Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Topiramate for migraine prevention in adolescents: a pooled analysis of efficacy and safety

OBJECTIVE: To characterize the efficacy and safety of topiramate for migraine prevention in adolescents from 3 randomized, 26-week, double-blind, placebo-controlled trials. BACKGROUND: Limited information is available regarding the efficacy and safety of prophylactic medications for treatment of adolescent migraine, a significant health problem. In studies that included adults and children, topiramate 100 and 200 mg/day were effective and generally well-tolerated in the prevention of migraine headache. METHODS: We performed a post hoc subset analysis of the efficacy and safety data from the 51 patients, ages 12-17 years, enrolled in 3 pivotal trials of topiramate for migraine prophylaxis. RESULTS: Daily treatment with topiramate 50, 100, and 200 mg for 26 weeks reduced monthly migraine frequency from baseline 46% (P= .07), 63% (P= .02), and 65% (P= .04), respectively, compared with placebo (16%). Similarly, topiramate reduced both the monthly mean number of migraine days (1, 4, and 5 days for topiramate 50, 100, and 200 mg/day, respectively, vs 1 day for placebo) and percentage of days during which acute migraine medications were administered (59%, 54%, and 67% for topiramate 50, 100, and 200 mg/day, respectively, vs 42% for placebo), although the treatment differences did not reach nominal statistical significance. Topiramate 200 mg/day did not appear to offer greater efficacy than 100 mg/day. Treatment was generally well-tolerated, although adverse events were most frequent in the 200 mg/day dose group. CONCLUSIONS: This post hoc subset analysis suggests that topiramate 100 and 200 mg/day, and possibly 50 mg/day, administered prophylactically for 26 weeks may reduce migraine in adolescents.     

Topiramate for migraine prevention in children: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To assess the efficacy and safety of topiramate for the prevention of pediatric migraine with or without aura in a double-blind, randomized, placebo-controlled trial. BACKGROUND: Treatment options for pediatric migraine are currently limited, and no migraine preventive agents are approved for use in children in the United States. Topiramate is an effective migraine preventive therapy in adults, as demonstrated in several large, randomized, placebo-controlled trials. METHODS: One hundred and sixty-two children with migraine (age, 6 to 15 years) were randomized in a 2:1 ratio to receive topiramate (n = 112) or placebo (n = 50). This study was designed to ensure that 150 participants were randomized to study medication. An additional 12 qualified patients were randomized because they had successfully completed the screening phase. The double-blind phase of the trial consisted of a titration period and a maintenance period. Topiramate was initiated at 15 mg/day and titrated over 8 weeks to 2 to 3 mg/kg per day, or maximum tolerated dose, whichever was less (maximum allowed dose was 200 mg/day). The target dose was maintained for 12 weeks. The primary efficacy variable was the change in mean number of migraine days per month (28 days) during the double-blind phase relative to the 4-week prospective baseline phase for each treatment group. RESULTS: Topiramate treatment was associated with a mean reduction over the entire double-blind phase of 2.6 migraine days per month, compared with a mean reduction of 2.0 migraine days per month for placebo (P = .061 topiramate vs. placebo). A significantly greater percentage of topiramate patients (32%) experienced a > or = 75% reduction in mean monthly migraine days compared with placebo (14%, P = .02). Discontinuation rates due to adverse events were low: 6.5% for the topiramate group and 4.0% for the placebo group. The adverse events that occurred most commonly in the topiramate group at an incidence rate greater than in the placebo group were: upper respiratory tract infection, anorexia, weight decrease, gastroenteritis, paresthesia, and somnolence. The mean average daily dose of topiramate during the maintenance period was 2.0 mg/kg per day. CONCLUSIONS: This pilot study suggests that topiramate may be an effective migraine preventive therapy in children. Topiramate was well tolerated in this population. Further randomized studies would be required to definitively establish the efficacy of topiramate for pediatric migraine prevention.     

Topiramate in migraine prevention: a double-blind, placebo-controlled study

OBJECTIVE: To evaluate the efficacy of topiramate in the preventative treatment of episodic migraine. BACKGROUND: Topiramate is a broad-spectrum antiepileptic drug effective for treatment of multiple seizure types in adults and children. Antiepileptic agents have demonstrated efficacy in migraine prevention, and open-label experience from our clinic has suggested that topiramate might be effective for this use. We consequently conducted a single-center, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topiramate for the preventative treatment of migraine. METHODS: Forty patients, aged 19 to 62 years (mean, 38.2 years), were randomly assigned in a 1:1 ratio to receive topiramate (n = 19; all women) or placebo (n = 21; 20 women, 1 man). Following a prospective baseline phase of 4 weeks, the study drug dose was titrated weekly in 25-mg increments over 8 weeks to 200 mg per day or to the maximum tolerated dose. The titration phase was followed by an 8-week maintenance phase. RESULTS: During the entire double-blind phase, topiramate-treated patients experienced a significantly lower 28-day migraine frequency (3.31 +/- 1.7 versus 3.83 +/- 2.1; P =.002) compared to placebo, irrespective of use of concomitant migraine prevention medications. The mean 28-day migraine frequency was reduced by 36% in patients receiving topiramate as compared with 14% in patients receiving placebo (P =.004). Twenty-six percent of the patients on topiramate and 9.5% of the patients on placebo achieved a 50% reduction in migraine frequency (P >.05). The mean dose of topiramate was 125 mg per day (range, 25 to 200 mg per day). Topiramate was well tolerated; 2 of 19 topiramate-treated patients discontinued treatment due to adverse events. Adverse effects that occurred more frequently in topiramate-treated patients included paresthesia, weight loss, altered taste, anorexia, and memory impairment. CONCLUSIONS: Preventative therapy with topiramate significantly reduced migraine frequency. Larger multicenter clinical studies may further delineate the role of topiramate in migraine prevention.     

Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study

The aim of this study was to evaluate the efficacy and tolerability of topiramate for the prevention of chronic migraine in a randomized, double-blind, placebo-controlled trial. Chronic migraine is a common form of disabling headache presenting in headache subspecialty practice. Preventive treatments are essential for chronic migraine management, although there are few or no controlled empirical trial data on their use in this patient population. Topiramate is approved for the prophylaxis of migraine headache in adults. Patients (18-65 years) who experienced chronic migraine (defined as > or =15 monthly migraine days) for > or =3 months prior to trial entry and had > or =12 migraine days during the 4-week (28-day) baseline phase were randomized to topiramate or placebo for a 16-week, double-blind trial. Topiramate was titrated (25 mg weekly) to a target dose of 100 mg/day, allowing dosing flexibility from 50 to 200 mg/day, according to patient need. Existing migraine preventive treatments, except for antiepileptic drugs, were continued throughout the trial. The primary efficacy measure was the change in number of migraine days from the 28-day baseline phase to the last 28 days of the double-blind phase in the intent-to-treat population, which consisted of all patients who received at least one dose of study medication and had one outcome assessment during the double-blind phase. Health-related quality of life was evaluated with the Migraine Specific Quality of Life Questionnaire (MSQ, Version 2.1), the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires, and tolerability was assessed by adverse event (AE) reports and early trial discontinuations. Eighty-two patients were screened. Thirty-two patients in the intent-to-treat population (mean age 46 years; 75% female) received topiramate (mean modal dose +/- SD = 100 +/- 17 mg/day) and 27 patients received placebo. Mean (+/-SD) baseline number of migraine days per 4 weeks was 15.5 +/- 4.6 in the topiramate group and 16.4 +/- 4.4 in the placebo group. Most patients (78%) met the definition for acute medication overuse at baseline. The mean duration of treatment was 100 and 92 days for topiramate- and placebo-treated patients, respectively. Study completion rates for topiramate- and placebo-treated patients were 75% and 52%, respectively. Topiramate significantly reduced the mean number of monthly migraine days (+/-SD) by 3.5 +/- 6.3, compared with placebo (-0.2 +/- 4.7, P < 0.05). No significant intergroup differences were found for MSQ and HIT-6. MIDAS showed improvement with the topiramate treatment group (P = 0.042 vs. placebo). Treatment emergent adverse events were reported by 75% of topiramate-treated patients (37%, placebo). The most common AEs, paraesthesia, nausea, dizziness, dyspepsia, fatigue, anorexia and disturbance in attention, were reported by 53%, 9%, 6%, 6%, 6%, 6% and 6% of topiramate-treated patients, respectively, vs. 7%, 0%, 0%, 0%, 0%, 4% and 4% of placebo-treated patients. This randomized, double-blind, placebo-controlled trial demonstrates that topiramate is effective and reasonably well tolerated when used for the preventive treatment of chronic migraine, even in the presence of medication overuse.     

Evaluation of Carisbamate for the Treatment of Migraine in a Randomized, Double-Blind Trial

Objective.— This study explored the dose‐response relationship of carisbamate administered at doses of 100 mg per day, 300 mg per day, or 600 mg per day, in the prevention of migraine. Background.— Carisbamate ([S]‐2‐O‐carbamoyl‐1‐o‐chlorophenyl‐ethanol; RWJ 333369) is a new chemical entity being studied for efficacy as adjunctive therapy in partial onset epilepsy. Because some antiepileptic drugs are also efficacious in migraine, for example, topiramate and valproate sodium, we tested carisbamate in migraine prophylaxis. Design/Methods.— This was a double‐blind, placebo‐controlled trial, approximately 22‐week duration. The primary efficacy variable was the percent reduction from baseline through the double‐blind phase in average monthly migraine frequency using a 48‐hour rule. Patients were randomized 1 : 1 : 1 : 1 to treatment with carisbamate 100, 300, or 600 mg per day, or placebo. Migraine attacks were counted during a prospective 4‐week baseline period, which was followed by a 2‐week titration period, a 12‐week maintenance period, a 1‐week medication reduction period, and a 3‐week observation period. Patients had an established history of migraine, with or without aura, for at least 1 year and a 3‐month history of 3‐12 migraine attacks per month. Results.— Patients (n = 323) were predominantly women (85%) and white (89%); mean age was 41 years. There were no statistically significant differences between any of the carisbamate groups and placebo (P ≥ .6) for the median (range) percentage reduction from baseline to end point in average monthly migraine frequency (P value vs placebo): 37% (?250%, 100%) for placebo; 33% (?210%, 100%; P = .7) CRS 100 mg/day; 27% (?100%, 100%; P = .8) CRS 300 mg/day; and 35% (?87%, 100%; P = .6) CRS 600 mg/day. Results for secondary efficacy measures (responder rate, percent reduction in average monthly migraine frequency using the 24‐hour rule, and percent reduction in average monthly migraine days) were consistent (P ≥ .075). The proportion of patients discontinuing because of adverse events was similar for placebo and carisbamate‐treated patients (13% each). The most common (occurring in ≥5% of patients) treatment‐emergent adverse events in patients treated with carisbamate were fatigue (17%) and nasopharyngitis (13%). Fatigue appeared to be dose related. Conclusions.— Carisbamate was not more efficacious in migraine prophylaxis than placebo in this well‐controlled study that included a suitable population. However, carisbamate monotherapy was well tolerated at doses up to 600 mg per day.     

Long-term migraine prevention with topiramate: open-label extension of pivotal trials

OBJECTIVE: To demonstrate that topiramate is an effective and generally well-tolerated migraine preventive therapy when used for up to 14 months. BACKGROUND: Topiramate 100 and 200 mg/d significantly reduced mean monthly migraine frequency during 2 large, 26-week, randomized, placebo-controlled trials. Only a small number of clinical trials have examined the long-term (> or =1 year) effectiveness and safety of migraine preventive therapies. METHODS: Five hundred sixty-seven patients with an established history of migraine with or without aura were enrolled in this 8-month, open-label extension of 2 large (49 US and 52 US and Canadian medical centers), randomized, double-blind, placebo-controlled, parallel group, 26-week trials of identical design. To be eligible for the open-label extension, patients were required to have either completed the double-blind phase of the 2 pivotal migraine prevention trials or withdrew after 4 weeks due to lack of efficacy. All eligible patients, regardless of type or dose of study medication (topiramate or placebo) received in the double-blind phase, were titrated to a clinically effective dose of open-label topiramate based on physician judgment of patient response. Efficacy of topiramate was measured as the change in mean monthly migraine frequency. RESULTS: The mean topiramate dose during the open-label extension phase was 124.7 mg/d and 150.3 mg/d for patients on placebo (n = 159) or topiramate (n = 408), respectively, during the double-blind phase (N = 567, 91% female, mean age 39.4 years). Patients on topiramate for up to 14 months had 2.2 +/- 2.4 (mean +/- SD) migraines per month after completion of the open-label extension phase (3.4 +/- 2.6 at double-blind endpoint). Patients on topiramate during the open-label extension phase only (placebo during the double-blind phase) had 3.0 +/- 2.9 migraines per month at open-label extension endpoint (4.9 +/- 3.0 migraines per month at double-blind endpoint). Discontinuation rates due to adverse events during the double-blind phase were 22.2% for patients on topiramate and 11.0% for patients on placebo. Discontinuation rates due to adverse events during the open-label extension phase were 8.6% for those patients who had already received topiramate during the double-blind phase and 20.9% for those patients who had previously received placebo. CONCLUSIONS: Patients receiving topiramate experienced a sustained reduction in migraine frequency for up to 14 months. The effectiveness and safety of topiramate was consistent with that observed during 2 26-week pivotal trials.     

Low-dose topiramate versus lamotrigine in migraine prophylaxis (the Lotolamp study)

OBJECTIVE: To assess the efficacy and safety of topiramate and lamotrigine for prophylaxis in patients with frequent migraine as compared to each other and to placebo. METHODS: Sixty patients with frequent migraine (more than 4 attacks per month) from the headache clinic at a tertiary referral centre in India were randomized to receive 50 mg topiramate/lamotrigine or matching placebo for 1 month each in 2 divided doses in 4 phases in a crossover manner with a washout period of 7 days in between. Primary efficacy measure was responder rate (50% decrease in mean migraine frequency/intensity). Secondary efficacy measures included reduction in mean monthly frequency, intensity, duration, rescue medication use, migraine associated symptoms, and adverse events. STATISTICAL ANALYSIS: Analysis was on intention to treat basis. Data were analyzed as correlated data. Generalized estimation equation was used to compute overall mean standard deviation and 95% confidence intervals for each of the outcome variables. Bonferroni's correction done for multiple comparisons. P value of < .017 was taken as significant. RESULTS: Fifty-seven patients comprised the intent-to-treat population. Four patients withdrew from the study at various phases, none because of the side effects. Responder rate for frequency was significantly higher for topiramate versus placebo (63% vs 30%, P < .001), and versus lamotrigine (63% vs 46 %, P = .02). For intensity of headache also a responder rate of topiramate versus placebo (50% vs 10%, P < .001), and versus lamotrigine (50% vs 41%, P = .01) was observed. Topiramate showed statistically significant benefits (P < .017) in most of the secondary efficacy measures while lamotrigine was beneficial for reduction in headache frequency, and migraine associated symptoms. Adverse events were similar. CONCLUSION: Low-dose topiramate is efficacious in migraine prophylaxis as compared to both placebo and lamotrigine. Lamotrigine in low doses might be beneficial for headache frequency; however, longer trials are required to establish its efficacy on the intensity and frequency of migraine.     

Assessing the ability of topiramate to improve the daily activities of patients with migraine

OBJECTIVE: To assess the impact of topiramate on the daily activities of patients with migraine. PATIENTS AND METHODS: We performed a randomized, double-blind, placebo-controlled multicenter trial Initiated on March 1, 2001, and completed on April 4, 2002. Patient-reported data from the Migraine Specific Questionnaire (MSQ) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) were collected at baseline and at weeks 8, 16, and 26 from an intent-to-treat population receiving either topiramate, 50, 100, or 200 mg/d, or placebo. Two activity-related MSQ domains (role restrictive [MSQ-RR] and role prevention [MSQ-RP]) and 2 activity-related SF-36 domains (role physical [SF36-RP] and vitality [SF36-VT]) were the prospectively designated secondary outcome measures. The changes in MSQ and SF-36 scores for each treatment group were calculated by measuring the area under the curve from week 8 (the beginning of the maintenance period) through week 26 of the double-blind phase, relative to the prospective baseline. A mixed-effect piecewise linear regression model was used to estimate average domain score over time. RESULTS: Patients receiving topiramate, 100 or 200 mg/d, had significantly reduced mean monthly (28-day) migraine frequency (P = .008 and P < .001, respectively) compared with placebo, but not patients receiving topiramate, 50 mg/d (P = .48). Topiramate significantly improved mean MSQ-RR domain scores (50 mg/d [P = .02], 100 mg/d [P< .001], and 200 mg/d [P < .001]) and mean MSQ-RP domain scores (50 mg/d [P = .007], 100 mg/d [P = .001], and 200 mg/d [P= .002]) vs placebo. Topiramate, 100 and 200 mg/d, significantly improved mean SF36-RP domain scores vs placebo (P = .02). Topiramate (all doses) improved SF36-VT domain scores, although not significantly vs placebo. Changes in prospectively designated domain scores were significantly correlated with changes in mean monthly migraine frequency (P < or = .001 [MSQ domains], P < or = .002 [SF-36 domains]). CONCLUSION: Patient-reported migraine-specific outcomes measured by the MSQ-RR and MSQ-RP domains improved significantly for those receiving topiramate (all doses) vs placebo. The SF36-RP domain scores improved significantly for patients receiving 100 or 200 mg/d of topiramate. Improvements in all 4 prospectively selected MSQ and SF-36 domains were significantly correlated with decreases in mean monthly migraine frequency.     

Prophylaxis of migraine,transformed migraine,and cluster headache with topiramate

OBJECTIVE: To assess the efficacy and tolerability of topiramate for prophylaxis of migraine and cluster headache via a retrospective chart analysis. BACKGROUND: Topiramate has multiple mechanisms of action that could potentially contribute to migraine prophylaxis. We conducted a retrospective chart review to assess the efficacy of topiramate as add-on therapy in patients with transformed migraine or cluster headache, and as first-line therapy in patients with episodic migraine. METHODS: Patients diagnosed with transformed migraine, episodic migraine, or cluster headache, who received topiramate either as add-on therapy or monotherapy were selected via retrospective chart review. Patients had begun topiramate therapy at 25 mg/day for the first week and increased their dosage by 25 mg/week to a maximum of 200 mg/day. Topiramate was used as add-on therapy for patients with transformed migraine and cluster headache, and as a first-line monotherapy in patients with episodic migraine who had no previous prophylactic therapy. The outcome parameters examined included a mean 28-day migraine frequency, migraine severity, number of headache days/month, number of abortive medication tablets/month, patient global evaluation, and the MIDAS scale. RESULTS: One hundred seventy-eight patients (transformed migraine: n = 96; episodic migraine: n = 70; and cluster headache: n = 12) were included in the retrospective analysis. The mean dose of topiramate for all patients was 87.5 mg/day. For patients with transformed migraine, mean migraine frequency decreased from 6.3/28 days to 3.7 (P = 0.005). Mean severity decreased from 7.1 to 3.8 on a 10-point scale, with 10 representing the most severe pain (P = 0.003). The mean number of headache days/month decreased from 22.1 to 9.6 (P = 0.001), and the mean number of abortive medication tablets decreased from 28.7/month to 10.6 (P = 0.001). Patient global evaluation indicated substantial or moderate improvement in 53% of patients with transformed migraine who used topiramate as add-on therapy. Mean MIDAS scale values decreased from 90.2 to 24.9 (P< 0.0001). The 70 episodic migraine patients who were administered topiramate as first-line therapy exhibited a decrease in mean migraine frequency (5.8/28 days to 1.9, P = 0.001), while mean migraine severity decreased from 8.1 to 2.0 (P = 0.003). Sixty-one percent of patients reported marked improvement. Nine of the 12 cluster headache patients exhibited substantial or moderate improvement in symptoms, whereas three had no improvement. The most common adverse effects were paresthesias (12%), cognitive effects (11%), and dizziness (6%). Eight patients discontinued topiramate due to adverse effects; cognitive effects were the most common reason. No patient discontinued topiramate treatment due to lack of efficacy. Twelve percent of patients lost more than 5 lbs during treatment (a range of 5-120 lbs). CONCLUSION: For both patients with transformed migraine (add-on therapy) and patients with episodic migraine (first-line monotherapy), topiramate yielded significant reductions in migraine frequency, migraine severity, number of headache days/month, and use of abortive medications. Topiramate also appears to be well tolerated and useful in the adjunctive treatment of cluster headache. Prospective double-blind, placebo-controlled trials will be required to confirm our results.     

Topiramate in Migraine Prevention

The efficacy of topiramate in migraine prevention (prophylaxis) was established in two multicenter, randomized, double-blind, placebo-controlled, pivotal trials. Topiramate has received regulatory approval for use in adults for migraine prophylaxis (prevention) in the US and numerous other countries, including France, Ireland, Switzerland, Brazil, Taiwan, Spain, and Australia. Treatment with 100 or 200 mg per day of topiramate was associated with significant reductions in the frequency of migraine headaches, number of migraine days, and use of acute medications. No increase in efficacy was observed between 100 and 200 mg per day of topiramate. Based on efficacy and tolerability, 100 mg per day of topiramate should be the initial target dose for most patients. The most common adverse events were paresthesia, fatigue, decreased appetite, nausea, diarrhea, weight decrease, and taste perversion. Topiramate is a first-line migraine preventive drug and should especially be considered as a preferred treatment for all patients who are concerned about gaining weight, who are currently overweight, or who have coexisting epilepsy.     

MEDICATION OVERUSE HEADACHE AND OTHER CHRONIC DAILY HEADACHES

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of chronic migraine. This was a double-blind, randomized, placebo controlled, parallel-group study. Patients suffering from chronic migraine with analgesic overuse were randomly assigned in a 1:1 ratio to receive topiramate or placebo. Following a baseline phase of eight weeks, the study drug was titrated in 25-mg increments over one week to 50 mg daily. Titration phase was followed by a 8-week maintenance phase. Number of days with headache during a 28-day period was the efficacy variable. At baseline, there was no difference in the number of days with headache between patients treated with topiramate and those treated with placebo (mean ± SD: 20.9 ± 3.2 and 20.8 ± 3.2, respectively). During the last 4 week-maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency in comparison to those treated with placebo (mean number of days with headache ± SD: 8.1 ± 8.1 vs. 20.6 ± 3.4, P < 0.0007). Topiramate at low doses proved to be an effective therapeutic approach to reduce headache frequency in patients with chronic migraine and analgesic overuse.
Comment: This is a fascinating study for a number of reasons. Topiramate (TPM) received a Food and Drug Administration (FDA) approvable letter for an indication for migraine in late 2003. In the large, randomized, controlled studies for episodic migraine, 100 mg was superior to 50 mg and placebo, and 200 mg was not significantly different from 100 mg, but had more adverse events associated with use. See the following :     

Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study

BACKGROUND: Several large, randomized, double-blind, placebo-controlled trials have found topiramate (TPM) to be effective and generally well tolerated as a preventive therapy for migraine. OBJECTIVE: This paper evaluates efficacy and safety data from a pilot study of TPM 200 mg/d as preventive therapy in adult subjects with a history of migraine with or without aura. METHODS: The pilot study had a randomized, double-blind, placebo-controlled design. Subjects were randomized in a 2:1 ratio to receive TPM 200 mg/d or placebo. The double-blind treatment phase consisted of an 8-week titration period (25 mg/d for the first week, followed by weekly increases of 25 mg) and a 12-week maintenance period. The primary efficacy measure was the change in mean monthly migraine frequency. Additional measures were the median percent reduction in monthly migraine frequency and the proportion of responders (those with > or =50%, > or =75%, or 100% reduction in monthly migraine frequency). RESULTS: The intent-to-treat (ITT) population included 211 subjects (138 TPM, 73 placebo; mean [SD] mean weight, 76.7 [18.7] kg). Of 45 subjects who discontinued the study in the TPM group, 21 discontinued during the titration period, compared with 3 of 13 subjects who discontinued in the placebo group. When the efficacy data were assessed using the per-protocol, analysis-of-covariance model, TPM 200 mg/d was not associated with a significant reduction in mean monthly migraine frequency compared with placebo. A post hoc analysis using a Poisson regression model in the ITT population suggested that TPM significantly reduced mean monthly migraine frequency compared with placebo (P=0.04). A significantly larger proportion of TPM-treated subjects had a > or =75% reduction in monthly migraine frequency compared with placebo (P=0.03). At least 1 adverse event was reported by 90.0% and 69.9% of the TPM and placebo groups, respectively. Treatment-emergent adverse events (AEs) occurring in > or =10% of subjects in the TPM group were paresthesia (45%), dizziness (16%), fatigue (16%), nausea (14%), and weight loss (14%). Most treatment-emergent AEs were rated mild or moderate in severity. Of 3 serious AEs (depression, abdominal pain, leg pain) occurring during the trial, none were considered related to either TPM or placebo. CONCLUSION: In this pilot study, mean monthly migraine frequency did not differ significantly between TPM and placebo.     

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.     

Effectiveness of topiramate in the prevention of childhood headaches

BACKGROUND: Migraine is a significant problem for many children. Topiramate has been suggested to be effective for the prophylaxis of migraine in adults, but has not yet been examined in children. The drug has been demonstrated to be safe and effective for childhood seizure disorders. The objective of this study was to demonstrate the safety and efficacy of topiramate for the prevention of pediatric migraine. METHODS: Children with frequent migraine were prescribed topiramate for headache prevention. Dosages, serum levels, and Serum Glutamic Oxalacetic Transaminase (SGOT) levels were monitored. Changes in frequency, severity, and duration of headaches were recorded and changes in headache-related disability using PedMIDAS also were measured. RESULTS: Ninety-seven children were treated with topiramate, and 75 were reevaluated 88.7 +/- 35.7 days later, 41 were seen at a second follow-up, and 17 were seen at a third follow-up evaluation. The daily dose reached at second evaluation was 84.0 +/- 38.6 mg/day or 1.42 +/- 0.74 mg/kg/day. This corresponded to a mean serum level of 2.8 +/- 1.6 micro g/mL. The mean headache frequency was reduced from 16.5 +/- 10.0 to 11.6 +/- 10.2 days per month (P<0.001) with a further reduction to 9.4 +/- 8.4 days by the second follow-up (P<0.001). Severity and duration of headache also were reduced. Headache disability improved, with a reduction of Pediatric Migraine Disability Assessment score from 36.0 +/- 42.3 to 20.8 +/- 34.0 at the first follow-up (P<0.05), 19.1 +/- 22.0 at the second follow-up (P<0.005), and 10.9 +/- 16.9 at the third follow-up (P<0.001). Most patients tolerated topiramate well. The most common side effects reported were cognitive (12.5%), weight loss (5.6%), and sensory (2.8%). CONCLUSIONS: Topiramate is potentially an effective prophylactic medication for children with frequent migraine.     

Topiramate as an adjunctive treatment for refractory partial epilepsy in the elderly

This double-blind, placebo-controlled study investigated the efficacy and tolerability of adjunctive topiramate in 86 elderly Chinese patients with refractory partial epilepsy. Patients who had at least four seizures per 4 weeks during an 8-week baseline period, despite medication with up to three standard antiepileptic drugs (AEDs), were randomly assigned to receive topiramate (n = 46) or placebo (n = 40). Topiramate dosages were titrated (target dose 200 mg/day orally) for 8 weeks and maintained at stable levels for another 12 weeks; concomitant AEDs continued at original dosages. All patients completed the study: 47.8% in the topiramate group and 7.5% on placebo reached ≥ 50% reduction in complex partial seizures. In the topiramate group, the most common adverse events were dizziness, somnolence, fatigue, headache and difficulty with memory; most events were transient and mild or moderate in severity. It was concluded that 200 mg/day topiramate was effective and well-tolerated in elderly patients with refractory partial epilepsy.     

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 ≥25% reduction: 68.6% vs 51.6% (P = .005); ≥50%: 37.3% vs 28.8% (P = .093); and ≥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.     

A double-blind, dose comparison study of topiramate for prophylaxis of basilar-type migraine in children: a pilot study

BACKGROUND: Basilar-type migraine (BM) is the most common migraine "variant," representing 3-19% of migraine in children.BMis characterized by attacks of dizziness, vertigo, visual disturbances, ataxia, and/or diplopia, followed by migraine headache. OBJECTIVE: The objective of this study is to assess the efficacy and safety of topiramate for prophylaxis of BM in children and adolescents (6-18 years). DESIGN: Outpatient, double-blind, parallel-group, dose comparison study with 2 phases: prerandomization (screening/washout and 4-week prospective baseline) and 12-week double blind (titration and maintenance). METHODS: Following consent and assent, subjects with BMs, as defined by the International Classification of Headache Disorders (second edition), and > or =4 migraines/month were randomized to receive either 25 mg per day or 100 mg per day of topiramate in a 1 : 1 ratio. RESULTS: Fourteen children (4 boys, 10 girls) completed the double-blind phase (7 in the 25-mg group and 7 in the 100-mg group). During the prospective baseline, the mean headache frequency of the combined group "all migraines" per month was 4.5/month (25 mg) and 4.8/month (100 mg). Average duration of migraine was 5.5 hours (25 mg) and 5.0 hours (100 mg) and average mean pain (5-point faces scale) was 3.3 for both (25 mg 100 mg). The reduction in median monthly migraine rate during the double-blind treatment phase relative to baseline was 2.9 (64.4%) and 3.6 (75.0%) for the 25-mg and 100-mg topiramate-treated groups, respectively (P < .001). The reduction in median monthly BM rate during the double-blind treatment phase relative to baseline was 2.5 (74.24%) and 2.3 (82.8%) for the 25-mg and 100-mg topiramate-treated groups, respectively. The overall reduction in BM attacks reduced from 2.84/month to 0.59/month (79.2%; P < .0042). Overall, 86% of patients responded with a greater than 50% reduction in migraine frequency (100%, 25 mg and 71%, 100 mg). Mean reduction in migraine duration was 18 minutes (25 mg) and 89 minutes (100 mg). There was no significant difference in migraine severity between the 2 groups. Parent Global Assessment was "very much" or "much improved" in 6 of 7 (25 mg) and 3 of 7 (100 mg) patients. Migraine disability as measured by PedMidas reduced from moderate to no disability (P < .001). There were no serious adverse events. CONCLUSIONS: Preventive therapy with topiramate resulted in reducing the overall migraine frequency and the frequency of attacks of BM at both 25 mg and 100 mg doses relative to the historical baseline and prospective baseline periods. The 2 treatment groups resulted in comparable outcomes.     

Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study

BACKGROUND: Topiramate and sodium valporate are anticonvulsants, demonstrated to be effective as monotherapy for migraine prevention in placebo-controlled trials. OBJECTIVES: To compare the relative efficacy of topiramate and sodium valporate in the prevention of migraine. PATIENTS AND METHODS: A 24-week, randomized, double-blind, crossover, clinical trial was conducted from October 2003 to September 2004. A total of 64 patients with migraine headache, aged 14 to 57 years, were randomly allocated to the 2 treatment groups. The first group received topiramate (25 mg daily increment over 1 week to 50 mg) for a total of 2 months. The second group received sodium valporate (200 mg daily increment over 1 week to 400 mg) for 2 months. Response to treatment was assessed at 0, 1, 8, 16, and 24 weeks after start of therapy. RESULTS: Topiramate appeared to be equivalent in efficacy and safety to sodium valporate. A significant decrease in duration, monthly frequency, and intensity of headache occurred in both groups. Of the 32 patients treated with sodium valporate, the mean standard deviation (SD) of monthly migraine frequency decreased from 5.4 (2.5) to 4.0 (2.8) episode per month, headache intensity from 7.7 (1.2) to 5.8 (1.7) by visual analog scale (VAS), and headache duration from 21.3 (14.6) to 12.3 (10.7) hours (P < .001). Correspondingly, in the 32 patients treated with topiramate, the mean SD of monthly headache frequency decreased from 5.4 (2.0) to 3.2 (1.9) per month, headache intensity from 6.9 (1.2) to 3.7 (1.3), and headache duration from 17.3 (8.4) to 3.9 (2.7) hours (P < .001). CONCLUSION: This study demonstrates that treatment with topiramate and sodium valporate both significantly reduce migraine headache. This effect of topiramate and sodium valporate has previously been shown to reduce migraine headache, and we postulate that treatment with topiramate and sodium valporate may have a similar benefit.     

Topiramate in the treatment of chronic migraine

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of chronic migraine. This was a double-blind, randomized, placebo controlled, parallel-group study. Patients suffering from chronic migraine with analgesic overuse were randomly assigned in a 1 : 1 ratio to receive topiramate or placebo. Following a baseline phase of eight weeks, the study drug was titrated in 25-mg increments over one week to 50 mg daily. Titration phase was followed by a 8-week maintenance phase. Number of days with headache during a 28-day period was the efficacy variable. At baseline, there was no difference in the number of days with headache between patients treated with topiramate and those treated with placebo (mean +/- SD: 20.9 +/- 3.2 and 20.8 +/- 3.2, respectively). During the last 4 week-maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency in comparison to those treated with placebo (mean number of days with headache +/- SD: 8.1 +/- 8.1 vs. 20.6 +/- 3.4, P < 0.0007). Topiramate at low doses proved to be an effective therapeutic approach to reduce headache frequency in patients with chronic migraine and analgesic overuse.