Migraine is a common and disabling illness, affecting

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1 original Research Sumatriptan/Naproxen Sodium as Early Intervention for Migraine: Effects on Functional Ability, Productivity, and Satisfaction in 2 Randomized Controlled Trials Frederick R. Taylor, MD, Jessica O. Heiring, MD, Edmund Messina, MD, Jill Braverman-Panza, MD, Michael H. Ames, PhD, Susan C. Byrd, RPh, Susan A. McDonald, MA, and Steven P. Burch, PhD Abstract Objective: To examine the effects of early intervention with sumatriptan/naproxen sodium for migraine on functional ability, productivity, and patient satisfaction. Design: 2 randomized, double-blind, parallel-group studies. Participants and setting: Migraineurs aged 18 to 65 years at 16 U.S. neurology and headache clinics treated with sumatriptan 85 mg formulated with RT technology/naproxen sodium 5 mg or placebo within 1 hour of pain onset. Measurements: Functional ability on a 5-point scale through 4 hours postdose, migraine-associated disability time through 24 hours postdose, and satisfaction on the Revised Patient Perception of Migraine Questionnaire (PPMQ-R). Results: Two and 4 hours postdose, approximately twice as many patients reported normal functional ability with sumatriptan/naproxen than placebo in each study (P <.1). Total disability time was 47% to 48% lower with sumatriptan/naproxen than placebo (2.7 versus 5.1 hours study 1; 2.7 versus 5.2 hours study 2; P <.1). Mean lost workplace productivity and lost nonworkplace activity time were lower with sumatriptan/naproxen than placebo (lost workplace productivity: 1.8 versus 3.1 hours study 1 [P <.1]; 1.7 versus 2.5 hours study 2 [P <.5]; lost nonworkplace activity time: 2.2 versus 4.1 hours study 1; 2.2 versus 4.3 hours study 2 [P <.1]). Mean satisfaction scores were significantly higher with sumatriptan/naproxen versus placebo for the efficacy, functionality, and ease of use subscales and the total score in both studies. Conclusion: Sumatriptan/naproxen confers rapid, restoration of functional ability and productivity in migraine and receives high patient satisfaction ratings. Migraine is a common and disabling illness, affecting about 18% of U.S. women and 6% of men [1,2]. Migraines have long been recognized as a major cause of work absenteeism and decreased work productivity [3 7], with the cost of productivity losses estimated between $5.6 to $17 billion per year [7,8]. Headache disability also impacts the sufferer s personal life and has been shown to reduce health-related quality of life [9]. Triptans are the mainstay of therapy for acute treatment of migraine, and their effectiveness has been well-established in controlled clinical trials. Sumatriptan has been shown to be effective in relieving headache and associated migrainous symptoms in long-term studies [1 12]. The positive effects of sumatriptan on health-related quality of life and productivity have also been established [13 15]. Naproxen has been available to consumers by prescription since 1976 and naproxen sodium has been available as an over-the-counter analgesic since Naproxen-containing products are indicated for multiple conditions, including arthritis and pain, but not migraine. To date, there have been no published large studies (> adults) that have evaluated the effects of naproxen after long-term episodic use in any condition. Despite this, migraine treatment guidelines recommend use of nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line therapy [16]. A sumatriptan/naproxen sodium tablet containing sumatriptan 85 mg formulated with RT technology and naproxen sodium 5 mg ( sumatriptan/naproxen henceforth) is being evaluated for the acute treatment of migraine. From the Park Nicolett Headache Clinic & Research Center and University of Minnesota School of Medicine, Minneapolis, MN (Dr. Taylor); the Minneapolis Clinic of Neurology, Minneapolis, MN (Dr. Heiring); Michigan Headache Treatment Network, Lansing, MI (Dr. Messina); Braverman-Panza Medical Group, Albany, NY (Dr. Braverman-Panza); and GlaxoSmithKline, Research Triangle Park, NC (Drs. Ames and Burch, Mss. Bird and McDonald). Vol. 14, No. 4 April 7 JCOM 195

2 sumatriptan/naproxen for migraine A proof-of-concept study demonstrated that sumatriptan 5 mg (encapsulated, no RT technology) and naproxen sodium 5 mg provided significantly higher response rates compared with sumatriptan 5 mg (encapsulated, no RT technology) alone [17]. An open-label study of the safety of sumatriptan/naproxen used as an acute treatment of moderate to severe migraines over a 12-month period showed that sumatriptan/naproxen was well tolerated and that there were no significant increases over time in the incidence of adverse events [18]. When using triptans as monotherapy, pain relief is enhanced by early treatment, that is, administration early during the course of a migraine attack while pain is mild and within 1 hour of onset [19 25]. The better pain-free response with early intervention compared with delayed treatment is linked to greater improvement in functional ability and reduction in migraine-associated productivity loss [26]. As with triptan monotherapy, the therapeutic benefits of sumatriptan/naproxen might be expected to be optimized through early intervention. We conducted 2 randomized, double-blind, placebo-controlled studies of early intervention with sumatriptan/naproxen that evaluated clinical efficacy and safety as well as secondary health outcome measures [27]. In this article, we report on the effects of the intervention on functional ability, productivity, and patient satisfation. Methods Patients Study participants were recruited from 16 U.S. neurology and headache clinics either fully invested in research or clinical care or both. Subjects were recruited using office posters and flyers, as well as newspaper and radio ads. Men and women were eligible for the studies if they were aged 18 to 65 years, had at least a 6-month history of migraine with or without aura as defined by 4 International Headache Society criteria [28], had an average of 2 to 6 migraine attacks monthly during the 3 months preceding the screening visit, typically experienced moderate to severe migraine pain preceded by an identifiable mild-pain phase, and could distinguish mild migraine pain from other types of headache. Women had to be physiologically incapable of becoming pregnant or, if they could become pregnant, agree to practice adequate contraception during the studies. Patients were excluded if they had headache 15 or more days per month during any of the 3 months before screening; uncontrolled hypertension (diastolic blood pressure 95 mm Hg or systolic blood pressure 16 mm Hg); confirmed or suspected cardiovascular or cerebrovascular disease; a history of cardiac arrhythmias requiring medication or clinically significant electrocardiogram abnormalities that in the investigator s opinion contraindicated study participation; a history of gastrointestinal ulceration in the past 6 months or gastrointestinal bleeding during the past year; a history of inflammatory bowel disease or of any bleeding disorder; or basilar or hemiplegic migraine. Other exclusion criteria included current use or use within 3 months before screening of migraine prophylactic medication containing ergotamine, an ergot derivative, or methysergide; use of a monoamine oxidase inhibitor within 2 weeks or preparations containing St. John s wort within 4 weeks before screening; and current use of an anticoagulant or antiplatelet agent (except low-dose aspirin 325 mg/day for cardioprotection). Patients were eligible for the studies regardless of whether they were triptan-naive. All patients provided written informed consent prior to study participation. Procedure Patients meeting eligibility criteria were randomized 1:1 to receive sumatriptan/naproxen or placebo for the outpatient treatment of a single migraine attack occurring within 8 weeks of the screening visit. Patients were instructed to treat a migraine attack within 1 hour of onset of mild pain and to treat only while pain was mild. Patients were asked to return to the clinic within 1 week of treating a migraine attack with study medication. Second doses of study medication were not provided. However, patients could take another acute migraine medication (excluding an ergotcontaining medication, an NSAID, or a triptan) beginning 2 hours postdose for persistent or recurrent pain. Prohibited medications were ergotamine-containing products, triptans, and NSAID-containing products within 24 hours before or after treatment with study medication; morphine-, codeine-, or opioid derivative containing analgesics, other headache medications, or antiemetics between 24 hours before and 2 hours after treatment with study medication; other analgesics between 6 hours before and 2 hours after treatment with study medication; and monoamine oxidase inhibitors throughout the study. Measures Clinical efficacy and safety data from the studies are reported elsewhere [27]. Health outcome measures included functional ability, productivity, and satisfaction with treatment. For the assessment of functional ability, patients recorded on diary cards their ability to perform normal daily activities immediately before dosing and 2 and 4 hours postdose on a 5-point scale (normal, mildly impaired, moderately impaired, severely impaired, required bed rest). For the productivity and satisfaction assessments, patients completed questionnaires 24 hours after dosing with study drug. The productivity questionnaire contained items on number of hours missed from work and activities other than paid work because of the migraine attack, number of hours worked with symptoms and continued activities other than 196 JCOM April 7 Vol. 14, No. 4

3 original Research paid work with symptoms, and effectiveness while continuing work activities and activities other than paid work with symptoms during the 24 hours after taking study medication [15,29,3]. The satisfaction questionnaire the Revised Patient Perception of Migraine Questionnaire (PPMQ-R) contained items that contribute to 4 subscales: tolerability (1 items), efficacy (11 items), functionality (4 items), and ease of use (2 items). The items contributing to the efficacy, functionality, and ease of use subscales were scored on a scale ranging from 1 (very dissatisfied) to 7 (very satisfied). The items contributing to the tolerability subscale were scored on a scale ranging from 1 (extremely bothersome) to 5 (not at all bothersome). The minimal clinically important difference (MCID) for the efficacy, functionality, and ease of use subscales as well as the total score is 5 points. The MCID has not been identified for the tolerability subscale. In addition to the items contributing to the efficacy, functionality, ease of use, and tolerability subscales, the PPMQ-R contains 3 global satisfaction items 1 each on overall satisfaction, satisfaction with medication effectiveness, and satisfaction with side effects. The global satisfaction items were scored on a scale ranging from 1 (very dissatisfied) to 7 (very satisfied). Two PPMQ-R items on cost were not included in the study questionnaire because patients did not pay for migraine medication in these studies. The PPMQ-R has demonstrated reliability and validity in measuring patient satisfaction with acute migraine treatment [31,32]. Analysis Data were analyzed for the intent-to-treat population, defined as randomized patients who treated a migraine attack with study medication and returned at least 1 postbaseline efficacy assessment. Patients who withdrew from the studies before treating a migraine attack were not replaced. Demographics and characteristics of the migraine attack treated during the studies were summarized by treatment group. For assessment of functional ability, the percentages of patients with normal functional ability 2 and 4 hours postdose were summarized by treatment group. Treatment groups were compared with the Cochran-Mantel-Haenszel test. For the productivity questionnaire, responses were summarized to yield a measure of total disability time: Total disability time = lost workplace productivity + lost activity time where: Lost workplace productivity = time missed from work due to symptoms + (time worked with symptoms [1% % effectiveness while experiencing migraine symptoms/1%]) and Lost activity time = time missed from nonworkplace activities + (time nonworkplace activities were carried on with symptoms [1% % effectiveness while experiencing migraine symptoms/1%]) Total disability time, lost workplace productivity, and lost activity time were compared between treatment groups with Wilcoxon rank sum tests. This method of measuring disability time has been employed successfully in other migraine studies [15,29,3]. For the PPMQ-R, scores for each of the 4 subscales (efficacy, functionality, ease of use, and tolerability) were calculated from item scores. Each subscale score ranges from to 1, with higher scores indicating greater satisfaction or tolerability. A total score, a composite of the subscale scores for efficacy, functionality, and ease of use, was also computed. Treatment groups were compared with analysis of variance for efficacy, functionality, and total scores. Because of the highly skewed distributions of scores on the ease of use and tolerability subscales, the Wilcoxon rank sum test was used to compare treatment groups for these measures. The subscales were tested according to a prespecified hierarchy to control for multiplicity. Previous research suggests that a 5-point difference in the efficacy, functionality, and ease of use subscale scores and the total score is clinically meaningful [31,32]. Global satisfaction items (effectiveness, side effects, and overall) were summarized as percentage of patients satisfied/very satisfied, and treatment groups were compared with the Cochran-Mantel-Haenszel test. The studies were approved by ethics committees or institutional review boards for each of the 16 investigational sites. Results Patients The numbers of patients randomized were 658 in study 1 (329 active intervention, 329 placebo) and 647 in study 2 (335 sumatriptan/naproxen, 312 placebo). Patients who took study medication and had at least 1 postbaseline efficacy evaluation comprised the intent-to-treat population: 576 patients from study 1 (28 sumatriptan/naproxen, 296 placebo) and 535 patients from study 2 (276 sumatriptan/naproxen, 259 placebo). Among randomized patients, the primary reason for not being included in the intent-to-treat population was not having the opportunity to treat a qualifying migraine episode before the studies ended (32 in study 1 and 44 in study 2). Demographics, baseline clinical characteristics, and characteristics of the intent-to-treat population were similar between studies and between treatment groups Vol. 14, No. 4 April 7 JCOM 197

4 sumatriptan/naproxen for migraine Table. Baseline Characteristics of Patients and the Treated Migraine Sumatriptan/ Naproxen Sumatriptan/ Naproxen Study 1 Disposition, demographics, baseline clinical characteristics Randomized, N Intent-to-treat population, n Mean age, yr (SD) 4.8 (11.1) 39.3 (1.6) Female, n (%) 257 (87) 245 (88) Race, n (%) African American/African 36 (12) 27 (1) heritage American Indian or Alaska 7 (2) 4 (1) native Asian 3 (1) 4 (1) White 249 (84) 243 (87) White and African American/ 1 (< 1) African heritage White and Asian 2 (< 1) Mean number of migraine attacks 3.7 (1.5) 3.7 (1.8) per month (SD) Mean onset age of migraine attacks, 23.4 (11.4) 21.9 (1.6) yr (SD) Mean days with headache per month in past year (SD) 7.1 (4.1) 7.4 (3.7) Baseline characteristics of treated migraine Awoke with migraine pain, n/n (%) 67/294 (23) 76/278 (27) Mean time to dosing, hr (SD).6 (.99).5 (.91) Pain severity, n (%) None 1 (< 1) Mild 255 (86) 247 (88) Moderate 37 (13) 27 (1) Severe 2 (< 1) 6 (2) Presence of migraine symptoms, n/n (%) Nausea 78/293 (27) 82/276 (3) Vomiting 2/292 (< 1) 5/275 (2) Phonophobia 212/293 (72) 197/276 (71) Photophobia 189/292 (65) 168/276 (61) Neck pain/discomfort 17/292 (58) 174/275 (63) Sinus pain/pressure 122/291 (42) 119/277 (43) Functional ability, n (%) Normal 34 (12) 35 (13) Mildly impaired 171 (58) 163 (58) Moderately impaired 65 (22) 67 (24) Severely impaired 12 (4) 5 (2) Required bed rest 13 (4) 1 (4) Study 2 Disposition, demographics, baseline clinical characteristics Randomized, N Intent-to-treat population, n Mean age, yr (SD) 41. (1.9) 4.8 (11.2) Female, n (%) 233 (9) 251 (91) Race, n (%) African American/African (8) 22 (8) heritage American Indian or Alaska 7 (3) 5 (2) native Asian 3 (1) 3 (1) White 225 (87) 24 (87) White and African American/ () 1 (< 1) African heritage Native Hawaiian/Pacific 1 (< 1) 2 (< 1) Islander Mean number of migraine attacks 3.9 (1.6) 3.8 (1.7) per month (SD) Mean onset age of migraine attacks, 22.7 (1.5) 21.6 (1.4) yr (SD) Mean days with headache per month in past year (SD) 7.4 (3.6) 7.3 (3.4) Baseline characteristics of treated migraine Awoke with migraine pain, n/n (%) 71/257 (28) 8/272 (29) Mean time to dosing, hr (SD).8 (4.6).5 (.6) Pain severity, n (%) None () () Mild 226 (87) 239 (87) Moderate 26 (1) 29 (11) Severe 7 (3) 6 (2) Presence of migraine symptoms, n/n (%) Nausea 83/255 (33) 95/276 (34) Vomiting 5/255 (2) 5/275 (2) Phonophobia 179/256 (7) 197/274 (72) Photophobia 156/257 (61) 174/276 (63) Neck pain, discomfort 16/256 (63) 173/275 (63) Sinus pain/pressure 117/256 (46) 144/276 (52) Functional ability, n (%) Normal 35 (14) 24 (9) Mildly impaired 144 (56) 154 (56) Moderately impaired 62 (24) 71 (26) Severely impaired 11 (4) 11 (4) Required bed rest 7 (3) 15 (5) 198 JCOM April 7 Vol. 14, No. 4

5 original Research Percent of patients Percent of patients Study Study 2 in each study (Table). The typical patient was female, aged 4 years, and white. Functional Ability At the time of dosing with study medication, the percentages of patients with normal functional ability were low and were similar between the sumatriptan/naproxen group and the placebo group in each study (study 1: 13% sumatriptan/ naproxen, 12% placebo; study 2: 9% sumatriptan/naproxen, 14% placebo). Two hours and 4 hours postdose, approximately twice as many patients in the sumatriptan/naproxen group compared with the placebo group reported normal functional ability in each study (P <.1 sumatriptan/naproxen versus placebo 2 and 4 hours postdose in each study) (Figure 1). Productivity Predose 14 Predose Sumatriptan/naproxen sodium Hours Sumatriptan/naproxen sodium 9 2 Hours 4 Hours 4 Hours Total disability time because of migraine was 47% lower with sumatriptan/naproxen than placebo in study 1 (2.7 versus 5.1 hours; P <.1) and 48% lower with sumatriptan/ naproxen than placebo in study 2 (2.7 versus 5.2 hours; 23 47* 49* * 71* Figure 1. Percentage of patients reporting normal functional ability at dosing and 2 and 4 hours after early intervention with sumatriptan/naproxen sodium or placebo for a migraine attack. Mean no. of hours Mean no. of hours Study P <.1) (Figure 2). Mean lost workplace productivity was 42% lower with sumatriptan/naproxen than placebo in study 1 (1.8 versus 3.1 hours; P <.1) and 32% lower with sumatriptan/naproxen than placebo in study 2 (1.7 versus 2.5 hours; P <.5) (Figure 2). Mean lost nonworkplace activity time was 46% lower with sumatriptan/naproxen than placebo in study 1 (2.2 versus 4.1 hours; P <.1) and 49% lower with sumatriptan/naproxen sodium than placebo in study 2 (2.2 versus 4.3 hours; P <.1) (Figure 2). PPMQ-R Results 2.7* Total disability time Sumatriptan/naproxen sodium Lost workplace productivity Lost activity time 6.5 Sumatriptan/naproxen sodium P =.22 versus placebo * Study 2 Total disability time Lost workplace productivity Lost activity time Mean PPMQ-R scores in study 1 and study 2 were significantly higher with sumatriptan/naproxen as compared * * 2.2* Figure 2. Total disability time, lost workplace productivity, and lost activity time 24 hours after early intervention with sumatriptan/naproxen sodium or placebo for a migraine attack. Lost time = hours missed + ([{1 % effectiveness}/1] hours continued working/activity with symptoms). Vol. 14, No. 4 April 7 JCOM 199

6 sumatriptan/naproxen for migraine Mean score Sumatriptan/naproxen sodium 86.3* * 63.1* * * Efficacy Functionality Ease of use Study 1 1 Sumatriptan/naproxen sodium 87.9* 8 78 Mean score 65.* 63.3* Total 72.1* Tolerability * Figure 3. PPMQ-R results for the 4 subscales and the total score: mean satisfaction scores for sumatriptan/naproxen sodium and placebo 24 hours after their use as early intervention for a single migraine attack. Total score is the composite of the efficacy, functionality, and ease of use subscales. Efficacy Functionality Ease of use Total Tolerability Study 2 with placebo for the efficacy, functionality, and ease of use subscales as well as the total score based on the composite of these 3 subscales (P <.1) (Figure 3). For the total score and each of these 3 subscales, differences between sumatriptan/ naproxen and placebo exceeded the 5-point threshold for a clinically meaningful difference, favoring sumatriptan/ naproxen in both studies. Both sumatriptan/naproxen and placebo were rated as being highly tolerable in both studies. Mean satisfaction scores on the tolerability subscale statistically differed between sumatriptan/naproxen and placebo in both studies (P <.1) (Figure 3), a finding reflecting slightly poorer tolerability with sumatriptan/naproxen than placebo. The percentages of patients satisfied/very satisfied with study treatment were significantly higher with sumatriptan/ naproxen than placebo in study 1 and study 2 for the global satisfaction items of effectiveness and overall satisfaction (P <.1) (Figure 4). For the global side effects item, the percentages of patients satisfied/very satisfied did not differ statistically between sumatriptan/naproxen and placebo in study 1 but significantly favored sumatriptan/naproxen over placebo in study 2 (P =.8) (Figure 4). Discussion In these randomized, double-blind clinical trials, early intervention with sumatriptan/naproxen for a migraine attack enhanced functional ability, reduced productivity loss, and significantly improved satisfaction compared with placebo. By 2 hours postdose, approximately half of sumatriptan/ naproxen patients reported that they were functioning JCOM April 7 Vol. 14, No. 4

7 original Research normally. This number increased to approximately 7 in 1 patients by 4 hours postdose. This early improvement was maintained through the 24-hour postdose period as demonstrated by the finding that total disability time, which reflects time missed from and reduced effectiveness at work and activities outside of paid work during the 24 hours after the initial dose of study medication, was approximately 5% lower with sumatriptan/naproxen than placebo. The rapid improvement in functional ability with sumatriptan/naproxen might be attributed to its effectiveness at conferring prompt, sustained relief of migraine pain and associated symptoms. Sumatriptan/naproxen was significantly more effective than placebo at conferring painfree response beginning 3 minutes postdose, the earliest measured time point in these studies (data reported elsewhere) [27]. Sumatriptan/naproxen was also more effective than placebo at relieving associated symptoms of migraine, including nausea, photophobia, phonophobia, neck pain and discomfort, and sinus pain and pressure [27]. Treatment with sumatriptan/naproxen was associated with high patient satisfaction. Mean scores for the tolerability subscale were high for patients in the placebo group and the sumatriptan/naproxen group, a finding that demonstrates that, on average, patients were not bothered by adverse events. However, the mean tolerability scores were significantly better for placebo than sumatriptan/ naproxen. Whether this statistical difference is clinically relevant is unknown as the MCID score for the tolerability subscale has not been determined. The high tolerability subscale score with sumatriptan/naproxen is consistent with the adverse event data from these studies (reported elsewhere): the only adverse events reported in 2% or more of patients were nausea and dizziness (nausea, 3% treatment group versus 1% placebo in study 1 and 4% versus 2% in study 2; dizziness: 1% versus % in study 1 and 2% versus < 1% in study 2) [27]. No serious adverse events were reported [27]. The higher ratings for sumatriptan/naproxen versus placebo on the global satisfaction item for side effects in study 1 and the ease of use subscale might be attributed to patients considering an entire regimen (ie, study medication plus rescue medication) when rating these attributes. -treated patients in these studies were more likely than sumatriptan/naproxen treated patients to use rescue medication, which might have influenced tolerability and ease of use ratings. The discrepancy between the statistical findings with the global satisfaction item on side effects item in study 1 (sumatriptan/naproxen better than placebo) and results on the tolerability subscale (high ratings in both groups; placebo better than sumatriptan/naproxen) might be attributed to the fact that the 2 measures assess slightly different Percent of patients Percent of patients Study 1 4 Effectiveness Sumatriptan/naproxen sodium Side effects 1 Sumatriptan/naproxen sodium 8 P =.8 versus placebo 61* Study * Effectiveness 52 Side effects Overall Overall 55* but overlapping constructs. The tolerability subscale asks patients whether they are bothered by side effects, whereas the global satisfaction item on side effects asks patients to rate their satisfaction with respect to side effects. Scores on the tolerability subscale reflected little bother or high tolerability of sumatriptan/naproxen, a finding consistent with the adverse event data. However, as the experience of any side effects might cause patients to be less than fully satisfied with treatment, patients experiencing side effects with rescue medication in study 1 might have assigned relatively low satisfaction ratings to treatment on the global satisfaction item for side effects. Rapid restoration of the migraineur s functional ability is important not only to the patient but also to society. Most of * Figure 4. PPMQ-R results on the 3 global satisfaction items: percentage of patients rating themselves satisfied or very satisfied with sumatriptan/naproxen sodium or placebo with respect to effectiveness, side effects, and overall satisfaction 24 hours after their use as early intervention for a single migraine attack Vol. 14, No. 4 April 7 JCOM 1

8 sumatriptan/naproxen for migraine the societal cost of migraine comes from missed time (55%) and productivity loss (38%) rather than from direct health care costs such as those of physician visits [7]. The results of these studies demonstrate that sumatriptan/naproxen compared with placebo significantly reduces both lost workplace productivity and lost activity time, the major contributors to the societal cost of migraine. The consistency between studies in the data on productivity and disability time lends credence to the results. The superior efficacy of sumatriptan/naproxen relative to its components might be explained by its multimechanismtargeted action. Migraine attacks are thought to begin with activation and sensitization of peripheral pain fibers, activity of which contributes to the central sensitization that may underlie a full-blown migraine attack [33 37]. Sumatriptan and naproxen sodium target different aspects of the trigeminal vascular processes in migraine such that together they theoretically reduce or prevent both peripheral activation of central pain pathways during the early stages of a migraine attack and the later developing central sensitization [35,36,38 41]. Although 3 oral doses (25 mg, 5 mg, 1 mg) of sumatriptan succinate tablets are available in the United States, sumatriptan 85 mg was chosen for the combination tablet in order to balance the efficacy and safety profile. Sumatriptan peak concentrations and early exposure (area under the curve through 2 hours postdose) are similar following administration of a single fixed-dose tablet of sumatriptan/ naproxen relative to a sumatriptan 1-mg tablet formulated with RT technology [42]. The results of these studies should be interpreted in the context of the limitation that patients self-reports were the source of the data on functional disability and productivity. These data are possibly subject to reporting bias. Patients may be motivated to underestimate or overestimate and/or to underreport or overreport lost work and reduced effectiveness attributed to migraine. The single-attack design is a second study limitation in that it does not allow assessment of maintenance of benefits of sumatriptan/naproxen over time. This limitation is being addressed in ongoing research examining the impact of sumatriptan/naproxen administered over multiple attacks. The results of these studies should also be balanced by the fact that the combination therapy was compared with placebo, and results might have been different had the combination therapy been compared with sumatriptan alone or naproxen alone or if the studies had been conducted in naturalistic or real-world settings. Further, the impact of acute migraine may also be addressed by either preventive treatments or acute nondrug therapies, and these were not evaluated. In conclusion, the results of these randomized, doubleblind, placebo-controlled studies show that sumatriptan/ naproxen confers rapid restoration of functional ability and lower productivity loss in migraine and receives high satisfaction ratings from patients. Sumatriptan/naproxen can help patients return to normal functioning at work and outside of work and ultimately may help to reduce the cost of migraine to society. Acknowledgments: The authors acknowledge Jane Saiers, PhD, for assistance with writing this manuscript. GlaxoSmithKline funded Dr. Saiers work. Corresponding author: Frederick R Taylor, MD, Park Nicollet Health Services, 649 Excelsior Blvd, E-5, Minneapolis, MN 55426, frederick.taylor@parknicollet.com. Funding/support: The studies were sponsored by POZEN, Inc. and supported by GlaxoSmithKline, Inc. 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