose being the primary recommended dose in most countries.17 The analysis evaluated the efficacy of both doses in menstrually associated migraine attacks using data from two masked, placebo-controlled clinical trials.
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Methods |
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Patients included in the studies were outpatients who had at least a 6-month history of migraine according to the criteria of the International Headache Society,19 were at least 18 years old, and typically had one to eight migraine attacks per month. All patients gave written informed consent.
For each of the two attacks treated in each study, patients were instructed to ingest the test medication when they developed a moderate or severe migraine headache that was not resolving spontaneously. The patients then rated headache severity and functional disability on a diary card and noted the presence of nausea, photophobia, phonophobia, and vomiting at the following time points: predose, 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, and 4 hours after taking the medication. Headache severity and functional disability were rated using four-point anchored scales (headache severity: 0 = no headache, 1 = mild headache, 2 = moderate headache, and 3 = severe headache; functional disability: 0 = normal, 1 = daily activities mildly impaired, 2 = daily activities severely impaired, and 3 = unable to do activities, requires bedrest). Any patient who still had a moderate or severe headache at 2 hours after taking the initial dose of test agent was allowed to take optional escape medications consisting of standard analgesics (opiates, acetaminophen, nonsteroidal anti-inflammatory drugs) or antiemetics. Analgesic medications were prohibited from 6 hours before to 2 hours after dosing, and patients were prohibited from taking ergotamine or other 5-HT1B/1D agonists for 24 hours before and after dosing. Patients were allowed to take standard antimigraine prophylactics. The procedures followed were in accordance with the ethical standards for human experimentation established by the Declaration of Helsinki 1975, revised 1983.
Patients attended the clinic for a prestudy visit and returned to the clinic within 7 days of treating each attack for an interim visit and a poststudy visit. There was a minimum 5-day washout period between the treatment of each of the two attacks. At each of the three clinic visits, the investigator asked the patient the date of onset of her last menstrual period. The date of the migraine attack was recorded by the patient on a diary card. In the analysis, a menstrually associated migraine attack was classified as one that occurred within 3 days before or after the date of onset of any recorded menstrual period for a given patient.
The analyses examined treatment effects at 2 hours after dosing. This corresponds to the last time before escape medications were allowed and therefore gives the least biased perspective on the efficacy of the test drug. The following measures were analyzed: percentage of patients with pain relief (reduction of headache from moderate or severe at baseline to mild or none); percentage of patients who were pain free (had no headache); percentage of patients with normal functional ability; percentage of patients without associated symptoms of nausea, photophobia, or phonophobia; percentage of patients who used escape medication. No data on vomiting are given, as there were very few attacks during which patients vomited (n = 32, 2%). Recurrence rates, defined as the return of headache to moderate or severe within 24 hours of dosing in patients who initially experienced pain relief at 2 hours after dosing, were also calculated, along with time to recurrence.
Women who took rizatriptan or placebo and had at least one efficacy evaluation after the initial dose were included in the analyses. Missing values were estimated by carrying forward the preceding values. However, no imputations were made for missing values at baseline or 0.5 hours. Less than 2% of values were imputed.
Two main types of analysis were performed. The first analysis included the subset of women who took rizatriptan or placebo for menstrually associated migraine attacks. For each variable, rizatriptan was compared with placebo using a logistic regression model with factors for treatment and study. The treatment-by-study interaction was not tested because of the small sample sizes; instead, the data were inspected visually to determine whether the treatment effects were similar in each study. Confidence intervals (CI) were calculated using the exact method derived from the binary distribution. In this analysis, a finding of statistically significant differences for rizatriptan over placebo would indicate that rizatriptan was effective in treating menstrually associated migraine attacks.
The second analysis included all women who took rizatriptan or placebo. For each variable, a logistic regression model with main effects for treatment, study, and menstrual association was fit to the data after testing that treatment-by-study and treatment-by-menstrual association interactions were not significant (P > .05). In this analysis, a finding of no statistically significant effects for menstrual association would indicate that rizatriptan was equally effective in treating menstrually associated and nonmenstrually associated migraine attacks. The analysis had 80% power to detect a clinically significant difference of six percentage points (eg, 65% compared with 71%) between menstrual and nonmenstrual groups with respect to the percentage of patients with pain relief at 2 hours (
= .05, two-tailed test), based on a sample size of 335 patients per group.
This software was used for both analyses not just for the second analysis. Data were analyzed using the PC SAS statistical software package (version 6.12; SAS Institute, Inc., Cary, NC).
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. Six patients had no evaluable data and were excluded from the analysis. Of the 1413 evaluable women who took rizatriptan or placebo, approximately one quarter (n = 335) had a menstrually associated first migraine attack.
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. Both doses of rizatriptan were numerically superior to placebo on all measures, as indicated by odds ratios (OR) greater than 1 (Table 2). The differences were statistically significant in most cases. However, the relatively small sample sizes resulted in marked variability and large CIs for some measures. An exploratory analysis using data from the second attack was done to determine whether the lack of significant differences for rizatriptan compared with placebo with regard to nausea was a consistent finding. In this case, a statistically significant difference was found for rizatriptan 10 mg (percentage of patients with no nausea was 80% for rizatriptan 10 mg compared with 61% for placebo; OR = 1.9, 95% CI 1.2, 5.3, P < .05). Although the treatment-by-study interaction was not formally tested in this analysis, the pattern of results appeared to be similar in each study. For example, more patients taking rizatriptan 10 mg or 5 mg reported pain relief at 2 hours compared with placebo in both studies (rizatriptan 10 mg, 75% compared with 55%, and 60% compared with 38%; rizatriptan 5 mg, 67% compared with 38%, and 73% compared with 55%).
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(rizatriptan 10 mg) and Figure 3 (rizatriptan 5 mg). Odds ratios and 95% CIs for the effect of menstrual association combined across treatments are given in Table 3. As anticipated, given the identical design of the two studies, there were no significant treatment-by-study interactions (P > .05), except for the no use of escape medications variable (P = .04). These findings support the validity of pooling data from the two studies. There were also no significant treatment-by-menstrual association interactions (P > .05), indicating that a similar pattern of response was observed for all treatments (rizatriptan 10 mg, rizatriptan 5 mg, and placebo) in menstrually associated compared with nonmenstrually associated attacks. As shown in Figures 2 and 3, rizatriptan was equally effective for menstrually associated and nonmenstrually associated attacks.
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To investigate whether the day of menstrual association had any effect on response rates, the percentages of patients with pain relief were plotted by day of menstrual association for rizatriptan 10 mg (Figure 4). There was no evidence that the efficacy of rizatriptan 10 mg was diminished when used to treat attacks occurring on the day of menstruation onset compared with attacks occurring immediately before or after onset of menstruation. However, the number of patients in each group was relatively small.
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Discussion |
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Our conclusion that rizatriptan is effective for treating menstrually associated migraine attacks is in agreement with single-attack data for other 5-HT1B/1D receptor agonists, including a retrospective analysis with sumatriptan 6 mg injection,22 retrospective analyses with oral zolmitriptan 2.5 to 10 mg,23 (Loder E, Silberstein SD. Efficacy of zolmitriptan in the acute treatment of menstrually associated migraine [abstract]. Headache 1999;39:366) and a prospective analysis with sumatriptan 6 mg injection.24 Each of those studies used a slightly different definition of menstrual association (sumatriptan studies used 1 day before to 4 days after, or 3 days before to 5 days after onset of menstruation; zolmitriptan studies used 2 days before to 3 days after onset of menstruation). (See MacGregor25 for discussion of issues about defining menstrual association.) In our analysis, a migraine attack was considered to be associated with menstruation if it occurred within 3 days before to 3 days after the date of onset of menstruation. The efficacy of rizatriptan did not appear to be diminished for attacks that occurred on the day of menstruation onset. The pain relief response rate for rizatriptan 10 mg on the day of menstruation onset was 78% compared with an average of 61% for attacks occurring on the 3 days immediately before menstruation onset, and an average of 67% for attacks occurring on the 3 days immediately after menstruation onset.
To date, only one double-masked, placebo-controlled study has examined treatment efficacy in patients who were reported to have consistent menstrually associated migraine attacks. (Gross MLP, Barrie M, Bates D, Dowson A, Elrington G. The efficacy of oral sumatriptan in menstrual migraine—a prospective study [abstract]. 1995;15(suppl):227.) The study examined the efficacy of oral sumatriptan 100 mg for four attacks in women who had a history of at least 80% of attacks in the last 6 months occurring between 3 days before to 5 days after onset of menstruation. In those patients sumatriptan appeared to be as effective at treating attacks occurring within the window for menstrual association as for those occurring outside the window. However, the historical diagnosis of consistent menstrual migraine was checked prospectively during the study and confirmed in only 11% of patients. Further studies are required to determine the efficacy of rizatriptan and other 5-HT1B/1D receptor agonists in the minority of women who consistently have migraine attacks associated with menstruation.
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Footnotes |
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Authors Silberstein, Massiou, and Le Jeunne have been paid consultants for and received study funding from Merck. Author Silberstein owns Merck stock. Authors Johnson-Pratt, McCarroll, and Lines are employees of Merck, and own Merck stock and stock options.
Received September 27, 1999. Received in revised form January 13, 2000. Accepted February 8, 2000.
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2. Johannes CB, Linet MS, Stewart WF, Celentano DD, Lipton RB, Szklo M. Relationship of headache to phase of the menstrual cycle among young women: A daily diary study. Neurology 1995;45: 1076–82.[Abstract]
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E. Loder Prophylaxis of menstrual migraine with triptans: Problems and possibilities Neurology, December 10, 2002; 59(11): 1677 - 1681. [Abstract] [Full Text] [PDF]
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