Reasons for nonevaluable data were failure to return diary cards, which resulted in an absence of efficacy data for analysis, or taking other migraine medications prior to treating with study medication, which confounded outcomes.
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Brandes JL, Kudrow D, Stark SR, et al. Sumatriptan-Naproxen for Acute Treatment of Migraine: A Randomized Trial. JAMA. 2007;297(13):1443–1454. doi:10.1001/jama.297.13.1443
Author Affiliations: Nashville Neuroscience Group, Nashville, Tenn (Dr Brandes); California Medical Clinic for Headache, Santa Monica (Dr Kudrow); The Innovative Clinical Research Center, Alexandria, Va (Dr Stark); Headache Institute, Newport Beach, Calif (Dr O’Carroll); Headache Wellness Center, Greensboro, NC (Dr Adelman); OrthoNeuro, Columbus, Ohio (Dr O’Donnell); Pozen Inc, Chapel Hill, NC (Dr Alexander and Ms Spruill); and GlaxoSmithKline, Research Triangle Park, NC (Drs Barrett and Lener).
Context Multiple pathogenic mechanisms may be involved in generating the migraine symptom complex, and multimechanism-targeted therapy may confer advantages over monotherapy.
Objective To evaluate the efficacy and safety of a fixed-dose tablet containing sumatriptan succinate and naproxen sodium relative to efficacy and safety of each monotherapy and placebo for the acute treatment of migraine.
Design, Setting, and Participants Two replicate, randomized, double-blind, single-attack, parallel-group studies conducted among 1461 (study 1) and 1495 (study 2) patients at 118 US clinical centers who were diagnosed as having migraine and received study treatment for a moderate or severe migraine attack.
Interventions Patients were randomized in a 1:1:1:1 ratio to receive a single tablet containing sumatriptan, 85 mg, and naproxen sodium, 500 mg; sumatriptan, 85 mg (monotherapy); naproxen sodium, 500 mg (monotherapy); or placebo, to be used after onset of a migraine with moderate to severe pain.
Main Outcome Measures Primary outcome measures included the percentages of patients with headache relief 2 hours after dosing, absence of photophobia, absence of phonophobia, and absence of nausea for the comparison between sumatriptan–naproxen sodium and placebo, and the percentages of patients with sustained pain-free response for the comparison between sumatriptan–naproxen sodium and each monotherapy.
Results Sumatriptan–naproxen sodium was more effective than placebo for headache relief at 2 hours after dosing (study 1, 65% vs 28%; P<.001 and study 2, 57% vs 29%; P<.001), absence of photophobia at 2 hours (58% vs 26%; P<.001 and 50% vs 32%; P<.001), and absence of phonophobia at 2 hours (61% vs 38%; P<.001 and 56% vs 34%; P<.001). The absence of nausea 2 hours after dosing was higher with sumatriptan–naproxen sodium than placebo in study 1 (71% vs 65%; P = .007), but in study 2 rates of absence of nausea did not differ between sumatriptan–naproxen sodium and placebo (65% vs 64%; P = .71). For 2- to 24-hour sustained pain-free response, sumatriptan–naproxen sodium was superior at P<.01 (25% and 23% in studies 1 and 2, respectively) to sumatriptan monotherapy (16% and 14% in studies 1 and 2), naproxen sodium monotherapy (10% and 10% in studies 1 and 2), and placebo (8% and 7% in studies 1 and 2). The incidence of adverse events was similar between sumatriptan–naproxen sodium and sumatriptan monotherapy.
Conclusion Sumatriptan, 85 mg, plus naproxen sodium, 500 mg, as a single tablet for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.
Trial Registration clinicaltrials.gov Identifiers: NCT00434083 (study 1); NCT00433732 (study 2)
Migraine is a prevalent, often debilitating disease manifested by attacks of bilateral or unilateral headache and associated symptoms, such as nausea, vomiting, and sensitivity to light and sound.1-3 The past 15 years have witnessed advances in migraine therapy with the introduction in the United States of several effective agents, including 7 triptans. However, therapeutic shortfalls remain. Some patients do not achieve headache relief by 2 hours after ingesting oral migraine medications, and recurrence of headache within 24 hours of initial dosing is common.4 Many patients treated with migraine-specific therapy are less than fully satisfied with treatment.5,6
The challenges in optimizing efficacy of migraine pharmacotherapy are partly attributed to the complex pathophysiology of migraine. None of the currently available monotherapeutic agents provides broad coverage of the multiple pathogenic processes in migraine, which is thought to involve multiple neural pathways that appear to be sequentially activated and sensitized as a migraine attack develops.3,7 Early in the course of a migraine attack, trigeminal nerve endings, possibly stimulated by cortical spreading depression, release vasoactive and inflammatory substances, including calcitonin gene-related peptide and kinins. Calcitonin gene-related peptide causes meningeal vasodilation, and kinins induce inflammatory prostaglandins.8 The resulting meningeal and vascular inflammation and vasodilation cause peripheral sensitization and stimulate trigeminal nociceptors to activate ascending pain pathways.9
The initial activation of central pathways during the early stages of a migraine attack depends on incoming pain signals from the periphery; without peripheral input, central activation ceases. With prolonged nociceptive stimulation, glia surrounding the trigeminal nucleus caudalis become activated and release neuromodulators, including prostaglandins. The prostaglandins may amplify the pain signal and, with other substances, cause trigeminal nucleus caudalis neurons to fire in a sustained, continuous manner that is characteristic of the central sensitization hypothesized to underlie a full-blown migraine attack.10,11 Unlike initial activation of central pathways during the early stages of a migraine attack, central sensitization appears to be independent of peripheral neural input.12-16
Because multiple pathogenic mechanisms are putatively involved in generation of the migraine symptom complex, multimechanism-targeted therapy may confer advantages over individual monotherapy. Drugs within 2 classes of migraine pharmacotherapy—triptans and nonsteroidal anti-inflammatory drugs (NSAIDs)—target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Triptans reduce calcitonin gene-related peptide–mediated vasodilation, inhibit release of inflammatory mediators from trigeminal nerves, and decrease transmission of pain impulses to the trigeminal nucleus caudalis.9,11 Data from animal models and studies in migraine patients suggest that triptans inhibit synaptic transmission between the peripheral and central neurons and thereby interrupt activation of central pathways during the early stages of a migraine attack—before central sensitization, which is independent of peripheral input, has developed.14,15 NSAIDs inhibit the synthesis of prostaglandins and may mitigate meningeal inflammation while preventing or reversing central sensitization arising from activation of glial cells in the brain stem.17 In a recent study, the NSAID naproxen suppressed sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus in an animal model of intracranial pain.18
Together, a triptan and an NSAID hypothetically alter both peripheral activation of central pathways during the early stages of a migraine attack and the later developing central sensitization that is independent of peripheral input. Results of several clinical studies support this possibility,19-22 particularly with the concomitant use of sumatriptan succinate and naproxen sodium. Data suggest that the combination of sumatriptan succinate and naproxen sodium may be useful both in enhancing acute relief and conferring a prolonged therapeutic response.19,20 The latter finding is consistent both with the aforementioned mechanistic considerations and with the long half-life (12-17 hours) of naproxen.23
A tablet specifically formulated with sumatriptan succinate, equivalent to sumatriptan, 85 mg, and naproxen sodium, 500 mg (hereafter sumatriptan–naproxen sodium), has been developed for the acute treatment of migraine. The technology used in the formulation of sumatriptan is a fast-disintegrating, rapid-release formulation designed to facilitate tablet disintegration and drug dispersion and mitigate the effects of gastric stasis that can accompany migraine. Development of a combination therapy was motivated by the rationale that concomitant use of a triptan and an NSAID might confer additive efficacy relative to that with use of either triptans or NSAIDs alone.19,20 This article describes the results of 2 replicate randomized, double-blind clinical trials conducted to evaluate the efficacy and safety of sumatriptan–naproxen sodium compared with placebo and with monotherapy with sumatriptan succinate or naproxen sodium in the acute treatment of migraine.
Men and nonpregnant, nonlactating women were eligible for the studies if they were between 18 and 65 years of age, had at least a 6-month history of migraine with or without aura as defined by the International Headache Society criteria,24,25 had an average of 2 to 6 moderate or severe migraine episodes monthly during the 3 months preceding the screening visit, and could distinguish migraine episodes from other types of headache. Women had to be physiologically incapable of becoming pregnant or, if they could become pregnant, had to agree to practice adequate contraception during the study. Site personnel asked each participant to self-identify their race and ethnicity and, if needed, the choices and/or further clarification would be provided to assist in the process. If the participant did not self-identify with any category, “other” or “unknown” was entered. For the purposes of this article, the categories were collapsed to white, black, and other.
Patients were excluded if they had more than 6 migraine attacks monthly during either of the 2 months before screening; chronic daily headache (≥15 days per month of nonmigraine headaches during each of the 3 months before screening); uncontrolled hypertension (diastolic blood pressure >95 mm Hg or systolic blood pressure >160 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; 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 regular use of any anticoagulant or NSAID (except aspirin, ≤325 mg/d, for cardiovascular prophylaxis).
Patients were eligible for the studies regardless of whether they were triptan-naive. All patients provided written informed consent prior to study participation.
The protocols for these multicenter studies were approved by ethics committees or institutional review boards for each of the 118 US study sites. Study sites included primary care practices, neurology clinics, and headache clinics. Patient recruitment methods included advertisements, regular office visits, and chart reviews. The studies, which were identically designed and conducted, consisted of a screening visit followed by outpatient treatment of a single migraine attack and a follow-up visit occurring 1 to 5 days after treatment. At the screening visit, patients meeting eligibility criteria were randomized 1:1:1:1 to receive one of the following: a single tablet containing sumatriptan–naproxen sodium; a single tablet containing sumatriptan, 85 mg; a single tablet of naproxen sodium, 500 mg; or placebo; and were dispensed blinded study medication. Patients were instructed to treat a migraine attack with study medication when pain intensity was moderate or severe. Patients were to treat a migraine within 6 weeks of the screening visit. If a patient failed to treat a migraine within these 6 weeks, he/she was allowed to return for rescreening and given another 6 weeks to treat. Patients were allowed to rescreen only once. Dosing regimens of migraine prophylaxis could not be changed (added, withdrawn, or dose changed) during the 2 weeks prior to treatment, including the use of calcium channel blockers, tricyclic antidepressants, β-blockers, or serotonergic medications for any other indication. No NSAIDs (except aspirin, ≤325 mg/d, for cardiovascular prophylaxis); analgesics containing morphine, codeine, or opioid derivatives; ergotamine-containing compounds; or serotonin agonists could be taken within 24 hours before treatment with study medication. No analgesics or acute migraine treatment (including antiemetics) could be taken within 6 hours before treatment with study medication. Patients were permitted to take rescue medication beginning 2 hours after dosing, as prescribed or recommended by their physicians, with the exception of ergot-containing medications, serotonin agonists, or NSAID-containing products. A second dose of study medication was not permitted.
Patients recorded on diary cards details about the migraine they treated with study medication and any use of study medication or concomitant medication. Pain severity was rated immediately before dosing; 0.5, 1, and 1.5 hours after dosing; and hourly from 2 to 24 hours after dosing on a 4-point scale (0 = none; 1 = mild; 2 = moderate; 3 = severe). Presence and absence of nausea, photophobia, and phonophobia were also recorded at these points. At 24 hours after dosing, patients indicated whether they had vomited any time during the 24-hour postdose period. Patients were required to stay awake to record pain and symptom assessments for the first 2 postdose hours. Sleeping was permitted between postdose hours 2 and 4 as long as patients awakened to record assessments at the 3- and 4-hour points. After 4 hours after dosing, patients were required to complete diary-card assessments only when awake. If a patient missed any recording time, the last recorded observation was carried forward to fill in the missed recording.
The primary objectives of the studies were (1) to determine the efficacy of sumatriptan–naproxen sodium vs placebo as assessed by headache relief and the incidences of photophobia, phonophobia, and nausea 2 hours after dosing as primary outcome measures and (2) to evaluate the efficacy of sumatriptan–naproxen sodium compared with each monotherapy, using sustained pain-free response as the outcome measure.
There were 6 primary outcome measures. The primary outcome measures were chosen because they represent the spectrum of the key symptoms responsible for disability in migraine and measure both the early (2-hour) and sustained (24-hour) relief of these symptoms. The first 4 of these outcome measures, which compared sumatriptan–naproxen sodium with placebo, were the percentages of patients who had headache relief 2 hours after dosing (ie, the reduction of pain from moderate/severe intensity to mild/no pain without use of rescue medication at each of the prespecified time points), absence of photophobia, absence of phonophobia, and absence of nausea. The other 2 outcome measures, which compared sumatriptan–naproxen sodium with its individual components, were the percentages of patients with sustained pain-free response (ie, moderate or severe pain at treatment reduced to no pain from 2 hours through 24 hours after dosing with no use of rescue medication).
A secondary efficacy outcome measure 2 hours after dosing was the percentage of patients with pain-free response (moderate or severe pain at treatment reduced to no pain). Secondary efficacy outcome measures also included the percentages of patients with sustained headache relief (ie, moderate or severe pain at treatment reduced to mild or no pain from 2 hours through 24 hours after dosing, with no use of rescue medication); sustained freedom from nausea, photophobia, and phonophobia from 2 through 24 hours after dosing; use of rescue medication through 24 hours after dosing; and headache recurrence (ie, return of moderate or severe pain within 24 hours of dosing among patients with headache relief 2 hours after dosing). The incidence of any vomiting through 24 hours after dosing was also evaluated.
Clinical safety was assessed by calculating the incidence of specific adverse events, defined as any untoward medical occurrences, regardless of their suspected cause, that were reported by a patient or noted by a clinician during the study.
Efficacy data were analyzed for the intention-to-treat population, defined as randomized participants who took study medication, recorded baseline pain as moderate or severe, and had at least 1 postbaseline efficacy evaluation. Participants who were randomized but who did not have an opportunity to treat a migraine during the study period were omitted from any analysis of safety or efficacy, including the intention-to-treat analysis.
Baseline migraine characteristics and each of the efficacy outcome measures (except recurrence, which was summarized with descriptive statistics only) were analyzed using the Cochran-Mantel-Haenszel test with 2 outcome categories and with pooled investigator sites as strata. Analyses of the outcome measures at 2 hours after dosing were adjusted for any baseline imbalances among treatment groups for the symptoms of interest. For key secondary efficacy outcome measures, a hierarchical step-down procedure was used to control for multiplicity.26-30 Outcome measures were tested in the order specified below, with the requirement that once the P value for a test on an outcome measure exceeded .05, outcome measures further down in the order were not considered to be statistically significant. The secondary comparisons were tested in the following order: pain-free response at 2 hours for sumatriptan–naproxen sodium vs placebo, sustained pain relief for sumatriptan–naproxen sodium vs placebo, sustained pain relief for sumatriptan–naproxen sodium vs sumatriptan, sustained freedom from symptoms for sumatriptan–naproxen sodium vs sumatriptan, use of rescue medication for sumatriptan–naproxen sodium vs sumatriptan, time to rescue for sumatriptan–naproxen sodium vs sumatriptan, pain relief at 4 hours for sumatriptan–naproxen sodium vs sumatriptan, freedom from symptoms at 4 hours for sumatriptan–naproxen sodium vs sumatriptan, pain relief at 2 hours for sumatriptan–naproxen sodium vs sumatriptan, and freedom from symptoms at 2 hours for sumatriptan–naproxen sodium vs sumatriptan. For the fourth secondary outcome measure of sustained freedom from symptoms, the outcome measures were adjusted for rescue medication and 3 separate analyses were performed. For patients who used rescue medication, the worst possible score (symptoms present) was substituted for the actual scores at the time of rescue and for all subsequent time points. For the hierarchical step-down procedure, statistically significant improvement with sumatriptan–naproxen sodium treatment in the associated symptoms (photophobia, phonophobia, and nausea) considered together was interpreted as meeting the significance criterion.
The sumatriptan–naproxen sodium group was compared with placebo in statistical analyses of all outcome measures except headache recurrence. The sumatriptan–naproxen sodium group was compared prospectively with the group given sumatriptan monotherapy in statistical analyses of all efficacy outcome measures except pain-free response 2 hours after dosing, any vomiting through 24 hours after dosing, and headache recurrence. The sumatriptan–naproxen sodium group was compared prospectively with the group given naproxen sodium monotherapy for the primary efficacy outcome measures 2 hours after dosing.
Adverse event data were summarized for the safety population, defined as all patients who took study medication and had available data. The Fisher exact test was used to compare incidences of adverse events in the sumatriptan–naproxen sodium group with those in the sumatriptan monotherapy group, the naproxen monotherapy group, and the placebo group. Only the incidences of overall adverse events and overall events considered to be treatment related were analyzed for treatment group differences. All analyses of efficacy and safety were conducted using SAS software, version 9.1 (SAS Institute Inc, Cary, NC).
The Figure summarizes the disposition of patients in each study. The numbers of patients screened for the study were 1768 in study 1 and 1875 in study 2. Of those screened, the numbers of patients randomized to receive treatment were 1677 in study 1 and 1736 in study 2. Safety analyses included the 1461 patients in study 1 and 1495 patients in study 2 who took study medication and had evaluable safety data. Efficacy analyses included 1441 patients in study 1 and 1470 patients in study 2 who took study medication, recorded baseline pain as moderate or severe, and had at least 1 postbaseline efficacy evaluation. Among randomized patients, the primary reason that 216 patients in study 1 and 241 in study 2 were not included in the safety and efficacy populations was because they did not have the opportunity to treat a qualifying migraine episode before the studies were concluded.
Demographics and baseline clinical characteristics were similar between studies and among treatment groups (Table 1 and Table 2). Across treatment groups, patients' mean age ranged from 39.4 years to 40.6 years, and most patients were female (84% to 89%) and white (86% to 90%). The majority of patients (71% to 79%) had migraine without aura. Usual prestudy migraine medications were similar between studies and among treatment groups. The most common usual prestudy migraine medications were NSAIDs and triptans. Characteristics of the treated migraine were generally similar between studies and among treatment groups, with the exception of baseline incidence of unilateral pain in study 2 and the baseline incidence of nausea among treatment groups for both studies.
Two-Hour Headache Relief: Sumatriptan–Naproxen Sodium vs Placebo. Sumatriptan–naproxen sodium was significantly more effective than placebo 2 hours after dosing for incidences of headache relief, absence of photophobia, and absence of phonophobia in both studies (P<.001 for all measures; Table 3). The incidences of headache relief 2 hours after dosing were 65%, 55%, 44%, and 28% with sumatriptan–naproxen sodium, sumatriptan monotherapy, naproxen sodium monotherapy, and placebo, respectively, in study 1 (P<.001 for sumatriptan–naproxen sodium, sumatriptan, and naproxen sodium vs placebo; P = .009 for sumatriptan–naproxen sodium vs sumatriptan). The corresponding percentages in study 2 were 57%, 50%, 43%, and 29% (P<.001 for sumatriptan–naproxen sodium, sumatriptan, and naproxen sodium vs placebo; P = .03 for sumatriptan–naproxen sodium vs sumatriptan). The incidence of headache relief as a function of baseline pain (moderate or severe), which was not a protocol-specified analysis, is also shown in Table 3. Eleven participants in study 1 and 13 participants in study 2 had missing headache pain scores at 2 hours after dosing. Without using the last observation carried forward to impute their 2-hour headache relief, the incidences of relief were still 65%, 55%, 44%, and 28% with sumatriptan–naproxen sodium, sumatriptan monotherapy, naproxen sodium monotherapy, and placebo, respectively, in study 1, with no change in statistical significance. Likewise, for study 2, the incidences of headache relief at 2 hours after dosing were unaffected by use of last-observation-carried-forward analysis on 13 participants.
A similar pattern of results was observed for absence of photophobia and absence of phonophobia. After adjustments due to baseline imbalances in incidences of nausea, the incidence of absence of nausea 2 hours after dosing was significantly higher with sumatriptan–naproxen sodium than with placebo in study 1 (71% vs 65%; P = .007) but did not differ between sumatriptan–naproxen sodium and placebo in study 2 (65% vs 64%; P = .71).
Twenty-Four-Hour Sustained Pain-Free Response: Sumatriptan–Naproxen Sodium vs Monotherapy. Sumatriptan–naproxen sodium was significantly more effective than sumatriptan monotherapy or naproxen sodium monotherapy for the incidence of 24-hour sustained pain-free response in both studies (Table 4). In study 1, the incidence of sustained pain-free response was 25% with sumatriptan–naproxen sodium compared with 16% with sumatriptan monotherapy (P<.01), 10% with naproxen sodium monotherapy (P<.001), and 8% with placebo (P<.001). The corresponding incidences in study 2 were 23% with sumatriptan–naproxen sodium compared with 14% with sumatriptan monotherapy (P<.001), 10% with naproxen sodium monotherapy (P<.001), and 7% with placebo (P<.001).
Two-Hour Pain-Free Response. Sumatriptan–naproxen sodium was significantly more effective than placebo in both studies for pain-free response 2 hours after dosing (Table 3). The incidence of pain-free response 2 hours after dosing with sumatriptan–naproxen sodium was 34% in study 1 and 30% in study 2 compared with 9% and 10% in the respective placebo groups (P<.001).
Sustained Efficacy (2-24 Hours After Dosing). In both studies, sumatriptan–naproxen sodium was significantly more effective than placebo for all measures of sustained efficacy, including sustained headache relief (P<.001), sustained freedom from nausea (P<.001), sustained freedom from photophobia (P<.001), sustained freedom from phonophobia (P<.001), and the occurrence of any vomiting through 24 hours after dosing (P<.005) (Table 4). In addition, fewer patients treated with sumatriptan–naproxen sodium compared with placebo used rescue medication or had headache recurrence in either study (inferential statistics not analyzed; Table 4).
Sumatriptan–naproxen sodium was superior to sumatriptan monotherapy for sustained headache relief, sustained freedom from photophobia, sustained freedom from phonophobia, and use of rescue medication in both studies and in study 1 for sustained freedom from nausea (Table 4).
The percentage of participants with missing 24-hour diary records was approximately 15% in both studies (14.8% in study 1 and 15.7% in study 2). However, since sustained response is dependent on use of rescue medication and relapse of migraine pain between 2 and 24 hours, missing data at 24 hours has less impact on evaluation of sustained response than it does on response at any given point. For example, although 444 participants (both studies) had missing data at the 24-hour point, only 14 (7 in study 1 and 7 in study 2) could not be evaluated for 24-hour sustained response without use of last-observation-carried-forward analysis. Excluding these participants from the sustained analyses did not alter the overall incidences or statistical interpretation of the treatment differences.
The percentages of patients with at least 1 adverse event (regardless of its suspected cause) were 27%, 24%, 13%, and 12% in patients treated with sumatriptan–naproxen sodium, sumatriptan monotherapy, naproxen monotherapy, and placebo, respectively, in study 1. The corresponding values for study 2 were 26%, 28%, 14%, and 10%. Adverse events reported in 2% or more of patients in any treatment group are shown in Table 5. Based on the incidences of overall adverse events and those considered to be treatment related, there were no statistically significant differences between sumatriptan–naproxen sodium and sumatriptan monotherapy.
No serious adverse events attributed to study medication were reported in study 2. One serious adverse event considered probably attributed to sumatriptan monotherapy was reported in study 1. The serious adverse event was heart palpitations resulting in hospitalization of a 58-year-old woman. The patient had several cardiovascular risk factors (body mass index of 35, 30-year history of smoking, hypercholesterolemia, hypertriglyceridemia, and type 2 diabetes). The medical history included bowel obstruction (in 1985), diarrhea requiring hospitalization (in 2003), tension headaches, depression, and anxiety. Concurrent medications included clonazepam, venlafaxine, propoxyphene + acetaminophen, vitamins, and metformin. The screening electrocardiogram was interpreted as showing nonspecific T-wave anterior flattening of no clinical significance. After administration of sumatriptan monotherapy, the patient experienced heart palpitations and was admitted to the hospital, where she received lorazepam, aspirin, and nitroglycerin. The event was reported as resolved several days after hospitalization.
These 2 studies constitute the first placebo-controlled assessments of a triptan and an NSAID contained in a single, fixed-dose tablet for the acute treatment of migraine. The development of the tablet was motivated by the rationale that concurrent use of 2 agents with complementary antimigraine mechanisms might confer additive benefit relative to that with either therapy alone. To thoroughly explore a possible benefit of the combination with respect to prolonged efficacy, as suggested by previous findings,19,20 the current studies included several measures of sustained response through the 24-hour postdose interval in addition to standard assessments obtained 2 hours after dosing. These studies used more rigorous evaluation of efficacy than any approved acute migraine treatment to date, with the incorporation of 6 primary outcomes, all of which should be statistically significant, as opposed to the usual single primary outcome of headache relief 2 hours after dosing. Previous studies used a combination of 2 separate tablets rather than a single fixed-dose tablet. Clinically, the lack of a single fixed-dose tablet may lead to variability in dosing and potentially higher levels of sumatriptan; ie, sumatriptan tablets and naproxen sodium tablets are each available in 3 doses, potentially resulting in numerous combinations, and if not administered concurrently, may lead to the suboptimal “step care approach” to treatment. This lack of standardization poses problems with extrapolation of the previously reported pharmacokinetic benefits of sumatriptan–naproxen sodium31 and the current safety profile.
The combination tablet uses a sumatriptan dosage strength of 85 mg and a naproxen sodium dosage strength of 500 mg. The dosages of the 2 components of the combination are within the respective ranges of the lowest and highest single daily doses recommended for use by adults in the United States. Whether a different combination of doses of sumatriptan and naproxen sodium might be more efficacious has not been studied. Sumatriptan and naproxen sodium doses for the combination tablet were chosen on the basis of known risks and benefits of the separate drugs. Benefits and risks were based on results of numerous other clinical trials in which, by convention, risks were not subjected to statistical analysis but the incidence was reported above the usual cutoff of more than 1% or 2%.
The superior efficacy of sumatriptan–naproxen sodium compared with sumatriptan monotherapy might be explained by its targeting of multiple pathogenic mechanisms in migraine. It is hypothesized that migraine attacks arise from neurally induced cranial vasodilation that produces painful inflammation of the surrounding nerves.3 Peripheral and central pain pathways appear to be sequentially recruited and sensitized as a migraine attack develops.12-16 Peripheral pain pathways originating from neurons with cell bodies in the trigeminal ganglion are recruited and sensitized first, then the peripheral nerve activity contributes to sensitization of central pain pathways originating from neurons with cell bodies in the dorsal horn of the spinal cord. The initial peripheral sensitization is thought to bring about the mild, often throbbing pain associated with the onset of a migraine attack, while central sensitization is thought to underlie a full-blown migraine attack. Whereas initiation of central sensitization depends on input from peripheral pathways, central sensitization can be maintained independently of peripheral input.13 Data from animal models and studies in persons with migraine suggest that triptans can alter initial peripheral sensitization but cannot appreciably affect central sensitization.14,15,32 NSAIDs, conversely, affect central sensitization.18,32 A triptan-NSAID combination, sumatriptan–naproxen sodium putatively affects both peripheral and central sensitization to alter a broader range of pathogenic processes involved in migraine than either medication administered as monotherapy.
The pharmacokinetic profile of naproxen when given as sumatriptan–naproxen sodium might also contribute to the superior efficacy of sumatriptan–naproxen sodium relative to sumatriptan monotherapy, particularly for measures of sustained response. When administered as sumatriptan, 85 mg, + naproxen sodium, 500 mg, sumatriptan is absorbed relatively quickly to confer rapid therapeutic response.31 With administration of sumatriptan–naproxen sodium relative to administration of naproxen sodium alone, the time to maximum concentration of naproxen is delayed (median, 6 hours vs 1 hour) and the maximum plasma concentration is reduced by approximately 26%.31 Differences in naproxen pharmacokinetic profiles observed between the sumatriptan–naproxen sodium and the naproxen sodium groups may possibly arise from the presence of sumatriptan succinate in the combination product. Sumatriptan has been reported to cause a delay in gastric emptying.33,34 The delay in naproxen maximum concentration and its long half-life of 12 to 17 hours23 may contribute to sustained efficacy.
The distinct pharmacokinetic profile of this single fixed-dose tablet of sumatriptan–naproxen sodium likely contributes to the acute and sustained efficacy demonstrated in these studies. Although the combination tablet substantially improved sustained pain-free response relative to the monotherapies, approximately one quarter of patients given active treatment had sustained pain-free response regardless of treatment group. Whether modifying treatment variables could improve the rate of sustained pain-free response is being investigated in other studies. For example, the impact of early intervention (ie, treating a migraine attack while pain is still mild instead of waiting for pain to become moderate or severe) on sustained pain-free response and other outcome measures is being evaluated with sumatriptan–naproxen sodium.
The incidences of adverse events overall and of specific adverse events were low across treatment groups, although all active treatments were associated with more frequent adverse events than placebo. While the incidence of adverse events was low across treatment groups, sumatriptan–naproxen sodium was associated with approximately twice the incidence of any adverse event as placebo. No specific adverse event or group of adverse events accounted for this difference. The nature of adverse events following treatment with sumatriptan–naproxen sodium did not differ meaningfully from events associated with sumatriptan monotherapy or naproxen sodium monotherapy in previously reported controlled trials,35-38 nor from those reported in a long-term, open-label safety study of sumatriptan-naproxen sodium.39
The results of these studies should be interpreted in the context of their limitations. Patients' most common prestudy migraine medications were NSAIDs and triptans, which are among the most common medications taken by persons with migraine generally. The degree to which the efficacy data from these studies can be extrapolated to NSAID- and triptan-naive patients and to patients with migraine refractory to NSAIDs and/or triptans is unknown. A second limitation is the inclusion of primarily white patients in the study. The degree to which the results generalize to other race/ethnicity groups is not known. However, there is no evidence to suggest that response to the combination or its components would be expected to differ by race or ethnicity. Finally, we did not compare sumatriptan–naproxen sodium with sumatriptan and naproxen sodium taken together as separate tablets. However, for patients in whom adherence to taking 2 pills is an issue, the combination pill has obvious advantages.
In conclusion, sumatriptan, 85 mg, plus naproxen sodium, 500 mg, administered as a single, fixed-dose tablet for acute treatment of migraine, resulted in superior clinical benefits over monotherapy with either sumatriptan or naproxen sodium and was well tolerated, as evidenced by the adverse event profile. Targeting multiple mechanisms of migraine with a specifically formulated single tablet of sumatriptan–naproxen sodium resulted in more favorable 2-hour pain relief and 24-hour sustained pain-free responses vs sumatriptan or naproxen sodium alone.
Corresponding Author: Jan Lewis Brandes, MD, Nashville Neuroscience Group, 300 20th Ave N, #603, Nashville, TN 37203 (email@example.com).
Author Contributions: Dr Brandes, as principal investigator, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Brandes, Adelman, Spruill, Barrett, Lener.
Acquisition of data: Brandes, Kudrow, Stark, O’Carroll, Adelman, O’Donnell, Spruill.
Analysis and interpretation of data: Brandes, Kudrow, Stark, O’Carroll, Adelman, O’Donnell, Alexander, Spruill, Barrett, Lener.
Drafting of the manuscript: Brandes, Kudrow, Stark, O’Donnell, Spruill.
Critical revision of the manuscript for important intellectual content: Brandes, Kudrow, Stark, O’Carroll, Adelman, O’Donnell, Alexander, Spruill, Barrett, Lener.
Statistical analysis: Spruill.
Obtained funding: Barrett, Lener.
Administrative, technical, or material support: Brandes, Kudrow.
Study supervision: Brandes, Adelman, Alexander, Barrett, Lener.
Financial Disclosures: Dr Brandes reports having received clinical research or educational support from Merck, GlaxoSmithKline, UCB Pharma, Allergan, Johnson & Johnson, AstraZeneca, Pfizer, Bristol-Myers Squibb, Winston Laboratories, Sanofi-Aventis, Elan Pharmaceuticals, Novartis, Endo, POZEN, Vernalis, Ortho-McNeil, Advanced Bionics, Forest Laboratories, MedPointe Pharmaceuticals, and Aradigm Corp. Dr Kudrow reports having received research grants from Ortho-McNeil, Pfizer, GlaxoSmithKline, Merck, and Eisai and has served on the speaker's bureau for Pfizer and GlaxoSmithKline. Dr Stark reports having received clinical research or educational support from GlaxoSmithKline, Proethics, Allergan, Ortho-McNeil, Pfizer, and Merck. Dr O’Carroll reports having received clinical research or educational support from Allergan, GlaxoSmithKline, Merck, Pfizer, Eli Lilly, Sanofi-Aventis, Cephalon, Forest Pharmaceutical, AstraZeneca, Ortho-McNeil, POZEN, and Ligand Pharmaceuticals. Dr Adelman reports having received clinical research support from GlaxoSmithKline and POZEN and having served on advisory boards or speaker's bureaus for GlaxoSmithKline, AstraZeneca, Pfizer, Merck, and Ortho-McNeil. Dr O’Donnell reports having received research support from Merck, GlaxoSmithKline, and Allergan; having served as a consultant for Merck, GlaxoSmithKline, and Ortho-McNeil; and having received speaker's honoraria from Merck, GlaxoSmithKline, Pfizer, and Ortho-McNeil. Dr Alexander is a previous employee and shareholder of POZEN. Ms Spruill is a previous employee of and currently serves as a consultant to POZEN. Ms Barrett is a previous employee of GlaxoSmithKline, serves as a consultant to GlaxoSmithKline, and is a stockholder in Pfizer. Ms Lener is an employee of GlaxoSmithKline.
MT400-301 Study Group:Alabama:Birmingham: Gregory M. Flippo, MD; Radiant Research, Birmingham, Gordon T. Connor, MD; Montgomery: Drug Research and Analysis Corp, Norman A. Garrison, Jr, MD; Arizona:Tucson: Northwest NeuroSpecialists PLLC, Jeanette Wendt; Arkansas:Hot Springs: Palmetto Clinical Research, Richard G. Pellegrino, MD; Little Rock: Clinical Study Centers LLC, Gordon L. Gibson, MD; California:San Diego: Medical Center for Clinical Research, William D. Koltun, MD; Santa Monica: California Medical Clinic for Headache, David Kudrow, MD; Oceanside: The Neurology Center, Benjamin M. Frishberg, MD; Walnut Creek: Neurological Research Institute of the East Bay, Michael Stein, MD; Florida:Hialeah: Medical Research Unlimited, Steven D. Wheeler, MD; Melbourne: Comprehensive Neuroscience Inc, Murray A. Kimmel, DO; Miami: Miami Research Associates Inc, Bruce Kohrman, MD; Palm Beach Gardens: Palm Beach Neurological Center, Michael M. Tuchman, MD; Plantation: Neurology Clinical Research Inc, Richard P. Singer, MD; Port Orange: Coastal Medical Research, Alex White, MD; West Palm Beach: Premiere Research Institute, Paul K. Winner, DO; Georgia:Augusta: Walton Headache Center, Marc Husid; Decatur: Neurology and Headache Specialists of Atlanta, Sarah E. DeRossett; Illinois:Chicago: Diamond Headache Clinic, Merle Lea Diamond, MD; Indiana:Evansville: MediSphere Medical Research Center LLC, Steven K. Elliott, MD; Research Solutions, Jennifer S. Wahle, MD; Indianapolis: Midwest Institute for Clinical Research, Phillip D. Toth, MD; Louisiana:Lake Charles: The Clinic, Alan Sconzert, MD, PhD; Metairie: New Orleans Medical Institute, Robert B. De Trinis, MD; Massachusetts:Milford: Milford Emergency Associates Inc, Anthony Puopolo, MD; North Dartmouth: Northeast Medical Research Associates Inc, S. David Miller, MD; Worcester: New England Regional Headache Center, Herbert G. Markley, MD; Michigan:Ann Arbor: Michigan Head-Pain and Neurological Institute, Todd Rozen, MD; Kalamazoo: Westside Family Medical Center, Gary Ruoff, MD; Missouri:St. Louis: Mercy Health Research, Timothy R. Smith, MD; Radiant Research Inc, Mohammed Z. Abudalu, MD; Nevada:Las Vegas: Lovelace Scientific Resources, James Snyder, MD; New Mexico:Albuquerque: Lovelace Scientific Resources, Lydia Lawson, MD; New York:Endwell: Regional Clinical Research Inc, Victor A. Elinoff, MD; New York City: Analgesic Development Ltd, Abraham Sunshine, MD; New York Headache Center, Alexander Mauskop, MD; North Carolina:Charlotte: Charlotte Clinical Research Inc, Greg V. Collins, MD; Greensboro: Headache Wellness Center, James U. Adelman, MD; Raleigh: Multi-Specialty Research Associates of North Carolina, John Rubino, MD; Ohio:Cincinnati: Community Research, Bruce C. Corser, MD; Radiant Research Inc, Michael J. Noss, MD; Oklahoma:Tulsa: Neurological Associates of Tulsa Inc, Harvey J. Blumenthal, MD, James Dean, MD; Oregon:Portland: Radiant Research Inc, Keith D. Klatt, MD; The Neurology Clinic, Hubert A. Leonard, MD, PhD; Pennsylvania:Lancaster: Oyster Point Family Health Center Research Across America, Michael Warren, MD; Philadelphia: Jefferson Headache Center, Stephen D. Silberstein, MD; Rhode Island:Warwick: Omega Medical Research, David L. Fried, MD; South Carolina:Mt Pleasant: Coastal Carolina Research Center, Cynthia Strout, MD; Summerville: Palmetto Clinical Research, Michael Otruba, DO; Tennessee:Nashville: Nashville Neuroscience Group PC, Jan Lewis Brandes, MD; Texas:Austin: Benchmark Research Austin, Teresa L. Coats, MD; Fort Worth: Benchmark Research, William Seger, MD; San Angelo: West Texas Medical Associates, Darrell T. Herrington, DO; San Antonio: Integra Clinical Research LLC, Susanne K. Gazda, MD; Radiant Research, San Antonio, William P. Jennings, MD; Richardson: KRK Medical Research, Roy S. Kiser, MD; Virginia:Roanoke: Blue Ridge Research Center, Gordon Burch, MD; Wisconsin:Milwaukee: Advanced Healthcare SC, Daniel J. Thompson, MD.
MT400-302 Study Group:Alabama:Huntsville: AmDoc Inc, Medical Affiliated Research Center Inc, Harry Lee McDaris, M.D; Mobile: USA Neurology, John F. Rothrock, MD; Arizona:Phoenix: Lovelace Scientific Resources Inc, Philip B. James, MD, Richard V. Albery, MD; Valley Neurological Headache Clinic, Carol Foster, MD; Scottsdale: Radiant Research-Scottsdale, Timm McCarty, MD; Tucson: Radiant Research-Tucson, Frank Dunlap, MD, Robert Hirsch, MD; Arkansas:Little Rock: Little Rock Family Practice Clinic, Kevin Roberts, MD; California:Carlsbad: Sanjeev Sharma, MD; Irvine: Radiant Research-Irvine, Sid Rosenblatt, MD; Newport Beach: Christopher Philip O’Carroll, MD; Northridge: Northridge Neurological Center; Ronald B. Ziman, MD; Redondo Beach: George J. Rederich, MD, PhD; Colorado:Denver: Radiant Research Inc, Leslie Moldauer, MD; Connecticut:Stamford: The New England Center for Headache, Alan M. Rapoport, MD; Stratford: Clinical Research Consultants Inc, Selwyn A. Cohen, MD; Florida:Clearwater: Tampa Bay Medical Research Inc, Steven C. Bowman, MD; Coral Gables: Clinical Research of South Florida, Jeffrey B. Rosen, MD; Ft Myers: Internal Medicine Associates-Department of Research, Stephen R. Zellner, MD; Gainesville: Florida Medical Research Institute PA, C. Richard King, MD; St Petersburg: Comprehensive NeuroScience Inc, Margarita Nunez, MD; Meridian Research, Mildred (Mimi) Farmer, MD; Georgia:Atlanta: Child Neurology Associates LLC, Frank Berenson, MD; Illinois:Peoria: NTouch Research, Daniel Brune, MD; Maryland:Towson: International Research Center, Alberto Yataco, MD; Minnesota:Plymouth: Clinical Research Institute, Gary Berman, MD; Missouri:Kansas City: The Center for Pharmaceutical Research, John Ervin, MD; Springfield: Headache Care Center, Roger Cady, MD; New Hampshire:Lebanon: Neurology Studies Group, Dartmouth-Hitchcock Medical Center, Thomas N. Ward, MD; New Jersey:Morristown: Neuroscience Center of Northern New Jersey, Stuart W. Fox, MD; Princeton: Global Medical Institute, Jeffrey Apter, MD; Ridgewood: Neurology Group of Bergen County, PA, Kenneth A. Levin, MD; New York:Albany: Upstate Clinical Research, James P. Wymer, MD; Manlius: Central New York Clinical Research, Douglas P. Zmolek, MD; North Carolina:Raleigh: North Carolina Clinical Research, Craig F. LaForce, MD; Winston-Salem: Piedmont Medical Research Associates, Thomas Littlejohn, MD; Ohio:Cleveland: Health Research Associates, Robert S. Kunkel, MD; Columbus: Columbus Neurological Group Inc, Kenneth A. Mankowski, MD; Radiant Research Inc, Douglas Schumacher, MD; Mogadore: Radiant Research Inc, Dennis C. McCluskey, MD; Toledo: Headache Center of Ohio, Gary Gerard, MD; West Chester: ClinExcel Research, Lisa K. Mannix, MD; Westerville: Ortho Neuro Inc, Francis O’Donnell, DO; Pennsylvania:Philadelphia: Radiant Research-Einstein Center One, Barry Packman, MD; South Carolina:Anderson: Radiant Research Inc, Harry I. Geisberg, MD; Greer: Radiant Research-Greer, William Travis Ellison, MD; Statesville: Statesville Research Institute, Neil M. Kassman, MD; Tennessee:Memphis: Wesley Headache Clinic, Stephen H. Landy, MD; Nashville: Clinical Research Associates Inc, Stephen C. Sharp, MD; Texas:Dallas: Harold Urschel, MD; Houston: The Houston Headache Clinic, Ninan T. Mathew, MD; Lubbock: Bhupesh Dihenia, MD; San Antonio: Texas Association of Pediatric Neurology PA, Jerry Tomasovic, MD; Utah:Salt Lake City: Jean Brown Research-JBA Research Inc, Gilbert Podolsky, MD; Vermont:Burlington: Department of Neurology, College of Medicine, University of Vermont, Robert Shapiro, MD; Virginia:Alexandria: The Innovative Clinical Research Center, Stuart R. Stark, MD; Washington:Spokane: Rockwood Research Department, Timothy W. Powell, MD, Steven Pugh, MD; Tacoma: Neurology and Neurosurgery Associates of Tacoma, John Huddlestone, MD; Wenatchee: Clinical Research-Wenatchee Valley Medical Center, James R. Cook, MD.
Funding/Support: The 2 clinical trials (MT-400:301 and MT-400:302) described in this article were funded by GlaxoSmithKline in partnership with POZEN, the IND sponsor of the investigational drug MT-400 (sumatriptan–naproxen sodium).
Role of the Sponsors: GlaxoSmithKline and Pozen Inc provided financial and material support, monitoring, data collection and management, and data analysis to the authors and study investigators.
Independent Statistical Analysis: Eugene Laska, PhD (director, Statistical Sciences Laboratory, Nathan S. Kline Institute for Psychiatric Research, and professor, Department of Psychiatry, New York University School of Medicine, Orangeburg), had full access to all of the efficacy data and was provided the SAS programs and statistical output produced by POZEN/GlaxoSmithKline. Dr Laska reviewed the appropriateness of the analytic approach to the analysis of the primary efficacy measures and select secondary outcomes, suggested additional analyses, and verified the primary results reported in the article. POZEN/GlaxoSmithKline Pharmaceutical Research and Development paid Dr Laska for the time he spent on the review. Research assistance was provided to Dr Laska by Joseph Wanderling, a research scientist at the Nathan S. Kline Institute for Psychiatric Research.
Acknowledgment: We acknowledge Meredith A. Cucuel, BA, of Nashville Neuroscience Group, Nashville, Tenn, for editorial assistance, Michael H. Ames, PhD, of GlaxoSmithKline, Research Triangle Park, NC, for statistical input, Jane Saiers, PhD, of The WriteMedicine Inc, Chapel Hill, NC, for assistance with preparation of the manuscript, and Susan A. McDonald, MA, of GlaxoSmithKline, Research Triangle Park, NC, for critical review of the manuscript. Ms Cucuel's work on the manuscript was funded by Nashville Neuroscience Group and Dr Saiers' work on the manuscript was funded by GlaxoSmithKline.
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