Headache C 2006 by American Headache Society Published by Blackwell Publishing

ISSN 0017-8748 doi: 10.1111/j.1526-4610.2006.00376.x

Research Submission
Acetaminophen, Aspirin, and Caffeine in Combination Versus Ibuprofen for Acute Migraine: Results From a Multicenter, Double-Blind, Randomized, Parallel-Group, Single-Dose, Placebo-Controlled Study
Jerome Goldstein, MD; Stephen D. Silberstein, MD; Joel R. Saper, MD; Robert E. Ryan, Jr., MD; Richard B. Lipton, MD
Objective.Compare the effectiveness of a combination analgesic containing acetaminophen, aspirin, and caffeine to that of ibuprofen in the treatment of migraine. Methods.Multicenter, double-blind, randomized, parallel-group, placebo-controlled, single-dose study. A total of 1555 migraineurs were included in the analysis. No patients were excluded solely because of severity of symptoms or degree of disability. A single 2-tablet dose for each of the 3 treatment groups: a combination product containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg per tablet (AAC); ibuprofen 200 mg per tablet (IB); or matching placebo. The primary efficacy endpoint was the weighted sum of pain relief (PAR) scores at 2 hours postdose (TOTPAR2) and an important secondary endpoint was the time to onset of meaningful relief. Results.There were 669 patients in the AAC group, 666 patients in the IB group, and 220 patients in the placebo group. The 3 treatment groups had similar demographic profiles, migraine histories, and baseline symptom profiles. While both active treatments were significantly better than placebo in relieving the pain and associated symptoms of migraine, AAC was superior to IB for TOTPAR2, as well as for PAR, time to onset of meaningful PAR, pain intensity reduction, headache response, and pain free. The mean TOTPAR2 scores for AAC, IB, and placebo were 2.7, 2.4, and 2.0, respectively (AAC vs. IB, P < .03). The median time to meaningful PAR for AAC was 20 minutes earlier than that of IB (P < .036). Conclusion.AAC and IB are safe, cost-effective treatments for migraine; AAC provides significantly superior efficacy and speed of onset compared with IB. Key words: acetaminophen, aspirin, caffeine, ibuprofen, migraine
(Headache 2006;46:444-453)

From the San Francisco Headache Clinic, San Francisco, CA (Dr. Goldstein); Jefferson Headache Center, Philadelphia, PA (Dr. Silberstein); Michigan Head Pain & Neurological Institute, Ann Arbor, MI (Dr. Saper); Ryan Headache Center, Chesterfield, MO (Dr. Ryan); and Department of Neurology, Albert Einstein College of Medicine, Bronx, NY (Dr. Lipton). Address all correspondence to Dr. Jerome Goldstein, San Francisco Headache Clinic, 909 Hyde Street, Suite 322, San Francisco, CA 94109. Accepted for publication December 14, 2005.

444

Headache Migraine is a chronic neurologic disorder characterized by episodic attacks of head pain and associated symptoms, including photophobia, phonophobia, nausea, vomiting, and aura.1 In the United States, about 28 million people have migraine; two thirds are women.2,3 Recent population-based studies suggest that adults with migraine average 1.8 attacks per month,4 but the frequency and severity of episodes tend to vary from person to person and within individuals over time. Like other chronic disorders, migraine imposes a significant economic and social burden on those with headache, their families, and the society.5 In American Migraine Study II, more than half (53%) of migraineurs reported severe impairment of activity. Approximately 31% missed at least 1 day of work or school in the 3 months preceding interview because of migraine.2 The vast majority of people with migraine use medication to treat their condition. About 41% use prescription medications, either alone or combined with over-the-counter (OTC) medications.3 Approximately 57% self-treat with OTC medications to the exclusion of prescription drugs.3 Widely used OTC medications for migraine include single-ingredient acetaminophen (APAP), aspirin (ASA), or ibuprofen (IB), as well as a combination analgesic containing acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg per tablet (AAC).2,3,6-10 In 3 well-controlled trials, AAC (Excedrin Migraine) has shown significant superiority to placebo in the treatment of migraine.11 Retrospective analyses of these data have confirmed that AAC is significantly more effective than placebo in treating subsets of migraineurs with severe head pain and associated symptoms12 and women with menstruation-associated migraine.13 Another randomized, controlled clinical study in the early treatment of migraine found that AAC was significantly more effective than sumatriptan, a leading prescription medication.14 Separate investigations have demonstrated the superiority of IB to placebo: the liquigel15 (Advil Migraine) formulation of IB in the treatment of migraine and the tablet16 (Motrin Migraine Pain) in the treatment of migraine pain. A single study also found that APAP was superior to placebo for relief of migraine pain.17 Despite the established efficacy and availability of several OTC alternatives for migraine, no comparative clinical trial

445 for treatment of migraine with OTC medications has yet been published. However, one recently published study, which included exclusively typical OTC patients, has shown that 2 tablets of a triple combination very similar to AAC (250 mg ASA + 200 mg APAP + 50 mg caffeine per tablet) were significantly superior to a treatment with 2 tablets of 250 mg ASA + 200 mg APAP, 2 tablets of 500 mg ASA, two tablets of 500 mg APAP, 2 tablets of 50 mg caffeine, and placebo in patients with migraine and episodic tension-type headache (TTH).18 Since AAC and IB are the approved OTC alternatives for migraine, we decided to compare their efficacy in a head-to-head clinical trial. Herein, we report the results of a multicenter, double-blind, randomized, parallel-group, placebo-controlled study assessing the effectiveness of AAC versus IB and placebo in treating a single migraine attack. Most previous OTC migraine studies11-17 enrolled patients who did not usually require bed rest with their headaches and patients who vomited with less than 20% of attacks. To assess the efficacy of these agents in an unrestricted patient population, we included the full range of those with migraine, without constraints on the level of disability or frequency of vomiting.

SUBJECTS AND METHODS Subjects.This study used a double-blind, randomized, parallel-group, placebo-controlled design. Patients were recruited with population-based (random-digit dialing) and traditional (eg, private practice, referrals, and local advertising) methods. A detailed clinical assessment, conducted by the investigator, ensured that each subjects headaches met International Headache Society (IHS) diagnostic criteria for migraine without aura (IHS 1.1) or migraine with aura (IHS 1.2).1 In addition, each subject was at least 18 years old, was in good general health, and had experienced a migraine attack at least once every 2 monthsbut no more than 6 times monthlyduring the prior 12 months. Untreated attacks were of at least moderate pain intensity. Patients whose headache symptoms may have been caused or aggravated by recent head or neck trauma and patients with cluster headache, specific migraine variants, or other serious nonmigraine causes

446 of headache were excluded. Patients who reported using analgesic drug products for headache on more than 12 days per month were also excluded. Unlike earlier studies of OTC medications for migraine,11-17 no patients were excluded based on the requirement for bed rest or the presence of frequent vomiting. Study DesignProtocol.The study was conducted in 4 phases: screening, selection, treatment, and follow-up. Trained interviewers identified potential patients at the screening phase. At the selection phase, patients provided written informed consent and a complete medical history. Physical and neurologic exams were also completed at this time. Female patients also underwent urine pregnancy testing. Qualified patients were randomly assigned (3:3:1 ratio) to receive double-blinded study medication containing a single, four-tablet dose consisting of 2 unbranded AAC tablets (APAP 250 mg, ASA 250 mg, and caffeine 65 mg) and 2 dummy IB tablets, 2 unbranded IB tablets (200 mg IB), and 2 dummy AAC tablets or 4 dummy tablets to treat the pain and associated symptoms of a single acute migraine attack. If the headache symptom profile met the criteria for migraine and was of at least moderate intensity, patients were instructed to take study medication. They were asked not to take rescue medication for at least 2 hours, if possible. All treatment information remained blinded until all queries were resolved and the database was locked. The authors affirm that an institutional review board at each investigative site reviewed and approved the study protocol and the conduct of the research. Efficacy Measurements.The prospectively defined primary efficacy endpoint was the weighted sum of pain relief (PAR) scores at 2 hours postdose (TOTPAR2). Other endpoints included TOTPAR at 4 hours (TOTPAR4), time to meaningful PAR, pain intensity difference from baseline (PID), 4-hour weighted sum of pain intensity differences from baseline (SPID4), proportion of patients with pain reduced to mild or none (headache response, HR), and proportion of patients with pain reduced to none (pain-free, PF). At baseline, patients rated pain intensity, functional disability, nausea, vomiting, photophobia, and phonophobia in the study diary. They also rated these symptoms along with PAR at 15, 30, 45, 60, 90, 120, 180, and 240 minutes postdose. The time to meaning-

March 2006 ful PAR (defined as that point in time after the subject ingested the study medication when relief of headache pain was considered meaningful by the subject) was assessed with a stopwatch. Patients rated PAR on a 5-point scale (0 = no relief; 1 = a little relief; 2 = some relief; 3 = a lot of relief; and 4 = complete relief). They rated pain intensity by means of a 4-point scale (0 = no pain; 1 = mild pain; 2 = moderate pain; and 3 = severe pain). They rated functional disability from 0 to 4 (0 = none; 1 = usual activities require a little additional effort; 2 = require some additional effort; 3 = require a great deal of additional effort; and 4 = unable to perform usual activities). The associated symptoms of nausea, vomiting, photophobia, and phonophobia were recorded as absent (0) or present (1) for each symptom. Safety Assessments.Patients recorded adverse experiences (AEs) in the diary, and investigators completed the AE evaluation during the follow-up phase. The AE type, intensity, duration, seriousness, relation to the study drug, and outcome were recorded. Clinical laboratory data were not routinely collected. Sample Size Calculation.Sample size calculations were based on the efficacy parameter TOTPAR4. The selected sample size of 665 patients per active treatment group provided at least 90% power to detect 0.7 units difference in TOTPAR4 (using a standard deviation estimate of 3.87 units) between the 2 treatment groups (2-sided, = 0.05). Statistical Analysis.Treatment group comparability was assessed using analysis of covariance (ANCOVA) for quantitative variables (eg, age) and chi-square tests for categorical variables (eg, sex). The treatment groups were compared with respect to demographics and baseline characteristics. Data missing for any scheduled postdose time point evaluation in otherwise evaluable patients (eg, patient fell asleep) were interpolated. For example, if the 30-minute observation was missing, it was replaced by the average of the 15-minute and the 45-minute observation value. For patients requiring rescue medication, postrescue medication intensity scores for pain intensity, functional ability, and nausea were assigned either the baseline or the last recorded value, whichever was higher. Postrescue medication PAR scores were assigned no relief.

Headache The primary efficacy analysis data set was the intent-to-treat subject patient population. Time to meaningful PAR was analyzed using Wilcoxon rank sums and nonparametric survival techniques, stratified by investigator. The analyses of PID, SPID, PAR, and TOTPAR were made at each time point using ANCOVA of treatment group and investigator as main factors and baseline pain intensity as the covariate. The CochranMantelHaenszel test, stratified by investigator and baseline pain intensity, was used to compare treatment groups with respect to cumulative proportions of patients who achieved meaningful PAR, PF, HR, and those who remedicated by each scheduled time point. The CochranMantel

447 Haenszel test, stratified by investigator, was used to analyze baseline characteristics of the treated headache, as well as the proportion of patients with nausea, photophobia, and phonophobia. Statistical significance was declared when P was less than or equal to .05.

RESULTS Patient Population.Of the 1714 randomized patients, 91.0% (1559) took study medication Figure 1. Of the 1559 patients who took study medication, 4 patients completed only the baseline assessment in the diary, leaving 99.7% (1555) of the patients in the primary efficacy analysis data set.

Eligible patients (N=1714)

Randomized to AAC (N=737)

Randomized to IB (N=734)

Randomized to placebo (N=243)

Took AAC (N=669) Lost to follow up=36 No HA=32

Took IB (N=669) Lost to follow up=38 No HA=27

Took placebo (N=221) Lost to follow up=15 No HA=7

Intent-to-treat (N=669) Excluded: 0

Intent-to-treat (N=666) Excluded: 3 --No postbaseline=3

Intent-to-treat (N=220) Excluded: 1 --No postbaseline=1

Efficacy-evaluable (N=656) Excluded: 13 HA not migraine=12 Other=1

Efficacy-evaluable (N=653) Excluded: 13 HA not migraine=9 Interfering med =1 Other=3

Efficacy-evaluable (N=215) Excluded: 5 HA not migraine=4 Rescue <1 hour=1

Fig 1.Summary of patient disposition.

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Table 1.Demographics and Migraine History of Intent-to-Treat Patients

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Table 2.Characteristics of Treated Attack

AAC IB Placebo Total (N = 669) (N = 666) (N = 220) (N = 1555) Mean age (year) 38.3 38.4 Sex (%) Male 21.2 18.5 Female 78.8 81.5 Race (%) White 74.3 76.6 Black 20.2 18.0 Asian 0.6 0.9 Hispanic 3.9 4.2 Other 1.0 0.3 Migraine type (%) Without aura 78.6 78.8 With aura 21.4 21.2 Usual pain without treatment (%) None 0 0 Mild 0 0.2 Moderate 20.0 17.7 Severe 80.0 82.1 Usual disability without treatment (%) None 0.1 0.3 Mild 1.3 1.5 Moderate 23.5 22.2 Severe 41.4 43.2 Incapacitating 33.6 32.7 Usual pharmacologic treatment (%) None 0.3 0.6 Nonprescription 57.0 55.1 only Prescription only 20.6 21.2 Both 22.1 23.1 38.3 18.6 81.4 73.6 20.0 2.7 3.6 0 82.7 17.3 0 0 20.0 80.0 0 0.9 25.5 40.0 33.6 0.5 56.4 23.2 20.0 38.3 19.7 80.3 75.2 19.2 1.0 4.0 0.6 79.3 20.7 0 0.1 19.0 80.9 0.2 1.4 23.2 42.0 33.2 0.5 56.1 21.2 22.3

AAC IB Placebo Total (N = 669) (N = 666) (N = 220) (N = 1555) Baseline pain (%) Moderate 57.2 56.3 Severe 42.8 43.7 Functional disability (%) None 0.7 0.9 Mild 8.4 6.6 Moderate 38.0 40.2 Severe 38.6 38.4 Incapacitating 14.3 13.8 Nausea (%) No 45.7 45.2 Yes 54.3 54.8 Vomiting (%) No 99.0 97.7 Yes 1.0 2.3 Photophobia (%) No 8.2 5.6 Yes 91.8 94.4 Phonophobia (%) No 10.2 9.9 Yes 89.8 90.1 Aura (%) No 80.9 81.2 Yes 19.1 18.8 Unilateral (%) No 32.3 34.4 Yes 67.7 65.6 Pulsating/throbbing (%) No 10.5 10.7 Yes 89.5 89.3 Aggravated by physical activity (%) No 13.5 13.1 Yes 86.5 86.8 Menstruating (%, females only) No 84.1 83.4 Yes 15.4 16.4 N/A 0.6 0.2

62.3 37.7 0 10.0 35.9 42.3 11.8 48.2 51.8 99.1 0. 9 7.3 92.7 10.0 90.0 83.6 16.4 35.5 64.5 8.2 91.8 12.3 87.7 81.6 18.4 0

57.6 42.4 0.7 7.8 38.6 39.0 13.8 45.9 54.1 98.5 1.5 6.9 93.1 10.0 90.0 81.4 18.6 33.6 66.4 10.2 89.8 13.1 86.8 83.4 16.3 0.3

The 3 treatment groups had similar demographic profiles and migraine histories (Table 1). The mean age was 38.3 years, 80.3% were female, and 75.2% were white. Untreated, usual migraine pain was mild in 0.1%, moderate in 19.0%, and severe in 80.9%. Usual disability untreated was mild in 1.4%, moderate in 23.2%, severe in 42.0%, incapacitating in 33.2%, and none in 0.2%. Migraine was usually treated with exclusively OTC medications in 56.1% of patients, with prescription medications only in 21.2%, with a combination of OTC and prescription medications in 22.3%, and with no medication in 0.5%. Symptom profiles for the treated headaches in the active and placebo groups were comparable at baseline (Table 2).

No statistically significant treatment-by-investigator interactions were detected for the primary efficacy variable. Pain Relief.AAC and IB achieved significantly greater TOTPAR scores than placebo at 2 (2.7, 2.4, and 2.0, respectively), 3 (5.1, 4.7, and 3.9, respectively), and 4 (7.8, 7.1, and 5.9, respectively) hours postdose (P < .006). Only AAC was significantly better than placebo for TOTPAR at all time points beginning as early as 1 hour postdose (P < .011). In addition, the mean TOTPAR values for AAC were significantly superior to IB at 2 hours (P < .03), 3 hours (P < .01), and 4 hours

Headache

449

*
2.5

Mean Pain Relief Score

* * *
AAC vs. IB AAC vs. IB p<0.05 p<0.10

2 1.5 1 0.5 0 0 15 30 45 60

90

120

180

240

M inutes Post Dose AAC Ibuprofen Placebo

Fig 2.Pain relief.

(P < .007) after patients took study medication (see PAR profile, Figure 2). The onset of meaningful PAR was significantly earlier for both AAC-treated and IB-treated patients than patients who took placebo (placebo 167.1 minutes vs. AAC 128.4 minutes, P < .001, and placebo 167.1 minutes vs. IB 147.9 minutes, P = .049). Furthermore, as shown in Figure 3, the median time to meaningful PAR for the AAC treatment group was significantly earlier (approximately 20 minutes) than for the IB treatment group (P = .036). AAC was significantly superior to placebo beginning at 45 minutes postdose (P < .018), and it remained significantly more effective than placebo at all subsequent time points (P < .002). IB provided significantly higher mean PAR scores than placebo beginning at 90 minutes after dosing (P < .003), and it remained significantly superior to placebo throughout the remainder of the study period (P < .005). AAC-treated patients had significantly higher mean PAR scores than IB-treated patients at 45 minutes postdose (P < .022), as well as at 2, 3, and 4 hours postdose (P < .022, .004, and .011, respectively). Pain Intensity Difference From Baseline.AAC and IB achieved significantly greater SPID scores than placebo over 1 (0.4, 0.3, and 0.2, respectively), 2 (1.5,

1.4, and 1.1, respectively), 3 (3.0, 2.7, and 2.2, respectively), and 4 (4.6, 4.2, and 3.3, respectively) hours postdose (P < .041). However, the mean SPID values for AAC were also significantly superior to IB at 2 hours (P < .045), 3 hours (P < .018), and 4 hours (P < .012) after patients took study medication (see PID profile, Figure 4). AAC-treated patients had significantly higher mean PID scores than placebo-treated patients beginning at 45 minutes postdose (P < .002); they remained significantly higher than placebo at all subsequent time points (P < .001). IB provided significantly higher mean PID scores than placebo beginning at 60 minutes after dosing (P < .035), and it remained significantly superior to placebo throughout the remainder of the study period (P < .007). However, AAC-treated patients had significantly higher mean PID scores than IB-treated patients at 45 minutes postdose (P < .049), as well as at 2, 3, and 4 hours postdose (P < .046, .010, and .013, respectively). Effects on Other Headache Characteristics. Figure 5 shows that the proportion of patients who became PF was significantly higher for both AAC and IB than for placebo at 3 and 4 hours postdose (P < .04). However, the PF rates for AAC exceeded those for IB at 3 and 4 hours postdose (P < .035). AAC

450

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80 70

Proportion of Subjects

60 50 40 30 20 10 0 0 15 30 45 60 90 120 180 240 Minutes Post Dose AAC Ibuprofen Placebo

AAC IB Placebo

Median Time (Minutes) 128.4 147.9 167.1

95% C.I. For Median Time (120, 142) (135, 163) (146, 221)

AAC vs IB 0.036

AAC vs Placebo 0.001

IB vs Placebo 0.049

Fig 3.Onset of meaningful pain relief.

also had a significantly higher PF rate than placebo at 2 hours postdose (P < .036). The proportion of patients whose pain intensity was reduced to mild or none (HR) was significantly higher for both AAC and IB than for placebo at 3 and 4 hours postdose (P < .04). Unlike IB, however, AAC HR rates were also significantly greater than placebo

at 45, 90, and 120 minutes postdose (P < .035). Additionally, the HR rate for AAC was significantly higher than IB at 2 hours postdose (AAC 67% vs. IB 62%, P < .046). The proportion of patients who were free of the migraine-associated symptoms (functional disability, nausea, photophobia, and phonophobia) were

1.8 1.6 1.4

* * * *
AAC vs. IB AAC vs. IB

Mean PID

1.2 1 0.8 0.6 0.4 0.2 0 0 15 30 45 60

p<0.05 p<0.10

90

120

180

240

Minutes Post Dose AAC

Fig 4.Pain intensity difference.

Ibuprofen

Placebo

Headache

451

60

Cumulative Proportion of Subjects

50 40 30 20
*

AAC vs. IB

p<0.05

10 0 0 15 30 45 60 90 120 180 240 Minutes Post Dose AAC Ibuprofen Placebo

Fig 5.Pain free.

generally comparable for AAC and IB, and significantly higher for both AAC and IB than for placebo at most of the time points postdose.

Table 3.Summary of Adverse Experiences by Body System

Adverse Experience

AAC% (N = 669)

IB% (N = 669)

Placebo% (N = 221)

Body as a Whole Abdominal pain Headache Fever Viral infection Cardiovascular Palpitation Tachycardia Digestive System Dyspepsia Nausea Vomiting Nervous System Confusion Dizziness Dry mouth Insomnia Nervousness Paresthesia Somnolence Respiratory System Special Senses Urogenital System

1.3 0.6 0.3 0 0 0.3 0 0.3 3.4 0.7 1.8 0.4 5.7 0.1 1.6 0.9 0.3 1.9 0.1 0.3 0.1 0.7 0.1

1.2 0 0.2 0 0.5 0 0 0 0.9 0.3 0.5 0.2 2.2 0 0.6 0.3 0 0.3 0 0.8 0.5 0.5 0.2

0.5 0 0 0.5 0 0.9 0.9 0 1.8 0.5 0.9 0.5 3.6 0.5 1.8 0 0 0.5 0.5 0.5 0 0 0

Rescue Medication.At 2 hours after treatment, the proportion of patients who required rescue medication was significantly higher in the IB (P = .025) and placebo (P < .001) treatment groups than for the AAC treatment group. While AAC maintained significant superiority versus placebo at 3 (P = .035) and 4 (P < .001) hours postdose, it did not sustain statistical significance at 3 or 4 hours postdose compared with IB. Safety Results.No serious AEs were reported, and the incidence of adverse events was low: 9.7% in the AAC group, 5.1% in the IB group, and 5.5% in the placebo group (Table 3). AAC-treated patients reported nervousness (1.9% vs. 0.3%) and nausea (1.6% vs. 0.4%) more frequently than IB-treated patients, but the IB treatment group reported somnolence more frequently than AAC treatment group (0.7% vs. 0.3%). Patients who received placebo had a higher incidence of dizziness (1.8%) than the AAC (1.6%) and the IB treatment groups (0.6%).

COMMENTS This multicenter, double-blind, randomized, parallel-group, placebo-controlled study shows that, while both AAC and IB were more effective than placebo in treating the full spectrum of migraine, AAC was superior to IB. The superiority was exhibited by

452 statistically significant and clinically greater effects in PAR, pain intensity reduction, earlier onset of meaningful PAR, as well as in PF and HR rates, which are among the efficacy variables that are most important to patients.19-21 In addition, significantly more IB patients than AAC patients required rescue medication, and significantly more AAC-treated patients reported complete PAR. In this study program, we used several recruitment methods, including random-digit dialing, local advertising, and clinical referrals to identify a broad range of the migraine population, including individuals who did and did not seek medical care. Unlike earlier migraine research with OTC medications,11-17 this trial did not exclude patients with the most severe migraine symptoms (eg, those whose attacks usually cause them to vomit or require bed rest). By demonstrating a therapeutic response in an unrestricted migraine population, both IB and AAC have shown that there is an appropriate role for OTC medications in the majority of patients with migraine. The epidemiologic profile and patterns of medication in this study are similar to results in population studies, suggesting that study patients in the United States are broadly representative of those with migraine.2,3 A limitation of this trial is the lack of collected data on headache recurrence or 24-hour PF rates. In addition, there was a high placebo response rate in this trial. Although placebo response in headache research is traditionally high, ranging from 30% to 40%,22 methodological issues may have further elevated levels in this study. For instance, several investigators have shown that high randomization ratios (ie, a high likelihood of getting active drug rather than placebo) can raise placebo response rates,23 as patients are more likely to believe they are receiving active medication. Future work may clarify issues with placebo in studies of headache patients. The per protocol primary efficacy variable was TOTPAR2. The choice of primary endpoints in acute migraine treatment trials is controversial; the value of the most widely used endpoint, 2-hour HR, has been widely and legitimately questioned.19,21,24 Although HR at 2 hours postdose remains a frequently used outcome measure, PAR and TOTPAR are the widely used endpoints in analgesic trials.24 Our study indi-

March 2006 cates that TOTPAR, which detected differences between the active treatment groups that HR failed to identify, may represent a valid and sensitive endpoint for detecting differences in pain response, particularly when 2 active drugs are compared in future migraine trials. These findings have important implications for medical professionals and their patients. For the first time, rigorous data show that OTC medications are safe and effective in an unrestricted migraine patient population, and that there are significant differences between the 2 approved OTC migraine therapies. Although additional comparative trials of OTC agents for migraine are recommended, these results show that both AAC and IB are safe, cost-effective treatments for a representative sample of people with migraine and that AAC provides significantly superior efficacy and speed of action compared with IB tablets. This study verifies the evidence-based evaluations of the U.S. Headache Consortium and the German Migraine and Headache Society, who in their most recent evidence-based therapeutic recommendations for the treatment of migraine and TTH considered the combination of ASA, APAP, and caffeine a reasonable firstline treatment for mild-to-moderate migraine attacks 25,26 and TTH.

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