Classification Of Neuropathic Pain Research Articles

Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system.

Chronic nociplastic pain affecting the musculoskeletal system: clinical criteria and grading system.

Field testing of the revised neuropathic pain grading system in a cohort of patients with neck and upper limb pain.

Background and aims In 2008, the International Association for the Study of Pain Special Interest Group on Neuropathic Pain (NeuPSIG) proposed a clinical grading system to help identify patients with neuropathic pain (NeP). We previously applied this classification system, along with two NeP screening tools, the painDETECT (PD-Q) and Leeds Assessment of Neuropathic Symptoms and Signs pain scale (LANSS), to identify NeP in patients with neck/upper limb pain. Both screening tools failed to identify a large proportion of patients with clinically classified NeP, however a limitation of our study was the use of a single clinician performing the NeP classification. In 2016, the NeuPSIG grading system was updated with the aim of improving its clinical utility. We were interested in field testing of the revised grading system, in particular in the application of the grading system and the agreement of interpretation of clinical findings. The primary aim of the current study was to explore the application of the NeuPSIG revised grading system based on patient records and to establish the inter-rater agreement of detecting NeP. A secondary aim was to investigate the level of agreement in detecting NeP between the revised NeuPSIG grading system and the LANSS and PD-Q. Methods In this retrospective study, two expert clinicians (Specialist Pain Medicine Physician and Advanced Scope Physiotherapist) independently reviewed 152 patient case notes and classified them according to the revised grading system. The consensus of the expert clinicians' clinical classification was used as "gold standard" to determine the diagnostic accuracy of the two NeP screening tools. Results The two clinicians agreed in classifying 117 out of 152 patients (ICC 0.794, 95% CI 0.716-850; κ 0.62, 95% CI 0.50-0.73), yielding a 77% agreement. Compared to the clinicians' consensus, both LANSS and PD-Q demonstrated limited diagnostic accuracy in detecting NeP (LANSS sensitivity 24%, specificity 97%; PD-Q sensitivity 53%, specificity 67%). Conclusions The application of the revised NeP grading system was feasible in our retrospective analysis of patients with neck/upper limb pain. High inter-rater percentage agreement was demonstrated. The hierarchical order of classification may lead to false negative classification. We propose that in the absence of sensory changes or diagnostic tests in patients with neck/upper limb pain, classification of NeP may be further improved using a cluster of clinical findings that confirm a relevant nerve lesion/disease, such as reflex and motor changes. The diagnostic accuracy of LANSS and PD-Q in identifying NeP in patients with neck/upper limb pain remains limited. Clinical judgment remains crucial to diagnosing NeP in the clinical practice. Implications Our observations suggest that in view of the heterogeneity in patients with neck/upper limb pain, a considerable amount of expertise is required to interpret the revised grading system. While the application was feasible in our clinical setting, it is unclear if this will be feasible to apply in primary health care settings where early recognition and timely intervention is often most needed. The use of LANSS and PD-Q in the identification of NeP in patients with neck/upper limb pain remains questionable.

Using stratified medicine to understand, diagnose, and treat neuropathic pain.

Neuropathic pain (NeuP) is defined as pain arising from a lesion or disease of the somatosensory nervous system[39; 88]. NeuP is common, affecting approximately 6-8% of the general population[14; 86] and currently treatment is inadequate due to both poor drug efficacy and tolerability[38]. Many different types of injury can cause neuropathic pain including genetic (e.g. SCN9A gain of function variants), metabolic (e.g. diabetic polyneuropathy), infective (e.g. HIV associated neuropathy, hepatitis), traumatic and toxic (e.g. chemotherapy induced neuropathy) causes. Such injurious events can impact on anatomically distinct regions of the somatosensory nervous system ranging from the terminals of nociceptive afferents (in small fiber neuropathy) to the thalamus (in post-stroke pain). Classification of neuropathic pain using etiology and location remains an important aspect of routine clinical practice; however, pain medicine is coming to the realization that we need more precision in this classification. The hope is that improved classification will lead to better understanding of risk, prognosis and optimal treatment of NeuP. Patient stratification is the process of identifying subgroups of patients, suffering from a disorder (such as NeuP) in order to better target medical intervention[92]. Such sub-groups may map to a particular pathogenic mechanism but could also simply be a constellation of clinical symptoms and signs or biomarker, which are predictive of treatment response. Personalized medicine aims to target intervention to individual patients and is therefore even more ambitious in scope[68]. Personalized medicine may be possible in rare cases of NeuP (usually associated with specific gene mutations) but for the most part we will discuss stratified pain medicine in this review. Both preclinical and clinical science, have identified an array of pathogenic mechanisms underlying NeuP ranging from ectopic activity in primary afferents to defective central pain modulation pathway (for a comprehensive review see [18]). It is not a new idea that we should be trying to understand pain mechanisms in patients [106; 107] although there are challenges in being able to assess specific mechanisms in individual patients. Stratification aims to achieve patient subgroupings that have utility in terms of diagnosis, prognosis or treatment and this may not relate to a single pathogenic mechanism. Fortunately our armamentarium for identifying patient subgroups (and in some cases directly assaying pathogenic mechanisms) in patients has greatly improved. In the first section of this manuscript we will review the means by which NeuP patients may be stratified and in the second section the potential benefits of stratification. Thomas Lewis said, ‘Diagnosis is a system of more or less accurate guessing, in which the endpoint achieved is a name. These names applied to disease come to assume the importance of specific entities, whereas they are for the most part no more than insecure and therefore temporary conceptions’. He was likely exaggerating for effect but we hope that patient stratification will not only reduce the uncertainty in diagnosis but also help improve prevention, prognostication and treatment.

Neuropathic Pain

Neuropathic pain is a common but complex condition. The pathophysiology and mechanisms are not fully understood. The evaluation should incorporate a detailed history and physical examination with the selective investigations. There is still no standard classification of neuropathic pain; however, it may be classified as central or peripheral or by location and etiology. The common etiologies of neuropathic pain include diabetes mellitus, chemotherapy, alcohol, inflammation, and HIV. Since neuropathic pain is a chronic condition and unlikely to be cured or to disappear, the goal of treatment includes pain control as well as improved physical functions, attenuated psychological distress, and improved quality of life. The team approach by integrating pharmacologic treatment, physical therapy, pain psychology, and complementary medicine would improve the patient’s quality of life and outcome. Key words: classification, diagnosis, etiology, neuropathic pain, treatment

Classification of neuropathic pain in cancer patients.

Neuropathic pain can affect up to 40% in patients with cancer, which could be related to the tumour, treatment or comorbid diseases. Effective assessment to diagnose neuropathic pain is crucial in order to choose the right treatment. There is to date no systematic classification system; the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain developed a neuropathic pain grading system intended to be used for both clinical and research purposes, and a recent review describes a step-by-step process for applying the grading system in a clinical setting for cancer pain. We have combined these recommendations to outline a clinically relevant process to classify neuropathic pain in patients with cancer.

An investigation of factors contributing to higher levels of placebo response in clinical trials in neuropathic pain: a systematic review and meta-analysis.

In new drug development in neuropathic pain (NeP), randomized, double-blind, placebo-controlled trials (PCTs) with long treatment durations in a parallel-group design are recommended for confirmatory trials. This study was conducted to identify potential factors contributing to elevated placebo response in parallel-group PCTs for oral drugs with at least a 4-week treatment duration. A literature search was conducted through MEDLINE and EMBASE, and was supplemented with data from ClinicalTrials.gov and US/Japanese regulatory approval review information. Using the 30 or 50% responder rate (RR), logistic regression analyses were performed to investigate the relationship between the degree of placebo response and several potential influencing factors. The search identified 71 trials (n=6,126). The estimated 50% RRs (95% confidence intervals) in the placebo group were as follows: peripheral neuropathic pain (P-NeP) 23% (21,26%); central neuropathic pain (C-NeP) 14% (10,19%); postherpetic neuralgia (PHN) 19% (15,24%); painful diabetic peripheral neuropathy (pDPN) 26% (23,29%); posttraumatic peripheral neuropathic pain (PT) 15% (10,20%). From the logistic regression analyses, it was found that there was a significant association between placebo response (50% RR and 30% RR) and NeP classification (P<0.05). Associations between placebo response and several factors were seen in univariate logistic regression analyses of 50% RR. Multivariate analyses showed that age and baseline pain intensity in PHN, and treatment duration, trial design (fixed-dose/flexible-dose) and baseline pain intensity in pDPN, were associated with placebo response, suggesting that a reduced placebo response correlated with increasing age and baseline pain intensity, and a higher placebo response correlated with a longer treatment period and flexible dosing regimen. A similar pattern observed in the analysis of 50% RR was suggested in the analysis of 30% RR, with the exception of treatment duration. In addition, investigations of trials with at least a 12-week treatment duration in pDPN found associations with the number of patients per site, patient enrolment rate, proportion of male patients and baseline pain intensity, suggesting that a higher placebo response correlated with an increasing number of patients per site, and a reduced placebo response correlated with increasing patient enrolment rate and proportion of male patients and baseline pain intensity. The results of this study suggest that NeP condition, trial design, and demographic and baseline characteristics may contribute to elevated placebo response in clinical trials in patients with NeP. In addition, the magnitude of placebo response and the effect of treatment duration are greater in pDPN than in PHN. These facts should be considered when planning and conducting confirmatory trials in NeP.

Classification of neuropathic pain in cancer patients: A Delphi expert survey report and EAPC/IASP proposal of an algorithm for diagnostic criteria

Neuropathic pain (NP) in cancer patients lacks standards for diagnosis. This study is aimed at reaching consensus on the application of the International Association for the Study of Pain (IASP) special interest group for neuropathic pain (NeuPSIG) criteria to the diagnosis of NP in cancer patients and on the relevance of patient-reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified 2-round Internet-based Delphi survey. Relevant topics investigated were: peculiarities of NP in patients with cancer, IASP NeuPSIG diagnostic criteria adaptation and assessment, and standardized PRO assessment for NP screening. Median consensus scores (MED) and interquartile ranges (IQR) were calculated to measure expert consensus after both rounds. Twenty-nine experts answered, and good agreement was found on the statement “the pathophysiology of NP due to cancer can be different from non-cancer NP” (MED=9, IQR=2). Satisfactory consensus was reached for the first 3 NeuPSIG criteria (pain distribution, history, and sensory findings; MEDs⩾8, IQRs⩽3), but not for the fourth one (diagnostic test/imaging; MED=6, IQR=3). Agreement was also reached on clinical examination by soft brush or pin stimulation (MEDs⩾7 and IQRs⩽3) and on the use of PRO descriptors for NP screening (MED=8, IQR=3). Based on the study results, a clinical algorithm for NP diagnostic criteria in cancer patients with pain was proposed. Clinical research on PRO in the screening phase and on the application of the algorithm will be needed to examine their effectiveness in classifying NP in cancer patients.

Prevalence of Neuropathic Pain According to the IASP Grading System in Patients with Chronic Non-Malignant Pain

The primary objective was to determine the prevalence of neuropathic pain according to the new International Association for the Study of Pain (IASP) grading system. The secondary objective was to compare the system classification of neuropathic pain with the classification of neuropathic pain according to a patient-administered screening questionnaire. A Multidisciplinary Pain Center. One hundred twenty patients with a variety of chronic pain conditions referred to a multidisciplinary pain center. Consecutively referred patients filled out the PainDETECT Questionnaire before the first consultation. During the first consultation, patients had pain history taken and bedside examination performed by a pain specialist. Patients were classified according to the score on the PainDETECT Questionnaire and graded according to the IASP grading system about the certainty of neuropathic pain. According to the IASP grading system, 22 patients (18.3%) classified as probable or definite neuropathic pain and 90 patients (75%) as unlikely neuropathic pain. According to the PainDETECT Questionnaire, 55 patients (45%) were classified as likely neuropathic pain and 13 patients (10.8%) as unlikely neuropathic pain. Eleven patients (20%) who were classified as neuropathic pain according to PainDETECT were also classified as probable or definite neuropathic pain by the new IASP grading system. According to the new IASP grading system, less than 20% of the patients referred to a multidisciplinary pain center fulfilled the criteria for neuropathic pain. The classification of neuropathic pain with the IASP system varies from the classification of neuropathic pain with the use of a self-administered screening questionnaire.

Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach

Patients with neuropathic pain present with various pain-related sensory abnormalities. These sensory features form different patterns or mosaics-the sensory profile-in individual patients. One hypothesis for the development of sensory profiles is that distinct pathophysiological mechanisms of pain generation produce specific sensory abnormalities. Several controlled trials of promising new drugs have produced negative results, but these findings could have been a result of heterogeneity in the patient population. Subgrouping patients on the basis of individual sensory profiles could reduce this heterogeneity and improve trial design. A statistical categorisation of patients with neuropathic pain showed that subgroups of patients with distinct sensory profiles who perceive their pain differently do exist across a range of neuropathic disorders, although some distinct disorder-specific profiles were also detected. Results of the first clinical trials to use the subgroup approach at baseline could show a superior effect of the study drugs in specific subgroups, rather than in the entire cohort of patients. WHERE NEXT?: A new classification of neuropathic pain should take into account subgroups of patients with different sensory profiles. Sensory phenotyping has the potential to improve clinical trial design by enriching the study population with potential treatment responders, and might lead to a stratified treatment approach and ultimately to personalised treatment.

Agreement and Correlation Between the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs and Douleur Neuropathique 4 Questions Neuropathic Pain Screening Tools in Subjects With Low Back–Related Leg Pain

ObjectiveThe self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and Douleur Neuropathique 4 Questions (DN4) neuropathic pain screening tools have been shown to be reliable, valid, and able to differentiate neuropathic pain from inflammatory or mixed pain syndromes. However, no studies have compared these tools to determine whether their outcomes are similar. This study evaluated agreement and correlation between the S-LANSS and DN4 in the identification of neuropathic pain in subjects with low back–related leg pain. MethodsThis observational study compared S-LANSS and DN4 scores in 45 patients with low back–related leg pain. The S-LANSS and DN4 cutoff scores of 12 and 4, respectively, were used to classify subjects as positive or negative for the presence of neuropathic pain for each screening tool. The κ statistic was used to determine whether there was agreement in classification of neuropathic pain between the 2 screening tools. Pearson correlation coefficient was used to determine correlation between scores of the 2 screening tools. ResultsNeuropathic pain was identified in 15 subjects (33%) using the S-LANSS and in 19 subjects (42%) using the DN4. Agreement on neuropathic pain classification was fair, with a κ value of 0.34. There was moderate to good correlation (r = 0.62; P < .001) between scores obtained from the 2 tools. ConclusionsThe finding of fair agreement suggests that despite the moderate to good correlation between scores, the cutoff points for the classification of neuropathic pain of the 2 tools may not be congruent.

Nonlinear dimension reduction and clustering by Minimum Curvilinearity unfold neuropathic pain and tissue embryological classes

Motivation: Nonlinear small datasets, which are characterized by low numbers of samples and very high numbers of measures, occur frequently in computational biology, and pose problems in their investigation. Unsupervised hybrid-two-phase (H2P) procedures—specifically dimension reduction (DR), coupled with clustering—provide valuable assistance, not only for unsupervised data classification, but also for visualization of the patterns hidden in high-dimensional feature space.Methods: ‘Minimum Curvilinearity’ (MC) is a principle that—for small datasets—suggests the approximation of curvilinear sample distances in the feature space by pair-wise distances over their minimum spanning tree (MST), and thus avoids the introduction of any tuning parameter. MC is used to design two novel forms of nonlinear machine learning (NML): Minimum Curvilinear embedding (MCE) for DR, and Minimum Curvilinear affinity propagation (MCAP) for clustering.Results: Compared with several other unsupervised and supervised algorithms, MCE and MCAP, whether individually or combined in H2P, overcome the limits of classical approaches. High performance was attained in the visualization and classification of: (i) pain patients (proteomic measurements) in peripheral neuropathy; (ii) human organ tissues (genomic transcription factor measurements) on the basis of their embryological origin.Conclusion: MC provides a valuable framework to estimate nonlinear distances in small datasets. Its extension to large datasets is prefigured for novel NMLs. Classification of neuropathic pain by proteomic profiles offers new insights for future molecular and systems biology characterization of pain. Improvements in tissue embryological classification refine results obtained in an earlier study, and suggest a possible reinterpretation of skin attribution as mesodermal.Availability: https://sites.google.com/site/carlovittoriocannistraci/homeContact: kalokagathos.agon@gmail.com; massimo.alessio@hsr.itSupplementary information: Supplementary data are available at Bioinformatics online.

Evaluation of Symptom Heterogeneity in Neuropathic Pain Using Assessments of Sensory Functions

Classification of neuropathic pain has been based on disease entities, anatomical localization, or histological observations. Over the past decade, there has been an explosion in our understanding of the basic mechanisms of neuropathic pain. The exciting advances in basic science are paralleled by the recognition from clinical investigations that neuropathic pain is not a monolithic entity, but instead presents as a composite of pain and other sensory symptoms. Attempts are under way to supplement the traditional classification with a classification that links pain and sensory symptoms with neurobiological mechanisms. This mechanism- or symptom-based classification takes both negative and positive sensory symptoms into account. By using a battery of several standardized quantitative sensory tests, the characteristic profile of sensory symptoms can be elucidated in each patient. Moreover, in questionnaires the verbal descriptors can depict the quality and intensity of the individual pain. The approach of classifying and subgrouping patients with neuropathic pain on the basis of symptoms or signs opens up new possibilities for stratifying patients in clinical trials. First, in clinical proof-of-concept trials the study population can be enriched prospectively on the basis of entry criteria defined a priori. This enrichment with patients who potentially require a specific treatment should increase the likelihood for positive trial outcomes. Second, in clinical practice it becomes possible to establish an individualized therapy--that is, to identify the particular patients who require a specific treatment option.

Tools for Identifying Cancer Pain of Predominantly Neuropathic Origin and Opioid Responsiveness in Cancer Patients

Neuropathic pain (NP) is a difficult issue, particularly in cancer which is a dynamic condition where multiple pain etiologies are concomitantly present. Cancer pain is often labeled as mixed mechanism pain and is not easily classified as exclusively nociceptive or NP. The aim of this study was to explore the value of evaluation tools such as Neuropathic Pain Questionnaire (NPQ), complete and short form (NPQ-SF), Leeds Assessment of Neuropathic Signs and Symptoms (LANSS) and Neuropathic Pain Symptom Inventory (NPSI). The secondary outcome was to evaluate the response to opioid titration, according to the hierarchical classification of definite, possible and unlikely NP. A consecutive sample of patients referred for treatment of cancer-related pain were eligible for participation in the study. The inclusion criterion was uncontrolled cancer pain requiring adjustment of opioid therapy. Patients were clinically classified into tertiles based according to graded evidence of nervous system lesion: definite NP, possible NP, or unlikely NP. Pain and symptoms intensities were measured before (T0) and at the end of opioid titration (T1). Patients were titrated with escalating doses of opioids, supported by symptomatic drugs, changing the route of administration, or by opioid switching according to the clinical response. At T1 the opioid response was clinically graded from 1 to 4. Opioid escalation index was calculated. A single independent investigator, blinded to the clinical assessment and treatment, collected data from NPQ, NPQ-SF, LANSS Pain Scale, and NPSI. One hundred and sixty-seven patients concluded the study. Sixty, thirty-six, and seventy-one patients were clinically assessed as having definite NP, possible NP, or unlikely NP, respectively. A relationship between the values of the assessment tools and clinician rating was found. Patients with the highest values of assessment tools were also more likely to be clinically labeled as definite NP, although sensibility and specificity were low. Patients with a clinical diagnosis of definite NP, possible NP, or unlikely NP showed significant differences in opioid response (P < .0005). Patients with "unlikely NP" had a lower pain intensity at T1 (P < .05), and patients with "definite NP" required more intensive treatment. Patients requiring more aggressive treatment showed significantly higher values of Opioid Escalation Index (OEI)mg. Screening tools may provide a basis to suggest a common language in cancer pain syndromes. A hierarchical grouping seems to be more flexible and fits cancer patient characteristics. This study also confirms that opioids are clinically effective in "definite NP" conditions although a more aggressive treatment requiring careful utilization of opioids and symptomatic drugs is strictly necessary.

Assessment and diagnosis of neuropathic pain

Classification of neuropathic pain has been based on disease entities, anatomical localization or histological observations. There is now recognition from clinical investigations that neuropathic pain is not a monolithic entity, but instead presents as a composite of pain and other sensory symptoms. Attempts are underway to supplement the traditional classification with a classification that links pain and sensory symptoms with neurobiological mechanisms. This mechanism or symptom-based classification takes negative and positive sensory symptoms into account. By using a battery of standardized quantitative sensory tests the characteristic profile of sensory symptoms can be elucidated in each patient with a bedside assessment. These procedures can be fostered by apparative neurophysiological analysis, imaging techniques and biopsies. Moreover, in questionnaires verbal descriptors can depict the quality and intensity of the individual pain. They have proven to be sensible screening tools for neuropathic pain components. Application of quantitative sensory testing and questionnaires can aid in more versatile descriptions of neuropathic pain symptoms. If it were possible to characterize the concert of the distinct mechanisms and symptoms that operate in one individual patient, an optimal polypharmacotherapy that addresses the specific combinations of mechanisms may be established for each patient.

Mechanisms of Disease: mechanism-based classification of neuropathic pain—a critical analysis

Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological mechanisms. Application of this approach in the clinic is problematic, however, owing to a lack of precise tools to assess symptoms and signs, and difficulties in correlating symptoms and signs with mechanisms. Development and validation of diagnostic methods to identify mechanisms, together with pharmacological agents that specifically target these mechanisms, seems to be the most logical and rational way of improving neuropathic pain treatment.

Current Trends in Neuropathic Pain Treatments with Special Reference to Fibromyalgia

Neuropathic pain and fibromyalgia are prevalent diseases which have major consequences on healthcare resources and the individual. From the clinical point of view neuropathic pains represent a heterogeneous group of aetiologically different diseases ranging from cancer to diabetes. Patients with fibromyalgia also display clinical features common in neuropathic pain suggesting that there might be some overlap. The mechanisms responsible for symptoms and signs in both diseases are still unknown. Recently, there have been numerous reports of various pharmacological treatments of neuropathic pain and fibromyalgia with often disappointing results. Most of the studies were of short duration, had high attrition rates, and displayed other methodological problems. Some compounds had high rates of adverse effects which makes it often difficult for the patients to tolerate the treatment, especially in the long-term. At present, the best options for medication treatment are tricyclic antidepressants in lower dosage than usual in psychiatric disorders and a wide range of anticonvulsants. Opioids are sometimes recommended but have been found to have minor efficacy. Recently, there have been more controlled trials, which are reported here if they had been published between 2002 and 2004. Various compounds have been tested in different studies. Treatment of fibromyalgia, which has many features in common with depressive symptoms, became the focus of interest. New promising studies with dual serotonin-norepinephrine reuptake inhibitors (duloxetine and milnacipram) and a newer antiepileptic drug (pregabalin) are in progress. Future research will have to apply new approaches (e.g., using a mechanism-based classification of neuropathic pain and carrying out studies in populations with the same symptom but not necessarily the same disease) in order to find effective treatments for these common and often debilitating diseases.

Neuropathic pain. (Kings College Hospital, London, United Kingdom) Hospital Med 2000;61:760–766.

Neuropathic pain is often a distressing and undertreated condition. This review examined the definition and classification of neuropathic pain. It also summarized clinically important underlying mechanisms and outlined current management strategies. Future directions for research and therapy were also discussed.

Neuropathic pain.

Neuropathic pain is a distressing, poorly understood and under-treated condition. In this review we seek to examine the definition and classification of neuropathic pain, summarize clinically important underlying mechanisms, outline current management strategies and look at future directions for research and therapy.