Chronic neck pain (CNP), a global health problem, involves a large amount of psychological and socioeconomic burdens. Not only physical causes but also behavioral disorders such as a fear-avoidance belief (FAB) can associate with the chronicity of neck pain. However, functional brain mechanisms underlying CNP and its related behavioral disorders remain unknown. The aim of the current resting-state functional magnetic resonance imaging (fMRI) study was to explore how the functional brain networks differed between CNP patients and age- and sex-matched healthy, pain-free controls (HCs). We also investigated whether these possible brain network changes in CNP patients were associated with fear avoidance belief (FAB) and the intensity of pain. We analyzed the resting-state fMRI data of 20 CNP patients and 20 HCs. FAB and the intensity of pain were assessed by Tampa Scale for Kinesiophobia (TSK) and Visual Analog Scale (VAS) of pain. The whole brain analysis showed that CNP patients had significant different functional connectivity (FC) compared with HCs, and the right dorsolateral prefrontal cortex (DLPFC) was a core hub of these altered functional networks. Furthermore, general linear model analyses showed that, in CNP patients, the increased FC between the right DLPFC and the right anterior insular cortex (aIC) significantly associated with increased TSK , and the FC between the right DLPFC and dorsal posterior cingulate cortex had a trend of inverse association with VAS (p = 0.04). Our findings suggest that aberrant FCs between the right DLPFC and aIC associated with CNP and its related FAB. Chronic neck pain (CNP), a global health problem, poses a large socioeconomic burden, including restrictions on social life, reduced work productivity, and the cost of healthcare. The global point prevalence of cervical pain was reported to be about 5%, and the large population of patients suffer neck pain-related disability., 2Numerous neuroimaging studies involving other musculoskeletal pain such as chronic low back pain (CLBP) have shown widespread structural and functional brain changes in individuals with chronic pain compared with healthy, pain-free controls (HCs)., 4 TheseOn the other hand, despite the large population of patients, neuroimaging analyses in CNP are still understudied. Neck pain often results in physical disorders in the upper part of the body and is accompanied by symptoms such as headache and shoulder stiffness. These unWe hypothesized that CNP patients would show different functional brain networks compared to individuals without pain in resting state. We also hypothesized that these disturbed networks would be associated with increased pain and FAB in CNP patients. For this purpose, we explored whether and how the resting-state FCs in CNP patients differed compared to HCs. In addition, we investigated whether these possible FC differences in CNP patients were associated with FAB and the severity of pain.This study was approved by the institutional ethics committee of Keio University School of Medicine (authorization number: 20160002), and all subjects provided their written informed consent in line with the Declaration of Helsinki. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (ID: 000024475).Twenty-one right-handed CNP patients from outpatients of Keio University Hospital and 25 age- and sex- matched HCs were enrolled. One CNP patient and 5 HCs were excluded due to a high rate of invalid volumes, as mentioned below. A total of 20 CNP patients and 20 HCs were analyzed in this study.Specific inclusion criteria for chronic neck pain were 1) experiencing pain at the neck, 2) pain persisting for three months or longer, and 3) pain of ≥4 on the Numerical Rating Scale  at the initial visit. Subjects with any psychiatric disorders or any brain anatomical abnormalities and ones who were expected to have difficulty keeping their head in the same position because of neck pain during fMRI scanning were excluded from the enrollment of the study.We measured the current pain on a Visual Analog Scale  and FAB on the short-version of Tampa Scale for Kinesiophobia ., 24 SubjA 3.0-T Sigma MRI system  with an 8-channel phased array coil was used to obtain brain imaging data. Anatomical images were acquired with 3-dimensional brain volume imaging with an extended dynamic range T1-weighted sequence: voxel size = 1 × 1 × 1 mm; inversion time (TI)/flip angle (FA) = 650 ms/8°; field of view (FOV) = 256 mm.Resting state functional images were acquired using gradient echo planner imaging: sequence = ascending; slice thickness/gap = 3.2/0.8 mm; FOV = 212 mm; acquisition matrix = 64 × 64 mm, repetition time (TR) = 2500 ms; echo time (TE) = 30 ms; and flip angle = 80°; number of slices = 40; resting scanning time = 8 min. All subjects were directed to stay awake with their eyes open without thinking of any specific thing during scanning. To confirm subjects’ state of awakeness during scanning, we performed the Stanford Sleepiness Scale The fMRI data were preprocessed using the CONN toolbox Version 17.f,  running The normality of the questionnaire data was assessed using the Shapiro-Wilk test. The clinical assessment measures were compared between the CNP and HC groups using Wilcoxon’s rank test with the JMP software program .Each voxel was assigned to 499 well-validated regions of interest (ROIs) for each participant . The parhttp://www.nitrc.org/projects/bnv/).[CONN calculated the Pearson’s correlation coefficients  of time courses of BOLD signals for all combinations of ROIs and then analyzed the FC using the Fisher’s transformed r-values. A general linear model (GLM) analysis and false discovery rate (FDR)-corrected p-values (p-FDR) < 0.05 were used to identify the significance of the whole-brain analysis for group-level comparisons after adjusting age and sex. The brain network results were visualized using the BrainNet Viewer (ts/bnv/).In the whole brain analysis, the right DLPFC had 15 FCs that were significantly different between CNP patients and HCs (p-FDR<0.05), thereby was identified as a ROI with the largest number of significant links. Moreover, these significant DLPFC FCs included ROIs in the SN and DMN which had the extensive a priori evidence regarding the involvement in chronic pain. Therefore, we regarded the right DLPFC as an important hub in the functional brain networks in CNP, and focused on the association between these 15 DLPFC FCs and clinical assessment measures (TSK and VAS). To identify this association, additional GLM analyses on TSK and VAS were performed specifying these DLPFC FCs as covariates of interest using the JMP software program . To determine the final GLMs, these 15 DLPFC FCs were examined in a stepwise backward and forward selection procedure using the criterion of P <0.1. After this selection process, we also considered the rationality of a parameter estimate of each FC retained in stepwise selection procedure. Namely, as for FCs that exhibited CNP>HC in the whole brain analysis, we considered a FC with positive parameter estimate in clinical association analysis in CNP patients to be a rational covariate to the model. Conversely, as for FCs that exhibited CNP<HC, we considered a FC with negative parameter estimate in clinical association analysis in patients to be rational. Accordingly, when the positive/negative of the estimate of each FCs retained in stepwise analysis contradicted the group-level contrast in the whole brain analysis, such FCs were excluded from the final model. The final GLMs of TSK and VAS were constructed by including age, sex, and the FCs selected by the process described above. For these two GLM analyses, Bonferroni correction for multiple testing was applied .http://surfer.nmr.mgh.harvard.edu/), an open-source software validated previously.[Gray matter volume (GMV) based on a T1-weighted structural image was preprocessed including skull stripping, gray and white matter segmentation, B1 bias field collection, non-linear registration to an MNI space, and surface labeling corresponding to a predetermined anatomical brain atlas  using Freviously.–35 We chDemographic data and questionnaire scores are shown in We identified 29 connections of 38 ROIs with significantly different FCs between the CNP patients and HCs . PCC subAfter a stepwise selection and a consideration of rationality of each parameter estimate, the FCs of the right DLPFC to the right aIC and the right Pcu were retained as significant determinants for TSK, and FCs to the dorsal PCC and the right supramarginal gyrus were retained for VAS. Thus, the final GLMs were constructed for the association of these FCs with TSK and VAS . The GLMThe dorsal PCC showed significantly lager GMV in CNP patients than in HC. No significant difference was found in GMV of the right DLPFC and the right aIC between the groups. There were no significant associations of the GMVs of these regions with TSK and VAS in CNP .Our data showed that, in the resting state, CNP patients had significant different functional brain networks compared with HCs, and the right DLPFC was a core hub of these altered functional networks. We also showed that the FC between the right DLPFC and the right aIC significantly associated with patients’ kinesiophobia, suggesting that aberrant right DLPFC connectivity to the right aIC may play a key role in FAB in CNP patients.The state of the brain in chronic pain encompasses both the disruption of whole-brain network and the disruption of local FCs. As a disorganized whole brain network is commonly observed in various chronic pain conditions, more generalizable neuroimaging analyses viewing large-scale brain functional reorganization have been proposed rather than analyses focusing on a specific local brain region. However,The DLPFC has been shown to be mainly related to cognitive processes such as attention, decision-making, working memory, planning ability, learning ability, and regulating emotion. –41 The DExperimental pain stimuli evoke bilateral DLPFC activation –45 and eOur results showed decreased FCs between the right DLPFC and PCC subregions in CNP patients compared to HCs. Furthermore, the FC between the right DLPFC and dorsal PCC had a trend of inverse correlation with the intensity of pain. The PCC, a key hub of the DMN, is another important region in pain modulation. , 56 In aAccording to previous studies, FAB is significantly stronger in chronic pain patients than in others, , 20 and The TSK, which was originally developed for the evaluation of FAB in low back pain patients, has also been validated for pain in other parts of the body, including neck pain. The TSK score has been suggested to be a sensitive predictor of the duration and degree of pain-related disability and resistance of treatment in neck pain patients.–62 A preThe aICs have abundant connections to other brain regions and play a key role in integrating perceptual, cognitive, and affective pain., 64, 65 While few studies to date have described the association of the DLPFC with FAB, the DLPFC activity has been reported to have negative correlations with pain unpleasantness. FurthermA structural brain change is another important aspect to understanding central mechanism underlying chronic pain. Structural MRI studies have shown gray matter abnormalities in the regions such as the DLPFC, IC, ACC, and PCC in chronic pain. , 67, 68 Several limitations associated with the present study warrant mention. First, most patients had used various medications, such as pregabalin, tramadol, and/or antidepressants, to relieve pain, so we were unable to exclude the possible effect of these medication on the brain functions. Second, no significant correlation was found between the TSK and the intensity of pain, suggesting that FAB may estimate chronicity of neck pain via the disruption of functional brain network, but not the degree of individual pain. More complex functional changes in the brain may associate with the augmentation of neck pain. Third, because of the cross-sectional study design, we were unable to demonstrate the causal relationship of FAB, pain, and the altered FCs of brain regions. Therefore, whether or not the altered FCs in the brain may affect FAB and thereby lead to the chronicity of pain remains unclear. To clarify these causal relationships, sequential data of neuroimaging and clinical evaluations from the onset of pain are required.The alteration of DLPFC connectivity may be involved in the pathology of CNP. Furthermore, an aberrant FC between the DLPFC and aIC may disrupt normal integration in processing the FAB in CNP patients. Therapeutic strategies amending FAB may restore normal brain functional network, consequently help stop the vicious cycle of CNP. Further prospective longitudinal and interventional studies are necessary to clarify these aspects.S1 File(XLSX)Click here for additional data file.


This study aims to examine the correlations between lumbar neuromuscular function and pain, lumbar disability in patients with nonspecific low back pain (NSLBP).Ninety patients, with ages 18 to 37 years old, with NSLBP were recruited in this study. The lumbar neuromuscular function was tested by the CON-TREX multijoint isokinetic test and training machine. This study uses the visual analog scale (VAS) and Roland–Morris Disability Questionnaire (RMDQ) to evaluate the pain and the dysfunction index of patients who have low back pain, respectively.Pearson correlation coefficient is used to evaluate the correlation between lumbar neuromuscular function and the VAS and RMDQ scores. VAS and RMDQ scores have correlations with the proprioception in the flexion of the lumbar vertebra flexion; the peak torque of both flexion and extension muscle groups; and average power and endurance at different angular velocities. The decrease of lumbar muscle strength, endurance, and lumbar proprioception of the lumbar vertebra leads to an increase in pain intensity and lumbar disability.This study suggests that patients with chronic low back pain require targeted training in muscle strength, endurance, and lumbar proprioception, providing a theoretical basis for prevention and treatment of chronic NSLBP patients. NSLBP does not only affect health, quality of life, and work but also brings heavy medical burdens and indirect social costs. Therefore, NSLBP has become one of the major reasons of manpower loss and medical costs.,5 In addition, patients with chronic low back pain experience a decrease in trunk activity because of the decrease in lumbar muscle strength and lumbar proprioception.,7Low back pain is one of the most common symptoms with a lifetime prevalence rate of 84%.,8 The neuromuscular function including several parts: muscle strength; muscle power; muscle endurance; voluntary muscle activation; and proprioception. The lumbar neuromuscular function may not only be responsible in improving the quality of patient's daily life and decreasing the pain, but also in maintaining the stability of the lumbar vertebra. Hence, the correlations of the lumbar neuromuscular function with pain and lumbar disability need to be explored. The lumbar neuromuscular function in this study includes 4 parts: lumbar proprioception, the strengths of lumbar flexion and extension muscle groups, average power, and endurance. The subjective evaluation index in this study is the visual analog scale (VAS), while the Roland–Morris disability questionnaire (RMDQ) allows the evaluation of the patient disability in daily life.The incidence rate of low back pain is high, and the daily lives of many patients have been affected.,13 revealed the correlation of VAS in low back pain cases with the muscle strength in flexion and extension muscle groups and the lumbar proprioception sense. These studies, however, cannot prove the correlations in lumbar disability. McGorry et al conducted the correlation of a longitudinal low back pain with function and suggested that pain–function correlations are stronger than those reported in cross-sectional studies over the course of low back pain. Most of these studies only show a unilateral correlation between lumbar neuromuscular function and pain and lumbar disability. According to the previous studies, we have found that the lumbar muscle strength and lumbar proprioception have a correlation with the VAS scores in low back pain cases. Moreover, in a longitudinal study, it has been proved that pain-function have a strong correlation even than cross-sectional studies. But few researches indicate both the correlation in pain and disability with lumbar neuromuscular function.Previous studiesTherefore, the present study uses isokinetic muscle strength and lumbar proprioception test techniques to evaluate the neuromuscular function of the NSLBP crowd and to analyze the relationship between the lumbar muscle strength, endurance, lumbar proprioception capacity, pain, and lumbar disability. This paper's results may provide us new information and theoretical basis on better treatment and rehabilitation of chronic NSLBP patients.22.1Before the intervention, each subject will be asked to sign a written informed consent. The study was approved by the ethics committee of the Shanghai University of Sport, China.2.2 published the correlation between pain intensity in low back pain patients and lumbar disability in 2004 with the correlation index at 0.422. In the present study, we used G∗Power Software: t-test , at effect size, test level (α), test efficacy (1–β), and total sample size of 0.4, 0.05, 0.90, and at least 47, respectively.Kovacs et al2.3We chose the chronic low back pain patients who received the treatment in the orthopedic hospital of Shanghai Sports University from May 2014 to March 2015 and the chronic NSLBP students from the same institution as test subjects. A total of 90 subjects from 18 to 37 years old participated in the study. All subjects should perform the x-ray and MRI to exclude specific low back pain. And the medical doctor did the lumbar functional test such as: lumbar flexion, extension and rotation. The inclusion criteria set were: subjects aging 18 to 60 years old who could understand the language and volunteered to participate; stable vital signs, conscious, and without cognitive impairment; and the course of low back pain ≧3 months. The exclusion criteria set were: previous intellectual disabilities; severe heart, liver, kidney, lung disability, tumor, pregnant women, and postoperative disability; cardiovascular and cerebrovascular diseases; mental illness or long-term use of sedatives; musculoskeletal system diseases that disturb neuromuscular function . The doctor has excluded the specific low back pain patients by asking the history; performing the physical examination and doing the laboratory test.2.4We used the CON-TREX multijoint isokinetic test and training machine  for the lumbar proprioception test. The specific test methods are as follows: attempted removal of visual and auditory effects in the subject; slow trunk flexion of the subject from the original position to a predetermined target angle by a constant-velocity machine and maintaining that position for 3 seconds, and reminding the subject to remember this predetermined target before the machine returns the trunk to the original position; and trunk movement with the subject holding the remote control and pressing the pause button at the target angle, which is recorded as the actual angle. The difference between the actual angle and the target angle is the absolute error angle, which is used to assess the ability of position sense. The test is measured in triplicates, and the absolute error angle is taken as an average. In addition, subjects can practice 3 times to adapt to this isokinetic test machine before conducting the formal proprioceptive test. The picture is shown in Fig. 2.5The isokinetic muscle strength test of the lumbar is performed using the CON-TREX multijoint isokinetic test and training machine . The test methods are as follows: The subjects take an upright position and fasten the shoulder blade and the pelvis with a drawstring. The power instrument axis aligns with the subject's trunk on L5–S1. The shoulder is fixed to the scapula, the hip joint is fixed to the pelvis, and the knee slightly bent and fixed above and below the feet placed on the adjustable pedals. The subject can familiarize with the process. The angular speed can be selected as 90°/s, and maximum contraction was performed 5 times as a warm-up exercise. Next, angular speed is selected as 60°/s, 120°/s, and 180°/s to begin the formal isokinetic strength test. Using centripetal–centripetal contraction at constant velocity, the subjects can individually use their best strength to flex and extend the lumbar 10 times at 3 different angular velocities. Each section rests ∼90 seconds. The picture is the same illustration shown in Fig. 2.6 evaluates pain intensity in patients with low back pain. VAS scores are measured on a 10-cm horizontal line, with “0,” “1–4,” “5–6,” “7–9,” and “10” indicating “no pain,” “mild pain,” “moderate pain,” “severe pain,” and “unbearable pain,” respectively.,15 The patients point out the score in the horizontal line. The picture is shown in Fig. The VAS2.7 The RMDQ has 24 yes–no questions. A “yes” answer is equivalent to 1 point, while “no” means 0 point. Out of the total score of 24 points, the higher the acquired point indicates a more serious problem in lumbar vertebra disability. Both scholars Fan and Yi,18 did the research in the reliability and validity on SCRMDQ (simplified Chinese version of RMDQ). The result showed that the Cronbach α value for internal consistency is 0.826 in Fan et al's paper and 0.874–0.883 in Yi et al's paper. The intraclass correlation coefficient (ICC) value is 0.949–0.952 in Yi et al's paper and 0.947 in Fan et al's paper. So the SCRMDQ has a good reliability and validity. In this research, we use SCRMDQ to evaluate the dysfunction index of patients with low back pain.RMDQ was used to evaluate the dysfunction index of patients with low back pain. The questionnaire was designed by Roland and Morris to mainly reflect the overall health of patients who have low back pain.2.8P <.05. The higher absolute value of Pearson correlation coefficient indicates a stronger correlation.,20 Scores of 0.0–0.2, 0.2–0.4, 0.4–0.6, 0.6–0.8, and 0.8–1.0 points represent “extremely weak or no correlation,” “weak correlation,” “moderate correlation,” “strong correlation,” and “extremely strong correlation,” respectively.Collected data were submitted to SPSS 17.0 and Microsoft Excel 2007 for analysis. The data is presented as “average ± standard deviation.” Pearson correlation coefficient was used to evaluate the correlation between lumbar muscles strength, endurance, proprioception, and the VAS and RMDQ scores. The significance level was 3r = 0.268, P = .011). RMDQ scores are correlated with the proprioception in lumbar vertebra flexion  and extension .The correlation between pain, disability, and proprioception in chronic NSLBP patients is shown in Table r = −0.504, P <.001) and with extension muscle at 60°/s , 120°/s , and 180°/s . RMDQ scores are correlated with flexion muscle at 60°/s  and with extension muscle at 60°/s , 120°/s , and 180°/s .The correlation between pain, disability with lumbar flexion, and extension peak torque in chronic NSLBP patients is shown in Table r = −0.257, P = .014) and 120°/s  and with average power in extension muscle at 60°/s . RMDQ scores have a correlation with average power in flexion muscle at 60°/s  and 120°/s  and with average power in extension muscle at 60°/s .The correlation between the pain and disability with the average power of the lumbar vertebra flexion and extension muscle in chronic NSLBP patients is shown in Table r = −0.88, P <.001), 120°/s , and 180°/s  and with extension muscle at 60°/s . RMDQ scores show correlation with flexion muscle at 60°/s  and 180°/s  and with extension muscle at 60°/s .The correlation between the pain and disability with the endurance of the lumbar vertebra flexion and extension muscle in chronic NSLBP patients is shown in Table 44.1 observed that pain intensity in 15 patients with chronic low back pain is correlated with proprioception sense and the worsening degree of proprioception from symptom aggravation. According to our research and Roosink's paper, the pain may decrease the sensitivity of the proprioceptive receptor so the NSLBP patients’ lumbar proprioception may worse than the normal persons. Conrad et al also found that the Oswestry disability index (ODI) in lumbar stenosis patients weakly correlate with the proprioception sense . Therefore, simulation of the proprioceptor and improvement of the proprioception sense are necessary to decrease the pain and improve the lumbar function in patients with low back pain.This study selects the joint location as an indicator of proprioception. The current test method for proprioception is the joint position test. The results indicated that the lumbar proprioception has correlations with pain and lumbar disability. Roosink et al4.2 have shown the good reliability of measuring peak torque in body isokinetic muscle strength test (ICC = 0.87–0.95). In this research, the peak torque has correlation with both lumbar pain and disability. These results confirmed the deeper pain intensity and the higher disability index in patients with chronic low back pain. When the lumbar and abdomen muscle weakens, lumbar stability decreases, and the symptoms of the lumbar worsen. Verbunt et al found that the pain intensity of 25 patients with chronic low back pain results to poor muscle activation ability. Therefore, training the shallow and deep core muscle is particularly important for patients with chronic low back pain.This study selects peak torque as an indicator for muscle strength. The isokinetic muscle strength test for peak torque is the “gold standard” method for evaluating muscle strength because of its high repeatability and accuracy. Guilhem et al4.3 confirmed the reliability of the average power indicator. Iwai et al evaluated the significant correlation between lumbar disability and average power in 53 patients with low back pain . In the isokinetic muscle strength assessment, the endurance index is the ratio of the last third of the work to the first third, where a higher ratio indicates higher fatigue resistance and better muscle endurance. Based on the VAS scores, ODI scores, lumbar muscle strength, and muscle endurance, the pain intensity, lumbar disability, and lumbar muscle endurance improved after 6-week suspension training of the chronic low back patients. These results indirectly show the correlation of pain intensity and lumbar disability with the lumbar muscle endurance in patients with chronic low back pain. Snekkevik et al established the correlation of fatigue with the intensities of pain and lumbar disability in 569 chronic low back pain patients, where the deeper intensity of lumbar disability indicates higher fatigue.The average power is a reflection of the work efficiency, and it is a common indicator for evaluating isokinetic muscle strength. Santos et al5This study is limited on the following disadvantages: The low back pain subjects are all young people with an average age of 23.98 years old. The age is between 20 and 34 years. Hence, the result cannot represent the entire human population. Rather than including the proprioception senses of motion perception and vibration perception, we only tested the position perception as motion and vibration perceptions are difficult to quantify. Hence, an accurate and comprehensive reflection of proprioception function is necessary and requires improvement as an important research direction. Muscle endurance reflects neuromuscular function. Further exploration of a better index replacement is necessary.6This study finds that the proprioception has correlations with pain and function in NSLBP patients. Hence, if we use the CON-TREX multijoint isokinetic test and training machine to do the lumbar proprioception training, low back pain patients may activate more proprioceptors to improve the proprioception.Both lumbar muscles strength and endurance have a correlation with pain and function in different flexion and extension angles. If we add the lumbar muscle strength and endurance training during the rehabilitation, the lumbar pain and dysfunction may decrease a lot. According to the results of the research we should do more training on muscle strength in flexion and endurance in extension.7This project uses the proprioception, isokinetic muscle strength, VAS, and RMDQ to evaluate the correlation among pain intensity, lumbar disability, lumbar muscle strength, proprioception, and muscle endurance in chronic NSLBP patients. The results suggest that patients suffering from chronic low back pain require targeted training in muscle strength, endurance, and lumbar proprioception. This study provides a theoretical basis for prevention and treatment of chronic NSLBP


A larger defect in the annulus fibrosus following lumbar discectomy is a well-known risk factor for reherniation. Procedures intended to prevent reherniation by sealing or occluding the annular defect warrant study in high-risk patients. This study sought to determine 3-year results of lumbar discectomy with a bone-anchored annular closure device (ACD) or lumbar discectomy only (controls) in patients at high risk for reherniation.This multicenter randomized trial enrolled patients with sciatica due to lumbar intervertebral disc herniation who failed conservative treatment. Patients with large annular defects after lumbar limited microdiscectomy were intraoperatively randomly assigned to receive ACD or control. Clinical and imaging follow-up was performed at routine intervals over 3 years. Main outcomes included rate of reherniations, reoperations, and endplate changes; leg and back pain scores on a visual analogue scale; Oswestry Disability Index (ODI); Physical Component Summary (PCS) and Mental Component Summary (MCS) scores from the SF-36; and adverse events adjudicated by a data safety monitoring board.P < 0.001), reoperation , leg pain , back pain , ODI , PCS , and MCS . The frequency of all-cause serious adverse events was comparable between groups .Among 554 randomized patients, the modified intent-to-treat population consisted of 272 patients in which ACD implantation was attempted and 278 receiving control; device implantation was not attempted in 4 patients assigned to ACD. Outcomes at 3 years favored ACD for symptomatic reherniation  contains supplementary material, which is available to authorized users. Lumbar discectomy is an effective surgery for chronic sciatica secondary to intervertebral disc herniation. However, symptom recurrence following surgery is a common risk that is influenced by patient- and surgery-related factors such as male sex, disc degeneration, and large post-surgical annular defect size . PatientThis was a multicenter, multinational, randomized controlled trial to determine the effectiveness and safety of lumbar discectomy with a bone-anchored implant designed to provide annulus fibrosus occlusion in patients at high risk for reherniation . Local ethics committees reviewed and approved the protocol. All participants provided written informed consent before trial participation. The design  and 2-yePreoperative imaging included magnetic resonance imaging (MRI) with T1- and T2-weighted axial and sagittal images, index-level low-dose multiplanar computed tomography (CT), and anteroposterior/lateral and flexion/extension x-rays. Important eligibility criteria for the study included diagnosis of a single-level lumbar disc herniation identified on preoperative imaging, and concurrent clinical findings  with leg pain  that were not responsive to at least 6 weeks of conservative treatment, and at least moderate disability (≥ 40 on the Oswestry Disability Index). A complete list of study entry criteria is provided in Supplement Table . Symptomatic reherniation was defined as a reherniation  that was confirmed during a reoperation, or identified on imaging with associated recurrent or new lumbar pain, leg pain, or neurological deficit. Reoperation included any repeat procedure at the index level of herniation including discectomy, supplemental fixation, fusion, or device explant. Key radiographic assessment by x-ray and CT included disc height, device status, and vertebral endplate changes (VEPC). Imaging evaluations were read by an independent core laboratory radiologist who was blinded to clinical outcomes. Clinical outcome parameters included leg and back pain severity, Oswestry Disability Index (ODI), SF-36 Physical Component Summary (PCS) score, and SF-36 Mental Component Summary (MCS) score. The minimal important differences (MID) were defined as a ≥ 20-point decrease from baseline for leg pain [Clinical and imaging follow-up occurred at 6 weeks, 3 months, 6 months, and at annual intervals for 3 years and included MRI, low-dose CT, and AP/lateral and flexion/extension x-rays. Patients in this study will remain in follow-up for 5 years. A schematic that lists the clinical and imaging tests performed at each study interval is provided in Supplement Table 2leg pain , ≥ 20-poleg pain , ≥ 15-poleg pain , and ≥ 6leg pain . Neurolot test for continuous data, Fisher’s exact test for categorical data, and log-rank tests for survival data. In patients who underwent a reoperation prior to the 3-year follow visit, leg pain, back pain, ODI, PCS, and MCS values at 3 years were substituted with baseline values. Statistical significance was set at P < 0.05 and hypothesis testing was two-sided. Statistical analyses were performed using SAS v9.4  and R v3.3.2 .Statistical analyses were performed on a modified intention-to-treat population consisting of randomized patients in whom the intended procedure was attempted. Preoperative group characteristics were reported as mean and standard deviation for continuous variables, and count and percentage for categorical variables. Group comparisons were performed with Student’s n = 276) or control (n = 278) at 21 hospitals (Study Group Appendix Table n = 4) or nerve root injury (n = 1). The mean age of all enrolled patients was 43 ± 11 years and 59% were men. Disc herniation was most commonly identified at L5-S1 (56%) or L4-L5 (41%). Patients typically presented with severe leg pain , severe disability , and moderate back pain     for leg pain, 23 vs. 30  for back pain, and 18 vs. 23  for ODI. Health-related quality of life scores at 3 years was higher in the ACD group; PCS scores were 47 vs. 44  and MCS scores were 52 vs. 49 . The percentage of patients achieving the MID was statistically greater in the ACD group for leg pain, ODI, PCS, and MCS; no statistical difference between groups was noted for back pain (P = 0.08) . Vertebral endplate changes were identified by the imaging core laboratory in 89% of ACD patients and in 41% of controls (P < 0.001). The median VEPC areas at 2- and 3-year follow-up were 0.42 cm3 and 0.49 cm3 with ACD, 0.29 cm2 and 0.42 cm2 for controls. Neither the frequency, area, nor growth trajectory of VEPC was associated with clinical sequelae.Disc height decreased by approximately 30% in each group relative to baseline. Average disc height at 3 years was 6.3 ± 2.2 mm with ACD and 6.4 ± 2.2 mm with controls (P = 0.26). Serious adverse events related to the device or procedure occurred in 10.7% of the ACD group and in 18.7% of controls (P = 0.008), and were mainly attributable to lumbar disc reherniation (Table n = 5), mesh detachment (n = 3), anchor migration (n = 3), and anchor fracture (n = 1). Reherniation was identified at the time of reoperation in four of these patients. The frequency of all serious adverse events , yet the reherniation rate on imaging irrespective of symptoms was lower with ACD (5% vs. 50%) . Our gro%, yet thPatient-reported outcomes statistically favored the ACD group at 3 years. However, the clinical implications of these findings are unclear since the mean differences between groups ranged from 0.3 to 0.6 MID units, depending on the outcome. A likely explanation for these modest differences is that this was a trial of a device intended to prevent, not treat, herniation recurrence. Since lumbar discectomy results in a durable surgical repair in 70–80% of cases, the benefit of an ACD would be realized only in the subsample of patients in which a reherniation was prevented but would not be anticipated to impact patient-reported outcomes otherwise. Based on the incidence of events and the risk reduction achieved with ACD, the number of patients needed to treat with ACD to prevent one symptomatic reherniation is 7; the number needed to treat to prevent one reoperation is 12.Important strengths of this study were the multicenter randomized design, large sample size sufficient to detect even rare adverse events, and comprehensive independent review of imaging and adverse events during the trial. There are also several limitations of this study. First, these results are not applicable to all patients undergoing lumbar discectomy, but only the approximately 30% of cases at high risk of reherniation due to a large post-surgical annular defect . The ACDThe addition of a bone-anchored ACD to lumbar discectomy in patients with large post-surgical annular defects reduces the risk of reherniation and reoperation, with a better long-term pain and disability relief over 3-year follow-up compared with lumbar discectomy only. While the ACD was associated with distinct risks such as implantation difficulties, device migration, mesh detachment, and VEPC, the overall risk of complications was comparable between groups.ESM 1(DOCX 64 kb)


Background: Obesity and cancer are recognized worldwide health threats. While there is no reported causal relationship, the increasing frequency of both conditions results in a higher incidence of obese patients who are being treated for cancer. Physiological data indicate that there is a relationship between obesity and susceptibility to pain; however, currently, there are no specific pharmacological interventions.Objective: To evaluate the self-reported intensity of postoperative pain in obese and nonobese lung cancer who receive either thoracotomy or video-assisted thoracic surgery (VATS) surgical therapy.Material and Methods: In 50 obese [mean body mass index (BMI) of 34.1 ± 3.2 kg/m2] and 62 nonobese (mean BMI of 24.9 ± 3 kg/m2) lung cancer patients, the intensity of pain was estimated every 4 h using a visual analog scale  beginning shortly after surgery (Day O) and continuing until the day of discharge (Day D).Results: The self-reported pain was more severe in obese than in nonobese patients, both at the time of the operation [Day O ] and at the day of discharge [Day D ]. This finding was consistent both in the patients after thoracotomy and after video-assisted thoracic surgery . The patients with severe pain shortly after surgery (VAS score >4) had significantly higher BMI  and were hospitalized longer than the remaining patients .Conclusion: The reported perception of pain in obese lung cancer patients is greater than in nonobese patients undergoing the same thoracic surgery. In obese patients, severe pain persisted longer. Pain management is an important consideration in the postoperative care of lung cancer patients, even more so with obese patients. Lung cancer is the most common cancer worldwide with 1.8 million new cases in 2012 and the highest incidence rates in Central and Eastern Europe . These rates create significant clinical, economic, and social problems. For example, more than 1.6 million people died due to lung cancer in 2012, and this total is expected to grow to 3 million by 2035 . ObesityPatients after thoracic surgical procedures are at very high risk of postoperative pain . StudiesThere is also close relation between increasing weight and more frequent occurrence of chronic pain. In morbidly obese persons, chronic pain occurs four times more frequently than in nonobese persons . In a reTherefore, it is important to assess how obesity affects the severity of postoperative pain in patients after lung cancer surgery. A careful review of the literature related to reported pain in obese and nonobese lung cancer patients undergoing surgical procedures found no studies. Thus, the aim of the study was to provide an initial evaluation of pain experienced by obese and nonobese lung cancer patients from shortly after surgery until discharge. A collateral question was current pain management practices that include medications to reduce pain.2 with a mean of 29.5 ± 5.83 kg/m2. There were 50 obese patients  and 62 nonobese patients (55.4%), including 30 overweight patients , 30 normal weight patients , and 2 underweight patients . There were 41 patients (36.6%) with adenocarcinoma, 40 patients (35.7%) with squamous cell carcinoma, 16 patients (14.3%) with lung metastases, 9 patients (8%) with large cell carcinoma, 3 patients (2.7%) with adenosquamous carcinoma, and 3 patients (2.7%) with carcinoid.A convenience sample of 112 patients , aged 40–84 years (mean 65 ± 6.9 years), was evaluated. Their body mass index (BMI) ranged from 15.6 to 42.9 kg/m2 and 28.4 ± 5.7 kg/m2).Thoracotomy was performed in 55 patients (49.1%), including pulmonectomy in 5 patients, lobectomy in 34 patients, and wedge resection in 17 patients. Video-assisted thoracic surgery (VATS) was performed in 57 patients (50.9%), including lobectomy in 53 patients and wedge resection in 4 patients. There was no significant difference between thoracotomy and VATS groups regarding BMI  and nonobese (BMI < 30 kg/m2) patients.After removal of the paravertebral catheter, intravenous morphine was replaced by subcutaneously administered doses of 5 mg every 4 h; the treatment with ketoprofen and pyralgin or paracetamol was continued. The evaluation of the pain was performed by two scorers independently: by a nurse shortly after surgery and by a doctor at the time of discharge. At Day D, the scorer was unaware of the score at Day O. The results were compared in the groups of obese . 12. The normality of variables was tested with Kolmogorov–Smirnov test. Data were compared using the Student’s The comparison of the groups of the obese and nonobese patients after surgical procedures for lung cancer is shown in The length of stay in hospital ranged from 4 to 78 days. The mean time of hospitalization was similar in obese and nonobese patients Table 2.In all the patients, the intensity of pain ranged from 0 to 8 both at Day O and at Day D, and its mean intensity was 3.9 ± 1.3 at Day O and 3.2 ± 1.3 at the time of leaving hospital, Day D. In the whole group, there were no significant differences in the pain scores between the values recorded in the morning/early afternoon hours (6.00–14.00) and afternoon/night hours (18.00–02.00) in the obese, overweight, and normal weight patients.2vs 28.8 ± 5.2, p < 0.01) and stayed longer in the hospital . Patients with intensity of pain exceeding 4 at Day O (mean 5.6 ± 0.9) still suffered from severe pain at Day D (mean 4.9 ± 1.2).There were 29 patients (26%) who suffered from severe pain (score >4) at day O. The patients suffering from severe pain, scored as exceeding 4, shortly after surgery as compared with the remaining patients had higher BMI  was greater than in the overweight patients (mean BMI 27.4 ± 1.6 kg/m2), and the intensity of pain in overweight patients was greater than in the normal weight and underweight patients (mean BMI 22.6 ± 2 kg/m2); the data is shown in The intensity of pain—both shortly after surgery and at the time of discharge from hospital—in the obese patients , the most intense pain was in the group of obese patients who underwent thoracotomy (4.9 ± 1.3) and the slightest in the nonobese patients who underwent VATS (3.0 ± 0.8). At the time of discharge from hospital (Day D), the most intense pain was in the group of obese patients who underwent thoracotomy (4.5 ± 1.4) and the slightest in the nonobese patients who underwent VATS (2.3 ± 0.6). In both Day O and Day D, the intensity of pain in obese patients exceeded the intensity of pain in nonobese patients by about two points using the VAS.The results of our study indicate that obese patients after surgical treatment of lung cancer suffer more from pain in the postoperative period than nonobese patients, both Day O and Day D. This finding is independent of the type of surgery, either thoracotomy or VATS.Similar results were observed in some, but not all, other studies comparing pain sensitivity after various surgical procedures . More seHowever, in the patients undergoing total hip arthroplasty, obesity was not associated with increased postoperative pain . RetrospThere are also a number of studies on the relation between obesity and non-postoperative, chronic pain, indicating that obese patients have lower pain thresholds . ObesityHowever, experimental data gave contradictory results. In experiments in animals, pain induced by thermal stimulus indicated increase in pain threshold related to diet-induced obesity . Pain inThe reason of different pain thresholds in the obese and nonobese patients has not been elucidated. Chronic inflammatory state is associated with obesity  and thusIt has been reported that the systemic inflammation due to the release of inflammatory mediators from macrophage accumulation is greater in obese than in nonobese patients. This might contribute to lower thresholds of pain in obese patients .Recently, among adipokines  such as leptin, adiponectin, and resistin, only the serum level of resistin was found to be related strongly to the severity of pain in the patients undergoing laparotomy . In anotThe authors of this paper speculate that one of the reasons of decreased pain threshold in obese patients might be nocturnal hypoxemia: There is a high percentage of sleep apnea among these obese patients, often undiagnosed and untreated. It has been shown that nocturnal episodes of arterial oxygen desaturations as a consequence of obstructive sleep apneas and hypopneas are associated with an increased pain . The pro2vs 28.8 ± 5.2, p < 0.01). The proportion of patients suffering from severe pain requiring interventional analgesics pain varies depending on the groups of patients. One large-scale retrospective study encompassing 1,736 patients found that, for 28.5% of patients in the study, obesity was an independent factor of postoperative pain requiring intervention  (More than one quarter of our patients (26%) suffered from severe pain (score exceeding 4 on VAS) in the post-general anesthesia unit. These patients had higher BMI than the patients with less intense pain (31.8 ± 5.6 kg/m= 0.001) .All our patients received the best analgesic treatment according to guidelines supervised mostly by nurses and modified, when needed, by doctors. The problem of unsatisfactory analgesic treatment in postsurgical period remains unresolved in other centers .In our patients, high ratings of pain intensity Day O and Day D are noted. This finding confirms individual differences in pain perception.The length of stay of our patients in hospital after surgery for lung cancer was similar in obese and nonobese patients. This is in accordance with a recent study of lung cancer obese and nonobese patients who underwent lobectomy . HoweverThere were significant differences in the pain sensation in obese and nonobese persons in the group of patients who underwent open thoracotomy or VATS, confirming our finding of close relation of pain sensitivity and increased BMI. Possible differences in pain intensity in the patients after VATS and open thoracotomy should be mentioned. In general, VATS is known as a procedure associated with less severe pain than open thoracotomy . HoweverThe strength of the study is appropriate number of the patients studied in compared groups. The other one is double check of pain intensity soon after surgical procedure and at the time of discharge home.The main limitation of this study is a use of only one scale for determination of pain intensity in the postoperative period. However, the scale used, VAS, is routinely performed scale for evaluation of pain in surgical unit of our Hospital, and both the nurses and the doctors are familiar with it. Neuropathic pain occurs usually with a delay of 7 days after thoracic surgery and persists thereafter ; thus, tIt would be interesting to continue the evaluation of the delayed, mostly neuropathic, pain in the obese and nonobese groups of the patients with the use of the scales for delayed postoperative pain.Taking into account that obese persons are at high risk of developing hypoxemia or hypoventilation during sleep due to obstructive sleep apnea syndrome  and thatObese patients undergoing surgery for lung cancer suffer more from the pain during the postoperative period than nonobese patients, and this observation may indicate higher sensitivity to pain in the patients with increased BMI. Severe pain in early post-surgical period is associated with a high probability of persisting severe pain at the time of discharge. There should be more rigorous supervision of analgesic treatment in postoperative period in the obese patients with lung cancer in order to prevent the patients’ suffering from severe pain.The routine analgesic treatment after surgery followed detailed guidelines in our hospital and according to national and international guidelines  and was MM, AB, CD, PB, and AR performed data acquisition, organization of the database, and statistical analysis. CD, AB, PB, AR, VVT, VNC, ASK, TIM, AM, SGK, SGS, CEK, and GA contributed to the design of the study, conception of the study, and writing of the manuscript. GA, CEK, SGS, and MM prepared the preparation and editing of the manuscript. All authors contributed to manuscript revisions and approved the submitted version.This work was supported by Russian Academic Excellence project “5-100” for the Sechnov University, Moscow, Russia. This research was partially also supported in part within the framework of the State Proposal 0090-2017-0018, and by the project of RAS Program “Fundamental Research for Biomedical Technologies’ .GA was employed by GALLY International Biomedical Research Consulting LLC, San Antonio, Texas, USA.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Worldwide, 80% of patients who undergo surgery receive opioid analgesics as the fundamental agent for pain relief. However, the irrational use of opioids leads to excessive drug dependence and drug abuse, resulting in an increased mortality rate and huge economic loss. The crisis of opioid overuse remains a great challenge. In this review, we summarize several key factors in opioid abuse, including race, region, income, genetic factors, age and gender, smoking and alcohol abuse, history of chronic pain and analgesic drug abuse, surgery, neuropsychiatric illness, depression and antidepressant use, human factors, national policies, hospital regulations, and health insurance under treatment of pain. Furthermore, we present several prevention strategies, such as perioperative measures, opioid substitutes, treatment of the primary illness, emotional regulation, use of opioid antagonists, efforts of the state, hospitals, doctors and pharmacy benefit managers, gene therapy, and vaccines. Greater understanding and better assessment are required of the risks associated with opioid abuse to ensure the safety and analgesic effects of pain treatment after surgery. Despite the increasing use of minimally invasive surgeries –3 and neIn the United States, deaths related to opioid exposure have reached 33,000 per year –27. ThisA larger number of studies have reported the risk factors for opioid abuse , 30, 31.According to a recent study, African Americans experience more acute pain than non-Hispanic white patients in a variety of acute medical situations. Furthermore, African Americans are more likely to receive nonsteroidal anti-inflammatory drugs (NSAIDs) instead of opioids. However, this racial difference, in the severity of acute posttraumatic pain, may not be explained by factors of socioeconomic status or accident characteristics . AnotherIn China, there is no solid evidence to show the effects of race, region, and income factors on opioid abuse. However, clinical experience indicates a relatively high incidence of opioid abuse in minority ethnic groups with low incomes, those who live in remote areas, and, especially, those who earn their living through manual labor.OPRM1. In another study, De Gregori et al. [OPRM1, COMT, and ESR1 genes substantially influenced morphine consumption after abdominal surgery. This highlights the important contribution of genetic variability in postoperative analgesia.Several studies have identified a number of genes that are related to opioid use. Smith et al.  found a i et al.  demonstrKringel et al. summarized the effects of gene polymorphism on opioid use and pain, as displayed in Taken together, some studies have reported a correlation between certain genes and opioid consumption, while others have shown different results. Therefore, further studies are needed to investigate the relationship between genetic viability and opioid use.Previous studies have indicated that elderly patients are more likely to develop persistent opioid use after surgery . One stuIt has been reported that nicotine dependence is associated with increased sensitivity to pain –52. DataChronic pain is a major contributing factor for increased opioid consumption. In Australia, patients with osteoarthritis are the main consumers of opioids, which results in a huge medical burden . In addiAccording to a study on the global volume of surgery in 2012, more than 300 million patients undergo surgical procedures each year . Pain isSoneji et al.  reviewedPrevious studies have shown that a history of psychiatric disorders and benzodiazepine use is associated with opioid overuse . During Sun et al.  conducteFinkelstein's study  found thConversely, Maughan et al.  demonstrMedical insurance and subsidies may be involved in opioids overuse. It has been shown that patients with medical assistance , 99 consThe reduction of opioid overuse is an urgent task for clinicians worldwide. Some people are worried that restricted opioid dosing guidelines might compromise the effect of opioid therapy for patients who could benefit from it. However, the risks associated with high-dose opioid therapy outweigh the benefits . TherefoWorldwide, more than 300 million patients undergo surgical treatment each year . Pain isERAS is a promising way to reduce opioid use after surgery . A recenRegional block of pain and infiltration with local anesthetics play an important role in pain control as well as in reducing the risk of opioid abuse after surgery. The benefits of these strategies have been demonstrated by a large number of studies following various surgical procedures, including total knee arthroplasty (TKA), ligamentum arthrodesis, hepatectomy, lumpectomy, colposcopy, and endoscopic surgeries .In addition, the combination of intravenous sedatives and acupuncture procedures can produce satisfactory postoperative analgesia, which may help to reduce the risk of opioid overuse. In a Cochrane review, Kwan et al.  includedHowever, Ladha et al.  analyzedPerioperative multimodal analgesia plays an important role in the prevention of opioid abuse after surgery. The combination of nonsteroidal anti-inflammatory (NSAID), dexmedetomidine, and weak opioids can produce satisfactory analgesia without significant adverse effects related to opioids , 87–89. Many surgeons and anesthesiologists prefer to use NSAIDs to control mild pain after surgery. While NSAIDs are beneficial to many patients, safety concerns are increasing as their use becomes more prevalent. Related negative effects, such as aggravating digestive ulcer and heart and kidney effects are needed to be considered, especially for elderly patients. To optimize safety and efficacy, its use should always be tailored to each individual patient. In addition, all patients prescribed NSAIDs should be monitored for gastrointestinal, cardiovascular, and renal functions . When apIt is the job of doctors to monitor opioid abuse. However, doctors can also be opioid abusers , 29. TheSensory dysfunction is a common symptom of neuropathic pain. Nerve injury as a result of surgical manipulation is a leading cause of neuropathic pain after surgery . SwensonA large number of surgical patients are nicotine dependent. Chiang et al.  demonstrIn addition, other medical workers, such as pharmacy benefit managers (PBM) help to limit opioid medication in opioid-naive patients to 7 total days for initial prescription, improving safety and convenience for consumers and employers as well as reducing prescription drug costs. Thus, efforts from PBM also play a positive role in the control of opioid abuse .In summary, doctors play an important part in perioperative opioid use. More efforts are needed to control the occurrence and development of pain during the preoperative, intraoperative, and postoperative periods.Gabapentin/pregabalin, another first-line drug for the treatment of neuropathic pain has been used for postoperative pain control , 114. A Opioid substitutes are agents which are expected to produce equivalent analgesic effects to opioids without opioid-related side effects or the risk of opioid abuse.A recent study demonstrated the efficacy of kappa opioid receptor (KOR) agonists in the treatment of cancer-induced bone pain in mice, without changing the tumor size or affecting cancer cell proliferation. This suggests that KOR agonists may be a promising target for cancer pain management .Methadone and buprenorphine are currently used to treat opioid use disorders. These drugs also appear to help reduce suicidality and crime . RecentlMore studies are still needed to clarify the effects and mechanisms of these nonopioid analgesics on cancer pain. In addition, it should be noted that death caused by methadone overdose has shown a tendency to increase in the United States .Control of the primary disease may help to reduce opioid consumption after surgery. Previous studies have suggested that opioids should not be used as the first-line treatment for peripheral neuropathic pain or polyneuropathy, resulting in a limited therapeutic effect and increased risk of drug dependence and overdose , 122. InThe experience of pain often leads to the occurrence and development of negative emotions. Conversely, the control of emotions, such as a state of relaxation, may help to relieve pain and prevent drug abuse. In a randomized controlled trial that studied pain management during childbirth, Smith et al.  reportedOpioid antagonists can be used to prevent opioid overuse. A recent study demonstrated that intranasal naloxone administration has the potential to be part of evolving clinical practice, in terms of opioid overdose prevention . HoweverGovernment policies, hospital regulations, and education of medical workers are also important factors in the control of opioid abuse. The formulation and implementation of education and guidelines for opioid treatment, as well as the prescription and clinical guidance of medical workers, play a positive role in the prevention of opioid overuse , 74, 75.Hurd et al.  examinedNew technologies and therapeutic approaches, such as vaccines and gene therapy, may fundamentally alter the opioid abuse epidemic; however, there is still a long way to go in this area of study.Worldwide, the epidemic of opioid abuse has been growing every year, resulting in disastrous consequences. There is an urgent need for governments, institutions, and each clinical practitioner to find effective means to prevent the current crisis. Therefore, a deep understanding of the prevalence and risk factors of opioid abuse is needed. Furthermore, pain issues must be dealt with a vigilant manner in such patient populations. National policies and regulations, hospital regulations, and doctors should play a critical role in this campaign for the reduction of opioid abuse. Of course, more scientific research is needed to identify more effective measures for prevention, possibly by targeting specific genes and developing vaccines, to benefit the maximal number of patients with the least possible side effects.


The aim of the present study was to explore the pain modulation effects of motor imagery (MI) and action observation (AO) of specific neck therapeutic exercises both locally, in the cervical region, and remotely. A single-blind, placebo clinical trial was designed. A total of 30 patients with chronic neck pain (CNP) were randomly assigned to an AO group, MI group, or placebo observation (PO) group. Pain pressure thresholds (PPTs) of C2/C3, trapezius muscles, and epicondyle were the main outcome variables. Secondary outcomes included heart rate measurement. Statistically significant differences were observed in PPTs of the cervical region in the AO and MI groups between the preintervention and first postintervention assessment. Significant differences were found in the AO group in the epicondyle between the preintervention, first and second post-intervention assessments. Regarding heart rate response, differences were found in the AO and MI groups between the preintervention and average intervention measurements. AO and MI induce immediate pain modulation in the cervical region and AO also induces remote hypoalgesia. OA appears to lead to greater pain modulation as well as a greater heart rate response, however, both should be clinically considered in patients with CNP. Chronic neck pain (CNP) is a common musculoskeletal disorder with a high prevalence, and is the fourth leading condition that generates significant disability ,2. PatieSNTE has also been shown to induce immediate pain modulation, similar to the hypoalgesia induced by aerobic or isometric exercise ,7. ThereIn recent years, both of these mental processes have been used in the acquisition of new motor gestures, range-of-motion enhancements, or for chronic pain management ,20,21. DThe aim of the present study was to explore the pain modulatory effects of MI and AO of SNTE in the cervical region. Our objective was to evaluate the hypoalgesic effects induced by MI and AO, both locally, in the cervical region, and remotely . We hypoThis study was a randomized, placebo clinical trial, with patient and evaluator blind, planned and conducted in accordance with Consolidated Standards of Reporting Trials (CONSORT) requirements, and was approved by a university ethics committee, with number CSEULS-PI-026/2019, Madrid, Spain.clinicaltrial.gov . All patients completed the informed consent document prior to the study.This study was registered in the United States Randomized Trials Registry on The participants had been referred to the primary care physiotherapy service, had been diagnosed with CNP by their family doctor, and met the study’s inclusion criteria at one physiotherapy center. Participants were recruited between April 2019 and May 2019.The inclusion criteria were as follows: (a) men and women aged between 18 and 65 years; and (b) a medical diagnosis of CNP with at least six months of neck pain symptoms. Exclusion criteria included the following: (a) patients with rheumatic diseases, cervical hernia or radicular pain, cervical whiplash syndrome, neck surgeries, or a history of arthrodesis; (b) systemic diseases; (c) vision, hearing, or vestibular problems; or (d) severe trauma or a traffic accident that had an impact on the cervical area.All data were collected at the La Salle University Center for Advanced Studies. All the participants were given an explanation of the study procedures, which were planned according to the ethical standards of the Helsinki Declaration.Randomization was performed using a computer-generated random sequence table with a non-balanced three-block design . An independent researcher generated the randomization list, and a member of the research team who was not involved in the assessment of the participants or the intervention was in charge of the randomization and maintained the list. The patients included were randomly assigned to one of the three groups using the random sequence list, ensuring concealed allocation.The assessments and treatments were performed by various therapists. The evaluator was blinded to the participants’ group assignment. All the intervention procedures were performed by the same physiotherapist who had experience in the field and was blinded to the purpose of the study. Patients were blinded to their group allocation. In addition, a different researcher, blinded to the objectives of the study, performed the data analysis.Patients in this group observed two SNTE typically used in the treatment of patients with CNP. Both exercises were based on the motor gesture of craniocervical flexion . PatientThe first exercise involved a resistance deep muscle contraction by performing continuous the cranio-cervical flexo-extension gesture with the resistance of an elastic band A. The seThe patients in this group performed a motor imagery protocol of the same cervical exercises observed by the AO group . PatientPatients in this group underwent a PO protocol. A video composed of only nature landscape clips was visualized for 4 minutes, without visualizing any motor gesture. This kind of PO protocol has been used in previous research ,23.2) attached to a pressure (force) gauge. The gauge displayed values in kilograms, but because the surface of the rubber tip was 1 cm2, the readings were expressed in kg/cm2. The range of the pressure algometer values was from 0 to 10 kg, in 0.1 kg intervals. The pressure was applied at a rate of 0.31 kg/second [A pressure pain threshold (PPT) is defined as the minimal amount of pressure at which a sense of pressure first changes to pain. The mechanical pressure algometer  used in this study consisted of a round rubber disk , the zygapophyseal joint of C2/C3, and the nondominant lateral epicondyle. All the assessments were performed in a quiet room. In order to familiarize the participants with the test procedure, pressure was first applied to an area that would not be tested during the study. Three consecutive measurements of the PPT at the four locations at intervals of 30 seconds and the mean of these three trials was used for the data analysis .r = 0.650–0.868).Heart rate (HR) was measured to determine how the patients were engaging in the interventions, because HR is under autonomic nervous system control. The heart rate was recorded to quantify the changes produced during the performance of the mental motor practice. The Garmin Forerunner VR 225 is a commercially available wrist-worn heart rate monitor that uses an optical green light sensor to detect pulse rate, which represents HR. The Garmin Forerunner VR 225 was programmed with the participants’ sex, age, weight, and height, and was fitted on the left forearm, according to the user manual. Previous studies have shown moderate to strong validity of the Garmin Forerunner VR 225 versus traditional electrocardiography measures (Pearson The movement imagery questionnaire—revised (MIQ-R) is an eight-item self-report inventory used to assess visual and kinesthetic motor imagery ability. Four different movements are included in the MIQ-R, which is comprised of four visual and four kinesthetic items. For each item, participants read a description of the movement. They then physically performed the movement and were instructed to resume the starting position after finishing the movement and before performing the mental task, which was to imagine the movement visually or kinesthetically. Next, each participant rated the ease or difficulty of generating the mental image on a seven-point scale, in which 7 indicated “very easy to see/feel” and 1 “very difficult to see/feel.” The internal consistencies of the MIQ-R have been adequate, with Cronbach’s α coefficients ranging above 0.84 for the total scale, 0.80 for the visual subscale, and 0.84 for the kinesthetic subscale .Mental chronometry (MC) is a reliable measure that has been widely used to record objective measurements of the ability to create mental motor images ,28,29. TPain-related fear of movement was assessed using the 11-item Spanish version of the Tampa Scale for Kinesiophobia, whose reliability and validity have been demonstrated . The TamThe Spanish version of the Pain Catastrophizing Scale assesses the degree of pain catastrophizing and is a reliable and valid form of measurement. It is composed of 13 items, with a three-factor structure of rumination, magnification, and helplessness that must be answered with a numeric value between 0  and 4 , with a maximum score of 52 points, with higher scores indicating greater pain catastrophizing .Disability was measured using the Spanish-validated Neck Disability Index (NDI), which consists of 10 items related to daily functional activities. Each question is measured on a scale from 0 (no disability) to 5, and an overall score out of 100 is calculated by adding each item score together and multiplying it by two. A higher NDI score indicates a patient’s greater perceived disability due to neck pain. It has been shown to have high “test–retest” reliability and to have appropriate psychometric properties .The level of physical activity was objectified through the International Physical Activity Questionnaire, which allows the participants to be divided into three groups according to their level of activity: high, moderate, and low or inactive . This qup < 0.001) [A visual analogue scale (VAS) was used to measure pain intensity. The VAS is a 100-mm line with two endpoints representing the extreme states “no pain” and “the maximum pain imaginable”. It has been shown to have good retest reliability  ,36.Each participant completed an informed consent document to participate in the study, in addition to a set of questionnaires to complete before starting the intervention. These questionnaires included psychometrics forms and a questionnaire about age, sex, medication, anthropometric measures, pain duration, and the predominant pain location. The psychological variables were evaluated with self-assessments and the pain intensity by VAS. Then, MIQ-R and mental chronometry were assessed. The preintervention PPT measurements were made at the four sites by an external assessor, in random order. Subsequently, an initial HR measurement was performed. The Garmin Forerunner VR 225 monitor was placed, the patients lay down for five minutes, and then sat upright for two more minutes. In both positions, the patients were instructed to maintain a comfortable position and relaxed breathing, with the aim of obtaining a baseline HR measurement. The first measurement was taken at the end of seven minutes, just before the start of the intervention (preintervention measure). At this time and in a sitting position, patients performed the AO protocol, MI or PO, according to the randomized group. HR measurements were taken during the intervention. A measurement was recorded every 15 seconds for four minutes; subsequently, the average of all the measurements was recorded (intervention average measure). The postintervention HR was recorded at the end of the four minutes of the intervention (postintervention measurement). Immediately after the intervention, a blinded evaluator measured the PPTs in all four locations (post-1). Following this, patients were asked to sit relaxed and comfortably, without movement, for 10 minutes, and the PPTs were again measured (post-2).d) were calculated according to Cohen’s method, in which the magnitude of the effect was classified as small (0.20–0.49), moderate (0.50–0.79), or large (>0.8) [The statistical data analysis was performed using statistical SPSS software version 22.0 . The normality of the variables was evaluated by the Shapiro–Wilk test. Descriptive statistics were used to summarize the data for continuous variables and are presented as mean ± standard deviation, 95% confidence interval. Additionally, we compared age, weight, and height between groups with a one-way ANOVA to explore whether the groups were homogeneous at baseline. The chi-squared test was used for the categorical variables that were presented as frequency and percentage. A mixed model analysis of variance (ANOVA) was conducted to study the effect of the between-participant “treatment group” factor in each of the three categories  and the within-participant “time” factor, also in each of the three categories , of all the dependent variables except for the HR. For the HR, the difference between the preintervention measurement, average intervention measurement, and the immediate postintervention measurement was evaluated . A post hoc analysis with Bonferroni correction was performed in the case of significant ANOVA findings for multiple comparisons between variables. Effect sizes (e (>0.8) . The α lp < 0.05)  .F = 3.04, p = 0.025, ƞ2 = 0.185) and time . The post hoc analysis revealed significant intragroup differences   .F = 3.42, p = 0.014, ƞ2 = 0.202) and time  The post hoc analysis revealed significant intragroup differences   .F = 4.16, p = 0.005, ƞ2 = 0.235) and time . The post hoc analysis revealed significant intragroup differences between the preintervention assessment and the post-1 measurement, with a large effect size , and between the post-1 and the post-2 assessments in the AO group, with a moderate effect size  . Finally, statistically significant differences were found between the AO and PO groups, with a large effect size   . In addi = 1.66) .F = 6.4, p < 0.001, ƞ2 = 0.321) and time . The post hoc analysis revealed significant intragroup differences only in the AO group , and between the pre-intervention assessment and the post-2 measurement, with a moderate effect size . In addition, intra-group differences were found in the PO group between the preintervention and post-2 intervention measurements, with a moderate effect size   .F = 18.52, p < 0.001, ƞ2 = 0.578) and time . The post hoc analysis revealed significant intragroup differences in the MI and AO groups between the preintervention assessment and the intervention average assessment . Statistically significant differences were observed between the preintervention assessment and the postintervention measurement, with a large effect size in the AO and MI groups . In addition, in both groups, statistically significant differences were found between the intervention average measurement and postintervention measurement .The ANOVA revealed significant changes in heart rate during group*time . In addition, significant intergroup differences were found in the postintervention measurement between the MI and AO groups, with a large effect size , and between the AO and PO groups   .The aim of the present study was to explore the immediate modulatory pain effects of MI and AO of SNTE in the cervical and remote regions. Our results show that both MI and AO induced an immediate pain modulation response in the cervical region (post-1), however, it was not sustained in the second measurement after the intervention. In the epicondyle, only AO induced pain reduction between the preintervention measurement and both postintervention measurements. AO and MI interventions provoked an increase in HR, however, AO showed significant differences in comparison with the PO and MI groups.Exercise-induced hypoalgesia is a well-documented phenomenon. Although most research has demonstrated modulating effects on pain by aerobic exercise, O’Leary et al. have shown that performing SNTEs, similar to those employed in the present study, produced local hypoalgesic responses in the cervical region . AccordiIn addition to the pain-trigger responses, another relevant factor could be pain-related fear. Previous research has shown that high levels of fear of movement directly affect the periaqueductal gray through the amygdala, which might have a direct negative effect on endogenous pain modulation . The stuA relevant finding of the present study is that MI and AO produced pain modulation responses compared to PO. This finding is important because previous studies have suggested that distraction might be a mechanism involved in pain modulation produced by mental practice ,47. AlthOn the other hand, our results showed that the AO provoked greater local and remote hypoalgesic responses and triggered a higher HR increase compared with MI. Possible differences between AO and MI remain unclear and more research is needed. HR is under autonomic control, which could give an estimate of the physiological responses produced by both interventions, although other measurements, such as skin conductance or temperature, are necessary to establish whether AO or MI caused increased activity of the autonomic nervous system. However, one of the main difficulties in interventions with mental motor practice is to know if the patient was engaging to the intervention in the correct form. Our HR date showed that in both groups, patients were engaged in the intervention, although in the AO group the HR increase was higher compared to the MI group. One potential factor that could influence this outcome is the exercises selected for the intervention. The selection of these exercises was based on their extensive clinical application, the pain modulation effects found with their real execution, and the intent to prevent fear in their execution. Fear responses to movements perceived as dangerous have been associated with increases in ANS activity and pain intensity ,58. HoweThe results of the present study showed that AO and MI could provoke pain modulatory effects in the cervical region. The implementation of mental practice in patients with persistent pain, is highly relevant, as they could be performed in clinical environments where in the early stages, it is not possible to perform motor gestures in a real way due to the presence of pain or psychosocial variables, like fear of movement. These tools offer opportunities to improve the different stages of rehabilitation for patients with dysfunctional and maladaptive pain. In addition, this approach could increase the effectiveness of the current treatments, thus, they should be considered due to their simple implementation and cost-effectiveness in everyday daily routines or clinical practice. In addition, mental practice may have additional positive effects on motor learning or increase patient adherence to exercising the rehabilitation process. Future studies should continue to investigate the benefits of AO and MI in patients with chronic pain, as well as their implementation in clinical practice.This study presents some limitations. First, the sample size was small, and thus, the results should be considered with caution. In addition, the results have only been considered in the short term, and the duration and type of intervention might have been insufficient for greater increases in pain modulation in patients with CNP, especially in the MI group. Second, changes in clinical pain were not evaluated. Longer mental practice interventions may determine changes in clinical pain, which is certainly a very relevant aspect. More research is needed to determine the role of mental practice in pain modulation in patients with chronic pain.Both the AO and MI of specific neck exercises are able to induce immediate pain modulation of the cervical region. Although both strategies led to increases in PPTs, AO appears to have led to greater local and remote pain modulation, as well as a greater response from the ANS. More research is needed in this area on the role and additional benefits of mental practice in terms of pain modulation and its implementation in clinical practice.


This study is comparing thermal radiofrequency ablation (TRFA) of the thoracic dorsal root ganglia (TDRG) guided by Xper CT and fluoroscopy with the standard fluoroscopy.n = 40) TRFA was done under integrated Xper CT-scan and fluoroscopy guidance, while it was done under fluoroscopy guidance only in standard group (n = 38). The primary outcome was pain intensity measured by visual analog scale (VAS) score, functional improvement and consumption of analgesics. The secondary outcome measures were patient global impression of changes (PGIC) and adverse effects.This randomized clinical trial included 78 patients suffering from chronic refractory pain due to chest malignancies randomly allocated into one of two groups according to guidance of TRFA of TDRG. In CT guided group (p < 0.001) and were lower in CT guided group up to 12 weeks. Pregabalin and oxycodone consumption was higher in the standard group at 1, 4 and 12 weeks (p < 0.001). Functional improvement showed near significant difference between the two groups  while the difference was statistically significant at week 12 (P = 0.04). PGIC showed near significant difference only at week 1 (P = 0.07) while the per-patient adverse events were lower in CT guided group (p = 0.027).VAS scores decreased in the two groups compared to baseline values .The study was retrospectively registered at  Thoracic pain represents approximately 3–5% of patient visits to pain clinic worldwide . Lung caPain is the presenting symptom in 20% of cases of lung cancer and it may be more distressing to patients with lung cancer than to patients with other cancers . Pain afThere are many technical difficulties in approaching the deep-seated thoracic dorsal root ganglia (DRG) through the transforaminal route. The spine is kyphotic, with the tip at T6, and slightly scoliotic to the right side even in normal subjects . SpinousThe extra guidance of Xper CT than conventional fluoroscopy may improve the success of the transforaminal approach to thoracic DRG considering all these factors of technical difficulties due to natural anatomical barriers lowering the efficacy of dorsal rhizotomy . The authors hypothesize that combining the Xper CT scan with fluoroscopy to guide RF ablation through the transforaminal route can enhance its efficacy and safety in relieving the intractable pain of chest malignancies. The current study aimed to compare the results of thermal radiofrequency ablation (TRFA) of the thoracic DRG under combined Xper CT - fluoroscopy guidance with the standard fluoroscopy technique.clinicaltrials.gov on 04/22/2018 (Registration No.: NCT03533413). The study fulfilled the principles of the Helsinki Declaration and followed the Medical Research Involving Human Subjects Act (WMO). This study adheres to CONSORT guidelines for reporting clinical trials. The purpose, benefits, possible risks and expectations were explained to all patients before their enrollment in the study and a written informed consent was obtained from each patient. Patients were recruited from the pain clinic. Eligible patients were 18 years or older and suffering from chronic moderate-to-severe pain (VAS score ≥ 40 mm), due to chest malignancies and pain was refractory to the maximally tolerated dose of opioids for at least four weeks [This single-blinded, parallel group, randomized clinical trial was conducted in the National Cancer Institute,Cairo University during the period from April 2017 to March 2018 after obtaining the approval of the Institutional Review Board . The study was retrospectively registered at ur weeks . The maln = 40) TRFA of the thoracic DRG was conducted under Xper Guided CT fluoroscopy guidance, while the procedure was conducted under fluoroscopy guidance only in the standard group (n = 40). The random number list was concealed and checked just before a patient’s allocation by personnel blinded to the study.Eighty patients were randomly allocated into one of two equal groups. In CT group  IV infusion was initiated. The procedure was conducted under the ASA recommendation of conscious alert sedation with a 0.5–1.0 μg/kg fentanyl IV  and a 0.5–1.0 μg/kg dexmedetomidine  IV in addition to propofol  IV boluses during TRFA application. The patient was placed prone on a small pillow located under the chest, and the back of the patient was sterilized using 8% povidone iodide and draped. The needle was a Baylis RF needle  . The selected level was checked by history, local examination for rib tenderness and possible neuropathic characters, e.g., allodynia. The fluoroscopic postero/anterior (PA) view was taken and squaring  of the targeted vertebra was attained by cephalocaudal orientation of the C-arm. An ipsilateral oblique view of 15° was completed and then the port of needle entry was located at the lower 1/3 to 1/4 of the lateral vertebral edge, under the articular pillar and the halo of the transverse process. As a rule, the port of needle entry must be within 4 cm of the midline (Rule of 4) to avoid injuring the parietal pleura [The procedure was conducted in the fluoroscopy room where all anesthetic and resuscitation facilities were available. ASA-standard monitors  were connected to the patient. A G20 intravenous (IV) line was fixed and OThe patient is placed prone on the angio table  Fig. .Fig. 2AIn both groups all patients were converted to as needed immediate release oxycodone (Oxynorm® 5- 10 mg Mundipharm) capsules and the average daily required dose to achieve adequate analgesia was calculated then given as sustained release formula (Oxycontin® 10–20-40 mg Mundipharm) in the first visit of the patient after 1 week. Regarding Pregabalin (Lyrica®50–75-150 mg Pfizer), the dose decreased by 25% each week according to patient response with maximum dose 600 mg per day.A junior clinician of the pain clinic team that was blinded to the study groups was assigned to collect the data. The demographic data included age, gender, chest pathology, body mass index (BMI), duration of the procedure, the side of lesioning, the number of levels/patient, the estimated dose of irradiation exposure (ED), baseline VAS, and medication use. The patient evaluation was conducted 1, 4, and 12 weeks after the procedure. The patients were not allowed to review their previous scores.The primary outcome measure was pain intensity measured by the visual analog scale (VAS). A 100 mm VAS was presented to the patient as a horizontal line with two ends; the left end represented no pain experienced and the right end represented experiencing the worst pain imaginable. The functional improvement was assessed as a self-reported score after pain procedures representing the percentage of pain reduction; 0–25% means no or minimal improvement, 25–50% means mild improvement, 50–75% means moderate improvement and 75–100% means marked relief . The conThe adverse effects were categorized into minor and major groups. The minor events included back pain, soreness, infection, hematoma, and bruises. The major events included pneumothorax, neuritis, motor deficits, and sensory changes, such as discomforting numbness and hypoesthesia, dysesthesia or anesthesia dolorosa.The required sample size was calculated using G*Power Software version 3.1.9 . There were no previous trials comparing the two studied groups of the current trial. The hypothesis was one of “superiority” . We hypothesized that a difference of 3 in the VAS at 12 weeks after treatment would be clinically meaningful. With this difference and a pooled standard deviation of 4, a total of 29 subjects were needed to detect the difference between the two groups at an alpha level of 0.05 and a power of 0.8. Owing to the repeated measures and possible drop outs, the sample was increased by 20% for each condition. Therefore, a sample of 40 patients in each group was recruited in the study.p value < 0.05 was considered significant.Data were analyzed using IBM© SPSS© Statistics version 23 . Data were summarized as a mean and standard deviation or median and range for quantitative data and frequency and percentage for categorical data. The comparisons between quantitative variables were made using the unpaired t-test or the Mann-Whitney test. For comparison of the serial measurements within each group, a mixed linear model was applied. Comparisons of categorical data were made using the Chi-square test or Fisher’s exact test as appropriate. All tests were two-tailed. A p < 0.001): the CT-guided group was 2 folds higher than the Standard group. The duration of the procedure was significantly longer in the C Group (p = 0.037) . There was no significant difference in VAS score between both groups at baseline (p = 0.380). The VAS scores were lower in the CT-guided group compared to the standard group at 1, 4, and 12 weeks after the procedure , as shown in Fig. P < 0.001), week 8 (P < 0.001), and week 12 (P = 0.001).The VAS scores decreased significantly in the two groups at all of the follow-up points compared to baseline values  was better (nearly significant) in the CT-guided group at weeks 1 and 4, while it was significant at week 12 Fig. .Fig. 8FPatient satisfaction (PGIC) showed a higher indication of improvement at weeks 1, 4, and 12, but these were not statistically significant apart from week 1 which was nearly significant Fig. .Fig. 9Pp = 0.027) (Table The per-patient adverse events occurrence was significantly lower in the CT-guided group (7) Table . No infeThe current study demonstrated that selective TRF rhizotomy of thoracic DRG through the inferior transforaminal approach in intractable chest pain cases associated with cancer seems to be of better efficacy if performed under the combined guidance of a CT scan and fluoroscopy .Interventional pain procedures are indicated for refractory pain when analgesic drugs are ineffective or associated with intolerable side effects . In thisParavertebral and intercostal nerve lesioning are efficient and simple procedures that can be performed at the bedside without guidance . They haDorsal chemical rhizotomy  may provide satisfactory analgesia for patients with lung cancer pain. However, it is associated by uncontrolled intraspinal spread and high risk for neurological deficits which ultimately limits its use in clinical practice , 20.Although PCC is efficient in cancer-related chest pain  it has mNumerous anatomical barriers against the transforaminal approach in the thoracic spine have been previously described , 9. For The authors assume that the technique of an inferior transforaminal approach may be superior to previously described approaches, e.g. the approach by Charles Gauci . First, In the current study, T2-T8 levels were selected to avoid the catastrophic vascular events that may occur below the T8 due to vascular insult of the artery of Adamkiewicz, “which is the main blood supply of the anterior spinal cord below T8 . Murthy The neuroablative RF was applied to the DRG and not the pulsed (neuromodulatory) RF for many reasons. Pulsed RF is for short-term pain relief , and itsIn the current work, the extra-guidance technique using the Xper CT reflected a better efficacy with a moderate increase of irradiation hazards (2 folds increase in ED). The implication of CT as a guidance tool has been used for interventional pain procedures, such as celiac plexus and lumbar sympathetic blocks , 37. It In conclusion, the integrated guidance of Xper CT-scan and fluoroscopy may improve the efficacy of TRF of thoracic DRG for the treatment of intractable chest pain in cancer patients. According to the authors’ knowledge, this is the first RCT studying the efficacy and safety of this technique for thoracic DRG-TRF in intractable chest cancer pain. Moreover, we stressed on the inferior transforaminal suprapedicular technique in the thoracic spine region.Limitations and recommendations, this study is a single center work and single blinded hence multi-centric meta-analysis is recommended with a larger sample size of patients for verification of the data of the current work. Furthermore, a longer duration of follow up might be helpful for better evaluation and stratification of guidelines in treating lung cancer pain. Surgical confidence was not considered in the current work and should be respected in further upcoming researches.


Dystonia is a key symptom in corticobasal syndrome (CBS), and upper limb dystonia is the most common phenotype. Dystonia‐associated pain is frequently reported and can be disabling, with poor benefit from oral treatments.To investigate the role of botulinum toxin A (BoTNA) in the treatment of dystonia and associated pain in CBS.Ten consecutive patients with a clinical diagnosis of probable CBS and dystonia with/without associated pain were treated with BoTNA every 3 months. Treatment efficacy was assessed during the first follow‐up visit, three months after the first injection, by means of caregiver impression (CI), evaluation of muscle tone with the Ashworth scale (AS), severity of pain measured with the visual analog scale (VAS).p = 0.003). CI ranged from mild to moderate benefit. All patients reported efficacy on pain, with a significant reduction of VAS score .Nine subjects underwent at least three treatments, four patients discontinued for progressive reduction in efficacy or disease progression, five patients are ongoing with good response, and one completed the 10th treatment. No local or systemic side effects were reported, and levodopa equivalent daily dose remained unchanged in most cases during the observational period. Significant improvement of AS was recorded , and upper limb dystonia is the most common phenotype. The role of botulinum toxin A (BoTNA) in the treatment of dystonia and associated pain in CBS has been not investigated so far Our study confirms safety, efficacy, and tolerability of BoTNA in the treatment of dystonia associated to CBS and related pain in 10 subjects. According to pathologically proven cases and current diagnostic criteria  in the treatment of painful dystonia occurring in Parkinson’s disease (PD) and parkinsonisms has been reported  was used to evaluate muscle tone. Even if the scale is validated for spasticity, it has been used in previous studies to assess muscle tone in dystonia because more specific tools are not available. Presence and severity of pain associated with dystonic posture were measured with the visual analog scale VAS, 0–10) and recorded during all the observational period. After clinical and electrophysiological evaluation, patients were treated with BoTNA (T0). Selection of muscles depended on clinical phenotype and neurophysiological recordings , VAS, and AS before and after treatment. Correlations were assessed using Spearman’s rank correlation coefficient.4p = 0.253).Ten consecutive patients  were included in the study Table . Dystonin = 1), 4th (n = 1), and 6th (n = 2) injection for progressive reduction in benefit or disease progression. Five patients are ongoing with good response, and one subject completed the 10th treatment.Patients were followed up and injected every 3 months up to 30 months. No local or systemic side effects were reported. One patient discontinued after the second treatment due to lack of efficacy, and 9 subjects underwent at least three treatments. Four patients discontinued, respectively, after 3rd . Levodopa dose increase was limited by side effects in three cases  and progression of dysphagia in one case. All subjects reported poor benefit on motor symptoms from oral treatment.LEDD remained unchanged in most cases during the observational period , without significant differences between first and last treatment . In three cases, remission of pain was not complete at T1, but further benefit was observed after the following treatments. Effect on pain remained stable over time even in those patients who discontinued treatment due to progressive loss of motor benefit.All patients complaining of pain at T0 reported a sustained benefit, with mean VAS score at T1 of 0.3 ± 0.5 in the whole population and 0.4 ± 0.5 in the Pain group. The VAS reduction was statistically significant , AS (p = 0.161), or disease duration at T0 (p = 0.849). CI at T1 showed correlation with the number of treatments (p = 0.005).No correlation was found between duration of treatment, expressed as number of treatments, and VAS score , facilitating hygiene and passive movements. Muscle tone reduction observed could have been underestimated due to low specificity of the Ashworth scale and lack of an intermediate evaluation between T0 and T1.In our cohort, it was not possible to demonstrate functional improvement, possibly limited by mean disease duration at T0 (40.6 months); however, similar results were reported in previous studies as part of the natural history of the disease. According to our results, local treatment can be helpful in a multimodal way, first of all by reducing hypertonia , with complete remission after the first injection in four patients. Pain is a disabling symptom affecting quality of life, and oral drugs are often burdened by side effects and cognitive worsening. Efficacy of BoTNA on dystonic pain in CBS has been reported, but validated outcome measures are not currently available. In a recent retrospective study, pain response was evaluated using the Clinical Global Impression scale .Secondary aim of our study was to identify predictors of good and prolonged response to improve selection of injected patients. According to our data, it is not possible to recognize statistically significant predictors, even if a positive CI suggests a prolonged efficacy expressed as total number of treatments (Our study has several limits, mainly the limited sample size and lack of a control group. Moreover, selection of patients was made on the basis of a clinical diagnosis of probable CBS.To our knowledge, this is the largest CBS population treated with BoTNA and evaluated with outcome measures focused on muscle tone and pain.6The present study confirms the safety, efficacy, and tolerability of BoTNA in upper limb and cervical dystonia associated with CBS.Our results underline the importance to consider local treatment as a valid alternative to oral treatment modulation, mainly in patients complaining of pain associated with dystonia.All the authors report no conflict of interest.