Neuropathic (increased excitability of neurons within the central

Neuropathic pain:

In 1986, the pain
defined by the International Association for the Study of Pain (IASP) as “a
sensory and emotional experience associated with real or potential injuries, or
described in terms of such injuries”. 1 Neuropathic pain is a nerve pain and a chronic type of pain caused by
damage or injury to the nerves in the central nervous system. Acute pain
is characterized by the fact of being delimited in time and disappearing with
the resolution of the pathological process. Chronic pain that persists for an
extended period of time is associated with chronic pathological processes and
causes suffering in multiple systems.1 The relation between pain and degree of injury is not obligatory.
Epidemiological studies on the prevalence of neuropathic pain indicate a high
incidence (?5%) (Bouhassira et al. 2008,Dieleman et al. 2008,
Torrance et al. 2006). Neuropathic pain may be peripheral (increased
responsiveness of peripheral nociceptors due to the action of chemicals
released around the site of injury), or central (increased excitability of
neurons within the central nervous system 11, 12. Damage to the nerves
results in structural and/or functional changes in the nervous system that
cause a variety of symptoms which may be continuous or intermittent in nature. Patients
commonly describe their pain symptoms using terms such as ‘burning’,
‘shooting’, ‘stabbing’ or ‘throbbing’.4,6 Patients may also experience
abnormal sensations such as ‘itching’, ‘numbness’, ‘tingling’ and ‘pins and
needles’4,6. Associated risk factors include gender, age, and anatomical site
of the injury. Emotional and cognitive factors influence how patients react to
chronic pain (Haythornthwaite et al. 2003), but it is much less certain if
these factors contribute to the risk of developing pain 4. The conventional
approach to neuropathic pain has been to classify and treat it on the basis of
the underlying disease (Dworkin et al. 2007). The primary disease and the
neural damage it causes are only the initiators of a cascade of changes that
lead to and sustain neuropathic pain. Although treatment targeted at the
primary pathology is obviously essential, understanding the mechanisms
responsible for the maladaptive plasticity offers specific therapeutic
opportunities to prevent the development of neuropathic hypersensitivity and
normalize function in established neuropathic pain. 4 It should be noted that
mechanisms underlying NeP are similar to those for central hypersensitivity. Central
hypersensitivity conditions differ from NeP conditions in that there is no
associated identifiable nerve damage and patients often experience sensitivity
to a variety of stimuli (e.g. light, odors, sounds) in addition to pain 5.

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Neuropathic pain (NP)
has recently been redefined as “pain arising as a direct consequence of a
lesion or disease affecting the somatosensory system.”Several recent studies
have shown that NP can adversely affect patients’ overall health-related
quality of life (HRQoL), including physical and emotional functioning,2-6 and
that it is associated with substantial societal costs.6-11Neuropathic pain is
challenging to manage, and many patients have pain that is refractory to
existing treatments.2 Comprehending the pathophysiology of peripheral neuropathy
and the mechanism of action for drugs requires a basic appreciation of the
anatomy of the somatosensory system, especially with respect to pain. Noxious
stimuli, such as thermal, chemical, and high-threshold mechanical stimuli, are
detected in the periphery and conducted to the spinal cord via two types of small
fibers. The C fibers are unmyelinated, slow-conducting, and localize pain poorly.
The A?fibers are thinly myelinated, faster-conducting, and localize pain
better.11,12 Larger and more thickly myelin-ated than A?fibers are A?and
A?fibers, which primarily transmit information about proprioception and vibration.13
It is primarily the A?and C fibers that are indiscriminately affected in the
different types of neuropathies (Figure 1). Measuring which type of fibers are
impacted is not trivial, but can be attempted by clinical examination; loss of
tactile or vibratory skin sensation or tendon reflexes are indicative of
large-fiber neuropathy, whereas alterations in lower-limb pinprick sensation
and a visual analog scale pain score >40 suggest small-fiber neuropathy.14 Small-fiber
neuropathy can  also be determined by
measuring intraepidermal nerve-fiber density following biopsy.15A?-fiber
neuropathy can be measured noninvasively by laser evoked-potential 16,17 and
contact heat-evoked potential.18,19 Nerve-conducting studies are a useful
technique for NeuP research, but less relevant for clinical studies, as they
primarily measure A?-fiber function, which supersedes small-fiber neuropathy20 and
is laborious.21 Receptors on primary sensory neurons convert environ-mental
stimuli, such as pain, into an electrical signal that is transmitted to the
dorsal root ganglia, with an important role for sodium channels.22,23 In the
terminals of the dorsal root ganglia, neurons subsequently convert this
electric signal into chemical signals by releasing neurotransmitters and neuro-peptides,
including glutamate, substance P, and calcitonin gene-related peptide into the
dorsal horn ( Figure 1). A significant event that occurs during the development
of a chronic pain state is central sensitization, where postsynaptic glutamate
(?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA and N-methyl-d-aspartate
NMDA) receptors become increasingly more adaptive in transmitting pain signals.24–28
Activation of presynaptic calcium channels can reduce the release of neurotransmitters
and dampen central sensitization (Figure 1).29,30 In the spinal cord, this
nocicep-tive signal can be modulated by inhibitory interneurons using ?-aminobutyric
acid (GABA) and glycine as their main neurotransmitters. Following the reception
of a pain signal in the cortical structures of the brain, the experience of
pain can still be suppressed by a descending system that originates from the
brain stem. This efferent system attenuates the afferent signal via
neurotransmitters, such as endogenous opioids, serotonin, and
noradrenaline.31–33 3

The two most common
types of peripheral neuropathic pain are post herpetic neuralgia (PHN) and
painful diabetic neuropathy (PDN). 7

Neuropathic pain:

In 1986, the pain
defined by the International Association for the Study of Pain (IASP) as “a
sensory and emotional experience associated with real or potential injuries, or
described in terms of such injuries”. 1 Neuropathic pain is a nerve pain and a chronic type of pain caused by
damage or injury to the nerves in the central nervous system. Acute pain
is characterized by the fact of being delimited in time and disappearing with
the resolution of the pathological process. Chronic pain that persists for an
extended period of time is associated with chronic pathological processes and
causes suffering in multiple systems.1 The relation between pain and degree of injury is not obligatory.
Epidemiological studies on the prevalence of neuropathic pain indicate a high
incidence (?5%) (Bouhassira et al. 2008,Dieleman et al. 2008,
Torrance et al. 2006). Neuropathic pain may be peripheral (increased
responsiveness of peripheral nociceptors due to the action of chemicals
released around the site of injury), or central (increased excitability of
neurons within the central nervous system 11, 12. Damage to the nerves
results in structural and/or functional changes in the nervous system that
cause a variety of symptoms which may be continuous or intermittent in nature. Patients
commonly describe their pain symptoms using terms such as ‘burning’,
‘shooting’, ‘stabbing’ or ‘throbbing’.4,6 Patients may also experience
abnormal sensations such as ‘itching’, ‘numbness’, ‘tingling’ and ‘pins and
needles’4,6. Associated risk factors include gender, age, and anatomical site
of the injury. Emotional and cognitive factors influence how patients react to
chronic pain (Haythornthwaite et al. 2003), but it is much less certain if
these factors contribute to the risk of developing pain 4. The conventional
approach to neuropathic pain has been to classify and treat it on the basis of
the underlying disease (Dworkin et al. 2007). The primary disease and the
neural damage it causes are only the initiators of a cascade of changes that
lead to and sustain neuropathic pain. Although treatment targeted at the
primary pathology is obviously essential, understanding the mechanisms
responsible for the maladaptive plasticity offers specific therapeutic
opportunities to prevent the development of neuropathic hypersensitivity and
normalize function in established neuropathic pain. 4 It should be noted that
mechanisms underlying NeP are similar to those for central hypersensitivity. Central
hypersensitivity conditions differ from NeP conditions in that there is no
associated identifiable nerve damage and patients often experience sensitivity
to a variety of stimuli (e.g. light, odors, sounds) in addition to pain 5.

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Neuropathic pain (NP)
has recently been redefined as “pain arising as a direct consequence of a
lesion or disease affecting the somatosensory system.”Several recent studies
have shown that NP can adversely affect patients’ overall health-related
quality of life (HRQoL), including physical and emotional functioning,2-6 and
that it is associated with substantial societal costs.6-11Neuropathic pain is
challenging to manage, and many patients have pain that is refractory to
existing treatments.2 Comprehending the pathophysiology of peripheral neuropathy
and the mechanism of action for drugs requires a basic appreciation of the
anatomy of the somatosensory system, especially with respect to pain. Noxious
stimuli, such as thermal, chemical, and high-threshold mechanical stimuli, are
detected in the periphery and conducted to the spinal cord via two types of small
fibers. The C fibers are unmyelinated, slow-conducting, and localize pain poorly.
The A?fibers are thinly myelinated, faster-conducting, and localize pain
better.11,12 Larger and more thickly myelin-ated than A?fibers are A?and
A?fibers, which primarily transmit information about proprioception and vibration.13
It is primarily the A?and C fibers that are indiscriminately affected in the
different types of neuropathies (Figure 1). Measuring which type of fibers are
impacted is not trivial, but can be attempted by clinical examination; loss of
tactile or vibratory skin sensation or tendon reflexes are indicative of
large-fiber neuropathy, whereas alterations in lower-limb pinprick sensation
and a visual analog scale pain score >40 suggest small-fiber neuropathy.14 Small-fiber
neuropathy can  also be determined by
measuring intraepidermal nerve-fiber density following biopsy.15A?-fiber
neuropathy can be measured noninvasively by laser evoked-potential 16,17 and
contact heat-evoked potential.18,19 Nerve-conducting studies are a useful
technique for NeuP research, but less relevant for clinical studies, as they
primarily measure A?-fiber function, which supersedes small-fiber neuropathy20 and
is laborious.21 Receptors on primary sensory neurons convert environ-mental
stimuli, such as pain, into an electrical signal that is transmitted to the
dorsal root ganglia, with an important role for sodium channels.22,23 In the
terminals of the dorsal root ganglia, neurons subsequently convert this
electric signal into chemical signals by releasing neurotransmitters and neuro-peptides,
including glutamate, substance P, and calcitonin gene-related peptide into the
dorsal horn ( Figure 1). A significant event that occurs during the development
of a chronic pain state is central sensitization, where postsynaptic glutamate
(?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AMPA and N-methyl-d-aspartate
NMDA) receptors become increasingly more adaptive in transmitting pain signals.24–28
Activation of presynaptic calcium channels can reduce the release of neurotransmitters
and dampen central sensitization (Figure 1).29,30 In the spinal cord, this
nocicep-tive signal can be modulated by inhibitory interneurons using ?-aminobutyric
acid (GABA) and glycine as their main neurotransmitters. Following the reception
of a pain signal in the cortical structures of the brain, the experience of
pain can still be suppressed by a descending system that originates from the
brain stem. This efferent system attenuates the afferent signal via
neurotransmitters, such as endogenous opioids, serotonin, and
noradrenaline.31–33 3

The two most common
types of peripheral neuropathic pain are post herpetic neuralgia (PHN) and
painful diabetic neuropathy (PDN). 7

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