Comprehensive Review Neuropathic pain: an updated grading system for research and clinical practice Nanna B. Finnerupa,*, Simon Haroutounianb, Peter Kamermanc, Ralf Barond, David L.H. Bennette, Didier Bouhassiraf,g, Giorgio Cruccuh, Roy Freemani, Per Hanssonj,k, Turo Nurmikkol, Srinivasa N. Rajam, Andrew S.C. Ricen,o, Jordi Serrap, Blair H. Smithq, Rolf-Detlef Treeder, Troels S. Jensena,s Abstract The redefinition of neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system,” which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the “definite” level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research. Keywords: Neuropathic pain, Definition, Grading, Possible, Probable, Definite 1. Introduction slightly modified version of this definition was proposed by the IASP In 1994, the International Association for the Study of Pain (IASP) Taxonomy Committee and accepted by the IASP: “pain caused by defined neuropathic pain as “pain initiated or caused by a primary a lesion or disease of the somatosensory nervous system.”16,17 lesion or dysfunction in the nervous system.” In 2008, a task force The omission of the term “dysfunction” excludes conditions initiated by the IASP Special Interest Group on Neuropathic Pain involving ill-defined changes in the nervous system and conditions (NeuPSIG) noted the need to distinguish neuropathic pain from with no known lesion of the somatosensory nervous system from nociceptive pain arising indirectly from neurological disorders and being classified as neuropathic pain. The restriction to the pain conditions with secondary neuroplastic changes occurring in somatosensory nervous system is important because conditions the nociceptive system, and proposed a new definition that omitted such as musculoskeletal pain (eg, due to spasticity) arising the term “dysfunction”: “pain arising as a direct consequence of indirectly from disorders of the motor system should not be a lesion or disease affecting the somatosensory system.”30 A confused with neuropathic pain. The term “primary” was omitted Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. a Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, b Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA, c Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa, d Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany, e Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, United Kingdom, f INSERM U-987, Centre d’Evaluation et de Traitement de la Douleur, CHU Ambroise Paré, Boulogne-Billancourt, France, g Université Versailles-Saint-Quentin, Versailles, France, h Department of Neurology and Psychiatry, Sapienza University, Rome, Italy, i Autonomic and Peripheral Nerve Laboratory, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA, j Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway, k Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, l Pain Research Institute, Neuroscience Research Centre, The Walton Centre NHS Foundation Trust, Liverpool, United Kingdom, m Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA, n Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, United Kingdom, o Pain Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom, p Neuroscience Technologies, Ltd, Barcelona, Spain, q Ninewells Hospital and Medical School, Division of Population Health Sciences, School of Medicine, University of Dundee, Dundee, Scotland, r Chair of Neurophysiology, Center of Biomedicine and Medical Technology Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany, s Department of Neurology, Aarhus University Hospital, Aarhus, Denmark *Corresponding author. Address: Danish Pain Research Center, Aarhus University, Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000 Aarhus C, Denmark. Tel.: 145 7846 4230; fax: 145 7846 3269. E-mail address: finnerup@clin.au.dk (N. B. Finnerup). PAIN 157 (2016) 1599–1606 © 2016 International Association for the Study of Pain. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://dx.doi.org/10.1097/j.pain.0000000000000492 August 2016 · Volume 157 · Number 8 www.painjournalonline.com 1599 1600 · N.B. Finnerup et al. 157 (2016) 1599–1606 PAIN® because of the difficulty in distinguishing between primary and the literature review and issues identified by committee members. At secondary causes of neuropathic pain; however, the omission the meeting, data on the use of the grading paper were presented, means that nociceptive pain conditions that—over time—may and individual participants provided short overviews on issues with cause secondary lesions in the somatosensory nervous system the grading system that had been identified before the meeting. could ultimately be considered as being partly neuropathic pain. Discussions pertaining to the issues identified before the meeting Recognizing the challenges of determining the presence of and new issues raised by participants at the meeting were used to neuropathic pain according to this new definition, NeuPSIG also inform modifications to the existing grading system. Before and after proposed a grading system30 to guide decisions on the level of the meeting, the process and update were discussed through certainty with which neuropathic pain can be determined in an e-mail, and after circulating draft manuscripts through e-mail, a final individual patient. Three levels of certainty—possible, probable, update was agreed through consensus by e-mail. and definite neuropathic pain—were proposed. As an activity in the Global Year Against Neuropathic Pain,15 NeuPSIG established 3. Background material a committee to (1) critically evaluate the use of the grading system in the 7 years after its publication, (2) assess the usefulness and A total of 731 publications were identified in Scopus as citing the limitations of the grading system, and (3) update the grading system original grading paper30 at the time of search, which represented if required, for improved application in clinical and research settings. about 5% of all publications in Scopus with the term “neuropathic The committee consisted of an expert panel of neurologists, clinical pain” in the title, abstract, or keywords in the same period. Of the neurophysiologists, neuroscientists, anesthesiologists, pain spe- 731 publications, 123 were not available as full-text at any of the 3 cialists, primary care physicians, and population health scientists. institutions, at which the reviewers were based or were in a language not understood by the reviewers. Hence, the full text of 608 publications was downloaded and used to evaluate the 2. Procedure use of the original grading paper since its publication in 2008. Of To generate background material and discussion points, we the 608 included publications, 269 were classified by the performed a systematic literature search using the Scopus reviewers as reviews or book chapters, 220 as clinical studies, database, which is an abstract and citation database of peer- 73 as experimental studies, and 46 as “others.” reviewed literature (including scientific journals, books, and confer- Of the 608 publications, 414 cited the grading paper30 in ence proceedings). This database was searched on February 6, relation to the definition of neuropathic pain (Fig. 1). Of these, 266 2015 for publications that cited the original NeuPSIG grading paper used the definition as it was presented (or very similar) in the from 2008.30 Three review authors (S.H., P.K., and N.B.F.) extracted original grading paper, whereas 48 applied the adapted 2011 the following data: (1) use of the citation, (2) classification of the IASP definition17 and 8 applied the 1991 IASP definition despite publication as a review, animal or human experimental paper, using the grading paper as the reference. Ninety-two presented a clinical study, or others, (3) criteria used for including or classifying other definitions of neuropathic pain, of which most had a wording patients with neuropathic pain in clinical studies, (4) comparison of consistent with the definition in the grading paper, whereas others the grading with other criteria for identifying neuropathic pain when presented a definition significantly different despite using the available, and (5) any issues raised with the grading system. grading paper as reference. The grading paper was cited in In addition, all committee members were asked to examine the relation to other statements, unrelated to the definition or grading grading system for possible deficiencies that could require system, in 190 publications. modification or amendment in a subsequent iteration of the grading Of the 220 clinical publications that included patients, only 56 system. Participants convened under the auspices of NeuPSIG in (25% of clinical studies, 9% of all studies citing the grading paper) Nice, France, on May 14, 2015. Before the meeting, all participants used the grading system to include or classify patients as having were provided with a documentation folder that included results from possible, probable, or definite neuropathic pain. A further 16 (7%) Figure 1. Summary of how the citations of the neuropathic pain grading paper30 were used. The figure indicates the percentage of 608 publications that cited the original grading paper30 for defining neuropathic pain and the number of clinical studies that used the grading system for identifying neuropathic pain. The insert indicates the total number of clinical studies and the number of studies using the grading system30 for identifying neuropathic pain per year. August 2016 · Volume 157 · Number 8 www.painjournalonline.com 1601 used other criteria for classification of pain, but retrospectively lesion or disease affecting the peripheral or central somatosensory noted whether the patients had possible, probable, or definite system” and criterion 3 “demonstration of the distinct neuro- neuropathic pain according to the grading system. The percent- anatomically plausible distribution by at least 1 confirmatory test” age of clinical studies citing the grading system that also used it to were available in the majority of trials (13-14 of 22), whereas include or classify patients with neuropathic pain increased from criterion 1 “pain with a distinct neuroanatomically plausible 5% (1/20) in 2009 to 30% (12/40) in 2014 (Fig. 1). Of the distribution” was available less often (10/22) and confirmation of remaining 148 studies that did not use the grading system for the underlying lesion of disease was rarely done (criterion 4, 7/22). patient classification, 115 used other criteria to include or classify This identifies 2 problems to be addressed in the present revision: neuropathic pain patients. Of these, 50 used one or more (1) plausibility of pain distribution and its assessment and (2) need questionnaires, 30 used Douleur Neuropathique en 4 questions, for establishing the neurological diagnosis by confirmatory tests. 11 used painDETECT, 8 LANSS (Leeds Assessment of Neuro- In addition, the following deficiencies were identified from the pathic Symptoms and Signs) or S-LANSS (self-report LANSS), paper reviews and discussed during the committee meeting: (1) 2 used McGill pain questionnaire, 1 used ID-Pain, 1 used Several screening tools (questionnaires) were developed before the standardized evaluation of pain, and 1 used the German pain redefinition of neuropathic pain by NeuPSIG and IASP3,13 but are questionnaire; 51 used various criteria including pain history, pain not positioned in the grading system; (2) Some clinicians and descriptors, clinical examination, and laboratory investigations; 2 investigators have difficulty in determining the topographical used patient self-report; and 12 did not mention the criteria used. location of a lesion and its pathology, as the approach used in Thus, the 2008 grading paper was mostly cited for the redefinition neurology of “where is the lesion?”, “what is the lesion?” is not of neuropathic pain. The redefinition has since been introduced in intuitive to other medical disciplines; (3) Certain sensory signs are the IASP terminology with minor modifications, and hence the not specific to neuropathic pain; and (4) Determination of lesion authors’ aim “to develop a more precise definition of neuropathic type and location does not necessarily prove that the pain is caused pain that will be useful for clinical and research purposes” has largely by that lesion or disease (uncertainty of causal relationship). been achieved. The adoption of the grading system has naturally Based on these limitations of the current grading system, we happened after a delay, and since 2011 a steady ratio of about 1/3 of propose a change to the order of the grading criteria to better clinical trials in the field have used it (Fig. 1). reflect clinical practice and have furthermore annotated the terms A meta-analysis of cancer trials4 indicated that of the 4 criteria of used to improve clarity (Fig. 2). In addition, a research agenda is the grading system, criterion 2 “a history suggestive of a relevant proposed to further address shortcomings of the grading system. Figure 2. Flow chart of updated grading system for neuropathic pain. aHistory, including pain descriptors, the presence of nonpainful sensory symptoms, and aggravating and alleviating factors, suggestive of pain being related to a neurological lesion and not other causes such as inflammation or non-neural tissue damage. The suspected lesion or disease is reported to be associated with neuropathic pain, including a temporal and spatial relationship representative of the condition; includes paroxysmal pain in trigeminal neuralgia. bThe pain distribution reported by the patient is consistent with the suspected lesion or disease (Table 1). cThe area of sensory changes may extend beyond, be within, or overlap with the area of pain. Sensory loss is generally required but touch-evoked or thermal allodynia may be the only finding at bedside examination. Trigger phenomena in trigeminal neuralgia may be counted as sensory signs. In some cases, sensory signs may be difficult to demonstrate although the nature of the lesion or disease is confirmed; for these cases the level “probable” continues to be appropriate, if a diagnostic test confirms the lesion or disease of the somatosensory nervous system. dThe term “definite” in this context means “probable neuropathic pain with confirmatory tests” because the location and nature of the lesion or disease have been confirmed to be able to explain the pain. “Definite” neuropathic pain is a pain that is fully compatible with neuropathic pain, but it does not necessarily establish causality. 1602 · N.B. Finnerup et al. 157 (2016) 1599–1606 PAIN® 4. Revised grading system nerve or root or the somatotopic representation of the body within the central nervous system, but it should be in a distribution that is The grading system is intended for determining the level of typical for the underlying disorder (see examples in Table 1). In certainty with which the pain in question is neuropathic. A finding painful channelopathies, the pain distribution may be unusual but of probable neuropathic pain in a given individual patient should should be consistent with the disorder, eg, familial episodic pain prompt consideration of treatment according to the neuropathic syndrome, in which pain is mainly localized to the chest and upper pain treatment guidelines,10 but the grading system is not arms, or inherited erythromelalgia, in which pain is localized to the intended for medico-legal purposes or to classify diseases. The extremities (feet and hands and in some cases ears). refinements in the present grading system (Fig. 2) follow the When both requirements 1 and 2 of the pain history are fulfilled, classical clinical method of diagnosis in that history, clinical the pain complaint may be termed possible neuropathic pain. examination, and diagnostic tests stepwise add to level of certainty that the pain in question is neuropathic. 4.2. Probable neuropathic pain 4.1. Possible neuropathic pain The next level of certainty requires supporting evidence obtained Evaluation of the patient according to the grading system should be by a clinical examination. The examination should optimally undertaken if the patient’s history suggests that pain could be confirm the presence of negative sensory signs, ie, partial or related to a neurological lesion or disease and not other causes complete loss to one or several sensory modalities concordant such as inflammation or non-neural tissue damage. At this stage, with the lesion or disease of the somatosensory nervous system pain descriptors, the presence of nonpainful sensory symptoms, (eg, light touch, cold temperature, Tables 1 and 2). and any aggravating and alleviating factors can be taken into Demonstrating sensory loss to one or more of these modalities account. Pain descriptions such as burning or hot, electric shocks and delineation of the area affected by the negative sensory or shooting, pricking or pins and needles, pain evoked by light phenomena are central to the determination as to whether touching or cold, and nonpainful sensations such as numbness and a nervous system lesion is the cause of the sensory disturbance tingling are suggestive, but not pathognomonic for neuropathic (ie, whether it is compatible with neuropathy). Negative sensory pain, and other descriptors may apply as well.3 The combination of signs may also be seen in nociceptive pain, but in these cases several descriptors, however, has a highly discriminant value and they lack neuroanatomically distinct borders and are not re- several screening tools (questionnaires) have been developed to producible.12,19 The sensory signs may or may not be accom- identify patients who may have neuropathic pain to alert the clinician panied by motor or autonomic signs. to undertake further assessment (though they cannot be used Positive sensory signs alone (eg, pressure-evoked hyperalgesia) alone to identify neuropathic pain).3,13,32 These include, but are not carry less weight towards neuropathic pain probability, in limited to the LANSS,2 the neuropathic pain questionnaire,18 the particular, if their distribution does not follow relevant neuroana- Douleur Neuropathique en 4 questions,6 the painDETECT,11 and tomical delineation. Positive sensory symptoms and signs may be ID-Pain.24 seen in patients with other conditions such as inflammatory pain, The following two criteria need to be fulfilled to reach the first pain of unknown origin, anxiety, and sleep deprivation, and can be level of certainty-“possible” neuropathic pain. affected by stress and negative emotions.25,34 It is important to emphasize that there are conditions where sensory loss is not a prerequisite for a neuropathic pain condition. In certain 4.1.1. A history of relevant neurological lesion or disease neuropathic pain conditions such as hereditary channelopa- There should be a clinical suspicion of a relevant lesion or disease thies1,33 and in subgroups of patients with, eg, peripheral nerve of the somatosensory nervous system (eg, an episode of acute injury,20 touch-evoked allodynia or thermal hyperalgesia may be herpes zoster or a traumatic nerve injury). The temporal relationship present without detectable sensory loss. The presence of such between the lesion or disease and the pain may vary, but a close positive signs may mask sensory loss in some of these patients. temporal relationship helps strengthen the clinical suspicion. The Idiopathic or classical trigeminal neuralgia is a special case. In onset of pain is usually immediate or within a few weeks of the trigeminal neuralgia, sensory deficits may not be found on clinical lesion or disease but may be delayed for up to several months after examination, although quantitative sensory testing may show injury (eg, after stroke) or for many years in conditions with an sensory abnormality.20 In these cases, a history of characteristic insidious onset such as diabetic neuropathy. In some cases, the triggering maneuvers may be counted as positive sensory signs. history of pain or sensory disturbances by themselves suggest They can sometimes be repeated by the examiner, who may thus a disease, eg, in polyneuropathy (peripheral neuropathy), where the evoke and see the characteristic tic. Another special case is insidious onset of distal pain or numbness may be the only history painful channelopathies as they are often paroxysmal and indicating the disease. Characteristic sudden short-lasting (usually sensory examination can be normal between attacks. A history a few seconds) paroxysmal pain in the face, which may recur of characteristic symptoms may be considered a surrogate for several times and may be separated by a refractory period (usually positive sensory signs. In phantom pain, a sensory examination is some minutes), suggests trigeminal neuralgia, where the pain is the not possible in the pain area. In these cases, the loss of the body only symptom indicating a relevant neurological disease. part where pain is perceived is counted as a surrogate for sensory signs within the pain distribution. Often, sensory changes to light touch, vibration, pinprick, cold, 4.1.2. Pain distribution neuroanatomically plausible or warmth can be confirmed by a clinical examination (Table 2), The pain distribution should be anatomically consistent with the but more detailed analysis using quantitative sensory testing may suspected location of the lesion or disease in the peripheral or be needed.13 Prolonged pain after herpes zoster is associated central somatosensory nervous system (as derived from the with sensory abnormalities in a neuroanatomically plausible patient’s history). This can be difficult to decipher in the single distribution in most, but not all cases.20 In rare cases where patient, as the distribution of pain can occupy a smaller area or sensory abnormalities are doubtful or lacking, documentation of extend somewhat outside the innervation territory of a peripheral a herpes zoster rash in the form of a photograph or clinical record August 2016 · Volume 157 · Number 8 www.painjournalonline.com 1603 Table 1 Common neuropathic pain conditions and neuroanatomically plausible distribution of pain symptoms and sensory signs. Neuropathic pain condition Neuroanatomically plausible distribution of Illustration of typical distribution pain and sensory signs Trigeminal neuralgia Within the facial or intraoral trigeminal territory. Postherpetic neuralgia Unilateral distributed in one or more spinal dermatomes or the trigeminal ophthalmic division. Peripheral nerve injury pain In the innervation territory of the lesioned nerve, typically distal to a trauma, surgery, or compression. Postamputation pain In the missing body part and/or in the residual limb. Painful polyneuropathy In feet, may extend to involve lower legs, thighs, and hands. Painful radiculopathy Distribution consistent with the innervation territory of the nerve root. Neuropathic pain associated with spinal cord At and/or below the level of the spinal cord lesion. injury Central poststroke pain Contralateral to the stroke. In lateral medullary infarction, the distribution can also involve the ipsilateral side of the face. Central neuropathic pain associated with Can be a combination of distributions seen in spinal multiple sclerosis cord injury and stroke. will add to the evidence of somatosensory pathway involvement, deep somatic types of pain. Innervation territories of nerves and allowing a subsequent designation of the condition as probable roots vary between individuals, they are not always clearly neuropathic pain. Sensory function is difficult to evaluate in deep demarcated, and there is often overlap between them. Because tissue and viscera. For that reason, a level of certainty beyond of central sensitization phenomena, the areas of allodynia and possible neuropathic pain can rarely be obtained for visceral or hyperalgesia may extend beyond the innervation territory.35 1604 · N.B. Finnerup et al. 157 (2016) 1599–1606 PAIN® Table 2 (2) annotated the terms used to improve clarity. Bedside sensory examination. (3) recognized the role of screening tools (questionnaires) in neuropathic pain evaluation. Modality Bedside assessment (4) emphasized that reaching the final level of certainty (definite Touch Cotton bud or ball, painter’s brush neuropathic pain) confirms clinically that a lesion or disease of Vibration Tuning fork the somatosensory nervous system can explain the pain but, Pinprick Pin, toothpick, cocktail stick Cold Cold metal, tube with cold water, cloth with surgical as often in neurology, it does not establish causality (ie, there spirit, Lindblom roller21 may still be other causes of the pain such as a diabetic ulcer). Warm Warm metal, tube with warm water, Lindblom The main purpose of the grading system is to help in the roller21 classification of the pain as neuropathic. Other types of pain include nociceptive pain, which is pain that arises from actual or threatened damage to non-neural tissue and is due to the 4.3. Definite neuropathic pain activation of nociceptors,16 and pain that does not fulfill the The final level of certainty requires that an objective diagnostic test criteria for either nociceptive or neuropathic pain, such as chronic confirms the lesion or disease of the somatosensory nervous widespread pain, fibromyalgia, and irritable bowel syndrome.31 system. This may not always be possible in the nonspecialist Furthermore, patients may have 2 or more types of pain, and the environment. Examples of such diagnostic tests include com- classification of pain may be particularly difficult if more than one puted tomography, magnetic resonance imaging, or other type of pain exist in the same area. imaging techniques to confirm the presence of stroke, multiple The grading system is intended for use in individual patients in sclerosis, spinal cord injury, or nerve lesion; skin biopsy showing the clinic and for research, but not for classification of diseases. reduced intraepidermal nerve fiber density, neurophysiological Some patients diagnosed with fibromyalgia may have small fiber tests such as nerve conduction velocity, heat and laser evoked pathology and may fulfill the criteria for neuropathic pain whereas potentials, nerve excitability tests, R1 blink reflex demonstrating others may not.9,26 In addition, patients with complex regional neural function compromise, microneurography with evidence of pain syndrome (CRPS) type II fulfill the criteria for neuropathic aberrant nociceptor activity; and genetic tests confirming pain, whereas patients with type I do not. Complex regional pain a hereditary neuropathic pain disorder such as inherited syndrome type I is by definition a condition in which no nerve erythromelalgia.13 In cases of amputation or a surgeon’s clear lesion can be verified.5 Although an inflammatory reaction, verification of an intraoperative nerve lesion, further diagnostic considered to be at the core of development of CRPS, can tests are not necessary to arrive at the grading of “definite” conceivably damage nociceptors, the current pathophysiological neuropathic pain, because direct anatomical or surgical evidence evidence for it is limited and inconsistent, and thus does not justify counts as a confirmatory test. the designation by default of CRPS type I as neuropathic pain.7,23 This final level is reached by using only positive criteria for the Similarly, individual patients with Parkinson’s disease may have location and nature of the neurological lesion or disease, without neuropathic pain if there is a documented lesion of the excluding other potential causes of the pain. Patients can have somatosensory system and they fulfill the grading criteria, but nociceptive pain in an area within the territory affected by an injury musculoskeletal pain is an important differential diagnosis. The or disease involving the nervous system. Examples include demonstration of reduced small nerve fibers obtained from skin spasticity-related pain below the level of injury in a patient with biopsies in patients with fibromyalgia and Parkinson’s disease is incomplete spinal cord injury, shoulder pain because of a lesion of at the moment not sufficient evidence per se for labeling pain in the rotator cuff tendons in the area with sensory abnormalities these patients as neuropathic. There is currently no evidence to after a stroke, inflammatory pain in the innervation territory of the indicate that patients with cluster headache or migraine have lesioned nerves after thoracotomy or herniotomy, and plantar lesions of the somatosensory system. fasciitis in a patient with polyneuropathy. In these cases, despite fulfilling all 4 criteria of the grading system, the pain may still not be 5. Limitations and future directions neuropathic. Thus, it is important to note that the final level does not completely rule out the possibility that other conditions such Based on the narrative literature review and discussions in the as tissue inflammation may fully or partially explain the pain. This committee, we identified several weaknesses in our current remaining uncertainty about causality between the identified knowledge about neuropathic pain and issues that need to be lesion or disease and the clinical presentation of the patient is addressed in the future. a common situation in neurological diagnostics. In this context, (1) The lack of positive criteria for identifying non-neuropathic the term definite neuropathic pain means that the clinician, by pain, and the lack of pathognomonic features of neuropathic using history, clinical examination and auxiliary testing, is able to pain make it difficult to reach a level of “definite” neuropathic reach the level of confirming clinically that a patient has pain. Previous attempts to define a gold standard for a neurological lesion that can explain the pain. Because the neuropathic pain have been hampered by the inherent circular grading system only determines the level of certainty with which bias imposed by the fact that the criteria for defining clinical the presence or absence of a lesion or disease of the neuropathic pain are also used as measures in newly somatosensory nervous system can explain the pain, it is always introduced tools. One important area of research will be to important to consider if other causes for the patient’s pain use the present grading system as a reference standard conditions may be present. against which other neuropathic pain approaches should be systematically validated. In this goal, it will be important to perform field testing of this system, in particular, to assess its 4.4. Summary test-retest reliability and inter-rater reliability. Compared to the grading system published in 2008, we have (2) The lack of pain diagnostic tools for low resource settings and (1) changed the order of the grading criteria to better reflect the need for more educational efforts.22 Screening tools may clinical practice. be helpful, but at a single-patient level, they may wrongly August 2016 · Volume 157 · Number 8 www.painjournalonline.com 1605 classify some patients (false-positive) or fail to identify other Conflict of interest statement patients (false-negative).3,32 The authors have no conflicts of interest to declare. (3) In research based only on clinical history, such as question- R-D. Treede and T. S. Jensen contributed equally to this work. naire surveys and patient interviews, only the level of “possible” Supported by the NeuPSIG of the International Association for the neuropathic pain can be reached and even then only Study of Pain. S.N. Raja was partly supported by NIGMS, NS26363. sometimes. Although validated questionnaires exist, these D.L.H. Bennett is a Wellcome Senior Clinical Scientist (Ref 095698z/ questionnaires were mostly developed based on the old and 11/z). D. Bouhassira, D.L.H. Bennett, R. Baron, N.B. Finnerup, T.S. less precise IASP definition, and there is no validated approach Jensen, A.S.C. Rice, and B.H. Smith are members of the DOLORisk to defining relevant pain distribution and history.29 consortium funded by the European Commission Horizon 2020 (4) Variability of innervation territories of roots, nerves and (ID633491). D.L.H. Bennett, N.B. Finnerup, and T.S. Jensen are fascicles as well as difficulty in quantitating sensory function members of the International Diabetic Neuropathy Consortium, the in deep tissues such as joints and muscles and visceral tissues Novo Nordisk Foundation, grant number NNF14SA0006. R. Baron can make it difficult to identify neuropathic pain in certain and R-D. Treede are members of the German Research Network on cases, and current textbook figures are based on often Neuropathic Pain (DFNS). R. Baron, D.L.H. Bennett, N.B. Finnerup, imprecise renditions of very old data from relatively small case A.S.C. Rice, J. Serra, T.S. Jensen, and R-D. Treede are members of series. In future, it is important to generate probabilistic maps of the IMI-Europain consortium. Ralf Baron has received grants/ innervation territories and to develop methods for the research support from Pfizer, Genzyme, Grünenthal, Mundipharma. assessment of sensory function in joints and muscles and He is a member of the EU Project No 633491: DOLOR-isk. A visceral tissues. Identification of appropriate control areas for member of the IMI “Europain” collaboration and industry members of specific conditions, establishment of inter- and intra-examiner this are: Astra Zeneca, Pfizer, Esteve, UCB-Pharma, Sanofi Aventis, reliability, and assessment of the use of patient self-examina- Grünenthal, Eli Lilly and Boehringer Ingelheim. German Federal tion14,27 are also needed. Ministry of Education and Re-search (BMBF): Member of (5) The possible presence of neuropathic pain in conditions where the ERA_NET NEU-RON/IM-PAIN Project. German Research lesions or diseases of the somatosensory nervous system Net-work on Neuropathic Pain, NoPain system biolo-gy. German occur secondary to an inflammatory condition is not clear. Research Foundation (DFG). He has received speaking fees from Examples are osteoarthritis, in which there may be a decrease Pfizer, Genzyme, Grünenthal, Mundipharma, Sanofi Pasteur, in the innervations in the synovial lining layer and increase in the Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Desitin, Teva innervations of cartilage with concomitant sensory abnormal- Pharma, Bayer-Schering, MSD, bioCSL. He has been a consultant ities in the skin,28 and chronic pancreatitis, in which histopa- for Pfizer, Genzyme, Grünenthal, Mundipharma, Allergan, Sanofi thology shows evidence of local nerve involvement.8 Pasteur, Medtronic, Eisai, Lilly, Boehringer Ingelheim, Astellas, Novartis, Bristol-Myers-Squibb, Biogenidec, AstraZeneca, Merck, 6. Conclusions Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals, bioCSL an Teva Pharma. Neuropathic pain is a term used for a group of conditions with a wide range of causes and different pain distributions. However, Article history: all these conditions are characterized by a lesion or disease Received 25 September 2015 affecting the somatosensory nervous system peripherally or Received in revised form 4 January 2016 centrally. The grading system represents a tool to determine the Accepted 6 January 2016 level of certainty that the pain in an individual is neuropathic in Available online 13 January 2016 nature. Such grading is naturally based on clinical judgment. Therefore, it relies heavily on the experience, skills, and resources References available for assessment. We anticipate that the rephrasing and reordering of the 4 [1] Bennett DL, Woods CG. Painful and painless channelopathies. Lancet Neurol 2014;13:587–99. criteria of the grading system will facilitate its use by both [2] Bennett M. The LANSS Pain Scale: the Leeds assessment of neuropathic neurologists and non-neurologists. The level “probable” should symptoms and signs. 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