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PAIN�

152 (2011) 2204–2205

Commentary

A new definition of neuropathic pain

1. Introduction

IASP has recently published a new definition of neuropathicpain according to which neuropathic pain is defined as ‘‘paincaused by a lesion or disease of the somatosensory system’’(www.iasp-pain.org/resources/painDefinition). This definition re-places the 17-year old definition that appeared in the Classificationof Chronic Pain published by IASP in 1994 [7], which defined neu-ropathic pain as ‘‘pain initiated or caused by a primary lesion, dys-function, or transitory perturbation of the peripheral or centralnervous system’’. Even though the definition has not been changeddramatically, there are two important changes in the new version:(1) the word ‘‘dysfunction’’ has been removed and (2) a lesion ordisease affecting the nervous system has been specified to be alesion or disease of the somatosensory system.

2. Background

The history behind this change dates back several years with along, and at times, heated debate about the inclusion of the term‘‘dysfunction’’ [5]. Clinicians with neurological training andbackground have found it difficult to accept conditions in whichsymptoms and signs were not reflected in abnormal neuropatho-physiology. It is regarded as essential, particularly in the clinicalneurological specialties, to examine and classify patients basedon the topography of the lesion and the underlying pathology.The debate about including/excluding the term dysfunction initi-ated a meeting among a group of neurologists, neurosurgeons,and clinical and basic neurophysiologists, both members andnon-members of IASP. This meeting, and a subsequent long corre-spondence, resulted in a consensus paper published in the journalNeurology in 2008 [9] focussing on how clinicians and clinical sci-entists distinguish neuropathic pain from nociceptive pain. Theconsensus group suggested that neuropathic pain should be de-fined as ‘‘pain arising as a direct consequence of a lesion or diseaseaffecting the somatosensory system’’ [9]. It is this criterion, whichis the basis for the almost identical definition proposed by the IASPTaxonomy Committee, that was accepted by the IASP council.

3. Why a new definition of neuropathic pain?

The reasons behind this change in the definition of neuropathicpain are:

1. Neuropathic pain is not a single disease, but a syndrome causedby a range of different diseases and lesions, which manifests asan array of symptoms and signs. The mechanisms underlyingthese different conditions are multiple. Some of the mecha-

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nisms are known, but many are not. Increased understandingof pain mechanisms should put us in a better position to treatpatients and design rational treatment strategies. There hasindeed been progress since the last update of the neuropathicpain definition 17 years ago. For example, primary erythromel-algia and paroxysmal extreme pain disorder are both rare painconditions for which we had no explanation 10 years ago, andtherefore pain associated with these could not then have beenclassified as neuropathic. It is now clear that both disordersare due to specific and separable mutations in the SCN9A genethat codes for one of the many subtypes of neuronal voltage-gated sodium channels: the Nav 1.7 channel [1]. While theseobservations have not yet resulted in a specific or preventivetreatment for the rare genetic pain states, there is now a cleartarget that can be addressed. Another pain condition that hasseen progress is Fabry’s disease, which can now be treated withenzyme replacement therapy [6]. Biomarkers for an inflamma-tory component in neuropathic pain are also being discovered,and again, these may lead to new specific treatments. Otherexamples will certainly be added as our knowledge of diseasesand their causes increases.

2. The other strength (although critics might say limitation) of thenew neuropathic pain definition is that the lesion in the ner-vous system has to be within the somatosensory system [3].This requirement means that lesions in the cerebellum or fron-tal cortices, for example, will not qualify as a lesion causing cen-tral neuropathic pain, unless future research establishes thatthese regions also belong to the somatosensory system. Theclassical conditions associated with central pain include stroke,multiple sclerosis, certain forms of spinal cord injury, and syr-inx of the central canal in the brainstem or spinal cord. Doesit matter how restrictive we are in the current approach? Wemaintain that it does make a difference. If clinical criteria aredistinct and precise, then the door is open not only for studyingthe pathophysiology of the condition, but also its epidemiology,and for testing specific treatments. The benefit of having well-defined criteria for defining pain disorders is clearly demon-strated by the wealth of excellent studies in the headache area.

3. The current therapy for neuropathic pain is not satisfactory;more than two-thirds of neuropathic pain patients obtain insuf-ficient pain relief, and this poor response is likely related to ourfailure to target relevant pain-generating mechanisms inindividual patients [2]. Our understanding of underlying neuro-pathic mechanisms will not be improved by including painconditions such as CRPS and fibromyalgia in the neuropathicpain syndrome, because the mechanisms causing pain in thesedisorders are even more obscure than in the classical neuro-pathic pain conditions, where pathology can be demonstrated.

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Commentary / PAIN�

152 (2011) 2204–2205 2205

The lack of structural abnormalities in so-called dysfunctionalstates (fibromyalgia, CRPS, vulvodynia, interstitial cystitis,etc.) prevents us from finding a relationship between structureand function, which is important in the study of a subjectiveexperience such as pain. If some patients with these disordersare found to represent cases of small-fiber neuropathies [4,8],then those patients would easily fall under the umbrella of neu-ropathic pain.

By excluding fibromyalgia and CRPS from the neuropathic painsyndrome does this imply a risk for not offering these patients atreatment otherwise approved for neuropathic pain? Antidepres-sants and gabapentinoids with an approved indication for neuro-pathic pain are nonspecific compounds with a general action onneuronal hyperexcitability. As neuronal hyperexcitability is amechanism shared by many chronic pain conditions, includingfibromyalgia and CRPS, treatment with antidepressants and gaba-pentinoids should definitely not be withheld from patients withthese dysfunctional conditions, certainly not because of the currentchange of the definition of neuropathic pain.

4. Consequence of a restrictive definition of neuropathic pain

It may be argued that by excluding syndromes such as CRPStype 1 and fibromyalgia from the neuropathic pain group, thereis a risk of stigmatizing this group of patients as having a somati-zation disorder, one without a true and demonstrable abnormality,as opposed to the patients who have a ‘‘real’’ physical illness. Firstof all, as pain is defined as what a person experiences, by definitionall pain is real and legitimate [7]. The clinical challenge is to iden-tify and ameliorate the cause(s) of the pain, which may be tissuedamage, damage to the body’s warning system, both, or neither.We are not doing the patients any good by giving them a diagnosticlabel for which there is no basis. To include patients suffering fromdisorders with unexplained mechanisms under a specific label incasu: neuropathic pain will only serve as a sleeping pillow insteadof sharpening our diagnostic search and attempts to dissect theunderlying mechanisms. Our approach as pain researchers shouldbe consistent with the IASP mission, which is to study the condi-tions in depth. The new definition offers a platform for doing fur-ther research experimentally, clinically, and pharmacologically,so as to better understand neuropathic pain syndromes. Also, itis our hope that the new definition will raise further scientificawareness and thus be an additional step in the direction of keep-ing up the scientific momentum and moving us from the domain ofbeliefs into evidence.

5. Conclusion

A definition of neuropathic pain is only useful if it distinguishesconditions in a clinically meaningful way. If the definition does notprovide additional benefit in terms of understanding and treatingthe condition(s), then there is no reason to keep it. Hopefully, thenew definition of neuropathic pain will act as a stimulant to dis-cuss the definition in more detail and provide input for studies thatcan be used to test the value of the definition.

Conflict of interest statement

The authors have no conflicts of interest to report.

References

[1] Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Nav1.7 andhuman pain disorders. Trends Neurosci 2007;30:555–63.

[2] Finnerup NB, Sindrup SH, Jensen TS. The evidence of pharmacological treatmentof neuropathic pain. Pain 2010;150:573–81.

[3] Haanpää M, Attal N, Backonja M, Baron R, Bennett M, Bouhassira D, Cruccu G,Hansson P, Haythornthwaite J, Iannetti G, Jensen TS, Kauppila T, Nurmikko T,Rice A, Rowbotham M, Serra J, Sommer C, Smith B, Treede R-F. NeuPSIGguidelines on neuropathic pain assessment. Pain 2011;152:14–27.

[4] Lauria G, Hsieh ST, Johansson O, Kennedy WR, Leger JM, Mellgren SI, Nolano M,Merkies IS, Polydefkis M, Smith AG, Sommer C, Valls-Solé J. European Federationof Neurological Societies; Peripheral Nerve Society. European Federation ofNeurological Societies/Peripheral Nerve Society Guideline on the use of skinbiopsy in the diagnosis of small fiber neuropathy. Report of a joint task force ofthe European Federation of Neurological Societies and the Peripheral NerveSociety. Eur J Neurol 2010;17:903–12.

[5] Max MB. Clarifying the definition of neuropathic pain. Pain 2002;96:406–7.[6] Mehta A, Beck M, Elliott P, Giugliani R, Linhart A, Sunder-Plassmann G,

Schiffmann R, Barbey F, Ries M, Clarke JT. Fabry Outcome Survey investigators.Enzyme replacement therapy with agalsidase alfa in patients with Fabry’sdisease: an analysis of registry data. Lancet 2009;374:1986–96.

[7] Merskey H, Bogduk N. Classification of chronic pain. Seattle, WA: IASP Press;1997. p. 205–13.

[8] Oaklander AL, Rissmiller JG. Postherpetic neuralgia after shingles: an under-recognized cause of chronic vulvar pain. Obstet Gynecol 2002;99:625–8.

[9] Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, HanssonP, Hughes R, Nurmikko T, Serra J. Redefinition of neuropathic pain and a gradingsystem for clinical use: consensus statement on clinical and research diagnosticcriteria. Neurology 2008;70:1630–5.

Troels S. Jensen⇑Department of Neurology and Danish Pain Research Center,

Aarhus University Hospital, Norrebrogade 44, Building 1A, DK-8000Aarhus C, Denmark

⇑ Tel.: +45 8949 4137; fax: +45 8949 3269E-mail address: tsjensen@ki.au.dk

Ralf BaronSektion für Neurologische Schmerzforschung und -therapie,

Klinik für Neurologie, Universitätsklinikum Schleswig-Holstein, CampusKiel, Kiel, Germany

Maija HaanpääDepartment of Neurosurgery, Helsinki University Central Hospital,

Helsinki, Finland

Eija KalsoDepartment of Anaesthesiology, Pain Clinic, Helsinki University,

Helsinki, Finland

John D. LoeserDepartment of Neurological Surgery, University of Washington,

Seattle, WA, USA

Andrew S.C. RicePain Research Group, Imperial College London,

Chelsea and Westminster Hospital Campus, London, UK

Rolf-Detlef TreedeChair of Neurophysiology, Medical Faculty Mannheim,

Heidelberg University, Mannheim, Germany