Pharmacokinetic and pharmacodynamic profiles of sumatriptan in migraine patients with headache recurrence or no response.

OBJECTIVES: Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with migraine do not experience headache relief after sumatriptan, and up to 40% may experience recurrence of headache within 24 hours. We studied whether pharmacokinetic or pharmacodynamic differences may explain these different clinical effects. METHODS: We compared the pharmacokinetic profiles of subcutaneous sumatriptan in 14 patients who consistently had headache relief without headache recurrence, in 12 patients who had headache recurrence in every attack, and in six patients who did not have headache relief after sumatriptan. Because the antimigraine action of sumatriptan may be mediated through vasoconstriction of cranial blood vessels, we also compared in these patients changes in blood vessel diameter and blood velocity in the common, internal, and external carotid arteries. RESULTS: Despite sufficient power of the study, no important differences in pharmacokinetic and pharmacodynamic profiles between the three patient groups were detected. CONCLUSION: Headache recurrence and lack of headache relief after sumatriptan do not appear to be explained by pharmacokinetic or pharmacodynamic differences between patients, which may be an important finding for the development of novel antimigraine drugs.

Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group.

BACKGROUND: Rizatriptan (MK-462) is a new 5-hydroxytryptamine1D (serotonin1D; 5-HT1D) receptor agonist for the acute treatment of migraine that has improved pharmacokinetic properties compared with sumatriptan succinate. OBJECTIVE: To assess the efficacy and tolerability of 10-, 20-, and 40-mg doses of oral rizatriptan vs a 100-mg dose of oral sumatriptan succinate and placebo for the acute treatment of migraine. DESIGN: Randomized, double-blind, parallel-group, placebo-controlled, outpatient trial. SETTING: Ten US and 4 Dutch investigator centers. PATIENTS: Patients who had migraine with or without aura (N = 449). MAIN OUTCOME MEASURE: The proportion of patients whose conditions improved from severe or moderate headache immediately before dosing to mild or no headache at 2 hours after drug administration (ie, headache relief). RESULTS: The proportion of patients with headache relief was 18% for placebo; 46% for sumatriptan; and 52% for 10-mg, 56% for 20-mg, and 67% for 40-mg rizatriptan. All differences with placebo were statistically significant (P < .001), and 40-mg rizatriptan was superior to sumatriptan (P = .01). The proportion of patients who became free of pain at 2 hours was 3% for the placebo-treated group; 22% for the sumatriptan-treated group; and 26%, 35%, and 47% for the group of patients who took the 10-, 20-, and 40-mg doses of rizatriptan, respectively (all differences with placebo, P < .005; 40-mg rizatripan vs sumatriptan, P = .001). The recurrence of headache within 24 hours was found to be equal across all treatment groups-approximately 40%. Adverse events (most commonly short-lasting mild or moderate dizziness and drowsiness) occurred more frequently after a 40-mg dose of rizatriptan was given than after the other treatments. CONCLUSIONS: The antimigraine effect of 10- and 20-mg rizatriptan was superior to placebo, and comparable with that of 100-mg sumatriptan succinate; the efficacy of 40-mg rizatriptan was superior to that of both placebo and 100-mg sumatriptan succinate, although it was associated with a high frequency of adverse events.

Sumatriptan in clinical practice: a 2-year review of 453 migraine patients.

The long-term and within-patient consistency of the efficacy and tolerability of subcutaneous and oral sumatriptan in migraine was studied by retrospective survey of 2 years with mailed self-administered questionnaires in our neurology outpatient clinic. Subjects were migraine patients with or without aura (N = 869). We measured long-term use of sumatriptan and within-patient consistency and change over time of headache relief, headache recurrence, and chest symptoms after sumatriptan. The questionnaire was returned by 735 (85%) patients; 453 had used sumatriptan for nearly 28,000 attacks during 25 (median) months (92% > 1 year). Sumatriptan provided headache relief, mostly within 2 hours, in 85% of patients in at least two-thirds of their attacks. Of all patients, 75% experienced (usually multiple) headache recurrences in at least some and 40% in (nearly) all attacks. Median time to recurrence was 8 to 12 hours (range 1 to 30). Recurrence of aura was reported as well. Over 2 years, efficacy of sumatriptan had waned in 18% of patients (mainly because of increase in headache recurrence) and improved in 12% (mainly because of reduction of headache recurrence or adverse events or increase of headache relief); the number of monthly doses of sumatriptan had increased in 20%, reduced in 35%, and not changed in 45% of patients. Chest symptoms occurred in up to 58% of patients in at least some and in up to 42% of patients in all attacks, causing discontinuation of sumatriptan in 10%. In total, 111 patients (25%) discontinued sumatriptan mainly because of headache recurrence, adverse events, insufficient headache relief, or high price. In most patients, the effects of sumatriptan were consistent within subjects and over time. In most patients, sumatriptan provided rapid headache relief. Multiple headache recurrence was the major limitation. Chest symptoms were frequent but usually not serious if patients were forewarned.

311C90, a new central and peripherally acting 5-HT1D receptor agonist in the acute oral treatment of migraine: a double-blind, placebo-controlled, dose-range finding study.

311C90 is a novel, centrally and peripherally, acting 5-hydroxytryptamine1D receptor agonist. We investigated the efficacy and safety of 1, 5, and 25 mg of oral 311C90 in the acute treatment of migraine in a randomized, double-blind, placebo-controlled, parallel-group clinical trial involving 84 patients. The proportion of patients in whom the headache improved within 2 hours from moderate or severe to mild or no pain (primary efficacy measure) was 15% for placebo-treated patients and 27% (1 mg), 62% (5 mg), and 81% (25 mg) for patients treated with 311C90. Treatment differences compared with placebo were 12% (95% CI - 12, 37; p = 0.460) for 1 mg 311C90, 47% (CI 21, 73; p < 0.005) for 5 mg 311C90, and 66% (CI 43,89; p < 0.001) for 25 mg 311C90. Photophobia and nausea also showed improvement after 311C90. Adverse events were generally mild and transient in all treatment groups. There were no clinically significant changes in ECG recordings, blood pressure, or laboratory tests. Oral 311C90 (5 and 25 mg) is highly effective and well tolerated in the acute treatment of migraine. The response rates and treatment differences compared with placebo in this study suggest possible superiority over existing antimigraine therapies. This needs to be confirmed in formal comparative trials.

Oral sumatriptan in preventing headache recurrence after treatment of migraine attacks with subcutaneous sumatriptan.

Headache recurrence (HR) may occur within 24 hours in approximately 40% of migraine attacks initially treated successfully with 6 mg subcutaneous (SC) sumatriptan. This may be due to the short plasma half-life of sumatriptan. We studied whether an additional dose of 100 mg oral sumatriptan 4 hours after treatment of a migraine attack with 6 mg SC sumatriptan could prevent HR. Patients (n = 667) treated up to three migraine attacks in a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. For each attack, they initially took open-label 6 mg SC sumatriptan by autoinjector. Four hours later all patients took either 100 mg oral sumatriptan or matched placebo. Patients could take an additional optional oral dose of 100 mg sumatriptan to treat HR. The primary efficacy end point was the number of successfully treated patients without HR within 24 hours after the initial SC injection for the first study attack. Two hundred twenty-five patients were not assessable for HR, mainly because of protocol violations. Of 442 assessable patients, 82/212 in the sumatriptan-treated group (39%) and 89/230 in the placebo-treated group (39%) reported HR in attack 1. Median times to recurrence were 15.6 hours after sumatriptan and 10.3 hours after placebo (p = 0.006). One hundred mg oral sumatriptan taken 4 hours after 6 mg SC sumatriptan does not prevent HR but significantly delays time to recurrence.

Rizatriptan: pharmacological differences from sumatriptan and clinical results.

Rizatriptan and sumatriptan are selective 5-HT(1B/1D) receptor agonists for theacute treatment of migraine. For oral formulations, the time to maximum plasma concentration is reached earlier with rizatriptan than with sumatriptan (1 h versus 2-2.5 h) and rizatriptan has greater bioavailability than sumatriptan (45% versus 15%). These pharmacological advantages appear to translate into a faster onset of action and a better overall response for oral rizatriptan versus oral sumatriptan. The two drugs have been directly compared in randomized, double-blind, placebo-controlled clinical trials of patients with moderate or severe migraine attacks. Rizatriptan 10 mg was generally superior to sumatriptan on a measure of time-to-pain-relief within 2 h, where pain relief was defined as a reduction of pain to mild or none (odds ratio for rizatriptan versus sumatriptan 100 mg = 1.21; odds ratios for rizatriptan 10 mg versus sumatriptan 50 mg = 1.14 and 1.10 in two studies). Rizatriptan 10 mg was also superior to sumatriptan on the International Headache Society recommended endpoint of the percentage of patients pain free at 2 h (40% for rizatriptan 10 mg, 33% for sumatriptan 100 mg, and 35% for sumatriptan 50 mg). Further advantages for rizatriptan were seen on stringent outcome measures of the percentage of patients who were completely free of all symptoms at 2 h, patient satisfaction with medication at 2 h, and 24-h sustained pain-free response. 5-HT(1B/1D) receptor agonists are contraindicated in patients with coronary artery disease because of their potential to cause vasoconstriction. In clinical trials which excluded such patients, rizatriptan and sumatriptan were both well-tolerated. The most common side-effects on both drugs occurred in <10% of patients and consisted of dizziness, drowsiness, and asthenia/fatigue. The adverse events were usually mild or moderate in severity and short-lasting.

The multinational impact of migraine symptoms on healthcare utilisation and work loss.

OBJECTIVE: To compare self-reported healthcare resource utilisation, paid work loss, unpaid work loss and loss of effectiveness at work due to migraine in a clinic-based adult migraine population. METHODS: The Migraine Background Questionnaire (MBQ) was translated and pilot-tested for use in 25 countries. The questionnaire was then self-administered by patients at a screening visit for 3 phase III clinical trials of rizatriptan [a selective serotonin (5-hydroxytryptamine) 5-HT1B/1D receptor agonist] in 23 US and 78 non-US sites. PARTICIPANTS: Persons 18 to 65 years of age with at least a 6-month history of moderate to severe migraines prior to the screening visit were surveyed. RESULTS: A total of 2670 persons (54.7% Europe, 16.5% Latin America, 23.1% North America, 5.5% other countries) completed the MBQ and had responses which could be analysed. On average, each patient reported 2.78 doctor visits, 0.53 emergency room visits and 0.06 hospitalisations related to migraine per year. Patients self-reported being only 46% effective while on the job with migraine symptoms. Extrapolation of patient self-reported work and productivity loss for the last 4 weeks to an annual basis suggested that clinic-based patients with migraine lose 19.5 workday equivalents (8.3 days due to absenteeism, 11.2 days due to reduced workday equivalents) due to migraine per year. In the US, the annual employer cost of this total migraine-related work loss is estimated to be $US3309 (2000 values) per patient with migraine. The levels of self-reported healthcare resources utilised for migraine and work loss were generally consistent across geographic regions. CONCLUSIONS: The impact of migraine symptoms on healthcare resource utilisation and work loss was similar across most measures in Europe, Latin America, North America and other countries. Total migraine-related work loss due to absenteeism and reduced workday equivalents accounts for most of the economic burden of migraine, regardless of country, in a clinic-based migraine population.

Long-term efficacy and tolerability of rizatriptan wafers in migraine.

CONTEXT: Rizatriptan is a selective 5-HT1B/1D receptor agonist for the acute treatment of migraine. It is available in a unique wafer formulation that dissolves rapidly in the mouth and can be taken without liquids, thereby offering patients a very convenient way to take treatment. OBJECTIVE: To investigate the long-term efficacy of rizatriptan 10-mg and 5-mg wafers in migraineurs. SETTING: 19 headache clinics in 5 countries. PATIENTS: 458 patients diagnosed with migraine according to International Headache Society criteria. DESIGN: 6-month, open-label, extension, which followed a double-blind, placebo-controlled study. INTERVENTIONS: Patients were randomly assigned to 1 of 3 treatments for moderate or severe migraines: rizatriptan 10-mg wafer, rizatriptan 5-mg wafer, or "standard care" (usual migraine treatment -- eg, nonsteroidal anti-inflammatory drugs [NSAIDs], analgesics, other triptans). Patients randomized to rizatriptan were blinded to the dose. MAIN OUTCOME MEASURES: Headache severity (none, mild, moderate, severe) and adverse events were recorded on a diary card. RESULTS: 181 patients treated 3393 attacks with rizatriptan 10-mg wafer, 191 treated 3254 attacks with rizatriptan 5-mg wafer, and 86 treated 1582 attacks with standard care. The median number of treated attacks per patient was 16 for rizatriptan 10-mg wafer, 13 for rizatriptan 5-mg wafer, and 14 for standard care. The median patient on rizatriptan 10-mg wafer reported pain relief at 2 hours (reduction of headache from moderate or severe at baseline to mild or none) in 82% of attacks, vs 73% of attacks for standard care (odds ratio [95% confidence interval] = 1.63 [1.14, 2.34], P <.01) and 72% of attacks for rizatriptan 5-mg wafer (OR [95% CI] = 1.60 [1.23, 2.08], P <.001). The median patient on rizatriptan 10-mg wafer was pain free at 2 hours in 46% of attacks, vs 30% of attacks for standard care (OR [95% CI] = 1.50 [1.06, 2.12], P <.05) and 25% of attacks for rizatriptan 5-mg wafer (OR [95% CI] = 1.93 [1.50, 2.49], P <.001). All treatments were generally well tolerated. Compared with standard care, rizatriptan 5-mg wafer was associated with fewer specific adverse events of asthenia/fatigue, back pain, nausea, pharyngeal discomfort, upper respiratory infection, and vomiting (P values <.05), and, compared with rizatriptan 10-mg wafer, fewer overall drug-related adverse events (P <.05). CONCLUSIONS: Rizatriptan 10-mg wafer was more effective than standard care and rizatriptan 5-mg wafer for treating intermittent moderate or severe migraine attacks occurring over periods of up to 6 months. Rizatriptan wafers were well tolerated.

Chest symptoms after sumatriptan: a two-year clinical practice review in 735 consecutive migraine patients.

OBJECTIVES: To assess, in clinical practice, the (i) incidence, (ii) within-patient consistency, and (iii) clinical spectrum of chest symptoms (chest symptoms) after subcutaneous (sc) and oral sumatriptan, and (iv) to identify risk factors for chest symptoms. DESIGN: Two-year retrospective survey with mailed self-administered questionnaire. SETTING: Neurology outpatient clinic of university hospital. SUBJECTS: Migraine patients with or without aura (n = 869). MAIN OUTCOME MEASURES: Incidence, within-patient consistency and characteristics of chest symptoms; demographic and clinical characteristics of patients. RESULTS: There were 735 (85%) respondents. Sumatriptan was used by 453 patients, during 25 months (median), for 28000 attacks (median: 33 attacks/patient). Of sumatriptan users, 41% (sc) and 24% (oral) had chest symptoms in all attacks, 39% (sc) and 58% (oral) in none, and the remaining in some attacks. Because of chest symptoms, 10% discontinued sumatriptan. Chest symptoms mostly consisted of heavy arms and chest pressure, started within 5 (sc) to 30 (oral) min, and lasted 30 (sc) to 60 (oral) min. Compared with patients without chest symptoms, patients with chest symptoms more often were females and younger, and went to rest immediately after sumatriptan administration (all p < 0.001); they also tended to have lower body mass indices, more severe attacks and less efficacy of sumatriptan (all 0.001 < p < 0.05). Patients with chest symptoms had no higher incidence of cardiovascular symptoms or risk factors. CONCLUSIONS: Chest symptoms are frequent, within-patients consistent, but rarely important, adverse events of (notably sc) sumatriptan. The risk of chest symptoms is patient-dependent and not related, even opposite, to cardiovascular disease. This contradicts the hypothesis that chest symptoms after sumatriptan are caused by cardiac ischemia. Patient acceptance of chest symptoms is improved by pre-advising on the risk and nature of chest symptoms.

Treatment of migraine attacks with subcutaneous sumatriptan: first placebo-controlled study. The Subcutaneous Sumatriptan International Study Group.

The results of the very first large-scale placebo-controlled dose-response trial with the novel selective 5-hydroxytryptamine1-like (5HT1-like) receptor agonist sumatriptan are presented. We studied the efficacy and tolerability of subcutaneous injections of 1 mg, 2 mg and 3 mg of sumatriptan in alleviating migraine attacks in a double-blind, placebo-controlled, parallel-group, multicentre clinical trial. Six-hundred and ninety patients were randomized and 685 received study medication. At 30 min, reduction of headache severity to mild or none (primary efficacy endpoint) was achieved in 22% (95% CI: 15-28%) of placebo-treated patients and in 39% (CI: 31-46%) of patients treated with 1 mg sumatriptan, 44% (CI: 36-51%) treated with 2 mg sumatriptan and 55% (CI: 48-63%) treated with 3 mg sumatriptan. Differences from placebo were 17% (CI: 8-27%) for 1 mg sumatriptan, 22% (CI: 13-32%) for 2 mg sumatriptan and 34% (CI: 24-44%) for 3 mg sumatriptan (p < 0.001 for all three comparisons). Other migraine symptoms were also more effectively treated by sumatriptan than by placebo. Subsequently, an open-label 3 mg dose subcutaneous sumatriptan was given to partial or non-responders. Thirty minutes after this open dose the response rate to sumatriptan had improved to between 70 and 80%. Adverse events after sumatriptan were minor and short-lived. We conclude that subcutaneous sumatriptan is well tolerated in doses up to 3 + 3 mg and may rapidly abort migraine attacks.

Risk factors for headache recurrence after sumatriptan: a study in 366 migraine patients.

Headache recurrence (HR) is the major limitation of sumatriptan in the acute treatment of migraine attacks. The risk of HR is mainly patient-dependent. We analyzed, in 366 migraine patients, clinical differences between patients who always have HR and patients who never have HR. We found remarkably few differences. HR more frequently occurred in patients with more severe attacks and longer untreated attack duration; in patients who experienced a sensation of a subclinically ongoing attack, despite headache relief after sumatriptan; and in females, mainly with menstruation-related migraine, most probably due to the more severe and longer lasting attacks these patients suffer, rather than due to hormonal factors. The incidence of HR was, among other factors, not related to the (other) clinical effects of sumatriptan, the timing of administration within the attack, the duration of use of sumatriptan, pharmacokinetic factors, or whether patients were experiencing HR after use of ergot alkaloids.

Sumatriptan-nonresponders: a survey in 366 migraine patients.

Sumatriptan, notably after subcutaneous administration, is highly effective in the acute treatment of migraine in the majority of patients. The response is consistent within patients and over time. To determine risk factors for nonresponse to sumatriptan, we compared clinical characteristics in responders and nonresponders and, within patients, between attacks with and without response. We found no differences at the strict level of significance (P < 0.001 because of multiple comparisons), but only tendencies for differences (0.001 < P < 0.05) in either the subcutaneous or oral groups. In the subcutaneous group, nonresponders had a higher body mass index, migraine onset at an earlier age, and, most importantly, they treated their migraine attacks earlier. In the oral group, nonresponders had attacks associated with more severe vomiting and photophobia, more often went to sleep or rest, and more frequently experienced initial worsening of the headache after sumatriptan administration. Within patients, no differences were found between attacks with and without response. In conclusion, we found few, if any, clinically relevant risk factors for nonresponse to sumatriptan. Administration of sumatriptan too early was the strongest indicator and should be avoided.

Dopamine D2-receptor imaging with 123I-iodobenzamide SPECT in migraine patients abusing ergotamine: does ergotamine cross the blood brain barrier?

Two migraine patients were studied by in vivo SPECT using the dopamine D2-receptor specific radioligand 123I-3-iodo-6-methoxybenzamide (123I-IBZM) during ergotamine abuse and after withdrawal. Results were compared with 15 healthy controls. Striatum/cerebellum and striatum/occipital cortex ratios of count rate density were calculated as a semiquantitative measurement for striatal dopamine D2-receptor binding potential. No differences were found in striatal uptake of 123I-IBZM between healthy controls and the patients when on or off ergotamine. Preliminary evidence suggests that ergotamine may not occupy striatal dopamine D2-receptors to a large extent and thus may not cross the blood brain barrier in large quantities.

Inhibition of gamma-endorphin generating endopeptidase activity of rat brain by peptides: structure activity relationship.

gamma-Endorphin generating endopeptidase (gamma EGE) activity is an enzyme activity which converts beta-endorphin into gamma-endorphin and beta-endorphin-(18-31). The inhibitory potency on gamma EGE activity of neuropeptides and analogues or fragments of neuropeptides was tested. Dynorphin-(1-13) (IC50: 0.14 microM), human beta-endorphin-(1-31) (IC50: 15.5 microM), porcine ACTH-(1-39) (IC50: 6.3 microM), and substance P (IC50: 26 microM) had an inhibitory activity on gamma EGE activity. beta-Endorphin-(18-31) (IC50: 0.35 microM) but not gamma-endorphin potently inhibited gamma EGE activity. The IC50 of poly (Lys)40-60 was 0.8 microM. It is concluded that 1) gamma EGE activity is strongly inhibited by its product beta-endorphin-(18-31), 2) the enzyme is strongly inhibited by peptides with an aromatic amino acid at the NH2-terminal and/or basic amino acids in the COOH-terminal of the peptide chain.

Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group.

Rizatriptan is a potent, oral, 5-HT1B/1D agonist with more rapid absorption and higher bioavailability than oral sumatriptan. It was postulated that this would result in more rapid onset of effect. This randomized, double-blind, triple-dummy, parallel-groups study compared rizatriptan 5 mg, rizatriptan 10 mg, sumatriptan 100 mg, and placebo in 1268 outpatients treating a single migraine attack. Headache relief rates after rizatriptan 10 mg were consistently higher than sumatriptan at all time points up to 2 hours, with significance at 1 hour (37% versus 28%, P = 0.010). All active agents were significantly superior to placebo with regard to headache relief and pain freedom at 2 hours (P < or = 0.001). The primary efficacy endpoint of time to pain relief through 2 hours demonstrated that, after adjustment for age imbalance, rizatriptan 10 mg had earlier onset than sumatriptan 100 mg (P = 0.032; hazard ratio 1.21). Rizatriptan 10 mg was also superior to sumatriptan on pain-free response (P = 0.032), reduction in functional disability (P = 0.015), and relief of nausea at 2 hours (P = 0.010). Significantly fewer drug-related clinical adverse events were reported after rizatriptan 10 mg (33%, P = 0.014) compared with sumatriptan 100 mg (41%). We conclude that rizatriptan 10 mg has a rapid onset of action and relieves headache and associated symptoms more effectively than sumatriptan 100 mg.

Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Rizatriptan Wafer Protocol 049 Study Group.

Rizatriptan is a potent, highly selective 5HT1B/1D agonist with rapid onset of action for acute treatment of migraine. Rizatriptan wafer is a novel, freeze-dried dosage formulation of rizatriptan which rapidly disintegrates on the tongue, is swallowed with saliva, and may be taken without liquids. The efficacy and tolerability of rizatriptan wafer were examined in a placebo-controlled, double-blind, outpatient study in 555 migraineurs. The primary efficacy endpoint was pain relief at 2 h. From 30 min onwards, significantly more patients experienced pain relief and became pain-free after rizatriptan 10-mg wafer compared to placebo. At 2 h, the percentage of patients with pain relief was significantly higher after rizatriptan 10-mg wafer (74%), 5-mg wafer (59%) compared with placebo (28%). Rizatriptan 10-mg wafer was superior to rizatriptan 5-mg wafer on pain relief at 1.5 and 2 h (p < 0.05). Significantly more patients were pain-free at 2 h after rizatriptan 10-mg wafer (42%), 5-mg wafer (35%) compared with placebo (10%). Both doses of rizatriptan wafer were well tolerated. Rizatriptan wafer is a convenient, highly effective new formulation for acute treatment of migraine.

Randomized, placebo-controlled trial of rofecoxib in the acute treatment of migraine.

OBJECTIVE: To investigate the clinical profile of rofecoxib, a long-acting (approximately 17-hour half-life) selective cyclo-oxygenase-2 inhibitor, for the acute treatment of migraine. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted. Patients age > or =18 treated a moderate or severe migraine headache with placebo (n = 182), rofecoxib 25 mg (n = 183), or rofecoxib 50 mg (n = 192). The primary efficacy measure was headache relief (mild or no pain) 2 hours after dose. RESULTS: The proportions of patients with migraine headache relief at 2 hours after dose were 34.3% for placebo, 54.0% for rofecoxib 25 mg (p < 0.001 vs placebo), and 56.7% for rofecoxib 50 mg (p < 0.001 vs placebo). Rofecoxib 25 and 50 mg were superior to placebo in providing pain freedom at 2 hours, 24-hour sustained headache relief, and 24-hour sustained pain freedom; in reducing photophobia, phonophobia, nausea (50 mg only), and functional disability at 2 hours after dose; and in improving some quality-of-life scores over 24 hours. More patients on rofecoxib 50 mg reported adverse events (39.6%) than patients on rofecoxib 25 mg (26.8%) or placebo (23.6%) regardless of drug relatedness; however, the incidences of drug-related adverse events were similar between treatment groups. These adverse events were generally mild or moderate in severity. The most commonly reported adverse events were dry mouth, dizziness, somnolence, nausea, dyspepsia, paresthesia, and asthenia, with similar incidences between treatment groups. CONCLUSION: Rofecoxib 25 and 50 mg were effective and generally well tolerated for the acute treatment of migraine attacks.