Neuropathic and Nociplastic Pain Profiles are Common in Adult Chronic Nonbacterial Osteitis (CNO).

Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21-41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41-64) of patients displayed central sensitization on CSI, 61% (50-72) screened positive for fibromyalgia on FiRST and 14% (7-23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4-5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach.

Incorporación a nivel nacional de tecnología no invasiva para valoración del dolor y/o disconfort neonatal / Incorporation of non-invasive technology for the assessment of neonatal pain and/or discomfort at national level / Incorporação a nível nacional de tecnologia não invasiva para avaliação da dor e/ou desconforto neonatal

Introducción: la exposición a estímulos dolorosos y estrés en la etapa neonatal, sin un correcto tratamiento, tiene consecuencias a corto y largo plazo. El diagnóstico adecuado es un desafío, ya que las escalas clínicas son subjetivas y se requieren herramientas de detección con mejor objetividad y capacidad de interpretación del disconfort/dolor neonatal. Newborn Infant Parasympathetic Evaluation (NIPE™) es una tecnología no invasiva de monitorización continua del dolor en neonatos, desarrollada recientemente dada la dificultad de objetivar el dolor mediante los métodos convencionales en la práctica clínica. Esta tecnología se basa en el análisis de la variabilidad de la frecuencia cardíaca (FC), lo que permite aproximarse a la actividad del sistema parasimpático. Objetivos: el objetivo de esta investigación fue valorar el disconfort en un modelo de cerdo recién nacido (RN) y en humanos neonatos expuestos a maniobras nociceptivas con la utilización de tecnología no invasiva (NIPE), en la maternidad del Hospital Universitario. Material y métodos: se realizó un estudio observacional, longitudinal, en seis cerdos RN, anestesiados, monitorizados hemodinámicamente y sometidos a un procedimiento quirúrgico mayor (toracotomía lateral izquierda con abordaje cardíaco, pericardiostomía y acceso vascular pulmonar transventricular derecho) y 12 procedimientos mínimamente invasivos de la práctica clínica habitual, como vacunación BCG, hemoglucotest y pesquisa, que generan un estímulo nociceptivo en ocho RN de término sanos. Se incluyeron RN sanos de término (EG entre 37-41 semanas más seis días) internados en el alojamiento conjunto madre-hijo, se excluyeron de la muestra los RN que presentaron alguna patología y aquellos cuyos padres no aceptaron la participación en el estudio. Resultados: se comparó la variabilidad de la FC mediante detección automatizada (NIPE™) para estimación objetiva del dolor/disconfort. Se comparó en la clínica con una escala validada y ampliamente utilizada en neonatos: Premature Infant Pain Profile (PIPP). Para valorar la asociación entre variables NIPE™ y FC se utilizaron correlación de Spearman, el test de Kruskall-Wallis o test de chi cuadrado con corrección de Fisher, según correspondiera. Se encontró una correlación negativa entre FC y NIPE™ tanto para el grupo de neonatos humanos (r=-1; p=0,008) como para el modelo animal (r=-0,6; p=0,0004). No se encontró asociación significativa entre NIPE™ y la escala PIPP. La variación entre valores de NIPE™ pre y posestímulo en RN humanos fue significativa (p=0,008). Conclusiones: determinamos que en ambos escenarios explorados los valores de NIPE™ descienden ante estímulos nociceptivos y los cambios en la FC se relacionan con sus valores, independientemente de la especie o la agresividad de la maniobra. Este trabajo es el primero a nivel nacional incorporando el uso de esta tecnología, creemos que tendrá impacto en la forma de evaluar y abordar el dolor por parte de los equipos asistenciales y de experimentación.

Introduction: exposure to painful stimuli and stress in the neonatal stage, without correct treatment, has short and long-term consequences. Proper diagnosis is a challenge since clinical scales are subjective, and we require more objective screening tools and a better ability to interpret neonatal discomfort/pain. Newborn Infant Parasympathetic Evaluation (NIPE™) is a non-invasive technology for continuous pain monitoring in neonates, recently developed given the difficulty to objectify pain using conventional methods in clinical practice. This technology is based on the analysis of heart rate variability (HR), which allows us to approximate the activity of the parasympathetic system. Objectives: the objective of this research was to assess discomfort in a newborn pig model (NB) and in human neonates exposed to nociceptive maneuvers with the use of non-invasive technology (NIPE), in the maternity ward of the University Hospital. Material and methods: an observational, longitudinal study was carried out in 6 NB pigs, anesthetized, hemodynamically monitored and subjected to a major surgical procedure (left lateral thoracotomy with cardiac approach, pericardiostomy and right trans ventricular pulmonary vascular access) and 12 minimally invasive procedures, from clinical practice. routine such as BCG vaccination, hemoglucotest and screening, which generate a nociceptive stimulus in 8 healthy term newborns. Healthy term newborns (GA between 37-41 weeks plus 6 days) admitted to the mother-child joint accommodation were included, We excluded those NB patients who presented some pathology or whose parents did not accept participation in the study. Results: HR variability was compared using automated detection (NIPETM) for objective estimation of pain/discomfort. It was compared in the clinic with a validated and widely used scale in neonates: Premature Infant Pain Profile (PIPP). We used the Spearman's correlation, the Kruskall-Wallis test or the Chi square test with Fisher's correction to assess the association between NIPE™ variables and HR, as needed. A negative correlation was found between HR and NIPETM for both the group of neonates. humans (r=-1; p=0.008) and for the animal model (r=-0.6; p=0.0004). No significant association was found between NIPETM and the PIPP scale. The variation between pre- and post-stimulus NIPE™ values in human NBs was significant (p=0.008). Conclusions: we conclude that in both scenarios explored, NIPE™ values decrease when faced with nociceptive stimuli and changes in HR are related to its values, regardless of the species or the aggressiveness of the maneuver. This paper is the first at a national level to incorporate the use of this technology, we believe it will have an impact on the way pain is assessed and addressed by healthcare and experimental teams.

Introdução: a exposição a estímulos dolorosos e ao estresse na fase neonatal, sem tratamento correto, traz consequências a curto e longo prazo. O diagnóstico adequado é um desafio, uma vez que as escalas clínicas são subjetivas e são necessárias ferramentas de triagem com melhor objetividade e capacidade de interpretar o desconforto/dor neonatal. A Avaliação Parassimpática do Recém-Nascido (NIPE™) é uma tecnologia não invasiva para monitoramento contínuo da dor em neonatos, desenvolvida recentemente devido à dificuldade de objetivar a dor usando métodos convencionais na prática clínica. Esta tecnologia baseia-se na análise da variabilidade da frequência cardíaca (FC), o que nos permite aproximar a atividade do sistema parassimpático. Objetivos: o objetivo desta pesquisa foi avaliar o desconforto em recém-nascido modelo suíno (RN) e em neonatos humanos expostos a manobras nociceptivas com uso de tecnologia não invasiva (NIPE), na maternidade do Hospital Universitário. Material e métodos: foi realizado um estudo observacional, longitudinal, em 6 suínos RN, anestesiados, monitorados hemodinamicamente e submetidos a um procedimento cirúrgico de grande porte (toracotomia lateral esquerda com abordagem cardíaca, pericardiostomia e acesso vascular pulmonar transventricular direito) e 12 procedimentos minimamente invasivos, da prática clínica. rotina como vacinação BCG, hemoglicoteste e triagem, que geram estímulo nociceptivo em 8 recém-nascidos a termo saudáveis. Foram incluídos recém-nascidos a termo saudáveis (IG entre 37-41 semanas mais 6 dias) internados no alojamento conjunto mãe-filho, foram excluídos do A amostra incluiu RNs que apresentavam alguma patologia e aqueles cujos pais não aceitaram a participação no estudo. Resultados: a variabilidade da FC foi comparada por meio de detecção automatizada (NIPETM) para estimativa objetiva de dor/desconforto. Foi comparado na clínica com uma escala validada e amplamente utilizada em neonatos: Premature Infant Pain Profile (PIPP). Para avaliar a associação entre as variáveis do NIPE™ e a FC, utilizou-se a correlação de Spearman, o teste de Kruskall-Wallis ou o teste Qui-quadrado com correção de Fisher, conforme apropriado. Foi encontrada correlação negativa entre a FC e o NIPETM para ambos os grupos de neonatos. (r=-1; p=0,008) e para o modelo animal (r=-0,6; p=0,0004). Não foi encontrada associação significativa entre o NIPETM e a escala PIPP. A variação entre os valores de NIPE™ pré e pós-estímulo em RN humanos foi significativa (p=0,008). Conclusões: concluímos que em ambos os cenários explorados, os valores do NIPE™ diminuem diante de estímulos nociceptivos e as alterações na FC estão relacionadas aos seus valores, independente da espécie ou da agressividade da manobra. Este trabalho é o primeiro a nível nacional a incorporar a utilização desta tecnologia, acreditamos que terá impacto na forma como a dor é avaliada e abordada pelas equipas de saúde e experimentais.

Comparison of the serum brain-derived neurotrophic factor (BDNF) between fibromyalgia and nociceptive pain groups; and effect of duloxetine on the BDNF level.

BACKGROUND: The primary objective was to compare the serum brain-derived neurotrophic factor (BDNF) level in the patients with two types of pain: fibromyalgia (FM) and non-FM nociceptive pain (non-FM NP). The secondary objective was to investigate the effect of duloxetine on serum BDNF in FM patients and assess the direction of BDNF changes' relation to clinical parameters' alterations. METHODS: This is a study on 73 patients (50 FM and 23 non-FM chronic non-inflammatory pain patients). Serum BDNF was first compared between both groups. Patients with FM, then prospectively, underwent standardized FM treatment with duloxetine maximized to 60 mg/day. The Revised Fibromyalgia Impact Questionnaire (FIQR), Short-Form Health Survey (SF-12), pain visualized analog scale (pain VAS), Beck Depression Inventory-II (BDI-II), polysymptomatic distress scale (PSD) and serum BDNF were measured and compared at baseline and 4 weeks after treatment in FM group. RESULTS: The mean of adjusted BDNF level in the FM group had no significant difference than the non-FM NP group ((5293.5 ± 2676.3 vs. 6136.3 ± 4037.6; P value = 0.77). Using linear mixed model, we showed that duloxetine reduced BDNF level significantly in FM patients, even after adjusting for depression, pain and severity of the disease (P < 0.01). The FIQR, BDI-II, PSD, and pain VAS improved significantly after duloxetine treatment. CONCLUSIONS: Non-significant BDNF level difference between FM and non-FM nociceptive pain suggested that peripheral BDNF is not a pathophysiological feature of FM. The decreased BDNF level parallel with improvement of PSD/pain scores after duloxetine treatment indicates BDNF alteration in the pain modulation process, regardless of cause and effect.

Nociplastic pain: towards an understanding of prevalent pain conditions.

Nociplastic pain is the semantic term suggested by the international community of pain researchers to describe a third category of pain that is mechanistically distinct from nociceptive pain, which is caused by ongoing inflammation and damage of tissues, and neuropathic pain, which is caused by nerve damage. The mechanisms that underlie this type of pain are not entirely understood, but it is thought that augmented CNS pain and sensory processing and altered pain modulation play prominent roles. The symptoms observed in nociplastic pain include multifocal pain that is more widespread or intense, or both, than would be expected given the amount of identifiable tissue or nerve damage, as well as other CNS-derived symptoms, such as fatigue, sleep, memory, and mood problems. This type of pain can occur in isolation, as often occurs in conditions such as fibromyalgia or tension-type headache, or as part of a mixed-pain state in combination with ongoing nociceptive or neuropathic pain, as might occur in chronic low back pain. It is important to recognise this type of pain, since it will respond to different therapies than nociceptive pain, with a decreased responsiveness to peripherally directed therapies such as anti-inflammatory drugs and opioids, surgery, or injections.

Angiotensin (1-7) Attenuates the Nociceptive Behavior Induced by Substance P and NMDA via Spinal MAS1.

The intrathecal (i.t.) injection of substance P (SP) and N-methyl-D-aspartate (NMDA) induce transient nociceptive response by activating neurokinin (NK) 1 and NMDA receptors, respectively. We have recently reported that angiotensin (Ang) (1-7), an N-terminal fragment of Ang II, could alleviate several types of pain including neuropathic and inflammatory pain by activating spinal MAS1. Here, we investigated whether Ang (1-7) can inhibit the SP- and NMDA-induced nociceptive response. The nociceptive response induced by an i.t. injection of SP or NMDA was assessed by measuring the duration of hindlimb scratching directed toward the flank, biting and/or licking of the hindpaw or the tail for 5 min. Localization of MAS1 and either NK1 or NMDA receptors in the lumbar superficial dorsal horn was determined by immunohistochemical observation. The nociceptive response induced by SP and NMDA was attenuated by the i.t. co-administration of Ang (1-7) (0.03-3 pmol) in a dose-dependent manner. The inhibitory effects of Ang (1-7) (3 pmol) were attenuated by A779 (100 pmol), a MAS1 antagonist. Moreover, immunohistochemical analysis showed that spinal MAS1 co-localized with NK1 receptors and NMDA receptors on cells in the dorsal horn. Taken together, the i.t. injection of Ang (1-7) attenuated the nociceptive response induced by SP and NMDA via spinal MAS1, which co-localized with NK1 and NMDA receptors. Thus, the spinal Ang (1-7)/MAS1 pathway could represent a therapeutic target to effectively attenuate spinal pain transmission caused by the activation of NK1 or NMDA receptors.

Estimación del dolor durante el perioperatorio: Una revisión narrativa de los dispositivos disponibles / Estimative pain measurement during perioperative period: a review of current available devices

Pain is a complex subjective organic function which is influenced by sensorial, emotional, cognitive and behavioral elements. Despite the wide offer of pain measurement devices in the perioperative period, none of them is completely validated for their transverse use in the anesthetic practice. The aim of this review is to present the existing devices for objective pain evaluation during the perioperative period along with the scientific evidence supporting each of them. Articles from the PubMed/MEDLINE literature search engine were reviewed. As result, 37 articles were selected due to its relevance, from which 13 pain assessment devices were described, regarding its clinical relevance as well as the amount of scientific evidence found. Among them are ANI, NOL, pupillometry, qNOX, and others. The nociceptive measurement performed by most of these is based mainly on the evaluation of the autonomic nervous system activity and variations of the electroencephalographic signal. However, it is not possible to recommend any particular device. This review aims to offer a broad overview of the available options in order to estimate the role that each of them could play in clinical anesthesiology practice.

El dolor es una experiencia subjetiva compleja en la que inciden elementos sensoriales, emocionales, cognitivos y conductua- les. A pesar de una amplia oferta de dispositivos para medir dolor en el perioperatorio, hoy no existe un instrumento de medición de analgesia validado y utilizado transversalmente en la práctica anestésica. El objetivo de esta revisión es presentar las actuales opciones disponibles para la medición del dolor agudo utilizadas en el período perioperatorio junto con la evidencia científica que respalda cada una de ellas. Se realizó una revisión de la literatura utilizando como fuente de búsqueda bibliográfica la base de datos MEDLINE/pubMed utilizando términos MESH. Como resultado, se seleccionaron 37 artículos de acuerdo a su importancia, a partir de los cuales se describen 13 dispositivos de valoración nociceptiva, a propósito de su relevancia clínica como también por la cantidad de evidencia científica encontrada. Entre ellos destacan ANI, NOL, pupilometría, qNOX, entre otros. La medición nociceptiva realizada por la mayoría de estos se basa principalmente en la evaluación de la actividad del sistema nervioso autónomo y variaciones de la señal electroencefalográfica. Sin embargo, no es posible recomendar algún dispositivo en particular. Esta revisión pretende ofrecer una visión amplia de las opciones disponibles con el fin de estimar el rol que cada uno de ellos podría desempeñar en la práctica clínica anestesiológica.

Efficacy of multimodal analgesic treatment of severe traumatic acute pain in mice pretreated with chronic high dose of buprenorphine inducing mechanical allodynia.

Managing severe acute nociceptive pain in buprenorphine-maintained individuals for opioid use disorder management is challenging owing to the high affinity and very slow dissociation of buprenorphine from µ-opioid receptors that hinders the use of full agonist opioid analgesics. In a translational approach, the aim of this study was to use an animal setting to investigate the effects of a chronic high dose of buprenorphine treatment on nociceptive thresholds before and after applying a severe acute nociceptive traumatic surgery stimulus and to screen postoperative pharmacological analgesic strategies. A chronic treatment of mice with a high dose of buprenorphine (BUP HD, 2 × 200 µg/kg/day; i.p.) revealed significant mechanical allodynia. One and two days after having discontinued buprenorphine administration and having induced a severe nociceptive acute pain by a closed tibial fracture, acute administration of morphine at a dose which has analgesic effects in absence of pretreatment (4.5 mg/kg; i.p.), was ineffective to reduce pain in the BUP HD group. However, mimicking multimodal analgesia strategy used in human postoperative context, the combination of morphine (administered at the same dose) with a NMDA receptor antagonist (ketamine) or an NSAID (ketoprofen) produced antinociceptive responses in these animals. The mouse model of closed tibial fracture could be useful to identify analgesic strategies of postoperative pain for patients with chronic exposure to opioids and suffering from hyperalgesia.

Assessment and Management of Chronic Pain in the Seriously Ill.

The intent of this article is to help clinicians to have practical knowledge and skills related to both assessment and pharmacotherapy of chronic pain in the seriously ill patients. Treating patients with chronic pain and progressive disease should include assessment of "total pain" (physical, psychological, and spiritual suffering) and the care givers as part of treatment team. Effective management of chronic pain starts with thorough assessment and diagnosis of the pain syndrome. A worldwide consensus endorses use of multimodal approach and opioid pharmacotherapy as the mainstay approach to moderate to severe pain in cancer and pain associated with serious illness.

Concurrent validity of a low-cost and time-efficient clinical sensory test battery to evaluate somatosensory dysfunction.

BACKGROUND: This study describes a low-cost and time-efficient clinical sensory test (CST) battery and evaluates its concurrent validity as a screening tool to detect somatosensory dysfunction as determined using quantitative sensory testing (QST). METHOD: Three patient cohorts with carpal tunnel syndrome (CTS, n = 76), non-specific neck and arm pain (NSNAP, n = 40) and lumbar radicular pain/radiculopathy (LR, n = 26) were included. The CST consisted of 13 tests, each corresponding to a QST parameter and evaluating a broad spectrum of sensory functions using thermal (coins, ice cube, hot test tube) and mechanical (cotton wool, von Frey hairs, tuning fork, toothpicks, thumb and eraser pressure) detection and pain thresholds testing both loss and gain of function. Agreement rate, statistical significance and strength of correlation (phi coefficient) between CST and QST parameters were calculated. RESULTS: Several CST parameters (cold, warm and mechanical detection thresholds as well as cold and pressure pain thresholds) were significantly correlated with QST, with a majority demonstrating >60% agreement rates and moderate to relatively strong correlations. However, agreement varied among cohorts. Gain of function parameters showed stronger agreement in the CTS and LR cohorts, whereas loss of function parameters had better agreement in the NSNAP cohort. Other CST parameters (16 mN von Frey tests, vibration detection, heat and mechanical pain thresholds, wind-up ratio) did not significantly correlate with QST. CONCLUSION: Some of the tests in the CST could help detect somatosensory dysfunction as determined with QST. Parts of the CST could therefore be used as a low-cost screening tool in a clinical setting. SIGNIFICANCE: Quantitative sensory testing, albeit considered the gold standard to evaluate somatosensory dysfunction, requires expensive equipment, specialized examiner training and substantial time commitment which challenges its use in a clinical setting. Our study describes a CST as a low-cost and time-efficient alternative. Some of the CST tools (cold, warm, mechanical detection thresholds; pressure pain thresholds) significantly correlated with the respective QST parameters, suggesting that they may be useful in a clinical setting to detect sensory dysfunction.

Clinical Decision-Making in Chronic Spine Pain: Dilemma of Image-Based Diagnosis of Degenerative Spine and Generation Mechanisms for Nociceptive, Radicular, and Referred Pain.

BACKGROUND: Spine-related pain is a complex heterogeneous condition. Excessive reliance on radiological imaging might lead to overdiagnosis of incidental asymptomatic spinal changes and unnecessary surgery. Approaches to the clinical management of spine pain should (1) identify pain generators, types, patterns, and mechanisms; (2) confirm clinical suspension with a diagnostic injection; and (3) ensure that treatment is aimed at controlling pain and improving patient function rather than image-based surgical success. METHOD: This case series (7 cases) discusses commonly seen clinical presentation of spine pain analytically, with illustrations of possible pain generators, mechanisms, pathways, and pain types. Each case discusses pain types and location (axial nociceptive, referred, and radicular neuropathic), generators (degenerated disc, herniated disc, facet joint, and sacroiliac joint), pathways (sinuvertebral ventral ramus and medial and lateral branches dorsal ramus), and radiculopathy versus radicular pain, elaborating on coccydynia and cervicogenic headaches, epimere versus hypomere muscle embryology, function, innervation, and role in spine-related pain. RESULTS: Multiple pain generators might coexist in the same patient causing mixed pain types and referral patterns with multiple mechanisms and pathways. History review, physical examination, and diagnostic injections are the mainstays of diagnosis. CONCLUSIONS: Image-detected spondylosis might be an asymptomatic process. Clinical presentation is related to stenosis or pain. The mechanism of pain is related to compression, inflammation, or microinstability. Spine pain can be nociceptive axial, neuropathic radicular, and/or referred pain. Although image findings are helpful in radicular neuropathic pain from disc herniation, they are unreliable in nociceptive pain, and correlation with clinical and diagnostic injections is mandatory.

Hyperacusis in chronic pain: neural interactions between the auditory and nociceptive systems.

OBJECTIVE: Sensory disturbances are common in chronic pain patients. Hyperacusis can be an especially debilitating experience. Here, we review published work on how the auditory and nociceptive systems might interact in chronic pain syndromes to produce pain-hyperacusis. DESIGN: Literature review. STUDY SAMPLE: The PubMed and Scopus databases were searched for relevant articles published between 2000 and 2017 using the primary search terms "hyperacusis"/"hyperacousis" and "pain". Ten papers were found using this strategy. Supplementary sources were identified by browsing textbooks and the reference lists of identified articles. RESULTS: The importance of central mechanisms in pain-hyperacusis was highlighted in the 10 selected papers. Hyperacusis is a significant but under-recognised symptom in conditions such as complex regional pain syndrome and fibromyalgia, and an integral feature of migraine. CONCLUSIONS: Nociceptive circuits become hypersensitive in acute and chronic pain; this sensitivity spreads from the periphery to spinal neurons and higher centres in the brain, leading to hyperalgesia or spontaneous pain even in the absence of peripheral nociceptive input. This "central sensitisation" may alter activity at sensory convergence points in the thalamus and brainstem centres such as the locus coeruleus, and give rise to hyperacusis in certain pain syndromes.

Grid-climbing Behaviour as a Pain Measure for Cancer-induced Bone Pain and Neuropathic Pain.

Despite affecting millions of people, chronic pain is generally treated insufficiently. A major point of focus has been the lack of translation from preclinical data to clinical results, with the predictive value of chronic pain models being a major concern. In contrast to current focus on stimulus-based nociceptive responses in preclinical research, development of behavioural tests designed to quantify suspension of normal behaviour is likely a more equivalent readout for human pain-assessment tests. In this study, we quantified grid-climbing behaviour as a non-stimulus-evoked behavioural test for potential use as a measure of neuropathic and cancer-induced bone pain in mice. In both models, the grid-climbing test demonstrated pain-related sparing of the affected leg during climbing. In both models, the behaviour was reversed by administration of morphine, suggesting that the observed behaviour was pain-specific.

Neuropathic pain.

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aß, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

Diagnosis of Neuropathic Components in Patients with Back Pain Before and After Surgery.

Background: The perception of back pain subjective is hard for physicians to measure. For this reason, questionnaires are an important instrument to evaluate the pain 1. The main point of this study was to verify differentiation of pain symptoms in patients with different pain mechanisms. The most important parameter was the PainDetect questionnaire, which can differentiate between nociceptive and neuropathic pain. Additional parameters were measured before and after surgery to characterise pain symptoms in detail. Material and Methods: We selected patients with diagnosed vertebral compression fracture, herniated disc or with spinal cord compression. To characterise the preoperative condition on admittance, we collected the data from the physical examination, as well as clinical data, including X-ray, CT and MRI. To characterise the pain, we used the painDetect questionnaire, the Oswestry Index questionnaire (ODI) and the visual analogue scale (VAS). Depending on the diagnosis, patients were treated by surgery (radiofrequency kyphoplasty, nucleotomy, spondylodesis). At 2 to 3 days and 6 months after surgery, we repeated the questionnaire and compared the results with those before the operation. Data on patient satisfaction and adverse events were also collected. Results: This study included 62 patients with vertebral compression fracture (group 1: VBF, 89 % female, mean age 71 years) and 77 patients with herniated disc or spinal cord compression (group 2: non-VBF, 55 % female, mean age 53 years). There was no difference between both groups in preoperative pain intensity (acute, maximum, average): median ordinal scale 0 to 10; group 1: 6, 8, 7; group 2: 6, 9, 7. The total score in the painDetect questionnaire differed significantly between the two groups (median group 1 = 9, group 2 = 17; effect size r = 0.5; p = 0.000). The existence of neuropathic pain was presumed (> 90 %) in 3 % of the patients in group 1 and in 13 % of patients it was not excluded. In contrast, in group 2 it was presumed (> 90 %) in 43 % of patients and in 30 % of patients it could not be excluded. Patients with vertebral compression fracture had greater pain intensity (VAS 71) than patients from group 2 (VAS 53). There was no difference in the total score of the Oswestry questionnaire between the two groups (56 % vs. 58 %). Pain intensity was significantly reduced in both groups after the operations. Six months postoperatively, pain intensity (median ordinal scale 0 to 10; acute, maximum, average) was 2, 5, 3 in group 1 and 2, 4, 2 in group 2. Moreover, the final scores of the painDetect questionnaires were significantly lower in both groups after the operations (4 in both groups). The median score of the ODI was reduced in both groups, with an effect size of 0.6. 98 % of the patients in group 1 and 94 % in group 2 were satisfied with the outcome of the operation. Conclusion: The preoperative pain characteristics of patients with vertebral compression fracture is different from those of patients with herniated disc or with spinal cord compression. 43 % of patients in group 2 exhibited a neuropathic pain component and in 30 % this could not be excluded. In contrast, in group 1 only 3 % of the patients exhibited a neuropathic pain component. Postoperatively, pain symptoms were significant reduced in both groups, so that the risk of chronic pain was considerably less.

Pain following cancer treatment: Guidelines for the clinical classification of predominant neuropathic, nociceptive and central sensitization pain.

BACKGROUND: In addition to fatigue, pain is the most frequent persistent symptom in cancer survivors. Clear guidelines for both the diagnosis and treatment of pain in cancer survivors are lacking. Classification of pain is important as it may facilitate more specific targeting of treatment. In this paper we present an overview of nociceptive, neuropathic and central sensitization pain following cancer treatment, as well as the rationale, criteria and process for stratifying pain classification. MATERIAL AND METHODS: Recently, a clinical method for classifying any pain as either predominant central sensitization pain, neuropathic or nociceptive pain was developed, based on a large body of research evidence and international expert opinion. We, a team of 15 authors from 13 different centers, four countries and two continents have applied this classification algorithm to the cancer survivor population. RESULTS: The classification of pain following cancer treatment entails two steps: (1) examining the presence of neuropathic pain; and (2) using an algorithm for differentiating predominant nociceptive and central sensitization pain. Step 1 builds on the established criteria for neuropathic pain diagnosis, while Step 2 applies a recently developed clinical method for classifying any pain as either predominant central sensitization pain, neuropathic or nociceptive pain to the cancer survivor population. CONCLUSION: The classification criteria allow identifying central sensitization pain following cancer treatment. The recognition of central sensitization pain in practice is an important development in the integration of pain neuroscience into the clinic, and one that is relevant for people undergoing and following cancer treatment.

Randall Selitto pressure algometry for assessment of bone-related pain in rats.

BACKGROUND: Deep pain is neglected compared with cutaneous sources. Pressure algometry has been validated in the clinic for assessment of bone-related pain in humans. In animal models of bone-related pain, we have validated the Randall Selitto behavioural test for assessment of acute and pathological bone pain and compared the outcome with more traditional pain-related behaviour measures. METHODS: Randall Selitto pressure algometry was performed over the anteromedial part of the tibia in naïve rats, sham-operated rats, and rats inoculated with MRMT-1 carcinoma cells in the left tibia, and the effect of morphine was investigated. Randall Selitto measures of cancer-induced bone pain were supplemented by von Frey testing, weight-bearing and limb use test. Contribution of cutaneous nociception to Randall Selitto measures were examined by local anaesthesia. RESULTS: Randall Selitto pressure algometry over the tibia resulted in reproducible withdrawal thresholds, which were dose-dependently increased by morphine. Cutaneous nociception did not contribute to Randall Selitto measures. In cancer-bearing animals, compared with sham, significant differences in pain-related behaviours were demonstrated by the Randall Selitto test on day 17 and 21 post-surgery. A difference was also demonstrated by von Frey testing, weight-bearing and limb use tests. CONCLUSION: Our results indicate that pressure applied by the Randall Selitto algometer on a region, where the bone is close to the skin, may offer a way to measure bone-related pain in animal models and could provide a supplement to the traditional behavioural tests and a means to study deep pain.

Evaluation of outcome of surgical excision of the nidus of osteoid osteoma of long bone.

Osteoid osteoma is a benign bone tumour usually found in the lower extremities of children and young adults. This tiny bone tumour causes pain out of all proportion to its size and hinders the daily activities. This Quasi-experimental study conducted in the department of Orthopaedic surgery of BSMMU from January 2008 to December 2009. Twenty one patients were included in the study where purposive sampling technique was used on the basis of inclusion and exclusion criteria and all the ethical conditions were fulfilled. Diagnosis was almost obtained by taking history, clinical examination, and relevant investigations. Clinical variables were age, sex, site, pain, swelling, deformity and outcome variables were painless active life, removal of swelling, prevention of deformity, rate of recurrence. After localization of the tumour with the help of C arm, the nidus was excised in a small block of bone. The outcome is categorized by consensus, as clinically successful, only if the patient was free of pain and was taking no medication. The treatment was considered to have failed if a subsequent procedure had been performed to remove tumour. Among 21 cases, 14(66.7%) were male and 7(33.7%) were female. Maximum number of patients 15(71.4%) was between 10 years to 20 years. Most of the patients (76.2%) affected by osteoid osteoma were young students and most of the patients (95.2%) experienced moderate aching pain, usually aggravating at night which was typically relieved by aspirin or other NSAIDs (71.4%). Lower limbs (76.2%) particularly femur and tibia were commonly affected. Out of 21 patients, 19(90.5%) patients have got immediate pain relief or required no medication. In only 2 patients (9.5%), subsequent procedure has been performed to relief pain. So, successful outcome (in 19 out of 21) was significantly (p<0.001) higher in comparison to failed. Surgical excision of the nidus is a simple and easy procedure and does not require extensive resection of bone. If localization is done properly success rate is high and patients can return to normal daily activities.

Visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction and low-grade inflammation in a subset of irritable bowel syndrome patients.

The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS (D-IBS). Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits (AML) protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls (P<0.001). Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin (P<0.001). We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.

Clinical characteristics of pain in patients with pituitary adenomas.

OBJECTIVE: Clinical presentation of pituitary adenomas frequently involves pain, particularly headache, due to structural and functional properties of the tumour. Our aim was to investigate the clinical characteristics of pain in a large cohort of patients with pituitary disease. DESIGN: In a cross-sectional study, we assessed 278 patients with pituitary disease (n=81 acromegaly; n=45 Cushing's disease; n=92 prolactinoma; n=60 non-functioning pituitary adenoma). METHODS: Pain was studied using validated questionnaires to screen for nociceptive vs neuropathic pain components (painDETECT), determine pain severity, quality, duration and location (German pain questionnaire) and to assess the impact of pain on disability (migraine disability assessment, MIDAS) and quality of life (QoL). RESULTS: We recorded a high prevalence of bodily pain (n=180, 65%) and headache (n=178, 64%); adrenocorticotropic adenomas were most frequently associated with pain (n=34, 76%). Headache was equally frequent in patients with macro- and microadenomas (68 vs 60%; P=0.266). According to painDETECT, the majority of the patients had a nociceptive pain component (n=193, 80%). Despite high prevalence of headache, 72% reported little or no headache-related disability (MIDAS). Modifiable factors including tumour size, genetic predisposition, previous surgery, irradiation or medical therapy did not have significant impact neither on neuropathic pain components (painDETECT) nor on headache-related disability (MIDAS). Neuropathic pain and pain-related disability correlated significantly with depression and impaired QoL. CONCLUSIONS: Pain appears to be a frequent problem in pituitary disease. The data suggest that pain should be integrated in the diagnostic and therapeutic work-up of patients with pituitary disease in order to treat them appropriately and improve their QoL.

Complexity of pain management among patients with nociceptive or neuropathic neck, back, or osteoarthritis diagnoses.

BACKGROUND: Approaches to pain management are diverse, requiring prescribers to evaluate an array of clinical issues and potential solutions. In addition to the difficult task of selecting a treatment option, pain treatment may be further complicated by multiple prescribers, multiple medications, and multiple mechanisms of pain origination. OBJECTIVE: To describe patient demographics (e.g., age, gender); comorbidities; office visits (e.g., physician, chiropractor, physical therapy, psychiatry, allergist); number of different prescribers overall prescription use; pain medications as classified by the World Health Organization's (WHO) pain ladder; adjuvant medications; nonpharmacologic procedures; and potential drug interactions in a broad sample of patients with nociceptive or neuropathic neck or back diagnoses, or osteoarthritis diagnoses, in a commercial population. METHODS: This claims-data analysis used a cross-sectional cohort comparison with a fixed 2-year observation period from September 1, 2006, to August 31, 2008, for patients in the PharMetrics national managed care database. The assigned cohorts were neuropathic-related neck/back diagnoses (NEURO); neuropathic and nociceptive neck/back diagnoses (NEURO/NOCI); nociceptive neck/back diagnoses without a neuropathic-related diagnosis (NOCI); and only osteoarthritis (OA) diagnoses. All analyses were conducted by cohort. The analysis included the following patient-descriptive variables: patient demographics, comorbidities, office visits, most frequent medical providers and number of different prescribers, all medications, pain medications as classified by the WHO pain ladder, adjuvant medications, adjuvant procedures and potential drug interactions. The goal for selecting these variables was to describe a range of data that might provide insight into the complexity of pain management decisions faced by clinicians. RESULTS: The study included 85,014 patients, classified as NEURO (n = 2,375), NEURO/NOCI (n = 37,019), NOCI (n = 39,496), and OA (n = 6,124). The most frequently occurring comorbidities (observed in > 40% of patients) included cardiovascular and neuropathic pain conditions. Considering all types of medication claims observed among all cohorts, the overall mean prescription claim count for the 2-year observation period was 57.9 claims (standard deviation 56.2). Weak opioids (WHO pain relief ladder rung 2) accounted for the majority of pain medication claims across all cohorts. Across cohorts, 25.7% of patients had 10 or more days of overlapping drug availability (for inducers or inhibitors of the cytochrome P450 system concomitantly), a measure of potential for drug interactions. CONCLUSIONS: Choosing the appropriate pain treatment involves assessing currently used medications for existing illnesses and deciding on the appropriate types of pain medications. However, potentially serious drug-drug interactions are a consequence of multiple drug use, and such a potential requires thoughtful consideration by those involved in patient care.