Article

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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    ABSTRACT: Botulinum toxin A (BTX-A) is approved for treatment of different cholinergic hyperactivity disorders, and, recently, migraine headache. Although suggested to act only locally, novel observations demonstrated bilateral reduction of pain after unilateral toxin injection, and proposed retrograde axonal transport, presumably in sensory neurons. However, up to now, axonal transport of BTX-A from periphery to CNS was identified only in motoneurons, but with unknown significance. We assessed the effects of low doses of BTX-A injected into the rat whisker pad (3.5 U/kg) or into the sensory trigeminal ganglion (1 U/kg) on formalin-induced facial pain. Axonal transport was prevented by colchicine injection into the trigeminal ganglion (5 mM, 2 μl). To find the possible site of action of axonally transported BTX-A, we employed immunohistochemical labeling of BTX-A-truncated synaptosomal-associated protein 25 (SNAP-25) in medullary dorsal horn of trigeminal nucleus caudalis after toxin injection into the whisker pad. Both peripheral and intraganglionic BTX-A reduce phase II of formalin-induced pain. Antinociceptive effect of BTX-A was prevented completely by colchicine. BTX-A-truncated SNAP-25 in medullary dorsal horn (spinal trigeminal nucleus) was evident 3 days following the peripheral treatment, even with low dose applied (3.5 U/kg). Presented data provide the first evidence that axonal transport of BTX-A, obligatory for its antinociceptive effects, occurs via sensory neurons and is directed to sensory nociceptive nuclei in the CNS.
    Neuroscience 07/2011; 186:201-7. DOI:10.1016/j.neuroscience.2011.04.026 · 3.33 Impact Factor
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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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    ABSTRACT: Botulinum toxin blocks the release of acetylcholine from motor nerve terminals and other cholinergic synapses. In animal studies botulinum toxin also reduces the release of neuropeptides involved in pain perception. The implications of these observations are not clear. Based on the personal experiences of headache therapists, botulinum toxin injections have been studied in patients with primary headaches, namely tension-type headache (TTH), chronic migraine (CM) and chronic daily headache (CDH). So far, the results of randomized, double-blind, placebo controlled trials on botulinum toxin in a total of 1117 patients with CDH, 1495 patients with CM, and 533 patients with TTH have been published. Botulinum toxin and placebo injections have been equally effective in these studies. In some of the studies, the magnitude of this effect was similar to that of established oral pharmacotherapy. This finding may help to explain the enthusiasm that followed the first open-label use of botulinum toxin in patients with headache. However, research is continuing to determine the efficacy of botulinum toxin in certain subgroups of patients with CM or CDH.
    Journal of Neural Transmission 02/2008; 115(4):647-51. DOI:10.1007/s00702-007-0832-3 · 2.87 Impact Factor
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