Biomedical Engineering Reference
In-Depth Information
inflammatory, or neuropathic) [
108
,
109
]. Chronic neuropathic pain may derive
from a previous nerve or tissue damage or may have unknown etiology and seems
to have no apparent utility [
110
-
112
]. Neuropathic pain occurs, at least, as a result
of primary lesion or chronic dysfunction in PNS or CNS pathways. It becomes a
pathophysiological condition that may persist indefinitely, also in absence of tissue
damage or noxious input, and can manifest as hyperalgesia (increased sensitivity to
normally painful stimulus) or allodynia (pain resulting from a normally sub-thresh-
old physical stimulus) [
113
]. In other words, neuropathic pain is associated with
severe painful sensory responses to innocuous or acute pain stimuli as well as to a
painful sensation, often of long duration, with no particular trigger [
111
,
114
,
115
].
The most common forms of neuropathic pain have been not clearly understood;
nonetheless they seem to involve important remodeling of pathways in both PNS
and CNS [
110
,
111
,
116
]. In particular at the beginning of pain sensation, peripheral
primary sensory afferent nerves are involved; specifically, those are medium-sized
thinly myelinated A
-fibers and small unmyelinated C-fibers, which have their
bodies in the dorsal root ganglia (DRG), that finally interface with the CNS
[
117
]. DRGs are connections located in the spinal column, they comprise the cell
body of sensory neurons which dendrites are situated in the skin, muscles, tendons,
joints, and internal organs. These afferent fibers are responsible of sensation as
touch, stretching, temperature, and pain [
118
]. Considering that chronic pain affects
about 1.5 million people worldwide and that despite the numerous treatment
options it is very difficult to practically achieve its handling, the possibility to
discover new treatments for neuropathic pain represents a great challenge. In fact,
to date, opioids are the best solution for the management of these syndromes;
nevertheless, their use in long-term therapy is not a suitable choice due to their
abuse potential and the wide range of side effects comprising low safety margins
[
111
,
119
,
120
]. It has been established that sodium channels are essential for the
capacity of DGR to transmit pain sensations. In fact, DRG neurons are
characterized by a complex pattern of sodium currents: they express both TTX-R
and TTX-S sodium currents characterized by a mixture of channels with slow and
fast kinetics [
121
]. As a consequence to trauma or injury these neurons exhibit
abnormal spontaneous activity and increased responses to a large variety of noxious
stimuli. Consistent data support the fact that hyperexcitability and spontaneous
firing are mediated by VGSCs.
d
3.2.1 VGSC Blockers for Neuropathic Pain
The current efforts to promote the use of sodium channel blockers in the treatment
of neuropathic pain translate the merging of multiple advances in related scientific
understanding. In fact, historically local anesthetics were used systemically to
alleviate pain since 1944 and phenytoin was employed for trigeminal neuralgia in
the early 1950s [
122
,
123
]. In 1962 it was reported, for the same pathology, the use
of the anticonvulsant carbamazepine [
124
]; although only in 1975 a common
mechanism of action for these drugs, involving their ability to block sodium
