Professional Documents
Culture Documents
Claudia Sommer
Purpose of review
To summarize the current understanding of clinical assessment,
pathophysiology, and treatment of pain in neuropathies,
focusing on selected entities in which the understanding of the
mechanisms underlying pain has advanced recently.
Recent findings
Ongoing studies are classifying the symptoms and signs of
painful neuropathies, assuming that this approach may indicate
particular pathomechanisms leading to more rational treatment.
Nerve injury induces a large number of cellular changes, the
relevance of which for the occurrence of pain is still under
investigation. In models of diabetic neuropathy, an altered
distribution of sodium channels, hyperexcitability of neurons,
and changes in spinal connectivity seem to underlie the
development of pain. The role of inflammatory mediators has
been explored in inflammatory and degenerative neuropathies.
Second messenger pathways contributing to hyperalgesia in
various neuropathies have been identified, opening up new
treatment options. A number of newer and older drugs have
been studied for their use in painful neuropathies in clinical
trials. Epidemiology has shown that, despite the availability of
drugs with moderate efficacy in the treatment of neuropathic
pain, a large percentage of patients do not gain access to them.
Summary
Advances in the standardization of assessment of patients with
painful neuropathies are beginning to have an impact on how
clinical studies are designed. Major progress has been made in
the understanding of cellular and molecular changes after nerve
injury, but their relevance for the pathophysiology of pain in
neuropathies has still to be determined.
Keywords
chemotherapy, diabetes, inflammation, neuropathy, pain
Curr Opin Neurol 16:623628.
DOI: 10.1097/01.wco.0000093106.34793.06
Introduction
Pain caused by peripheral neuropathies is a major
health problem, particularly in individuals with diabetes, but also in patients with inammatory neuropathies, those undergoing chemotherapy, and in many
others. It is still unclear why neuropathies of apparently equal aetiology can be painful or painless.
Prototypes of painful polyneuropathies are those with
the prominent involvement of small unmyelinated
bres (C-bres), such as the amyloid neuropathies
and Fabry disease. However, neuropathies with nonselective bre loss such as the alcoholic, dysproteinaemic, and some toxic neuropathies can be equally
painful, as well as some neuropathies with selective
large bre loss. This review will summarize recent
ndings on the pathophysiology of pain in various
types of neuropathies. The treatment of neuropathic
pain is presently guided by experience and evidence
from clinical trials. An improved understanding of the
particular mechanisms leading to pain in these diseases
is expected to give rise to improved and more selective
treatment strategies.
Characteristics
Quality
Intensity
Temporal pattern
Negative sensory symptoms
Positive sensory symptoms
and without pain in distal symmetrical diabetic neuropathy. In diabetic lumbosacral radiculoplexus neuropathy, inammatory changes seem to be the underlying
cause of the deep aching radicular pain [24,25]. An
impaired glucose tolerance test in the absence of overt
diabetes mellitus may be associated with a small-bre
neuropathy, which is often painful [26,27].
Most data on the pathogenesis of pain in diabetic
neuropathy are derived from the model of streptozotocin-induced diabetes in rats. As in traumatic nerve injury
[28 . .], a dysregulation of the sodium channels in dorsal
root ganglion neurons can be found in streptozotocininduced diabetes, in particular an upregulation of
messenger RNA and protein for the Nav1.3, Nav1.6,
and Nav1.9 sodium channels, and a downregulation of
Nav1.8 mRNA [29 .]. These changes occur between 1
and 8 weeks after the onset of allodynia to tactile stimuli.
An upregulation of Nav1.3 would be expected to
increase the overall neuronal sodium channel density
and to introduce a rapidly repriming current. These
changes should lead to a lowered ring threshold and to
higher than normal ring frequencies. The upregulation
of Nav1.6 channels would be expected to contribute to
intrinsic burst activity and thus to hyperexcitablity of the
neurons. Furthermore, impaired potassium conductances
in myelinated bres may contribute to increased
excitability [30]. In fact, in a study using mechanical
stimulation and single-bre recording [31 .], Ad- and Abbres had lower activation thresholds and augmented
responses to von Frey hairs. Increased spontaneous
activity was also found in C-bres in a skin-nerve
preparation from diabetic rats [32 .]. Neurogenic inammation, as measured by basal and capsaicin-induced
calcitonin gene-related peptide release from the skin, is
increased in diabetic rats compared with controls [33],
indicating an increased sensibility of C-bres to capsaicin
and related stimuli.
At the level of the spinal cord, prostaglandin E2 levels, as
measured by haemodialysis, are elevated in diabetic rats
after formalin injection into the hind-paw, indicating a
pathway by which increased excitability is transmitted to
the central nervous system [34]. The spinothalamic tract
neurons of diabetic rats display a higher spontaneous
discharge activity and enlarged receptive elds, as well
as lower thresholds and augmented responses to
mechanical stimulation [35 .]. Interestingly, the responses of spinothalamic tract neurons to noxious stimuli
are reduced by morphine in non-diabetic but not in
diabetic rats, suggesting decreased morphine sensitivity.
The calcium channel alpha2delta-1 subunit, which has
previously been shown to play a role in allodynic
responses of spinal nerve-injured rats, is also upregulated
in streptozotocin-induced diabetes, but not in vincristine
Conclusion
A standardized assessment of patients with painful
neuropathies will be the prerequisite for adequately
evaluating outcomes in practice and in clinical trials.
Preclinical research has provided us with a large body of
knowledge on cellular changes after nerve injury.
Closing the gap to clinical research will be necessary to
understand their relevance for the pathophysiology of
pain in neuropathies.
Acknowledgements
The authors research has been supported by Deutsche Forschungsgemeinschaft, VolkswagenStiftung and Wilhelm-Sander-Stiftung.
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