**2. Mechanism of onabotulinumtoxinA**

OnabotulinumtoxinA, one of the seven serotypes secreted by the *Clostridium botulinum* bacteria, is currently approved for use in several conditions including strabismus, blepharospasm, cervical dystonia, and glabellar lines. Only serotypes A and B are used in the medical context. The toxin works by blocking various activities at neuron junctions that depend on intracellular vesicle trafficking to the membrane, such as neurotransmitter release [21, 22]. Normally, stored acetylcholine is transmitted via intracellular vesicles that fuse at the surface outer membrane. OnabotulinumtoxinA cleaves the SNAP-25 protein at the surface membrane, inhibiting the SNARE complex system of vesicular fusion and thus preventing subsequent neurotransmitter release into the nerve junction [23]. In the context of pure cosmetic treatments, this mechanism inhibits contractions of superficial musculature on the face, eliminating the folding of skin. In the context of migraine treatment, the toxin likely works by inhibiting both motor and sensory neurons. Similar to cosmetic treatment, motor neuron inhibition is beneficial to the migraine patient. If nerve irritation is caused by impingement from an overactive muscle, the myorelaxant effect would reduce this irritation. On the other hand, another mechanism of migraine headaches genesis is hypersensitivity of sensory neurons, specifically nociceptor neurons. BTX-A acts as a direct analgesic by blocking these hyperexcitable nociceptors. Studies have shown that BTX-A blocks the release of a number of nociceptive mediators, preventing the hypersensitization of peripheral nociceptors [24]. By blocking peripheral pain signaling to the central nervous system, BTX-A thus indirectly blocks central sensitization. Additionally, BTX-A has direct effects on nerves. In animal studies, BTX-A has been shown to both prevent and reverse sensitization of nociceptors [25]. If given prophylactically, BTX-A reduces the increase in spontaneous firing rate caused by later sensitization. It also reduces the spontaneous firing rate of already sensitized nociceptors [25]. Due to inhibition of the SNARE complex, the activity of chemoreceptors (TRPA1 and TRPV1) required for nociception is also reduced [26]. Importantly, recent evidence suggests that depositing BTX-A closer to nerves increases its effect, versus being distributed within a muscle group [26]. Therefore, the toxin's benefit in the prophylactic treatment of chronic migraines is likely due to several interacting effects including the inhibition of overactive motor neurons and the prevention/ reversal of nociceptor sensitization [27].

of well-designed large-scale studies demonstrated that this neurotoxin to be effective in reducing several measures of migraine symptomology [5–11]. The first major landmark study, called the PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) trials, indicated that BTX-A is indeed effective and safe in treating migraine headaches. These studies showed a statistically significant reduction in the primary endpoint of headache day frequency in chronic migraine patients. They also demonstrated significant reductions in several other measures of migraine symptomology such as cumulative hours of headaches, headache days, and days of moderate/severe headaches [9]. Further studies indicated efficacy in reducing disease burden based on patient quality of life questionnaires [10, 11]. However, studies evaluating the effect of BTX-A on episodic migraines so far have not shown significant benefits [12–15]. This led to BTX-A being approved by the Food and Drug Administration (FDA) for the treatment of chronic migraine headaches. The injection paradigm used in the PREEMPT trails was designed based on the initial injection sites reported in earlier phase II trials [16, 17]. While the PREEMPT injection protocol is proven to be effective, research is ongoing with several other BTX-A injection techniques that have been developed. One in particular is the targeted approach, which was first done to pre-screen surgical decompression and later developed into a more formal

Currently, BTX-A is used to provide safe and effective long-term treatment for chronic migraine headaches. To appreciate the differences and advantages in BTX-A injection techniques between the two specialties, it is important to understand the different targets of injection, the trigger point and nerve compression hypothesis, mechanism of action of BTX-A in the treatment of migraines, and the anatomy of various muscles and nerves has only recently been elucidated by studies done between Cleveland and Dallas [6, 7, 18–20]. In this chapter, we discuss the PREEMPT injection paradigm and the Anatomical Regional Targeted (ART)

OnabotulinumtoxinA, one of the seven serotypes secreted by the *Clostridium botulinum* bacteria, is currently approved for use in several conditions including strabismus, blepharospasm, cervical dystonia, and glabellar lines. Only serotypes A and B are used in the medical context. The toxin works by blocking various activities at neuron junctions that depend on intracellular vesicle trafficking to the membrane, such as neurotransmitter release [21, 22]. Normally, stored acetylcholine is transmitted via intracellular vesicles that fuse at the surface outer membrane. OnabotulinumtoxinA cleaves the SNAP-25 protein at the surface membrane, inhibiting the SNARE complex system of vesicular fusion and thus preventing subsequent neurotransmitter release into the nerve junction [23]. In the context of pure cosmetic treatments, this mechanism inhibits contractions of superficial musculature on the face, eliminating the folding of skin. In the context of migraine treatment, the toxin likely works by inhibiting both motor and sensory neurons. Similar to cosmetic treatment, motor neuron inhibition is beneficial to the migraine patient. If nerve irritation is caused by impingement from an overactive muscle, the myorelaxant effect would reduce this irritation. On the other hand, another

technique used solely for preventative treatment purposes.

130 Current Perspectives on Less-known Aspects of Headache

**2. Mechanism of onabotulinumtoxinA**

BTX-A paradigm.
