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Mechanisms of Disease: mechanism-based classification of neuropathic pain—a critical analysis Nanna B Finnerup* and Troels S Jensen INTRODUCTION

S U M M A RY 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. KEYWORDS allodynia, mechanism-based classification, neuropathic pain

REVIEW CRITERIA PubMed was searched using Entrez for articles published up to August 31 2005, including electronic early-release publications. Search terms included “mechanism based”, “classification”, “neuropathic pain”, “postherpetic neuralgia”, “randomized” and “allodynia”. The abstracts of retrieved citations were reviewed and relevant full articles obtained, and references were checked for additional material when appropriate.

Classification of neurological diseases according to their cause is an essential step towards their elimination and prevention. In chronic pain conditions, however, including those caused by neurological disorders, elimination of the causative agent is rarely possible, and symptomatic treatment of pain is often the best solution that can be offered. It is still unclear how such symptomatic treatment should be carried out. A strategy directed at disease entities has shown efficacy for various conditions,1,2 but it also has limitations, which are in part reflected in treatment outcome. In recent years, we have gained increasing knowledge of the mechanisms that are involved in generating and maintaining pain.3 In this review, we present a critical analysis of this mechanismbased classification of NEUROPATHIC PAIN, and examine the possibility of dissecting mechanisms that contribute to pain in individual patients with neuropathic pain disorders. If the pathophysiological mechanisms that contribute to the pain can be identified, and if such mechanisms translate into specific symptoms and signs, then it is assumed that this will lead to improved treatment of neuropathic pain disorders. As we will discuss, however, there is as yet no simple way to establish how mechanisms translate into human symptoms and signs, or vice versa.4 WHY IS A MECHANISM-BASED CLASSIFICATION OF NEUROPATHIC PAIN WARRANTED?

NB Finnerup is a clinical scientist at the Danish Pain Research Center, and TS Jensen is a consultant in neurology and Professor of Experimental and Clinical Pain Research, at the Aarhus University Hospital, Aarhus, Denmark. Correspondence *Danish Pain Research Center and Department of Neurology, Aarhus University Hospital Aarhus Sygehus, Norrebrogade 44, DK-8000 Aarhus C, Denmark [email protected] Received 6 July 2005 Accepted 2 December 2005 www.nature.com/clinicalpractice doi:10.1038/ncpneuro0118

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The classical approaches to classifying neuropathic pain are based on the etiology of the lesion or its location. For example, a disorder might be attributable to ischemic, immunological, metabolic, toxic or other etiological factors, and located in either the CNS or the periphery. Pain classification according to etiology has been the basis for a series of trials of various pharmacological agents in pain, including anticonvulsants, tricyclic antidepressants, and opioids. The available evidence from these studies shows that pain relief of more than 50% is possible in less than

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GLOSSARY NEUROPATHIC PAIN Pain initiated or caused by a primary lesion or dysfunction in the nervous system ALLODYNIA Pain due to a stimulus that does not normally provoke pain DYSESTHESIA An unpleasant abnormal sensation, which can be spontaneous or evoked PARESTHESIA An abnormal skin sensation that can include tingling, pricking or numbness

one-third of patients.5 This insufficient pain relief could indicate that the treatments themselves were only partially effective, or that the wrong patients were recruited to the trial. As discussed by Baron in this issue,3 a classification of neuropathic pain based on disease or location has considerable shortcomings. The proposal of a mechanismbased classification, however, is of value only if it results in a better treatment for the patients, and, as we will discuss, the evidence to support such an achievement is not yet available. MECHANISM-BASED CLASSIFICATION: DREAM OR REALITY? What are the requirements for a mechanism-based classification?

To develop an effective mechanism-based classification of neuropathic pain, we need to be able to identify its occurrence, its underlying mechanisms, and its symptoms and signs. Then, we need to relate the symptoms and signs to the mechanisms, and identify specific treatments for specific mechanisms. There are several reasons why it is difficult to obtain a classification based solely on mechanisms, and, in the sections that follow, we will discuss the progress that has been made towards fulfilling these requirements. Identification of neuropathic pain

At present, a diagnostic test to determine or refute the existence of neuropathic pain does not exist, and it is unclear whether a specific pattern of symptoms can predict the mere presence of neuropathic pain. Owing to the lack of a gold standard for confirming the presence of neuropathic pain, a grading system has been proposed that categorizes such pain as, for example, “definite”, “possible” or “unlikely” neuropathic pain.6 In a study examining 214 patients with suspected neuropathic pain that used this grading system, there was no single symptom or descriptor that separated patients with definite neuropathic pain from patients who were unlikely to have neuropathic pain.6 Moreover, in the same group of patients, ALLODYNIA was the only feature that separated the “unlikely” neuropathic pain patients from the other two categories, indicating a large overlap between patients, even when mechanisms are identified. Other studies have shown that the presence of a cluster of symptoms rather than a single symptom allows separation of neuropathic pains from non-neuropathic pains.7–9 These

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studies used questionnaires such as DN4, the Neuropathic Pain Questionnaire, and the LANSS (Leeds Assessment of Neuropathic Symptoms and Signs) pain scale, which include descriptors of pain or DYSESTHESIA/PARESTHESIA, and items related to sensory changes (hypoesthesia or hyperesthesia). The diagnostic sensitivity of these questionnaires was 78–83%, and the specificity was 78–90%. Similar sensitivity and specificity findings were observed using the short form of the McGill Pain Questionnaire.10 As is the case for all studies of this nature, circularity might limit the usefulness of the investigations, as some of the questionnaires being tested are likely to also have been used as the basis for the ‘gold standard’ diagnosis. The predictive value of such tests will depend not only on the prevalence of neuropathic pain in the population, but also on the prevalence of neurological disease, because patients with sensory disturbances are likely to score high in the tests even though their pain is nociceptive. For example, in a spinal-cord-injury rehabilitation center, all patients are likely to score at least 4 on the DN4 owing to their neurological lesion (tingling, numbness, and hypoesthesia to touch and prick). The value of such questionnaires therefore largely depends on the clinical setting in which it is used. Part of the rationale for separating neuropathic pain from non-neuropathic pain is that the nature of the pain is expected to make a difference from a treatment perspective. This supposition is not always borne out by the evidence, however, as illustrated by an openlabel study that showed that a tricyclic antidepressant—a treatment commonly prescribed for neuropathic pain—seemed to have similar pain-relieving effects in neuropathic and nonneuropathic pain.11 This observation, despite its open-label basis, raises the question of whether separation of pain states into neuropathic and non-neuropathic makes a difference, at least with regard to the existing nonspecifically acting drugs that are available for neuropathic pain. Identification of molecular and cellular mechanisms

A mechanism-based classification is an analysis of different pain states based on neurobiological mechanisms and, over the past few decades, experimental studies have outlined a series of neurobiological events that might cause neuropathic pain.3,12–16 Mechanisms can be analyzed from various angles, and with different degrees

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of resolution: anatomically (e.g. peripheral vs central), physiologically (e.g. C-mechano-sensitive units vs C-mechano-insensitive units), cellularly (e.g. spontaneous discharges vs reduced threshold), and molecularly (e.g. Nav1.3 sodium channels vs Nav1.7 sodium channels). An obvious requirement for a mechanismbased classification is that the mechanisms can be identified in the clinical setting. At the molecular level, formation of new channels, upregulation of certain receptors and downregulation of others, expression of novel receptors, and changes in gene expression, are some of the biological mechanisms occurring after experimental nerve injury that, alone or in concert, might contribute to peripheral hyperexcitability. Similar changes can occur in the spinal cord and brain relay stations after CNS injury or as a consequence of increased or decreased peripheral input—a phenomenon termed central sensitization. Central sensitization involves activation of sodium and calcium channels, and activation of glutamate and substance-P receptors in postsynaptic cell membranes, causing release of intracellular calcium. This mechanism in turn results in a release of protein kinase C and production of nitric oxide, which again leads to posttranscriptional changes and phosphorylation of receptors, including the N-methyl-d-aspartate (NMDA) receptor, resulting in a lowering of sensitivity to glutamate.16–18 Cellular manifestations of the peripheral molecular changes include spontaneous discharges in nociceptors, reduced threshold to depolarization of cell bodies, an increased response to suprathreshold stimulation, and recruitment of silent nociceptors. Central cellular manifestations include abnormal TEMPORAL SUMMATION, expansion of receptive fields, and altered response properties of central neurons to non-noxious stimuli.16–18 The clinical expression of these cellular changes, however, is more speculative (see below). Another obstacle to identifying clinically relevant mechanisms for neuropathic pain is the extent to which we can translate animal work into humans. For example, one discrepancy that has been observed between animal models and human studies is the lack of analgesic effect of neurokinin-1/substance-P-receptor antagonists in clinical pain in humans.19–21 Species differences in physiology, receptor distribution and other factors, might account for some of the differences observed between animal and

human studies. Another general problem is that evoked responses are the most common outcome measure in animal research, and these types of responses might not always reflect ongoing and evoked pain in humans. Identification of symptom and signs

Pain is a complex sensory experience that includes sensory–discriminative, affective– motivational and cognitive–evaluative aspects for which there is no simple wording. Because of the subjective nature of pain, there is no measure that permits a precise and accurate assessment of the experience. Nevertheless, the starting points in an analysis of mechanisms are the symptoms and signs. These pain phenomena include spontaneous ongoing pain, which might be continuous and burning, aching, or pricking in character, or might present as paroxysms of pain, and abnormally evoked pain.22,23 Stimulusevoked pain might present itself as allodynia— including dynamic mechanical allodynia where light brush evokes a sensation of pain, or cold and warm allodynia where a normally nonpainful thermal stimulus evokes a pain sensation—and HYPERALGESIA, including punctuate hyperalgesia (pain evoked by pricking the skin) and thermal hyperalgesia. Besides the subjectivity of these symptoms, we face the problem of not having reliable tests for many of these symptoms and signs. In pain studies, various methods have been used to assess different forms of mechanical and thermal allodynia (Table 1), and the validity and reliability of these tests have not been evaluated.

GLOSSARY TEMPORAL SUMMATION A mechanism whereby repeated stimuli elicit increasing responses in spite of unchanged stimulus intensity HYPERALGESIA An increased response to a stimulus that is normally painful

Translation of research into the clinic

From mechanisms to symptoms The clinical manifestations of the array of neuronal events after nerve lesion are not clear, but they probably include exaggerated and prolonged pains, different types of evoked pains, and an extraterritorial spread of pain to nondamaged tissue.4,24,25 One mechanism might, however, give rise to different symptoms/signs— for example, upregulation of sodium channels in C-fibers causing increased and ectopic C-fiber activity, resulting in burning pain, paroxysms, and dynamic mechanical allodynia due to central sensitization.26 In addition, much of our present knowledge about mechanisms has been obtained from animal studies, and these do not necessarily translate into human clinical pain symptoms and signs.4 In the behavioral responses recorded

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Table 1 Pharmacological agents for which evidence from randomized controlled trials indicates effects on mechanical and cold allodynia in different neuropathic pain conditions.a Main drug mechanism

Dynamic mechanical allodyniab

Cold allodynia or hyperalgesiac

Sodium-channel blockade

Lidocaine i.v.59,60,64–67 Lidocaine topical54,68

Lidocaine i.v.67

Mexiletine oral69

Lamotrigine oral70

i.v.27,35,71,72,73(d),74

NMDA antagonist

Ketamine

Opioid

Alfentanil i.v.27,35,72,74

Ketamine i.v.27,35 Alfentanil i.v.27,35

Morphine i.v.64,71,75 Oxycodone oral76,77 Tramadol oral78(d) GABAA agonist

Propofol i.v.79

Serotonin noradrenaline reuptake inhibitor

Venlafaxine oral80

aNote

that the effect on these pain symptoms is rarely studied in trials using anticonvulsant and antidepressant agents. bAssessed by questionnaire asking for ‘skin pain’ or touch-evoked pain, by brush or cotton-wisp stroking with variable number, length, and rate of strokes, or using an electric toothbrush. cAssessed by acetone droplet, cold pain detection threshold, pain at cold pain detection threshold, or suprathreshold cold stimuli using a thermotest. dReferences 73 and 78 show the correlation between reduction in allodynia and ongoing pain. GABA, γ-aminobutyric acid; i.v., intravenous; NMDA, N-methyl-D-aspartate.

GLOSSARY DIFFUSE NOXIOUS INHIBITORY CONTROL Inhibition of nociceptive neurons in the spinal and trigeminal dorsal horns by noxious stimulation of widespread areas of the body distant from the neurons’ receptive field

in animals, there is often a motor component, which might not reflect processing of normal and abnormal noxious inputs. The increasing use of operant escape responses requiring cortical processing probably better reflects the evoked types of pain seen in humans. From symptoms to mechanisms Because patients report symptoms rather than mechanisms of pain, the main clinical problem is to extrapolate mechanisms from symptoms or clusters of symptoms. There are three main reasons why it is difficult to translate symptoms and signs into mechanisms. First, one symptom/sign can be caused by several initiating mechanisms. For example, cold allodynia might, speculatively, be caused by disproportionate loss of Aδ fibers and sensitization of cold receptors in peripheral neuropathic pain,27 whereas cold allodynia in central pain clearly has to be explained by other mechanisms. Second, the pain system is dynamic in nature. Neurobiological events can change over time; for example, central sensitization initiated by irritable nociceptors might eventually become independent of peripheral input.16,28,29 One possible explanation for this phenomenon could be that ongoing afferent activity causes a protracted induction of apoptosis and a loss of, for example, γ-aminobutyric-acid (GABA)-releasing interneurons.30 This potential irreversible loss of central inhibition might cause permanent changes


in the function of the CNS. The complexity is underscored by the fact that pain itself alters the processing of somatosensory information; for example, DIFFUSE NOXIOUS INHIBITORY CONTROL can occur in response to noxious stimuli,31 and functional changes in descending facilitatory and inhibitory control might modify and maintain central sensitization.32,33 Third, there is a temporal and anatomical sequence of events in the generation and maintenance of neuropathic pain, and a primary pathology might give rise to a series of secondary events (Figure 1). The symptoms can vary from day to day, perhaps because of plastic changes that depend on sensitization, inhibition and facilitation. To date, no studies have documented the stability of different phenomena in any given patient. If a treatment is effective in one of the final paths in this cascade of events— for example, acting on central sensitization or descending facilitation—it might be effective in several neuropathic pain conditions in which the symptoms and signs are caused by different primary mechanisms. The treatment might also modulate symptoms and signs without targeting mechanisms.34 ARE WE CLOSE TO OBTAINING A VIABLE MECHANISM-BASED CLASSIFICATION?

When translating symptoms/signs into potential mechanisms, phenotypic characterization is crucial, as illustrated by the following scenarios.



A

Nerve injury

Peripheral

Nav

Nav

Nav

Injury B

Glu

Nav mGlu NMDA AMPA Nav

Ca2+

Central

C

Nav mGlu NMDA AMPA Glu Nav1.3

Figure 1 Cascade of events following peripheral and central nervous system lesion resulting in central sensitization. After peripheral nerve injury, increased sodium-channel expression on sensitized primary afferents leads to spontaneous activity with increased glutamate release from the nerve endings. This excess of glutamate acts on glutamate receptors (N-methyl-D-aspartate, α-amino-3hydroxy-5-methyl-4-isoxazole propionic acid, kainate and metabotropic glutamate receptors), thereby triggering intracellular changes. These changes contribute to sustained central sensitization, with increased spontaneous impulse discharges, reduced thresholds, increased response to peripheral stimuli, and expanded receptive fields of central neurons.24,46 After CNS lesion (pink shading in panel C), glutamate levels increase because of neuronal activity and loss of glutamate-transporter expression in the lesion vicinity.81 Glutamate-receptor expression also changes,82 resulting in similar plastic changes of cellular excitability in central transmission neurons (i.e. central sensitization). Loss of tonic inhibitory control (÷ in panel B) by neurons containing γ-aminobutyric acid83 and increased expression of Nav1.3 sodium channels84 might contribute to increased gain in the pain transmission system. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Glu, glutamate; mGlu, metabotropic glutamate; NMDA, N-methyl-D-aspartate.

Single symptoms/signs

At present, we have little evidence to indicate that specific symptoms respond to specific drugs. For example, as shown in Table 1, dynamic mechanical and cold allodynia—hallmarks of neuropathic pain—respond to a variety of drugs with different pharmacological actions. Evoked pain is rarely, however, a primary efficacy measure (with some exceptions27,35), and studies usually have insufficient power to exclude an effect.

Paroxysms are another example of a symptom that is not caused by one mechanism only, and is therefore not treated with only one type of drug. Paroxysms are traditionally considered to be generated by abnormal activity at sodium channels, and can therefore respond to sodium-channel blockers. Paroxysms can, however, also be seen in patients with smallfiber neuropathy and deafferentation, pointing to a central mechanism,36 and are reported to




be relieved by tricyclic antidepressants and the serotonin–noradrenaline reuptake inhibitor venlafaxine.37,38 Cluster of symptoms/signs

On the basis of clusters of symptoms and signs, patients with postherpetic neuralgia (PHN) are suggested to fall into three groups with different mechanisms:39 an ‘irritable nociceptor’ group with allodynia; a deafferentation group with allodynia; and a deafferentation group without allodynia. Patients with the irritable nociceptor type of PHN present with preserved cutaneous innervation,40 minimal deficits in the sensation of heat stimuli or even hyperalgesia to heat,41 severe pain, marked dynamic mechanical allodynia, and worsened pain and allodynia with topical capsaicin.42 It is assumed that chronically irritable nociceptors with ongoing nociceptive afferent input cause a central sensitization, with pain being generated by low-threshold Aβ afferents.43–46 Patients with deafferentation with or without allodynia have thermal sensory deficits47 and reduced histamine-evoked axon reflex reactions,48 indicating degeneration of C-fibers. Possible mechanisms for pain and allodynia in this group of patients include central changes due to spinal cord infection, disinhibiton by downregulation of GABA receptors due to deafferentation or diminished A-fiber-mediated inhibition, denervation bursting activity and supersensitivity,49,50 and synaptic reorganization or unmasking of existing connections within the dorsal horn.51 It is possible that, in some of these cases, ectopic activity in the dorsal root ganglia of C-fibers that have degenerated only in peripheral branches, or in nociceptors of deep somatic tissues, might contribute to pain and allodynia.39 Furthermore, it is likely that both mechanisms can coexist in a single patient. If this mechanistic grouping of PHN patients is to be of clinical relevance, it should have treatment implications. Two open-label trials with limited numbers of patients have indicated that PHN patients with dynamic mechanical allodynia respond to topical lidocaine, whereas patients without allodynia fail to do so.52,53 Subsequent randomized controlled trials have confirmed the effect of topical lidocaine in allodynic PHN patients,54,55 and it was assumed that the irritable nociceptor group would be those responding to lidocaine. It was not until very recently, however, that this idea was tested.


In a randomized crossover trial studying the effect of the lidocaine patch 5%, 18 patients with PHN and mechanical allodynia were separated into two groups: 6 patients with sensitized nociceptors (no sensory loss and histamineinduced flare and pain), and 12 patients with functional deafferentation (elevated heat pain thresholds, impaired histamine-induced flare, and no pain evoked by histamine).56 Subgroup analysis showed a statistically significant reduction in spontaneous pain and allodynia in patients with impaired nociceptor function, and a nonsignificant relief of pain and allodynia in patients with preserved or sensitized nociceptors. In a similar vein, an uncontrolled study showed that skin biopsies, quantitative sensory testing, and sensory nerve conduction studies, were not predictive of response to a lidocaine patch in patients with polyneuropathy, and even patients with complete loss of epidermal-nerve-fiber densities showed a response to a lidocaine patch.57 On the basis of these observations, the mechanisms for PHN are likely to include a spectrum of different mechanisms that are weighted differentially among individual patients. Although some preliminary results indicate that topical lidocaine is effective only in PHN patients with allodynia, there is insufficient evidence to indicate that separation into mechanisms involving sensitized nociceptors and deafferentation has therapeutic implications. Similar observations have been made in patients with peripheral nerve injury, pain and allodynia (Gottrup H et al., unpublished data). Predictive value of symptoms/signs

The presence of mechanical allodynia has been suggested to be predictive of the response of ongoing pain to lamotrigine in spinalcord-injury-related neuropathic pain,58 and to intravenous lidocaine in patients with peripheral neuropathic pain.59 This mechanism-based treatment approach was investigated in patients with pain following spinal cord injury.60 The primary purpose of this randomized trial was to examine whether evoked pain was a predictor for the effect of the sodium-channel blocker lidocaine, which was given intravenously over 30 minutes in a dose of 5 mg/kg in a crossover trial. Twelve patients with evoked pain (including dynamic mechanical allodynia, pinprick hyperalgesia and cold allodynia) and 12 patients without evoked pain completed the



trial. Lidocaine significantly reduced spontaneous pain and brush-evoked dysesthesia in patients with evoked pain, and spontaneous pain in patients without evoked pain, with no significant difference in the effect size between the two groups, indicating that central neuronal hyperexcitability exists in patients both with and without allodynia. Therefore, no randomized trial with the predefined purpose of studying predictive values has yet confirmed a positive predictive value of allodynia for the effect of sodium-channel blockers in neuropathic pain. Pharmacological tests

Assuming that there are drugs that act on specific neuropathic pain mechanisms, pharmacological tests might aid the identification of these mechanisms. Theoretically, intravenous lidocaine, ketamine, or fentanyl tests should reveal whether abnormal activity of sodium channels, NMDA receptors or opioid receptors, respectively, play a role in the mechanism underlying the pain. Such tests might predict the effect of oral analogs, but low tolerability and lack of specificity of the available drugs makes it difficult to find appropriate drugs for oral treatment. In complex regional pain syndrome, some patients might respond to sympathetic blockade, although the long-term effect of such treatment is not well studied.61 A sympatholytic intervention—for example, systemic α-adrenergic blockade with phentolamine—has been used to identify patients with sympathetically maintained pain and to predict the effect of sympathetic therapy.61–63 CONCLUSIONS

It is becoming clear that we have not yet obtained a viable mechanism-based classification of neuropathic pain, although, admittedly, only a few studies have rigorously tested the mechanism-based approach. Several approaches can be envisaged to test this possibility and attempt to validate the measures used. One approach could be to study predictive values of symptoms and signs of neuropathic pain syndromes; for example, is dynamic mechanical allodynia a positive predictor for the effect of sodium-channel blockers on ongoing pain? Another approach is to study clusters of symptoms and signs (e.g. by precise phenotypic mapping3), and to test in pharmacological or other treatment trials whether such a grouping of patients is in fact of clinical relevance; that is, does one pain phenotype respond better to a certain treatment

than another? More-advanced methods, such as microneurography, skin-punch biopsies, functional MRI and laser-evoked potentials, could complement bedside and quantitative sensory testing examination in the grouping of phenotypes and in understanding pathophysiology. These methods have been used in a very limited number of patients, and their usefulness remains to be evaluated. Only time will tell whether we can identify mechanisms in individual patients and treat the patient accordingly. A mechanism-based approach for classifying neuropathic pain is attractive, because it attempts to analyze the most likely culprits for causing pain. We are still far from having produced a viable mechanism-based classification of human pain conditions, but 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 to improve neuropathic pain treatment. KEY POINTS ■ Classification of neuropathic pain on the basis of disease or location has considerable shortcomings, and an approach based on disease mechanisms might provide a viable alternative ■ To develop an effective mechanismbased classification, we need to be able to relate symptoms and signs to mechanisms, and to identify specific treatments for specific mechanisms ■ One mechanism might give rise to different symptoms and signs; for example, upregulation of sodium channels in C-fibers increases fiber activity, resulting in burning pain, paroxysms and dynamic mechanical allodynia ■ Similarly, one symptom or sign can be caused by several initiating mechanisms; for example, cold allodynia can be attributed to different mechanisms in peripheral and central neuropathic pain ■ It is becoming clear that we have not yet obtained a viable mechanism-based classification for neuropathic pain, and more-rigorous studies are required to test this approach References 1 McQuay and Moore (1998) An evidence based resource for pain relief. Oxford: Oxford University Press 2 Finnerup NB et al. (2005) Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118: 289–305 3 Baron R (2006) Mechanisms of Disease: neuropathic pain—a clinical perspective. Nat Clin Pract Neurol 2: 95–106




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Competing interests The authors declared they have no competing interests.
