Pain-Free Rates With Zolmitriptan 2.5 Mg ODT in the Acute Treatment of Migraine: Results of a Large Double-Blind Placebo-Controlled Trial*

Key words: Efficacy – Migraine – Orally disintegrating tablet – Tolerability – Zolmitriptan

ABSTRACT

Context: Zolmitriptan 2.5 mg orally disintegrating tablets (ODT) allow patients to take the medication without fluids, which is convenient and avoids the risk of fluid-induced exacerbation of nausea/ vomiting.

Objective: To evaluate the efficacy and tolerability of zolmitriptan 2.5 mg ODT taken as soon as possible after onset of a migraine.

Design: Multicenter, double-blind, parallel-group, placebo- controlled two-attack trial.

Setting: Outpatient headache clinics in the US.

Patients: 608 patients were randomized; 566 patients treated at least 1 migraine and were included in the tolerability assessment (565 patients were included in the intent-to-treat population).

Intervention: Patients were randomized to either zolmitriptan 2.5 mg ODT or placebo. Patients treated up to 2 migraine attacks as soon as possible after the start of their migraine pain.

Main outcome measure: Pain-free rates at 2 h.

Results: Zolmitriptan 2.5mg ODT (n = 281) demonstrated a significant pain-free rate vs. placebo (n = 284) at 2 h (40% vs. 20%, p < 0.001), 1.5h (25% vs. 15%, p < 0.001), and 1 h (13% vs. 8%, p = 0.004). Sustained pain-free rate was significantly higher than placebo (31% vs. 15%; p < 0.001). Return to normal activities favored zolmitriptan 2.5 mg ODT at 1 h (p = 0.004), 1.5 h (p < 0.001), and 2 h (p < 0.001). Adverse events associated with zolmitriptan 2.5 mg ODT were those commonly reported with the use of triptans.

Conclusions: Zolmitriptan 2.5 mg ODT, taken as early as possible after onset of a migraine attack, is effective in the treatment of migraine, producing a significantly higher pain-free rate than placebo 2 h post-dose, and also at the earlier time points of 1 h and 1.5 h post-dose.

Introduction

Migraine is a debilitating chrome condition characterized by recurrent attacks of severe headache, and gastrointestinal and neurological symptoms. It is associated with a significant disability and socioeconomic impact, with the annual direct cost of treating migraine estimated at $1 billion (in 1999 US dollars) and indirect costs due to lost productivity at $13 billion1. Symptoms include pain, gastrointestinal disturbances, and hypersensitivity to light and/or sound2,3.

Gastrointestinal events, including nausea, vomiting, abdominal cramps or diarrhea, are almost universally associated with migraine attacks3. In a study that evaluated migraine-associated symptoms, more than 90% of migraineurs reported that nausea sometimes occurred with headache attacks, one-third of whom experienced nausea during every attack3. In addition, vomiting during some attacks was reported by about 70% of those surveyed, with one-third of these patients vomiting during more than 50% of attacks3.

Although conventional oral tablet therapy is currently the most widely prescribed form of migraine treatment, gastric paresis, nausea and vomiting during an attack may interfere with this route of drug administration and rate of drug absorption4. Fluid intake for dose administration may further exacerbate the patient’s gastrointestinal symptoms. Despite this, patient survey results show that the preferred route of administration is an oral delivery medication5,6.

Thus, an oral drug formulation that dissolves rapidly on the tongue without the need for fluid intake may provide a preferred option for the delivery of anti-migraine medication.

Zolmitriptan, a selective serotonin IB/ID (5-HT^sub 1B/1D^) receptor agonist, is highly effective for the acute treatment of migraine, relieving both headache pain and the associated symptoms7- 10. Zolmitriptan orally disintegrating tablets (ODT) are uniquely formulated to dissolve on the tongue without the need for fluid intake, and are effective in the treatment of moderate to severe migraine in adults11. This formulation allows patients to take the dose as soon as possible following onset of headache pain, even in situations where fluids are not readily available, thereby facilitating improved migraine care since early intervention during migraine attack improves the response to triptan therapy11.

Historically, clinical studies of acute migraine therapy have required subjects to wait until the headache was of moderate or severe intensity; mild migraine was excluded from treatment. The primary endpoint has traditionally been headache response at 2h. However, the endpoint of pain-free at 2 h is a more objective and consistent way to determine treatment success and represents the treatment outcome most valued by patients with migraine. The first study demonstrating that zolmitriptan treatment of migraine during mild pain led to improved outcomes was published in 1998. This study showed higher pain-free rates with zolmitriptan 5 mg when treatment occurred while pain was still mild12. Since then, numerous additional studies have replicated these findings13,14. However, methodological aspects of these studies have been criticized, in particular the use of retrospective data analysis and evaluation of data from protocol violators12-14. We sought to prospectively evaluate both the pain-free endpoint and treatment of migraine as soon as possible after onset of pain (of any severity) under conditions that closely replicate clinical practice.

Methods

Study design

This multicenter, double-blind, parallel-group, placebo- controlled trial included patients from 25 centers across the United States. Patients were randomized in a 1:1 ratio to receive either zolmitriptan 2.5 mg ODT or matching placebo for the treatment of 2 migraine attacks of mild, moderate, or severe headache intensity over a 6-week period. Patients were allocated to treatment in balanced blocks and were assigned a patient number on a sequential basis as they entered the study. The first patient was enrolled on December 4, 2000 and study completion date was September 7, 2001. Approval from the ethics committee or institutional review board for each center was obtained, and all patients provided informed written consent. This study was performed in accordance with the regulations of the Declaration of Helsinki15.

At the screening visit, a medical and migraine history was obtained. In addition, a physical examination, clinical laboratory blood testing, and an electrocardiogram were performed. Eligible patients returned within 7 days (visit 2) to receive their trial medication. At the end of a 6-week treatment period or after 2 migraine attacks had been treated, whichever occurred first, patients returned to the clinic for diary review, assessment of any adverse events, and end-of-study evaluations. If patients did not treat 2 migraine attacks during the first 6-week period, a further 6 weeks were allowed or the patient could withdraw from the study. Patients who continued in the study returned to the clinic for end- of-study evaluations at the end of the treatment period or earlier if 2 migraine attacks had been treated (Table 1).

Patients

Patients between 18 years and 65 years of age with an established diagnosis of migraine headache (onset age < 50 years), as defined by International Headache Society (IHS) criteria for migraine, were eligible to participate in this study16. Patients had to have had at least 2 migraine attacks per month, with or without aura, and non- migraine headache symptoms on fewer than 10 days of each month for 3 months prior to study entry. To ensure that the efficacy data would reflect the effect of the study medication, patients also had to be able to distinguish non-migraine from migraine headache. During the trial, women of childbearing potential were required to use a reliable method of birth control.

Table 1. Procedure for two-attack study comparing zolmitriptan 2.5 mg ODT and placebo

Patients with a history or symptoms suggestive of ischemic heart disease or other vascular diseases, clinically significant electrocardiographic abnormalities, or uncontrolled hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 90 mm Hg) were excluded from the study. Patients with a history of basilar, ophthalmoplegic, or hemiplegic migraine or a serious neurological condition associated with headaches were also excluded. Patients were not eligible if they were receiving concomitant treatment with propranolol or cimetidine or had used a monoamine oxidase inhibitor within 2 weeks of randomization. Patients who initiated therapy with a selective serotonin reuptake inhibitor without a stabilized dose within 2 weeks of randomization were also excluded. Other exclusion criteria included prior serious adverse events or hypersensitivity to any 5-HT^sub 1B/1D^ agonist, prior history of alcohol or drug abuse, pregnancy or lactation, severe renal or hepatic impairment, history of phenylketonuria, or use of any experimental medication within 30 day s of the study.

Treatment administration

Patients were instructed to take a single oral dose of trial medication as soon as possible at the onset of a migraine headache. The headache pain could be mild, moderate, or severe in intensity. Patients were instructed to allow a zolmitriptan 2.5 mg ODT or placebo to dissolve on the tongue; no water was permitted during treatment administra\tion. A second tablet or placebo could be taken between 2h and 24h if adequate pain relief was not achieved with the initial treatment dose. Escape medications (i.e., nonsteroidal anti- inflammatory drugs, anti-emetics, analgesics, or sedatives) were permitted 2h after the initial dose of trial medication and after completion of a 2-h assessment period. The use of any other 5- HT^sub 1B/1D^ agonist or ergot derivative was not permitted within 24h after any dose of trial medication. Intake of alcohol or other recreational drugs within 48h after trial medication was not allowed.

Efficacy measures

Migraine activity and response to treatment, including the date and time of onset of the migraine attack and when the trial medication was started, were recorded by patients on daily diary cards. The primary efficacy end-point was pain-free rate at 2h after initial treatment with trial medication. Pain-free was defined as an improvement in migraine headache pain intensity from mild, moderate, or severe to no pain. Secondary endpoints included pain-free rate at 0.5h, 1h, and 1.5h after treatment and sustained pain-free rate at 24h. Sustained pain-free was defined as being pain-free at 2 h with no need for re-medication, and free from headache recurrence from 2h to 24h. Headache recurrence was defined as mild, moderate or severe pain going to no pain by 2h following treatment and return of mild, moderate or severe pain within the 24 h following treatment. Other parameters evaluated were the incidence of migraine symptoms, return to normal activities at 0.5h, 1h, 1.5h, and 2h after treatment, medication preference, incidence of recurrence, and incidence and time of re-medication. Re-medication meant that the patient either took the second dose of trial medication or used an escape medication.

Tolerability assessment

Patients receiving at least 1 dose of trial medication were included in the tolerability assessment. Investigators, together with each patient, reviewed the diaries for any adverse events to determine the intensity, duration, and potential relationship to the study medication. Tolerability data included any adverse events occurring within 24 h after dose administration and any serious adverse events occurring anytime following the first dose of study medication.

Statistical analysis

Primary and secondary efficacy endpoints were analyzed according to intention-to-treat principles. The intention-to-treat population included all randomized patients who treated at least 1 migraine attack with the trial medication and had evaluable baseline and posttreatment assessments for the same efficacy parameter. A per- protocol analysis was performed only for the primary efficacy endpoint. The per-protocol population was comprised of the subset of intention-to-treat patients who did not have major deviations from the protocol. Because each attack was evaluated separately for the occurrence of a major protocol deviation, a perprotocol patient might have 1 attack included in the analysis, but the other attack excluded.

The primary analysis specified in the protocol was based on the 2- attack data. Between-treatment group comparisons of pain-free response rates at 2 h over the multiple migraine attacks were performed using the generalized estimating equations (GEE) approach. The logistic link for the binomial error structure was used to model the probability of success. Because only 2 migraine attacks were treated from the same patient, compound symmetry was the correlation structure of choice. The estimated treatment odds ratio (between zolmitriptan and placebo), the corresponding p-values, and 95% confidence intervals (CIs) were presented. The odds ratio and CI were obtained by calculating the antilogarithms of the estimate and the 95% CI of the treatment effect.

Formal statistical analyses for treatment differences were performed using a 2-sided hypothesis test, with a significance level of 0.05 on selected endpoints, including pain-free rate, return to normal activity, time to re-medication, and non-migraine symptoms. For the remaining parameters, only descriptive summary statistics were provided.

It was calculated that a sample size of 482 evaluable patients (241 per treatment group) would provide a 95% chance of showing a between-group difference (two-sided 5% level of significance) in the 2-h pain-free rate, based on the assumption that 2-h pain-free rates would be 20% for placebo and 35% for zolmitriptan 2.5 mg ODT Assuming an 18% rate of withdrawals and unevaluable patients, the study needed to enroll approximately 600 patients.

Results

Patients

Of a total of 608 randomized patients, 566 patients (281 treated with zolmitriptan 2.5mg ODT and 285 treated with placebo) with at least 1 migraine attack treated with trial medication were included in the tolerability assessment (Figure 1). One patient in the placebo group who did not record any efficacy data was included only in the tolerability assessment. Another patient in the placebo group inadvertently took zolmitriptan 2.5mg ODT to treat 1 of the 2 attacks, but it was not known which attack was treated with which medication. This patient was included in the zolmitriptan 2.5mg ODT group for tolerability assessment and in the placebo group for intent-to-treat analysis of efficacy.

The intent-to-treat population included 565 patients (281 treated with zolmitriptan 2.5 mg ODT and 284 treated with placebo) and the per-protocol population included 549 patients (276 treated with zolmitriptan 2.5 mg ODT and 273 treated with placebo). The most common protocol deviations were sleep before the 2-h assessment after the initial dose of trial medication, taking a second dose of trial medication or using escape medication before the 2-h assessment, and taking an ergotamine derivative or triptan within 24 h before or after treatment. A total of 549 patients (90.3%) completed the trial; 32 patients (5.2%) who withdrew did so because they failed to return for follow-up (8 treated with zolmitriptan 2.5 mg ODT and 5 treated with placebo), or were of the opinion that the trial medication was ineffective (5 treated with zolmitriptan 2.5 mg ODT and 14 treated with placebo). Four patients (0.7%) withdrew from the study due to adverse events; 3 because of nonserious adverse events (2 treated with zolmitriptan 2.5 mg ODT and 1 treated with placebo) and 1 (from the group treated with zolmitriptan 2.5 mg ODT) because of a serious adverse event (dyspnea).

For the intent-to-treat population, baseline demographics and migraine histories were similar for the two treatment groups. The intensity and incidence of associated migraine symptoms were also similar between the zolmitriptan 2.5mg ODT and placebo groups (Table 2).

Efficacy

Pain-free rates at 2h

In the intent-to-treat population, a pain-free outcome at 2 h was achieved in a significantly greater proportion of attacks treated with zolmitriptan 2.5 mg ODT compared with placebo (40% vs. 20%, p < 0.001; OR 3.01, CI 2.15, 4.20). The results for the per-protocol population were similar, with a pain-free outcome at 2 h achieved for 42% of attacks treated with zolmitriptan 2.5 mg ODT versus 21% treated with placebo (OR 3.00, CI 2.14,4.21; p < 0.001). A greater pain-free response was seen within 30min after dose administration in patients treated with zolmitriptan 2.5mg ODT compared with placebo; this difference reached statistical significance at 1h, 1.5h, and 2h (Figure 2; 30min: OR 1.23, CI 0.53, 2.87; p = 0.626; 1h: OR 1.91, CI 1.22, 2.99; p = 0.004; 1.5h: OR 2.03, CI 1.40, 2.95; p < 0.001).

Figure 1. Patient recruitment, participation and drop-outs in the 2-attack study. A patient may have had the first attack included in the per-protocol analysis and the second attack excluded due to major protocol deviation

Similar 2-h pain-free rates were seen for zolmitriptan 2.5mg ODT compared with placebo when each attack was analyzed separately (attack 1: 41% vs. 20%; attack 2: 39% vs. 20%).

Two-hour pain-free rates with zolmitriptan 2.5mg ODT were highest in attacks with migraine headache of mild baseline intensity (48.2% vs. 23.8% with placebo), followed by those of moderate (37.4% vs. 14.9%, respectively) and severe (31.2% vs. 26.7%, respectively) baseline intensity, although it should be noted that headache was severe at baseline in only a small proportion of attacks, as patients could treat at any baseline intensity.

Figure 2. Pain-free rates (intent-to-treat population). Significantly more patients treated with zolmitriptan 2.5mg ODT achieved pain-free rates at 1h, 1.5h, and 2h following treatment. Analysis includes up to 2 attacks per patient

Table 2. Demographic and migraine history characteristics (intent- to-treat population)

Zolmitriptan 2.5mg ODT also was superior to placebo in keeping patients pain-free for the first 24 h after administration. A sustained pain-free response was achieved for 31% (161/517) of all attacks treated with zolmitriptan 2.5mg ODT versus 15% (75/514) of all attacks treated with placebo (OR 2.96; CI 2.03; 4.34, p < 0.001). The mean time to treatment during this study was 30min, despite being instructed to take the medication as soon as possible after onset of migraine pain.

Return to normal activities

Zolmitriptan 2.5mg ODT was more effective than placebo in permitting patients to return to normal activities at 0.5h, 1h, 1.5h, and 2 h after treatment (Figure 3). Patients were able to return to normal activities within 30min of dose administration for 16% of the attacks treated with zolmitriptan 2.5mg ODT (48/307) compared with 10% of attacks treated with placebo (27/267; OR 1.68, CI 0.99, 2.84; p = 0.055). At all time points thereafter, this difference was statistically significant (p < 0.005; 1h: OR 1.80, CI 1.21, 2.66; 1.5h: OR 2.28, CI 1.55, 3.35; 2h: OR 2.61, CI 1.76, 3.86).

Recurrence and re-medication rates

Among the patients who were pain free at 2h, 22% (24/108) of first migraine a\ttacks recurred in patients treated with zolmitriptan 2.5mg ODT versus 14% (7/49) in patients treated with placebo. For the second attack treated, recurrence rates were similar for both groups (18% [17/94] of attacks treated with zolmitriptan 2.5 mg ODT versus 18% of attacks treated with placebo [8/44]). Because the recurrence rate is based on the subgroup of responders, statistical analysis was not performed on this endpoint.

Figure 3. Return to normal activities (intent-to-treat population). Significantly more patients treated with zolmitriptan 2.5mg ODT were able to return to routine activities (work, school, or other daily activities) as early as 1h following treatment

Time to re-medication was significantly shorter for attacks treated with placebo. The median time to remedication after the first attack treated with placebo was 2.5 h compared with 20.8 h for the first attack treated with zolmitriptan 2.5mg ODT (p < 0.001). Similarly, the median time to re-medication after the second attack treated with placebo was 2.5 h versus 20h for the second attack treated with zolmitriptan 2.5mg ODT (p < 0.001).

Table 3. Resolution of non-headache symptoms for the first migraine attack, in patients experiencing the symptom at baseline (intent-to-treat population)

Zolmitriptan 2.5 mg ODT was significantly more effective than placebo in resolving nonheadache symptoms associated with migraine (Table 3). Zolmitriptan 2.5mg ODT was significantly superior to placebo in resolving nausea at 0.5h, 1.5h, and 2h after treatment; this difference did not reach statistical significance at 1h (p = 0.22). Reduction in photophobia was significantly superior to placebo at 1h, 1.5h; and 2h, and significantly superior to placebo in resolving phonophobia at 1.5h and 2h.

Tolerability and side effects

Zolmitriptan 2.5mg ODT was well tolerated. Overall, 33% (92/282) of patients treated with Zolmitriptan 2.5mg ODT experienced adverse events versus 14% (41/284) of placebo-treated patients. Treatment- related adverse events occurred in 27% (75/282) and 12% (33/284) of patients treated with Zolmitriptan 2.5mg ODT and placebo, respectively (Table 4). The adverse events most commonly reported in patients treated with zolmitriptan 2.5mg ODT were those commonly associated with the use of triptans, including dizziness, somnolence, paresthesia, tightness, and asthenia.

Although the incidence of adverse events was generally higher in patients treated with zolmitriptan 2.5mg ODT, adverse events were transient and mainly of mild or moderate intensity. There were three serious adverse events reported (acute cholecystitis, acute bronchospasm, chest pain with esophageal dilation), all in patients treated with zolmitriptan 2.5mg ODT. Only 1.1% (3/282) of the patients who received zolmitriptan 2.5mg ODT and 0.4% (1/284) of those treated with placebo withdrew from the trial due to adverse events.

Table 4. Treatment-related adverse events experienced by ≥ 1% of patients in either treatment group

Discussion

The results of this trial demonstrated that zolmitriptan 2.5mg ODT taken as soon as possible after onset of migraine pain was effective and well tolerated. Zolmitriptan 2.5mg ODT was superior to placebo for the primary efficacy endpoint of pain-free rates at 2h. A greater pain-free rate reached a statistically significant difference by 1 h after treatment with zolmitriptan 2.5mg ODT vs. placebo. A higher proportion of patients treated with zolmitriptan maintained a pain-free status for 24 h compared with placebo. Pain- free rate is an ideal patient outcome, and the ability of a medication to work for a 24-h period is important in achieving patient treatment goals.

The high rate of efficacy reported for zolmitriptan 2.5mg ODT in the present study – 40% pain-free rate at 2h – may reflect the fact that patients were not obliged to wait until the pain was of moderate or severe intensity before treating migraine attacks, as is normally required in traditional headache efficacy studies. In this trial, patients were asked to treat migraine as soon as possible after onset, regardless of pain intensity. Despite this, patients waited an average of 30min before treating their attack, and more than 60% of each treatment group treated migraine of moderate or severe intensity. Only one previously reported prospective study has shown that a greater response is obtained when treatment is given early following onset of migraine pain17.

The design of this study approximates what is now commonly recommended in clinical practice [based on previous clinical reports12-14,18) for migraine because patients are generally instructed to: (1) treat early after onset and (2) treat while pain is of mild intensity. Similar to clinical practice, all the patients did not adhere to these recommendations; only one-third treated when attacks were of mild intensity. The pain-free rates in this study may resemble those that practicing physicians may observe in clinical practice, with only about one-third of patients actually adhering to physician recommendations to treat early when pain is mild. Reasons for delaying taking medication may reflect managed care-based medication restrictions, accessibility to medication, and convenience. This study was not designed to prospectively evaluate early vs. late treatment, and the benefit of early treatment on patient outcomes; therefore, analysis of efficacy for treating mild, moderate or severe migraine pain is not provided. However, several other studies have already been done, both prospective and retrospective, that suggest early treatment and treatment of mild migraine confers clinical benefits vs. treating when pain is more severe or later in the course of an attack, respectively12-14,18.

The results of this study are generalizable to typical clinical practice, as patients were instructed to treat as soon as possible after the onset of pain, and when pain was still mild in intensity. Indeed, approximately 35% of patients followed the physician’s instructions, thereby illustrating the importance of education needs of patients regarding how and when to take their migraine medication in order to optimize response to therapy, reduce need for rescue, and reduce overall migraine suffering and disability.

This study is the second study to demonstrate the clinical efficacy of zolmitriptan 2.5mg ODT for the acute treatment of migraine”. However, to date, there are many studies that evaluate headache response as a primary endpoint, yet this is among one of the few studies to prospectively evaluate pain-free rates as the primary endpoint.

Conclusions

Zolmitriptan 2.5mg ODT, taken as soon as possible after migraine onset, achieved a significantly higher pain-free rate than placebo at 2 h post-dose (primary endpoint). In addition, zolmitriptan 2.5 mg ODT produced significantly higher pain-free rates than placebo at the earlier 1-h and 1.5-h post-dose time points. Furthermore, zolmitriptan 2.5mg ODT was significantly superior to placebo in maintaining pain-free status at 24h. Zolmitriptan 2.5mg ODT formulation provides high and fast efficacy and good tolerability in a convenient formulation.

Acknowledgments

This study was supported in full by AstraZeneca LP, manufacturers of zolmitriptan (ZOMIG).

At the time this study was conducted and analyzed, Susan Abu- Shakra, MD, served as the leading physician responsible for this trial and was employed by AstraZeneca. Dr. Abu-Shakra currently is employed by Eisai Pharmaceuticals. This study was designed by selected authors and Jerry Torres, MD, who was employed by AstraZeneca at the time this study was started in 2000.

The Zolmitriptan Study 014 Study Group are: A. Berstein, Santa Rosa, CA; H. Blumenthal, Tulsa, OK; R. Cady, Springfield, MO; J. Couch, Oklahoma City, OK; M. Diamond, Chicago, IL; D. Dodick, Scottsdale, AZ; A. Elkind, Mount Vernon, NY; C. Foster, Phoenix, AZ; J. Klapper, Denver, CO; D. Kudrow, Encino, CA; M. Levin, Lebanon, NH; S. Lucas, Seattle, WA; N. Mathew, Houston, TX; R. Nett, San Antonio, TX; A. Rapoport, Stamford, CT; G. Ruoff, Kalamazoo, MI; J. Saper, Ann Arbor, MI; T. Smith, St. Louis, MO; E. L. H. Spierings, Boston, MA; M. Tuchman, Palm Beach Gardens, FL; J. Walker, Atlanta, GA; T. Ward, Lebanon, NH; P. K. Winner, West Palm Beach, FL.

* Material in this manuscript has previously been presented in preliminary, unpublished form at the following meetings: 6th Congress of the European Federation of Neurological Societies, Vienna, Austria, 26-29 Oct 2002; 55th Annual Meeting of the American Academy of Neurology, Hawaii, USA, 29 Mar – 5 April 2003

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2813_4, Accepted for publication: 20 January 2005

Published Online: 23 February 2005

doi:10.1185/030079905X28926

Elizabeth Loder(a), Frederick G. Freitag(b), James Adelman(c), Starr Pearlman(d) and Susan Abu-Shakra(e) on behalf of the Zolmitriptan Study 014 Study Group

a Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA

b Diamond Headache Clinic, Finch University of Health Sciences/ Chicago Medical School, Chicago, IL, USA

c Headache Wellness Center, Greensboro, NC, USA

d Savannah, GA, USA

e Teaneck, NJ, USA

Address for correspondence: Professor Elizabeth W. Loder, Assistant Professor of Medicine, Harvard Medical School, Director, Pain and Headache Management Programs, Spaulding Rehabilitation Hospital, 125 Nashua St., Boston, MA 02114, USA. Tel.: +1 617 573 2493; Fax: +1 617 573 2489; email: eloder@partners.org

Copyright Librapharm Mar 2005