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Abstract

Ensuring the proper management of neuropathic pain is a contemporary challenge for professionals who care for patients with this type of pain. The estimated prevalence of neuropathic pain in Europe is 7%–8%. The objective of this study was to perform a non-systematic review on the diagnosis, screening, and quantification of neuropathic pain. For this purpose, a search was conducted of the PubMed/Medline, ScienceDirect, OVID, and SciELO databases for available evidence. The findings highlight the common occurrence of chronic neuropathic pain in clinical practice. However, diagnosing and managing this type of pain pose challenges due to its complexity and the individualized nature of cases. Precise diagnosis is crucial for effective management, involving therapeutic approaches that go beyond traditional pain treatments. It is noteworthy that until recent times, general questionnaires were utilized to assess neuropathic pain, lacking the ability to distinguish it from nociceptive pain or evaluate its broader impact on well-being. Biomarker pain panels hold promise in identifying treatable pain causes and evaluating treatment effectiveness. In conclusion, this review describes the diagnostic methods and tools for screening and quantifying neuropathic pain.

Keywords

Pain neuropathic diagnosis screening quantification complimentary tests

Introduction

Neuropathic pain is generally considered a chronic condition, with a prevalence of 7%–8%¹; however, it is a complex pain, whose treatment is a challenge for most professionals in daily clinical practice. The main types of pain are nociceptive, neuropathic and mixed pain as well as nociplastic pain, recently defined by the International Association for the Study of Pain (IASP).² Nociceptive pain is induced by tissue injury and neuropathic pain by disease or damage of the somatosensory system, while nociplastic pain is caused by an alteration in nociception when there is no clear evidence of actual or threatened tissue damage that would activate peripheral nociceptors or signs of somatosensory system disease or injury that might be responsible for the pain.

Neuropathic pain arises from complex physiological changes following peripheral nerve injury. These alterations involve ion channels, receptors, and proteins, resulting in abnormal nerve cell activity and heightened excitability.³ Dysfunctional voltage-gated sodium channels notably contribute to increased firing, a key element in neuropathic pain development. Additionally, neurotransmitter release intensifies post-injury, activating pain pathways and magnifying pain perception. Excessive glutamate release, a major neurotransmitter, triggers receptor activation and synaptic changes that heighten pain sensitivity.⁴

Central nervous system plasticity deepens neuropathic pain, characterized by heightened spinal neuron activity and reduced inhibition. This intricate interplay leads to elevated pain signaling, touch sensitivity, and pain responses.⁵ MicroRNA-mediated gene regulation emerges as a pivotal mechanism governing this plasticity. Glial cells, crucial elements in neuropathic pain, become hyperactive post-injury, releasing inflammatory molecules that amplify pain signals through neuroinflammation.⁶ Recent research identifies potential avenues for intervention, targeting glial activation through receptors like Toll-like receptors and the NLRP3 inflammasome.⁷

Recent investigations encompass shifts in ion channels, neurotransmitter release, central nervous system plasticity, and glial activation. Precise diagnosis remains challenging due to neuropathic pain’s complexity, demanding meticulous assessment of somatosensory symptoms. Accurate diagnosis, coupled with in-depth explorations of these mechanisms, remains pivotal for effective treatment development. This on-going progress promises new avenues for improving the lives of those suffering from neuropathic pain.⁸

Neuropathic pain is a devastating condition whose diagnosis requires detailed anamnesis, gathering the patient’s history of pain, and a proper neurological examination. Information on its etiology can be obtained by performing complementary studies, including blood and serological tests, electrophysiological studies, and imaging procedures.⁹ Advances in treatment are likely to develop in parallel with the increased availability of improved diagnostic techniques. Acute neuropathic pain is also observed; it is regarded as nociceptive in nature but is mixed in a small percentage of cases, with an additional neuropathic component (e.g., acute herniated disc or post-surgical pain). The seriousness of acute neuropathic pain lies in its high risk of progression to a persistent debilitating state. Acute neuropathic pain is defined by a time period of 6–12 weeks.^1,10 Differentiation between neuropathic and nociceptive pain and identification of the nociceptive component of mixed pain require detailed analysis of somatosensory abnormalities in each case. The combination of classical methods to diagnose neuropathic pain with novel biomarkers, sensory profile stratification and other diagnostic tools may help to elucidate the pain experience of these patients and to quantify the damage to nociceptive pathways, facilitating more personalized, targeted and effective analgesic therapy.^11,12 However, unlike other symptoms and signs (e.g., motor deficit), pain is difficult to evaluate, being a non-observable and subjective sensory symptom that involves not only physical but also psychological and emotional factors.^13,14 The objective of this article was to carry out a non-systematic review on the diagnosis, screening, and quantification of neuropathic pain.

Methods

A search was conducted between June and December 2022 of PubMed/Medline, ScienceDirect, OVID, SciELO databases using the following search terms: neuropathy, neuropathic pain, neuropathic pain diagnosis, neuropathic pain-screening, neuropathic pain quantification, including only original articles published in English. Abstracts of retrieved items were screened, selecting articles with relevant content and checking their references for additional material. Three researchers (AH, RG, and MK) then individually reviewed the selected articles before arriving at a consensus on the data to be included and discussed in this review.

Results

According to the last Revised Definition of the IASP, pain is defined as “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”¹⁵ The definition was expanded upon by the addition of the etymology of the word (pain) explaining that “pain” can be traced back to its Middle English origins, from Anglo-French “peine” (pain, suffering), from Latin “poena” (penalty, punishment), in turn from Greek “poinē” (payment, penalty, recompense) and addition of the following six key Notes¹⁶:

Pain is always a personal experience that is influenced to varying degrees by biological, psychological, and social factors.

Pain and nociception are different phenomena. Pain cannot be inferred solely from activity in sensory neurons.

Through their life experiences, individuals learn the concept of pain.

A person’s report of an experience as pain should be respected.

Although pain usually serves an adaptive role, it may have adverse effects on function and social and psychological well-being.

Verbal description is only one of several behaviors to express pain; inability to communicate does not negate the possibility that a human or a non-human animal experiences pain.

The diagnosis of neuropathic pain can be particularly challenging, but various tools are available for this purpose, with varying degrees of objectivity¹²:

Laboratory biomarkers, offering the highest degree of objectivity when combined with imaging and electrophysiological tests.

Quantitative sensory testing (QST), which is relatively objective but based on the patient’s responses.

Neurological examination, based on the patient’s responses and the experience and perceptions of the examiner.

Pain questionnaires with clinical descriptors, entirely dependent on the patient’s subjective perception.

Medical history

There is general agreement in the literature that a detailed amanuensis is the first step in the diagnosis and evaluation of neuropathic pain.⁹ It should seek the following information from the patient: a description of the qualities and duration of pain and its intensity; changes in the pain pattern over time, the context of pain onset, the type of pain, factors/actions that relieve or worsen the pain, its impact on daily activities and sleep, and the presence of other symptoms, such as paraesthesia.¹⁷ It is also necessary to explore the possible contribution of psychological, social, and environmental factors. The combination of these data with examination findings can help to identify the specific pathophysiological mechanisms responsible for the pain.^18,19 Neuropathic pain, is a neurological symptom caused by a lesion or disease of the central or peripheral somatosensory nervous system and is always subjective and thus does not have a confirmatory test by itself.¹⁸ In addition, pain is often a novel life experience for individuals, who may therefore lack appropriate verbal descriptors or even analogies, further hampering the reliability of their pain evaluation.²⁰

Clinical manifestations, physical examination, and complementary tests

Clinical manifestations

The diagnosis of neuropathic pain and its differentiation from nociceptive pain can be facilitated by the precise analysis of somatosensory abnormalities. Neuropathic pain is indicated by abnormal sensations or tenderness in affected parts, possibly associated with sensory-impaired areas of skin (Figure 1). Clinical manifestations of neuropathic pain include: a history of episodes of spontaneous pain (burning, oppressive, stabbing, or electrical) and the presence at examination of hyperalgesia (exaggerated response to a painful stimulus) or allodynia (pain in response to a stimulus that is not painful under normal conditions) Allodynia and hyperalgesia indicate central sensitization or a hyperactive response to normal or subthreshold afferent stimuli. Central sensitization is a sign of increased severity.¹³

Figure 1.

Assessment of sensory symptoms and signs in patients with neuropathic pain.

Physical examination

The evaluation of neuropathic pain requires a general physical examination and complete neurological study. Special attention should be paid to the somatosensory system (touch, pain, cold, and heat) to identify areas of mechanical and/or thermal hypoesthesia, hyperalgesia or allodynia and to check for the possible presence of Tinel’s sign. It is recommended to map areas with sensory impairment on schematic charts of the front and back of patients.¹² Repetition of this mapping in follow up visits can reveal somatosensory changes, although these are not always directly related to the intensity and severity of neuropathic pain. This examination can be performed at the bedside by any qualified physician using simple instruments (cotton, paper clip, glass tubes, tuning fork, Weber compass, needle esthesiometers, von Frey filaments).²¹ The anamnesis and neurological examination should be completed before complementary tests are performed.

Complementary tests

Complementary tests (neurophysiological, neuroimaging, biopsy) can be useful to explore the etiology of pain, identify underlying pathophysiological mechanisms, and measure the effectiveness of treatments. Not all tests are available in all settings, and some have only been used for research purposes, although their utilization is recommended in neuropathic pain units within pain clinics or neurology departments.²² The most used are described below:

Clinical neurophysiology

The evolving landscape of neurophysiological techniques has led to the development of advanced methodologies that offer unique insights into the mechanisms underlying neuropathic pain. To facilitate a deeper understanding of these techniques and their contributions,⁸ Table 1 serves as a comprehensive guide, outlining the fundamental principles, applications, advantages, and limitations of each approach.

Table 1.

Neurophysiological techniques in the assessment of neuropathic pain.

Technique	Principle	Stimulus	Measurement	Application	Advantages	Limitations
Pinprick Evoked Potentials²³	Neural response to pinprick	Mechanical nociceptive	Evoked potentials via EEG/MEG	Assessing Aδ-fiber function and pain perception	Direct insight into neural processing of mechanical pain stimuli; functional integrity assessment	Limited to specific fibers; specialized equipment and expertise needed
Cold evoked potentials²⁴	Neural response to cold	Controlled temperature	Evoked potentials via EEG/MEG	Evaluating cold-specific nociceptive pathways	Assessment of cold-sensitive Aδ-fibers; cold pain processing insights	Specialized equipment and expertise required; limited availability
Laser evoked potentials²⁵	Activation of nociceptors	Laser-generated heat pulses	Evoked potentials via EEG/MEG	Directly studying the nociceptive pathway	Captures brain response to nociceptor activation; precise activation of Ad and C fibers	Focuses on evoked potentials; not continuous monitoring
Contact heat evoked potentials²⁶	Activation of nociceptors	Controlled heat stimuli	Evoked potentials via EEG/MEG	Assessing the nociceptive pathway	Study of nociceptive pathway; quantitative sensory testing	Not universally available; limited to nociceptor activation
Functional MRI²⁷	Blood flow changes	Neural activity changes	BOLD signal changes	Examining brain regions and processing	Visualization of pain-related brain areas; non-invasive; dynamic imaging	Indirect measure of neural activity; expensive equipment; subject to motion artifacts
Positron emission tomography²⁸	Tracer uptake and decay	Regional cerebral flow/metabolism	Radioactive tracers	Investigating brain activity and connectivity	Quantitative assessment; provides functional information	Invasive due to radiation exposure; limited availability
Transcranial magnetic stimulation²⁹	Magnetic field effects	Magnetic fields	Motor cortex modulation	Exploring cortical excitability and pain modulation	Non-invasive; modulates neural activity; cortical insights	Focuses on modulation; limited to cortical areas
Microneurography³⁰	Single nerve fiber activity	Direct nerve recording	Single fiber recordings	Studying nociceptive fiber firing patterns	Real-time nerve activity insights; direct recordings; mechanistic understanding	Invasive; requires skilled operators; limited to specific nerve recordings

In the quest to unravel the complexities of neuropathic pain, researchers and clinicians have turned to cutting-edge methods that extend beyond conventional assessments. These advanced neurophysiological techniques encompass a diverse array of approaches, each tailored to capture specific facets of pain processing and neural responses.³¹ For instance, they facilitate the direct measurement of nerve fiber activities, allowing for a precise examination of nociceptive signaling pathways. Additionally, these techniques enable the visualization of brain regions implicated in pain perception, shedding light on the neural correlates of pain experience.³² Each method brings its unique set of capabilities and considerations, such as the capacity to assess pain modulation mechanisms, such as descending pain inhibition pathways or facilitation processes. These nuanced applications hold significant implications for both researches, including the investigation of underlying mechanisms of chronic pain, and clinical practice, where improved pain management strategies can be developed.³²

Nociceptive reflexes

Trigeminal reflex testing is an instrumental diagnostic tool in discerning between idiopathic and symptomatic trigeminal neuralgia (TN).³² When sensory branches of the trigeminal nerve are stimulated, individuals with idiopathic neuralgia often exhibit an exaggerated reflex response, characterized by intense facial muscle contractions and pain due to heightened neural excitability. This hyperactive response is indicative of the spontaneous nature of idiopathic neuralgia. On the other hand, symptomatic neuralgia resulting from nerve compression, such as by vascular structures, may display a dampened or altered reflex due to the presence of underlying pathology affecting nerve function. This abnormal or reduced reflex reaction serves as an indicator of an external factor contributing to the neuralgia. By thoroughly evaluating the trigeminal reflex response, clinicians can gain critical insights into the condition’s origin and tailor treatment strategies to the specific underlying cause, leading to more effective management and improved patient well-being.^33,34

Nociceptive flexion reflex

The nociceptive flexion reflex (NFR) is a withdrawal reflex in response to the activation of A-delta nociceptors (pain signaling, fast nerve fibers) and involves numerous spinal cord synapses. An electromyogram is used to measure muscle activity in the upper leg (biceps femoris) while increasing electrical stimulation is applied to the homolateral lower leg (sural nerve). The intensity of the stimulus at which the NFR is evoked is commonly the intensity at which the subject reports pain onset, and increasing NFR intensity correlates with the pain intensity experienced. This test is used in research to verify the efficacy of treatments.³⁵

Quantitative sensory tests

QSTs are increasingly employed in clinical trials to measure sensory thresholds for painful, tactile, vibratory, and hot/cold sensations. Specific fiber functions are assessed: Aδ fibers, with detection thresholds for cold and for cold and pain; C fibers, with detection thresholds for heat and for heat and pain; and large fibers (Aαβ), with detection thresholds for vibration. Elevated sensory thresholds are associated with sensory losses and reduced thresholds with such conditions as allodynia and hyperalgesia.³⁶ Results obtained allow researchers to quantify the effect of treatments on hyperalgesia and allodynia. However, the usefulness of QSTs in clinical practice is limited, because they are laborious and do not differentiate between neuropathic and non-neuropathic pain.^37,38

Autonomic function tests

Autonomic signs may be a direct consequence of nerve injury or a spinal or supraspinal reflex. Evaluation of autonomic functions is important in patients with suspected neuropathic pain. This is because of anatomical similarities between pain fibers and autonomic fibers outside the central nervous system (CNS) and also because patients with disorders responsible for neuropathic pain frequently have signs/symptoms of autonomic dysfunction (dry eyes/mouth, changes in skin color/temperature, sweating disorders, orthostatic hypotension, heart rate responses to deep breathing, edema, etc.).³⁹ Most autonomic tests measure skin temperature as well as sudomotor, baroreceptor, vasomotor and cardio-vagal responses.⁴⁰

Microneurography

Microneurography has emerged as a sophisticated neurophysiological technique with notable implications for the assessment of neuropathic pain. By employing ultrafine electrodes to facilitate real-time recordings of individual nerve fiber activity within peripheral nerves, this method offers a unique avenue for investigating the complex interplay between altered neural dynamics and the manifestation of neuropathic pain.⁴¹ Although historically hindered by safety concerns and invasiveness, recent advancements in needle design, procedural techniques, and imaging modalities have substantially improved the safety profile of microneurography, rendering it a more viable tool for both research and clinical applications.⁴² Of particular significance is microneurography’s capacity to directly correlate spontaneous neuronal activity with the subjective experience of pain. This attribute endows the technique with the ability to bridge the gap between objective electrophysiological findings and the nuanced realm of pain perception.⁴³ Consequently, microneurography not only validates the existence of neuropathic pain but also provides a mechanistic understanding of how altered neural firing patterns are transduced into the sensation of pain. Moreover, this technique permits the discernment of specific nerve fiber types involved in generating pain signals, thereby enabling a comprehensive mapping of pain pathways.⁴⁴ These advancements collectively contribute to the evolving landscape of neuropathic pain assessment, offering novel insights into pathophysiological processes and laying the groundwork for tailored therapeutic interventions.⁴⁵

Functional neuroimaging

Functional magnetic resonance imaging (fMRI) stands out among the modalities available to study neuropathic pain. It is based on changes in the blood oxygenation level-dependent (BOLD) signal, which simultaneously reflects local cerebral blood flow changes and variations in deoxyhemoglobin content.⁴⁶ The most frequently examined neuropathic pain conditions include painful diabetic neuropathy, peripheral neuropathy, complex regional pain syndrome (CRPS), TN and spinal cord injury (SCI).⁴⁷ In this way, patients with TN have increased gray matter volume in the sensory thalamus, amygdala, periaqueductal gray, and basal ganglia in comparison to healthy controls.⁴⁸ In the future, this imaging modality will allow practitioners to follow up the therapeutic response in a systematic manner. Nevertheless, many challenges remain in the implementation of imaging as a biomarker for neuropathic pain. For instance, there is a large overlap between chronic pain and areas activated in other commonly associated disease conditions, such as anxiety and depression, hampering the isolation of a pain signature.⁴⁹

Biopsy

The skin biopsy is used to count the number of sensitive nerve endings and to observe abnormalities. It is increasingly proposed as a technique not only to diagnose small fiber neuropathy but also to follow the course of neuropathic pain.⁵⁰ When repeated in time, the loss or even gain of sensitive nerve fibers can be verified. Skin or nerve biopsy is recommended to distinguish neuropathic pain from painful sensory neuropathy.⁵¹

Other additional tests

Other tests that may be of great value in patients with neuropathic pain and specifically in focal pain syndromes (e.g., CRPS) include scintigraphy, bone densitometry, and nerve or sympathetic ganglion blocks. Serum immunoelectrophoresis may be helpful in painful polyneuropathies associated with monoclonal gammopathies and in acquired amyloid polyneuropathy.⁵² Specific serum antibody tests are of value in painful neuropathies associated with neoplasia, celiac disease, and human immunodeficiency virus.⁵³

Biomarkers in neuropathic pain

Research in molecular biology over recent decades has led to the development of specific biomarkers for the diagnosis of neuropathic pain, although this approach is costly and requires highly specialized techniques. Biomarkers have proven to be strong predictors of pain intensity and chronification, besides being useful to monitor the therapeutic response.⁵⁴ For instance, microRNAs (RNA molecules of 19–25 nucleotides) play a major role in cellular physiology, and the presence of miR-30c-5p in plasma and cerebrospinal fluid has been associated with a certain type of neurological disorder.^55,56

Other biomarkers of the severity/intensity of neuropathic pain include the expression of genes related to nerve inflammatory processes, which are altered in chronic neuropathic pain. In this way, two-fold higher serum levels of IL-2, TNF were observed in patients with painful neuropathy compared to those without pain.^57,58

The published series suggest that specific urinary, serum, cerebrospinal fluid, and salivary biomarkers, (Table 2), may help identify those patients at risk of disease development, and function as a prognostic indicator for disease progression and treatment response.^59
–61 However, current individual and panel-based biomarkers have limited usability in regards to informing clinical decision-making at this time.⁵⁶

Table 2.

Biomarkers and relevance in chronic pain pathology.

Biomarker	Role in chronic pain
Urinary biomarkers^59 –61
Foundation pain index	Validated for assessing chronic pain and correlates with clinical assessments
Prostatic exosomal proteins	Detect symptomatic progression of chronic prostatitis/chronic pelvic pain syndrome
VEGF, VEGF-R1, MMP-9	Associated with urological chronic pelvic pain syndrome and urinary symptoms
Serum biomarkers⁶²
Proinflammatory cytokines (IL-6, TNF-α, IL-8, IL-1β)	Correlated with pain intensity and neuropathies
Anti-inflammatory markers (IL-4, IL-10)	Lower in subjects with lesser or no pain, indicating potential analgesic effects
TNF-α	Correlated with pain intensity, higher in patients with painful neuropathies
IL-21 and IL-17	Elevated in disc herniation patients, suggesting involvement in lumbar disc herniation
RANTES	Associated with pain levels and activity limitation in chronic low back pain
Proteins (APO-L1, APO-M, TN, IGL)	Predictive for pain in psychiatric patients
IL-8 and MCP-1	Elevated in fibromyalgia patients, correlated with pain severity
Cerebrospinal fluid biomarkers^56,63
Serum AVP levels	Higher in chronic pain patients
IL-8	Increased in lumbar disc herniation patients
GDNF and SST	Lower in chronic migraine and fibromyalgia patients
Autotaxin	Increased in fibromyalgia patients
TNF-β and TRAIL	Elevated in TN patients and decreased after treatment
Cystatin C	Elevated in obstetric patients with severe labor pain
Salivary biomarkers^62,64
Cortisol	Higher in fibromyalgia patients, diurnal cortisol slope blunted
Transaldolase, calgranulin A, calgranulin C, phosphoglycerate mutase I	Over-expressed in fibromyalgia patients, reduced with treatment
Glutamate	Elevated in chronic migraine and temporomandibular disorder patients
NGF and BDNF	Decreased in temporomandibular disorder patients
Alpha-amylase, IgA, MIP4	Increased in burning mouth syndrome patients

VEGF: vascular endothelial growth factor; VEGF-R1: VEGF receptor-1; MMP-9: matrix metallopeptidase 9; IL: interleukin; TNF: tumor necrosis factor; RANTES: regulated on activation, normal T cell expressed and secreted; APO: apolipoprotein; TN: tetranectin; IGL: immunoglobulin light chain; MCP-1: monocyte chemotactic protein-1; AVP: arginine vasopressin; GDNF: glial cell line-derived neurotrophic factor; SST: somatostatin; TRAIL: TNF-related apoptosis inducing ligand; IgA: immunoglobulin A; MIP4: macrophage inflammatory protein-4.

Confocal microscopy of the cornea

Corneal confocal microscopy is another non-invasive technique increasingly applied in the diagnosis of neuropathic pain conditions (Brines). It is used in patients with diabetes mellitus sacoidosis or Fabry disease to detect possible peripheral fine fiber neuropathies. Its advantages include its simplicity, reliability and reproducibility. It can also be used to follow the course of neuropathy by periodically evaluating the density, length, and branching patterns of corneal nerve fibers.^65,66

Phenotyping

The treatment of neuropathic pain according to its phenotype has long been proposed by authors and appears to be increasingly relevant. It has been estimated that first-line treatments are beneficial for less than 50% of patients in standard etiology-based clinical practice and have obtained a low response rate in clinical trials.⁶⁷ The stratification of patients with neuropathic pain by QST-evaluated sensory profile has been shown to improve the design of clinical trials and may assist future therapeutic strategies. Three main profiles have been proposed⁶⁸: mechanical sensory loss and thermal alteration, henceforth “sensory loss”; hyperalgesia without impaired sensory function of small fibers, known as “thermal hyperalgesia”; and loss of thermal sensation, henceforth “mechanical hyperalgesia.”

Positive and negative symptoms and signs of neuropathic pain

The examination of patients with neuropathic pain should consider the following components: touch, pinprick, pressure, cold, heat, vibration, and temporal summation; Figure 1 depicts the methods used to evaluate possible positive/negative symptoms and signs.^37,69
–73

Neuropathic pain questionnaires

Over the past 2 decades, neuropathic pain-screening tools relying on verbal descriptions have emerged, either with or without clinical examination. These tools aim to differentiate neuropathic from nociceptive pain, gauge pain intensity, and assess treatment responses.⁷⁴ General-use questionnaires, such as simple verbal scales, numerical scales (0–10),⁷⁵ and visual analogue scales (VAS), are widely used and reliable, with VAS being the preferred choice for pain intensity measurement.⁷⁶ Specific neuropathic pain questionnaires like Leeds neuropathic symptom assessment scale (LANSS),⁷⁷ neuropathic pain diagnostic questionnaire (DN-4),⁷⁸ neuropathic pain questionnaire (NPQ),⁷⁹ PAIN DETECT,⁸⁰ ID-Pain,⁸¹ and Diagnostic tool⁸² employ specific descriptors to enhance neuropathic pain diagnosis. These tools simplify and systematize neuropathic pain assessment.⁷⁰

Leeds neuropathic symptom assessment scale

The LANSS comprises seven pain-related items, five on symptoms and two on clinical examination findings, scoring items from 1 to 5. Psychometric study found that a LANSS score of ⩾12 (out of maximum of 24) indicates neuropathic pain.⁷⁷ A self-assessment version, the S-LANSS, has also been validated.⁸³

Neuropathic pain diagnostic questionnaire

The DN4 comprises seven items on pain-related symptoms in the past 24 h and three items on clinical examination findings, scoring 1 for a positive response to each item. A total score of ⩾4 (out of a maximum of 10) indicates neuropathic pain. The seven sensory descriptors are also used in a self-assessment questionnaire, obtaining similar results.⁷⁸ DN4 has been validated and used in large epidemiological studies to estimate the prevalence of neuropathic pain, both in the general population and in specific clinical situations.^{10,17,84
–90}

Neuropathic pain questionnaire

The NPQ consists of 12 items, including 10 related to sensations and sensory responses and two to the emotional sphere of pain. It has demonstrated a sensitivity of 66% and specificity of 74% with respect to the clinical diagnosis. There is also a short version with only three items (tingling, numbness, and pain increasing in response to touch) that offers the same discriminatory capacity.⁷⁹

The painDETECT scale

This questionnaire was initially developed and validated in Germany. It comprises nine items that do not require clinical examination, seven items related to sensory descriptors, and two related to the spatial (radiant) and temporal characteristics of the pain pattern. Pain is referred to both the present time and the previous 4 weeks.⁸⁰

The ID-pain neuropathic pain-screening questionnaire

ID-Pain consists of five sensory descriptor items and one item related to whether the pain is in the joints (used to identify nociceptive pain) and whether clinical examination is required. Each item scores 1 point except for pain localization in joints, which scores −1. ID-Pain was designed to detect the probable presence of a neuropathic component. In the validation study, 22% of the nociceptive group, 39% of the mixed group, and 58% of the neuropathic group scored >3 points, the recommended cutoff score.⁸¹

Diagnostic tool

This tool is specifically designed for the diagnosis of localized neuropathic pain, which is described as confirmed, probable (high suspicion), or possible (low suspicion). It consists of four items related to: data in the medical history raising suspicion of nerve disease/injury; the possible neuroanatomical distribution of pain; sensory test findings of possible positive or negative signs in the area where the lesion is presumably located, and the size of the painful area (larger or smaller than an A4 sheet).⁸²

Description of neuropathic pain-screening questionnaires

NPQs have been endorsed by different authors as valid to distinguish neuropathic from nociceptive pain one, Table 3 displays the main characteristics, including psychometric properties, of the questionnaires used to detect neuropathic pain.

Table 3.

Characteristics of the questionnaires used for the detection of neuropathic pain.

Questionnaires (Authors)	LANSS (Bennett, 2001)⁷⁷	DN4 (Bouhassira et al., 2005)⁷⁸	NPQ (Krause and Backonja, 2003)⁷⁹	painDETECT (Freynhagen et al., 2006)⁸⁰	ID-pain (Portenoy, 2006)⁸¹	Diagnostic tool “Localized neuropathic pain (LNP)” (Mayoral et al., 2018)⁸²
Administration method	- Administration by the clinician - S-LANSS: self-assessment⁸³	- Administration by the clinician - 7-item version: self-assessment	Self-administered	Self-administered	Self-administered	- Administration by the clinician
Questions (related to the area of pain)	5 items (yes / no) - Strange and unpleasant sensations (pricking, tingling, pins and needles) - Skin that looks different from normal (mottled, red, or pink) - Skin abnormally sensitive to touch (unpleasant sensations when stroking, pain when wearing tight clothing) - Electric shocks, bursts and jumping - Hot, burning	7 items (yes / no)- Burning - Painful cold - Electric shock - Tingling - Pins or needles - Numbness - Itching	12 items quantified (0: no pain to 100, worst pain imaginable) - Burning pain - Too sensitive to the touch - Sudden pain - Numbness - Electrical pain - Tingling - Feeling of tightness - Freezing pain - Unpleasant - Devastating - Increased pain due to rubbing - Increased pain due to weather changes	Pain grading: - 7 quantified items (0: barely noticeable to 5: very strong) - Burning (for example, nettles) - Tingling or itching (ants, electrical tingling) - Is it painful to light touch (clothing, a blanket)? - Are there sudden attacks of pain such as electric shocks - Is cold or heat (water bath) sometimes painful? - Numbness - Does a slight pressure, for example, with a finger, trigger the pain? - Pain pattern: 4 patterns Persistent pain, with slight fluctuations Persistent pain with mild attacks Attacks of pain, no pain between them Pain attacks with pain between them - Radiated pain (yes/no)	6 dichotomous items (yes/no) - Pins and needles - Hot/burning - Numbness - Electric shock - Does the pain get worse when you touch clothes or sheets? - Do your joints hurt? This last item is assessed with: Yes = −1, No = 0 The rest of the items Yes = 1, No = 0	4 items: - First: determine whether the patient has a history that raises suspicion of disease or injury to the nerves - Second: attempt to find out the possible neuroanatomical distribution of pain - Third: perform sensory tests to determine any possible positive or negative sign in the area where the injury is presumably located. and diagnostic test that confirms the injury or disease that cause neuropathic pain - Fourth: attempt to determine whether the painful area is larger or smaller than an A4 size sheet
Physical examination items (in the area of pain)	2 items (yes/no) - Allodynia: pain or unpleasant sensations (tingling, nausea), with rubbing - Altered pinprick threshold	3 items (yes/no) -Hypoesthesia to touch - Hypoesthesia to pinprick - Allodynia to brushing	None	None	None	None
Assessment	The items have variable coefficients (0: no, 1–5: yes) total score of 24 - Score ⩾12: probable neuropathic mechanisms - Score <12: not probable neuropathic mechanisms	Each item, 1 (yes) or 0 (no) Total score: sum of the 10 items Cut off value ⩾4	Items with variable coefficient Value of each item × coefficient (−0.008 to 0.020) Total score × −1408 discriminant function Score of 0 or >0: predicts neuropathic pain Score <0: does not predict neuropathic pain	- Pain grading items from 0 to 5 - Items of assumed pain pattern: −1, 0, +1 - Radiating pain: 0 (no) to +2 (yes) Total score: ⩾19: likely neuropathic component ⩽12: unlikely neuropathic component - Between these: uncertain	Score from −1 to 5, the highest score indicates neuropathic component 4 or 5 = very likely 2 or 3 = probable 0 or 1 = possible −1 = unlikely	1- History: Suggests nerve injury or disease 2- Anatomy: Neuroanatomical distribution consistent with pain) - 1 and 2 = Possible NP 3- Tests: A- presence sensory aberrations (negative or positive). B- diagnostic test that confirms the injury or disease that cause neuropathic pain (etiology) - A or B = Probable NP - A and B = Confirmed NP 4- Extension of the painful area Probable or Confirmed NP with extension Less than A4 = Localized neuropathic pain
Sensitivity	83% (study 1)	83%	66.6%	85%	Not evaluated	95.5%
Specificity	87% (study 1)	90%	74.4%	80%	Not evaluated	89.1%
ROC	Not shown	AUC: 0.92	Not shown	AUC: 0.91	C: 0.69

NP: neuropathic pain; ROC: Receiver Operating Characteristic; AUC: area under the ROC curve; C: concordance index (a measure of discriminatory accuracy in general).

Diagnostic and grading algorithms for neuropathic pain

One of the emerging trends in neuropathic pain diagnosis is a personalized approach that tailors treatment plans based on individual patient characteristics. This might involve genetic profiling, sensory testing, and response to previous treatments to design a treatment strategy that addresses the specific underlying mechanisms of a patient’s neuropathic pain. Diagnosing neuropathic pain is a dynamic process that encompasses clinical acumen, patient narratives, advanced imaging, and evolving scientific insights. The goal is not only to accurately diagnose the condition but also to understand its underlying mechanisms, enabling tailored and effective pain management strategies.⁹¹

A number of grading systems have been proposed over the past 2 decades; in 2008, an expert group of neurologists, neuroscientists, neurophysiologists, neurosurgeons and members of the IASP developed a system to grade the likelihood that the pain in a given individual is neuropathic. Two questions are posed to arrive at the neurological diagnosis: Where is the injury located? And what is the type of injury? The neuropathic pain grading system addresses four criteria: pain with plausible neuroanatomic distribution, presumptive history of relevant injury or disease involving the peripheral or central somatosensory system, plausible neuroanatomic distribution of pain with at least one positive test for neuropathic pain, and the confirmed presence of injury or relevant disease.⁹² Martínez-Salio et al.,⁹³ proposed another grading system in which neuropathic pain is confirmed after completing the following sequential steps: History, Neurological examination, Topographic diagnosis of lesion, and Etiological diagnosis. These authors also mentioned the potential role of screening tools in differentiating between neuropathic and nociceptive pain. In 2008, the group of experts published an updated grading system,⁹² changing the order of steps to better reflect clinical practice and recommending screening tools (questionnaires) to evaluate neuropathic pain. The four criteria proposed are: History, including pain descriptors, the presence of non-painful sensory symptoms, and aggravating and alleviating factors suggesting a relationship between pain and neurological lesion; association of suspected lesion/disease associated with patient-reported pain distribution; extension of sensory changes beyond, within or overlapping the area of pain; and outcome, describing a positive result as “probable neuropathic pain requiring confirmatory tests” when the location and nature of the lesion/disease can explain the pain, although it may not be possible to confirm a causal relationship.^73,90

Central neuropathic pain

Central neuropathic pain (CNP) is defined as a neurological disorder resulting from damage to the CNS sensory pathways including the brain, brain-stem, and/or spinal cord.⁹⁴

This condition is among the most complex, intriguing, and challenging pain syndromes to treat. It can stem from various CNS injuries, including vascular problems (such as ischemia or hemorrhage), strokes (both ischemic and hemorrhagic), infectious diseases (like abscesses, encephalitis, or myelitis), demyelinating multiple sclerosis, traumatic injuries (to the brain or spinal cord), or neoplastic conditions. However, in the majority of cases, it is triggered by strokes, multiple sclerosis, or spinal cord injuries.⁹⁵

Typically, the symptoms of CNP closely resemble those of peripheral neuropathic pain, including sensations of burning, painful cold, tingling, pricking, jumping, stabbing, pressing, and constriction. Chronic itching, viewed as equivalent to pain, is also prevalent. It is important to note that some of these symptoms might also indicate musculoskeletal pain in individuals with prior neurological issues. Therefore, the presence or absence of these described symptoms alone cannot definitively confirm or negate the diagnosis.^8,96 Furthermore, allodynia (pain triggered by a normally non-painful stimulus) and hyperalgesia (increased pain response to a typically painful stimulus) are prominent symptoms in patients with neuropathic pain, occurring in various peripheral neuropathies and central pain disorders,⁹⁷ although it is noted that these symptoms might be less common in central pain.⁹⁸

CNP can exhibit characteristics of continuous or intermittent pain, which may occur spontaneously or be triggered, often presenting as a combination of these features, which is the most common pattern. It can manifest as superficial, deep, or a combination of both. Typically, its intensity is described as moderate to severe, occasionally being debilitating. Furthermore, mood disturbances and sleep disorders are observed, significantly contributing to the overall morbidity associated with central neuropathic pain.^99
–101

During patient evaluations, it is crucial to assess changes in sensitivity to pricking and temperature since the development of central pain relies on dysfunction in the spinothalamic tract, responsible for transmitting these sensations. The absence of such changes makes CNP diagnosis less likely. Additionally, central pain must be localized within the area affected by the CNS injury, but it does not need to encompass the entire region.^96,98

There is some evidence regarding the use of neuroimaging in CNP, it is suggested that the magnitude and presence of neuropathic pain (NP) following SCI results in both adaptive and maladaptive structural plasticity of sensorimotor regions, alongside altered metabolism of brain areas involved with descending pain modulation, pain perception, and sensory integration.¹⁰²

MRI is particularly helpful for visualizing lesions within the CNS of individuals experiencing central pain. In cases of central poststroke pain originating in the thalamus, the use of high-resolution MRI and a digital atlas of the thalamus for lesion mapping can be valuable in identifying patients at risk of developing pain shortly after thalamic injuries.¹⁰³ Positron emission tomography (PET) scans may also reveal a decrease in metabolic activity in the thalamus among patients with thalamic pain; however, it is essential to note that this finding can also be associated with peripheral NP.^104,105

However, the neurophysiological mechanisms of CNP are not known or not clear. Neurophysiological assessment techniques such as electroencephalography (EEG) and magnetoencephalography (MEG) offer insights into CNS mechanisms disrupted by CNP. These techniques map abnormal neural activity patterns within the CNS, a distinction from peripheral neuropathic pain (PNP) assessment, where they predominantly focus on peripheral nerve function. The unique neural signatures obtained from these assessments contribute to unraveling the intricacies of CNP pathophysiology within the CNS.⁹⁶ In individuals with multiple sclerosis (MS) who experience CNP, there are central nervous system changes that contribute to disruptions in cortical communication.¹⁰⁶

The distinction between peripheral and central NP requires a thorough analysis of clinical history and physical examination. It is essential to confirm a history of SCI, stroke, MS, or other CNS lesions through imaging techniques such as computed tomography, MRI, neurophysiological tests, or biochemical assessments whenever needed.^8,96

Different questionnaires have been developed for the identification of NP (e.g., LANSS,⁷⁷ the NPQ,⁷⁹ the DN4,⁷⁸ and painDETECT⁸⁰), but they have been examined in only a few studies in central pain, and in general, such questionnaires cannot be used as the sole diagnostic tool for an individual patient.

The integration of emerging technologies and biomarkers into CNP assessment capitalizes on the CNS focus. Genetic profiling, pharmacogenomics, and neural connectivity patterns provide insights into the unique features of CNP.¹⁰⁷ The incorporation of these methodologies bolsters the precision and personalized nature of CNP assessment.

Novel technologies such as smartphone apps, wearable devices, and machine learning algorithms provide real-time data collection, catering to the unique attributes of CNP. This innovation sets apart CNP assessment from PNP, where sensory quantification remains primarily peripheral in nature.¹⁰⁸

NP and quality of life

There is wide consensus that NP is associated with poor physical, psychological, and social health.^1,109 NP has been found to impair the quality of life and sleep of sufferers and increase their anxiety and depression to a greater degree in comparison to pain without neuropathic features or the absence of pain. Patients with NP have also been reported to make greater use of health service and to consult neurology and pain specialists more frequently. The impact on health, which is greater with more intense pain, is exacerbated by the particularly unpleasant signs and symptoms of NP. Furthermore, patients with NP often respond poorly to drug therapy.¹¹⁰ Several generic questionnaires have been designed to measure the health-related quality of life of patients with chronic diseases and have been validated for patients with pain. These include the 36-item Short-Form health survey (SF-36),¹¹¹ the Nottingham Health Profile (NHP),¹¹² and the WHO quality of life questionnaire (WHOQOL).^113,114 A version of the SF-36 adapted to pain clinics has also been published, named “Treatment Outcomes of Pain Survey” (TOPS),¹¹⁵ while the “NP Impact on Quality of Life questionnaire” (NePIQoL) was specifically developed to measure the quality of life in patients with NP.¹¹⁶ Various sleep scales have been used in patients with NP, including the 11-item Pittsburg Sleep Quality Index for sleep interruption,¹¹⁷ and the Medical Outcomes Study (MOS) scale, one of the most used to assess the interference of pain in sleep,^118,119 Other scales have been applied to evaluate depression (Beck depression inventory¹²⁰ and Zung self-administered depression scale¹²¹) and anxiety (hospital anxiety and depression scale (HAD)¹²² and Pain Anxiety Symptoms Scale (PASS)¹²³).

Discussion

While various guidelines and recommendations exist such as the recommendations of The National Institute for Health and Care Excellence (NICE)¹²⁴ and NP Special Interest Group (NeuPSIG) of the IASP (NeuPSIG),¹²⁵ it is important to note that the field of NP diagnosis remains complex and evolving. Clinicians often face challenges in determining the topographical localization and pathology of lesions, and certain sensory signs are not specific to NP.¹¹ In addition, there is often uncertainty about the possible inference of causal relationships. It appears that not all physicians consistently apply NPQs, and some may even be unaware of their availability, potentially limiting their ability to diagnose and characterize this pain accurately.¹²⁶ The subjectivity of NP has prompted the development and widespread use of specific clinical questionnaires validated in different languages, with many of them rooted in the original but less precise IASP model. NP, being a heterogeneous entity with multiple possible etiologies, necessitates a meticulous and precise diagnostic approach aimed at identifying the etiology of the pain and underlying mechanisms.¹²⁷

NP affects the peripheral and central nerve systems. Its differences with inflammatory or nociceptive disorders (e.g., osteoarthritis) include pain onset after nervous system injury or disease, distinct pain quality descriptors, allodynia, and sensory loss. A detailed history and physical examination are required in individuals with suspected NP to identify the cause and key comorbidities requiring action.⁴⁰ A multidisciplinary approach is needed to achieve comprehensive NP evaluation and treatment with minimal risks, side effects, and costs. The best evidence now supports antidepressant and anticonvulsant medicines as first-line therapy, but they show low effectiveness, and many patients gain little benefit. Novel and improved treatments can be expected from the expansion of knowledge on the underlying causes of NP and its behavior.¹²⁸ While this review paper endeavors to offer valuable insights into the current landscape of NP evaluation tools, it is important to acknowledge a few limitations. Firstly, the scope of the review may not encompass all potentially relevant research due to specific inclusion criteria. While we aimed to ensure a representative selection of literature, there may be valuable studies inadvertently omitted. Secondly, as research in the field of NP is continually evolving, some of the latest tools and approaches may have emerged after the completion of this review. Additionally, although we strived to provide an impartial assessment of the existing evidence, a certain degree of subjectivity in the interpretation of findings and study selection is intrinsic to non-systematic reviews. Consequently, readers should consider these limitations when interpreting the findings.

Conclusion

It is very important to achieve an early diagnosis of NP. This requires a careful pain history, proper neurological examination and complementary studies, including blood/serological tests, electrophysiological studies, and imaging procedures to determine the etiology and differentiate between neuropathic and nociceptive pain. In addition, pain-screening tools based on verbal pain description have been developed and validated for application with or without a limited clinical examination to guide evaluation of the neuropathic component of the pain. Specific biomarkers may help identify those patients at risk of disease development and function as a prognostic indicator for disease progression and treatment response. In the future, phenotyping strategies will facilitate the prescription of individualized therapies, independent of the etiology, allowing the targeted treatment of each component.

Footnotes

Acknowledgements

The authors are grateful to Richard Davies M.A. for editorial assistance.

Authors’ contributions

The three authors contributed to the literature review. AH wrote the first draft of the review, which was critically revised by RG and MK.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Consent for publication

Not applicable.

Ethics approval

Not applicable.

Informed consent

Not applicable.

ORCID iD

Anas Hamdan

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Shedding light on neuropathic pain: Current and emerging tools for diagnosis,screening,and quantification

Abstract

Keywords

Introduction

Methods

Results

Medical history

Clinical manifestations, physical examination, and complementary tests

Clinical manifestations

Physical examination

Complementary tests

Clinical neurophysiology

Nociceptive reflexes

Nociceptive flexion reflex

Quantitative sensory tests

Autonomic function tests

Microneurography

Functional neuroimaging

Biopsy

Other additional tests

Biomarkers in neuropathic pain

Confocal microscopy of the cornea

Phenotyping

Positive and negative symptoms and signs of neuropathic pain

Neuropathic pain questionnaires

Leeds neuropathic symptom assessment scale

Neuropathic pain diagnostic questionnaire

Neuropathic pain questionnaire

The painDETECT scale

The ID-pain neuropathic pain-screening questionnaire

Diagnostic tool

Description of neuropathic pain-screening questionnaires

Diagnostic and grading algorithms for neuropathic pain

Central neuropathic pain

NP and quality of life

Discussion

Conclusion

Footnotes

Acknowledgements

Authors’ contributions

Declaration of conflicting interests

Funding

Consent for publication

Ethics approval

Informed consent

ORCID iD

References