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The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for ≥3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP's Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain.

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., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Persistent postoperative pain is a common complication of surgery, including surgical interventions for cancer. So far, there is limited information about the prevalence and clinical characteristics of pain after lymph node biopsy and dissection in patients with malignant melanoma. In this study, a questionnaire was sent out to all surviving patients (n=402) after surgery for cutaneous malignant melanoma at the Aalborg Hospital Department of Plastic Surgery, Aalborg, Denmark. Of patients responding, sentinel node biopsy (SNB) and/or lymph node dissection (LND) was performed in 175 patients. All patients with pain and a control group were invited to a clinical examination. Altered sensation and pain were significantly more common after LND (82% and 34%, respectively) than after SNB (32% and 14%, respectively). In patients with LND, 12% reported at least moderate pain and 14% impact of pain on quality of life, while in patients with SNB, 3% reported at least moderate pain and 2% pain impact on quality of life. The most important predictor of pain was sensory abnormalities. At the clinical follow-up, 10 out of 12 patients with pain both met the criteria of the recently proposed grading system for probable neuropathic pain and used descriptors on the DN4 questionnaire suggestive of neuropathic pain. Different patterns of sensory profiles were observed in single patients, suggesting heterogeneous sensory processing within single patients. This study suggested that nerve injury was the main underlying mechanism of persistent pain after lymph node excision., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The statins are a well-established class of drugs that lower plasma cholesterol levels by inhibiting HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A) reductase. They are widely used for the treatment of hypercholesterolemia and for the prevention of coronary heart disease. Recent studies suggest that statins have anti-inflammatory effects beyond their lipid-lowering properties. We sought to investigate whether statins could affect neuropathic pain by mediating nerve injury-associated inflammatory responses. The effects of hydrophilic rosuvastatin and lipophilic simvastatin were examined in the mouse partial sciatic nerve ligation model. Systemic daily administration of either statin from days 0 to 14 completely prevented the development of mechanical allodynia and thermal hyperalgesia. When administered from days 8 to 14 after injury, both statins dose-dependently reduced established hypersensitivity. After treatment, the effects of the statins were washed out within 2 to 7 days, depending on dose. Effects of both statins in alleviating mechanical allodynia were further confirmed in a different injury-associated neuropathic pain model, mental nerve chronic constriction, in rats. Both statins were able to abolish interleukin-1β expression in sciatic nerve triggered by nerve ligation. Additionally, quantitative analysis with Iba-1 and glial fibrillary acid protein immunoreactivity demonstrated that rosuvastatin and simvastatin significantly reduced the spinal microglial and astrocyte activation produced by sciatic nerve injury. The increase of interleukin-1β mRNA in the ipsilateral side of spinal cords was also reduced by the treatment of either statin. We identified a potential new application of statins in the treatment of neuropathic pain. The pain-alleviating effects of statins are likely attributable to their immunomodulatory effects., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible., (Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

In patients with distal symmetric polyneuropathy we assessed non-nociceptive Abeta- and nociceptive Adelta-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 150 patients with distal symmetric polyneuropathy (68 with pain and 82 without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard nerve conduction study (NCS) to assess Abeta-fibre function, and laser-evoked potentials (LEPs) to assess Adelta-fibre function. Patients with pain had the same age (P>0.50), but a longer delay since symptom onset than those without (P<0.01). Whereas the LEP amplitude was significantly lower in patients with pain than in those without (P<0.0001), NCS data did not differ between groups (P>0.50). LEPs were more severely affected in patients with ongoing pain than in those with provoked pain (P<0.0001). Our findings indicate that the impairment of Abeta-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that this type of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds., (Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Neuropathic pain can be caused by a variety of nerve lesions and it is unsettled whether it should be categorised into distinct clinical subtypes depending on aetiology or type of nerve lesion or individualised as a specific group, based on common symptomatology across aetiologies. In this study, we used a multivariate statistical method (multiple correspondence analyses) to investigate associations between neuropathic positive symptoms (assessed with a specific questionnaire, the Neuropathic Pain Symptom Inventory [NPSI]) and aetiologies, types of nerve lesion and pain localisations. We also examined the internal structure of the NPSI and its relevance to evaluation of symptoms of evoked pains by exploring their relationships with clinician-based quantified measures of allodynia and hyperalgesia. This study included 482 consecutive patients (53% men; mean age: 58+/-15 years) with pain associated with peripheral or central lesions. Factor analysis showed that neuropathic symptoms of the NPSI can be categorised into five dimensions. Spearman correlation coefficients indicated that self-reported pain evoked by brush, pressure and cold stimuli strongly correlated to allodynia/hyperalgesia to brush, von Frey hairs and cold stimuli (p<0.0001, n=90). Multiple correspondence analyses indicated few associations between symptoms (or dimensions) and aetiologies, types of lesions, or pain localisations. Exceptions included idiopathic trigeminal neuralgia and postherpetic neuralgia. We found that there are more similarities than differences in the neuropathic positive symptoms associated with a large variety of peripheral and central lesions, providing rationale for subgrouping aetiologically diverse neuropathic patients into a specific multidimensional category for therapeutic management.

We aimed to locate a chronic pain-associated QTL in the rat (Rattus norvegicus) based on previous findings of a QTL (pain1) on chromosome 15 of the mouse (Mus musculus). The work was based on rat selection lines HA (high autotomy) and LA (low autotomy) which show a contrasting pain phenotype in response to nerve injury in the neuroma model of neuropathic pain. An F(2) segregating population was generated from HA and LA animals. Phenotyped F(2) rats were genotyped on chromosome 7 and chromosome 2, regions that share a partial homology with mouse chromosome 15. Our interval mapping analysis revealed a LOD score value of 3.63 (corresponding to p=0.005 after correcting for multiple testing using permutations) on rat chromosome 2, which is suggestive of the presence of a QTL affecting the predisposition to neuropathic pain. This QTL was mapped to the 14-26cM interval of chromosome 2. Interestingly, this region is syntenic to mouse chromosome 13, rather than to the region of mouse chromosome 15 that contains pain1. This chromosomal position indicates that it is possibly a new QTL, and hence we name it pain2. Further work is needed to replicate and to uncover the underlying gene(s) in both species.

Thirty-four patients with various forms of neuropathic pain have been examined with respect to two parameters of dynamic mechanical allodynia: the effect of repetitive stimulation on pain intensity; and refractory period. Pain intensity increased with repetitive stimulation ('windup') in most patients with neuropathic pain of peripheral origin, while it was not observed in patients with central neuropathic pain. While a non-responsive period occurs after tactile allodynic elicitation in patients with trigeminal neuralgia (Kugelberg and Lindblom, 1959), it was not seen in any case of neuropathic pain, including trigeminal neuropathy. The findings have implications for diagnosis, and require pathophysiological elucidation in terms of revealed differences.

This study identified discrete categories of pain severity in a sample of patients with painful diabetic peripheral neuropathy (DPN), through derivation of cut-points on a 0-10 scale of pain severity (Brief Pain Inventory-DPN, BPI-DPN). Subjects were participants in a burden of illness survey (N=255). Serlin and colleagues' method establishing cut-points for cancer pain was adapted, considering all possible cut-points between 4 and 8. Optimal cut-points were those that created three pain severity categories producing maximum between-category differences on the seven BPI-DPN Interference items, using MANOVA. Cut-points of 4 and 7 optimally classified the sample for both Worst Pain and Average Pain, creating categories of mild, 0-3; moderate, 4-6; severe, 7 and higher (Hotelling's T(2)=22.95 and 16.20 for Worst and Average Pain, P<0.0001). Mean BPI-DPN Interference was 2.1 (SD=2.1), 4.9 (SD=1.9) and 7.4 (SD=1.6) for the mild, moderate and severe pain categories. Patients in the three categories differed significantly on patient-rated outcomes (Medical Outcomes Study Short Form-12v2 Mental and Physical Component Summaries and EuroQOL utility score), and on DPN-related healthcare visits (P<0.001). The labels 'mild, moderate and severe' Worst and Average Pain corresponded with patients' ratings of their pain using a verbal rating scale. This research shows that three categories of DPN pain severity can be identified based on interference with daily function, and that these categories are associated with patient outcomes and medical utilization.

The study sought to determine if symptoms and signs cluster differentially in groups of patients with increasing evidence of neuropathic pain (NP). We prospectively looked at symptoms and signs in 214 patients with suspected chronic NP of moderate to severe intensity. According to a set of clinical criteria the patients were a priori classified as having the so-called 'Definite NP' (n = 91), 'Possible NP' (n = 71), or 'Unlikely NP' (n = 52). A recording of symptoms including pain descriptors, intensity of five categories of pain, Short Form McGill Pain Questionnaire, and Major Depression Inventory were done. Sensory tests including repetitive pinprick stimulation, examination for cold-evoked pain by an acetone drop and brush-evoked pain were carried out in the maximal pain area and in a control area. High intensity of superficial ongoing pain, and touch or cold provoked pain was associated with chronic pain classified as definite or possible neuropathic. Intensity of deep ongoing pain, and 'paroxysms' was similar in the three groups. Brush-evoked pain was more frequent in definite NP. The McGill Pain Questionnaire and the used pain descriptors could not distinguish between the three clinical categories. Although certain symptoms (touch or cold provoked pain) and signs (brush-evoked allodynia) are more prominent in patients with definite or possible NP, we found considerable overlap with the clinical presentation of patients with unlikely NP.

In some herpes zoster patients, pain persists for more than 3 months or more after healing of vesicular eruptions; this condition is termed postherpetic neuralgia (PHN). We have recently reported the association of the human histocompatibility leukocyte antigens (HLA) haplotype, HLA-A*3303-B*4403-DRB1*1302 with PHN patients; however, it has not been determined whether the haplotype is also associated with herpes zoster that did not develop subsequent PHN. To distinguish whether the haplotype is associated with herpes zoster or the development of PHN, we examined if herpes zoster patients without subsequently PHN are also associated with the HLA haplotype or not. Herpes zoster patients were followed up for more than 6 months, and HLA alleles and haplotypes were compared among the PHN patients (n = 52) the herpes zoster patients who did not develop PHN (n = 42) and healthy controls (n = 125). The frequencies of the risk haplotype in the PHN patients, in the healthy controls and in the herpes zoster patients without subsequent PHN were 16.3, 5.2 and 4.8%, respectively. While the frequency of the risk haplotype was significantly higher in the PHN patients than in the healthy controls (P = 0.0006) no difference was observed between the herpes zoster patients without subsequent PHN and the healthy controls. No significant association was found between the duration of symptoms or the site of herpes zoster and the HLA alleles and the haplotype. These results suggest that the HLA-A*3303-B*4403-DRB1*1302 haplotype plays an important role in the development of PHN after herpes zoster, but not in the onset of herpes zoster.

Patients with sensory disturbances of painful and non-painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in-patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1mm). Thresholds and stimulus-response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2mm). Allodynia was tested by light stroking with a brush, Q-tip, and cotton wisp. Perceptual wind-up was tested by trains of punctate stimuli at 0.2 or 1Hz. Intradermal injection of capsaicin (n=7) and A-fiber conduction blockade (n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52+/-0.45 log2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by -1.94+/-0.46 log2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02+/-0.48 log2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus-response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus-response function with a decrease in slope). Perceptual wind-up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism-based classification of neuropathic pain.