Treatment of severe, disabling migraine attacks in an over-the-counter population of migraine sufferers: results from three randomized, placebo-controlled studies of the combination of acetaminophen, aspirin, and caffeine.

OBJECTIVE: To examine the benefits of acetaminophen, aspirin, and caffeine (AAC) in the treatment of severe, disabling migraine attacks, in a population of migraine sufferers for whom over-the-counter (OTC) medications are appropriate. BACKGROUND: Subjects (n = 1220) who met the International Headache Society criteria for migraine with or without aura were included in three independent clinical studies. DESIGN/METHODS: Post-hoc analysis of 172 subjects who met the criteria for severe, disabling migraine reported a history of migraine attacks characterized by at least severe pain and severe disability, and treated attacks with severe pain and at least severe disability. Subjects who usually vomited with 20% or more of their migraine attacks, and those with incapacitating disability (subjects who required bed rest for more than 50% of their attacks) were not eligible for enrollment. RESULTS: From 1 h and continuing through 6 h postdose, the proportion of responders was significantly greater (p< or =0.01) for AAC than placebo. The pain intensity difference from baseline was significantly greater (p< or =0.05) for AAC than placebo from 0.5 h through 6 h. The proportion of subjects reporting improvement in functional disability, photophobia, and phonophobia was significantly greater for AAC than placebo from 2 h through 6 h postdose. CONCLUSIONS: The nonprescription combination of AAC was well tolerated and effective.

Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen, aspirin, and caffeine: results from three randomized, placebo-controlled studies.

This retrospective study sought to examine the benefits of the nonprescription combination of acetaminophen, aspirin, and caffeine (AAC; Excedrin Migraine, Bristol-Myers Squibb Company, New York, New York) for the treatment of menstruation-associated migraine compared with migraine not associated with menses. Data were derived from 3 double-masked, randomized, placebo-controlled, single-dose trials enrolling subjects who met the International Headache Society's diagnostic criteria for migraine with or without aura. Subjects with incapacitating disability (attacks requiring bed rest >50% of the time) and those who usually experienced vomiting > or =20% of the time were excluded. Retrospective analysis of the 1220 subjects included in the efficacy-evaluable data set indicated that 185 women treated menstruation-associated migraine, 781 women treated migraine not associated with menses, and 1 woman provided no information regarding menstrual status. At baseline and at 0.5, 1, 2, 3, 4, and 6 hours postdose, subjects assessed the intensity of headache pain, functional disability, nausea, photophobia, and phonophobia. Pain intensity, nausea, photophobia, and phonophobia were rated on a 4-point scale ranging from 0 = none to 3 = severe; functional disability was rated on a 5-point scale ranging from 0 = none to 4 = incapacitating. For both menstruation-associated migraine and migraine not associated with menses, the proportion of subjects with pain intensity reduced to mild or none (responders) was significantly greater with AAC than with placebo at all postdose time points from 0.5 through 6 hours (P< or =0.05), with no statistically significant difference in treatment effect between menstruation-associated migraine and migraine not associated with menses at any postdose time point. Migraine characteristics such as photophobia, phonophobia, and functional disability were significantly improved in AAC-treated subjects at all time points from 1 through 6 hours (P< or =0.01) in both the menstruating and nonmenstruating groups. Significant relief from nausea was experienced in both menstruation-associated migraine and migraine not associated with menses, but relief appeared earlier in the AAC nonmenstruating subjects (2 hours postdose, P< or =0.01) than in the menstruating subjects (6 hours postdose, P< or =0.05). Beginning at 3 hours postdose, significantly fewer subjects treated with AAC required rescue medication (P< or =0.05) for menstruation-associated migraine (AAC 6%, placebo 15%) and migraine not associated with menses (AAC 7%, placebo 14%). The most commonly used rescue medications in both the menstruating and nonmenstruating groups were nonsteroidal anti-inflammatory drugs, prescription combination analgesics/narcotics, and prescription migraine preparations. AAC was well tolerated in both menstruation-associated migraine and migraine not associated with menses; in general, adverse experiences were similar in both groups. The proportion of subjects who had 1 or more adverse experiences was significantly higher among those receiving AAC than among those receiving placebo (menstruation-associated migraine: AAC 26.4%, placebo 12.6%, P = 0.025; nonmenstruation-associated migraine: AAC 18.6%, placebo 11.4%, P = 0.005). Adverse experiences were similar in type and severity to those previously associated with single doses of acetaminophen, aspirin, or caffeine. Thus the nonprescription combination of AAC was highly effective in treating the pain, disability, and associated symptoms of both menstruation-associated migraine and migraine not associated with menses.

Use of the factorial design and quadratic response surface models to evaluate the fosinopril and hydrochlorothiazide combination therapy in hypertension.

The combination of angiotensin converting enzyme (ACE) inhibitor and thiazide diuretic has advantages over monotherapy for the treatment of hypertension. Previous study designs have often been inadequate to demonstrate the details of interactions between these antihypertensive agents. This study used a modified 4 x 4 factorial randomized, double-blind, placebo-controlled, parallel group design to study the efficacy of 17 different doses of fosinopril (Fos), a phosphinic acid derived ACE inhibitor, and hydrochlorothiazide (HCTZ) in 550 patients with mild to moderate hypertension. Data from these variables were fit to quadratic response surface models (QRSM) using polynomial functions in the doses of the two components. Using QRSM, seated systolic (SeSBP) and diastolic blood pressure (SeDBP) responses at 8 weeks were predicted for actual doses and interpolated for intermediate doses not studied. Fos and HCTZ alone and in combination produced a dose-related reduction in SeSBP and SeDBP. Using 10 mg Fos + 12.5 mg HCTZ reduced the adjusted mean SeDBP 6.3 mm Hg and 20 mg Fos + 12.5 mg HCTZ lowered the same measure 9.1 mm Hg. Coadministration of Fos and HCTZ produced an additive antihypertensive effect. This study of combination agents for hypertension using a factorial design with QRSM accurately predicts dose responses and is a valuable clinical trial methodology.

Efficacy and safety of fosinopril/hydrochlorothiazide combinations on ambulatory blood pressure profiles in hypertension. Fosinopril/Hydrochlorothiazide Investigators.

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was used to assess the antihypertensive efficacy and safety of the angiotensin converting enzyme (ACE) inhibitor fosinopril (Fos) in combination with hydrochlorothiazide (HCTZ) in doses of 10/12.5 mg and 20/12.5 mg taken once daily versus placebo in patients with mild-to-moderate hypertension. In two methodologically identical studies, the antihypertensive effects were evaluated by 24-h ABPM and by seated office diastolic (DBP) and systolic (SBP) blood pressures. After a 4- or 5-week placebo washout, 79 patients received randomized, double-blind treatment for 8 weeks with either the Fos/HCTZ 10/12.5-mg dose combination (n = 41) or placebo (n = 38), and in the second study, 62 patients were treated with either the Fos/HCTZ 20/12.5-mg dose combination (n = 30) or placebo (n = 32). Changes from baseline in mean 24-h systolic and diastolic ABPM were significantly different from placebo for both doses (SBP/DBP with 10/12.5 mg, -18.2/ -10.1 mm Hg, P