A Review of Neuropathic Pain: From Diagnostic Tests to Mechanisms
A Review of Neuropathic Pain: From Diagnostic Tests to Mechanisms
Andrea Truini 0
0 A. Truini (&) Department of Neurology and Psychiatry, Sapienza University , Rome , Italy
Neuropathic pain develops when the somatosensory nervous system is affected by a lesion or disease. Diagnostic tests aimed at assessing somatosensory afferent pathway damage are therefore useful for diagnosing neuropathic pain. Neuropathic pain manifests with a range of different symptoms such as ongoing burning pain, squeezing or pressure pain, paroxysmal electric shock-like sensations, stabbing pain, or mechanical dynamic allodynia. The various types of neuropathic pain are associated with different underlying nerve fiber abnormalities. This article summarizes the available methods of somatosensory afferent pathway assessment and discusses the potential pathophysiology underlying the most representative neuropathic pain types, i.e., ongoing burning pain, paroxysmal pain, and mechanical dynamic allodynia. Funding: Pfizer, Italy.
Allodynia; Ongoing burning pain; Paroxysmal pain
Neuropathic pain is due to a lesion or disease of
the somatosensory nervous system . Besides
clinical examination, diagnostic tests assessing
non-nociceptive and nociceptive afferent
pathways are useful in patients with suspected
neuropathic pain, as they provide definite evidence
of somatosensory nervous system damage.
Different diseases of the peripheral and central
nervous system may cause neuropathic pain
(e.g.. diabetic neuropathy, postherpetic
neuralgia, multiple sclerosis) [1, 2].
Neuropathic pain manifests as a range of
different symptoms, including ongoing burning
pain, pain similar to squeezing or pressure,
paroxysmal electric shock-like sensations or
stabbing pain, and mechanical dynamic
allodynia . This article summarizes the available
methods for assessing neuropathic pain and
discusses the potential pathophysiology underlying
various neuropathic pain phenotypes.
Compliance with Ethics Guidelines
This article is based on previously conducted
studies and does not involve any new studies of
human or animal subjects performed by the
There are several available methods for the
assessment of somatosensory afferent pathways in
patients with suspected neuropathic pain (Fig. 1).
Fig. 1 Laboratory tests for diagnosing neuropathic pain
Reproduced with permission from Truini A.,
Garcia-Larrea L. & Cruccu G. Reappraising neuropathic pain in
humans—how symptoms help disclose mechanisms. Nat
Rev Neurol. 2013;9:572–82
Quantitative Sensory Testing
Quantitative sensory testing (QST) is a
psychophysical technique that measures
perception in response to controlled skin stimuli of
ascending and descending orders of magnitude
in patients with suspected neuropathic pain .
QST enables clinicians to assess small-fiber
neuropathies (SFNs), which are often
misdiagnosed with clinical examination and not
apparent on standard nerve-conduction studies.
QST measures the perception of mechanical,
thermal, and painful stimuli, and is particularly
suited to assess mechanical and thermal
allodynia and hyperalgesia. However, as sensory
abnormalities are often reported in
non-neuropathic pain, QST is insufficient to determine
differential diagnoses .
Neurophysiological techniques include nerve
conduction studies and measurement of
somatosensory-evoked potentials (SEPs),
trigeminal reflexes, laser-evoked potentials
(LEPs), contact-heat-evoked potentials (CHEPs),
and microneurography [3, 4]. These techniques
assess large non-nociceptive and small
nociceptive afferent fibers, and are therefore useful
in the diagnosis of central nervous system (CNS)
and peripheral nervous system (PNS) diseases.
Standard nerve conduction studies and SEPs
are considered to be first-line techniques in
patients with suspected neuropathic pain .
The standard nerve conduction study is the
reference standard technique for a definite
diagnosis of peripheral neuropathy. SEPs are
used to assess patients with CNS disorders, such
as multiple sclerosis and spinal cord injury .
Trigeminal reflexes are considered the best
neurophysiological tool for investigating
patients with trigeminal disease. They consist of
different reflex responses. The most widely used
trigeminal reflex responses are the blink reflex
and the masseter inhibitory reflex; these
responses allow for assessing the three
trigeminal nerve divisions . Although nerve
conduction studies, somatosensory evoked
potentials, and trigeminal reflexes are widely
used for assessing somatosensory afferent
pathway damage, they are responses mediated by
non-nociceptive fibers, and thus they do not
provide any information on the nociceptive
LEPs and CHEPs are widely used for
investigating the nociceptive system. Laser-generated
heat pulses and contact heat stimuli selectively
activate Ad and C mechano-thermal
nociceptors, evoking scalp potentials associated with
Ad fiber activation [3–5].
Microneurography is a minimally invasive
method for recording action potential from
nociceptive C axons . However, this
technique is time consuming, has limited
availability, and requires an expert investigator and a
cooperative patient; therefore, its use in routine
practice is not yet well established.
Punch skin biopsies with immunostaining
allow for visualization and assessment of
intraepidermal nerve fiber (IENF) density .
Biopsies are analyzed by bright-field
immunohistochemistry or immunofluorescence,
typically with antibodies against the protein gene
product 9.5, a nonspecific panaxonal marker
[7, 8]. Decreased IENF density is indicative of
SFN, and is a reliable method of establishing
this diagnosis . Biopsies are commonly used
to investigate small-fiber involvement in
patients with diabetic neuropathy, or
neuropathy of infectious or inflammatory etiology
[7, 8]. However, the relationship between skin
biopsy data and neuropathic pain is complex;
IENF density may be associated with the
existence of neuropathic pain, but does not
correlate with pain intensity .
TYPES OF NEUROPATHIC PAIN
Ongoing Burning Pain
Ongoing burning pain is one of the most
representative types of neuropathic pain. In
patients with distal symmetrical peripheral
neuropathy, the burning pain results from
hyperexcitability of irritable nociceptors or
regenerating nerve sprouts .
Microneurography has shown that, in patients with
length-dependent painful neuropathy (e.g.,
postherpetic neuralgia or radiculopathy), the
ongoing pain is caused by abnormal
spontaneous C fiber activity [
]. In other
neuropathic pain conditions, the cause is anatomical
denervation in which a primary lesion affects
the neuronal cell body or postganglionic axon
exposing the postsynaptic membrane of the
second-order neuron to local transmitters,
consequently causing spontaneous firing .
This process, called ‘‘denervation
supersensitivity’’, is associated with burning pain .
Paroxysmal pain is often described as a
shooting, electric-shock like or stabbing sensation.
Previous studies have associated paroxysmal
electric shock-like with non-nociceptive
Ab fiber abnormalities in patients with
postherpetic neuralgia or carpal tunnel syndrome
]. In these patients, neurophysiological
test findings suggest that the paroxysmal pain
may originate from focal demyelination of Ab
In trigeminal neuralgia, the most
representative neuropathic pain condition manifesting
with paroxysmal pain, focal compression by
aberrant vessels or benign tumors mechanically
damages large myelinated fibers and causes
]. Ab fiber demyelination
increases the susceptibility of neurons to
ectopic excitation and high-frequency discharges,
which leads to typical paroxysmal pain [
Allodynia is the experience of pain from a
non-painful stimulation of the skin, such as
light touch; this is in contrast to hyperalgesia,
which is experiencing more intense pain than
would be expected from stimuli that normally
cause pain. Dynamic mechanical allodynia (i.e.,
elicited by light, moving, tactile stimuli)
develops when a pain pathway lesion causes changes
in the reactivity of central nociceptive neurons,
such that they respond to low-threshold Ab
afferent fibers [
]. Examples of dynamic
mechanical allodynia include pain caused by
skin contact with clothing in patients with
postherpetic neuralgia, or contact between feet
and bed sheets in patients with peripheral
neuropathy. Dynamic mechanical allodynia
therefore appears to be caused by Ab fiber
abnormalities . Selective blockade of A fiber
signaling in patients with neuropathic pain
abolishes allodynia, but has no effect on
burning pain, which is mediated by C fiber afferents
]. The slow conduction velocity through Ad
and C fibers means these fibers are unlikely to
contribute to the initial explosive onset of
dynamic allodynia, but their hyperexcitability
may modulate and maintain the ongoing
after-sensations and play a role in the observed
CNS changes . This hypothesis is supported
by studies showing that allodynia is relieved by
topical lidocaine in patients with postherpetic
Most investigators consider allodynia to be a
CNS phenomenon occurring as a result of
central sensitization, but others propose that
allodynia is caused by peripheral sensitization.
Indirect support for the latter hypothesis comes
from studies using QST and LEPs. QST testing
shows that thermal-pain sensation is preserved
in many patients with postherpetic neuralgia
who experience allodynia . A previous study
showed that patients with painful neuropathy
and allodynia have partially preserved LEPs
compared with patients with painful
neuropathy and no allodynia . However, the most
convincing evidence that sensitized peripheral
nociceptors are the primary determinant of
allodynia comes from microneurographic
studies. These studies showed that allodynia occurs
secondary to abnormal firing of C nociceptors
in response to light mechanical stimulation
Diagnostic tests reliably provide evidence of
somatosensory afferent pathway damage, thus
supporting the diagnosis of neuropathic pain.
Neuropathic pain manifests with different
symptoms. Evidence suggests that each
symptom is mediated by a distinct mechanism. This
has implications for treatment.
Pharmacological treatment should be targeted to the specific
This supplement has been sponsored by Pfizer,
Italy. The article processing charges for this
publication were also funded by Pfizer, Italy.
Andrea Truini thanks Ce´cile Duchesnes, PhD, of
Springer Healthcare Communications who
wrote the outline, and Sarah Greig, PhD, of
Springer Healthcare Communications who
wrote the first draft of this manuscript. This
medical writing assistance was funded by Pfizer,
Italy. The named author meets the
International Committee of Medical Journal Editors
(ICMJE) criteria for authorship for this
manuscript, takes responsibility for the integrity of
the work as a whole, and has given final
approval for the version to be published.
Disclosures. Andrea Truini has received
honorarium from Pfizer, as well as research
grant, consulting fees, and/or payments for
lectures from Alfasigma Group, Angelini, and
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not involve any new studies of human
or animal subjects performed by the author.
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution-NonCommercial 4.0 International
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to the original author(s) and the source, provide
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indicate if changes were made.
Truini A, Biasiotta A, Di Stefano G, et al. Does the
epidermal nerve fibre density measured by skin
Cohen J , Fadul C , Jenkyn L , Ward T. Disorders of the nervous system : Chapter 19-Pain . 2008 .
https://www.dartmouth.edu/*dons/part_2/ chapter_19.html#chpt_19_deafferentation. Accessed 28 Apr 2017 .
Cruccu G , Sommer C , Anand P , et al. EFNS guidelines on neuropathic pain assessment: revised 2009 .
Eur J Neurol . 2010 ; 17 ( 8 ): 1010 - 8 .
Cruccu G , Deuschl G. The clinical use of brainstem reflexes and hand-muscle reflexes . Clin Neurophysiol . 2000 ; 111 ( 3 ): 371 - 87 .
Lauria G , Hsieh ST , Johansson O , et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society . Eur J Neurol . 2010 ; 17 ( 7 ): 903 - 12 ( e44 - 9 ).
10. Kleggetveit IP , Namer B , Schmidt R , et al. High spontaneous activity of C-nociceptors in painful polyneuropathy . Pain . 2012 ; 153 ( 10 ): 2040 - 7 .
11. Ochoa JL , Campero M , Serra J , Bostock H . Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy . Muscle Nerve . 2005 ; 32 ( 4 ): 459 - 72 .
12. Zimmermann M. Pathobiology of neuropathic pain . Eur J Pharmacol . 2001 ; 429 ( 1-3 ): 23 - 37 .
13. Truini A , Galeotti F , Haanpaa M , et al. Pathophysiology of pain in postherpetic neuralgia: a clinical and neurophysiological study . Pain . 2008 ; 140 ( 3 ): 405 - 10 .
14. Truini A , Padua L , Biasiotta A , et al. Differential involvement of A-delta and A-beta fibres in neuropathic pain related to carpal tunnel syndrome . Pain . 2009 ; 145 ( 1-2 ): 105 - 9 .
15. Burchiel KJ . Abnormal impulse generation in focally demyelinated trigeminal roots . J Neurosurg . 1980 ; 53 ( 5 ): 674 - 83 .
16. Burchiel KJ . Ectopic impulse generation in focally demyelinated trigeminal nerve . Exp Neurol . 1980 ; 69 ( 2 ): 423 - 9 .
17. Koltzenburg M , Torebjork HE , Wahren LK . Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain . Brain . 1994 ; 117 (Pt 3): 579 - 91 .
18. Rowbotham MC , Davies PS , Fields HL . Topical lidocaine gel relieves postherpetic neuralgia . Ann Neurol . 1995 ; 37 ( 2 ): 246 - 53 .
19. Rowbotham MC , Davies PS , Verkempinck C , Galer BS . Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia . Pain . 1996 ; 65 ( 1 ): 39 - 44 .