revue neurologique 175 (2019) 16–25

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Neuropathic pain

Neuropathic pain: Definition, assessment

and epidemiology

D. Bouhassira
Inserm U987, ‘‘Pathophysiology and Clinical Pharmacology of Pain’’, centre d’évaluation et de traitement de la douleur,
hôpital Ambroise Paré, 9, avenue Charles de Gaulle, 92100 Boulogne-Billancourt, France

info article abstract

Article history: Neuropathic pain has been a very active and productive clinical research field over the last
Received 30 August 2018 15 years. Studies have concerned multiple aspects of these complex chronic pain syndromes
Accepted 17 September 2018 including their very definition, the elaboration of new diagnostic algorithms, the develop-
Available online 29 October 2018 ment of specific tools for their screening and measurement and their epidemiology. In this
review, we summarize these recent evolutions that have impacted the way these pain
Keywords: syndromes are conceptualized and managed both in daily practice and in the clinical
Pain research setting.
Chronic pain # 2018 Elsevier Masson SAS. All rights reserved.
Neuropathic pain
Assessment
Epidemiology

1. Introduction with other deficits (motor, cognitive etc.), depending on the

Neuropathic pain, which refers to pain caused by a lesion or
disease of the somatosensory system, represents a broad
category of pain syndromes encompassing a wide variety of
peripheral of central disorders. Epidemiological studies have
shown that their prevalence in the general population may be
as high as 7 to 8% [1,2], accounting for 20 to 25% of individuals
with chronic pain.
Clinically, neuropathic pain syndromes are characterized
by the combination of positive and negative phenomena. The
positive phenomena include various painful symptoms,
paresthesia and/or dysesthesia, which, by definition, are
abnormal nonpainful sensations (e.g., tingling, numbness,
pins and needles). Negative phenomena usually include
neurological sensory deficits in the painful area, together
location of the lesion.
Classical etiologies of peripheral neuropathic pain include
painful peripheral neuropathies, post-herpetic neuralgia and
traumatic nerve injury. However, many other groups of
patients present with mixed pain syndromes involving both
neuropathic and non-neuropathic mechanisms, such as
lumbar or cervical radiculopathies, which are among the most
frequent causes of peripheral neuropathic pain in the general
population [2]. Central pain syndromes are not uncommon, as
they are observed in up to 8% of patients after a stroke, in
approximately 30 to 50% of patients with a spinal cord injury, a
large majority of whom present with a syringomyelia, and up to
20 to 25% of patients with multiple sclerosis [3–5].
Neuropathic pain research has been very dynamic other
the last two decades. Besides the explosion of experimental

E-mail address: didier.bouhassira@apr.aphp.fr.

https://doi.org/10.1016/j.neurol.2018.09.016
0035-3787/# 2018 Elsevier Masson SAS. All rights reserved.
 revue neurologique 175 (2019) 16–25
studies in various animal models, a large number of clinical
studies have contributed to the development of a new
conceptualization of these chronic pain syndromes.
In this review, we summarize recent evolutions regarding
the definition, diagnostic criteria, epidemiology and assess-
ment of neuropathic pain that have impacted the manage-
ment of the patients, both in daily practice and clinical
research.
2. Definition of neuropathic pain
Neuropathic pain was defined in 1994 by the International
Association for the Study of Pain (IASP) as: ‘‘pain initiated or
caused by a primary lesion or dysfunction in the nervous
system’’. This definition has been widely criticized, mostly
because of the term ‘‘dysfunction’’ regarded by many experts
as too vague and a source of diagnostic ambiguities. In
particular, some chronic pain associated with non-neurolo-
gical conditions such as fibromyalgia or irritable bowel
syndromes that involve central dysfunctions of the nocicep-
tive systems (e.g., central sensitization and/or alteration of
pain modulation), could in principle be regarded as neuropa-
thic according to this definition. Thus, in 2008, a group of
experts proposed a new definition: ‘‘pain arising as a direct
consequence of a lesion or disease affecting the somatosen-
sory system’’ [6] which was endorsed by the IASP in 2011 [7].
The restriction to the somatosensory system was included in
the new definition in order to distinguish neuropathic pain
from other types of pain such as musculoskeletal pain (e.g.,
spasticity related pain) that may be associated with disorders
of the motor system. Finally, a slightly modified version,
omitting the term ‘‘primary’’ because of the difficulty in
separating primary and secondary causes, was proposed by
the IASP Taxonomy Committee and accepted by the IASP.
Although the new definition of neuropathic pain is
generally regarded as clearer than the former one, it is not
completely devoid of ambiguity. It emphasizes the importance
of the neurological lesion. However, if the presence of a
neurological lesion can be regarded as a necessary condition, it
is definitely not a sufficient condition for the development of
neuropathic pain, which occurs only in a minority of the
patients with a peripheral or central lesion, whatever its
etiology. Actually, neuropathic pain is due to the secondary
peripheral and central changes in nociceptive systems (i.e.
dysfunctions) induced by the lesion rather than to the lesion
itself. Another issue is related to the term ‘‘somatosensory
system’’ which is not clearly defined. In addition to the
classical ascending nociceptive pathways, the somatosensory
systems include the multiple pain modulation systems, non-
nociceptive tactile and proprioceptive systems, thermoregu-
latory systems and visceral afferents. All these subsystems
involve a very large number of brain areas which are
themselves connected to many other areas.
3. Diagnosis of neuropathic pain
In the absence of pain biomarkers, neuropathic pain is identified
only on the basis of clinical criteria. The challenge is to
17
differentiate neuropathic pain from other types of pain and to
diagnose the lesion or disease potentially causing the pain.
Patients may present with various combinations of
symptoms including spontaneous pain, continuous or paro-
xysmal and evoked pain. Evoked pain, which can be more
distressing than spontaneous pain, is termed allodynia when
it is triggered by normally non-noxious stimuli and hyper-
algesia when it corresponds to an exaggerated response to a
normally noxious stimulus. Evoked pain can be triggered by
mechanical or thermal stimuli. Mechanical allodynia can be
preferentially triggered by moving stimuli (i.e., dynamic
mechano-allodynia), or by pressure or punctate stimuli (i.e.
static mechano-allodynia). Evoked pain can also be triggered
by thermal stimuli, either heat or cold, but cold allodynia/
hyperalgesia is much more frequent than heat allodynia/
hyperalgesia in these patients [8–10].
Listening to the patients is a first and major step for the
identification neuropathic pain. It has repeatedly been shown
over the last 10 years that the words used by the patients to
describe their pain (i.e., pain descriptors) differ between
patients with neuropathic and non-neuropathic pain. Indeed,
despite its many causes, neuropathic pain is characterized by
the combination of a relatively small number of ‘‘core’’ pain
qualities (particularly burning pain, electric shock-like pain,
dysesthesia and brush allodynia) that distinguish it from other
types of chronic pain [11,12]. This observation has led to the
development and validation of a number of clinical tools in the
form of simple symptom-based questionnaires for the
screening and identification of neuropathic pain in clinical
practice (see below).
Identification of the neurological lesion or disease relies
primarily on the physical examination, which should be
guided by a tentative diagnosis based on the information
collected during the interview with the patient. The examina-
tion aims to detect possible abnormalities suggestive of a
lesion of the somatosensory system, mostly thermal and/or
mechanical sensory deficits. Simple devices such as a brush, a
vibrating tuning fork, cotton wool, cold and warm metallic
rollers or a pin are used to test different sensory modalities.
The patients present with various combinations of quantita-
tive (hyperesthesia and hypoesthesia), qualitative (e.g., allo-
dynia, dys- or paresthesia), spatial (e.g., faulty localization)
and temporal (e.g., after sensation) somatosensory aberra-
tions, in the innervation territory of the affected peripheral or
central nervous structure [9]. It is important to emphasize that
the physical examination cannot prove that pain is neuropa-
thic, it only provides supporting evidence for a neurological
lesion or disease that could potentially be the cause of pain. In
addition, pain located in an area of sensory deficit is not
necessarily neuropathic (e.g., ischemic pain or osteoarthritis
pain in the lower limbs of patients with diabetic neuropathy or
spastic pain in patients with multiple sclerosis).
Various tests, such as standard electromyography, quanti-
tative sensory testing (see below), brain or spinal cord imaging,
biochemistry, nerve or skin biopsies, can be used, depending
on the clinical context, to identify and characterize the
neurological lesion potentially underlying the pain. However,
these tests do not measure pain per se and cannot directly
confirm the causal relationship between the identified lesion
and the pain. The diagnosis of neuropathic pain is, therefore,
18 revue neurologique 175 (2019) 16–25

Table 1 – Screening tools for neuropathic pain and their psychometric properties.
Tools LANSS NPQ DN4 DN4-Interview ID-Pain PainDetect
Leeds Neuropathic Douleur
assessment of pain neuropathique
neuropathic questionnaire en 4 questions
symptoms and
signs
Authors Bennett, 2001 Krause and Bouhassira et al., Bouhassira et al., Portenoy et al., Freynhagen
Backonja, 2003 2005 2005, 2008 2006 et al., 2006
Type of Clinician- Self- Clinician- Self- Self- Self-
administration administered questionnaire administered questionnaire questionnaire questionnaire
Self-assessment 7 items version
validated validated for self-
assessment
(S-LANSS)
(Bennett 2005)
Sensitivity 83% (study 1) 66.60% 83% 81.60% Not assessed 85%
Specificity 87% (study 1) 74.40% 90% 85.7% unaided Not assessed 80%
ROC Not shown Not shown AUC: 0.92 C: 0.69 AUC: 0.91

Conditions for Cancer Diabetic Diabetic Breast cancer Diabetic

which neuropathy neuropathy neuropathy
discriminatory
properties have
been
established
Diabetic Spinal cord Postherpetic
neuropathy injury neuralgia
(Greek version)
Leprosy Spinal cord
injury
Breast cancer Low back pain
surgery
Cancer
Low back pain

Validation in Amharic, Arabic, Arabic (NPQ-SF), Amharic, Arabic, Arabic, Mandarin, Thai Arabic, Dutch,
other Greek, Japanese Mandarin, Dutch, English, Dutch English, Hindi,
languages Korean, Turkish Farsi/Persian, Japanese,
Mandarin, Greek, Hindi, Korean, Spanish,
Portuguese, Portuguese, Swedish, Turkish
Spanish Spanish,
Swedish, Turkish

still dependent on the clinician’s judgment and the inter-
pretation of test results in a specific clinical context.
3.1. Neuropathic pain screening tools
Over the last 15 years several clinical tools in the form of
questionnaires making use of common verbal pain descriptors
(burning, electric shocks, tingling, pricking, pins and needles,
numbness, itch, pain evoked by brushing) have been develo-
ped and validated. These tools were specifically designed to be
very simple and easy to use for helping clinicians to identify
neuropathic pain, particularly in complex conditions. Five
questionnaires have been validated: the leeds assessment of
neuropathic symptoms and signs (LANSS) [13], neuropathic
pain questionnaire (NPQ) [14], douleur neuropathique en 4
questions (DN4) [15], PainDetect [16], and ID Pain [17], but only
three of them (LANSS, DN4 and PainDetect) are widely used.
Two of these tools, the LANSS and the DN4, include a brief
sensory bedside examination, but self-administered versions
of these tools have also been validated for postal surveys
[2,15,18]. The great success and rapid spread of these
questionnaires, which have already been translated in over
90 languages, highlights a previously unmet need in this field.
Validation studies showed excellent sensitivity (ranging
from 74% to 85%) and specificity (ranging from 76% to 90%) for
discriminating between neuropathic and non-neuropathic
pain and this was confirmed in many subsequent studies in
multiple languages (Table 1).
The major application of screening tools is the identifica-
tion of neuropathic pain in daily practice in various medical
settings by specialists or non-specialists, including doctors,
nurses, physiotherapists, dentists, etc (Table 2). They have
also been largely used for the detection of neuropathic pain in
surveys in the general population or in specific conditions with
a high prevalence worldwide, including leprosy and diabetes
in many non-Western countries including Morocco, Libya,
South Africa, United Arab Emirates, Saudi Arabia, Kuwait,
Brazil, South Korea, Japan, Benin, Burkina Faso, Ethiopia or
 revue neurologique 175 (2019) 16–25 19

Table 2 – Prevalence of neuropathic pain or painful neuropathy in the general population and in various neurological
conditions, based on results obtained with screening tools (studies published since 2011 or landmark studies before 2011,
with at least 50% return rate for studies in the general population; n I 100 patients).
Condition explored Author, year Nature of Geographic Sample Screening tool Prevalence
the study origin size
Neuropathic pain in the Bouhassira 2008 Cross sectional France 30155 DN4 interview 6.9%
general population
Harifi 2013 Morocco 5328 10.3%
DeMoraes 2012 Brazil 1597 DN4 10%
Adounokou 2014 Benin 2314 S LANSS 6.3%
Torrance 2006 UK 6000 PainDetect 8%
Torrance 2013 UK 8000 8.9%
Elzahaf 2016 Lybia 1212 3.9%
Inoue 2017 Japan 10000 3.20%
Painful diabetic neuropathy Bouhassira 2013 Cross-sectional France 855 DN4 17.9%
in type I or II diabetes
Van Acker 2009 Belgium 1111 14.1%
Jacovides 2014 South Africa 1046 30.3%
Halawa 2010 Saudi Arabia 1039 65.3%
Jambart 2011 Middle East 3989 53.7%
Neuropathic pain in type I Celik 2016 Cross-sectional Turkey 1357 DN4 23.0%
or II diabetes (90% type 2)
Aslam 2015 UK 204 S LANSS 30.3%
Liberman 2014 Israel 342 46.5%
(100% type 2)
Postherpetic neuralgia after Bouhassira 2012 Prospective France 1032 DN4 6.4%
herpes zoster at 12 months
Cho 2014 UK 305 S LANSS 6.2%
at 12 months
Poststroke neuropathic Aprile 2015 Cross-sectional Italy 106 DN4 10.5% at rehabilitation
pain
Harno 2014 Prospective Finland 824 PainDetect 5.9%
Neuropathic pain in Truini 2012 Prospective Italy 302 DN4 14%
multiple sclerosis
Heitmann 2016 Germany 377 PainDetect 4.2% at early stage
Neuropathic pain in Buhman 2017 Cross-sectional Germany 181 PainDetect 15.3%
Parkinson disease

Senegal [12]. This highlights the universal nature of the terms
used to describe neuropathic pain, and the high utility of these
clinical tools for public health and education worldwide.
Several studies showed the direct impact of neuropathic
screening tools on the management of patients. For example,
the incorporation of the DN4 questionnaire into the generic
pain chart for nurses significantly increased the likelihood of
detecting early postoperative neuropathic pain [19] A large
French national web-based survey of primary care physicians
showed that neuropathic pain recognition based on case
reports was very efficient when based on items from the DN4
questionnaire (88%) [20]. In Germany, three quarters of
clinicians considered PainDetect to be useful for the detection
of undiagnosed neuropathic pain in their patients with cancer
[21]. The practical and educational value of these tools was
also reported in non-European countries. A large survey
conducted in Saudi Arabia from 100 outpatient clinics
indicated that the number of patients treated specifically for
neuropathic pain increased by more than two thirds following
completion of the DN4 questionnaire [22]. In France, the DN4
questionnaire is now recommended by the French Pain
Society and hospital pain committees for the early detection
of neuropathic pain by nurses or doctors in surgical wards
(www.sfetd-douleur.org/la-douleur-neuropathique). An elec-
tronic version of the PainDetect is currently used in Germany,
by about 700 doctors in private practice and hospitals,
generating data for over 10,000 patients per month.
Like any clinical tool, neuropathic pain screening question-
naires have several limitations. In particular, as they provide no
information about the history of pain and sensory examination
is succinct or completely absent, they should be used only as a
first step in the diagnostic workup for the identification of
neuropathic pain. As stated above, a general examination of
the patient, to identify the potential cause of neuropathic pain,
remains essential. Furthermore, screening tools have been
validated for the detection of neuropathic pain in patients with
focal areas of pain. For patients with pain in several areas, such
as lumboradicular pain, it is recommended to apply these tools
to the area of the most severe pain or successively to each
painful area (e.g., the lower back and the leg) [23].
3.2. Grading system for the classification of neuropathic
pain
Concomitantly with the new definition of neuropathic pain,
the same group of experts proposed a grading system
algorithm for the classification of neuropathic pain [6]. This
algorithm was slightly revised in 2016 [24].
This grading system includes four criteria based on relevant
history, pain distribution, sensory signs and a diagnostic test
20 revue neurologique 175 (2019) 16–25
confirming a lesion or disease of the nervous system, making it
possible to classify the pain as unlikely, possible, probable or
definite neuropathic pain, depending on the number of criteria
satisfied. Thus, according to this algorithm, pain is considered as
possibly neuropathic if the patient’s clinical history is compa-
tible with the presence of a neurological lesion or disease and if
the pain has a plausible neuroanatomical topography. It is
regarded as probably neuropathic if, in addition to the previous
criteria, physical examination reveals a sensory deficit and/or
hyperalgesia/allodynia in the same plausible neuroanatomical
area of the body. Finally, neuropathic pain is regarded as
‘‘definite’’ only if a lesion or disease affecting the somatosensory
system can be objectively demonstrated.
This algorithm has the theoretical advantage of proposing a
common language and classification for neuropathic pain
syndromes. It has mostly been used for research purposes,
including, in particular, the classification of patients with
neuropathic pain in clinical trials [24]. However, this diagnostic
algorithm, which has not been formally endorsed by the IASP,
has some limitations. In, particular, it corresponds to an expert
consensus without proper validation, at least in terms of its
test-retest and inter-rater reliability, for use in different clinical
settings (i.e., by neurologists, pain specialists, other specialists
and general practitioners). In addition, the practical value of the
distinction between ‘‘probable’’ and ‘‘definite’’ for guiding the
management of neuropathic pain in daily practice is questio-
nable since these two classes of neuropathic pain are treated in
the same way [24]. Another issue is related to the fact that this
algorithm designed by and for neurologists necessitates a
training in neurology, whereas the vast majority of patients
with chronic pain do not consult neurologists. Finally, this
grading system was designed for patients suffering from
‘‘pure’’ neuropathic pain associated with a typical neurological
lesion or disease (e.g. diabetic polyneuropathy, postherpetic
neuralgia, poststroke pain etc.), but it does not seem to be
appropriate for a number of painful conditions described as
‘mixed pain’ syndromes (e.g. lumbar radiculopathy, cancer
pain, postsurgical pain), which are, by far, the most frequent in
clinical practice. In particular, in these patients, it is usually
very difficult or even impossible to confirm the neurological
lesion objectively and, therefore, to reach the level of ‘‘definite
neuropathic pain’’, or even ‘‘probable neuropathic pain’’.
The grading system is now more and more frequently used
in clinical research, but the limitations mentioned above
probably account for its very limited use in clinical practice. In
this context, screening questionnaires that are easy-to-use,
simple, but perform very well, have an undeniable advantage,
probably accounting for their success worldwide. Interestin-
gly, several clinical studies have shown that there is a fair-to-
excellent correlation between the presence of probable or
definite neuropathic pain according to this algorithm and the
results of DN4 [25–27] or PainDetect [28], although other
studies had less favorable results [29–31].
4. Epidemiology of neuropathic pain
Epidemiology has long been a neglected aspect of clinical
research related to neuropathic pain and until recently there
was no reliable information regarding the epidemiology of this
type of pain, most notably prevalence and incidence in the
general population. This was due notably to the lack of
validated operational diagnostic criteria that could be used in
surveys in the general population. The only available
information was mostly based on studies in cohort of patients
seen in specialized centers and concerned only specific
etiologies. Some well conducted prospective studies provided
valid estimations regarding the prevalence, incidence and
impact on health related QoL of neuropathic pain not only in
post-herpetic neuralgia (PHN) (estimated prevalence: 8–10%)
[32,33] and painful diabetic polyneuropathy (DPN) (estimated
prevalence: 14–26%) [34–37], but also neuropathic pain related
to surgery (estimated prevalence: 10–50% depending on the
surgery) [25,38–42], multiple sclerosis (estimated prevalence:
20–30%) [43–47], spinal cord injury (estimated prevalence: 30–
40%) [48,49], stroke (estimated prevalence: 5–11%) [50,51] or
cancer (estimated prevalence: 17–19%) [52–54]. However,
despite their scientific qualities, these works did not allow
to estimate the overall prevalence of neuropathic pain in the
general population.
The situation has considerably evolved over the last few
years, owing to the development and validation of screening
tools in the form of simple questionnaires (see above). The
specificity and sensitivity of these clinical tools for the
identification of chronic pain with neuropathic characteristics
(NC) was regarded as good enough to use them in postal or
telephone surveys. Several large epidemiological surveys
using this screening tools have been carried out in different
countries. Despite some limitations, inherent to the issues
related to the very definition and diagnostic criteria of
neuropathic pain (see above), these studies have provided
new and valuable information regarding the prevalence and
health-related burden of chronic pain with NC in the general
population.
Two large population-based postal surveys have been
carried out to estimate for the first time the overall prevalence
of chronic pain with neuropathic characteristics in the general
population in the UK and in France. The UK study used the S-
LANSS [13,18] to estimate the prevalence of chronic pain of
predominantly neuropathic origin (POPNO) in six family
practices in three UK cities [1]. This study included about
3000 participants. The return rate of the mailed questionnaire
was 52.4%. The prevalence of chronic pain (defined as pain or
discomfort, either all the time or on and off for more than
three months) was 48%. The estimated prevalence of chronic
pain with neuropathic characteristics, based on the responses
to S-LANSS (i.e. score  12) was 8.2%.
The French survey conducted in 2007 [2] used the DN4 [15]
in a representative sample of 30,155 people aged 18 years or
older in France. The estimated prevalence of neuropathic pain
was about 7%, and that of moderate-to-severe pain with
neuropathic characteristics was 5% (response rate about 81%).
Similar prevalence estimates (i.e. 6–10%) have been reported in
studies using the same questionnaire in non-European
countries including Benin [55] Brazil [56] and Morocco [57].
Other large-scale studies have been conducted with the LANSS
[58] or PainDetect [59].
Neuropathic pain was generally more frequent in patients
older than 60 years than in younger patients, and in women
than in men, and was more severe than non-neuropathic pain
 revue neurologique 175 (2019) 16–25
[1,2,55–58]. The back and legs were the most affected body
parts suggesting that lumbar radiculopathies are the most
common causes of chronic neuropathic pain in the general
population.
Screening questionnaires have also been used in several
prospective or cross-sectional studies to estimate the pre-
valence of, and risk factors for, neuropathic pain in patients
with type 1 or 2 diabetes, [34,22,60–63], postherpetic neuralgia
[33,64], multiple sclerosis [65], Parkinson’s disease [66] or
stroke [67]. These studies have suggested that chronic
neuropathic pain has a greater effect on sleep, quality of life,
anxious and depressive symptoms, and healthcare use than
non-neuropathic pain. Reduced quality of life and sleep
impairment have been specifically related to the number
and severity of neuropathic symptoms, as assessed by the DN4
questionnaire [68]. These findings indicating that neuropathic
pain is associated with a larger burden of disease than may
contribute to explain the difficulty to treat this type of chronic
pain.
Predictors for the development of chronic pain have also
been identified. In two prospective studies of patients with
herpes zoster, the presence or severity of neuropathic pain
assessed during the acute phase with the DN4 or LANSS
questionnaires, predicted postherpetic neuralgia at 3 or 12
months, independently of pain intensity, the severity of
infection or age [33,64]. In the surgical context, it was also
shown that higher scores or the presence of neuropathic pain
on the DN4 questionnaire immediately after surgery predicted
chronic postsurgical neuropathic pain independently of acute
postoperative pain or hyperalgesia [69,70].
5. Clinical assessment of neuropathic pain
The assessment/measurement of neuropathic pain is mostly
based on questionnaires and scales. Several specific ques-
tionnaires have been developed for this purpose. Quantitative
sensory testing (QST) can also be useful but, these time-
consuming methods have mostly been used in research
studies.
5.1. Neuropathic pain questionnaires
Pain intensity is usually measured by one-dimensional visual
analog or numerical scales. This overall assessment can be
complemented by questionnaires, such as the neuropathic
pain scale [71] or the neuropathic pain symptom inventory
(NPSI) [72], specifically developed and validated for the
assessment of different components of neuropathic pain.
Two other questionnaires — the McGill Short-Form Question-
naire 2, derived from the widely used McGill Short-Form
Questionnaire, a generic questionnaire applicable to any type
of pain [73] and the Pain Quality Assessment Scale, derived
from the Neuropathic Pain Scale [74] — have been validated for
assessment of both neuropathic and non-neuropathic pain.
Like the screening tools mentioned above, these question-
naires are based on pain descriptors, but the items selected
and the validation methods used differ from those for the
screening tools [11,12]. For example, the NPSI includes 10 pain
descriptors, the intensity of which is rated on numerical scales
21
from 0 to10, and two temporal items designed to assess the
duration of spontaneous ongoing pain and the number of pain
paroxysms over 24 hours. The 10 pain descriptors of the NPSI
have been shown to relate to five different clinically relevant
dimensions (superficial spontaneous pain, deep spontaneous
pain, paroxysmal pain, evoked pain, paresthesia/dysesthesia).
The NPSI has shown sensitivity to several treatments, with
differential effects on the various neuropathic pain dimen-
sions. It has been used in many large international multicenter
trials with different drugs over the last few years [11,12,75,76].
These questionnaires, which have been translated and
validated into a large number of languages (e.g., over 80 for the
NPSI), are also useful in clinical practice. They allow a more
accurate quantification of neuropathic pain than that done
with a global measure of pain intensity and a better
characterisation of the symptoms reported by patients with
neuropathic pain. They are therefore useful to assess the
effects of treatments on the different components of neuropa-
thic pain. In particular, they help to identify which neuropa-
thic symptoms (e.g., pain evoked by brushing) or dimensions
(e.g., paroxysmal pain) are preferentially alleviated by treat-
ment. In research settings, these questionnaires are being
increasingly used to phenotype patients for pathophysiologi-
cal studies and have identified phenotypic profiles of
responders in therapeutic studies, which should lead to a
more individualised therapy for neuropathic pain (see below).
5.2. Quantitative sensory testing
Quantitative sensory testing (QST) can be used in complement
to the traditional neurological bedside examination in the
analysis of somatosensory anomalies [77–79]. These methods,
derived from experimental psychophysics, are based on the
measurements of responses (i.e., non-painful sensations and
pain) to mechanical, thermal and vibration stimuli, the
intensity of which is controlled by automated devices [79].
QST can be used to determine sensory detection thresholds for
innocuous stimuli and pain thresholds, but can also be used to
assess the sensations induced by suprathreshold stimuli. The
main advantage of QST over more conventional assessment
methods is, therefore, that they can be used to quantify
various types of somatosensory deficits and allodynia or
hyperalgesia subtypes (i.e., in response to cold, heat, brushing
or pressure), which improve the characterization of individual
somatosensory phenotypes. QST is also useful in pharmaco-
logical studies, in which it can be used to document treatment
effects on subtypes of evoked pain. The homologous area of
the body on the contralateral side is generally used as a
control, but normative data for thermal and mechanical
detection and pain thresholds for the hand, foot and face have
been proposed, based on data for a large group of healthy
volunteers [80,81]. The repeatability of these measurements
has also been assessed [82]. However, the range of thermal
pain thresholds is very large between individuals and
repeatability is lower than for detection thresholds, highlight-
ing the difficulties involved in interpreting the results obtained
for pain thresholds in individual patients. QST is thus
considered more appropriate for comparisons of group data.
The sensitivity and specificity of QST have been little assessed
in comparisons with standard clinical examination, and the
22 revue neurologique 175 (2019) 16–25
outcomes of QST and bedside testing are not necessarily
consistent [77]. One reason for this discrepancy may be that
QST analyses focus on a restricted part of the painful area,
whereas more qualitative bedside examinations test a large
part of the innervation territory of the injured nervous system
structure. These time-consuming and costly techniques
remain difficult to implement in large samples of
patients in the clinical setting. However, the use of QST in
pharmacological trials has provided valuable information
regarding the differential effects of various drugs on the
different components of neuropathic pain and the identifica-
tion of potential predictive factors for the response to
treatments [83–85].
6. Neuropathic pain syndromes are
heterogeneous and multidimensional
The presence of a neurological lesion confers particular
qualities to the painful symptoms, justifying the consideration
of neuropathic pain as a relevant clinical entity. However, it is
now well established that neuropathic pain syndromes are
heterogenous and that this clinical entity is multidimensional.
Studies based on symptom-based questionnaires have indi-
cated that neuropathic pain syndromes include up to five
different components/dimensions (i.e. superficial burning
pain, deep pain, paroxysmal pain, evoked pain and dyses-
thesia/paresthesia) and that several subgroups of patients
could be defined on the basis of their sensory profiles defined
on the basis of combinations of specific symptoms and signs
[8,72,86,87]. QST-based studies also suggested that patients
with neuropathic pain can be assigned to several subgroups
(clusters) on the basis of combinations of symptoms and
signs [88].
The different dimensions of neuropathic pain which are
present, albeit at different frequencies, in peripheral or central
neuropathic pain syndromes are not related to the etiology,
but may rather reflect the pathophysiological mechanisms [8].
Thus, the patients presenting with different sensory profiles
(phenotypes) may respond differently to the treatment
[8,11,89,90]. According to this new conceptualization, the
current way of selecting patients in clinical trials on the basis
of the disease or topography of the lesion is not the most
appropriate or rational approach. The multidimensional
nature of NeP syndromes supports the relevance of including
patients with different aetiologies and to analyse the effects of
treatment on the different components (dimensions) of NeP in
order to identify specific responder profiles.
This new approach of neuropathic pain syndromes, which
is advocated by a growing number of experts, may help to
improve treatment and may replace the traditional etiology-
based classification of neuropathic pain that still prevails in
clinical, experimental and pharmacological studies [11,89,90].
7. Conclusions
Neuropathic pain has been a very active clinical research field
over the last 15 years. Studies have concerned multiple
aspects of these complex chronic pain syndromes including
their very definition, the elaboration of new diagnostic
algorithms the development of specific tools for their
screening and measurement. Overall, this has led to changes
in the way these pain syndromes are conceptualized.
However, there are still many challenges related to the
pathophysiology and treatment of these chronic pain syn-
dromes which are still among the most difficult to manage in
daily practice.
Disclosure of interest
The author declares that he has no competing interest.
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