Chronic musculoskeletal pain (MSP) affects more than 40% of adults aged 50 years and older and is the leading cause of disability in the USA. Older adults with chronic MSP are at risk for analgesic-related side effects, long-term opioid use, and functional decline. Recognizing the burden of chronic MSP, reducing the transition from acute to chronic pain is a public health priority. In this paper, we report the protocol for the Brief EducaTional Tool to Enhance Recovery (BETTER) trial. This trial compares two versions of an intervention to usual care for preventing the transition from acute to chronic MSP among older adults in the emergency department (ED).: full intervention ; video-only intervention ; or usual care. Data collection will occur at baseline and at 1 week and 1, 3, 6, and 12 months after study enrollment. The primary outcome is a composite measure of pain severity and interference. Secondary outcomes include physical function, overall health, opioid use, healthcare utilization, and an assessment of the economic value of the intervention.Three hundred sixty patients from the ED will be randomized to one of three armsThis trial is the first patient-facing ED-based intervention aimed at helping older adults to better manage their MSP and reduce their risk of developing chronic pain. If effective, future studies will examine the effectiveness of implementation strategies.NCT04118595. Registered on 8 October 2019.ClinicalTrials.gov  Musculoskeletal pain (MSP) is estimated to affect more than 40% of US adults age 50 years and older and results in more than $200 billion in healthcare costs annually , 2. ChroChronic MSP generally begins with an acute pain episode that persists. For example, approximately 9% of individuals transition from acute to chronic MSP following an episode of acute low back pain,  ~ 26% afSeveral sources of evidence suggest that acute MSP interventions can reduce the transition to chronic MSP , 16. In We have developed an ED-based intervention for patients with acute MSP based on a shared decision-making (SDM) model . This inThe BETTER trial is an NIH-funded, assessor-blinded, randomized controlled trial approved by the Institutional Review Board at the University of North Carolina-Chapel Hill. ED patients aged 50 years and older presenting to the ED with acute MSP are screened for eligibility. All eligible and willing patients sign a consent form given to them by an RA in the ED, which includes permission to communicate with their PCP, as well as a Health Information Privacy form, which authorizes the research team to access their medical record.Patients are randomized to one of three arms Table . Those rAll patients complete a baseline research assessment in the ED, a phone call at 1 week post-discharge to assess processes that might mediate recovery, and phone calls at 1, 3, 6, and 12 months following study enrollment to assess outcomes. The primary outcome is pain intensity and interference. Secondary outcomes include measures of physical function, opioid use, analgesic side effects, overall health, and healthcare utilization.The study enrolls 360 patients aged 50 years and older who present to an acute care setting (ED or urgent care) in the University of North Carolina Hospitals healthcare system in the USA with MSP. Patients are excluded if they do not speak English, have been admitted to the hospital in the past 30 days, have pain due to self-injury, have an Emergency Severity Index score of one, are a prisoner, or have a diagnosis of somatoform disorder, schizophrenia, dementia, or bipolar disorder. Patients are also excluded if their pain is not musculoskeletal, such as pain due to ischemia or infection, or if their pain is located in the head, chest, or abdomen.Patients who meet initial eligibility requirements are approached by the Research Assistant (RA) for an in-person assessment of additional exclusion criteria: current pain intensity rating < 4  or for those who have received pain medication, a pain intensity rating < 4 prior to receipt of pain medication, pain that began > 7 days prior to the ED visit, previous medical care for their pain, opioid use in the past 3 months (excluding the day of the ED visit), residence in a nursing home or homelessness, or at-risk alcohol use (≥ 5 drinks in a single day or ≥ 15 drinks in a single week). Patients must also have a working phone number for follow-up calls. Patients meeting all eligibility are invited to enroll in the study.Patient randomization utilizes 1:1:1 allocation with randomly permuted blocks of random sizes. Randomization is stratified based on two dichotomous characteristics: age (50–64 years or ≥ 65 years) and access to a PCP (yes or no). The latter is assessed with the question, “Do you have access to a primary care provider who you can arrange a follow-up appointment within the next two weeks?” The study statistician created a program for generating the randomization schedule in SAS, version 9.4 . The Lead Data Manager updated the random number generation seed in the Statistician’s program, generated the final randomization schedule, and uploaded the resulting schedule into the secure randomization module in the Research Electronic Data Capture (REDCap) database. To ensure allocation concealment, the Lead Data Manager is the only member of the study team with access to the final randomization schedule. Throughout data collection, the primary RA collecting all follow-up data and the study statistician are blinded to patient treatment arm.After baseline data is collected, a second unblinded RA randomizes the patient and meets with the patient to either show them the educational video or to conclude the acute care portion of the study. There is the potential for unblinding during follow-up interviews if a patient refers to intervention components. The primary outcome is assessed at the beginning of each interview to reduce the likelihood of unblinding for this outcome. If unblinding occurs, a different RA will complete that patient’s subsequent follow-up calls.The full intervention includes three components.The video was created in partnership with a local video production company . The goal of the video is to educate patients and provide them with options for managing pain on their own. The video first discusses when and how to use the most common classes of pain medications , and opioids) and then discusses recovery-promoting behaviors  are with the patient, the RA asks the patient if they would like these individuals to remain present before showing the video and documents the number of individuals who decide to remain in the room.The telecare component is adapted from previous telecare trials aimed at optimizing pharmacological and behavioral treatment of pain in primary care and specialty settings –43. In tThe telecare conversation follows a standardized script that assesses pain symptoms; medication use, dosing, contraindications, and side effects; and use of and barriers to use of recovery promoting behaviors . The language and content of the telecare call is designed to support a partnership between the patient and the nurse with an emphasis on respect for the patient’s experience and perspective, an explicit desire to understand what is important to the patient, and recognition that the patient will be making most treatment decisions without direct input from a medical provider. Consistent with this approach, the script utilizes open-ended questions, such as “what are you doing to manage your pain and get back to your usual activities?” rather than yes or no questions. In order to optimize the therapeutic value of the call, training for calls emphasizes supporting decisions and behaviors already undertaken by the patient that promote recovery. When a barrier, challenge, or problem is reported, the nurse acknowledges the problem and then direct the conversation to supporting the patient in identifying solutions. If indicated, the nurse may recommend use and dosing of acetaminophen, NSAIDs, and opioids. Since the nurse cannot prescribe opioids, nurse recommendations for use of opioids are limited to patients who received a prescription for opioids from the emergency provider. The call concludes with the research nurse encouraging PCP follow-up and providing information about how to obtain a PCP if the patient does not have one.Several steps are taken to ensure adherence to the script. First, the nurse conducting the telecare call receives training from the investigative team on how to implement the script and completes three practice calls with feedback from the study principal investigator. Further, all telecare calls with patients are recorded and the duration of each call is tracked. The principal investigator for the study will listen to the first 25 calls and a random 10% sample of subsequent calls to assess adherence. If deviation from the duration, content, or style is observed, further education for the nurse is performed.The final component is electronic communication with the patient’s PCP regarding the ED visit and treatment plan. The communication with the PCP is intended to support a transition of care from the ED provider to the PCP, allowing the PCP to reinforce the safe and effective use of analgesics and recovery-promoting behaviors and to adjust the treatment plan as needed. The communication with the PCP reflects our understanding of optimal pain management as an iterative process .After completing telecare, the research nurse sends the patient’s PCP a summary of their condition and treatment plan, reporting date, time, location, and reason for the ED visit; results of ED diagnostics studies; discharge prescriptions and recommendations; a summary of the video, including the link; a summary of the telecare conversation including pain symptoms, medication use, and use of recovery promoting behaviors; and encouragement for follow-up and engagement with the patient regarding pain symptoms, safe and effective use of medication, and reinforcement of the need for recovery promoting behaviors. Messages are sent through an electronic message in the electronic health record to providers who use Epic, a common electronic health record system. For providers who do not use Epic, messages are sent through secure email or fax.Patients in this arm view the interactive educational video as described above; however, they do not receive a telecare call from the research nurse nor is a message sent to their PCP. The reason for testing a video-only version of the intervention is that it is easier to implement, so if the video-only version has greater efficacy compared to usual care, then the video-only version may be the preferred approach for implementation efforts. Alternatively, a hybrid approach that uses either the full intervention or the video-only intervention based on patient factors that predict response to treatment might be developed.Patients randomized to the usual care arm receive analgesic recommendations, prescriptions, and advice regarding recovery behaviors as provided by the patient’s acute care provider and nurse. We recognize that the amount of time spent by providers and nurses on education about pain management during an acute care visit is varied but often brief. We have chosen not to include a sham intervention or enhanced usual care because the intent of the study is to determine if the intervention improves upon what is typically done for patients .Consistent with this intent, no restrictions are placed on the care from acute care providers for any of the study arms. Discontinuation of interventions is not anticipated since this is an education-based intervention. However, participants may request to stop the study at any time. If a medication or behavior recommended in the video or telecare causes a concerning side effect for the participant, the participant will be advised to stop the behavior or medication and consult their PCP. Patients are compensated for their participation throughout the study, and there is no post-trial care upon completion of the study.Patients complete a baseline interview in the ED to assess their (1) history of pain symptoms and current pain, (2) attempted treatments to manage pain including both analgesics and recovery-promoting behaviors, 3) perceived efficacy in their ability to manage pain, and (4) overall health  at 1, 3, and 6 months. Secondary outcomes include physical function , analgesic use and side effects , overall health , and individual components of the BPI , and total number of hospitalizations and days hospitalized. Data on healthcare utilization are collected using two approaches: (1) patient report and (2) review of electronic health record (EHR) data. Recognizing that we have incomplete access to EHRs for patients whose primary care is not within our healthcare system, patient reported healthcare utilization will be the primary source of information for the economic analysis. If there are sufficient patients with EHR data, then a separate subgroup analysis will be conducted in these patients.We calculated power for comparing mean change in the BPI total score across the three trial arms using a standard approach for linear mixed models . FollowiLinear mixed models will be used in the primary analysis with intention-to-treat group assignments, controlling for baseline variables that are known to influence pain recovery: ED pain, age, gender, race, comorbidities, baseline intermittent opioid use, history of chronic pain, and access to a PCP. We will first test a 6 degrees of freedom (df) linear contrast of the overall null hypothesis of no mean difference in the primary outcome at any of the 1-, 3-, and 6-month follow-up assessments across the 3 groups at the 5% significance level. If the overall null hypothesis is rejected, we will then conduct separate 3 df contrasts to compare each of the intervention groups with the control group using a Bonferroni-adjusted 2.5% significance level. We will secondarily estimate mean pairwise differences along with 95% confidence intervals at each time point, including data collected at the 12-month follow-up time point. We will conduct secondary analyses to estimate the effect of treatment on secondary outcomes  using a similar approach. A per-protocol analysis, which will exclude patients who were found to meet exclusionary criteria after enrolling in the study, specifically those who are admitted to the hospital and who are found to have pain that is not musculoskeletal in origin, will also be performed for all outcomes.To estimate the change in healthcare cost resulting per case of moderate or severe pain prevented with the full or the video-only intervention, we will calculate an incremental cost-effectiveness ratio Fig.  48–50].–50.48–50The BETTER trial is a three-arm efficacy trial of two versions of an SDM-based intervention for older adults receiving care for acute MSP. Our goal is to evaluate the effects of the full intervention and video-only intervention on long-term pain severity and pain interference compared to usual care; secondarily, it assesses the effect on analgesic-related side effects and adverse events, function, quality of life, long-term opioid use, and healthcare utilization. Although the full intervention includes multiple components of SDM , the educational video on its own would be more feasible for implementation and is therefore included as one of the trial arms. In the pilot study for BETTER, clinically important differences in pain symptoms and opioid use between both versions of the intervention and the usual care group were observed at 1 month . We willThe video we developed provides patients with information regarding medication and behaviors to inform their pain management decisions during conversations with their provider and after the visit. The video also encourages specific medications and behaviors which are likely to be beneficial during recovery. Understanding of analgesics and recovery-promoting behaviors among older adults is often poor, and patients who lack a basic understanding of analgesic names, dosing, and contraindications are at increased risk for side effects and adverse events . AdditioAlthough we consider the study to be an efficacy trial, we made several deliberate choices to increase the clinical relevance of the study in order to facilitate subsequent implementation. First, the inclusion criteria broadly include patients with acute MSP and we anticipate the study sample will be diverse in regard to etiology of pain symptoms as well as race, ethnicity, and formal education. Second, the video and telecare are brief (approximately 15 min in duration) so that they could be administered during an acute care visit and by a nurse, respectively. Third, we decided to allow family members and friends to remain in the room during the viewing of the video, recognizing that this is what is likely to happen during implementation.There are several anticipated challenges to the conduct of this trial. One challenge is loss to follow-up. In our prior work, follow-up rates ranged from 76 to 93% , 53. SevThe NIH has declared a need to prevent the transition from acute to chronic MSP, especially among older adults. The BETTER trial is the first clinical trial to address this problem using an SDM approach in an acute care setting. Given the large number of older adults receiving care annually for acute MSP, the results of this trial have the potential to inform implementation and dissemination efforts that could have a positive impact on the burden of chronic MSP and long-term opioid use among older adults.The trial is registered on ClinicalTrials.gov under NCT04118595. The study is using Study Protocol Version 1, October 23, 2019. The first participant was enrolled on February 3, 2020. The estimated completion date of recruitment is June 1, 2022.Additional file 1. Informed consent


A relevant subsample of patients with chronic low back pain (CLBP) have manifested augmented central pain processing, central sensitisation (CS). Patients with CLBP have limited functioning and participation. Theoretically, physical functioning in patients with CLBP can plausibly be linked to CS; however, evidence to explain such association is scarce. Moreover, there is no gold standard for CS diagnosis. The objectives of the study are: (1) to analyse the association between instruments assessing reference symptoms and signs attributed to CS; (2) to analyse whether reference symptoms and signs attributed to CS are associated with functioning measurement outcomes; and (3) to analyse whether changes (between baseline and discharge) in reference symptoms and signs attributed to CS are related to changes in each of the functioning measurement outcomes.A cross-sectional and longitudinal observational study is performed with measurements taken at baseline and discharge of an interdisciplinary rehabilitation programme. A sample size of 110 adult patients with CLBP has been calculated for the study. CS measurements are: Central Sensitisation Inventory, quantitative sensory testing and heart rate variability. Functioning measurements are: lifting capacity, maximal aerobic capacity, accelerometry and reported functioning. Statistical analyses to be performed are: (1) correlation between CS measurements, (2) multiple regression between functioning (dependent variable) and CS measurements (independent variable), and (3) multiple regression between changes in scores of functioning (dependent variable) and CS measurements (independent variable), and corrected for sex and age.The study obtained the clearance to its implementation from the Medical Research Ethics Committee of the University Medical Center Groningen in July 2017. The results will be disseminated through scientific publications in peer-reviewed journals, presentations at relevant conferences, and reports to stakeholders.NTR7167/NL6980. Novel and comprehensive approaches for the assessment of the presence of central sensitisation (CS).Extensive amount of measurements from multiple domains for the determination of functioning status.Longitudinal study with measurements at baseline and discharge of an interdisciplinary rehabilitation programme implemented as ‘Care As Usual’.Strategies allocated to promote participation and adherence, and to mitigate selection bias to the largest extent possible.Statistical analyses are performed with selections of CS and functioning measurements, and these selections may influence study results.Twenty per cent of the general population experiences prolonged or recurrent pain for at least 3 months, such pain is then considered to be chronic.In the past decennia, a relevant subsample of patients with chronic pain, including individuals with CLBP, have shown an increased responsiveness to noxious and non-noxious stimuli, described as central sensitisation (CS).Chronic pain is a multifactorial condition which has an impact on physical or body structures and functions, on psychological processes and on daily activities and quality of life of individuals.Patients with CLBP are likely to be less physically active, and be more deconditioned and disabled.The study described in this research protocol has been created to improve the assessment and management of pain and disability of centrally sensitised patients with CLBP and fill the existing gaps in knowledge. On the one hand, it intends to assist on the phenotyping of centrally sensitised patients with CLBP. To this purpose, an integrated assessment of CS combining the use of various instruments which measure different reference clinical symptoms of CS is aimed. Instruments like Central Sensitisation Inventory (CSI),The objectives of the studies covered by this research protocol are:To analyse the association between three instruments assessing reference symptoms and signs attributed to CS in patients with CLBP: CSI, QST and HRV.To analyse whether reference symptoms and signs attributed to CS are associated with functioning measurement outcomes in patients with CLBP. Specifically, to analyse the association between the three instruments assessing CS  and: lifting capacity, aerobic capacity, PA levels and/or PA distribution or patterns, and patient-reported measurements.To analyse whether changes (between baseline and discharge) in reference symptoms and signs attributed to CS are related to changes in each of the functioning measurement outcomes in patients with CLBP. Specifically, to analyse whether decreases in CS described as: a lower CSI score, an increase in the pain thresholds (QST) and an increase in parasympathetic/vagal tone (HRV) are related to a better functioning described as: an increase in lifting capacity, an increase in aerobic capacity, an increase in PA levels and/or a change in PA distribution or patterns, and better outcome scores in patient-reported measurements.An observational study project with both cross-sectional and longitudinal designs is being conducted from September 2017 to September 2019 in the Center for Rehabilitation of the University Medical Center Groningen (CvR-UMCG) in the Netherlands.The personnel of the CvR-UMCG collaborate in the study, in particular, the Pain Rehabilitation team during patient management and data collection process and the central exercise lab team on data collection process. The authors wish to express their gratitude to the collaborators and to the patients who participate.Consecutive patients between 18 and 65 years of age at the time of recruitment who are primarily referred to the outpatient Pain Rehabilitation Department of the CvR-UMCG due to a chronic primary low back pain and who are assessed for the interdisciplinary pain rehabilitation programme are eligible to participate in the study. Chronic primary low back pain is defined as a low back pain recurrent for more than 3 months, related to emotional distress and/or functional disability and whose pain is not a result of any other diagnosisMeasurements are performed as part of ‘Care As Usual’ (CAU) for outpatients following the pain rehabilitation guidelines of the CvR-UMCG. However, not all measurements of the research protocol belong to the battery of assessments of the CvR-UMCG, as pointed out in the legend of During the first appointment of the patients with the rehabilitation physician, patients are invited to participate in the studies if based on their file they are eligible according to the criteria defined for the studies. Eligible patients who are invited to participate and receive information about the study, but have not reacted, are contacted in a week’s time to remind them about the study participation. Those who sign the informed consent, fill in forms with their relevant personal information during the baseline assessment and are given vouchers for the travel expenses during the discharge assessment. Participating patients follow CAU trajectory with the Pain Rehabilitation team in terms of assessments, screening and implementation of the interdisciplinary rehabilitation programme. As part of the research protocol, the performance of additional assessments and filling up of questionnaires on CS and functioning are required. CSI, lifting capacity and HRV results are collected as CAU. Aerobic capacity, QST, objective PA monitoring, and pain intensity and functioning questionnaires’ results are collected as additional to CAU. All CS measurements, objective PA monitoring and capacity tests are measured at two time points, baseline and discharge. Pain intensity and functioning questionnaires, on the other hand, are measured at 13 time points, baseline and once a week during the 12-week rehabilitation programme. Pain Disability Index (PDI) is the only functioning questionnaire collected as CAU at baseline but as additional during the rehabilitation programme. A diagram of the project procedure is presented in In order to comprehensively assess the symptoms and signs attributed to CS, data are obtained from a questionnaire (CSI) and two physical assessments (QST and HRV).The inventory is a self-reported questionnaire with two sections to estimate the severity of CS-related symptoms. Section A is a 25-item questionnaire to assess the presence of the most common CS-related symptoms. Each of the questions is measured on a 5-point Likert scale from 0 (never) to 4 , and the total score ranges from 0 to 100, where higher scoring is associated with more severe symptomatology. Section B is a 10-item questionnaire to assess the previously diagnosed CS syndromes (CSS) and/or conditions related to CS. Higher amount of CSS is associated with higher chances of CS being present. This instrument has shown excellent test–retest reliability (intraclass correlation coefficient (ICC)=0.82–0.97) and internal consistency (Cronbach’s α=0.87–0.91) in the general population and in patients with chronic pain,A battery of standardised sensory tests quantifies the function of the somatosensory system. QST tests the characteristics of various sensation and nociceptive processes as representative of afferent nerve fibres and central pathways performance. The whole assessment lasts for 1 hour, and it consists of six sensory tests, which are measured in seven different predefined body locations: one training location to familiarise the patient with the tests, the most painful location (as pointed out by the patient), and five control locations. See 10.1136/bmjopen-2019-031592.supp1Supplementary dataDynamic mechanical allodynia (DMA)—to test the presence of abnormal stimuli-evoked pain—is assessed with a soft brush  that is swiped 1–2 cm over the skin. This is performed on a single repetition and on a train of three repetitions (wind-up response). At each of the seven body locations —to test the ability to perceive sharp, pricking or stinging stimuli—is assessed with a set of standardised weighted pinprick stimulators with seven different intensities  and with a modified method of limits. Starting at the lowest intensity (8 mN), it progressively increases until patients report the stimulus to change from touch to painful . The intensity of the pinprick that produces the first painful stimulus in millinewtons is recorded in each of the seven locations (see ions see .46–49 ThWind-up ratio (WUR)—to test the nervous system’s painful stimuli temporal summation or responsiveness to repeated noxious stimuli. Such test is assessed with a suprathreshold pinprick stimulator of 256 mN , which is applied on a single repetition and on a train of 10 repetitions in an area of 1 cm2 with intervals of 1 s (wind-up response). The pain intensity measured with an NRS ranging from 0 (no pain) to 100 (most intense pain imaginable) for both the single repetition and the series is recorded in each of the seven body locations —to test the ability to detect light touch—is assessed with a standardised set of von Frey filaments  with a modified method of limits.Pressure pain threshold (PPT)—to test the ability to perceive pressure pain stimuli on muscles—is assessed with an electronic pressure algometer . With this tool, the pressure in the contact point (1 cm2 tip) is progressively but steadily increased until patients report to feel pressure change towards painful . The intensity in newtons when pressure becomes painful and its pain intensity with an NRS ranging from 0 (no pain) to 100 (most intense pain imaginable) scale is recorded in each of the seven body locations (see ions see .32 The PCPM—to test the nervous system’s descending pain processing. The CPM test methodology selected for this study follows the recommendations of the EFIC meeting (2013).2/Hz as very-low-frequency (0.0033–0.04 Hz) indicator for long-term regulation and sympathetic tone, low frequency (0.04–0.15 Hz) for sympathetic and parasympathetic/vagal tones and high frequency (0.15–0.40 Hz) for parasympathetic/vagal tone related to breathing rate; and normalised coherence indicator for HRV stable or regular pattern over time in percent, where higher scores mean more harmonic signal.The test provides an indication of the function and balance of the autonomic nervous system (ANS), which is responsible for the control of internal functions including self-regulation, adaptability and resilience capacities.In order to determine the functioning status of individuals with chronic pain in multiple domains, data are obtained from two physical assessments (lifting and aerobic capacity tests), an accelerometer (PA level) and a battery of reported functioning questionnaires.The floor-to-waist lift capacity test is based on the WorkWell Functional Capacity Evaluation (FCE) protocol2max), a respiratory exchange ratio higher than 1.15 and/or an HR higher than 85% of the predicted maximal HR.2max in mL/min and per kilogram in mL/min/kg is collected as the mean of VO2 over the last 30 seconds of exercise. Along with VO2max, the following measures are collected: peak workload in watts, HR at end of test in beats per minute, breathing frequency at end of test in breaths per minute, expiratory tidal volume in litres, peak energy expenditure in metabolic equivalent of task (MET), test duration in minutes, and the patient-reported and the assessor-observed mechanical effort as measured with Borg’s rating of perceived exertion (RPE) scale. Borg’s RPE scale ranges from 6  to 20 The maximal aerobic capacity is assessed with a cardiopulmonary exercise test (CPET). The test is performed with a cycle ergometer  following a defined continuous ramp protocol. Before any cycling begins, patients are interviewed about their daily activities, and their resting heart rhythm and function are recorded with an ECG . Patients then have an unloaded warm-up of 3 minutes at 60–70 rotations per minute before the test begins. At the start of the test, an experienced exercise physiologist in discussion with a specialised physician or nurse determines the starting workload (25–100 W) and ramp (5–25 W increase per minute) depending on patients’ estimated fitness level. During the test, patients are asked to maintain a constant cadence while the working load is progressively being increased. Also, they are continuously being verbally encouraged to obtain their maximum performance. The maximal performance is determined by various parameters: a temporary loss of strength and energy (=exhaustion), a plateau in the peak oxygen uptake . The accelerometer is a small and light device that monitors wearers’ daily PA and energy expenditure. Participating patients wear the accelerometer attached at their hip level for 1 week continuously during walking hours, in order to ensure the minimum of 4 full-day recordings as recommended by activity monitoring reviewers and experts.Data from this domain are obtained from four questionnaires sent to patients and filled up by them via internet. All the questionnaires require 10–15 minutes to be filled in.Physical functioning . The Rand36 is a health-related quality of life survey that measures the impact of health on patients’ well-being and ability to function. Patients are asked to answer only the Physical Functioning (PF) subscale which looks at the limitations patients experience during their daily activities. Each of the 10 items belonging to the PF subscale has a three-level response choice ranging from 0 (limited a lot) to 100 , the total average score ranges from 0 to 100 too; where a higher score is associated with a greater limitation in performing daily activities. For the purposes of the study, the Dutch translation of the Rand36 is used, which has shown good internal consistency (Cronbach’s α=0.92) and test–retest reliability (r=0.72–0.82) in the general population.Disability (Pain Disability Index—PDI). The index is a 7-item questionnaire which measures the interference of pain with the ability to function in different daily life activities: family/home responsibilities, recreation, social activity, occupation, sexual behaviour, self-care and life support activity. Each item ranges from 0 (no interference) to 10 , and the total score ranges from 0 to 70; where scoring higher is associated with higher interference in daily life activities. The PDI has shown modest test–retest reliability (r=0.44) and high internal consistency (Cronbach’s α=0.86) in patients with chronic pain.Work ability (Work Ability Score—WAS). The score is a single-item question which compares patient’s current work ability with their lifetime best. The result is a score ranging from 0 (unable to work) to 10 (best working ability). The single-item question is part of the Work Ability Index (WAI), a questionnaire which measures work ability and has shown to be test–retest reliable (difference between test and retest=−0.53) in construction workers.Patients fill in a form with their details when the QST assessment takes place. Such details include: age, sex, nationality, height, weight, pain characteristics , educational level and employment characteristics .Pain intensity . The scale is a single-item question to assess the current pain intensity in adults. It is a straight line with ‘no pain’ (score=0) at one end and ‘pain as bad as it could be’ (score=100) at the other, in which patients are asked to mark the line at the level that represents their pain level. The score is the distance between the mark and the ‘no pain’ end, where scoring higher is associated with greater pain intensity. The VAS Pain has shown good validity (r=0.62–0.91) and good test–retest reliability (literate r=0.94 and illiterate r=0.71) in patients with rheumatic pain conditions.Body response to a straining exercise (Pain Response Questionnaire—PRQ).These questionnaires measure psychosocial features common to CSS that have demonstrated to affect pain experience and functioning.Pain Catastrophizing Scale (PCS). The 13-item questionnaire measures in a 5-point Likert scale  the degree to which patients have had catastrophic thoughts or feelings during their pain experience and accounts for three subscales or dimensions: rumination, magnification and helplessness.Injustice Experience Questionnaire (IEQ). The 12-item reported questionnaire assesses in a 5-point Likert scale from  four different aspects of the perceived injustice due to injury: severity, blame, unfairness and irreparability. The questionnaire has shown to have good internal consistency (Cronbach’s α=0.92) and test–retest reliability (ICC=0.98) in a group of patients with fibromyalgia.Brief Symptom Inventory (BSI). The inventory is a 53-item reported questionnaire which assesses patient’s current level of psychological distress with 5-point Likert scale questions , the amount of symptoms present and their severity.Due to the limited amount of relevant previous or similar studies, the sample sizes for the several analyses described in this research protocol are estimated a priori with GPower , and are exploratory as a result.The following sample size calculations, as well as the planned statistical analyses later described, will be performed with proxies for the main variables. Additionally, due to the influence of patient’s sex and age in the assessment outcomes, all analyses will include these variables for a moderator effect.Sample size for objective 1: to analyse the association between instruments assessing reference symptoms and signs attributed to CS. Correlation analyses will be performed for this objective. The correlation between the different CS measurements is expected to be weak as reported on associations between certain CS measures and tests.Sample size for objective 2: to analyse whether reference symptoms and signs attributed to CS are associated with functioning measurement outcomes; and for objective 3: to analyse whether changes (between baseline and discharge) in reference symptoms and signs attributed to CS are related to changes in each of the functioning measurement outcomes. Multiple regression analyses will be performed for objectives 2 and 3. Based on the associations between CSI and psychosocial and cognitive behavioural factors,Data records from the different tests and questionnaires will be collected and merged into one database. The database management will be done by the project team and handled according to the internal regulations of the UMCG. The analyses of the study will be performed with SPSS software version 22.0 (IBM).Before any analysis, data will be prepared:Variables need to be calculated: body mass index; DMA, WUR and CPM tests ; PDI, Rand36-PF, PCS, BSI and IEQ questionnaires.HRV: data will be preprocessed to correct for any artefacts that may be present at the beginning or at the end of the recording.QST: the overall value of each sensory test is the mean at the most painful location and the five control locations together, provided that at most two locations are missing.To perform the analyses to respond to objective 3, delta scores are computed (difference in scores between baseline and discharge) for CS, functioning and those confounder variables which are also measured at the same time points as the main measurements.2max/kg for the maximal aerobic capacity, the daily vector magnitude (VM) counts for PA and the average score of Rand36-PF for reported physical functioning.Proxies of the main measurements were selected to perform analyses. CS variables are: the sum score of CSI part A and the RMSSD for HRV. For QST, no variables are predefined, variables that correlate most strongly with each of the functioning measures will be selected. Functioning variables are: the maximal weight lifted for lifting capacity, the VOThe presence of missing data will be checked. If a variable has more than 10% of missing data cases, its distribution will be further examined. When the distribution of missing data is missing completely at random, analyses with pairwise deletions are planned. If data are not missing completely at random, other suitable solutions will be applied such as multiple imputation.Statistical approach for objective 1: to analyse the association between instruments assessing reference symptoms and signs attributed to CS. Multiple partial correlation analyses will be performed and corrected for potential confounders. CS measurements will be the main variables and sex and age will be covariates. Additional covariates may enter the partial correlations based on their correlation coefficient with CS instruments and if p<0.01. Results will be reported as correlation coefficients (Pearson’s r and/or Spearman’s rho) and p values, with and without controlling for covariates. The significance level for all analyses is established at 0.01, to account for the potential type I error due to the multitude of partial correlation analyses.Statistical approach for objective 2: to analyse whether reference symptoms and signs attributed to CS are associated with functioning measurement outcomes. First, multiple correlation analyses, followed by multiple regression analyses with data obtained at baseline, will be performed. Each of the main outcomes from functioning measurements will be introduced in the models as dependent variable, CS measurements as independent variables, and sex, age and other demographic characteristics and/or test-related variables as potential confounders and/or moderators.Statistical approach for objective 3: to analyse whether changes (between baseline and discharge) in reference symptoms and signs attributed to CS are related to changes in each of the functioning measurement outcomes. A similar approach to objective 2 will be performed: first, multiple correlation analyses will be performed with data obtained at baseline and discharge, followed by multiple correlation analyses using delta scores of the data and, finally, multiple regression analyses again using delta scores. As in objective 2, each of the main outcomes from functioning measurements will be introduced in the models as dependent variable, CS measurements as independent variables, and sex, age and other demographic characteristics and/or test-related variables as potential confounders and/or moderators.Confounders entering the final models of objectives 2 and 3 will be selected based on their partial correlation coefficient with CS and functioning, and they will be included if p≤0.10. All multiple regression models will have the assumptions checked. Results of objectives 2 and 3 will be reported as coefficient (b), CIs (95% CI), p values and explained variance, with and without controlling for confounders and/or moderators. Due to the large amount of correlation analyses and the risk of high type I error, a stricter significance level for correlation analyses is established, p<0.01. For multiple regression analyses the significance level is at 0.05.Several patients with CLBP have shown common manifestations with other chronic pain conditions, which may evidence the presence of CS in these patients. Yet, knowledge on CS, especially in patients with CLBP, and on its association with functioning is developing. This research protocol aims to bridge that gap of knowledge with a novel approach. In the first place, the study (objective 1) will describe the mechanisms of CS in patients with CLBP using instruments that assess reference symptoms of CS from different perspectives. Furthermore, the study (objectives 2 and 3) will also analyse longitudinally whether the presence of CS and changes of CS can be associated with changes in physical functioning performance, for which functioning will be assessed with several objective monitoring and capacity tests, and self-reported measurements.Within the constraints of CAU and in the absence of a single gold standard instrument that can diagnose CS, in this research protocol multiple instruments have been selected to examine reference symptoms and signs attributed to CS. (1) The hypersensitivity unrelated to mechanical stimulus is assessed with CSI. A questionnaire designed to measure CS, as it has been shown to be associated to factors known to contribute to CS and is able to identify somatic and emotional symptoms related to CSS.2max, can be best assessed with a maximal aerobic capacity test such as the CPET. The cycle ergometer and the treadmill are the most used assessments for aerobic capacity, but the cycle ergometer is most appropriate for patients.Various functioning assessments are selected for the research protocol to determine the functioning status of centrally sensitised patients with CLBP, including several objective monitoring and capacity tests, and self-reported measurements. (1) The floor-to-waist lifting capacity test is a physical assessment from the FCE that has demonstrated the best predictability for return to work in CLBP.2max corrected for the body mass of the individual, due to the effect of body mass on VO2max; and for PA the daily VM counts, because it characterises movement duration and intensity.Data collected for this project are large and the measurements of CS and functioning collected involve a broad amount of variables. As a result, proxies will be used for the statistical analyses. Previous research in CS assessments, on the one hand, and in functioning assessments, on the other, have reported different methodologies and outcome parameters. The reason for which, even if authors have selected the proxy variables based on their relevance and/or contribution to the purposes of the current studies, the selection of the following measurements as proxies may not be beyond debate: for HRV the RMSSD, as it is a measurement of the parasympathetic/vagal tone which is not influenced by breathingThere are circumstances that might have influenced the results, in spite of the team’s efforts to obtain the most extensive insights of CS and its association with functioning. To begin with, it should be considered that patients participating in the study are volunteers. Moreover, the exclusion criteria, despite being based on patients’ files, are also dependent on doctor’s judgement. The impact of these circumstances is so far unknown to the authors. Likewise, given the CAU design of the study the choice of measurements has to be feasible and compatible with the regular clinical procedures. As a consequence, the functional MRI, a commonly mentioned instrument to measure CS, could not be performed in the study. The HRV, on the other hand, although less often used, can be an insightful and innovative approach to the assessment of one of the indicators of CS. Additionally, the sample sizes are estimated a priori for the analyses due to insufficient previous studies and, therefore, they are of exploratory nature and used as a guide. Also, despite the efforts of the team to promote the study participation and participant retention, it is likely that patient recruitment may be slower than anticipated and that the patient may not have a complete follow-up. However, since the measurement period is ample, the calculations are vigilantly made with generous margins , and the literature related to the topic has shown smaller sample sizes.All things considered, the results obtained from the measurements described in this research protocol can, first, help better describe and understand the mechanisms involved in CS, particularly the ones affecting the functioning of patients with CLBP; and second, can be used to optimise the effectiveness of pain management interventions. To the authors’ knowledge, the study described in this research protocol is the first of its kind and it may become an important breakthrough for researchers involved in the study of pain, for the treatment strategy of patients with chronic pain by healthcare professionals and for patient’s pain education.All participating patients sign the informed consent before any assessment takes place. Formal ethical clearance to perform the study has been obtained from the Medical Research Ethics Committee (METc) of the University Medical Center Groningen (the Netherlands) in July 2017 (METc 2016/702). All procedures are in accordance with the ethical standards of the Helsinki Declaration of 1975 as revised in 2014The dissemination strategy of the research study results will be through scientific publications in peer-reviewed journals and presentations in relevant national and international conferences. In addition to it, reports will be sent by post to participants, and reports and presentations in meetings will be provided to stakeholders.


Even patients with lymphoproliferative diseases may develop a persistent chronic pain not responsive to usual treatments due to changes in antibody production and to some treatments like radiotherapy, chemotherapy, and the administration of monoclonal antibodies, which further impair the immune defense and induce chronic inflammatory phenomena acting as a substrate for a persistent chronic pain. Five patients with indolent lymphoproliferative diseases were treated for severe pain nonresponsive to other pain reliever treatments with SCS applied with an All-in-One Shot (OS) procedure. For all patients, the estimated survival time was of 5 years or more. All patients showed a significant reduction of the intensity of pain: the mean Numerical Rating Scale was 7.4 before treatment and 2.2 after. No patient developed adverse events. Supported by the data of this study, we believe that the habit to deprive patients with an indolent form of lymphoproliferative diseases of the possibility to reduce the intensity of chronic pain by SCS treatment is extremely reductive and frustrating. The pain is an epiphenomenon of several pathological processes. A constant stimulation of the nociceptive pathways produces changes in the ion channels, receptors, and nerve synapses, which, together with an increased diffusion of neurotransmitters and neuromodulators, facilitates the depolarization of peripheral and central neurons –5. Theredura mater with loss of cephalorachid fluid, infections and paresis due to possible compression of the spinal cord, extravasation of serum at the pulse generator plant site, feeling of numbness or persistent pain localized to the area below the implant or at the electrode implant site, allergic reactions, and attempts of rejection for implanted materials. Over time, a stimulation change may occur due to cellular changes in tissues surrounding the electrodes caused by the displacement of the electrodes, loosening of the electrical connections, defects in the lead, or alterations in the charge of the batteries. Spinal cord stimulation is mainly applied in the failed back surgery syndrome (FBSS), neuropathic pain, peripheral ischemic pain, amputation pain and visceral pain  is among the main innovative techniques to control the otherwise intractable chronic pain. SCS uses low voltage current that reaches the spinal cord through the application of epidural leads that stimulate nerve fibers blocking or weakening the transmission of pain –21. The ral pain , 29, andLymphoproliferative diseases can be classified as aggressive or indolent. The aggressive forms need immediate intensive treatment to improve the expectancy of life. Instead, Indolent lymphoproliferative diseases have a slow growth and are usually treated only in case of systemic symptoms, symptomatic splenomegaly, bulky mass over 7 cm, and progressive leukemic serum effusions. The indolent forms require a 3- to 6-month watch-and-wait period to verify whether the disease may turn aggressive; this strategy is linked to three main reasons: the good long-term prognosis measured in years, the absence of benefits with chemotherapy that however may induce severe side effects, and the possibility of these indolent forms going through multiple reactivations over time requiring different chemotherapy treatment , 31. ChrIn the last 2 years, five patients with B-cell lymphoproliferative diseases with a life expectancy of more than 5 years complaining for an intense persistent pain resistant to numerous pain-relieving treatments were treated with SCS at the Department of Pain Therapy Monaldi Hospital—AORN Ospedali dei Colli, Naples, Italy. Before implanting the SCS apparatus, individual prognostic scores were examined.The International Prognostic Score (CLL-IPI) was calculated for two CLL patients, the FLIPI was calculated for two follicular lymphoma (FL) patients, and the International Prognostic Scoring System (ISSWM) was calculated for one patient with WM. The SCS stimulation was considered effective when a pain reduction >50% was obtained. The intensity of pain was assessed according to the McGill Pain Questionnaire (MPQ), recording the Numerical Rating Scale (NRS) of the pain average: minimum pain, maximum pain, and pain during exertion . At the baseline visit, each patient signed an informed consent for the anonymous use in clinical investigation and scientific publication, according to Italian laws on privacy and with the rules of our ethics committees. All patients were evaluated with ECOG Performance Status (PS). Patients, according to the CARE guidelines, underwent physical examination, routine blood chemistry tests, and serum markers of HBV, HCV, and HIV infections  –42. To rp < 0.05). We assessed individual NRS changes in pain before and after SCS with the Wilcoxon signed-rank test using the Reliable Change Index, which indicates whether a change in the NRS score is significantly greater than expected based on the reliability test–retest. In the reliable change, index X1 represents a subject's pre-test score, X2 represents the post-test score in the same subject, and Sdiff is the standard error of the difference between the two test scores. Sdiff can be computed directly from the standard error of measurement (SE) according to the following: RC: X1 – X2/SDIFF, where SDIFF = √2(SE) 2, and SE is computed as follows: SE = s√1 – rxx. We used a 95% confidence interval, meaning that we considered RCI values of 1.96 or higher statistically significantly.The Wilcoxon signed-rank test was used to evaluate changes in NRS before and after SCS in each patient, a non-parametric test useful for assessing whether two repeated measurements in a single patient differ significantly  and a slight decrease in gamma globulin serum levels. He had an IGHV mutated status, no cytogenetic abnormalities, serum β2 macroglobulin = 2 mg/L, and PS = 2. His CLL-IPI showed an intermediate risk with 79.3% 5-years survival possibility. He was negative for serum markers of HBV, HCV, and HIV infections. In February 2019, he was treated with OS dorsal SCS, implanting two leads with tip in T7; the chosen waveform was BURST DR with the following parameters: frequency 40 Hz, intraburst 500 Hz, pulse length 1,000 ms, Max Amplitude 2 mA  pulsed radiofrequency treatment (PRF). She was affected by CLL stage II according to Rai staging. A lymphocytosis  and a slight decrease in gamma globulin serum levels were the only abnormalities in the blood tests. She had an IGHV mutated status, no cytogenetic abnormalities, serum β2 microglobulin = 3 mg/L, and PS = 2. Her CLL-IPI showed a low risk with a 93.2% possibility of 5-year survival. He was negative for serum markers of HBV, HCV, and HIV infections. The NRS was 8 in April 2019 when she was treated with an OS dorsal SCS implanting two leads with a non-aligned tip in T6 (left) and T7 (right); the chosen waveform was BURST DR with the following parameters: frequency 40 Hz, intraburst 500 Hz, pulse length 1,000 ms, Max Amplitude 2 mA  and serum B2-microglobulin = 2.2 (mg/L). Her ISSWM was 0 with a median survival of 142 months. Her PS was 2. All serum markers of HBV, HCV, and HIV infections were negative. She was treated with an OS SCS implanting one lead with tip in C2–C3 in July 2019; the chosen waveform was high frequency at 10 kHz; the sweet spot of the electric field was set in the e1–e2 dipole  for pulmonary FL. No other side of the disease was demonstrated by a [18f] fluoro-D-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) performed in February 2019. At that time, the LDH serum value was 200 IU/L, and all other blood tests were normal. In March 2019, he performed a RT (24Gy) and in May 2019, a FDG-PET/CT showed a complete remission of pulmonary lesion.No pain relief was observed after DRG pulsed radio frequency (PRF) thermal ablation of the transverse process of D4 performed in May 2019. The patient was in stage IE according to Ann Arbor staging, his PS was two, and his FLIPI was one, a value indicating a low-risk category with a 10-year overall survival of about 70%. Serum markers of HBV, HCV, and HIV did not show an ongoing infection, while an anti-HBc positivity was a clue of a past HBV infection. In September 2019, still suffering for an intractable persistent intercostal pain with NRS of 6, he was treated with right D3 and D5 DRG stimulation. The implant was done using an OS procedure with the following parameters: continuous stimulation frequency, 30 Hz; pulse width, 300 ms; max amplitude range, 0.350–0.450 mA . The NRSz = −2.12; p = 0.034). The reliable change index for NRS score at the two different time points showed a RCI of 2.07 and an effective size of 3.11. These data confirm that HFSCS has produced a significant reduction of pain in our five patients.Five patients with lymphoproliferative diseases were treated for severe pain nonresponsive to other pain reliever treatments with SCS, two had CLL, one had WM, and two had FL; two were females and three were males; the median age of the patients was 69 years (range 53–70). The PS was two in all cases. The SCSs implanted were lumbar in one patient, cervical in two, and ganglionic in two. For all patients, the estimated survival time was of 5 years or more. The mean NRS before treatment was 7.4, with highest peak at 10 and the lowest at six, whereas the mean NRS after treatment was 2.2, with highest peak at five and lowest at one . The WilWe conclude that the high-frequency SCS was useful for all patients with lymphoproliferative diseases included in the present study.No patient had ongoing HIV, HCV, and HBV infections. None of these five patients experienced adverse events or infections signs.The most common indications for SCS are FBSS, complex regional pain syndrome, brachial plexopathy, diabetic neuropathy, post-herpetic neuralgia not responding to other treatments, and pain associated with vascular pathology or secondary to damage of peripheral nerves. All these indications do not foresee their use in the onco-hematological patients. In these patients, the greater risk of both systemic and local infections could jeopardize the success of the implant. The reduced prognosis of these patients, the greatest risk of infections and the high cost of the procedure are the reasons for the scarce use of this technique in this patient setting. Unfortunately, changes of the immune system occurring in patients with lymphoproliferative diseases may favor the onset of intractable persistent chronic pain. Furthermore, some treatments like radiotherapy, chemotherapy, and the administration of monoclonal antibodies may further impair the immune defense of these patients and generate chronic inflammatory phenomena acting as a substrate for the development of persistent chronic pain. Some surgical diagnostic techniques like VATS in our patient 1 may contribute to generate a chronic persistent pain syndrome. Therefore, in patients with lymphoproliferative diseases, there are reasons inducing a persistent chronic pain not responsive to usual treatments for whom the SCS should be taken into consideration.All five patients in this study were in good general condition, with a PS of 2, and had an indolent lymphoproliferative disease, and for all of them, a survival of 5 years or more was expected. The implant and use of the SCS in a one-shot procedure were safe in all five treated patients who did not develop adverse events and infections. Of note, this procedure is reversible in case of ineffectiveness .The habit to deprive patients with lymphoproliferative diseases of the possibility of being treated with SCS just because for them a reduced survival duration is expected is extremely reductive and frustrating. Even if in an evaluation of the cost-effectiveness ratio, the expected duration of life has a relevant role, it is inhumane not to reserve also for patients with indolent lymphoproliferative diseases the possibility to take advantage of the benefits SCS may offer. All this considering, there is no reason to deny these patients the possibility of accessing SCS treatment. The data presented in this study might confirm this opinion, but further studies are needed to conclude on this topic.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Written, informed consent was obtained for the publication of these case reports.AS and AP: conceptualization. AS, CS, MD, PB, AMS, ESag, ESar, and DT: data curation and investigation. AS and BC: methodology. AS: project administration, writing—original draft, and writing—review and editing. All authors have read and agreed to the published version of the manuscript.The 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.


In addition, the receiver operating characteristic curve analysis showed that the area under the curve of pain duration after lumbar surgery was 0.680 , with an optimal cut-off value of ≤14 months, sensitivity of 51.5%, and specificity of 81.4% Our results suggest that an early intervention using combined epidural adhesiolysis and balloon decompression in lumbar PLS patients may be associated with a favorable outcome, even though it has limited effectiveness.Post-laminectomy syndrome (PLS) is characterized by chronic pain and complex pathological entity after back surgery. An epidural adhesiolysis is considered an effective treatment option for lumbar PLS. In this study, we retrospectively analyzed the outcome and evaluated the predictive factors of combined epidural adhesiolysis and balloon decompression using inflatable balloon catheters in lumbar PLS cases. One hundred and forty-seven subjects were retrospectively assessed and analyzed. The percentages of patients who exhibited treatment response were 32.0%, 24.5%, and 22.4% of the study population at 1, 3, and 6 months, respectively. In multivariate logistic regression analysis, the pain duration was independently associated with the treatment response six months after combined epidural adhesiolysis and balloon decompression (odds ratio = 0.985, 95% confidence interval = 0.971–0.999;  Recurrent and chronic lower back pain (LBP) with or without sciatica is one of the leading causes of a poor quality of life. To manage LBP and sciatica, investigations are ongoing to evaluate the evidence of superiority between conservative management and surgical treatment ,2. A recWe analyzed retrospectively collected data from patients diagnosed with lumbar PLS and treated with combined epidural adhesiolysis and balloon decompression using an inflatable balloon catheter in a single pain clinic of a tertiary medical center in Seoul, Republic of Korea. All participants gave informed consent and this study protocol was approved by the Ethical Committee of the Asan Medical Center . This study was conducted in accordance with the Declaration of Helsinki.We searched our institution’s Information Technology of Service Management (ITSM) system between January 2014 and March 2018 using the terms “history of lumbar spinal surgery”, “epidural adhesiolysis using an inflatable balloon catheter”, and “chronic low back or leg pain”. Patients were included in the study only if they met the following criteria: (1) at least 20 years of age; (2) had a history of spinal surgery in the lumbar spine confirmed with imaging; (3) chronic back and leg pain with severity of at least 6 points on the numerical rating pain scale (NRS) within three months after spinal surgery ; and (4)®, JUVENUI, Seoul, Korea; After sterile preparation before the procedure, a local anesthetic  was infiltrated under the skin and soft tissue. While waiting for sufficient local anesthesia, the balloon of the catheter  to 10 (worst possible pain) to determine the pain intensity of both leg and lower back; and the Korean version of the 10-item Oswestry Disability Index (ODI) questionnaire  to determine the physical functional status. For analysis of the patient’s satisfaction and improvement after the procedure, the global perceived effect (GPE) after the procedure according to a 7-point Likert scale was also measured.According to previous studies, we defined the responder group with some modifications: (1) 50% (or ≥4-point) decrease of NRS score from baseline; (2) ≥30% (or ≥2-point) decrease of NRS score from baseline together with any one of the following criteria: (i) ≥30% or ≥10-point) decrease in ODI from baseline or (ii) ≥5 points on the GPE scale ,9,10. Su-point dep-value < 0.05 was considered to be statistically significant. The ability of pain duration after lumbar surgery to predict successful response after combined epidural adhesiolysis and balloon decompression was determined by calculating the area under the receiver operating characteristic (ROC) curve. The area under the ROC curve was calculated and the value with the highest sensitivity and specificity was set as the optimal cut-off value. The data were analyzed using the Statistical Package for the Social Sciences Version 21.0  and MedCalc version 11.3.3 .Continuous demographic data from the non-responders and responders were compared using the Student’s t-test or the Mann–Whitney U-test and are presented as means with standard deviations or medians with interquartile ranges as appropriate. Categorical demographic data were compared using a chi-square test or a Fisher’s exact test. Using univariate and multivariate regression analyses, the factors associated with a successful treatment response six months after combined epidural adhesiolysis and balloon decompression were analyzed. The most relevant factors associated with treatment response were included in the univariate logistic regression analysis. The inclusion of variables in the final multivariate logistic regression analysis to evaluate independent factors associated with treatment responses was based on biological plausibility, clinical importance, and statistical considerations. The quality of fit of the model was assessed with the Hosmer–Lemeshow test. A two-tailed p = 0.002, The overall baseline demographic characteristics of the 147 patients are shown in p = 0.042). In addition, according to our previous study [p-value for statistical difference in the comparison of patient characteristics to be 0.2, the number of target lumbar levels was included in the multivariate logistic regression analysis. After adjusting for demographic differences, clinical importance, and biologic plausibility in the multivariate regression analysis, only pain duration was independently associated with a successful outcome at six months after balloon adhesiolysis , with an optimal cut-off value of ≤14 months, sensitivity of 51.5%, and specificity of 81.4%  = 0.986, 95% confidence interval (CI) = 0.972–0.999, of 81.4% .The complications observed during balloon adhesiolysis are shown in To date, diagnosing PLS remains a controversial issue . The conAs mentioned above, determination of the predictive factors of response after the balloon procedure in lumbar PLS is important. Multivariate regression analysis in this study showed that a short duration of pain after lumbar surgery may be associated with a favorable outcome after combined epidural adhesiolysis and balloon decompression. Moreover, the present ROC curve analysis found that an optimal cut-off value was ≤14 months of pain duration after lumbar surgery to predict the successful response to combined epidural adhesiolysis and balloon decompression. This result could be explained based on the duration of post-operative adhesion formation. Presumably, an old fibrotic adhesional scar is harder than a recent one. The degree of fibrotic adhesion is directly proportional to the effectiveness of adhesiolysis and drug administration at the targeted sites. Additionally, when compared to our previous study , the anaOur previous study showed the effectiveness of combined epidural adhesiolysis and balloon decompression in patients with chronic intractable lumbar radicular pain without previous lumbar surgery ,9,23. DeWith regards to complications, one patient with lumbar PLS experienced temporary motor weakness after balloon decompression. Even though this motor weakness spontaneously resolved, interventionists should consider the possibility of this neurologic deficit after the procedure, especially in patients with lumbar PLS. The occurrence of this complication may be attributable to transient ischemia during ballooning. Therefore, the balloon should be gently inflated while observing the patient’s response. If the patient complains of severe pain during balloon inflation, no further balloon decompression should be attempted. In addition, the rate of dura puncture during the balloon procedure in patients with lumbar PLS is two times that in patients without previous lumbar surgery ,10. The This study had some limitations. Firstly, we did not include medication use in the analysis of the outcomes. In most cases, patients were taking sufficient amounts of pain killers including opioids, the use of which may lead to meaningful variations in the outcome . To overThe combined epidural adhesiolysis and balloon decompression approach may have limited effectiveness in patients with lumbar PLS. However, early intervention with combined epidural adhesiolysis and balloon decompression after development of lumbar PLS may be associated with favorable outcomes.


Even though the lack of statically significant differences in most of the muscular oxygenation variables failed to refine the definite pathogenic mechanisms underlying nonspecific neck pain, the findings of modulatory strategies of faster deoxygenation implied that near-infrared spectroscopy appears to have practical potential to provide relevant physiological information regarding muscular oxidative metabolism and constituted convincing preliminary evidences of the adaptive manipulations rather than pathological responses of oxidative metabolism capacity of sternocleidomastoid muscles in nonspecific neck patients with mild disability.Since there is merit in noninvasive monitoring of muscular oxidative metabolism for near-infrared spectroscopy in a wide range of clinical scenarios, the present study attempted to evaluate the clinical usability for featuring the modulatory strategies of sternocleidomastoid muscular oxygenation using near-infrared spectroscopy in mild nonspecific neck pain patients. The muscular oxygenation variables of the dominant or affected sternocleidomastoid muscles of interest were extracted at 25% of the maximum voluntary isometric contraction from ten patients  and asymptomatic individuals  using near-infrared spectroscopy. Only a shorter half-deoxygenation time of oxygen saturation during a sternocleidomastoid isometric contraction was noted in patients compared to asymptomatic individuals (10.43 ± 1.79 s vs. 13.82 ± 1.42 s,  Various epidemiological data indicates that neck pain has become a general reason that people seek medical assistance and a primary cause of disability worldwide ,3,4,5,6.Furthermore, near-infrared spectroscopy (NIRS) utilizes optical properties such as absorption and scattering to provide pathophysiological information from biological system. Briefly, near-infrared wavelength light between approximately 650 and 1000 nm is emitted into the muscle of interest from a source, and a detector tracks the attenuation of the intensity of the emitted light. Subsequently, both changes in the oxygenated and deoxygenated hemoglobin concentration could be further deduced from changes in the light intensity through algorithmic transformation governed by the modified Beer-Lambert law. Recent evidences have shown the potential of NIRS in various medical applications, including functional analysis of the brain and continuous monitoring of changes in local muscular oxygenation ,43,44,45Because of the capability of NIRS for offering non-invasive monitoring of tissue oxygenation in a wide range of clinical scenarios, alternative potential modulatory mechanisms from a muscular oxidative metabolism viewpoint for neck-related neuromuscular conditions have also been considered ,47,48,49All the experimental procedures were approved by the Institutional Review Board of Kaohsiung Medical University Chung-Ho Memorial Hospital (No. KMUH-IRB-20120078) and performed in accordance with relevant guidelines of the Declaration of Helsinki. Prior to participation, all voluntary participants clearly understood the major objectives of the current and written informed consent was obtained from each individual participant. p < 0.01). Moreover, the groups did not differ in terms of age, gender distribution, weight, BMI and sternocleidomastoid skinfold thickness (p > 0.05).Two groups of volunteers were enrolled: one group of ten participants with nonspecific neck pain  who had sought medical treatment within the past 6 weeks with no medical histories of spinal neurological and orthopedic problems, such as spinal vertebral fracture, abnormal spinal lordosis, spinal spondylosis or spinal osteoarthritis. One group of ten participants  with no history of cervical surgery, cervical trauma, cervical pain or neuromuscular problems. Anthropometric details were initially recorded. Next, the level of neck functional disability and adipose tissue thicknesses at the site of the probe were respectively assessed for each participant using the Neck Disability Index (NDI)  and skin2], the deoxygenated hemoglobin concentration [Hb] and the total hemoglobin concentration [tHb] ([HbO2]+ [Hb] µM). In this investigation, the characteristics of sternocleidomastoid muscular oxygenation were continuously monitored during isometric flexion by a commercial frequency-domain NIRS system  in real time at a 25 Hz sample rate. On the other hand, as previous work had mentioned that the frequency-domain multiple-distance system with over distances in the range of 1.5 to 4.5 cm could minimize the influence of between-subjects variations in adipose tissue thickness on NIRS signals and accurately quantify the optical properties of the superficial muscle , the mulAfter completing the experimental setup and instrument calibration to acquire the effective optical coefficients, all of the participants were familiarized with the experimental protocol followed by the conduction of three brief, voluntary, maximum isometric contractions for three seconds separated by a rest period of at least five minutes. The contraction with the highest exerted force recorded using custom-designed force-measurement device that consisted of a tension/compression minibean load cell was selected as the maximum voluntary contraction (MVC) and used for the calculation of the target levels for submaximal contractions. Next, all participants performed a trapezoid isometric muscle action of the sternocleidomastoid muscles, which displayed a linear increasing sternocleidomastoid isometric contraction from the baseline to 25% MVC at a rate of 10% MVC/s, a submaximal constant force of the target 25% MVC for 20 s, and a linear decrease back the baseline at 10%MVC/s. All recruited participants were instructed to maintain their force output as close as possible to the target force. Trials were repeated if the actual force production varied more than 5% from the target force and a sufficient rest period of at least ten minutes was provided between each trial to avoid muscle fatigue. A visual template and feedback trace of the force output during the trapezoid isometric muscle action and verbal encouragements were available to facilitate the achievement of the requested task .2] and the deoxygenated hemoglobin concentration [Hb] were recorded. To further clarify the dynamic balance of O2 delivery and consumption of the target muscles during contraction and recovery periods, the StO2 was expressed using the following formula [All continuous muscular oxygenation variables including the oxygenated hemoglobin concentration [HbO formula ,52,55:(1A hyperbolic tangent equation (tanh) was applied to fit the oxygen saturation curves (Y) as a function of time (t) during the contraction and recovery periods to constitute muscular oxygenation kinetics  Figure :(2)Y=a ×2 (%) was estimated from the maximum and minimum oxygen saturation values of while the requested task was performed from the parameters d - a and d + a, respectively. From the two derived coefficients, c/b, which represents half-deoxygenation time of StO2, implying the flection time taken to reach 50% of the maximal oxygen consumption during the contraction phase, while it stands for half-reoxygenation time of StO2 in the recovery phase, accounting for the time interval from the end of a contraction to the time that the muscular oxygenation returns to the half-baseline value [Using the least-square error method, the best-fit coefficients, a, b c and d of the muscular oxygenation kinetics were extracted. ΔStOne value .2 data were multiplied with a Hanning window and padded with zeros to 7500 data points to increase the resolution of the frequency spectrum. Next, the features of spontaneous oscillations of muscular oxygenation, such as the peak and median frequencies, were extracted to clarify the potential modulatory mechanisms of sternocleidomastoid muscular oxygenation in nonspecific neck pain condition. All of data analysis was processed using self-developed computational code in the M MATLAB programming language .In addition to the time-domain view, the periodic nature of muscular oxygenation oscillations during the contraction and recovery period was further observed using a fast Fourier transform (FFT) algorithm. Before the FFT analysis, raw StO®, IBM Corporation, Armonk, NY, USA). Descriptive statistics were used to characterize the group means and standard deviations for the demographic data and muscular oxygenation variables of interest for participants with nonspecific neck pain and asymptomatic individuals. Because of non-normal distribution of these variables verified by the Kolmogorov–Smirnov test, a nonparametric Mann–Whitney U test was chosen to further determine whether differences existed between the two tested populations. The results were considered to be statistically significant if the p-value was below 0.05.Statistical procedures were performed with commercial Statistical Package for the Social Science software (SPSS 20.02), which means the flection time taken to reach 50% of the maximal oxygen consumption during the contraction phase [p < 0.001), but no any statistically significant differences in other muscular oxygenation variables (p > 0.05) were observed between these two groups. On the other hand, there were also no any differences between males  and females  in adipose tissue thickness, and muscular oxygenation variables .Except for time-domain analysis of oxygen saturation kinetics, the periodic nature of muscular oxygenation oscillations was further investigated using spectral analysis. 2, oxygen extraction, half-reoxygenation time of StO2 and patterns of the spontaneous oscillations of muscular oxygenation between nonspecific neck pain patients and asymptomatic individuals failed to refine the definite pathogenic mechanisms, the findings of the shorter half-deoxygenation time of StO2 implied that NIRS appears to have practical potential to provide relevant physiological information regarding muscular oxidative metabolism for mild nonspecific neck pain patients. It could be deduced from our findings that the mild pathological condition for the recruited nonspecific neck patients was not associated with oxidative metabolism capacity of sternocleidomastoid muscles. Most importantly, neck pain patients with mild disability displaying shorter half-deoxygenation time of StO2 and detectable but not statistically significant increase in the median frequency of muscular oxygenation oscillations soundly constituted preliminary evidences for the appearance of adaptive strategies of muscular oxygenation while executing a sternocleidomastoid isometric contraction.The present study attempted to evaluate the clinical usability for featuring the modulatory strategies of sternocleidomastoid muscular oxygenation in nonspecific neck pain patients with mild neck disability. We, therefore, testified whether sternocleidomastoid muscular oxygenation variables, the dynamic balance of oxygen delivery and consumption and the periodic nature of muscular oxygenation oscillations would be comparable between patients with mild nonspecific neck pain and asymptomatic individuals. Even though the lack of statically significant differences in most of the muscular oxygenation variables, including baseline StO2 of the sternocleidomastoid muscle in contrast to asymptomatic individuals, reflecting a need for greater oxygen extraction. Now that another important finding from the present work revealed comparable changes in oxygen saturation between the nonspecific neck pain and asymptomatic groups, it is reasonably inferred that the nonspecific neck pain patients would be likely to raise the capacity of muscle perfusion to achieve the acceleration of oxygen delivery, again hinting an adaptive mechanism to sustain a balance between oxygen delivery and utilization in sternocleidomastoid muscle.On the top of that, the nonspecific neck pain patients displayed shorter half-deoxygenation time of StO2 of the erector spinae muscle have been demonstrated in patients with low back pain [2 of the trapezius muscles in neck pain patients after one set of isometric exercises was executed [2 after contraction of the sternocleidomastoid muscles between the nonspecific neck pain and asymptomatic groups. Different muscles and muscular pathogenic conditions investigated in both the current and previous studies would interpret these discrepancies. Additionally, the enrollment of experimental volunteers with mild neck disability in the present work was likely to result in rather unexpected results. Previous efforts indicated the physiological relevance of muscular oxygen metabolism for muscle function in healthy and pathological conditions, and it is generally thought that adaptive manipulations of muscular oxygenation are associated with various neuromuscular deficiencies ,59,60,61ack pain  and indiexecuted ,56. Thes2 of the extensor carpi radialis and the trapezius muscles during low level sustained muscular contractions were detected. The findings of no group differences in oxygen extraction during contraction found from the current studies complied with the proven inference, which stated that early pathogenic condition or fatigue of patients with work-related muscle pain did not seem to be associated with muscular oxygenation and hemodynamics [Although our findings were contrary to common hypotheses of disturbed muscular oxygenation characteristics associated with neuromuscular deficiencies ,59,60,61dynamics .2 while initiating contraction, a conceivable modulatory strategy of sternocleidomastoid muscular oxygenation in nonspecific neck pain patients with mild neck disability could be deduced. The adaptive manipulation of faster oxygen delivery may be due to urgent requirement of oxygen supply for facilitating the augmentation of the initial discharge rates of the activated motor units. A noteworthy issue for discussion is the relevant role of oxygen availability for modulating motor unit recruitment and discharge patterns of activated motor units during contraction ,63. It iFurther, the periodic nature of muscular oxygenation oscillations was characterized and approximately analogous patterns of the spontaneous oscillations of muscular oxygenation between the nonspecific neck pain and asymptomatic groups were identified. Specifically, the appearance of a low-frequency distinctive peak at less 0.1 Hz was noted in accordance with previous finding ,64, whicSince the proposed frequency-domain NIRS system possesses practical potential for featuring the characteristics of the modulatory strategies of sternocleidomastoid muscular oxidative metabolism in mild nonspecific neck pain, comparing the characteristics of sternocleidomastoid muscular oxidative metabolism between nonspecific neck pain patients and asymptomatic individuals provide an auxiliary approach to differentiate on earth adaptive manipulations or pathological responses of oxidative metabolism capacity of sternocleidomastoid muscles in nonspecific neck patients with mild disability. Even the understanding of the characteristics of sternocleidomastoid muscular oxidative metabolism in nonspecific neck pain with different severities allow guiding the clinicians to evaluate the extent of impairment of the cervical spine and monitor the efficacy of rehabilitation programs in clinical practice.Besides, because of the limited sample size and the enrollment of patients with mild neck disability, the significance relating to the preliminary findings from the current work and the comparisons thereof is exploratory and not confirmative. Next, using muscle contraction force instead of direct electromyography assessment for ensuing muscle activation level is another methodological limitation. For these reasons, the present findings should be interpreted with more caution. Further research is warranted to resolve these deficiencies and comprehensively elucidate the pathogenic mechanisms of neck pain.2 during a sternocleidomastoid isometric contraction in the nonspecific neck pain patients. It could be at least partly speculated the adaptive manipulations rather than pathological responses of oxidative metabolism capacity of sternocleidomastoid muscles in nonspecific neck patients with mild disability. In addition, in keeping with our previous finding of the reinforcement of motor unit recruitment firing rates [Taken together, except for cervical kinematic and kinetic assessments, potential pathological mechanisms from a muscular oxidative metabolism viewpoint for neck-related neuromuscular conditions could be considered alternatively since the preliminary proof of clinical applicability of NIRS for noninvasive monitoring local muscular oxygenation. Another key point to mention is that, even if nearly sound oxidative metabolism capacity of sternocleidomastoid muscles, as evidenced by no statistically significant differences in most of the features of muscular oxygenation variables between the neck pain and asymptomatic groups, the current work corroborated a shorter half-deoxygenation time of StOng rates , it was


A retrospective review was performed for patients in the Veterans Administration Healthcare System who underwent prophylactic stabilization of the femur for metastatic disease. The goal was to evaluate indications for prophylactic stabilization through Mirels criteria.All veterans who underwent inpatient prophylactic femoral stabilization between October 2010 and September 2015 were identified. Procedure and demographic variables were collected by using chart review. Provider notes and radiographs were reviewed to calculate Mirels scores.Ninety-two patients underwent confirmed prophylactic stabilization for metastatic bone disease. Lung cancer and multiple myeloma accounted for most lesions. The mean Mirels score was 10.3 (range 7 to 12). 3.2% of patients had a score of 7, and 6.5% had a score of 8. Most lesions were peritrochanteric (66%) and lytic (85%). There was more variability in size (mean 2.3), with 15% being under one third of bony width and 38% between one and two-thirds. The mean pain score was 2.5; 73% reported functional pain. Of lytic and peritrochanteric lesions , 55% were less than two-thirds the cortical width and 31% lacked functional pain.This retrospective study of prophylactically stabilized metastatic lesions revealed that more than 90% of patients had Mirels scores greater than 8, suggesting a substantial risk of pathologic fracture. Over half of all stabilized lesions were peritrochanteric and lytic. These criteria alone achieve a minimum Mirels score of 8; however, one-third of these lacked functional pain. Notably, Mirels' original paper found location and type criteria to be the least predictive of impending fracture. Contrariwise, functional pain was the most accurate predictor. Multiple studies have found poor specificity of the Mirels criteria. The high scores achievable by the location and type criteria may represent an overrepresentation of their contribution to fracture risk. Reconsideration of the relative weights of each criterion warrants further examination. This system incorporates lesion size, location, type, and pain characteristics. Each of these four subcategories are evaluated on a 1 to 3 scale and summed. Total scores above an eight are considered at high risk of fracture, therefore warranting stabilization. A score of exactly 8 is considered borderline, and clinical judgment is used to make a final treatment decision.Several authors have proposed predictive models for identifying metastatic lesions that represent impending pathological fractures.12-14 When a hard score cutoff of ≥9 is used, it has been shown to be highly sensitive (>91%) but significantly less specific (35%) for predicting fracture. Some authors recommend using the system as a guide with heavier weight given to mechanical pain.15Mirels' criteria have been shown to be valid, reliable, and reproducible in subsequent studies for both upper and lower extremity lesions.Currently, there is little known about actual practice patterns and indications used for prophylactic stabilization of metastatic lesions. To this end, a retrospective review was performed for patients in the nationwide Veterans Administration Healthcare System who underwent prophylactic stabilization of the femur for metastatic disease. The goal was to evaluate indications for prophylactic stabilization through Mirels criteria.This retrospective study was approved by the institutional review board. All veterans who underwent inpatient prophylactic femoral stabilization between October 2010 and September 2015 were identified using common procedural terminology codes 27495 or 27181 through the Veterans Affairs Informatics and Computing Infrastructure Corporate Data Warehouse database. Those receiving care outside VA hospitals but paid for by the VA were excluded. Procedure date and location and demographic variables were collected from Veterans Affairs Informatics and Computing Infrastructure Corporate Data Warehouse using Structured Query Language.16 This study was designed and reported using the guidelines of Strengthening the Reporting of Observational Studies in Epidemiology.17All electronic medical records identified were manually reviewed to establish the accuracy of common procedural terminology codes. Ninety-two eligible patients were found to have undergone prophylactic stabilization for femoral metastasis. Provider notes and biopsy results were reviewed to identify histological diagnosis and the pain subscores for the Mirels criteria. Multidirectional preoperative radiographs were reviewed by the authors to determine location, size, and type subscores. Descriptive statistics were performed. Statistical analysis was performed using R version 2.4.3.Ninety-two patients were identified who underwent confirmed prophylactic stabilization for metastatic bone disease. Histopathological diagnoses are shown in Table Fifty-three percent of patients had lytic and peritrochanteric lesions. Of these, approximately half (55%) were less than two-thirds the cortical width and 31% lacked functional pain.19 Prophylactically stabilizing a metastatic lesion  is cost-effective, lessens the burden on the healthcare system, and is associated with an improvement in overall survival.21 Furthermore, these surgeries tend to be less morbid with shorter hospital stays and higher likelihood of discharge to home rather than a facility.This national retrospective study of prophylactically stabilized metastatic lesions revealed that more than 90% of patients had Mirels scores greater than 8, suggesting a substantial risk of pathologic fracture. Patients who sustain a pathological fracture have worse quality of life and are at higher risk for depression and anxiety, and Saad et al. reported that pathological fracture is associated with a 20% to 32% increased risk of death compared with patients with metastatic lesions that did not fracture.Location and lesion type showed very little variation; stabilized lesions were overwhelmingly lytic and located in the peritrochanteric region Figure . There w14 Reconsideration of the relative weights of each of the subcriteria warrants further study.One third of the current patients lacked functional  pain. As Mirels' original study noted functional pain to be the most accurate predictor of impending fracture, the high scores achievable by the more poorly predictive location and type criteria alone combined with the low prevalence of functional pain may imply an overrepresentation of the lesion size and character criteria. This likely represents the driving force behind the very poor specificity of the Mirels criteria demonstrated in previous studies, including a rather poor 33% in Mirels' original paper.22 reported moderate success in predicting pathological femur fractures in patients with breast cancer based on the lesion's size, cortical involvement, and pain. Fidler,10 in 1981, endorsed basing the decision to prophylactically stabilize on the amount of cortex affected as judged using orthogonal radiographs. They set a threshold of 50% to 75% of cortex involvement for consideration of stabilization. Harrington6 suggested that indications for prophylactic stabilization include lesions larger than 2.5 cm or comprising more than half the bone's diameter, lytic lesions, or refractory pain. CT-based structural rigidity analysis and finite element analysis have also been studied, with improved predictive accuracy, sensitivity, and specificity when compared with the Mirels criteria.24Alternative predictive rubrics exist but are much less often employed and lack the abundant validation studies of the Mirels system. Snell and Beals25 We did not investigate the timing of radiation, use of narcotics, or any interaction with chemotherapy. In addition, for understanding the indications for prophylactic stabilization, we would ideally identify all femurs at risk for fracture. While complex from an informatics perspective, the VA data may provide an avenue to further our understanding of these important topics in subsequent investigations. Verification and comparison with other healthcare delivery systems may be warranted. Demonstrating the indications for prophylactic nailing as currently practiced is important to future research on interventions aimed to minimize both the risk of pathologic fracture and unnecessary surgery.This study was limited to patients that that underwent surgery; additionally, women as well as patients with breast cancer are underrepresented in the VA healthcare system. Strengths include the number of patients, external generalizability across a national healthcare system, and the direct review of radiographs and chart notes. We did not include patients whose metastatic lesions were treated prophylactically with an arthroplasty, and there remains controversy on when intramedullary nailing versus arthroplasty is indicated.