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Botulinum toxin type a treatment of painful focal neuropathies New evidence for efference of afferents.

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34. Dai X, Lercher LD, Clinton PM, et al. The trophic role of
oligodendrocytes in the basal forebrain. J Neurosci 2003;23:
5846 –5853.
35. Du YZ, Dreyfus CF. Oligodendrocytes as providers of growth
factors. J Neurosci 2002;68:647– 654.
DOI: 10.1002/ana.21466
Botulinum Toxin Type A
Treatment of Painful Focal
Neuropathies: New
Evidence for Efference of
Afferents
Without question there is a need for improved treatments for neuropathic pain, defined as pain caused by
disease or dysfunction of the nervous system.1 An ideal
treatment would be safe, effective, long-lasting, and relatively free from adverse effects, as well as inexpensive
and easy to administer. Ranoux and colleagues’ recent
clinical trial,2 published in this issue of Annals, provides Class 1 evidence in support of an effective new
approach to the treatment of focal neuropathic pain.
Although this study is an important landmark in the
treatment of neuropathic pain, limitations apply. Standard definitions of neuropathic pain encompass a variety of neuropathic processes resulting in pain, including thalamic stroke, myelopathy, radiculopathy,
neuroma, focal neuropathy, and small-fiber neuropathy. These processes lead to different abnormalities in
nociceptive signaling that share a common feature of
pain; it is unlikely that a single therapy will address all
causes of neuropathic pain. In this recent study, neuropathic pain was limited to that occurring in patients
with postherpetic neuralgia or focal nerve injury experiencing both spontaneous pain and mechanical allodynia over a defined area. Although restrictive case definitions are necessary for successful clinical trials, this
does limit the application of therapies to broader patient populations, and use of botulinum toxin type A
for all patients with neuropathic pain cannot be recommended based on this one clinical trial. Nonetheless, patients with postherpetic neuralgia and painful
focal neuropathies are an especially important group
because the current (systemic) approaches to treating
this form of neuropathic pain are limited in effectiveness and associated with potentially disabling effects on
236
Annals of Neurology
Vol 64
No 3
September 2008
cognition.3,4 Some context is necessary to interpret the
application of these results to future studies.
There is persistent controversy over the effects of
BTX-A on cutaneous pain processing. The main controversies revolve around several important questions:
(1) Are nociceptive modalities mediated by exocytic
processes? (2) If so, is the “machinery” for exocytic
pain signaling (soluble NSF attachment receptors, vesicles, pain-active molecules) present within the pertinent cell types at baseline or only in the setting of preexisting pathology? (3) Is the in vitro evidence
supportive of peripheral exocytic processes in afferent
signaling? (4) What are the relevant preclinical and
clinical pain models?
Regarding the first question, it is clear that basic signaling of painful sensations does not require exocytic
signaling in the periphery. The transduction and peripheral nerve transmission of painful heat, painful
cold, and painful pressure sensations all occur independent of peripheral exocytosis, and indeed, these pain
modalities have been little affected by treatment with
BTX-A.5–7 The processes relating to various forms of
altered pain processing, including “neurogenic inflammation,” are more complex; this is discussed later in
the context of preclinical models.
There has been some controversy surrounding
whether primary pain afferents contain the “machinery” necessary to support exocytic signaling in the periphery. In fact, a single article stands out in the literature advancing the position that essential exocytic
proteins are not present in peptidergic and nonpeptidergic small dorsal root ganglia neurons or in cutaneous nerve fibers.8 However, these findings have been
countered by prior and subsequent work.9,10 A related
question is whether primary pain afferents synthesize
and package compounds that if released would produce
pain or augment pain signaling. Intradermal application of substance P is not distinctly painful11 but more
typically produces mild itching sensations. Certainly
glutamate, the classical neurotransmitter associated
with primary afferents, is reported by some as painful
when injected subcutaneously,12 and vesicular glutamate transporter type 2 is detectible in cutaneous nerve
fibers.10 Coinjection of substance P and glutamate recently has been shown to strongly increase C-fiber discharges in vivo, whereas the effects of either alone are
more moderate.13 Calcitonin gene–related peptide
(CGRP) has been implicated in inflammatory pain signaling, and accumulating evidence supports the notion
that sensory neurons can support peripheral vesicular
release of this and other neuroactive compounds.14 –16
Interestingly, the phenotypic diversity of primary afferents means that peripheral afferent exocytosis is not
necessarily autocrine.17 Because phenotypically diverse
afferents are known to be in close proximity in peripheral C fibers,18 the implication is that afferent exocy-
tosis may result in paracrine effects, that is, release
from peptidergic axons affecting nearby nonpeptidergic
afferents. Although the interaction of phenotypically
diverse fiber types in peripheral structures is at this
point speculative, the accumulation of CGRP in cutaneous nerve vesicles is well established.19
Although in most clinical settings, BTX-A is used to
selectively block cholinergic transmission at the neuromuscular junction, there are multiple lines of in vitro
evidence to support the action of BTX-A in neurons
that are noncholinergic. BTX-A has been shown to
cleave synaptosome-associated protein of 25 kilodaltons
(SNAP-25) and persistently inhibit potassium-evoked
release of glutamate from cultured cerebellar granule
cells that are primarily glutamatergic.20 Glutamate release from hippocampal neurons was inhibited by
BTX-A,21 as was CGRP release from rat trigeminal
neurons.22 Notably, BTX-A was more potent in inhibiting potassium-induced CGRP release than that induced by capsaicin. Finally, cultured dorsal root ganglion neurons have been shown to be highly sensitive
to the effects of BTX-A on potassium-evoked substance
P release.23 In this system, BTX-A produced a persisting suppression of neurotransmitter release. The conclusion to be drawn from these studies is that BTX-A
effects are not limited to cholinergic neurons, and that
mechanisms of action other than muscle paralysis may
be important to the action of BTX-A, especially in the
context of pain processing. The extent to which peripheral treatment with BTX-A modulates central nociceptive signaling remains undefined.
The most challenging questions highlighted by the
use of BTX-A for neuropathic pain are those regarding
the mechanisms associated with various models of persistent pain and the extent to which these pain processes are mediated by exocytosis of neuroactive compounds. Unlike neuropathic pain, it is likely that most
nociceptive pain does not require peripheral exocytosis
as noted. By contrast, there is extensive evidence to
support a role for exocytosis in painful inflammatory
conditions; examples of this include upregulation of
glutamate receptors in inflamed skin24 and increased
levels of CGRP in models of interstitial cystitis.25 In
the bladder model system, BTX-A has been shown to
inhibit substance P and CGRP release after acute injury and chronic bladder inflammation. Particularly
challenging, however, are the laboratory models of neuropathic pain. These are multiple ranging from subcutaneous injection of capsaicin and ultraviolet B skin irradiation used in humans to formalin injection and
nerve ligation approaches used in animal models. Each
of these models needs to be considered separately and
weighed for relevance to human forms of neuropathic
pain before discarding BTX-A as ineffective against
neuropathic pain. It is possible using these criteria to
categorize prior studies into those where the findings
suggest possible BTX-A inefficacy at early time point,
ultraviolet B26; those where the findings may support a
dose or treatment area dependence, capsaicin and electrical stimulation studies7,27,28; and those studies that
indicate a response to BTX treatment, formalin and
sciatic nerve injury models.29 –31
Going forward, the clinical trial of BTX-A reported
here represents a significant advance in the treatment
of painful focal neuropathies. Independent confirmation of these results incorporating a multicenter treatment design would be valuable for determining the application of this technique in diverse clinical settings.
This study was exceptional in evaluating multiple outcome measures, and demonstrated efficacy in both the
primary outcome measure and in some of the associated quality-of-life measures. Including these measures
in future studies is valuable for those advising patients
and referring physicians contemplating this treatment
approach. Finally, treatment of postherpetic neuralgia
and painful focal neuropathies with BTX-A offers several distinct benefits compared with existing treatment
options. Effective, long-lasting, and potentially free
from cognitive side effects, BTX-A is a welcome addition to the treatment armamentarium.
Beth B. Murinson, MD, PhD
Department of Neurology
Johns Hopkins University School of Medicine
Baltimore, MD
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DOI: 10.1002/ana.21488
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