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10 Articles in Volume 9, Issue #8
Adjunctive Psychiatric Pain Management Treatment
Deep Cervical Muscle Dysfunction and Head/Neck/Face Pain–Part 2
Hackett-Hemwall Dextrose Prolotherapy for Unresolved Elbow Pain
Intradermal BTX-A Reduces Frequency and Severity of Pain for MMD
Keeping Prescribers on Board if Certification Becomes Part of REMS
Magneto-Laser Therapy of Pulpitis and Vertebra Column Osteochondrosis
Pain and Self-regulation
Pain Care of Severely Neurally-Compromised Patients
Simultaneous Use of Opioid and Electromagnetic Treatments
The Experience of Pain

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.

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.

Figure 1. BTX affects glutamate, Substance P, CGRP, and also increases enkephalin release and resudces cholecystokinin (CCK) expression. (Adapted from Sheehan, Current Pain and Headache Reports, 2002, 6:460-469 ISSN1531-34)

Figure 2. Fixed site injections to the muscles of mastication.

For issues involving the head and neck dental pain practice, patients are much more frequently examined in a more acute phase of pain. Since the key symptom is pain, often the clinician is able to identify this is secondary to the structural dental/orthopedic/musculoskeletal irregularities. In this more acute environment, it is essential that the practitioner utilize a thorough examination to develop an accurate diagnosis. As Mahan and Okeson point out: probably greater than 75% of all “TMD” cases are essentially dysfunction of the muscles of mastication (MMD). Evaluation will usually reveal that either this is some sort of idiopathic problem (think recent restoration and/or malocclusion) or that there is a more central pathologic condition underlying MMD. If a simple dental solution has been ruled out, the practitioner is faced with a complex number of issues that can cause or mimic everything from headache to limb numbness. In a percentage of these MMD cases, the pain can be related to parafunctional activity, however it is defined. Unfortunately, the etiology of these parafunctional movements remains elusive but past research may indicate this is a habitual activity or engram. Engrams are a hypothetical means by which memory traces are stored as biophysical or biochemical change in the brain (and other neural tissue) in response to external stimuli. Karl Lashley, the behavioral psychologist who is best associated with his description of the scintillating scotoma in migraine aura, was an early proponent of engrams. As a prolific researcher into behavior and memory, including various hypothesis concerning engrams, he postulated many theories more current research can now substantiate. For example, he conceptualized that neural tissue can change over time. Current research into what is now defined as neural plasticity has lead to a much greater understanding of chronic pain models. Distilling this to its simplest elements for the dental pain practice: if analgesia and muscular spasm can be controlled15 or reduced early in treatment, positive outcomes are obtained in less time with more patient comfort?16 The typical patient presents with “TMJ” pain often diagnosed erroneously as an intra-articular issue and treated with some form of oral splint and anti-inflammatory agents. If, in fact, as the literature suggests, this often is actually pain secondary to muscles of mastication driven by parafunctional habits, then early and effective intervention might be able to subvert the neural plastic issues that may drive acute pain conditions into a chronic form.

Study Methods

We identified 32 patients with a variety of facial pain disorders from pain management and headache practice and craniofacial pain practice for treatment with BTX-A. Twenty-four were female and eight were male. Average age was 38.7 years (range = 21-73). In all cases, patients were being treated with one or more regimes including agents to reduce neuropathic pain, headache prophylaxis medications, anti-inflammatory agents and orthotic stabilization. Some of these agents were tapered in cases where BTX-A had reduced pain severity or frequency. Initially, patients in the pain clinic were treated with 25-50 units of BTX and 80-100 units in the craniofacial clinic. Then, it was decided to use a uniform dose of 100 units for each subsequent patient. In all cases, BTX-A was given intradermally. In the case of painful cervical spasm with headaches and MMD, the skin overlying the greater and lesser occipital nerve inlets was injected (see Figure 3). A skin wheal was raised in 2-3 areas in both sites. In the case of muscles of mastication disorder (MMD), fixed site injections (see Figure 3) were utilized, as we are studying this approach to treating MMD in an ongoing manner.

Figure 3. Intramuscular injection sites to the masseter and deep masseter muscles.

Results

All patients treated with intradermal BTX-A, (ID) had reductions in frequency and severity of pain. In patients with MMD and headache, average pain reductions were 85.2% based on VAS, with an average response time of 9.5 weeks (range 4-21 weeks). In patients with MMD and painful cervical spasm, there was a 71.6% reduction (VAS) in average headache frequency over an average of 8 weeks (range 4-18 weeks). In those patients with head or neck CRPS type 1 with MMD, all responded with pain reduction as well as reduced burning and allodynia. Pain reduction averaged 68.4% (VAS) over an average of 8.5 weeks (range 3-20 weeks).

A second group was identified from existing clinic patients in the craniofacial pain practice and a data analysis was done on 12 additional patients with similar symptomatic MMD who had been treated with 100 units of BTX-A intramuscularly (IM) to the masseter and deep masseter muscles bilaterally (see Figure 4). The results parallel the intradermal group as all patients treated in this second group experienced a reduction in symptoms. Average pain reduction for the ID group was 87.3% VAS with an average duration of 10.5 weeks (range 5-26 weeks). Uniformly this group also demonstrated some slight weakness of the injected muscles of mastication that was not present in the intradermal group (see Figure 5).

Figure 4. Comparison of intradermal (ID) and intermuscular (IM) injections of BTX-A on VAS pain score.

Conclusion

The results reinforce the conclusion that administering intradermal BTX-A in painful MMD states—with and without co morbid issues—suggest an excellent ability of BTX-A to reduce nocioceptive symptoms by mechanism(s) other than motor inhibition of muscle contraction. Using this novel administration of the BTX-A, the toxin fragment presumably interrupts ongoing pain signals that promote central sensitization, windup or long-term potentiation in chronic pain and headache states. Whether blockade of glutamate, Substance P, CGRP or other neuromodulators is primarily involved in this process is not known at this time. There is growing evidence to suggest an interaction of BTX-A with sensory afferents in nocioceptive fibers.17 With rapid pain reduction onset and control averaging 8.5 weeks, clinicians have ample time to initiate a coordinated approach to long term resolution.18 Likewise, other recent research also demonstrates very positive results with BTX-A injection both into the intra-articular space and into trigger points.19,20 However, the intradermal approach appears to be as effective and has the additional advantage of simplicity.

Last updated on: February 21, 2011
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