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Pain intensity has been reported to fluctuate during the day in some experimental and clinical conditions, but the mechanisms underlying these fluctuations are unknown. Although the circadian timing system is known to regulate a wide range of physiological functions, its implication in pain regulation is largely unknown. Using highly controlled laboratory constant-routine conditions, we show that pain sensitivity is rhythmic over the 24 h and strongly controlled by the endogenous circadian timing system. We found that the circadian component of pain sensitivity can be modelled with a sinusoidal function, with a maximum in the middle of the night and a minimum in the afternoon. We also found a weak homeostatic control of pain sensitivity, with a linear increase over the 34 h of prolonged wakefulness, which slowly builds up with sleep pressure. Using mathematical modelling, we describe that the circadian system accounts for ∼80% of the full magnitude of pain sensitivity over the 24 h, and that sleep-related processes account for only ∼20%. Overall, our data reveal the neurobiological mechanisms involved in driving the rhythmicity of pain perception in humans. We show that pain sensitivity is controlled by two superimposed processes: a strong circadian component and a modest homeostatic sleep-related component. Our findings highlight the need to consider time of day in pain assessment, and indicate that personalized circadian medicine may be a promising approach to pain management. [ABSTRACT FROM AUTHOR]

Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock–like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients. [ABSTRACT FROM AUTHOR]

Among the different types of pain observed in Parkinson's disease, parkinsonian central pain (PCP) has the highest severity, and is poorly characterized and difficult to describe not only by patients but also by neurologists. Thus PCP remains not strictly defined and is difficult to distinguish from other types of pain on the basis of clinical description. Yet, standardizing PCP diagnosis is critical to improve the treatment of this debilitating pain subtype, but also to homogenize further studies investigating the pathophysiological mechanisms underlying this condition. Accounting for the lack of reliable validated positive clinical criteria for PCP, and as the clinical features of PCP are difficult to specify, we suggest to consider so far the gold standard diagnosis of PCP mainly based on exclusion criteria. We propose a new algorithm aiming to disentangle PCP from other chronic pain subtypes in Parkinson's disease, by sequentially ruling out what PCP is not. [ABSTRACT FROM AUTHOR]

Background and Purpose: In these guidelines, we aimed to develop evidence‐based recommendations for the use of screening questionnaires and diagnostic tests in patients with neuropathic pain (NeP). Methods: We systematically reviewed studies providing information on the sensitivity and specificity of screening questionnaires, and quantitative sensory testing, neurophysiology, skin biopsy, and corneal confocal microscopy. We also analysed how functional neuroimaging, peripheral nerve blocks, and genetic testing might provide useful information in diagnosing NeP. Results: Of the screening questionnaires, Douleur Neuropathique en 4 Questions (DN4), I‐DN4 (self‐administered DN4), and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) received a strong recommendation, and S‐LANSS (self‐administered LANSS) and PainDETECT weak recommendations for their use in the diagnostic pathway for patients with possible NeP. We devised a strong recommendation for the use of skin biopsy and a weak recommendation for quantitative sensory testing and nociceptive evoked potentials in the NeP diagnosis. Trigeminal reflex testing received a strong recommendation in diagnosing secondary trigeminal neuralgia. Although many studies support the usefulness of corneal confocal microscopy in diagnosing peripheral neuropathy, no study specifically investigated the diagnostic accuracy of this technique in patients with NeP. Functional neuroimaging and peripheral nerve blocks are helpful in disclosing pathophysiology and/or predicting outcomes, but current literature does not support their use for diagnosing NeP. Genetic testing may be considered at specialist centres, in selected cases. Conclusions: These recommendations provide evidence‐based clinical practice guidelines for NeP diagnosis. Due to the poor‐to‐moderate quality of evidence identified by this review, future large‐scale, well‐designed, multicentre studies assessing the accuracy of diagnostic tests for NeP are needed. [ABSTRACT FROM AUTHOR]

Diabetic polyneuropathy (DPN) is one of the most distressing, but still under-recognized complications of diabetes. A cross-sectional study was carried out in 40 Belgian diabetes clinics to estimate the prevalence of DPN and of painful DPN (PDPN). Validated and inexpensive tools were used for the diagnosis of DPN (Neuropen®) and of PDPN (DN4 questionnaire in Neuropen®positive patients reporting pain in their legs). A cohort of 1194 type 1 and type 2 diabetic patients participated in this study. The overall prevalence was 43% for DPN and 14% for PDPN. The prevalence rates of both DPN (51%) and PDPN (18%) were higher in the subgroup of type 2 diabetic patients (n=784) in comparison with type 1 diabetic patients (DPN: 25%; PDPN: 6%). Comparison of patients without and with DPN showed, with p<0.05, that DPN patients were on average older (644±11 vs. 53±16 years) and had a longer duration of diabetes (164±10 vs. 13±10 years). Other metabolic syndrome parameters that were more prevalent in DPN patients were: a higher BMI (30± 6 vs. 28±6) and waist circumference (103±15 vs. 97±16 cm), a higher systolic blood pressure (137±17 vs. 133±18 mmHg), higher triglyceride (152±99 vs. 133±94 mg/dl) and lower HDL-C (53±19 vs. 59±19) plasma levels. In addition, DPN patients more frequently suffered from other diabetic complications: micro/macroalbuminuria (42.2% vs. 23.3%), moderate to severe renal failure (24.8% vs. 14.1%), retinopathy (39% vs. 25%), and foot complications (12.1% vs. 0.9%). There were no differences in gender or HbA1c. Multivariate analysis showed the following variables to be independently associated with DPN: age, diabetes duration, type 2 diabetes, nephropathy, retinopathy, foot problems and HDL-C. In conclusion, DPN and PDPN are frequent complications of diabetes that can be easily diagnosed with costless tools that do not require special expertise. The higher prevalence of DPN in type 2 diabetic patients could be due to the involvement of metabolic syndrome-associated disturbances. DPN and PDPN are often associated with other diabetic complications that should be looked for with the aim to optimize the patients' outcome. [ABSTRACT FROM AUTHOR]

The thermal grill illusion of pain is significantly increased in patients with fibromyalgia or irritable bowel syndrome. The thermal grill illusion of pain (TGIP) is a paradoxical burning pain sensation elicited by the simultaneous application of innocuous cutaneous warm and cold stimuli with a thermode ("thermal grill") consisting of interlaced heated and cooled bars. Its neurophysiological mechanisms are unclear, but TGIP may have some mechanisms in common with pathological pain, including central sensitization in particular, through the involvement of N-methyl- d -aspartate receptors. However, few studies have investigated TGIP in patients with chronic pain and its clinical relevance is uncertain. We hypothesized that the TGIP would be increased in comparison with controls in patients with fibromyalgia or irritable bowel syndrome, which are regarded as typical "nociplastic" primary pain syndromes related to changes in central pain processing. We compared the sensations elicited by a large range of combinations of temperature differentials between the warm and cold bars of a thermal grill applied to the hand between patients with fibromyalgia (n = 30) or irritable bowel syndrome (n= 30) and controls (n = 30). The percentage of TGIP responses and the intensity and unpleasantness of TGIP were significantly greater in patients than controls. Furthermore, positive correlations were found between TGIP intensity and clinical pain intensity and between TGIP intensity and the cold pain threshold measured on the hand. These results are consistent with our working hypothesis of shared mechanisms between TGIP and clinical pain mechanisms in patients with nociplastic chronic pain syndromes and suggest that TGIP might represent a clinical marker of central sensitization in these patients. [ABSTRACT FROM AUTHOR]

Patients with active chronic inflammatory rheumatism have impaired diffuse noxious inhibitory control, as assessed by conditioned pain modulation. The decrease in diffuse noxious inhibitory control was correlated with pain intensity. Persistent pain despite satisfactory disease treatment is frequent in rheumatoid arthritis (RA) and spondyloarthritis (Spa) and may result from specific changes in central pain processing. We assessed these mechanisms further by systematically comparing thermal pain thresholds and conditioned pain modulation (CPM) between patients with active RA or Spa and healthy controls. We included 50 patients with RA and 50 patients with Spa and 100 age-matched and sex-matched controls. Heat and cold pain thresholds (HPT-CPT) were measured on the dominant forearm, and CPM was assessed by applying conditioning stimuli (immersion in a cold-water bath) to one foot and the nondominant hand in 2 successive randomized sequences. Descending pain modulation was assessed as the difference in HPTs (in °C) before and after conditioning. Larger HPT differences (ie, a larger CPM effect) reflected more efficient descending inhibition. Potential associations between changes in CPM and clinical data, including disease activity, pain intensity, and psychological and functional variables, were systematically assessed. Heat pain threshold and cold pain threshold were similar in patients and controls. The mean CPM effect was significantly weaker in patients than that in controls for conditioning applied to either the foot (0.25°C ±2.57 vs 2.79°C ±2.31; P < 0.001) or the nondominant hand (0.57°C ±2.74 vs 2.68°C ±2.12; P < 0.001). The smaller CPM effect in patients was correlated with average pain intensity, but not with disease activity or other clinical characteristics, suggesting a significant pathophysiological role for changes in endogenous pain modulation in the mechanisms of chronic pain associated with inflammatory rheumatism. [ABSTRACT FROM AUTHOR]

Objectives: Neurological complications including pain are common after treatment for breast cancer. This prospective study investigated the symptoms, intensity and interference of chemotherapy-induced peripheral neuropathy. (CIPN) in the feet and hands compared to surgery- and radiation-induced neuropathy in the breast and upper arm. Methods: Consecutive patients referred to surgery for breast cancer were included in a prospective study and completed a questionnaire at baseline and a follow-up questionnaire and interview after one year. CIPN was assessed with the CIPN20 questionnaire and the Michigan Neuropathy Screening Instrument questionnaire (MNSIq). Pain intensity was rated on a numeric rating scale (NRS, 0-10). Results: In total 144 patients were included, of which 73 received chemotherapy. At one-year follow-up, symptoms of polyneuropathy were more common in patients treated with chemotherapy. Tingling or numbness in the feet in those treated/not treated with chemotherapy was reported by 44 (62%) and 15 (21%), respectively. Pain was present in 22 (30%) and 10 (14%), respectively. Pain in the area of surgery was reported by 66 (46%). Although less common, pain in the feet in those treated with chemotherapy was rated as more intense and with more daily life interference than pain in the surgical area (NRS 5.5 (SD 1.9) vs. 3.1 (SD 1.9). Conclusions: Neurological complications including pain following surgery and chemotherapy represent a burden to breast cancer survivors. In those who had received chemotherapy, pain in the feet was less common than pain in the surgical area, but pain in the feet was more intense and had a higher interference with daily life. Our study emphasizes the need for either baseline data or a control population for improved estimation of the presence and severity of CIPN and pain from questionnaires. [ABSTRACT FROM AUTHOR]

Abstract: Neuropathic pain highly affects quality of life, well-being, and function. It has recently been shown based on cluster analysis studies that most patients with neuropathic pain may be categorized into 1 of 3 sensory phenotypes: sensory loss, mechanical hyperalgesia, and thermal hyperalgesia. If these phenotypes reflect underlying pathophysiological mechanisms, they may be more relevant for patient management than underlying neurological diagnosis or pain intensity. The aim of this study was thus to examine the impact of these sensory phenotypes on mental health, functionality, and quality of life. Data of 433 patients from the IMI/EuroPain network database were analyzed, and results of HADS-D/A, Pain Catastrophizing Scale, Euro Quality of Life 5D/-VAS, Brief Pain Inventory, and Graded Chronic Pain Scale between the sensory phenotypes were compared using multiple regression analysis. There was no difference in chronic pain grade, pain intensity, depression, or anxiety scores between phenotypes. Pain interference (Brief Pain Inventory) was higher (P = 0.002); self-reported health state lower (Euro Quality of Life 5D VAS, P = 0.02); and problems regarding mobility (P = 0.008), usual activities (P = 0.004), and self-care (P = 0.039) more prominent (EQ5-D) in the sensory loss compared with the thermal hyperalgesia phenotype. Patients with sensory loss also showed higher pain catastrophizing scores (P = 0.006 and 0.022, respectively) compared with the 2 other groups. Sensory phenotype is associated with the impact of neuropathic pain conditions on well-being, daily functionality, and quality of life but is less associated with pain intensity. These results suggest that the somatosensory phenotype should be considered for personalized pain management. [ABSTRACT FROM AUTHOR]

Abstract: This manuscript aimed to characterize the clinical profile of various neuropathic pain (NeP) disorders and to identify whether patterns of sensory symptoms/signs exist, based on baseline responses on the Neuropathic Pain Symptom Inventory (NPSI) questionnaire and the quantitative sensory testing (QST). These post hoc analyses were based on data from 4 randomized, double-blind, placebo-controlled clinical studies of pregabalin (150–600mg/day) in patients with NeP syndromes: central poststroke pain, posttraumatic peripheral pain, painful HIV neuropathy, and painful diabetic peripheral neuropathy. The NPSI questionnaire includes 10 different pain symptom descriptors. QST was used to detect sensory thresholds of accurately calibrated sensory stimuli and to quantify the intensity of evoked sensation. To identify symptoms/signs clusters and select the number of clusters, a principal component analysis (PCA) and hierarchical clustering methods with clinical input were used. Analysis of the NPSI pain qualities and individual QST measures at baseline indicated no clear association between particular symptoms/signs profiles and etiologies. Based on NPSI symptoms, PCA identified 3 pain dimensions: provoked, deep, and pinpoint. A hierarchical cluster analysis identified 3 clusters with distinct pain characteristics profiles independent of NeP syndrome. Based on QST signs, PCA identified 2 pain dimensions: evoked by cold and evoked by touch. A hierarchical cluster analysis identified 4 clusters with distinct pain characteristics profiles. These “trans-etiological” profiles may reflect distinct pathophysiological mechanisms and therefore, potential differential responses to treatment. [Copyright &y& Elsevier]

Abstract: We compared the effects of systemic morphine on normal (heat and cold) pain and paradoxical burning pain evoked by the simultaneous application of innocuous warm and cold stimuli to the skin. Twelve healthy volunteers participated in a randomised, double-blind, cross-over study to compare the effects of intravenous administration of morphine (0.025 or 0.1mg/kg) or placebo (saline). Stimuli were applied to the palm of the right hand with a thermode (“thermal grill”) composed of six bars, whose temperatures were controlled by Peltier elements. For each session, we measured the heat and cold pain thresholds and then successively measured the intensity of: (i) paradoxical pain evoked by a combination of non-noxious warm and cold stimuli; (ii) “normal” pain evoked by suprathreshold heat or cold stimuli; (iii) non-painful sensations evoked by warm or cold stimuli at temperatures used to produce paradoxical pain. Measurements were performed before 20min after the administration of morphine or placebo and 5min after the administration of the morphine antagonist, naloxone. The administration of 0.1mg/kg of morphine, but not 0.025mg/kg, induced a significant and naloxone-reversible reduction of paradoxical pain intensity, which was directly correlated with the reduction of normal cold pain. No differences were observed for non-painful thermal sensations. The paradoxical burning pain evoked by a thermal grill can be modified pharmacologically by analgesics and share some mechanisms with normal pain. This unique experimental “illusion of pain” may represent a new model to test analgesics in healthy volunteers. [Copyright &y& Elsevier]

Pain is a frequent, but poorly studied symptom of Parkinson's disease (PD). DoPaMiP survey aimed to assess the prevalence of chronic pain in PD, to describe PD patients with chronic pain, and to record analgesic consumption. About 450 parkinsonian patients underwent structured standardized clinical examination and completed self-reported questionnaires in a cross sectional survey. Pains related or unrelated to PD were identified according to predefined criteria. About 98 patients with other chronic disorders than PD were examined to assess if pain was more frequent in PD than in this population. Two thirds parkinsonian patients (278 of 450) had chronic pain. Twenty-five patients with non-chronic pain (<3-month duration) were excluded from subsequent analysis. Twenty six percent (111 of 425) parkinsonian patients had pain unrelated to PD ('non-PD-pain', caused mainly by osteoarthritis), while 39.3% (167 of 425) had chronic pain related to PD ('PD-pain'). In this last group, PD was the sole cause of pain in 103 and indirectly aggravated pain of another origin (mainly osteoarthritis) in 64. Parkinsonian patients with 'PD-pain' were younger at PD onset, had more motor complications, more severe depressive symptoms than those without pain or with 'non-PD pain.' 'PD-pain' was more intense ( P = 0.03), but was less frequently reported to doctors ( P = 0.02), and was associated with less frequent analgesic consumption than 'non-PD-pain.' Pain was twice more frequent in PD patients than in patients without PD after adjustment for osteo-articular comorbidities (OR = 1.9; 95% CI 1.2-3.2). Chronic pain is frequent but underreported in PD. Awareness of this problem should be increased and the assessment of analgesic strategies improved. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Abstract: There is no current consensus on the taxonomy of the different forms of idiopathic orofacial pain (stomatodynia, atypical odontalgia, atypical facial pain, facial arthromyalgia), which are sometimes considered as separate entities and sometimes grouped together. In the present prospective multicentric study, we used a systematic approach to help to place these different painful syndromes in the general classification of chronic facial pain. This multicenter study was carried out on 245 consecutive patients presenting with chronic facial pain (>4 months duration). Each patient was seen by two experts who proposed a diagnosis, administered a 111-item questionnaire and filled out a standardized 68-item examination form. Statistical processing included univariate analysis and several forms of multidimensional analysis. Migraines (n=37), tension-type headache (n=26), post-traumatic neuralgia (n=20) and trigeminal neuralgia (n=13) tended to cluster independently. When signs and symptoms describing topographic features were not included in the list of variables, the idiopathic orofacial pain patients tended to cluster in a single group. Inside this large cluster, only stomatodynia (n=42) emerged as a distinct homogenous subgroup. In contrast, facial arthromyalgia (n=46) and an entity formed with atypical facial pain (n=25) and atypical odontalgia (n=13) could only be individualised by variables reflecting topographical characteristics. These data provide grounds for an evidence-based classification of idiopathic facial pain entities and indicate that the current sub-classification of these syndromes relies primarily on the topography of the symptoms. [Copyright &y& Elsevier]

Repetitive transcranial magnetic stimulation (rTMS) has been proposed to treat neuropathic pain but the quality of evidence remains low. We aimed to assess the efficacy and safety of neuronavigated rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in neuropathic pain over 25 weeks. We carried out a randomized double-blind, placebo-controlled trial at four outpatient clinics in France. Patients aged 18-75 years with peripheral neuropathic pain were randomly assigned at a 1:1 ratio to M1 or DLPFC-rTMS and rerandomized at a 2:1 ratio to active or sham-rTMS (10 Hz, 3000 pulses/session, 15 sessions over 22 weeks). Patients and investigators were blind to treatment allocation. The primary end point was the comparison between active M1-rTMS, active DLPCF-rTMS and sham-rTMS for the change over the course of 25 weeks (Group × Time interaction) in average pain intensity (from 0 no pain to 10 maximal pain) on the Brief Pain Inventory, using a mixed model repeated measures analysis in patients who received at least one rTMS session (modified intention-to-treat population). Secondary outcomes included other measures of pain intensity and relief, sensory and affective dimensions of pain, quality of pain, self-reported pain intensity and fatigue (patients diary), Patient and Clinician Global Impression of Change (PGIC, CGIC), quality of life, sleep, mood and catastrophizing. This study is registered with ClinicalTrials.gov NCT02010281. A total of 152 patients were randomized and 149 received treatment (49 for M1; 52 for DLPFC; 48 for sham). M1-rTMS reduced pain intensity versus sham-rTMS (estimate for Group × Session interaction: -0.048 ± 0.02; 95% CI: -0.09 to -0.01; P = 0.01). DLPFC-rTMS was not better than sham (estimate: -0.003 ± 0.01; 95% CI: -0.04 to 0.03, P = 0.9). M1-rRMS, but not DLPFC-rTMS, was also superior to sham-rTMS on pain relief, sensory dimension of pain, self-reported pain intensity and fatigue, PGIC and CGIC. There were no effects on quality of pain, mood, sleep and quality of life as all groups improved similarly over time. Headache was the most common side effect and occurred in 17 (34.7%), 23 (44.2%) and 13 (27.1%) patients from M1, DLPFC and sham groups, respectively (P = 0.2). Our results support the clinical relevance of M1-rTMS, but not of DLPFC-rTMS, for peripheral neuropathic pain with an excellent safety profile. [ABSTRACT FROM AUTHOR]

Abstract: Pain is a common nonmotor symptom in patients with Parkinson disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into 3 groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory and McGill pain questionnaire [MPQ], PDQ-8 quality of life score, MDS-UPDRS scores, and nonmotor symptoms). 159 nondemented PD patients (disease duration 10.2 ± 7.6 years) and 37 healthy controls were recruited in 4 centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's Brief Pain Inventory and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression, and anxiety measures. Moderate intrarater and interrater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain. [ABSTRACT FROM AUTHOR]

Abstract: The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire. A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia are just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy, whereas hyperalgesia was more frequent in painful mononeuropathy (compared with painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions. Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide and that painful and painless neuropathic conditions may mechanistically blend into one another. [ABSTRACT FROM AUTHOR]

Background Pain is one of the main symptoms associated with spinal cord injury (SCI) and can be associated with changes to the central nervous system (CNS). Purpose This article provides an overview of the evidence relating to CNS changes (structural and functional) associated with pain in SCIs. Data Sources A systematic review was performed, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations, on PubMed, Embase, and Web of Science in March 2018. Study Selection Studies were selected if they concerned changes in the CNS of patients with SCI, regardless of the type of imagery. Data Extraction Data were extracted by 2 blinded reviewers. Data Synthesis There is moderate evidence for impaired electroencephalographic function and metabolic abnormalities in the anterior cingulate in patients experiencing pain. There is preliminary evidence that patients with pain have morphological and functional changes to the somatosensory cortex and alterations to thalamic metabolism. There are conflicting data regarding the relationships between lesion characteristics and pain. In contrast, patients without pain can display protective neuroplasticity. Limitations and Conclusion Further studies are required to elucidate fully the relationships between pain and neuroplasticity in patients with SCIs. However, current evidence might support the use of physical therapist treatments targeting CNS plasticity in patients with SCI pain. [ABSTRACT FROM AUTHOR]

Chronic eye pain, which has previously been assumed to be due to ocular surface abnormalities (ie, "dry eye [DE] disease"), has recently garnered attention as a potential indicator of neuropathic ocular pain in some patients. The purpose of this study was to evaluate the psychometric properties of a modified version of the Neuropathic Pain Symptom Inventory in individuals with eye pain (NPSI-Eye). Enrolled participants (n = 397) completed the NPSI-Eye, general pain severity questionnaires, DE symptom report, and psychological health indices. Participants also underwent mechanical pain sensitivity testing of the cornea, tear film assessment, and evaluation of the efficacy of anesthetic eye drops to relieve pain. Short-term test-retest reliability of the NPSI-Eye was excellent (intraclass correlation coefficient = 0.98, P < 0.001). Correlations between the NPSI-Eye and indicators of general eye pain were ≥0.65 (P < 0.001), whereas correlations between the NPSI-Eye and DE symptom severity and psychological health indices were lower (rho = 0.56, 0.32, 0.37; all P < 0.001). Individuals who reported little or no decrease in pain after anesthetic eye drops (hypothesized to indicate eye pain with at least partial central involvement) had significantly higher NPSI-Eye scores than participants whose eye pain was completely relieved by anesthetic (P < 0.05). Overall, our results support preliminary validation of the NPSI-Eye, yielding similar metrics to those reported in Bouhassira et al.'s original NPSI publication (2004). However, additional evaluation and refinement of some questions may be desirable, including the potential elimination of items that were not highly endorsed. [ABSTRACT FROM AUTHOR]

Women with hormone-dependent breast cancer are treated with aromatase inhibitors (AI) to slow disease progression by decreasing estrogen levels. However, AI have adverse effects, including pain, with potentially serious impact on quality of life (QOL) and treatment compliance. We evaluated quality of life during the first year of AI treatment, focusing particularly on the impact of pain. In a multicenter cohort study of 135 women with early-stage breast cancer, free of pain at the initiation of AI treatment, quality of life (by the EORTC QLQ-BR23), somatic and psychic symptoms, psychological characters, temperament and coping strategies were assessed at baseline and at each follow-up visit (1, 3, 6 and 12 months). The impact of treatment-induced pain on quality of life during follow-up was determined with repeated-measures regression models. These models were constructed to assess the effects of pain and pain type on quality of life during follow-up, taking into account predictors associated with quality of life at baseline. Prior ganglion resection, taxane treatment and chemotherapy, a high amplification score on the pain catastrophizing scale, and a high harm avoidance score on the personality questionnaire were associated with a significantly lower baseline QOL. Fifty-seven percent of women developed pain of five different types: upper or lower limb joint pain, diffuse pain, neuropathic pain, tendon pain and mixed pain. A significant decrease in QOL was noted in the women with pain, particularly for body image, sexual functioning and future perspectives. Moreover, the impact of pain on QOL depended on the type of pain experienced. In conclusion, women treated with aromatase inhibitors display changes in quality of life and the degree of change in quality of life depends mostly on the type of pain experienced. Oncologists and patients should be aware of painful adverse effects of AI and encouraged to provide or receive earlier and more appropriate management of these effects. [ABSTRACT FROM AUTHOR]

Background and Aim The Fibromyalgia Rapid Screening Tool (Fi RST) is a brief, simple, and straightforward self-administered questionnaire that was developed by Perrot et al. for the detection of fibromyalgia syndrome in patients with diffuse chronic pain. The aim of our study was to develop and validate the Greek version of Fi RST. Methods The study was set up as a prospective observational study. The original French version of Fi RST was adapted into Greek using forward and backward translation. Patients with chronic diffuse pain with a clinical diagnosis of fibromyalgia and osteoarthritis based on the criteria of the American College of Rheumatology were invited to participate to the study. Results Of the 101 patients who met our inclusion criteria, 42 were diagnosed with fibromyalgia and 59 with osteoarthritis. The 2 groups did not differ significantly regarding gender and pain characteristics (duration, intensity). Cronbach's alpha coefficient was 0.79. Receiver operating characteristic analysis showed an area under the curve of 89% (95% confidence interval = 83 to 95%; SE: 0.032, P < 0.001). At a cutoff score of ≥ 5, Fi RST showed a sensitivity of 86%, a specificity of 83%, a positive predictive value of 78%, and a negative predictive value of 89%. The intraclass coefficient for the test-retest reliability was 0.96. Conclusion The Greek version of Fi RST is a valid screening tool for fibromyalgia in daily practice. [ABSTRACT FROM AUTHOR]

In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5. [ABSTRACT FROM AUTHOR]

Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: The association between inadequate sleep and type 2 diabetes has garnered much attention, but little is known about sleep and type 1 diabetes (T1D). Our objectives were to conduct a systematic review and meta-analysis comparing sleep in persons with and without T1D, and to explore relationships between sleep and glycemic control in T1D.Methods: Studies were identified from Medline and Scopus. Studies reporting measures of sleep in T1D patients and controls, and/or associations between sleep and glycemic control, were selected.Results: A total of 22 studies were eligible for the meta-analysis. Children with T1D had shorter sleep duration (mean difference [MD] = -26.4 minutes; 95% confidence interval [CI] = -35.4, -17.7) than controls. Adults with T1D reported poorer sleep quality (MD in standardized sleep quality score = 0.51; 95% CI = 0.33, 0.70), with higher scores reflecting worse sleep quality) than controls, but there was no difference in self-reported sleep duration. Adults with TID who reported sleeping >6 hours had lower hemoglobin A1c (HbA1c) levels than those sleeping ≤6 hours (MD = -0.24%; 95% CI = -0.47, -0.02), and participants reporting good sleep quality had lower HbA1c than those with poor sleep quality (MD = -0.19%; 95% CI = -0.30, -0.08). The estimated prevalence of obstructive sleep apnea (OSA) in adults with TID was 51.9% (95% CI = 31.2, 72.6). Patients with moderate-to-severe OSA had a trend toward higher HbA1c (MD = 0.39%, 95% CI = -0.08, 0.87).Conclusion: T1D was associated with poorer sleep and high prevalence of OSA. Poor sleep quality, shorter sleep duration, and OSA were associated with suboptimal glycemic control in T1D patients. [ABSTRACT FROM AUTHOR]

No study has directly compared the effectiveness of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) in neuropathic pain (NP). In this 2-centre randomised double-blind sham-controlled study, we compared the efficacy of 10-Hz rTMS and anodal 2-mA tDCS of the motor cortex and sham stimulation contralateral to the painful area (3 daily sessions) in patients with NP due to lumbosacral radiculopathy. Average pain intensity (primary outcome) was evaluated after each session and 5 days later. Secondary outcomes included neuropathic symptoms and thermal pain thresholds for the upper limbs. We used an innovative design that minimised bias by randomly assigning patients to 1 of 2 groups: active rTMS and tDCS or sham rTMS and tDCS. For each treatment group (active or sham), the order of the sessions was again randomised according to a crossover design. In total, 51 patients were screened and 35 (51% women) were randomized. Active rTMS was superior to tDCS and sham in pain intensity (F = 2.89 and P = 0.023). Transcranial direct-current stimulation was not superior to sham, but its analgesic effects were correlated to that of rTMS (P = 0.046), suggesting common mechanisms of action. Repetitive transcranial magnetic stimulation lowered cold pain thresholds (P = 0.04) and its effect on cold pain was correlated with its analgesic efficacy (P = 0.006). However, rTMS had no impact on individual neuropathic symptoms. Thus, rTMS is more effective than tDCS and sham in patients with NP due to lumbosacral radiculopathy and may modulate the sensory and affective dimensions of pain. [ABSTRACT FROM AUTHOR]

Background: Data from previous studies suggest that botulinum toxin A has analgesic effects against peripheral neuropathic pain, but the quality of the evidence is low. We aimed to assess the safety and efficacy of repeated administrations of botulinum toxin A in patients with neuropathic pain.Methods: We did a randomised, double-blind, placebo-controlled trial at two outpatient clinics in France (Clinical Pain Centre, Ambroise Paré Hospital, APHP, Boulogne-Billancourt, and Neurological Centre, Hôpital Dupuytren, Limoges) and one in Brazil (Neurological Department, Hospital das Clínicas da FMUSP, São Paulo). Patients aged 18-85 years with peripheral neuropathic pain were randomly assigned (1:1) by block randomisation, according to a centralised schedule, to receive two subcutaneous administrations of botulinum toxin A (up to 300 units) or placebo, 12 weeks apart. All patients and investigators were masked to treatment assignment. The primary outcome was the efficacy of botulinum toxin A versus placebo, measured as the change from baseline in self-reported mean weekly pain intensity over the course of 24 weeks from the first administration. The primary efficacy analysis was a mixed-model repeated-measures analysis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01251211.Findings: Between Oct 2, 2010, and Aug 2, 2013, 152 patients were enrolled, of whom 68 were randomly assigned (34 per group), and 66 (37 [56%] men) were included in the primary analysis (34 in the botulinum toxin A group and 32 in the placebo group). Botulinum toxin A reduced pain intensity over 24 weeks compared with placebo (adjusted effect estimate -0·77, 95% CI -0·95 to -0·59; p<0·0001). Pain on injection was the only adverse effect reported, and occurred in 19 (56%) participants in the botulinum toxin A group and 17 (53%) of those in the placebo group (p=1·0). Severe pain was experienced by ten (29%) participants in the botulinum toxin A group and 11 (34%) in the placebo group (p=0·8).Interpretation: Two administrations of botulinum toxin A, each of which comprised several injections, have a sustained analgesic effect against peripheral neuropathic pain. Several factors, such as the presence of allodynia and a limited thermal deficit, may be useful in predicting treatment response and should be investigated further.Funding: Institut National de la Santé et de la Recherche Médicale (INSERM) and Fondation CNP (France). [ABSTRACT FROM AUTHOR]

Surgical nerve injury sometimes leads to chronic postsurgical neuropathic pain (CPSNP). The risk factors for this condition are not well understood. We prospectively assessed 46 patients scheduled for iliac crest bone harvest, 2 days (D2) and 3 months (M3) after surgery, to determine the time course of nerve fiber degeneration and expression of the TNF-α and NGF genes in skin punch biopsies. Mechanical and thermal detection and pain thresholds were evaluated at D2 and M3, by quantitative sensory testing. Skin punch biopsies were also obtained from the thighs ipsilateral and contralateral to iliac crest bone harvest. Intraepidermal nerve fiber density (IENFD) and cutaneous TNF-α and NGF gene expression were analyzed. Forty-five volunteers matched for age, sex, skin color were examined as controls. Chronic postsurgical neuropathic pain was defined as pain in an area of hypesthesia with a positive Douleur Neuropathique 4 questionnaire score. Overall, 73% (N = 32) of patients developed hypesthesia and 40% (N = 13) of these patients had developed CPSNP at M3. Quantitative sensory testing results, IENFD, and skin TNF-α and NGF gene expression at D2 and M3 did not differ between patients with and without CPSNP. However, in patients with CPSNP, burning, compression, and pain provoked by brushing were correlated with IENFD at M3, suggesting a possible association between partial nerve lesions and more intense CPSNP, than with total nerve lesion. Furthermore, preoperative pain and opioid use were higher in patients who developed CPSNP than in those without CPSNP. These findings suggest that the predictors of CPSNP development are clinical rather than histological or biochemical. [ABSTRACT FROM AUTHOR]

For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic "entry level" set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of "possible" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC "entry level" set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability. [ABSTRACT FROM AUTHOR]

Clinical and human experimental pain studies often include so-called "healthy" controls in investigations of sensory abnormalities, using quantitative sensory testing (QST) as an outcome measure. However, the criteria for what is considered "healthy" vary among the different studies and between study centers and investigators, partly explaining the high variability of the results. Therefore, several aspects should be considered during inclusion of healthy volunteers in QST-based trials to have homogenous groups of healthy controls with less variability between human experimental studies, so that results are less likely to be false negative or false positive because of subject-related factors. The EUROPAIN and NEUROPAIN consortia aimed to define factors influencing the variability in selection of healthy subjects in QST-based studies before the start of both projects and to give recommendations how to minimize it based on the current literature and expertise of the participants. The present suggestions for inclusion criteria of healthy volunteers into QST-based trials describe a 2-level approach including standardized questionnaires enabling the collection of relevant information on sociodemographic data, medical history, current health status, coping strategies in dealing with pain, and the motivation of the volunteer to participate in the study. These suggestions are believed to help researchers interpret their results in comparison with others and improve the quality of clinical studies including healthy volunteers as controls or in human experimental pain studies. They aim to reduce any confounding factors. Furthermore, the acquired information will allow post hoc analyses of variance for different potential influencing factors. [ABSTRACT FROM AUTHOR]

The simultaneous application of innocuous cutaneous warm and cold stimuli with a thermal grill can induce both paradoxical pain and paradoxical warmth (heat). The goal of this study was to investigate further the relationships between these paradoxical sensations. Stimuli were applied to the palms of the right hands of 21 volunteers with a thermode consisting of 6 bars, the temperature of which was controlled by Peltier elements. We assessed the quality and intensity of the sensations evoked by series of stimuli consisting of progressively colder temperatures combined with a series of given warm temperatures. We applied a total of 116 series of stimuli, corresponding to 785 combinations of warm and cold temperatures. The 2 paradoxical phenomena were reported for most of the series of stimuli (n = 66). In each of these series, the 2 phenomena occurred in the same order: paradoxical warmth followed by paradoxical pain. The difference between the cold–warm temperatures eliciting paradoxical warmth was significantly smaller than that producing paradoxical pain. The intensities of the warmth and unpleasantness evoked by the stimuli were directly related to the magnitude of the warm–cold differential. Our results suggest that there is a continuum between the painful and nonpainful paradoxical sensations evoked by the thermal grill that may share pathophysiological mechanisms. These data also confirm the existence of strong relationships between the thermoreceptive and nociceptive systems and the utility of the thermal grill for investigating these relationships. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives The objective was to compare the extent of pain interference and pain medication among persons who were classified as obese [body mass index ( BMI) ≥30 kg m−2] and normal weighted ( BMI ≤25 kg m−2), before a hip or knee replacement surgery. Methods Patients candidate for an orthopaedic surgery were successively enrolled, over a 6-month period, and classified in either the normal weight ( BMI ≤25 kg m−2) or the obese ( BMI ≥30 kg m−2) categories. Data were collected using self-administered questionnaires with items concerning pain characteristics, pain medication and pain interference. Two standardized questionnaires were associated: the Brief Pain Inventory ( BPI) and the Hospital Anxiety and Depression scale ( HAD). Results Fifty-two obese patients (candidates for 24 hip replacements and 28 knee replacements) and 51 non-obese (23 hip replacements and 28 knee replacements) were enrolled. Obese patients suffered from a higher rate of acute pain episodes than non-obese patients (65 versus 44%, P < 0.05). Pain interference on walking distance, sleep and relations with others was higher in obese patients. HAD score showed no significant difference between groups. The use of strong opioids and of non-steroidal anti-inflammatory drugs ( NSAIDs) was significantly more important in obese patients (13 versus 0% and 31 versus 14%). Conclusions Obese patients suffer more significantly of unrelieved chronic pain, which lowers considerably their quality of life. Pain relief is more difficult to obtain, as it requires stronger pain medication and NSAIDs. [ABSTRACT FROM AUTHOR]

The aim of our study was translation and assessment of validity and reliability of the Persian version of DN4 questionnaire. The goal was to fill the gap caused by the absence of a validated instrument in Persian to facilitate discrimination of neuropathic pain. In this study, the adaptation and validation of the questionnaire was carried out in 4 steps, including translation, retranslation, semantic, and literal assessments, and a pilot study for practicability and potential perception difficulties of the final Persian version on 45 patient samples. The questionnaire validation performed on 175 patients, 112 (64%) females with the mean age of 52.53 ( SD = 14.98) ranging from 22 to 87 years of age with neuropathic ( N = 86) and non-neuropathic pain ( NNP) ( N = 89). Sensitivity, specificity, and Youden Index in cut-off point ≥ 4 were 90%, 95%, and 0.85, respectively, which are noteworthy findings among other validation studies. The Cronbach's alpha coefficient of the whole questionnaire was 0.852. Inter-rater agreement and test-retest reliability were significant intraclass coefficient ( ICC = 0.957 and ICC = 0.918, respectively). The Persian version of DN4 questionnaire is a reliable, valid, feasible, and easily administered tool for precise discrimination neuropathic pain from NNP in Farsi. The characteristics of this test can assist practitioner to diagnose neuropathic pain accurately for both clinical and research purposes. [ABSTRACT FROM AUTHOR]

Background and aims: The French Pain Society published guidelines for neuropathic pain management in 2010. Our aim was to evaluate the compliance of GPs with these guidelines three years later. Methods: We used “e” case vignette methodology for this non interventional study. A national panel of randomly selected GPs was included. We used eight “e” case-vignettes relating to chronic pain, differing in terms of the type of pain (neuropathic/non neuropathic), etiology (cancer, postoperative pain, low back pain with or without radicular pain, diabetes) and symptoms. GPs received two randomly selected consecutive “e” case vignettes (with/without neuropathic pain). We analyzed their ability to recognize neuropathic pain and to prescribe appropriate first-line treatment. Results: From the 1265 GPs in the database, we recruited 443 (35.0%), 334 of whom logged onto the web site (26.4%) and 319 (25.2%) of whom completed the survey. Among these GPs, 170 (53.3%) were aware of the guidelines, 136 (42.6%) were able to follow them, and 110 (34.5%) used the DN4 diagnostic tool. Sensitivity for neuropathic pain recognition was 87.8% (CI: 84.2%; 91.4%). However, postoperative neuropathic pain was less well diagnosed (77.9%; CI: 69.6%; 86.2%) than diabetic pain (95.2%; CI: 90.0%; 100.0%), cancer pain (90.6%; CI: 83.5%; 97.8%) and typical radicular pain (90.7%; CI: 84.9%; 96.5%). When neuropathic pain was correctly recognized, the likelihood of appropriate first-line treatment prescription was 90.6% (CI: 87.4%; 93.8%). The treatments proposed were pregabaline (71.8%), gabapentine (43.9%), amiptriptylline (23.2%) and duloxetine (18.2%). However, ibuprofen (11%), acetaminophen-codeine (29.5%) and clonazepam (10%) were still prescribed. Conclusions: The compliance of GPs with clinical practice guidelines appeared to be satisfactory, but differed between etiologies. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the role of glutamate N-methyl-d-aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double-blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15mg/kg in a 10-minute bolus followed by continuous infusion of 6μg/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor-evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS-induced analgesia. Ketamine injection significantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not influenced by rTMS following the administration of either saline or ketamine. Thus, rTMS-induced analgesia depends on glutamate NMDA receptors and may involve long-term potentiation-like mechanisms. [Copyright &y& Elsevier]

Chronic pain impairs cognition but whether cognitive function may predict chronic pain is unknown. In a prospective surgical cohort, Attal et al. show that limited cognitive flexibility and memory capacity, as assessed using simple neuropsychological tests, predict the occurrence of chronic pain at 6 and 12 months post-surgery.It is well established that chronic pain impairs cognition, particularly memory, attention and mental flexibility. Overlaps have been found between the brain regions involved in pain modulation and cognition, including in particular the prefrontal cortex and the anterior cingulate cortex, which are involved in executive function, attention and memory. However, whether cognitive function may predict chronic pain has not been investigated. We addressed this question in surgical patients, because such patients can be followed prospectively and may have no pain before surgery. In this prospective longitudinal study, we investigated the links between executive function, visual memory and attention, as assessed by clinical measurements and the development of chronic pain, its severity and neuropathic symptoms (based on the ‘Douleur Neuropathique 4’ questionnaire), 6 and 12 months after surgery (total knee arthroplasty for osteoarthritis or breast surgery for cancer). Neuropsychological tests included the Trail-Making Test A and B, and the Rey-Osterrieth Complex Figure copy and immediate recall, which assess cognitive flexibility, visuospatial processing and visual memory. Anxiety, depression and coping strategies were also evaluated. In total, we investigated 189 patients before surgery: 96% were re-evaluated at 6 months, and 88% at 12 months. Multivariate logistic regression (stepwise selection) for the total group of patients indicated that the presence of clinical meaningful pain at 6 and 12 months (pain intensity ≥ 3/10) was predicted by poorer cognitive performance in the Trail Making Test B (P = 0.0009 and 0.02 for pain at 6 and 12 months, respectively), Rey-Osterrieth Complex Figure copy (P = 0.015 and 0.006 for pain at 6 and 12 months, respectively) and recall (P = 0.016 for pain at 12 months), independently of affective variables. Linear regression analyses indicated that impaired scores on these tests predicted pain intensity (P < 0.01) and neuropathic symptoms in patients with pain (P < 0.05), although the strength of the association was less robust for neuropathic symptoms. These results were not affected by the type of surgery or presurgical pain, similar findings being obtained specifically for patients who initially had no pain. In conclusion, these findings support, for the first time, the notion that premorbid limited cognitive flexibility and memory capacities may be linked to the mechanisms of pain chronicity and probably also to its neuropathic quality. This may imply that patients with deficits in executive functioning or memory because of cerebral conditions have a greater risk of pain chronicity after a painful event. [ABSTRACT FROM AUTHOR]

Background: In a context of change in the demographic profile of the older population, to identify an age threshold for increased risk and burden of herpes zoster (HZ) in 70+ patients. Methods: Post hoc analysis of the 12-month French nationwide prospective observational ARIZONA cohort study. HZ was assessed by means of the following validated questionnaires: Neuropathic Pain Symptom Inventory (NPSI), Zoster Brief Pain Inventory (ZBPI), Short-Form health survey (SF-12), and Hospital Anxiety and Depression Scale (HADS). Results: 644 general practitioners included 1,358 volunteer patients with acute HZ in the ARIZONA study; 609 patients (45%) were 70+. In 70+ patients, age did not increase rash severity or HZ-related pain intensity at diagnosis, but increased by 64% the frequency of ophthalmic zoster (from 5.5% in 70–74 years age-group to 9.0% in 85+ patients, p = NS). Age was significantly associated with low physical health as assessed by the SF-12 Physical Component Summary (SF-12 PCS) score and bad mood as assessed by the HADS depression score (p < 0.001). Within the year following HZ, post-herpetic neuralgia (PHN) was systematically but not significantly more frequent in 85+ patients than in the 70–74, 75–79, or 80–84 years age-groups (19.0% vs. 13.3%/15.3%/11.6% at month 3; 15.1% vs. 7.3%/11.0%/12.2% at month 6; 15.2% vs. 6.0%/8.0%/6.0% at month 12, respectively). SF-12 PCS and HADS depression scores improved from day 0 to month 12 in all patients (p < 0.001). 85+ patients were more impaired than younger patients (p < 0.001), but without clear difference according to PHN. Conclusions: This study did not show in 70+ patients a clear and significant age threshold at which disease burden increased, although for some domains the impact seemed higher among the oldest patients; the cut-off of 70 years remains thus relevant for clinical and epidemiological studies. However, at individual level, assessment of the burden of HZ and HZ-related pain appears necessary to improve management and prevent functional decline in the most vulnerable 70+ patients. [ABSTRACT FROM AUTHOR]

This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated. [ABSTRACT FROM AUTHOR]

Abstract: Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods. [Copyright &y& Elsevier]