Botulinum is a product of the anaerobic bacterium, Clostridum Botulinum. Of the seven known immunologically distinct serotypes of these extremely potent neurotoxins, types A, B, C1, D, E, F, and G, types A and B are the only types available for routine clinical practice. Two type A preparations, Botox® (Allergan, Inc. Irvine, CA) and Dysport (Ipsen Ltd., Berkshire, UK), have been developed for commercial use and while Dysport is currently being evaluated in the US, only Botox® is available in the US at this time. Type B toxin is currently commercially available as Myobloc™ in the US and as Neurobloc in Europe. While each of these neurotoxins is similar in that they are proteins, they vary with respect to molecular weight, mechanism of action, duration of effect, and adverse effects. The bacteria synthesize each toxin initially as a single chain polypeptide. Bacterial proteases then "nick" both type A as well as type B proteins resulting in a di-chain structure consisting of one heavy and one light chain. Type A is nicked more than Type B and there is less than a 50% homology between the two toxins.
The mechanism of action of these toxins was initially linked to their ability to inhibit the release of acetylcholine from cholinergic nerve terminals; however, for many years it has been generally acknowledged that this effect does not appear to explain the apparent analgesic activity of some of these toxins. In fact much recent research has been directed toward examining other potential and actual mechanisms of action of these toxins that might better explain its analgesic effects. Inhibition of the release of glutamate, substance P, and calcitonin-gene related peptide reduced afferent input to the central nervous system through effects of the toxins on muscle spindles, and other possible effects on pain transmission independent of the effect on cholinergic transmission of these neurotoxins have been proposed based upon the results of many laboratory experiments in which it has been proposed that through a mechanism similar to that which inhibits the release of acetylcholine, these other neurotransmitters are inhibited as well.
The mechanism by which acetylcholine is released by these neurotox-ins is a multi-step process. At present, it is clearly much better understood than the mechanism by which these neurotoxins may exert their analgesic effects, although much work has been recently completed regarding its potential analgesic effect. The toxin must be internalized into the synaptic terminal for it to exert its anticholinergic effect. The first step in this process is the binding of the toxin to a receptor on the axon terminals of the cholinergic terminals. Each botulinum toxin serotype binds specifically to its own receptor irreversibly and each neither binds to nor inhibits the other serotypes' receptor. After the toxin is bound, an endosome is formed that carries the toxin into the axon terminal. The final step involves cleavage of one of the known synaptic proteins which are required for acetylcholine to be released by the axon. Botulinum toxins A, E, and C cleave synaptosome-associated protein - 25 (SNAP-25). Botulinum toxins B, D, F, and G cleave synaptobrevin also known as vesicle-associated membrane protein (VAMP). Botulinum toxin type C also cleaves syntaxin. The specific manner in which each toxin type may cleave the synaptic protein as well the specific differences in effect on inhibiting acetylcholine as well as other neurotransmitter release is under active investigation, is quite fascinating but it is beyond the scope of this chapter. In addition, it is not presently known how these differences translate into various observed beneficial as well as adverse effects.
Following injection of the toxin into the muscle, weakness occurs within a few days to a week, peaks most often within 2 weeks, and then gradually resolves with a slow return to baseline. The recovery of strength is associated with sprouting of the affected axon, and the return, for example, of cholinergic synaptic activity to the original nerve terminals. Regeneration of the cleaved synaptic protein is also required for recovery to occur. The duration of the clinical effect of the currently available neurotoxins appears to be approximately 3 months but may clearly vary from individual to individual. Additionally, the possible differences in duration of action of these toxins for different clinical conditions, for example, cervical dystonia vs. migraine headache vs. chronic low back pain has not been well studied to date. In my clinical experience, the analgesic effect of botulinum toxin depends upon the serotype used (type A - Botox typically longer than type B - Myobloc) but is almost always less than 12 weeks.
Perhaps one of the major drawbacks of botulinum toxin use is its cost. One could therefore argue that before its use is considered a degree of certainty about the presence of muscle spasm should be present, possibly accompanied by a response, even if it is partial, to muscle relaxant medication. Further, given that muscle spasm may exist on its own or be precipitated by another condition, such as prolapsed intervertebral disk, facet joint degeneration or ligament damage, response to botulinum toxin if used on its own can only be partial if the initiating condition is not adequately dealt with. If the muscle spasm is present as the only condition, then it is likely that the response to botulinum toxin may be more complete.
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