Critical analysis of the use of onabotulinumtoxinA (botulinum toxin type A) in migraine

Abstract

OnabotulinumtoxinA, a neurotoxin, has been studied in numerous trials as a novel preventive therapy for migraine headache. The data would support that it may be effective at reducing headache days in patients suffering from chronic migraine (≥15 headache days/month, with eight or more of those migraine headache days). The mechanism by which onabotulinumtoxinA exerts its effects on migraine is not yet understood. It is known to inhibit acetylcholine release at the neuromuscular junction, but this probably does not explain the observed antinociceptive properties noted in preclinical and clinical trials. This review will discuss the known mechanisms of action of botulinum toxin type A, and will review the available randomized, placebo-controlled trials that have looked at its efficacy as a migraine preventative. We also describe the onabotulinumtoxinA injection sites used at our institution.

Keywords: botulinum toxin; mechanism; migraine; onabotulinumtoxinA; prevention; prophylaxis.

Figure 1

Mechanism of botulinum neurotoxin type A (BoNT-A) at the neuromuscular junction. (A) Normal neurotransmitter release requires fusion of the vesicle membrane to the membrane of the presynaptic nerve terminal. This process is guided by the fusion of three proteins that make up the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex: the vesicle-associated membrane protein (VAMP or synaptobrevin) and the membrane-bound syntaxin and synaptosomeassociated protein of 25 kDa (SNAP-25). ACh is released from the vesicle, diffuses across the synaptic cleft, and binds to the acetylcholine (Ach) receptor, resulting in normal muscular contraction. (B) The heavy chain of BoNT-A binds to a ganglioside acceptor in the plasma membrane of the presynaptic nerve terminal. This leads to receptormediated endocytosis of the neurotoxin. The acidic environment of the synaptic vesicle or endosome leads to a conformational change in the toxin and eventual reduction of the linking disulfide bond, freeing the light chain. The light chain translocates to the cytosol and cleaves the C-terminal of the SNAP-25 protein. This inhibits SNARE complex formation and therefore inhibits neurotransmitter release. Note: Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.

Figure 2

US Food and Drug Administration box warning included on package insert for onabotulinumtoxinA (BOTOX^®).

Figure 3

OnabotulinumtoxinA injection sites used by the authors (see Table 3 for dosing). Note: Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.