Painful neuropathies

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.

2003 Lippincott Williams & Wilkins.

Department of Neurology, University of Wurzburg, Wurzburg, Germany

Correspondence to Dr Claudia Sommer, Neurologische Universitatsklinik, JosefSchneider Strasse 11, D-97080 Wurzburg, Germany
Tel: +49 931 201 23763; fax: +49 931 201 23697;
e-mail: sommer@mail.uni-wuerzburg.de
Current Opinion in Neurology 2003, 16:623628
Abbreviation
ERK

extracellular signal-regulated kinase

# 2003 Lippincott Williams & Wilkins

1350-7540

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.

The phenomenology of pain in neuropathies

The typical clinical picture in painful neuropathies is a
combination of the loss of sensation, positive sensory
phenomena like paraesthesias and evoked pain, and
spontaneous pain (Table 1). Major efforts are being
made to describe and classify the symptoms of painful
neuropathies better, motivated by the hypothesis that
the individual symptoms may indicate particular
pathomechanisms that in turn may point to a specic
treatment strategy [1,2,3 . .,4]. In a recent study of 81
patients with diabetic and non-diabetic painful neuropathy [5 . .], deep aching pain was the most prominent
symptom, not the supercial burning or paroxysmal
pain traditionally regarded as most typical of neuropathic pain. The need for standardized assessment is
obvious; questioning about symptoms differs widely
between studies and case series, and the few available
scales for the assessment of neuropathic pain have not
found a major distribution [6,7]. Evaluation schemes
and standardized scales are presently being developed
to assess neuropathic pain more uniformly [3 . .,8]. The
information gained by detailed assessment of individual symptoms has already partly been used in clinical
drug trials, such that in these the effectiveness of a
particular drug on either burning pain, paroxysmal
stabbing pain or deep tissue pain can be determined
[9,10].
623

624 Neuromuscular diseases: nerve

Table 1. Clinical features of pain in neuropathies

Parameter

Characteristics

Quality

Burning, lancinating, shooting, dull,

aching, throbbing
From mild to excruciating
Constant, lancinating, or both
Loss of sensation: hypaesthesia,
hypoalgesia, thermhypaesthesia,
pallhypaesthesia
Spontaneous pain: paraesthesias,
dysaesthesias pins and needles,
burning pain, shock-like pain
Evoked pain: allodynia, normally nonpainful stimuli evoke pain
Hyperalgesia: a painful stimulus evokes
pain of higher intensity

Intensity
Temporal pattern
Negative sensory symptoms
Positive sensory symptoms

Pathophysiology of pain in neuropathies

Since neuropathic pain can be due to diverse aetiologies,
concepts on neuropathic pain in general may not be valid
in specic neuropathies, some of which will therefore be
described separately.
General concepts on neuropathic pain

Most of the current knowledge on the mechanisms of

neuropathic pain is based on animal models of acute
nerve injury or on in-vitro models. For up-to-date
reviews of these ndings see Dworkin [4], Hill [11],
Zimmermann [12], Quasthoff and Sommer [13] and
Malmberg [14]. Although a wealth of data has emerged
from the nerve injury models, it is unclear to what extent
they relate to polyneuropathies in humans, which are of
variable aetiologies and mostly have a slowly progressive
course. A large number of distinct cellular changes that
are triggered by nerve injury have been identied, which
may or may not be relevant to the development of pain.
An important goal will be to nd out which of these
changes are essential for the pain process and which are
of minor importance or are secondary events [15]. As in
the acute nerve injury models, in polyneuropathies there
is a coexistence of injured and adjacent uninjured nerve
bres within the same peripheral nerve. The role of
injured versus uninjured bres has recently been
extensively investigated, and there is now good evidence
that uninjured bres within an injured nerve take part in
the signalling of pain, exhibiting spontaneous activity
[16 .] and sensitization [17 .,18 .], and undergoing phenotypic shifts regarding the expression of cytokines [19]
and neurotrophic factors [20].
Diabetic neuropathies

Studies of the prevalence of diabetic neuropathy give

estimates of approximately 34% of diabetic patients, and
the prevalence of painful diabetic neuropathy may be
1120% [21,22 . .]. The cause of chronic neuropathic pain
in diabetic neuropathy is still unclear [23 .]. There are
few morphological differences between patients with

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

Painful neuropathies Sommer 625

neuropathy, indicating specic mechanisms of allodynia

in the different types of neuropathy [36 .]. With regard to
intracellular signalling mechanisms, a signicant upregulation of active extracellular signal-regulated kinase
(ERK) 1 and 2, components of the ERK cascade was
found [37 .], which correlated with the onset of
streptozotocin-induced hyperalgesia. The intrathecal
administration of a selective mitogen-activated protein
kinase/ERK inhibitor dose-dependently blocked allodynia in this model.
Elevated glucose levels as such have also been
implicated in the pathogenesis of pain in diabetic
neuropathy. Recent experimental studies showed mechanical hyperalgesia induced by a local increase in
glucose concentration at the sciatic nerve or the
respective dorsal root ganglia [38]. In a small group of
type I diabetic patients, pain ratings were not correlated
with individual blood glucose levels, but the group with
painful neuropathy had a greater glucose ux and
possibly poorer diabetes control than the group with
painless neuropathy [39]. In contrast, in a larger group of
type II diabetic patients, glycaemic control was not a
predictor of painful neuropathy [40].
Chemotherapy-induced neuropathy

A mostly sensory and painful neuropathy is caused by

cisplatin, oxaliplatin, and carboplatin. Vincristine, taxol,
and suramin can induce a sensorimotor neuropathy with
or without the involvement of the autonomic nervous
system [41 .]. Vincristine neuropathy, in particular, lends
itself to the investigation of its pathophysiology, because
good animal models in the mouse and rat are available.
In the rat model, protein kinase A, protein kinase C and
nitric oxide second messenger pathways contributed to
mechanical hyperalgesia [42]. An abnormal temporal
pattern of evoked afferent activity was found in C-bres
from vincristine-treated rats, which may contribute to the
development of pain [43 .]. Oxaliplatin alters sodium
channel inactivation kinetics, and the sodium antagonist
carbamazepine may reduce symptoms as well as prevent
neurotoxicity after oxaliplatin exposure [44]. Of interest
is the fact that patients with a pre-existing neuropathy,
either hereditary or acquired, are particularly susceptible
to chemotherapy-induced neuropathies [4547]. The
pathomechanism of this phenomenon is not yet known,
but the practical consequence should be to screen
patients peripheral nerve function before initiating
potentially neurotoxic chemotherapy.
Inflammatory neuropathies

Pain is a prominent feature in most of the inammatory

neuropathies such as chronic inammatory demyelinating neuropathy, GuillainBarre syndrome or vasculitic
neuropathies, provided that the sensory system is
involved. Fifteen to 50% of AIDS patients suffer from

distal predominantly sensory neuropathy, which is often

painful. In 36 HIV-1-infected patients with painful
(n = 20) and non-painful (n = 16) sensory neuropathy
investigated by quantitative thermal testing, a more
pronounced impairment of C-bre-mediated innocuous
warm perception was found in patients with painful
neuropathy [48 .]. Patients with sarcoidosis may have a
vasculitic neuropathy [49], or a painful small-bre
neuropathy [50 .]. Although the pathogenesis of the
latter has not yet been elucidated, it is important to
recognize this entity in a patient with sarcoidosis and
pain.
In the inammatory neuropathies, pain is thought to be
induced by a combination of changes caused by axonal
injury, such as the altered distribution of sodium
channels and the increased release of inammatory
mediators in the vicinity of the nerve bres. Inammatory mediators, in particular in combination (inammatory soup), have long been known to increase the
excitability of nociceptors after injury [51]. The
expression of proinammatory cytokines in peripheral
nerves is increased in most vasculitic neuropathies [52],
and in particular in specimens from patients in whom
pain is a prominent symptom [53]. Recent studies
focusing on the effect of TNF-a have shown an
increased ring rate in injured but also in adjacent
uninjured nerve bres after the application of TNF
[17 .]. The induction of hyperalgesia by TNF-a is
dependent on p38 mitogen-activated protein kinase,
the inhibition of which also reduced behavioural signs
of pain in an animal model [54 .]. A protein kinase Adependent pathway is also involved [18 .]. The spinal
upregulation of cytokines may partly underlie morphine
tolerance [55].
Spinal and peripheral prostaglandins are involved in
hyperalgesia after nerve injury [56,57 .], and the prostaglandin analogue carbaprostacyclin increased the ectopic
activity of dorsal root ganglia and dorsal horn neurons in
a model of nerve injury [58]. Prostaglandin E2 is elevated in injured nerves and may contribute to hyperalgesia [59]. Cyclooxygenase 2 is upregulated in nerve
biopsy specimens from patients with chronic inammatory demyelinating neuropathy [60]. Cyclooxygenase 2
inhibitors also seem to reduce nerve damage in
experimental autoimmune neuropathy [61].
Another mediator released in tissue inammation is
serotonin (5-hydroxytryptamine). In the periphery,
serotonin has algesic properties mainly through its action
on 5-hydroxytryptamine 3 receptors. Nerve injury entails
an increase in serotonin locally, and mice with lowered
serotonin levels in the nerve as a result of a deciency of
the serotonin transporter do not develop thermal
hyperalgesia after nerve injury [62 .].

626 Neuromuscular diseases: nerve

Current treatment of painful neuropathies

Treatment of pain in neuropathies is often unsatisfactory. However, this may not only be the result of a lack
of adequate drugs. Out of 151 patients with neuropathic
pain of diverse origin (55.6% diabetic neuropathies)
completing a questionnaire, 72.8% complained of
inadequate pain control [63]. Opioids, tricyclic antidepressants and anticonvulsants had never been tried by
41.1%, 59.6% and 72.2% of these patients, respectively.
New antineuropathic analgesics (e.g. gabapentin) were
being used by only 16.6% of the patients. The authors
concluded that new and even conventional therapies
were often not pursued in these patients, despite
inadequate pain control. Similar results were obtained
when the use of opioids was specically investigated
[64].
The mainstay of the treatment of pain in neuropathies
are tricyclic antidepressants and anticonvulsants. The
available evidence for the efcacy of these drugs has
repeatedly been reviewed, and treatment algorithms
have been developed [6569]. Gabapentin, initially
investigated for the treatment of painful diabetic
neuropathy and postherpetic neuralgia, has meanwhile
proved efcacious for a variety of neuropathic pain states
[10]. Among the older anticonvulsants, sodium valproate
has recently proved effective in reducing neuropathic
pain in patients with type 2 diabetes [70]. Opioids,
formerly thought to be ineffective in neuropathic pain,
have recently been found to reduce neuropathic pain in
several randomized controlled trials [71,72].
The value of alpha-lipoic acid for pain treatment in
diabetic neuropathy has been judged to be controversial
in diverse trials. A recent trial again seemed to be in
favour of a positive effect of intravenous alpha-lipoic acid
at a dose of 600 mg per day [73]. Similar controversial
ndings have been found in trials with topical capsaicin.
A recently published small trial again reported a positive
effect [74 .].
In a small study [75], a single intravenous application of
the non-competitive N-methyl-D-aspartate antagonist
amantadine (200 mg) improved pain in diabetic neuropathy for at least one week. Another N-methyl-Daspartate antagonist, dextrometorphan, was efcient in
selected patients with a painful diabetic neuropathy in a
dose-related fashion [76]. A trial with the glycine antagonist GV196771 gave a negative result [77]. L-Acetylcarnitine is a drug that reduces pain in animal models of
neuropathic and acute pain, probably by a central
indirect cholinergic mechanism and via the upregulation
of spinal mGlu2 receptors [78,79]. In a multicentre trial,
L-acetylcarnitine improved nerve conduction parameters
and reduced pain in patients with diabetic neuropathy
[80 .]. A moderate effect on pain was found with

isosorbide dinitrate spray, given under the rationale of

an impaired nitric oxide production in diabetic nerves
[81]. The role of botulinum toxin in the treatment of
neuropathic pain is still unclear [82,83]. Drug combinations have so far very rarely been tested. In two recent
studies [84,85 .], the addition of either amitriptyline or a
cholecystokinin 2 antagonist to opioids did not improve
the outcome.

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.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:
.
of special interest
..
of outstanding interest
1

Jensen TS, Gottrup H, Sindrup SH, Bach FW. The clinical picture of
neuropathic pain. Eur J Pharmacol 2001; 429:111.

Hansson P. Neuropathic pain: clinical characteristics and diagnostic workup.

Eur J Pain 2002; 6:4750.

Jensen TS, Baron R. Translation of symptoms and signs into mechanisms in

neuropathic pain. Pain 2003; 102:18.
This paper discusses the value of a mechanism-based classification and gives a
practical guideline for the clinical examination of patients with neuropathic pain.
3

..

Dworkin RH. An overview of neuropathic pain: syndromes, symptoms, signs,

and several mechanisms. Clin J Pain 2002; 18:343349.

Otto M, Bak S, Bach FW, et al. Pain phenomena and possible mechanisms
in patients with painful polyneuropathy. Pain 2003; 101:187192.
One of very few studies available at present that provide detailed data on the
phenomenology of pain in patients with neuropathies.

..

Galer BS, Jensen MP. Development and preliminary validation of a pain

measure specific to neuropathic pain: the Neuropathic Pain Scale. Neurology
1997; 48:332338.

Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic

symptoms and signs. Pain 2001; 92:147157.

Bouhassira D, Attal N, Fermanian J, et al. Cross-validation of a specific

questionnaire for the evaluation of neuropathic pain with quantitative sensory
testing. Abstracts of the 10th World Congress on Pain. San Diego, 2002,
406.

Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in

painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose
response trials. Anesthesiology 2002; 96:10531061.

10 Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain:

evidence from randomized, placebo-controlled clinical trials. Clin Ther
2003; 25:81104.
11 Hill RG. Molecular basis for the perception of pain. Neuroscientist 2001;
7:282292.
12 Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001;
429:2337.

Painful neuropathies Sommer 627

13 Quasthoff S, Sommer C. Pain mechanisms in nerve injury: peripheral
mechanisms. In: Sommer C, editor. Pain in peripheral nerve disease. Basel:
Karger; 2001. pp. 110148.
14 Malmberg A. Central changes. In: Sommer C, editor. Pain in peripheral nerve
disease. Basel: Karger; 2001. pp. 149167.
15 Devor M. Neuropathic pain: what do we do with all these theories? Acta
Anaesthesiol Scand 2001; 45:11211127.
16 Wu G, Ringkamp M, Murinson BB, et al. Degeneration of myelinated efferent
fibers induces spontaneous activity in uninjured C-fiber afferents. J Neurosci
2002; 22:77467753.
The finding of this study, showing that the electrical characteristics of uninjured
fibres in the vicinity of injured fibres are profoundly changed, may be of major
impact for the understanding of painful neuropathies.

17 Schafers M, Lee DH, Brors D, et al. Increased sensitivity of injured and

adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis
factor-alpha after spinal nerve ligation. J Neurosci 2003; 23:30283038.
This experimental study illustrates how the response to a proinflammatory cytokine
is altered in injured and adjacent uninjured nerve fibres.

32 Suzuki Y, Sato J, Kawanishi M, Mizumura K. Lowered response threshold

and increased responsiveness to mechanical stimulation of cutaneous
nociceptive fibers in streptozotocin-diabetic rat skin in vitro correlates of
mechanical allodynia and hyperalgesia observed in the early stage of
diabetes. Neurosci Res 2002; 43:171178.
Using single-fibre recording from rat skinsaphenous nerve in-vitro preparations,
the authors show an increased proportion of C-fibres with spontaneous activity,
suggesting a role of these hyperactive fibres in the generation of pain in diabetic
neuropathy.

33 Ellington HC, Cotter MA, Cameron NE, Ross RA. The effect of cannabinoids
on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from
the isolated paw skin of diabetic and non-diabetic rats. Neuropharmacology
2002; 42:966975.
34 Freshwater JD, Svensson CI, Malmberg AB, Calcutt NA. Elevated spinal
cyclooxygenase and prostaglandin release during hyperalgesia in diabetic
rats. Diabetes 2002; 51:22492255.

18 Zhang JM, Li H, Liu B, Brull SJ. Acute topical application of tumor necrosis
factor alpha evokes protein kinase A-dependent responses in rat sensory
neurons. J Neurophysiol 2002; 88:13871392.
This study elegantly combines data on changes in the excitability of afferent fibres
with information about the signalling pathway involved.

19 Schafers M, Geis C, Svensson CI, et al. Selective increase of tumour

necrosis factor-alpha in injured and spared myelinated primary afferents after
chronic constrictive injury of rat sciatic nerve. Eur J Neurosci 2003; 17:791
804.
20 Obata K, Yamanaka H, Fukuoka T, et al. Contribution of injured and uninjured
dorsal root ganglion neurons to pain behavior and the changes in gene
expression following chronic constriction injury of the sciatic nerve in rats.
Pain 2003; 101:6577.
21 Schmader KE. Epidemiology and impact on quality of life of postherpetic
neuralgia and painful diabetic neuropathy. Clin J Pain 2002; 18:350354.
22 Simmons Z, Feldman EL. Update on diabetic neuropathy. Curr Opin Neurol
2002; 15:595603.
This is an excellent update on the current knowledge about diabetic neuropathies.

..

23 Calcutt NA. Potential mechanisms of neuropathic pain in diabetes. Int Rev

Neurobiol 2002; 50:205228.
This paper summarizes the current knowledge on the pathophysiology of pain in
diabetic neuropathy, focusing on the central mechanisms.

24 Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus neuropathies: new insights into pathophysiology and treatment.
Muscle Nerve 2002; 25:477491.

35 Chen SR, Pan HL. Hypersensitivity of spinothalamic tract neurons associated

with diabetic neuropathic pain in rats. J Neurophysiol 2002; 87:27262733.
This is an elegant demonstration of central sensitization and reduced responses to
morphine in a model of diabetic neuropathy.

36 Luo ZD, Calcutt NA, Higuera ES, et al. Injury type-specific calcium channel
alpha 2 delta-1 subunit up-regulation in rat neuropathic pain models
correlates with antiallodynic effects of gabapentin. J Pharmacol Exp Ther
2002; 303:11991205.
This study exemplifies how a molecular finding can be correlated to sensitivity to an
analgesic drug, and gives an example of how different molecular mechanisms can
underlie the same neuropathic symptom.

37 Ciruela A, Dixon AK, Bramwell S, et al. Identification of MEK1 as a novel

target for the treatment of neuropathic pain. Br J Pharmacol 2003; 138:751
756.
An increase in the activity of the mitogen-activated protein kinase/ERK cascade is
shown in the spinal cord of rats with diabetic and traumatic neuropathy. Inhibitor
studies suggest that enzymes in this pathway represent potential targets for the
treatment of neuropathic pain.

38 Dobretsov M, Hastings SL, Romanovsky D, et al. Mechanical hyperalgesia in

rat models of systemic and local hyperglycemia. Brain Res 2003; 960:174
183.
39 Oyibo SO, Prasad YD, Jackson NJ, et al. The relationship between blood
glucose excursions and painful diabetic peripheral neuropathy: a pilot study.
Diabet Med 2002; 19:870873.
40 Sorensen L, Molyneaux L, Yue DK. Insensate versus painful diabetic
neuropathy: the effects of height, gender, ethnicity and glycaemic control.
Diabetes Res Clin Pract 2002; 57:4551.
41 Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J
Neurol 2002; 249:917.
An up-to date review on chemotherapy-induced neuropathies.

25 Said G, Lacroix C, Lozeron P, et al. Inflammatory vasculopathy in multifocal

diabetic neuropathy. Brain 2003; 126:376385.

42 Aley KO, Levine JD. Different peripheral mechanisms mediate enhanced

nociception in metabolic/toxic and traumatic painful peripheral neuropathies in
the rat. Neuroscience 2002; 111:389397.

26 Singleton JR, Smith AG, Bromberg MB. Painful sensory polyneuropathy

associated with impaired glucose tolerance. Muscle Nerve 2001; 24:1225
1228.

27 Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in

diabetes and impaired glucose tolerance. Neurology 2003; 60:108111.
28 Wood JN, Akopian AN, Baker M, et al. Sodium channels in primary sensory
neurons: relationship to pain states. Novartis Found Symp 2002; 241:159
168.
This is a comprehensive review on the changes in sodium channels after nerve
injury and their relevance to pain.

..

29 Craner MJ, Klein JP, Renganathan M, et al. Changes of sodium channel

.
expression in experimental painful diabetic neuropathy. Ann Neurol 2002;
52:786792.
This study uses steptozotocin-induced diabetes to demonstrate that changes in
dorsal root ganglion sodium channel expression not only occur in traumatic nerve
injuries but also in diabetic neuropathy.
30 Kriz J, Padjen AL. Intra-axonal recording from large sensory myelinated
axons: demonstration of impaired membrane conductances in early experimental diabetes. Diabetologia 2003; 46:213221.
31 Khan GM, Chen SR, Pan HL. Role of primary afferent nerves in allodynia
caused by diabetic neuropathy in rats. Neuroscience 2002; 114:291299.
Using single unit recording, the authors unequivocally show that abnormal sensory
input from Ad- and Ab-fibres is related to tactile allodynia in the steptozotocin
model of diabetic neuropathy.

43 Tanner KD, Reichling DB, Gear RW, et al. Altered temporal pattern of evoked
afferent activity in a rat model of vincristine-induced painful peripheral
neuropathy. Neuroscience 2003; 118:809817.
An elegant study demonstrating the hyperresponsiveness to mechanical stimulation of C-fibres in vincristine neuropathy as a possible pathomechanism of pain in
this condition.
44 Lersch C, Schmelz R, Eckel F, et al. Prevention of oxaliplatin-induced
peripheral sensory neuropathy by carbamazepine in patients with advanced
colorectal cancer. Clin Colorectal Cancer 2002; 2:5458.
45 Chaudhry V, Chaudhry M, Crawford TO, et al. Toxic neuropathy in patients
with pre-existing neuropathy. Neurology 2003; 60:337340.

46 Trobaugh-Lotrario AD, Smith AA, Odom LF. Vincristine neurotoxicity in the

presence of hereditary neuropathy. Med Pediatr Oncol 2003; 40:3943.
47 Kalfakis N, Panas M, Karadima G, et al. Hereditary neuropathy with liability to
pressure palsies emerging during vincristine treatment. Neurology 2002;
59:14701471.
48 Martin C, Solders G, Sonnerborg A, Hansson P. Painful and non-painful
neuropathy in HIV-infected patients: an analysis of somatosensory nerve
function. Eur J Pain 2003; 7:2331.
A valuable attempt to elucidate the mechanisms underlying pain by comparing
patients with painful and painless neuropathies of the same aetiology.

49 Said G, Lacroix C, Plante-Bordeneuve V, et al. Nerve granulomas and

vasculitis in sarcoid peripheral neuropathy: a clinicopathological study of 11
patients. Brain 2002; 125:264275.

628 Neuromuscular diseases: nerve

50 Hoitsma E, Marziniak M, Faber CG, et al. Small fibre neuropathy in
sarcoidosis. Lancet 2002; 359:20852086.
This paper focuses attention on a hitherto underrecognized cause of painful smallfibre neuropathy.

67 Jensen TS. Anticonvulsants in neuropathic pain: rationale and clinical

evidence. Eur J Pain 2002; 6 (Suppl. A):6168.
68 Wolfe GI, Barohn RJ. Painful peripheral neuropathy. Curr Treat Options
Neurol 2002; 4:177188.

51 Michaelis M, Vogel C, Blenk KH, et al. Inflammatory mediators sensitize

acutely axotomized nerve fibers to mechanical stimulation in the rat. J
Neurosci 1998; 18:75817587.

69 Backonja MM. Use of anticonvulsants for treatment of neuropathic pain.

Neurology 2002; 59 (Suppl 2):S14S17.

52 Heuss D, Schlotter-Weigel B, Sommer C. Diagnosis and therapy of vasculitic

neuropathy [in German]. Fortschr Neurol Psychiatr 2003; 71:172186.

70 Kochar DK, Jain N, Agarwal RP, et al. Sodium valproate in the management
of painful neuropathy in type 2 diabetes a randomized placebo controlled
study. Acta Neurol Scand 2002; 106:248252.

53 Lindenlaub T, Sommer C. Cytokines in sural nerve biopsies from

inflammatory and non-inflammatory neuropathies. Acta Neuropathol 2003;
105:593602.
54 Schafers M, Svensson CI, Sommer C, Sorkin LS. Tumor necrosis factor
induces mechanical allodynia after spinal nerve ligation by activation of p38
MAPK in primary sensory neurons. J Neurosci 2003; 23:25172521.
This experimental study suggests a sequential role for TNF-a and p38 mitogenactivated protein kinase in the induction of neuropathic pain. The parallel inhibition
of p38 activation and allodynia may represent a clinically relevant therapeutic
window.

55 Raghavendra V, Rutkowski MD, DeLeo JA. The role of spinal neuroimmune

activation in morphine tolerance/hyperalgesia in neuropathic and shamoperated rats. J Neurosci 2002; 22:99809989.
56 Ma W, Du W, Eisenach JC. Role for both spinal cord COX-1 and COX-2 in
maintenance of mechanical hypersensitivity following peripheral nerve injury.
Brain Res 2002; 937:9499.
57 Ma W, Eisenach JC. Morphological and pharmacological evidence for the
.
role of peripheral prostaglandins in the pathogenesis of neuropathic pain. Eur
J Neurosci 2002; 15:10371047.
Although widely recognized for their role in inflammatory pain, not much is known
about the role of prostaglandins in neuropathic pain. This is one of the papers
starting to fill in this knowledge.
58 Omana-Zapata I, Bley KR. A stable prostacyclin analog enhances ectopic
activity in rat sensory neurons following neuropathic injury. Brain Res 2001;
904:8592.
59 Schafers M, Marziniak M, Sorkin LS, et al. Cyclooxygenase inhibition in nerve
injury and TNF-induced hyperalgesia in the rat. Abstract Viewer/Itinerary
Planner. Washington, DC: Society for Neuroscience; 2002. CD-ROM. 2002;
Program Number: 756.758.
60 Kawasaki T, Oka N, Akiguchi I, et al. Up-regulation of cyclooxygenase-2 in
inflammatory demyelinating neuropathy. Acta Neuropathol (Berl) 2001;
101:154158.
61 Miyamoto K, Oka N, Kawasaki T, et al. New cyclooxygenase-2 inhibitors for
treatment of experimental autoimmune neuritis. Muscle Nerve 2002; 25:280
282.
62 Vogel C, Mossner R, Gerlach M, et al. Absence of thermal hyperalgesia in
serotonin transporter-deficient mice. J Neurosci 2003; 23:708715.
This study adds to the knowledge on the role of serotonin in neuropathic pain,
giving strong evidence for peripheral sensitization of thermosensitive fibres through
increased tissue serotonin levels.

71 Rowbotham MC, Twilling L, Davies PS, et al. Oral opioid therapy for chronic
peripheral and central neuropathic pain. N Engl J Med 2003; 348:1223
1232.
72 Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain
in diabetic neuropathy: a randomized controlled trial. Neurology 2003;
60:927934.
73 Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic
polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.
Diabetes Care 2003; 26:770776.
74 Forst T, Pohlmann T, Kunt T, et al. The influence of local capsaicin treatment
on small nerve fibre function and neurovascular control in symptomatic
diabetic neuropathy. Acta Diabetol 2002; 39:16.
This is a small clinical trial, whose value lies not only in showing the efficacy of the
drug tested, but in giving additional information on its action on Cfibres.

75 Amin P, Sturrock ND. A pilot study of the beneficial effects of amantadine in

the treatment of painful diabetic peripheral neuropathy. Diabet Med 2003;
20:114118.
76 Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in
painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose
response trials. Anesthesiology 2002; 96:10531061.
77 Wallace MS, Rowbotham MC, Katz NP, et al. A randomized, double-blind,
placebo-controlled trial of a glycine antagonist in neuropathic pain. Neurology
2002; 59:16941700.
78 Ghelardini C, Galeotti N, Calvani M, et al. A. Acetyl-L-carnitine induces
muscarinic antinocieption in mice and rats. Neuropharmacology 2002;
43:11801187.
79 Chiechio S, Caricasole A, Barletta E, et al. L-Acetylcarnitine induces
analgesia by selectively up-regulating mGlu2 metabotropic glutamate
receptors. Mol Pharmacol 2002; 61:989996.
80 De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment
of diabetic neuropathy. A long-term, randomised, double-blind, placebocontrolled study. Drugs RD 2002; 3:223231.
This long-term trial with 294 patients suggests an interesting new option for the
treatment of patients with diabetic neuropathy.

81 Yuen KC, Baker NR, Rayman G. Treatment of chronic painful diabetic

neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled
cross-over study. Diabetes Care 2002; 25:16991703.
82 Argoff CE. A focused review on the use of botulinum toxins for neuropathic
pain. Clin J Pain 2002; 18 (Suppl):S177S181.

63 Gilron I, Bailey J, Weaver DF, Houlden RL. Patients attitudes and prior
treatments in neuropathic pain: a pilot study. Pain Res Manag 2002; 7:199
203.

83 Kern U, Martin C, Scheicher S, Muller H. Treatment of phantom pain with

botulinum-toxin A. A pilot study [in German]. Schmerz 2003; 17:117124.

64 Gilron I, Bailey JM. Trends in opioid use for chronic neuropathic pain: a
survey of patients pursuing enrollment in clinical trials:. Can J Anaesth 2003;
50:4247.

84 McCleane GJ. A randomised, double blind, placebo controlled crossover

study of the cholecystokinin 2 antagonist L-365,260 as an adjunct to strong
opioids in chronic human neuropathic pain. Neurosci Lett 2003; 338:151
154.

65 Sindrup SH, Jensen TS. Antidepressants in the treatment of neuropathic

pain. In: Hansson P, Fields HL, Hill RG, Marchettini P, editors. Neuropathic
pain: pathophysiology and treatment. Seattle: IASP Press; 2001. pp. 169
183.

66 Sommer C. Symptomatic treatment of painful neuropathies. In: Sommer C,

editor. Pain in peripheral nerve disease. Basel: Karger; 2001. pp. 171195.

85 Mercadante S, Arcuri E, Tirelli W, et al. Amitriptyline in neuropathic cancer

pain in patients on morphine therapy: a randomized placebo-controlled,
double-blind crossover study. Tumori 2002; 88:239242.
Drug combinations are rarely studied in formal trials for neuropathic pain. This is a
useful trial with a negative result, showing that in the population studied the
addition of amitriptyline to morphine did not improve analgesia.