Treatment of chronic migraine: a 3-month comparator study of naproxen sodium vs SumaRT/Nap.

OBJECTIVE: To compare the use of a combination of 85 mg sumatriptan plus 500 mg naproxen sodium in a combination tablet with 500 mg naproxen sodium in an identically appearing tablet when used as a daily preventative and acute treatment for 1 month and episodic acute treatment for an additional 2 months in patients with chronic migraine. BACKGROUND: To date, there has been minimal study of acute medications for patients with chronic migraine. Consequently, there is a paucity of study methodology or evidence-based guidance on the use of acute treatment medications in patients with chronic migraine. METHODS: This two-center, double-blind, randomized, parallel-group, comparator pilot trial of 28 subjects, 18 to 65 years of age, with ICHD-II defined chronic migraine, was designed to generate hypotheses about the efficacy of 2 established acute migraine medications used both as a daily preventive treatment (month 1) and episodic acute treatment (months 1, 2, and 3). Subjects were randomized 1:1 to treat daily with SumaRT/Nap (85 mg sumatriptan + 500 mg naproxen sodium) (group A) or naproxen sodium (500 mg) (group B) in a prophylactic strategy for 1 month followed by 2 months of the same medications used for episodic acute treatment. RESULTS: The combination of SumaRT/Nap used over a 3-month period did not appear to significantly reduce the number of migraine headache days. In the subset of subjects using naproxen sodium and completing the study per protocol, there was a marked reduction in migraine headache days (P < .02 vs 0.25, respectively). Duration of migraine from treatment to pain free decreased in both groups, but was more robust in group B from baseline to month 3. Subjects in group B completing the study per protocol reported a 56% reduction in headache days vs 8% for group A. Subjects in group A and group B completing the study per protocol had considerably better 2-hour headache relief than subjects withdrawing early from the study. More subjects in group B prematurely withdrew from the study because of lack of efficacy (5 vs 1, respectively). Despite using significant quantities of acute medication during month 1, there was a reduction of acute medication in month 2 and 3 vs baseline vs month 1, particularly in the naproxen group. CONCLUSION: A combination of SumaRT/Nap (group A) did not appear to reduce migraine headache frequency over a 3-month period. Subjects using naproxen sodium (group B) alone and completing the study per protocol had a marked statistically significant reduction in migraine headache days. Both groups completing the study per protocol had experienced clinically meaningful 2-hour headache relief. This suggests there may be a subset of patients with chronic migraine that are responsive to high doses of naproxen as an acute intervention with a significant prophylactic benefit. Subjects randomized to SumaRT/Nap experience benefit, primarily as an acute intervention. This hypothesis may warrant future larger scale clinical trials. Frequent dosing of SumaRT/Nap or naproxen sodium was well tolerated in this study.

SumaRT/Nap vs naproxen sodium in treatment and disease modification of migraine: a pilot study.

OBJECTIVE: This pilot study explored the potential for 2 recognized acute migraine medications, 85 mg of sumatriptan plus 500 mg of naproxen sodium in a combination tablet (SumaRT/Nap) and 500 mg of naproxen sodium, to treat and modify the disease progression of migraine. In other words, can these medications both abort an acute attack of migraine and reduce the number of future migraine attacks? BACKGROUND: Patients suffering with moderate to severe attacks of migraine desire acute treatment. As migraine frequency increases, so does the need for more frequent relief of acute attacks. This may lead to medication overuse and potentially medication overuse headache (MOH). Ideally, acute medication would have the ability to abort an attack of migraine and reduce the likelihood of future attacks. STUDY DESIGN: The primary endpoint of this study was a reduction in migraine headache days from baseline through month 3 of the study. Subjects were randomized 1:1 to treat 14 or fewer migraines per month with SumaRT/Nap (Group A) or naproxen sodium (Group B) for 3 months. Subjects in group A utilized SumaRT/Nap were encouraged, but not required, to treat migraine headache within 1 hour of onset of headache when the pain was mild. They could re-treat if needed after 2 hours. Subjects in group B utilized the same treatment strategy with 500 mg of naproxen sodium. Tablets of study medication were identical for both groups. Subjects recorded headache days, migraine attacks, duration of attacks, treatment, and treatment results daily on paper diaries. Subjects took the Migraine Disability Assessment Test (MIDAS) at randomization and 3 months later at the end of study. RESULTS: Naproxen sodium was associated with a statistically significant reduction in migraine headache days at month 3 compared to baseline (P = .0002). SumaRT/Nap was also associated with a reduction of migraine headache days, but this decrease did not reach statistical significance (P = .2). In addition, subjects in the naproxen sodium group had a statistically significant reduction of migraine attacks in all 3 months of the study compared to baseline. A greater than 50% reduction in the number of migraine headache days at month 3 occurred in 43% (6/14) of subjects in group B compared to 17% (3/18) of subjects in group A. Consistent with large regulatory studies comparing the efficacy of SumaRT/Nap with naproxen sodium, SumaRT/Nap in this study was statistically superior to naproxen sodium at 2 hours in reducing headache severity during months 2 and 3. There was a reduction of acute medication used from baseline to month 3 and improvement in MIDAS scores for both groups. CONCLUSION: Naproxen sodium, when used as a sole acute treatment early in attacks, appears to reduce the frequency of headache days and migraine attacks for a select number of subjects over a 3-month period. SumaRT/Nap is more effective at 2-hour headache reduction than naproxen sodium alone, but has less impact on reducing attack frequency or the number of headache days. Both treatments were well tolerated, and there was no convincing evidence that either medication led to MOH.

Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study.

OBJECTIVE: The study sought to evaluate whether topiramate prevents development of chronic daily headache (CDH, ≥15 headache days per month) in adult subjects with high-frequency episodic migraine (HFEM, 9-14 migraine headache days/month). A secondary objective was to assess the efficacy of topiramate as preventive migraine treatment in this population. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study comparing topiramate 100 mg/day and placebo for 26 weeks. The primary efficacy variable was new-onset CDH at month 6. Secondary efficacy measures included migraine and headache days. Adverse events (AEs) were evaluated. RESULTS: A total of 159 topiramate subjects and 171 placebo subjects were efficacy-evaluable. At month 6, 1.4% of topiramate subjects versus 2.3% of placebo subjects had CDH (p = .589). Compared with placebo, topiramate treatment was associated with statistically significant reductions in mean number of migraine days (6.6 vs. 5.3/28 days; p = .001) and headache days (6.6 vs 5.3/28 days; p = .001). Most commonly reported AEs in the topiramate versus placebo group included paresthesia (32.4% vs. 7.0%), fatigue (14.8% vs. 8.6%), dizziness (11.4% vs. 7.6%) and nausea (10.8% vs. 9.2%). CONCLUSION: Topiramate 100 mg/day did not prevent the development of CDH at six months in subjects with HFEM. Topiramate was effective in reducing headache days and migraine headache days and generally well tolerated.

Innovative delivery systems for migraine: the clinical utility of a transdermal patch for the acute treatment of migraine.

Migraine is a disabling, painful primary headache disorder that is associated with various combinations of neurological, gastrointestinal, autonomic and pain symptoms. Gastrointestinal disturbances associated with migraine, including nausea and vomiting, affect a majority of migraineurs and often result in a delay in taking or avoidance of pharmacological intervention. Gastric stasis and vomiting may lead to delayed or inconsistent absorption of orally administered medications. Many migraineurs awake early in the morning with their attack progressing and already associated with nausea and vomiting. As a result, there is a need for a novel, non-invasive, non-oral delivery system for fast and effective acute treatment of migraine. There are two non-oral delivery systems currently available in the US for the acute treatment of migraine: three nasal sprays and two injectable formulations. Although nasal sprays depend partially on nasal mucosal absorption, a significant amount of drug is swallowed, transits the stomach and is absorbed in the small intestine, which is not as rapid or effective a route of delivery for those migraineurs with gastric stasis. Sumatriptan is rapidly absorbed by subcutaneous injection with or without a needle, but the invasiveness and discomfort of the delivery, the high incidence of adverse events and the high recurrence rate all limit its use for many patients. Iontophoretic delivery of medication is a non-invasive transdermal approach that uses small amounts of electrical current to promote rapid movement of the ionized drug through the skin and into the systemic circulation. This delivery bypasses hepatic first-pass metabolism and also avoids gastric transit delay and slowing of small intestinal absorption associated with gastrointestinal stasis in migraineurs. Two pharmacokinetic studies have demonstrated that iontophoretic transdermal delivery of sumatriptan results in rapid and consistent achievement of therapeutic plasma concentrations. These studies also suggest that, by avoiding patient exposure to a rapid rise in and high plasma concentrations of sumatriptan as seen with injectable sumatriptan, transdermal delivery using iontophoresis may significantly reduce typical triptan-related adverse events. A large, randomized, double-blind, placebo-controlled, multicentre clinical trial showed statistically significant efficacy, good tolerability and virtually no triptan-related adverse events. Iontophoretic delivery of sumatriptan, with a novel transdermal patch device, offers patients a migraine-specific medication that is non-invasive and non-oral. Clinically, transdermal delivery provides rapid and effective relief of migraine while bypassing the gastrointestinal tract, with minimal classic triptan-related adverse effects. This unique approach facilitates the rapid absorption of this migraine-specific triptan, which should improve the chances of consistently achieving a therapeutic plasma concentration of sumatriptan, resulting in effective migraine relief.

Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.

BACKGROUND: Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. OBJECTIVES: To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. METHODS: Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. RESULTS: For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. CONCLUSIONS: Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.

Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures.

OBJECTIVE: To define yet more clearly the utility of topiramate in the treatment of chronic migraine, we evaluated prespecified secondary endpoints from a recent randomized, double-blind, placebo-controlled, multicenter clinical trial. BACKGROUND: We previously reported that topiramate 100 mg per day produced a statistically significant reduction in mean monthly migraine/migrainous and migraine headache days compared with placebo treatment and that it was safe and generally well tolerated. METHODS: Variables analyzed included between-treatment group differences in percent responders, change in the mean monthly rate of total headache days and headache-free days, change in average and worst daily headache severity, change in the mean monthly use of acute headache medications, and absolute change and percent change in a headache index. Additional analyses included evaluation of changes in: the associated symptoms of photophobia, phonophobia, and nausea; Migraine-Specific Quality of Life Questionnaire scores; Migraine Disability Assessment Scale scores; and Physician's and Subjects Global Impression of Change. RESULTS: The intent-to-treat population consisted of 306 patients (topiramate, n = 153; placebo, n = 153). Categorical responder rates of reductions in mean monthly migraine/migrainous days for topiramate- vs placebo-treated subjects were as follows: for > or =25% reduction: 68.6% vs 51.6% (P = .005); > or =50%: 37.3% vs 28.8% (P = .093); and > or =75%: 15.0% vs 9.2% (P = .061). The decrease in mean monthly total headache days and headache-free days for topiramate vs placebo treatment was 5.8 vs 4.7 days (P = .067). Compared with placebo, topiramate treatment resulted in statistically significant mean improvements in the Role Restrictive (P = .028) and Emotional Function (P = .036) domains of the Migraine-Specific Quality of Life Questionnaire, in the worst daily severity of migraine (P = .016), severity of photophobia (P = .032), frequency of vomiting (P = .018), photophobia (P = .038), phonophobia (P = .010), unilateral pain (P = .015), pulsatile pain (P = .023), and pain worsened because of physical activity (P = .047). In addition, there were trends observed (favoring topiramate) in average daily severity of migraine (P = .077), acute headache medication use (P = .127), severity of nausea (P = .098), frequency of nausea (P = .166), the Role Preventive domain of the Migraine-Specific Quality of Life Questionnaire (P = .061), and severity of phonophobia (P = .062). CONCLUSIONS: In addition to significantly reducing mean monthly migraine/migrainous and migraine headache days, treatment of chronic migraine with topiramate was effective with regard to several traditionally important and clinically relevant secondary outcomes in migraine prevention trials. Treatment with topiramate was well tolerated and not associated with serious adverse events.

Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs.

OBJECTIVE: The primary objective of this study was to compare the efficacy and tolerability of topiramate and amitriptyline in the prophylaxis of episodic migraine headache. METHODS: This was a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority study. Adults with 3 to 12 migraines per month were randomized in a 1:1 ratio to receive an initial dose of 25 mg/d of either topiramate or amitriptyline, subsequently titrated to a maximum of 100 mg/d (or the maximum tolerated dose). The primary efficacy outcome was the change from prospective baseline in the mean monthly number of migraine episodes. Secondary efficacy variables included changes from the prospective baseline phase to the end of the double-blind phase in the mean monthly (28-day) rate of days with migraine, mean monthly rate of days with headache (migraine and nonmigraine), mean monthly rate of acute abortive medication use, mean monthly migraine duration, and mean monthly migraine severity. Additional secondary efficacy variables included changes in the mean monthly severity of migraine-associated symptoms (photophobia, phonophobia, and nausea), change in the mean monthly frequency f migraine-associated vomiting, and response rates (based on monthly migraine days and total headache days). The Migraine-Specific Quality of Life Questionnaire (MSQ) and the Weight Satisfaction Scale Questionnaire, which measures subjective satisfaction with current weight, were administered. Treatment-emergent adverse events (TEAEs) were monitored through the end of double-blind treatment. RESULTS: The intent-to-treat population included 331 subjects (172 topiramate, 159 amitriptyline; 84.9% female; 84.6% white; mean [SD] age, 38.8 [11.0] years; mean weight, 77.1 [20.1] kg) who provided at least 1 efficacy assessment. The least squares mean (LSM) change from baseline in the mean monthly number of migraine episodes was not significantly different between the topiramate and amitriptyline groups (-2.6 and -2.7, respectively; 95% CI, -0.6 to 0.7). There were no significant differences between treatment groups in any of the prespecified secondary outcome measures. Subjects receiving topiramate had a significantly greater improvement in mean functional disability scores during migraine attacks compared with amitriptyline (LSM change: -0.33 vs -0.19; 95% CI, -0.3 to 0.0; P = 0.040) and in the role function-restrictive, role function-preventive, and emotional function domains of the MSQ (P = 0.012, P = 0.014, and P = 0.029, respectively). Subjects receiving topiramate had a mean weight loss of 2.4 kg, compared with a mean weight gain of 2.4 kg in subjects receiving amitriptyline. Subjects in the topiramate group reported an overall improvement from baseline in weight satisfaction, whereas the amitriptyline group reported an overall deterioration in weight satisfaction (P < 0.001, topiramate vs amitriptyline). TEAEs of mild or moderate severity were reported in 118 subjects (66.7%) in the topiramate group and 112 subjects (66.3%) in the amitriptyline group. Among the most common TEAEs (reported in +/-5% of subjects during the double-blind phase) in the topiramate group were paresthesia (29.9%), fatigue (16.9%), somnolence (11.9%), hypoesthesia (10.7%), and nausea (10.2%). The most commonly reported TEAEs in the amitriptyline group were dry mouth (35.5%), fatigue (24.3%), somnolence (17.8%), weight increase (13.6%), dizziness (10.7%), and sinusitis (10.7%). CONCLUSIONS: In this noninferiority study, topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes and all prespecified secondary efficacy end points. Topiramate was associated with improvement in some quality-of-life indicators compared with amitriptyline and was associated with weight loss and improved weight satisfaction.

Epidemiology, risk factors, and treatment of chronic migraine: a focus on topiramate.

The term chronic daily headache refers to a heterogeneous group of headache disorders characterized by a frequency of headaches on > or = 15 days per month. Chronic migraine is a subtype of chronic daily headache. The prevalence of chronic migraine is approximately 1%. Baseline attack frequency and acute medication overuse have been identified as potential risk factors for the progression of migraine from an episodic disorder to a chronic condition. There is an unmet patient need for effective and safe treatments for patients with chronic migraine, but data from rigorous controlled trials are limited. Previous studies have demonstrated that topiramate is an effective and safe preventive treatment for episodic migraine. In addition, pilot studies have suggested the utility of topiramate for the prevention of chronic migraine. Two randomized, double-blind, placebo-controlled, multicenter trials investigating the efficacy and safety of topiramate in the treatment of patients with chronic migraine have recently been completed. This review presents comparative data from these 2 clinical trials, which suggest that topiramate at a dose of 100 mg daily is effective and generally well tolerated in chronic migraine.

Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment.

OBJECTIVE: To evaluate the efficacy and tolerability of coadministration of rizatriptan and acetaminophen in the acute treatment of migraine. BACKGROUND: Rizatriptan is a selective 5-HT1B/1D agonist approved for the acute treatment of migraine. Acetaminophen has been studied for acute migraine treatment. In consideration of the prominent central and peripheral mechanisms in migraine, the use of "multi-mechanism therapy" is gaining momentum in the treatment of acute migraine attacks. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled trial conducted at 10 centers. Eligible patients with migraine according to International Headache Society criteria treated a single migraine attack of moderate or severe intensity within 4 h from pain onset. Patients were randomized into 1 of 4 groups (rizatriptan 10 mg + acetaminophen 1000 mg [RA], rizatriptan alone [R], acetaminophen alone [A], and placebo [P]). There were 3 co-primary hypotheses tested sequentially for 2-h pain relief: (1) RA would be superior to P; (2) if the first was fulfilled, RA would be superior to A; and (3) if the first 2 were fulfilled, RA would be superior to R. RESULTS: Of 173 patients who treated a migraine, 123 patients (71.5%) achieved pain relief within 2 h. RA (90%) was significantly better than P (46%) and A (70%), but only numerically better than R (77%) for 2-h pain relief. No significant differences were seen between the active treatment groups in adverse events. CONCLUSION: Rizatriptan coadministered with acetaminophen achieved 2 of the 3 primary hypotheses, proving superior to both acetaminophen and placebo for 2-h pain relief, but failing to achieve superiority to rizatriptan alone. RA was as well tolerated as each of the individual agents.

Analysis of safety and tolerability data obtained from over 1,500 patients receiving topiramate for migraine prevention in controlled trials.

OBJECTIVE: Topiramate is an effective and generally well-tolerated migraine preventive therapy, as shown in three large, randomized, double-blind, placebo-controlled registration trials. Based upon efficacy/tolerability, topiramate 100 mg/day (50 mg BID) is the recommended target dose for most patients with migraine. To further assess the safety and tolerability of topiramate for migraine prevention, we analyzed safety data from 1,580 patients who participated in the three pivotal registration trials or an earlier pilot, randomized, double-blind, placebo-controlled trial. METHODS: The safety population consisted of all patients who took >or=1 dose of study medication during the double-blind phase (topiramate 50 mg/day [N = 235], 100 mg/day [N = 386], 200 mg/day [N = 514], or placebo [N = 445]). Safety assessments included adverse event (AE) reports, physical examination, and clinical laboratory tests. RESULTS: Paresthesia was the most common topiramate-associated AE (35%, 51%, and 49% of patients receiving topiramate 50 mg/day, 100 mg/day, or 200 mg/day, respectively [6% on placebo]). The most common topiramate-associated AE were generally mild or moderate in severity and occurred at consistently higher rates during the titration period, compared with the maintenance period of the double-blind phase. AEs leading to withdrawal from the recommended dose of topiramate 100 mg/day included paresthesia (8%), fatigue (5%), nausea (2%), and difficulty with concentration (2%). Serious AEs were infrequent, occurring in 2% of 1,135 topiramate-treated patients and 3% of 445 placebo-treated patients. Patients on topiramate experienced significant decreases in mean body weight compared with placebo. CONCLUSIONS: Topiramate is generally safe and reasonably well tolerated for the prevention of migraine in adults. The most common topiramate-associated AEs were mild or moderate in severity and occurred more frequently during titration to target doses.

Elimination of migraine-associated nausea in patients treated with rizatriptan orally disintegrating tablet (ODT): a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To confirm the efficacy of rizatriptan 10 mg orally disintegrating tablet (ODT) for the elimination of migraine-associated nausea. BACKGROUND: Pooled studies of rizatriptan analyzing elimination of nausea as a secondary endpoint showed that 65% of rizatriptan patients reported elimination of nausea at 2 hours compared with 41% of patients taking placebo. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled single-attack trial enrolling adult patients with at least a 6-month history of migraine who typically experience migraine-associated nausea. Patients treated a moderate or severe migraine headache at the earliest sign of nausea with either rizatriptan 10 mg ODT or placebo (2 : 1). The primary endpoint was elimination of nausea at 2 hours postdose, and the secondary endpoint was pain relief at 2 hours postdose. RESULTS: Although not statistically significant, a greater percentage of patients had elimination of nausea at 2 hours with rizatriptan compared with placebo (70.3% vs 62.0%, P = .165, odds ratio [95% CI] = 1.45 [0.86, 2.46]). When patients were grouped by baseline headache severity, rizatriptan showed a greater advantage than placebo for patients with moderate pain (rizatriptan 72.8% vs placebo 57.4%), but no difference for patients with severe pain (rizatriptan 67.7% vs placebo 66.7%). There were significantly more patients who achieved 2-hour pain relief with rizatriptan (69.7% vs 54.3%, P = .012, odds ratio [95% CI] = 1.94 [1.16, 3.25]). CONCLUSION: Although the efficacy of rizatriptan 10 mg ODT for the elimination of migraine-associated nausea was comparable to that seen in previous rizatriptan trials, the higher-than-usual placebo response prevented a finding of a statistically significant difference. There was a sizable difference in placebo response between patients who treated moderate vs severe migraine. Rizatriptan was effective for 2-hour pain relief.

The impact of topiramate on health-related quality of life indicators in chronic migraine.

BACKGROUND: Chronic migraine is a disabling primary chronic daily headache disorder that significantly impacts the daily activities of patients with this disorder. To our knowledge, this is the first report of a large, randomized, double-blind, placebo-controlled trial that assessed the impact of topiramate on the daily activities, emotional distress, headache-related disability, and global impression of change in patients with chronic migraine. OBJECTIVE: To assess whether topiramate 100 mg/day reduces migraine-related disability and limitations of daily activities in patients with chronic migraine. STUDY DESIGN/METHODS: Patients aged > or =18 years with chronic migraine were randomized 1 : 1 ratio to topiramate 100 mg/day or placebo. The double-blind period lasted 16 weeks. Three patient-reported outcome measures were administered: Migraine Disability Assessment, Migraine-Specific Quality of Life Questionnaire (Domains: Role Function Restrictive and Preventive and Emotional Function), and Subject's Global Impression of Change. Investigators completed a Physician's Global Impression of Change for each patient. Subject's Global Impression of Change and Physician's Global Impression of Change were completed one time, at the end of study, and measured on a 7-point scale (1 = very much improved to 7 = very much worse). The Migraine-Specific Quality of Life Questionnaire was analyzed using analysis of covariance (last observation carried forward) approach. Results were not adjusted for multiplicity. RESULTS: A total of 328 patients were randomized (topiramate, n = 165; placebo, n = 163), and 306 patients were included in the intent-to-treat population. Mean age was 38.2 years, and a majority of the patients were female (85.3%). Fifty-six percent of topiramate-treated patients vs 45% of placebo-treated patients reported >50% improvement from baseline in Migraine Disability Assessment scores (P = .074). The Migraine-Specific Quality of Life Questionnaire analysis demonstrated significant improvements at week 4 in all 3 domains, and at weeks 8 and 16 in both Role Function-Restrictive and Emotional Function domains (P < .05). Role Function-Preventive approached, but did not reach significance, at week 8 (P = .053). Seventy-five percent and 72% of topiramate-treated patients vs 61% and 59% of placebo-treated patients reported improvements on the Subject and Physician's Global Impression of Change scales (P = .025 and P = .037, respectively). CONCLUSION: Compared with placebo-treated patients, topiramate 100 mg/day appears to contribute to reductions in migraine-related limitations on daily activities and emotional distress beginning as early as week 4 and continuing up to week 16 after treatment. Physician's Global Impression of Change results are very similar with Subject's Global Impression of Change, indicating concordance between the physician's and the subject's assessment of improvement.

Analysis of pooled data from two pivotal controlled trials on the efficacy of topiramate in the prevention of migraine.

CONTEXT: A substantial proportion of the patient population with migraine headache should be considered for preventive treatment based on the frequency and disability associated with this disorder. Use of the anticonvulsant topiramate was previously examined in two large, double-blind, randomized, placebo-controlled clinical trials of a subset of patients who have 3 to 12 migraine episodes per month. OBJECTIVE: To better characterize the efficacy of topiramate for prevention of migraine, with or without aura, by pooling and analyzing data from the two large clinical trials. METHODS: The pooled intent-to-treat population included 937 patients receiving topiramate at one of three dosages (50 mg/d, 100 mg/d, 200 mg/d) or placebo. Outcome measures included change in mean monthly migraine frequency and categorical responder rate throughout the 26-week doubleblind phase. RESULTS: At daily doses of 100 and 200 mg, topiramate was associated with significant reductions in mean monthly migraine frequency throughout the double-blind phase compared with placebo (P<.001). Significantly more patients treated with these topiramate doses exhibited high-percentage reductions in monthly migraine frequency (>/=50% [P<.001], >/=75% [P<.001], 100% [P=.049]) versus placebo. The most common adverse events included anorexia, cognitive deficits, diarrhea, fatigue, nausea, and paresthesia. Topiramate (100 mg/d, 200 mg/d) was associated with significant and sustained reductions in mean monthly migraine frequency beginning as early as 1 week into therapy. CONCLUSION: Pooled efficacy data from two large, similarly designed, placebo-controlled migraine-prevention trials demonstrated that a statistically significant proportion of patients using topiramate met or exceeded two main outcome guidelines recommended by the International Headache Society (>/=50% and >/=75% reduction in frequency of monthly attacks). Based on efficacy and tolerability, topiramate at a dosage of 100 mg per day (50 mg twice daily) should be the target dosage for most patients with migraine.

Pharmacological approaches to managing migraine and associated comorbidities--clinical considerations for monotherapy versus polytherapy.

Comorbidity is defined as an illness that occurs more frequently in association with a specific disorder than would be found as a coincidental association in the general population. Conditions that are frequently comorbid with migraine include depression, anxiety, stroke, epilepsy, sleep disorders, and other pain disorders. In addition, many common illnesses occur concomitantly (at the same time) with migraine and influence the treatment choice. Migraine management, and especially migraine prevention, can be challenging when patients have comorbid or concomitant illnesses. The objectives of this initiative are to review the literature on managing patients who have migraine and common comorbidities, present additional clinical approaches for care of these difficult patients, and evaluate the areas in which research is needed to establish evidence-based guidelines for the management of migraine with associated comorbid conditions.

Sumatriptan 6 mg subcutaneous as an effective migraine treatment in patients with cutaneous allodynia who historically fail to respond to oral triptans.

The objective of the study was to assess the efficacy of 6 mg subcutaneous (s.c.) sumatriptan to treat migraine and the relationship between response of migraine and cutaneous allodynia in a population of migraine patients who historically failed to respond to oral triptan medications. This was an open-label study consisting of patients with migraines who historically failed to respond to oral triptan medications. Forty-three patients were asked to treat three migraine attacks with 6 mg s.c. sumatriptan. The primary efficacy endpoint was the percentage of patients achieving relief of headache at 2 h. Ninety-one percent of the patients responded to a single dose of s.c. sumatriptan 6 mg. Fifty percent of all patients were pain-free by 2 h and over 30% had a 24-h sustained pain-free response. When administered within 90 min from the onset of migraine (i.e., during the developing phase of cutaneous allodynia), s.c. 6 mg sumatriptan proved to be effective despite the occurrence of allodynia in a group of patients, who historically had failed to respond to oral triptan medications. These findings suggest that the window of opportunity to treat allodynic patients with injectable triptans may be longer (up to 2 h) than with oral triptans (up to 1 h).

Characterization and prediction of emergency department use in chronic daily headache patients.

OBJECTIVE: To examine the characteristics of chronic daily headache sufferers who use emergency departments (EDs) and identify factors predictive of ED visits. BACKGROUND: Several large clinical trials have found that a sizable subset of headache patients uses EDs frequently, although such visits should be preventable. METHODS: Participants in two large clinical trials provided baseline data on ED use, hospitalizations, disability, daily activities, and quality of life. RESULTS: Of the 785 patients included, 182 (23.2%) reported at least 1 ED visit over the past year. Most of these patients (82.9%) reported one to six visits; however, 4.4% reported>/=21 visits (mean 5.0; SD 8.5). The percentage of patients with overnight hospitalizations during the previous year was significantly greater in the ED user group than non-ED user group (17.6% vs 1.7%; P<.001), as was the number of visits to healthcare practitioners (median 24.3 vs 11.8; P<.001). Compared with non-ED users, a higher percentage of ED users reported severe disability on the Migraine Disability Assessment Scale (MIDAS) (85.7% vs 69.3%, P<.001) and indicated that their headache more negatively impacted mood and daily activities (all P<.05). ED users also had significantly higher depression scores and lower scores on all domains of the Short Form--36 (SF--36) (all P<.05). In a logistic regression model, patient age, neurologist visit, severe (vs not severe) rating on the MIDAS, Role Physical (SF--36), and prior overnight hospitalization were significant predictors of ED use (max--rescaled R(2)=21.0%). CONCLUSIONS: Patients seeking ED treatment for chronic daily headache are more severely affected and have more unmet medical needs than those who do not use the ED. Management strategies that help prevent frequent ED use might be possible.

Evidence-based review of patient-reported outcomes with botulinum toxin type A.

This review systematically examines the effects of botulinum toxin type A (BTX-A) on patient-reported outcomes across disorders using evidence-based criteria. The evidence provided by these studies ranged from randomized, controlled trials to case series. The effects of BTX-A on quality of life or global treatment outcomes were assessed in 48 studies across 16 different conditions. All but 7 of these reported benefits of BTX-A over baseline or the comparator condition (placebo or other treatment). The effects of BTX-A on impairment, activities, or participation were assessed in 46 studies across 17 different conditions. All but 4 reported benefits of BTX-A over baseline or the comparison group. The effects of BTX-A on satisfaction or preference were assessed in 14 studies across 11 different conditions, all of which reported high rates of satisfaction with BTX-A or preference over the comparator. These studies provide evidence that BTX-A exerts meaningful benefits on the quality of life of patients treated with this biologic agent.

Divalproex sodium extended-release for the prophylaxis of migraine headache.

The Diamond Headache Clinic first began using valproic acid in 1984. Subsequently, a variety of open-label and then placebo-controlled trials were carried out with valproic acid, followed by an enteric-coated formulation known as divalproex sodium delayed-release. These trials demonstrated a consistent pattern of efficacy and the delayed-release form improved tolerability while offering a twice-daily dosing schedule. This led to the development of an extended-release formulation. This formulation further improved tolerability and led to a once-daily dosing. The pivotal trial conducted in patients with migraine with the extended-release formulation demonstrated efficacy similar to that seen with the delayed-release form.