A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches

Our aim was to evaluate the safety and efficacy of botulinum toxin type A (BoNTA; BOTOX) for prophylaxis of episodic migraine. In this double-blind, placebo-controlled study, patients were randomized to 225, 150 or 75 U of BoNTA or placebo after a 30-day placebo run-in for three 90-day treatment cycles. The primary efficacy end-point was the mean reduction from baseline in the frequency of migraine episodes at day 180 in the placebo non-responder stratum. All groups (N = 495) improved, with no significant differences. At day 180, the frequency of migraine episodes was reduced from baseline means of 4.3, 4.7, 4.7 and 4.4 by 1.6, 1.7, 1.5 and 1.4 for BoNTA 225 U, 150 U and 75 U and placebo, respectively. The primary end-point was not met. Treatment-related adverse events were transient and mild to moderate. BoNTA treatment was safe and well tolerated but did not result in significantly greater improvement than placebo in this study. Several factors may have confounded the results.     

Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial

OBJECTIVES: To identify a treatment-responsive population for botulinum toxin type A (BoNTA) and to evaluate the safety and efficacy of 3 different doses of BoNTA as prophylactic treatment of chronic daily headache (CDH). PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study of BoNTA in patients with CDH was conducted from July 6, 2001, through November 7, 2003, at 28 North American study centers. Eligible patients were injected with BoNTA at 225 U, 150 U, 75 U, or placebo and returned for additional masked treatments at day 90 and day 180. Patients were assessed every 30 days for 9 months. The primary efficacy end point was the mean change from baseline in the frequency of headache-free days at day 180 for the placebo nonresponder group. RESULTS: For this study, 702 patients were enrolled and randomized. The primary efficacy end point was not met. Mean improvements from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 headache-free days per month were observed in the placebo nonresponder group treated with BoNTA at 225 U, 150 U, 75 U, or placebo, respectively (P=.44). An a priori-defined analysis of headache frequency revealed that BoNTA at 225 U or 150 U had significantly greater least squares mean changes from baseline than placebo at day 240 (-8.4, -8.6, and -6.4, respectively; P=.03 analysis of covariance). Only 27 of 702 patients (3.8%) withdrew from the study because of adverse events, which generally were transient and mild to moderate. CONCLUSIONS: Although the primary efficacy end point was not met, all groups responded to treatment. The 225 U and 150 U groups experienced a greater decrease in headache frequency than the placebo group at day 240. The placebo response was higher than expected. BoNTA was safe and well tolerated. Further study of BoNTA prophylactic treatment of CDH appears warranted.     

Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc.) for the prophylactic treatment of chronic daily headache (CDH). BACKGROUND: Several open-label and small controlled trials suggest that BoNT-A may be effective in the prophylactic treatment of headache. DESIGN AND METHODS: This was an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducted at 13 North American study centers. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders, eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT-A or placebo every 90 days and assessed every 30 days for 9 months, a period encompassing three treatment cycles. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches (per 30-day period), the proportion of patients with a decrease from baseline of 50% or greater in the frequency of headaches per 30-day period, acute medication use, and adverse events were also assessed. RESULTS: Of 571 patients assessed over the baseline period, 355 (mean age, 43.5 years; 300/355 [84.5%] female) were enrolled and randomized. At the end of the placebo run-in period, 279 patients (79%) were classified as placebo nonresponders and 76 patients (21%) as placebo responders. Subsequently, patients were randomized within each group to receive either BoNT-A or placebo. In the placebo nonresponder stratum, the mean number of headache-free days at baseline was 5.8 (+/-4.7) for BoNT-A- versus 5.5 (+/-4.7) for placebo-treated patients. At day 180, placebo nonresponders treated with BoNT-A had an improved mean change from baseline of 6.7 headache-free days per 30-day period compared to a mean change from baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored BoNT-A treatment, although the difference between the groups was not statistically significant. However, a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of BoNT-A patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). Also, the mean change from baseline in the frequency of headaches per 30-day period at day 180 was -6.1 for BoNT-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 BoNT-A patients (2.3%) discontinued the study due to adverse events. The majority of treatment-related adverse events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A treatment resulted in patients having, on average, approximately seven more (1 week) headache-free days compared to baseline. Although at the primary time point (day 180) the BoNT-A treatment resulted in a 1.5 between-group difference compared to placebo, this difference was not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days, in addition to statistically significant reductions in headache frequency. BoNT-A was also well tolerated in patients with CDH.     

Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study

OBJECTIVE: To assess the efficacy and safety of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc., Irvine, CA) for the prophylaxis of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic medications. BACKGROUND: Several open-label studies and an 11-month, randomized, double-blind, placebo-controlled study suggest that BoNT-A may be an effective therapy for the prophylaxis of headaches in patients with CDH. DESIGN AND METHODS: This was a subgroup analysis of an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of adult patients with 16 or more headache days per 30-day periods conducted at 13 North American study centers. All patients had a history of migraine or probable migraine. This analysis involved data for patients who were not receiving concomitant prophylactic headache medication and who constituted 64% of the full study population. Following a 30-day screening period and a 30-day single-blind, placebo injection, eligible patients were injected with BoNT-A or placebo and assessed every 30 days for 9 months The following efficacy measures were analyzed per 30-day periods: change from baseline in number of headache-free days; change from baseline in headache frequency; proportion of patients with at least 30% or at least 50% decrease from baseline in headache frequency; and change from baseline in mean headache severity. Acute medication use was assessed, and adverse events were recorded at each study visit. RESULTS: Of the 355 patients randomized in the study, 228 (64%) were not taking prophylactic medication and were included in this analysis (117 received BoNT-A, 111 received placebo injections). Mean age was 42.4+/-10.90 years; the mean frequency of headaches per 30 days at baseline was 14.1 for the BoNT-A group and 12.9 for the placebo group (P=.205). After two injection sessions, the maximum change in the mean frequency of headaches per 30 days was -7.8 in the BoNT-A group compared with only -4.5 in the placebo group (P=.032), a statistically significant between-group difference of 3.3 headaches. The between-group difference favoring BoNT-A treatment continued to improve to 4.2 headaches after a third injection session (P=.023). In addition, BoNT-A treatment at least halved the frequency of baseline headaches in over 50% of patients after three injection sessions compared to baseline. Statistically significant differences between BoNT-A and placebo were evident for the change from baseline in headache frequency and headache severity for most time points from day 180 through day 270. Only 5 patients (4 patients receiving BoNT-A treatment; 1 patient receiving placebo) discontinued the study due to adverse events and most treatment-related events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A is an effective and well-tolerated prophylactic treatment in migraine patients with CDH who are not using other prophylactic medications.     

Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study

We studied the safety and efficacy of 0 U, 50 U, 100 U, 150 U (five sites), 86 Usub and 100 Usub (three sites) botulinum toxin type A (BoNTA; BOTOX); Allergan, Inc., Irvine, CA, USA) for the prophylaxis of chronic tension-type headache (CTTH). Three hundred patients (62.3% female; mean age 42.6 years) enrolled. For the primary endpoint, the mean change from baseline in the number of TTH-free days per month, there was no statistically significant difference between placebo and four BoNTA groups, but a significant difference favouring placebo vs. BoNTA 150 was observed (4.5 vs. 2.8 tension headache-free days/month; P = 0.007). All treatment groups improved at day 60. Although efficacy was not demonstrated for the primary endpoint, at day 90, more patients in three BoNTA groups had >or=50% decrease in tension headache days than did placebo (P 相似文献   

A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis.

We examined the effects of multiple treatments with low doses of botulinum toxin type A (BoNTA; BOTOX(R), Allergan Inc., Irvine, CA) versus placebo for prophylaxis of episodic migraine. This was a series of 3 sequential, randomized, controlled studies of 418 patients with a history of 4 to 8 moderate to severe migraines per month. In study I, patients were randomized to treatment with placebo or BoNTA (7.5 U, 25 U, or 50 U) in predetermined fixed injection sites on the front and sides of the head only. In study II, patients continued to receive, or were randomized to, 2 consecutive treatments with 25 U or 50 U. In study III, patients were randomized to placebo or continuation of 25 U or 50 U. Injection cycles were each 4 months long. BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines at each time point examined (P >or= .201). No consistent, statistically significant differences were observed for any efficacy variable. Adverse events were similar among the groups within each study. In these exploratory studies of episodic migraine patients, repeated injections of low doses of BoNTA into fixed frontal, temporal, and glabellar sites were not more effective than placebo. BoNTA was safe and well tolerated. PERSPECTIVE: Beneficial effects of BoNTA in the treatment of migraine have been reported, but positive results are not universal, possibly because the optimal patient population and regimen are not yet definitively established. This study explores the effects of multiple injections of low BoNTA doses into fixed sites for episodic migraine.     

Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues

Objective.— To examine the efficacy and safety of and satisfaction with botulinum toxin type A (BoNTA; BOTOX^®: Allergan, Inc., Irvine, CA) for prophylactic treatment of migraine headache in patients previously failing prophylaxis because of issues pertaining to compliance. Background.— Numerous factors (eg, adverse effects, tolerability, cost, frequency of dosage, hesitancy to take daily medication, failure to complete treatment) negatively influence compliance with the preventive pharmacology for migraine prophylaxis. BoNTA may offer benefit in improving compliance because of its long duration of action, injectable route of administration, and its tolerability (adverse event [AE]) profile. Methods.— This was a randomized, double‐blind, single‐center, placebo‐controlled study (months 1 to 3) of BoNTA with a cross‐over to open‐label BoNTA treatment (months 4 to 6). Criteria for enrollment included patients with disabling headache (International Headache Society, International Classification of Headache Disorders [ICHD‐I] diagnosis 1.1, 1.2, 1.7, or 2.2, and Headache Impact Test [HIT]‐6 scores ≥56) previously failing prophylaxis because of compliance, tolerability, or adherence issues. After baseline evaluation, subjects were randomized 2 : 1 to a single set of BoNTA (139 units [U] total; 17 sites/6 muscle groups) or placebo injections. After month 3, only placebo‐treated subjects were eligible to receive BoNTA in the open‐label continuation study. Treatment outcomes were evaluated by headache episodes and days and maximum headache severity. Headache impact was assessed by the HIT‐6, Migraine Disability Assessment (MIDAS) score, and Quality of Life (QoL) questionnaires. Treatment satisfaction was assessed with the Migraine Impact Questionnaire (MIQ), which included MIDAS and QoL. Results.— Of the 73 subjects screened, 61 (40 BoNTA; 21 placebo) with migraine headache diagnosis 1.1 and 1.2 who met all study criteria were enrolled in the 3‐month, blinded study, with 54 completing the study; 19 of 21 placebo‐treated subjects participated in the open‐label period (months 4 to 6), with 18 completing the study. Between‐group comparisons, demonstrated through analysis of the subjects' headache diaries, did not reach statistical significance at months 1 to 3 for the number of headache episodes or days (primary endpoint). At month 2, a decrease from baseline in the number of headache episodes (?0.99 ± 2.38; P = .0147 vs 0.42 ± 3.23; P = not significant [NS]) and headache days (?1.52 ± 3.84; P = .0194 vs 0.23 ± 4.67; P = NS) was noted in the BoNTA‐treated subjects but not in the placebo‐treated subjects, respectively. During the open‐label study, BoNTA‐treated subjects had a decrease in the number of headache episodes at months 5 and 6 (?1.58 ± 2.88 and ?1.58 ± 2.85, respectively; P < .05 vs baseline for both) and headache days at months 5 and 6 (?2.84 ± 4.47 and ?2.73 ± 4.86, respectively; P < .05 vs baseline for both). BoNTA did not affect maximum headache severity compared with baseline or placebo during the first 3 months of the study. A decrease in HIT‐6 scores was significantly greater for BoNTA‐treated subjects than for placebo‐treated subjects at month 3 (?7.77 vs ?3.58, P = .0466). Within‐group decreases in HIT‐6 scores were significant in BoNTA‐treated subjects during each month of the blinded trial (?5.10 ± 8.85, ?6.63 ± 7.49, ?7.77 ± 8.78 for months 1 to 3, respectively; P < .0001 for all vs baseline) and throughout the open‐label portion of the study (?7.89 ± 6.48, ?10.39 ± 10.81, ?9.00 ± 11.12 for months 4 to 6, respectively; P < .01 for all vs baseline). The within‐group decrease in placebo‐treated subjects was significant at months 1 and 3 (?3.35 ± 6.07 and ?3.58 ± 5.40, respectively; P < .05 for both). At 3 months, BoNTA was significantly better than placebo (P = .001) in the reduction of MIDAS total score. The change from baseline in the MIDAS total scores was significant in BoNTA‐treated subjects (?21.62 ± 38.70; P < .0001) but not in placebo recipients (4.76 ± 18.85; P = NS). BoNTA‐treated subjects showed improvement in 11 of 13 and 7 of 13 assessments of treatment satisfaction in MIQ at months 3 and 6, respectively, while the placebo group showed no improvement at any measured time interval in the study. At month 3 (blinded period), there were no treatment‐related AEs reported in both groups. However, there were 18 possible/probable occurrences of treatment‐related AEs in the BoNTA group. At month 6 (open‐label period), 4 treatment‐related AEs were reported, along with 2 possible occurrences. The majority of treatment‐related AEs were transient and mild to moderate in severity, with no subjects discontinuing the study because of AEs. Conclusions.— BoNTA‐treated subjects showed improvements from baseline in measures of headache frequency, and improvements from baseline and in comparison with placebo treatment in headache impact and treatment satisfaction at multiple time points in this study. However, BoNTA‐treated subjects did not differ from placebo‐treated subjects in measures of headache frequency and severity. BoNTA may be a useful treatment option for headache patients demonstrating poor compliance, adherence, or AE profile with oral prophylactic regimens.     

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.     

The prophylactic treatment of chronic daily headache

Chronic daily headache (CDH), a heterogeneous group of headache disorders occurring on at least 15 days per month, affects up to 4% to 5% of the general population. CDH disorders include transformed (or chronic) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Patients with CDH have greater disability and lower quality of life than episodic migraine patients and often overuse headache pain medications. To date, only topiramate, gabapentin, tizanidine, fluoxetine, amitriptyline, and botulinum toxin type A (BoNTA) have been evaluated as prophylactic treatment of CDH in randomized, double-blind, placebo-controlled, or active comparator-controlled trials. The evidence supporting the use of BoNTA as prophylaxis of CDH is composed of larger and longer trials, as over 1000 patients were evaluated for up to 11 months duration. Compared with placebo BoNTA has significantly reduced the frequency of headache episodes, a recommended efficacy measure for headache trials and has been demonstrated to be safe and very well tolerated with few discontinuations due to adverse events. Side effects are generally transient, mild to moderate, and nonsystemic. The results of clinical trials using traditional oral pharmacotherapy, while supportive of their use as prophylactic treatment of CDH, are limited by several factors, including small numbers of patients, the choice of efficacy measures, and short treatment periods. The use of oral agents was associated with systemic side effects, which may limit their effectiveness as prophylactic treatment of CDH.     

Chronic daily headache prophylaxis with tizanidine: a double-blind,placebo-controlled,multicenter outcome study

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.     

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.     

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.     

Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine

OBJECTIVE: To compare the efficacy and safety of botulinum toxin type A (BoNTA; BOTOX: Allergan, Inc.) and divalproex sodium (DVPX; DEPAKOTE: Abbott Laboratories) as prophylaxis in reducing disability and impact associated with migraine. BACKGROUND: There is a need for effective, well-tolerated prophylactic treatment of migraine. DESIGN/METHODS: This was a randomized, double-blind, single-center prospective study. Fifty-nine patients received either BoNTA 100 U/placebo-DVPX bid or placebo-BoNTA/DVPX 250 mg bid. BoNTA/placebo injections were given at Day 0 and at Month 3. Patients were evaluated at Months 1, 3, 6, and 9. RESULTS: Both treatments showed significant improvements in migraine disability scores and reductions in headache days and headache index. A trend to decreased headache severity was observed with BoNTA. A greater percentage of DVPX patients reported adverse events possibly related to treatment (DVPX 75.8% vs BoNTA 50%, P = .04) and discontinued because of adverse events (DVPX 27.6% vs BoNTA 3.3%, P = .012). CONCLUSIONS: Both BoNTA and DVPX significantly reduced disability associated with migraine; BoNTA had a favorable tolerability profile compared with DVPX.     

Divalproex sodium in migraine prophylaxis: a dose-controlled study

Objective : To evaluate the efficacy and safety of divalproex sodium (DVPX) when used as prophylactic monotherapy in patients with migraine. Design : Multicenter, double-blind, placebo-controlled, parallel group. Patients were previously untreated or had failed no more than two adequate trials of prophylactic therapy. During the 4-week (single-blind) baseline, patients received placebo and completed a headache diary. Patients with two or more migraine attacks during the baseline were randomized to receive a DVPX daily dose of 500, 1000, or 1500 mg, or to placebo. The experimental phase (EP) lasted 12 weeks, the first 4 weeks for dose escalation to randomized dose, and the remaining 8 weeks for maintenance at that dose. The primary efficacy variable was 4-week migraine attack frequency during the EP. Results : One-hundred-and-seventy-six patients (44 placebo, 132 DVPX) were randomized; 171 provided efficacy data and 137 completed the study. During the EP, after adjustment for differences in baseline migraine attack frequencies, mean reductions in the DVPX groups were 1.7 (500 mg), 2.0 (1000 mg) and 1.7 (1500 mg) migraine attacks per 4 weeks compared to a mean reduction of 0.5 migraine attacks in the placebo group ( p 0.05 vs placebo). Forty-four to 45% of DVPX-treated patients, compared to 21% of patients in the placebo group achieved 50% reduction in their migraine attack frequencies ( p 0.05 vs placebo). The recommended initial dose of DVPX in migraine prophylaxis is 500 mg per day, although some patients may benefit from higher doses. Adverse events were similar in the DVPX and placebo treatment groups except for nausea, dizziness and tremor, in which incidence rates were significantly higher in the DVPX 1500 mg group (nausea was also higher in 500 mg group) than in the placebo group. Conclusion : Divalproex sodium is an effective prophylactic treatment in migraine and is generally well tolerated.     

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 :     

Laser acupuncture in children with headache: a double-blind, randomized, bicenter, placebo-controlled trial

To investigate whether laser acupuncture is efficacious in children with headache and if active laser treatment is superior to placebo laser treatment in a prospective, randomized, double-blind, placebo-controlled trial of low level laser acupuncture in 43 children (mean age (SD) 12.3 (+/-2.6) years) with headache (either migraine (22 patients) or tension type headache (21 patients)). Patients were randomized to receive a course of 4 treatments over 4 weeks with either active or placebo laser. The treatment was highly individualised based on criteria of Traditional Chinese medicine (TCM). The primary outcome measure was a difference in numbers of headache days between baseline and the 4 months after randomization. Secondary outcome measures included a change in headache severity using a 10 cm Visual Analogue Scale (VAS) for pain and a change in monthly hours with headache. Measurements were taken during 4 weeks before randomization (baseline), at weeks 1-4, 5-8, 9-12 and 13-16 from baseline. The mean number of headaches per month decreased significantly by 6.4 days in the treated group (p<0.001) and by 1.0 days in the placebo group (p=0.22). Secondary outcome measures headache severity and monthly hours with headache decreased as well significantly at all time points compared to baseline (p<0.001) and were as well significantly lower than those of the placebo group at all time points (p<0.001). We conclude that laser acupuncture can provide a significant benefit for children with headache with active laser treatment being clearly more effective than placebo laser treatment.     

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.     

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.     

Topiramate as an adjunctive treatment in migraine prophylaxis

BACKGROUND: Anticonvulsants now are commonly used for headache prevention. Topiramate, one of the newer anticonvulsants, recently has been demonstrated to be effective as monotherapy for migraine prophylaxis. OBJECTIVE: To assess the efficacy, safety, and tolerability of topiramate as adjunctive prophylactic therapy for migraine. MATERIAL AND METHODS: A prospective trial involving patients with more than 3 migraine attacks per month was performed. Patients continued their usual prophylactic treatment. Baseline analgesic use and frequency and duration of migraine attacks were recorded. A 4-point visual analog scale evaluated severity. Laboratory tests, electrocardiogram, and computed tomography or magnetic resonance imaging were performed before study entry. After informed consent was obtained, patients were instructed to take 25 mg of topiramate per day, with 25- to 50-mg weekly increments to a maximum of 100 mg per day. Safety was assessed at the first month; tolerability and efficacy were assessed every week for the first month and then every month for 3 months. Effectiveness was assessed by comparing baseline and on-treatment migraine status, and data were analyzed by the Fisher exact test. RESULTS: Twenty-five women and 11 men (mean age, 44 years) were evaluated. Existing prophylactic treatment was either propranolol or flunarizine (or both) in 80% of the patients. At 3 months of therapy with topiramate, headache frequency decreased from 17 to 3 episodes per month, headache duration from 559 to 32 minutes, and intensity from 9 to 1 by visual analog scale (P <.001). Improvement in frequency and severity of migraine was observed in 83% of patients. Slight or no changes in headache were observed in 6 patients. Tolerability was good in 30 patients. The most common side effects were acroparesthesias, weight loss, sleepiness, and headache worsening. No adverse interaction with propranolol or flunarizine was observed. CONCLUSIONS: These results suggest that topiramate is efficacious and safe as an adjunctive treatment in patients with migraine whose prior response to prophylactic management has been less than satisfactory.     

Migraine Prophylaxis with Salmon Calcitonin: a Cross-over Double-blind, Placebo-controlled Study

SYNOPSIS
Ten women with histories of migraine attacks and with diagnosis of classic or common migraineconcluded a double-blind, placebo controlled, cross-over study to assess the effectiveness of syntheticsalmon calcitonin 100 MRC U. i.m. a day in preventing migraine attacks. After a two-month run-in phase thewomen were randomly allocated to one of the following two-month sequences: placebo-calcitonin orcalcitonin-placebo. The patients filled in every day a standard card with number, duration and severity ofattacks. The mean migraine frequency per month on calcitonin was 3.7±0.7 (s.e.m.) and on placebo 7.7±1.3(r<0.01). The ratio of total score of headache intensity to the number of days of observation on calcitoninwas 0.18±0.03 and on placebo was 0.30±0.04 (r<0.01). It is concluded that calcitonin is effective forprophylactic treatment of migraine and should be useful when other first-choice treatments arecontraindicated.