Botulinum toxin type A prophylactic treatment of episodic migraine: A randomized, double-blind, placebo-controlled exploratory study

Swedish Medical Center Seattle, Seattle, Washington, United States
Headache The Journal of Head and Face Pain (Impact Factor: 3.19). 04/2007; 47(4):486-99. DOI: 10.1111/j.1526-4610.2006.00624.x
Source: PubMed

ABSTRACT This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin type A (BoNTA; BOTOX, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine headaches.
This was an 11-month randomized, double-blind, placebo-controlled, exploratory study. Patients were screened during a 30-day baseline period, and eligible patients with 4 or more migraine episodes and < or =15 headache days entered a single-blind 30-day placebo run-in period. Patients were classified as placebo nonresponders (PNR) if they had at least 4 moderate-to-severe migraine episodes and did not experience at least a 50% decrease from baseline in the frequency of migraine episodes following their placebo treatment. All other subjects were classified as placebo responders (PR). Patients were randomized within each stratum (PNR, PR) to 3 treatments with BoNTA (110 to 260 U of BoNTA per treatment cycle) or placebo at 90-day intervals using a modified follow-the-pain treatment paradigm. The primary efficacy outcome measure was the mean change from baseline in the frequency of migraine episodes for the 30 days prior to day 180 in the PNR group. Secondary efficacy measures included the proportion of patients with a decrease from baseline of 50% or more migraine episodes per 30-day period. Patients were allowed to take concomitant acute and prophylactic headache medications. Adverse events were reported.
A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20 to 65 years) entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean total dose of BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint was not met. Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the PNR stratum treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the end of the study (day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50% or more migraine episodes per 30-day period. However, in the group of patients with > or =12 headache days at baseline (and < or =15 headache days), BoNTA patients experienced a mean change from baseline of -4.0 headache episodes at day 180 compared with -1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related adverse events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due to adverse events (6 BoNTA, 1 placebo).
There were no statistically significant between-group differences in the mean change from baseline in the frequency of migraine episodes per 30-day period. There were substantial, sustained improvements during the course of the study in all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated over an active treatment period lasting 9 months.

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    • "Although comparison of doses in rats and humans can always be questioned, dose used in our experiment (3.5 U/kg) corresponds to 245 U dose in 70 kg human. BTX-A doses typically used in migraine treatment range from 100 to 260 U (Aurora et al., 2007), and in recent study which resulted in FDA approval for migraine treatment, from 155 to 195 U (Dodick et al., 2010). "
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    • "To explain these experiences, it was hypothesized that the experiences were mainly the result of a pronounced placebo effect of BoNT=A injections. Earlier, this hypothesis was denied (Blumenfeld 2004), but is supported by the data from the more recent RCTs (Mathew et al. 2005; Silberstein et al. 2005; Aurora et al. 2007; Relja et al. 2007), in which patients from both the BoNT=A and the placebo groups benefited equally from the injections they received. The magnitude of that benefit was similar to that of approved migraine treatments, such as divalproate sodium or topiramate. "
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