Study
Study design
Population and treatment
Results
Topiramate
Silvestrini et al. [5]
Double-blind, randomized, placebo-controlled, parallel group trial
Low dose treatment (50 mg/day), 28 patients with chronic migraine and medication overuse, 9-week treatment phase
Baseline headache frequency 20.8 days.
28-day headache frequency 8.1 ± 8.1 with topiramate versus 20.6 ± 3.4 for placebo (P < 0.0007),
Silber-stein et al. [6]
Double-blind, randomized, placebo-controlled, parallel group, multicenter trial
306 patients (intent-to-treat population) with chronic migraine,aand without medication overuse
153 in treatment group and 153 given placebo, 16 weeks treatment (4-week titration period, 12-week maintenance phase)
Topiramate, 6.4 ± 5.8 days (baseline frequency 17.1 days)
Placebo, 4.7 ± 6.1 days (baseline frequency 17.0 days)
Significant reduction in mean number of migraine days per month, P = 0.01:
Diener et al. [7]
Double-blind, randomized, placebo-controlled, parallel-group, multicenter trial
59 patients (intent-to-treat population) with chronic migraine,bmost of whom had medication overuse with triptans
32 in treatment group and 27 given placebo, 16 weeks treatmentc
Significant reduction from baseline in the mean number of migraine days per month, P = 0.02
Topiramate, baseline frequency 15.5 ± 4.6, reduction 3.5 ± 6.3 days
Placebo, baseline 16.4 ± 4.4, reduction 0.2 ± 4.7 days
There was a key difference between the US and EU trials: patients were allowed to take acute rescue medication as usual during the EU trial, but not during the US trial. Remarkably, the benefits of topiramate extended to the subgroup of patients overusing acute medications, as demonstrated by significant reductions in mean monthly migraine days over placebo (−3.5 days for topiramate vs. +0.2 days for placebo). Topiramate decreased the number of days per month with acute medication intake versus placebo (reduction of 3 days/month for topiramate vs 0.7 days/month for placebo). The difference, however, was not statistically significant. Adverse events of topiramate were consistent with those observed in previous clinical trials: paresthesia and nausea. A particular finding in the European study was the absence of a placebo response, considering the fact that patients continued to overuse acute headache medications throughout the study. Both trials demonstrated the efficacy and safety of topiramate in chronic migraine patient populations, and the efficacy was maintained regardless of the presence or absence of medication overuse [9].
Combination therapy of topiramate plus propranolol versus topiramate alone was investigated in a randomized, double blind trial in 171 patients with CM [10]. Combination therapy was not superior to monotherapy and therefore cannot be recommended [4].
8.1.2 Onabotulinum Toxin Type A
Onabotulinum toxin type A has been reported to relieve pain associated with a variety of conditions [11–14], and is approved for use as prophylactic therapy in patients with chronic migraine. Unlike its function at the neuromuscular junction, the mechanism of action of onabotulinum toxin type A in migraine relief is at present not understood. A number of placebo-controlled trials in episodic migraine and chronic daily headache failed to show the efficacy of onabotulinum toxin type A [15–20]. Post-hoc analyses indicated that perhaps migraine patients with frequent headache might benefit from this treatment [21]. Therefore, the Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program evaluated the efficacy and safety of onabotulinum toxin type A as a prophylactic treatment for adults with chronic migraine. Two phase 3, multicenter studies (PREEMPT 1 and 2) were conducted. A total of 1384 patients with chronic migraine were enrolled across both trials [22, 23]. Patients were randomized (1:1) to either onabotulinum toxin type A or placebo injections and stratified based on whether they were overusing acute headache medication at baseline. The minimum dose of onabotulinum toxin type A was 155 U, administered to 31 sites in seven head and neck muscles [24]. PREEMPT 1 failed its primary endpoint, which was reduction in headache episodes. A statistically significant improvement from baseline in frequency of headache episodes was greater for onabotulinum toxin type A than for placebo in PREEMPT 2, although this was not the primary endpoint, which was changed prior to breaking the blind to headache days. Statistically significant reductions from baseline in frequency of headache days were observed after onabotulinum toxin type A treatment compared with placebo treatment in both PREEMPT 1 and 2. In the pooled analysis, the reduction in headache days after 6 months was 8.4 days from a baseline frequency of 19.9 days for onabotulinum toxin type A and 6.6 days from baseline 19.8 days for placebo with a therapeutic gain of ±11 % [24]. In a study in Spain, the long-term efficacy of onabotulinum toxin type A was investigated in 132 patients with chronic migraine. Efficacy was achieved in 82 % after 1 year. Treatment beyond 1 year results in failure in 14 out of 108 patients [25]. This indicates that onabotulinum toxin type A shows the efficacy beyond the time period studies in randomized trials. In an open study in the UK with 254 patients with CM, onabotulinum toxin type A significantly reduced the number of headache and migraine days [26]. Onabotulinum toxin type A is the only drug approved for the treatment of chronic migraine by the FDA (Table 8.2)
Table 8.2
Results from phase III trials of onabotulinum toxin type A
Study site | End points | Results |
|---|---|---|
PREEMPT 1 [22] | ||
56 sites in the USA | Primary: change in frequency of headache episodes at week 24 compared with baseline Secondary: change in frequency of headache days at week 24 compared with baseline | No significant improvement in frequency of headache episodes Significant reduction in frequency of headache days, P = 0.006 |
PREEMPT 2 [23] | ||
50 sites in the USA and 16 sites in Europe | Primary: change in frequency of headache days at week 24 compared with baseline Secondary: change in frequency of headache episodes at week 24 compared with baseline | Significant reduction in frequency of headache days, P < 0.001 Significant improvement in frequency of headache episodes |
Pooled analysis of results from PREEMPT 1 and 2 [24] | ||
NA | NA | Significant reduction in headache days after 6 months in treatment vs placebo groups, P <0.001: Treatment, 8.4 days (baseline frequency 19.9 days) Placebo, 6.6 days (baseline frequency 19.8 days) with a therapeutic gain of ±11 %. Significant difference in other efficacy variables, favoring treatment, including: frequency of migraine episodes, migraine days, and severe headache days; cumulative hours of headache/day; proportion of patients with severe disability. Intake of medication to treat acute migraine attacks was not different between placebo and treatment groups (however, in post hoc analysis, intake of triptans was significantly reduced in treatment group) < div class='tao-gold-member'>
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