Pharmacological Probes to Validate Biomarkers for Analgesic Drug Development.

There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.

Thoracolumbar interfascial plane block for postoperative analgesia in spine surgery: A systematic review and meta-analysis.

INTRODUCTION: Thoracolumbar interfascial plane (TLIP) block has been discussed widely in spine surgery. The aim of our study is to evaluate analgesic efficacy and safety of TLIP block in spine surgery. METHOD: We performed a quantitative systematic review. Randomized controlled trials that compared TLIP block to non-block care or wound infiltration for patients undergoing spine surgery and took the pain or morphine consumption as a primary or secondary outcome were included. The primary outcome was cumulative opioid consumption during 0-24-hour. Secondary outcomes included postoperative pain intensity, rescue analgesia requirement, and adverse events. RESULT: 9 randomized controlled trials with 539 patients were included for analysis. Compared with non-block care, TLIP block was effective to decrease the opioid consumption (WMD -16.00; 95%CI -19.19, -12.81; p<0.001; I2 = 71.6%) for the first 24 hours after the surgery. TLIP block significantly reduced postoperative pain intensity at rest or movement at various time points compared with non-block care, and reduced rescue analgesia requirement ((RR 0.47; 95%CI 0.30, 0.74; p = 0.001; I2 = 0.0%) and postoperative nausea and vomiting (RR 0.58; 95%CI 0.39, 0.86; p = 0.006; I2 = 25.1%). Besides, TLIP block is superior to wound infiltration in terms of opioid consumption (WMD -17.23, 95%CI -21.62, -12.86; p<0.001; I2 = 63.8%), and the postoperative pain intensity at rest was comparable between TLIP block and wound infiltration. CONCLUSION: TLIP block improved analgesic efficacy in spine surgery compared with non-block care. Furthermore, current literature supported the TLIP block was superior to wound infiltration in terms of opioid consumption.

Efficacy and safety of paravertebral block versus intercostal nerve block in thoracic surgery and breast surgery: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the analgesic efficacy and safety of paravertebral block (PVB) versus intercostal nerve block (INB) in thoracic surgery and breast surgery. METHODS: The PubMed, Web of Science, Embase and the Cochrane Library were searched up to February 2020 for all available randomized controlled trials (RCTs) that evaluated the analgesic efficacy and safety of PVB compared with INB after thoracic surgery and breast surgery. For binary variables, odds ratio (OR) and 95% confidence interval (CI) was used. For continuous variables, weighted mean difference (WMD) and 95% confidence interval (CI) were used. RevMan5. 3 and Stata/MP 14.0 were used for performing the meta-analysis. RESULTS: A total of 9 trials including 440 patients (PVB block:222 patients; INB: 218 patients) met the inclusion criteria. In the primary outcome, there was no significant differences between the two groups with respect to postoperative visual analogue scale (VAS) at 1h (Std. MD = -0. 20; 95% CI = -1. 11to 0. 71; P = 0. 66), 2h (Std. MD = -0. 71; 95% CI = -2. 32to 0. 91; P = 0. 39), 24h (Std. MD = -0. 36; 95% CI = -0. 73 to -0. 00; P = 0. 05) and 48h (Std. MD = -0. 04; 95% CI = -0. 20 to 0. 11; P = 0. 57). However, there was significant difference in VAS of non Chinese subgroup at 1h (Std. MD = 0. 33; 95% CI = 0. 25to 0. 41; P<0. 00001) and VAS of Chinese subgroup at 24h (Std. MD = -0.32; 95% CI = -0.49 to-0.14; P = 0.0003). In the secondary outcome, the analysis also showed no significant difference between the groups according to the rates of postoperative nausea and vomit (OR = 0. 63; 95% CI = 0. 38 to 1. 03; P = 0. 06) and the rates of postoperative additional analgesia (OR = 0. 57; 95% CI = 0. 21 to 1. 55; P = 0. 27). There was significant difference in postoperative consumption of morphine (Std. MD = -14. 57; 95% CI = -26. 63 to -0.25; P = 0. 02). CONCLUSION: Compared with INB, PVB can provide better analgesia efficacy and cause lower consumption of morphine after thoracic surgery and breast surgery.

Diagnosis of lumbar radiculopathy using simultaneous MR neurography and apparent T2 mapping.

We sought to assess the utility of simultaneous apparent T2 mapping and neurography with the nerve-sheath signal increased by inked rest-tissue rapid acquisition of relaxation-enhancement imaging (SHINKEI-Quant) for the quantitative evaluation of compressed nerves in patients with lumbar radiculopathy. Thirty-two patients with lumbar radiculopathy and 5 healthy subjects underwent simultaneous apparent T2 mapping and neurography with SHINKEI-Quant. Regions of interest (ROIs) were placed in the lumbar dorsal root ganglia (DRG) and the spinal nerves distal to the lumbar nerves bilaterally at L4-S1. The T2 relaxation times were measured on the affected and unaffected sides. The T2 ratio was calculated as the affected side/unaffected side. Pearson correlation coefficients were calculated to determine the correlation between the T2 relaxation times or T2 ratio and clinical symptoms. An ROC curve was used to examine the diagnostic accuracy and threshold of the T2 relaxation times and T2 ratio. We observed no significant differences in the T2 relaxation times between the nerve roots on the left and right at each spinal level in healthy subjects. In patients, lumbar neurography revealed swelling of the involved nerve, and prolonged T2 relaxation times compared with that of the contralateral nerve. The T2 ratio correlated with leg pain. The ROC analysis revealed that the T2 relaxation time threshold was 127 ms and the T2 ratio threshold was 1.07. To our knowledge, this is the first study to show the utility of SHINKEI-Quant for the quantitative evaluation of lumbar radiculopathy.

Associations between Age-Related Changes in the Core Vestibular Projection Pathway and Balance Ability: A Diffusion Tensor Imaging Study.

OBJECTIVE: We investigated the changes of the vestibulospinal tract (VST) and parietoinsular vestibular cortex (PIVC) using diffusion tensor imaging (DTI) and relation to balance between old and young healthy adults. METHODS: This study recruited eleven old adults (6 males, 5 females; mean age 63.36 ± 4.25 years) and 12 young adults (7 males, 5 females; mean age 28.42 ± 4.40 years). The lateral and medial VST and PIVC were reconstructed using DTI. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume were measured. The six-minute walk test (6-MWT), the timed up and go test (TUG), and the Berg balance scale (BBS) were conducted. Spatiotemporal parameters during tandem gait and values of sway during one-leg standing using the wearable sensors were measured. All parameters between two groups were analyzed by the Mann-Whitney U test and independent t-test. RESULTS: Statistically significant decrease in old adults was detected in the tract volume of lateral (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (p = 0.005) and medial VST (. CONCLUSION: The results suggested that there was a relationship between DTI parameters in the vestibular neural pathway and balance according to aging.

Comparison between ultrasound-guided paravertebral nerve block and subarachnoid block for elderly male patients under unilateral-opened inguinal hernia repair operation: A randomised controlled trial.

BACKGROUND: Paravertebral block (PVB) as a sole anesthetic technique is difficult even in experienced hands. Hence, this study was undertaken to study the safety and efficacy of PVB and to compare with subarachnoid block (SAB) for inguinal hernia repair surgery (IHRS) in elderly male patients. MATERIALS AND METHODS: Sixty-five male patients aged 65 to 89 scheduled for IHRS were allocated randomly by computer-generated randomisation sequence into two groups. They underwent PVB (Group PVB: 33 patients were injected with 10 ml ropivacaine 0.5% at each level from T12 to L1) or SAB (Group SAB: 32 patients were injected with 15 mg ropivacaine 0.5% at L3-L4 level). Primary outcomes were hemodynamic changes and duration of postoperative analgesia. Secondary outcomes were dosage of remedial analgesics, time to perform the block, side effects and satisfaction of patients. RESULTS: The hemodynamics in the Group PVB were more stable than those in the Group SAB during surgery (P < 0.05). The duration of post-operative analgesia was significantly longer in the Group PVB (P < 0.001). The total dose of fentanyl was smaller in the Group PVB in the first 24 h (P < 0.001). The time to perform the block was significantly longer in the Group PVB (P < 0.001). There was a significant difference in the visual analogue scales (VAS) scores between the two groups at 4 h, 6 h, 8 h and 10 h (P < 0.05) but not at 2 h, 12 h and 24 h (P > 0.05). The VAS scores were lowest at 2 h for both the 2 groups, highest at 12 h for Group PVB and at 8 h for Group SAB respectively. The Group PVB had fewer adverse effects (P < 0.05) and higher satisfaction of patients (P < 0.05). CONCLUSION: Ultrasound-guided PVB can ensure the anesthetic effects of unilateral-opened IHRS in elderly male patients. It has a small impact on hemodynamics, a longer postoperative analgesia time and less complications.

Regenerating Corticospinal Axons Innervate Phenotypically Appropriate Neurons within Neural Stem Cell Grafts.

Neural progenitor cell grafts form new relays across sites of spinal cord injury (SCI). Using a panel of neuronal markers, we demonstrate that spinal neural progenitor grafts to sites of rodent SCI adopt diverse spinal motor and sensory interneuronal fates, representing most neuronal subtypes of the intact spinal cord, and spontaneously segregate into domains of distinct cell clusters. Host corticospinal motor axons regenerating into neural progenitor grafts innervate appropriate pre-motor interneurons, based on trans-synaptic tracing with herpes simplex virus. A human spinal neural progenitor cell graft to a non-human primate also received topographically appropriate corticospinal axon regeneration. Thus, grafted spinal neural progenitor cells give rise to a variety of neuronal progeny that are typical of the normal spinal cord; remarkably, regenerating injured adult corticospinal motor axons spontaneously locate appropriate motor domains in the heterogeneous, developing graft environment, without a need for additional exogenous guidance.

High contrast between lumbar nerve roots and surrounding structures using dual echo 3D turbo spin echo additional fusion images.

PURPOSE: We performed lumbar spinal magnetic resonance imaging of three-dimensional (3D) dual echo volumetric isotropic turbo spin echo acquisition (DE-VISTA) and constructed DE-VISTA additional fusion images (DE-VISTA-AFI), which is the addition of DE-VISTA proton density-weighted images (DE-VISTA-PDWI) to DE-VISTA T2-weighted images (DE-VISTA-T2WI). The aim of this study was to clarify whether DE-VISTA-AFI was able to clearly delineate spinal nerve roots. METHODS: A total of 677 patients underwent lumbar MR imaging, and the signal ratio (SR) between cerebrospinal fluid and nerve roots inside the dural sac and the SR between fat and nerve roots outside the dural sac were estimated using DE-VISTA-AFI, DE-VISTA-PDWI, DE-VISTA-T2WI, and 2D-T2WI. RESULTS: The SR between cerebrospinal fluid and nerve roots inside the dural sac on DE-VISTA-AFI was higher than that on DE-VISTA-PDWI (p < 0.0001) and on 2D T2WI (p < 0.0001). The SR between the fat tissue and nerve roots outside the dural sac on DE-VISTA-AFI was higher than that on DE-VISTA-PDWI (p < 0.0001) and 2D T2WI (p < 0.0001). CONCLUSION: DE-VISTA-AFI could clearly delineate the entire length of the lumbar nerve roots that run from the cauda equina in the spinal fluid through to the fat in the lateral recess, intervertebral foramen, and outside the intervertebral foramen.

Intraosseous basivertebral nerve ablation for the treatment of chronic low back pain: a prospective randomized double-blind sham-controlled multi-center study.

PURPOSE: To evaluate the safety and efficacy of radiofrequency (RF) ablation of the basivertebral nerve (BVN) for the treatment of chronic low back pain (CLBP) in a Food and Drug Administration approved Investigational Device Exemption trial. The BVN has been shown to innervate endplate nociceptors which are thought to be a source of CLBP. METHODS: A total of 225 patients diagnosed with CLBP were randomized to either a sham (78 patients) or treatment (147 patients) intervention. The mean age within the study was 47 years (range 25-69) and the mean baseline ODI was 42. All patients had Type I or Type II Modic changes of the treated vertebral bodies. Patients were evaluated preoperatively, and at 2 weeks, 6 weeks and 3, 6 and 12 months postoperatively. The primary endpoint was the comparative change in ODI from baseline to 3 months. RESULTS: At 3 months, the average ODI in the treatment arm decreased 20.5 points, as compared to a 15.2 point decrease in the sham arm (p = 0.019, per-protocol population). A responder analysis based on ODI decrease ≥ 10 points showed that 75.6% of patients in the treatment arm as compared to 55.3% in the sham control arm exhibited a clinically meaningful improvement at 3 months. CONCLUSION: Patients treated with RF ablation of the BVN for CLBP exhibited significantly greater improvement in ODI at 3 months and a higher responder rate than sham treated controls. BVN ablation represents a potential minimally invasive treatment for the relief of chronic low back pain. These slides can be retrieved under Electronic Supplementary Material.

[Relationship between the distribution of spinal nerve posterior ramus and locations of acupoint in low back].

OBJECTIVE: To explore the relationship between the distributions of posterior ramus of spinal nerve (PRSN) and locations of acupoint in low back through anatomical observation. METHODS: The regional anatomy was performed at five corpses to observe the distribution of erector spinae muscle and PRSN in areas of Jiaji points and back-shu points in low back. RESULTS: The T12, L1, L2, L3 and L4 PRSN distributed on both sides of the spine; the medial branches of PRSN travelled between spinalis thoracis muscle and longissimus thoracis muscle, while the lateral branches of PRSN travelled between longissimus thoracis muscle and iliocostalis lumborum muscle. CONCLUSIONS: Jiaji points and back-shu points in low back are closely associated with PRSN, particularly T12, L1, L2, L3 and L4.

Traumatic spinal cord injury.

Traumatic spinal cord injury (SCI) has devastating consequences for the physical, social and vocational well-being of patients. The demographic of SCIs is shifting such that an increasing proportion of older individuals are being affected. Pathophysiologically, the initial mechanical trauma (the primary injury) permeabilizes neurons and glia and initiates a secondary injury cascade that leads to progressive cell death and spinal cord damage over the subsequent weeks. Over time, the lesion remodels and is composed of cystic cavitations and a glial scar, both of which potently inhibit regeneration. Several animal models and complementary behavioural tests of SCI have been developed to mimic this pathological process and form the basis for the development of preclinical and translational neuroprotective and neuroregenerative strategies. Diagnosis requires a thorough patient history, standardized neurological physical examination and radiographic imaging of the spinal cord. Following diagnosis, several interventions need to be rapidly applied, including haemodynamic monitoring in the intensive care unit, early surgical decompression, blood pressure augmentation and, potentially, the administration of methylprednisolone. Managing the complications of SCI, such as bowel and bladder dysfunction, the formation of pressure sores and infections, is key to address all facets of the patient's injury experience.

Rosai-Dorfman disease of the subdural spine with a long segment lesion: A case report and literature review.

Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy is a rare benign disorder usually characterized by massive painless cervical lymphadenopathy and systemic manifestations. Extranodal involvement, especially spinal involvement, is extremely rare. We report a 41-year-old man who presented with only intermittent dorsodynia. His condition was diagnosed as non-specific inflammatory disease on the basis of preoperative puncture biopsy results. We performed total surgical resection. Histopathological findings showed distinctive emperipolesis and immunohistochemistry results were positive for cluster of differentiation CD68 and S100 and negative for CD1a. A good prognosis was confirmed at the 3-month follow-up visit. This is the first case of RDD of the subdural spine with such a long segment lesion. There is still no consensus regarding appropriate therapy for this type of RDD and the preoperative diagnosis remains challenging. The unusual presentation of our case serves as a reference when diagnosing and treating RDD.

Relação da oclusão dentária na presença de curvaturas não fisiológicas da coluna vertebral / Relationship between dental occlusion and non-physiological curvature of the vertebral column

O objetivo desse trabalho foi verificar a relação entre a oclusão dentária e as curvaturas não fisiológicas da coluna vertebral. A amostra foi composta por 88 indivíduos com diagnóstico médico e radiográfico confirmado de desvio postural, atendidos em Ambulatório Médico-Odontológico noEstado de João Pessoa-PB. Para a coleta de dados realizou-se um exame clínico da oclusão dentária em relação vertical de normalidade, mordida em topo, aberta e profunda. Posteriormente a relação transversal de oclusão foi qualificada em normalidade, desvio de linha média, apinhamento inferior e/ou superior e mordida cruzada posterior uni ou bilateral. A relação ântero-posterior foi determinada conforme classificação de Angle em: normalidade, classe I, II e III. Os dados obtidos foram submetidos ao tratamento estatístico pelo teste Exato de Fisher com nível de significância de 5%. Os resultados demonstraram uma diferença estatisticamente significante entre as curvaturas não fisiológicas da coluna vertebral e as relações vertical e ântero-posterior de oclusão, assim como diversos tipos de mal oclusão dentária entre indivíduos com curvaturas não fisiológicas da coluna vertebral. Não foi observada relação estatisticamente significante entre gênero e idade nos indivíduos examinados. Conclui-se que há um desequilíbrio no sistema manducatório pode estar intimamente relacionado a presença de alterações posturais na coluna vertebral.

This study aims to verify the relation between dental occlusion and no physiological curvature of the spinal column. The sample consisted of 88 individuals with a clinical diagnosis and confirmed radiographic postural deviation, treated at Medical-Dental Clinic in the state of Joao Pessoa-Pb. For data collection it was carried out a clinical examination of the dental occlusion in vertical relationship of normality, bite the top, open and deep. Later the transversal occlusion was qualified inrelation normality, midline deviation, crowding and posterior crossbite. The vertical anterior-posterior occlusion relation was determined according to Angle classification: normal, class I, II and III. The obtained data were subjected to statistical analysis by Fisher exact test with a significance level of 5%. It was found that there was a difference statistically significant between the non-physiological curvatures of the spine and the vertical and ânterior-posterior occlusion relation as well as various types of dental malocclusion among individuals with no physiological curvature of the spine. No statistically significant relationship between gender and age it was observed. Data suggest there isan imbalance in the system can be closely related to the presence of postural changes in the spine.

The Peridural Membrane of the Human Spine is Well Innervated.

There is evidence that low back pain may originate from a peridural membrane (PDM) at the inferior and medial aspect of neural foramen of the lumbar spine. The objective of this investigation was to determine if this membrane contains neural elements suggestive of sensory innervation with nociceptive function. Spines of four embalmed and three non-embalmed human cadavers were dissected using a sagittal approach to the neural foramen. Seventeen samples of the peridural membrane overlying the neural foramen were collected for immunohistochemistry (IHC) examination by light microscopy and transmission electron microscopy (TEM). Chromagin tagged antibodies to protein gene product 9.5 (PGP9.5) and S-100, and fluorescent antibodies to substance P and calcitonin gene related peptide (CGRP) were used to label neural structures in tissue sections cut from paraffin embedded blocks. This approach allows good visualization of all neural elements, small sensory, and nociceptive nerve fibers in particular. Neural elements were found in all samples. Marked presence of small nerve fibers was observed in 12 of 15 samples. IHC and TEM evaluation revealed myelinated as well as unmyelinated fibers in the peridural membrane. CGRP and substance P immunoreactive fibers indicative of nociceptive function were abundant. These findings confirm and expand evidence that the peridural membrane in human is well innervated and contains sensory nociceptive nerve fibers suggestive of a nociceptive function of the membrane.

Comprehensive anatomical and immunohistochemical review of the innervation of the human spine and joints with application to an improved understanding of back pain.

BACKGROUND: Pain of spinal origin contributes significantly to cervical, thoracic, and lower back pain presentations. Such pain originates in the nerve fibers supplying the joints or the surrounding ligaments and intervertebral discs. Although there has been little detailed discussion of spinal bony innervation patterns in the literature, the clinical implications of these patterns are anatomically and medically significant. METHODS: The present review provides a detailed analysis of the innervation of the spine, identifying the unique features of each part via online search engines. CONCLUSIONS: The clinical implications of these various studies lie in the importance of the innervation patterns for the mechanism of spinal pain. Immunohistochemical studies have provided further evidence regarding the nature of the innervation of the spine.

Pain medication use after spine surgery: is it assessed in the literature? A systematic review, January 2000-December 2009.

BACKGROUND: Spine surgery is one of the most difficult areas in which to achieve a good clinical outcome and pain medication is often used for a long period of time after surgery. The purpose of this study was to investigate whether pain medication use after spine surgery has been assessed previously with respect to clinical outcome. METHODS: A systematic review of PubMed/MEDLINE databases was conducted from Jan 1st 2000 to Dec 31st 2009 using the search key words, "spine surgery" and "clinical outcome." All publications reporting clinical outcomes were examined and analyzed for outcome measures and data with respect to pain medication use after spine surgery. RESULTS: In total 990 articles met the inclusion criteria. Among them, 56 articles (5.7%) described definitive pain medication use after spine surgery; 98 articles (9.9%) used clinical outcome measures that incorporate pain medication assessment, although only one such study included a definitive description of pain medication use. CONCLUSIONS: Pain medication use after spine surgery was assessed in 15.5% of articles published during the last decade. The use of pain medication following spine surgery can affect clinical outcome and, therefore, needs to be taken into consideration for clinical assessment. In future studies, a detailed description of pain medication use and/or clinical outcome measures that incorporate pain medication assessment are advocated when reporting clinical outcomes after spine surgery so that it can be better assessed.

Spinal pain.

The spinal pain, and expecially the low back pain (LBP), represents the second cause for a medical consultation in primary care setting and a leading cause of disability worldwide [1]. LBP is more often idiopathic. It has as most frequent cause the internal disc disruption (IDD) and is referred to as discogenic pain. IDD refers to annular fissures, disc collapse and mechanical failure, with no significant modification of external disc shape, with or without endplates changes. IDD is described as a separate clinical entity in respect to disc herniation, segmental instability and degenerative disc desease (DDD). The radicular pain has as most frequent causes a disc herniation and a canal stenosis. Both discogenic and radicular pain also have either a mechanical and an inflammatory genesis. For to be richly innervated, facet joints can be a direct source of pain, while for their degenerative changes cause compression of nerve roots in lateral recesses and in the neural foramina. Degenerative instability is a common and often misdiagnosed cause of axial and radicular pain, being also a frequent indication for surgery. Acute pain tends to extinguish along with its cause, but the setting of complex processes of peripheral and central sensitization may influence its evolution in chronic pain, much more difficult to treat. The clinical assessment of pain source can be a challenge because of the complex anatomy and function of the spine; the advanced imaging methods are often not sufficient for a definitive diagnosis because similar findings could be present in either asymptomatic and symptomatic subjects: a clinical correlation is always mandatory and the therapy cannot rely uniquely upon any imaging abnormalities. Purpose of this review is to address the current concepts on the pathophysiology of discogenic, radicular, facet and dysfunctional pain, focusing on the role of the imaging in the diagnostic setting, to potentially address a correct approach also to minimally invasive interventional techniques. Special attention will be done to the discogenic pain, actually considered as the most frequent cause of chronic low back pain.