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Intradermal BTX-A Reduces Frequency and Severity of Pain for MMD

Intradermal Botulinum Toxin in painful dysfunction of the muscles of mastication (MMD) suggest an excellent ability of BTX-A to reduce nocioceptive symptoms by mechanism(s) other than motor inhibition of muscle contraction.
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Ever since German physician Justinus Kerner first described possible therapeutic applications of clostri-dium botulinum toxin in 1822,1 there has been an increasing interest in pursuit of new treatment with this toxin. In the past several decades, the pace of investigating this unusual toxin has blossomed exponentially. Today we know of seven distinct and separate serotypes (collectively BTX) with varying potency, species specificity and target receptors which result in neuromuscular blocking effect. The toxin was first used clinically in the 1950s but a useful presence to the medical community became apparent when Alan Scott2 utilized it in clinical trials in the 1970s. Allergan® purchased the rights to the “A” serotype (BTX-A) and, by 1989, Botox® was approved by the FDA. Myobloc® was approved in for cervical dystonia in December 2000 and Dysport® was approved in April 2009. In July of 2009, new drug names were established for various marketed forms of botulinum toxin. Botox and Botox Cosmetic® are identified as onabotulinumtoxinA, Myobloc as rimabotulinumtoxinB and Dysport as abobotulinumtoxinA.

The BTX molecule is synthesized as a single 150kD (kilodalton, a measure of atomic mass) chain formed in two parts connected by a disulfide chain. The molecule is further characterized by its light (50kDa) and heavy (100kDa) chains. Essentially, BTX is shown to work through inclusion in the cholinergic nerve endings, cleavage and binding to SNARE (soluble NSF attachment receptor) protein receptors thus preventing acetylcholine release into the synaptic cleft. This activity results in the well-established effect of muscle paresis, often explained as “three days to take effect, three weeks to maximal and three-six months duration.” Complete recovery and original neuromuscular junction regeneration has been demonstrated. In the early years of clinical use, physicians and patients experienced effects that could not easily be explained by the then accepted model of action. Pain relief was reported that did not coincide in proportion with its activity on muscle locally.3

BTX Mode of Action

Current research now appears to reconfirm the findings of Wiegand in 19764 suggesting axonal migration and secondary central effects.5 Just recently, Antonucci was able to demonstrate “intracellular trafficking” of active BTX-A.6 The key relevance here is the data showing retrograde transport of BTX-A from facial motor neurons to the ipsilateral side of the facial nucleus in the brain stem. Once present centrally, multiple effects seem to be taking place including changes in cortical excit-ability, sensory input and neuronal plastic changes secondary to denervation.7-9

Research data and post marketing reports confirm that BTX has more diverse pharmacological effects that go beyond its action on cholinergic motor nerve fibers. The number of studies and trials has grown exponentially as the mode of action for BTX becomes more transparent. In addition, the FDA has established a black box advisory dealing with distant transport of the toxin (see Table 1).

Table 1. FDA black box advisory for BTX
Distant Spread of Toxin Effect
Post marketing reports indicate that the effects of BOTOX® and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses.

Distant Spread of Toxin Effect

Post marketing reports indicate that the effects of Botox and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children and adults, and in approved indications, cases of spread of effect have occurred at doses comparable to those used to treat cervical dystonia and at lower doses.

From the original understanding that BTX blocks acetylcholine, we now have research that there may be a number of entities in the pain pathway that BTX may affect. Coupled with novel approaches to delivery (intramuscular, intradermal, intra-articular, epidural, intrathecal) there may indeed be reason to be optimistic that BTX could be a useful new mode for treating multiple kinds of painful disorders. Recent studies have shown that BTX appears to have an independent anti-nocioceptive action.10 Investigations suggest that the actions of BTX affect glutamate, substance P, calcitonin gene-related peptide (CGRP), as well as acetylcholine. These elements play prominent roles in nociceptive responses in peripheral sensitization. This can result in central sensitization in the spinal cord in chronic painful states. BTX has been thought to act on peripheral nociceptive sites but data also exists supporting a central analgesic effect from BTX transport to the CNS. In addition to the effects on glutamate, Substance P and CGRP, it appears that BTX also increases enke-phalin release and reduces cholecystokinin (CCK) expression.11-14 (See Figure 2.) While the use of BTX in managing pain disorders is still in its infancy, there are clinical trial-supported uses in augmenting conventional treatments of a myriad of pain and headache issues.

Last updated on: February 21, 2011
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