Migraine Headache Days Research Articles

Topiramate Treatment of Chronic Migraine: A Randomized, Placebo‐Controlled Trial of Quality of Life and Other Efficacy Measures

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. 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. 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. 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). 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.

Two different doses of Amitriptyline ER in the prophylaxis of migraine: long‐term results and predictive factors

The rationale for our study was to examine the prophylactic benefit of two doses of amitriptyline over a 6-month observational period in patients with migraine. We aimed at evaluating whether 50 mg of amitryptiline extended release was more effective than 25 mg in reducing the number of migraine days. Primary outcome measure was the reduction of migraine days in time course (i.e., 3 and 6 months after patient enrolment). As secondary analyses, predictors of treatment response were evaluated. Treatment response was defined as reduction of > or =30% and > or =50% in migraine headache days in time course. The intent-to-treat population comprised 132 patients (female 96; male 36) with migraine. Median migraine days per month were reduced from 7 days (range: 6-15) at baseline, to 6 days (range: 4-12; P < 0.001) at 3 months, and to 6 days (range: 3-12; P < 0.001) at 6 months, respectively. However, no statistically significant difference in the number of migraine days was seen between the two treatment groups at 3 and 6 months. As a result of secondary analyses, the number of migraine days per month at baseline was the only independent predictor of response to amitriptyline treatment (for both definitions of treatment response, i.e., response rate > or =30% and response rate > or =50%) at 6 months. The prophylactic effect of amitriptyline seen in our study was rather weak and did not differ between the two treatment groups. The results of this 6-month, prospective, open-label clinical observation are therefore not encouraging.

Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study of the Cortical Spreading Depression Inhibiting Agent Tonabersat in Migraine Prophylaxis

Tonabersat is a novel putative migraine prophylactic agent with an unique stereospecific binding site in the brain. Tonabersat has been shown, in animal models, to inhibit experimentally induced cortical spreading depression, the likely underlying mechanism for migraine aura, and cerebrovascular responses to trigeminal nerve stimulation. The aim was to study the potential for tonabersat as a migraine preventive. A randomized, double-blind, placebo-controlled, multicentre, parallel group study recruited patients with migraine with and without aura experiencing between two and six migraine attacks per month. After a 1-month baseline they received tonabersat 20 mg daily for 2 weeks and 40 mg daily for a further 10 weeks. The primary end-point was the change in mean number of migraine headache days between the third month and the baseline period in the intention-to-treat population comparing the placebo (n = 65) and tonabersat (n = 58) groups. At the primary end-point there was a 1.0-day (95% confidence interval -0.33, 2.39; P = 0.14) difference in reduction in migraine days between tonabersat and placebo. There were 10 secondary efficacy end-points, of which two were statistically significant. In month 3 of treatment, the responder rate, defined as a 50% reduction in migraine attacks, was 62% for tonabersat and 45% for placebo (P < 0.05), and the rescue medication use was reduced in the tonabersat group compared with placebo by 1.8 days (P = 0.02). Placebo responses were particularly high for all end-points. At least one treatment-emergent adverse event was reported in the tonabersat group in 61% of patients compared with 51% in the placebo group; none was worrisome. Placebo responses were unexpectedly high in this trial, complicating straightforward interpretation of the study results. The good tolerability and promising efficacy results support further exploration of higher doses of tonabersat in larger controlled trials.

Effects of tonabersat on migraine with aura: a randomised, double-blind, placebo-controlled crossover study

Migraine with aura is thought likely to be caused by cortical spreading depression (CSD). Tonabersat inhibits CSD, and we therefore investigated whether tonabersat has a preventive effect in migraine with aura. In this randomised, double-blind, placebo-controlled crossover trial, 40 mg tonabersat once daily was compared with matched placebo in patients who had at least one aura attack per month during the past 3 months. Randomisation was by computer-generated list. Patients kept a detailed diary to enable objective diagnosis of each attack as migraine with aura, migraine without aura, or other type of headache. Primary endpoints were a reduction in aura attacks with or without headache and a reduction in migraine headache days with or without an aura. Analysis was per protocol. This trial is registered, number NCT00332007. 39 patients were included in the study, of whom 31 were included in the statistical analysis of efficacy. Median (IQR) attacks of aura were reduced from 3.2 (1.0-5.0) per 12 weeks on placebo to 1.0 (0-3.0) on tonabersat (p=0.01), whereas the other primary outcome measure, median migraine headache days with or without aura, was not significantly different between placebo and tonabersat groups (3.0 days in each group; p=0.09). Tonabersat was well tolerated but overall had more side-effects than placebo. Tonabersat showed a preventive effect on attacks of migraine aura but no efficacy on non-aura attacks, in keeping with its known inhibitory effect on CSD. The results support the theory that auras are caused by CSD and that this phenomenon is not involved in attacks without aura. Minster Pharmaceuticals; Lundbeck Foundation.

Divalproex Sodium Extended‐Release for the Prophylaxis of Migraine Headache in Adolescents: Results of a Stand‐Alone, Long‐Term Open‐Label Safety Study

The objective of this long-term open-label study in adolescents was to assess the safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches. Two formulations of divalproex sodium have demonstrated efficacy in the prevention of migraine headaches in adults. However, no medications are currently approved for this indication in adolescents, and long-term safety data on agents for migraine prevention are lacking for this younger population. Therefore, the current study was conducted to assess the long-term safety and tolerability of divalproex extended-release in adolescents with migraine headaches. This was a 12-month, phase 3, open-label, multicenter study of adolescents aged 12 to 17 years with migraine headaches diagnosed by International Headache Society criteria. Divalproex sodium extended-release was initiated at 500 mg/day for 15 days then increased to 1000 mg daily, with subsequent adjustments permitted within a dosing range of 250-1000 mg daily. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety was evaluated by adverse event collection, laboratory assessments, physical and neurological examinations, vital signs, electrocardiograms, the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, the Wechsler Abbreviated Scale of Intelligence, and the Behavioral Assessment Scale for Children. Efficacy was evaluated by following the number of migraine headache days reported in subjects' headache diaries over sequential 4-week intervals for the duration of the trial. A total of 241 subjects were enrolled and treated. The most frequently reported adverse events were nausea (19%), vomiting (18%), weight gain (12%), nasopharyngitis (11%), migraine (10%), and upper respiratory tract infection (10%). Ten (4%) subjects experienced serious adverse events, and 40 (17%) subjects discontinued because of an adverse event. Increases in ammonia levels were observed. No other clinically significant changes were observed in laboratory values, vital signs, rating scales, or electrocardiograms. Median 4-week migraine headache days decreased 75% between the first and the fourth months of the study (from 4.0 to 1.0) and remained at or below this level for the remainder of the study. In this long-term open-label study of adolescents with migraine, the safety and tolerability profile of divalproex sodium extended-release was consistent with findings from previous trials in adults, as well as 2 studies recently completed in adolescents. In general, divalproex sodium extended-release was well-tolerated in adolescents with migraine.

Migraine preventive therapy with topiramate reduces the number of migraine auras: results from PROMPT, a randomised, placebo-controlled trial

Rationale: To evaluate topiramate efficacy for prevention of migraine aura's in addition to migraine headaches. Methods: After a 4–8-week baseline period, patients entered a 26-week open-label phase (OL); topiramate was titrated from 25 to 100mg/day in weekly 25-mg steps, and could be further adjusted (range: 50–200mg/day). Dosing was kept stable for the last 4 weeks, and patients were randomised to continue this dose (n=254) or switch to placebo (n=258) for 26 weeks in the double-blind phase (DB). Trial subjects recorded the occurrence of migraine auras with or without subsequent migraine headache in a diary. The number of monthly aura days was asssessed for subjects reporting an aura at least once troughout the study, and the change in monthly aura days versus baseline was calculated for the various visits. Results: 6-month treatment with topiramate was completed by 571/818 entered subjects (70%) who experienced a significant reduction in mean monthly migraine days from 8.86at start to 4.78at month-6 (mean change: -4.08 days; p<0.001)[1]. Migraine auras were reported by 269/818 entered subjects (33%) who experienced a significant reduction in mean monthly aura days from 3.01at start to 1.66at month-6 (mean change: -1.36 days; p<0.001). Topiramate was well tolerated and adverse events were consistent with those previously observed. Conclusion: Migraine preventive treatment with topiramate resulted in a reduction in monthly aura days similar to the reduction in monthly migraine headache days. Reference: Diener HC, et al. Lancet Neurology 2007;6:1054–62.

Migraine Intervention With STARFlex Technology (MIST) Trial

Patent foramen ovale (PFO) is prevalent in patients with migraine with aura. Observational studies show that PFO closure resulted in migraine cessation or improvement in approximately 80% of such patients. We investigated the effects of PFO closure for migraine in a randomized, double-blind, sham-controlled trial. Patients who suffered from migraine with aura, experienced frequent migraine attacks, had previously failed > or = 2 classes of prophylactic treatments, and had moderate or large right-to-left shunts consistent with the presence of a PFO were randomized to transcatheter PFO closure with the STARFlex implant or to a sham procedure. Patients were followed up for 6 months. The primary efficacy end point was cessation of migraine headache 91 to 180 days after the procedure. In total, 163 of 432 patients (38%) had right-to-left shunts consistent with a moderate or large PFO. One hundred forty-seven patients were randomized. No significant difference was observed in the primary end point of migraine headache cessation between implant and sham groups (3 of 74 versus 3 of 73, respectively; P=0.51). Secondary end points also were not achieved. On exploratory analysis, excluding 2 outliers, the implant group demonstrated a greater reduction in total migraine headache days (P=0.027). As expected, the implant arm experienced more procedural serious adverse events. All events were transient. This trial confirmed the high prevalence of right-to-left shunts in patients with migraine with aura. Although no significant effect was found for primary or secondary end points, the exploratory analysis supports further investigation. The robust design of this study has served as the model for larger trials that are currently underway in the United States and Europe.

Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double‐Blind, Placebo‐Controlled Trial

To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

A Prospective, Multicenter, Randomized, Double Blind, Placebo-Controlled Trial to Evaluate the Efficacy of Patent Foramen Ovale Closure with the STARFlex Septal Repair Implant to Prevent Refractory Migraine Headaches: the MIST Trial

Observational studies demonstrated that patent foramen ovale (PFO) closure in stroke and decompression sickness patients led to the resolution of migraine in 65-90% of patients. The MIST (Migraine Intervention with STARFlex® Technology) Trial is the first trial to attempt to investigate these observations with a prospective, double-blind, placebo-controlled design. Patients aged 18-60 years with migraine with aura (according to International Headache Society 1988 classification) that was refractory to two or more classes of prophylactic medications and who had a minimum of 5 migraine headache days and 7 headache-free days per month were recruited. Transthoracic contrast echocardiography was used to detect right-to-left shunts …