Multiple myeloma is a bone marrow cancer that often causes bone pain, but little is known about the pain characteristics and mechanisms in this condition. This clinical study aims to: 1. characterize the type, location and intensity of pain in myeloma patients, and its effect of quality of life, and 2. investigate whether the nerve fibers in the bone of myeloma patients are altered. We will also explore whether pain intensity is correlated to blood indicators of inflammation or bone damage. Study results will help identify the mechanisms of myeloma-induced bone pain, allowing the development of new analgesics for these patients.Multiple myeloma (MM) is a bone marrow neoplasia that causes bone pain in 70% patients. While preclinical models of MM have suggested that both nerve sprouting and nerve injury may be causative for the pain, there is a lack of clinical data. Thus, the primary aims of this clinical study are: (1) to provide a deep characterization of the subjective experience of pain and quality of life in MM patients; (2) to investigate disturbances in the bone innervation of MM patients. Secondary aims include exploring correlations between pain and serum inflammatory and bone turnover biomarkers. In a prospective, observational study , patients with suspected MM requiring a diagnostic iliac crest biopsy at Sheffield Teaching Hospital (UK) are invited to participate. Consenting patients answer seven standardized questionnaires assessing pain, quality of life and catastrophizing. Bone turnover biomarkers and inflammatory cytokines are measured in fasting serum samples, and bone innervation is evaluated in diagnostic biopsies. MM patients are invited to a follow-up upon completion of first line treatment. This will be the first deep characterization of pain in MM patients and its correlation with disturbances in bone innervation. Understanding how bone turnover and inflammation correlate to pain in MM is crucial to identify novel analgesic targets for this condition. Multiple myeloma (MM) is a hematological disorder in which terminally differentiated B-lymphocytes are abnormally cloned in the bone marrow, causing solitary plasmacytomas or spreading systemically to other bones. MM is usually associated with elevated serum or urine levels of paraprotein, while formal disease diagnosis requires the presence of ≥10% myeloma cells in the bone marrow and either end-organ damage  or a defined biomarker of malignancy . In mostWhile MGUS is considered an asymptomatic disorder, pain is a main cause of physician consultation in MM patients , and is MM is commonly considered a disease of the elderly, as age is an important risk factor for its development . ImportaAs novel therapies are being developed, a growing subset of patients live with myeloma as a long-lasting disease, alternating between phases of clinical remissions and relapses. Thus, understanding and improving the pain and subsequent QoL of myeloma patients has become increasingly important. The aim of this study is to provide a deep characterization of the perception of pain and QoL in firstly diagnosed MM patients. Because pain is a subjective, multidimensional experience that comprises sensory, emotional and cognitive dimensions, this study aims to collect patient information through a constellation of standardized, validated questionnaires; data from MM patients will be compared with that from patients receiving a negative myeloma diagnosis (presumably MGUS patients). To further understand the mechanisms of myeloma-induced bone pain, bone innervation and serum inflammatory and bone turnover biomarkers will be evaluated in MM patients and compared with patients with a negative myeloma diagnosis. Moreover, data from MM patients at diagnosis will be compared with data collected upon completion of first-line treatment, and correlations between pain, bone innervation and serum biomarkers will be investigated.A prospective, observational study in a cohort of patients undergoing a diagnostic bone marrow biopsy for suspected MM. This is a single-center study within an international collaboration; patients will be recruited and samples obtained at Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. Sample analyses will be performed at University of Copenhagen, Copenhagen, Denmark, or University of Southern Denmark, Odense, Denmark. The Danish Association for Multiple Myeloma was contacted during conceptualization; they confirmed the study’s relevance to MM patients. A flow diagram of the study design can be found in To provide a deep characterization of the subjective experience of pain  and QoL in MM patients at diagnosis, compared to patients with a negative myeloma diagnosis .To evaluate disturbances in bone innervation  in MM patients at diagnosis, compared to patients with a negative myeloma diagnosis.The primary study aims are:Secondary aims of this study include evaluating the levels of bone turnover biomarkers and serum inflammatory cytokines in MM patients at diagnosis, compared to patients with a negative myeloma diagnosis.Additionally, data on pain parameters and QoL, bone innervation and serum biomarkers from MM patients at diagnosis will be compared with data collected following first-line treatment. Correlations between pain and disturbances in bone innervation and serum biomarkers in MM patients before and after treatment will also be investigated.All patients undergoing a diagnostic bone marrow biopsy for suspected MM between October 2019 and June 2021 will be invited to participate by their Hematology Consultant during their scheduled medical appointment. Inclusion and exclusion criteria are specified in To provide an in-depth characterization of the subjective experience of pain and QoL in MM patients through the completion of standardized questionnaires regarding general pain, bone pain, neuropathic pain, QoL and catastrophizing. Questionnaires from MM patients will be compared with those of patients receiving a negative myeloma diagnosis (control group).To evaluate disturbances in the presence, location and density of sensory and sympathetic nerve fibers innervating the bone marrow of myeloma patients. Biopsies from MM patients will be compared with those of patients receiving a negative myeloma diagnosis (control group).To evaluate changes in the levels of serum biomarkers of bone turnover  in MM patients. Levels of bone turnover biomarkers in the serum of MM patients will be compared with those of patients receiving a negative myeloma diagnosis (control group).To evaluate the levels of inflammatory serum cytokines and chemokines in MM patients. Levels of inflammatory biomarkers in the serum of MM patients will be compared with those of patients receiving a negative myeloma diagnosis (control group).To compare data on pain and QoL, bone innervation and serum biomarkers of bone turnover and inflammation in MM patients at diagnosis and following first-line treatment.To evaluate correlations between the self-reported experience of pain and disturbances in bone innervation in MM patients at diagnosis and following first-line treatment.To evaluate correlations between the self-reported experience of pain and serum levels of bone turnover biomarkers in MM patients at diagnosis and following first-line treatment.To evaluate correlations between the self-reported experience of pain and serum levels of inflammatory cytokines in MM patients at diagnosis and following first-line treatment.BPI : two-factor questionnaire assessing the severity and interference of pain ,16. The FACT–BP : Initially developed for the assessment of pain in bone metastases, it measures bone pain and its effect on quality of life. This will provide information on whether myeloma patients suffer from bone pain, compared to controls. Moreover, this questionnaire is sensitive to clinical changes following therapy , and wilPCS : assessment of the extent of catastrophizing, which is subdivided in three domains: rumination, magnification and helplessness . MountinEORTC QLQ-C30 : assessment of quality of life in cancer patients. This questionnaire contains a measure of global health status, functional scales  and symptoms scales  . As thisEORTC MY20 : Supplementary module to administer alongside the EORTC QLQ-C30 for the assessment of disease symptoms, side effects of treatment, future perspective and impact of disease on body image perception [EORTC CIPN : assessment CIPN through a sensory, a motor and an autonomic scale . AdminispainDETECT: identification of a possible neuropathic component of pain . This quPatients who consent to participate will receive a booklet with a total of seven standardized questionnaires , which wAdditionally, patients will be asked to fill in a customized demographic questionnaire regarding their marital status, whether they cohabitate with their children, their postal code, country of origin, level of education and employment status. Patients will also be asked to answer the question: “is there any important information regarding your pain experience or quality of life that you feel has not been covered in the given questionnaires?”Patients will receive the questionnaire booklet during their routine hospital visits, and will be asked to return it in person or mail it back to Sheffield Teaching Hospital, U.K. If a patient consents to participate in the study but feels too unwell to answer the questionnaires on her/his own, a structured interview, in which a researcher asks the questions and notes down the answers, will be offered. Record of self-assessed questionnaires vs. structured interviews will be kept.Current guidelines for the diagnosis of MM require the presence of at least 10% clonal cells infiltrating the bone marrow [2) of all PGP9.5-positive nerve profiles and of the nerve fibers’ subtypes, their association with a nerve cluster [Upon finalizing the standard pathology procedures, the research team will access the bone biopsies (both diagnostic and following first-line treatment) and perform an immunohistological characterization of the existence, location and density of neuronal fibers. Bone biopsies from MM patients will be compared to those from patients with a negative myeloma diagnosis. Serial sections will be subjected to multiplex-immunostainings for the pan-neuronal marker PGP9.5 (protein gene product 9.5) combined with the sympathetic nerve fiber marker TH (tyrosine hydroxylase), allowing the distinction between sympathetic and non-sympathetic (presumably sensory) fibers, and the myelinated axon marker NF200 (neurofilament 200), allowing the distinction between myelinated and non-myelinated fibers. A similar protocol for nerve characterization in human bone biopsies has previously been optimized in-house . The ana cluster  and the Following first-line treatment, it is standard of care to extract a new bone biopsy to evaluate the presence of malignant plasma cells and assess treatment efficacy. Follow-up biopsies from enrolled MM patients will be analyzed to address the differences in bone innervation at diagnosis and upon completion of first-line treatment. Analyses will be performed by a researcher blinded to patient’s disease diagnosis.To assess the levels of bone turnover or inflammatory biomarkers in MM patients and patients receiving a negative myeloma diagnosis, fasting serum samples will be collected. Bone resorption and formation biomarkers  will be quantified by enzyme-linked immunosorbent assay. Serum inflammatory chemokines and cytokines will be quantified using a multiplex array system; measurements will include (but not be limited to) chemokine (C-C motif) ligand 3 (CCL3), epidermal growth factor (EGF), fibroblast growth factor (FGF-2), granulocyte colony-stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon α2 and γ, interleukins 1α, 1β, 2, 3,4,5,6,7,8,9,10,13, 15, 18, platelet derived growth factor (PDGF), transforming growth factor (TGF)α, and tumor necrosis factor (TNF) α and β. Fasting serum samples from MM patients will also be collected following first-line treatment; changes in bone turnover and inflammatory biomarkers in MM patients upon completion of first-line treatment will be evaluated.Data on bone innervation and serum bone turnover and inflammatory biomarkers in MM patients will be correlated to self-reported measures of pain, both at diagnosis and following first-line treatment.Power calculations for this study have been performed in relation to pain intensity scores between firstly diagnosed, untreated, MM patients and patients receiving a negative myeloma diagnosis (control group). The power calculation has been performed on the primary aim: pain in multiple myeloma, as measured in the numeric rating scale contained in the BPI, in which worse pain is scored in the 11-point numeric scale . Power calculations were performed using a pain intensity difference and a standard deviation of 2.75 in the 11-point numeric scale, as previously reported for MM patients . For a pThe recruitment phase of this study will take place from October 2019 to June 2021. Based on historical experience, it is expected that 50 eligible study candidates will be identified and at least 35 are expected to participate, as the study involves minimal invasive procedures. We expect that at least half of the enrolled patients will be diagnosed with multiple myeloma, and data from patients with a negative myeloma diagnosis (MGUS or SMM patients) will be used as control.Pain is one of the most prevalent and feared cancer symptoms, and, together with fatigue, the main complain of MM patients ,7. The aOver the last few decades, methods to monitor symptoms and adverse effects, which ultimately contribute to the patients’ QoL, have gained attention. Traditionally, adverse effects are monitored by the clinicians following the Common Terminology Criteria for Adverse Events guidelines . HoweverTo correlate the pain results to QoL, recruited patients will fill out the EORTC QLQ-C30 and EORTC QLQ-MY20, which are commonly used questionnaires for the evaluation of QoL in cancer and myeloma patients, respectively. As both these questionnaires have commonly been used in clinical studies with MM patients, they will allow comparisons to the published data regarding QoL in other patient cohorts ,32.Due to the preclinical evidence of nerve disturbances in the bones of myeloma-bearing mice presenting pain-like behaviors ,14, we sA common limitation of PRO to monitor HRQoL in longitudinal studies is the lack of compliance, which can compromise the power of clinical studies  and cofoIn the clinic, diagnosis of MM requires the immunohistological characterization of clonal plasma cells in the bone marrow. In this study, we will access diagnostic iliac crest biopsies. Sensory and sympathetic nerve profiles will be evaluated in serial sections, allowing the study of correlations between disturbances in bone innervation and pain parameters. We have previously observed tumor-induced nerve injury in a mouse model of myeloma-induced bone pain, which we hypothesize may be causative for the pain , while nAs MM is characterized by the uncoupling of bone resorption and formation and the consequent development of osteolytic bone lesions, we will quantify bone turnover through analyzing the systemic levels of CTX-1 and P1NP. Presently, it remains unclear whether osteolytic lesion development is a direct driver of bone pain, as bisphosphonate treatment has shown dramatic effects on bone remodeling but their analgesic effect on bone cancer remains controversial . To our To date, data characterizing pain and QoL from the “real” MM population  or across different disease stages  is scarce . A possiA major limitation of this study is the lack of appropriate bone biopsy controls. In this study, all patients undergoing diagnostic bone biopsies for suspected MM are invited to participate, thus including a subpopulation of confirmed MM patients and another with a negative diagnosis , who will serve as negative controls. However, it should be noted that biopsies from MGUS patients may also display bone or nerve disturbances, as they may also present low levels of abnormal clonal cells in the bone marrow. Obtaining bone biopsies from healthy volunteers could be considered, but due to the high invasiveness of the procedure, which often causes pain and discomfort for the patient, it was considered unattainable.Another important limitation of the study is the area from which the biopsy will be extracted. Diagnostic trephine bone biopsies are generally extracted from the iliac crest, while MM patients may present bone pain, nerve disturbances or plasmacytomas in any other body area. Obtaining a pain-guided bone biopsy  could be considered. However, all patients undergoing diagnostic bone biopsies at Sheffield Teaching Hospital will be included in this study, whether they present with bone pain or not, in an attempt to characterize pain in the entire MM population. Furthermore, collecting extra bone biopsies solely for research purposes would expectably decrease the number of consenting patients in the study. For that reason, only diagnostic biopsies will be evaluated and systemic bone innervation changes are expected to be observed. As hip is a common site of bone pain in MM , we expeThis study is conducted in agreement with the Declaration of Helsinki and local laws and regulations. Eligible patients are informed about the study and given enough time to consider whether they want to participate. Written information is provided to all patients who may be interested in participating. Written informed consent is obtained by the research team.Data will be analyzed with the appropriate statistical software and will be reported in compliance with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines , while iPersonal data will be handled confidentially. Patients will be initially approached by members of their standard health care team, and only after receiving explicit consent, research staff will approach them and invite them to participate in the study. Study participants will be assigned a unique personal study code. All research data, including the physical questionnaires’ booklets administered to the patients, will be pseudo-anonymized to this personal code. An Excel spreadsheet where the study code is linked to the patient´s hospital code  will be stored in a password-protected National Health Service computer and backed up on a secure, encrypted National Health Service share drive. All physical files containing personal data, such as consent sheets, will be stored in a secure location in a locked office, in a building protected by CCTV cameras and security guards. No identifiable data will be exported outside the United Kingdom, and patients will be explicitly consented to allow access to their personal data to research staff outside the medical team that is directly implicated in their standard of care.The results of this study will be disseminated by publication in peer-reviewed scientific journals and participation in scientific conferences; authorship will be based upon the Vancouver recommendations. A layman summary of the study results will be administered to the study participants who consent to it.


Central sensitization is an amplification of neuronal signaling within the central nervous system. The Central Sensitization Inventory was introduced in 2012. A Polish version of the CSI (CSI-Pol) was developed in 2019, but it was not psychometrically validated. The aim of this study was to validate the CSI-Pol in a sample of Polish-speaking patients with chronic spinal pain and compare them with a group of healthy control subjects.The CSI-Pol was administered to 151 patients with chronic spinal pain recruited from two centers. It was re-administered 7 days later. The psychometric properties were then evaluated, including test-retest reliability, construct validity, factor structure and internal consistency. We correlated the CSI-Pol with functional scales, depression and social support scales and compared CSI-Pol scores in the clinical subjects with 30 healthy control subjects recruited from medical staff and their families.The CSI-Pol demonstrated excellent internal consistency  and test-retest reliability (Intraclass Correlation Coefficients - ICC =0.96), as well as significant positive associations with other patient-reported scales, including the Neck Disability Index (r = 0.593), Revised Oswestry Low Back Pain Disability Questionnaire (r = 0.422), and other measures of functional and depressive states. An exploratory factor analysis resulted in a 4-factor model. CSI-Pol scores in the clinical sample (35.27 ± 17.25) were significantly higher than the control sample (23.3 ± 8.9).The results of this study suggest that the CSI-Pol may be a useful clinical tool for assessing central sensitization related symptoms and guiding appropriate treatment in Polish-speaking patients with spinal pain.The online version contains supplementary material available at 10.1186/s12883-021-02510-3. ChronicChronic spinal pain is one of the most common problems seen in clinical practice. It is estimated that more than 80% of people will experience low back pain at some point during their lives . FortunaCLBP is the leading cause of disability and results in more global disability than any other major medical condition in both developed and developing countries . A varieMore recently the role of central sensitization (CS) and other mechanisms have been implicated in chronic spinal pain. Central sensitization has recently been recognized as a pathophysiological mechanism underlying many pain conditions, including fibromyalgia, temporomandibular joint disorder, tension-type headache and chronic spinal pain –16. Varihttps://www.pridedallas.com/questionnaires), including Spanish, Italian, Serbian, Japanese, Dutch and others [The Central Sensitization Inventory (CSI) was developed as a tool to identify patients whose symptoms may be related to CS and/or be associated with a Central Sensitivity Syndrome . The ited others –28. All d others .Patients seek treatment in Poland for chronic spinal pain in primary care settings and specialty clinics, such as orthopedists, rheumatologists, neurologists, physiotherapists, and physiatrists. Most of those specialists have not completed extensive specialization in pain management. It is often difficult to classify and differentiate between predominant nociceptive, neuropathic and CS-related pain. A proper identification is essential for optimizing treatment strategies. A Polish version of the CSI (CSI-Pol) was developed in 2019, but it was not psychometrically validated . TherefoIn the present study we evaluated the CSI-Pol on a group of chronic spinal subjects and a separate group of control subjects. The study was approved by the Ethical Board of the Warsaw Medical University (Poland) (Consent number: KB/66/2019 obtained 15/04/2019). All participants in this study agreed to participate and signed informed consent forms before the study. All methods were performed in accordance with the relevant guidelines and regulations.We recruited 152 outpatients with chronic spinal pain  from the Neurological Outpatient Clinic and the Rehabilitation Clinic from National Institute of Geriatrics Rheumatology and Rehabilitation Clinic, Poland. The inclusion criteria were: age between 20 and 80 and chronic spinal pain with more than 3 months of pain duration. We excluded patients with cancer in the brain or in the spine, and other neurological diseases which could cause primary neuropathic pain as polyneuropathies , no patients had history of heavy alcohol consumption; dementia, previous spine surgery, or recent trauma in anamnesis and poor Polish comprehension skills. Patients with cervical or lumbar herniations with clinical symptoms awaiting surgery, were also excluded. All of the 152 patients completed the CSI-Pol, but one patient was excluded due to incomplete data, leaving 151 patients for analysis, including 24 with chronic neck pain (CNP) and 73 with CLBP and 54 with both CNP and CLBP. The control group consisted of 30 healthy subjects, with no reported spinal pain conditions, who were recruited from medical staff and their families, and agreed complete the CSI-Pol.All of the 151 chronic spinal pain patients completed a battery of patient-reported measures. The 30 healthy subjects completed the CSI-Pol only. Additional demographic data were also collected.Pain intensity was measured with a Numeric Pain Rating Scale (NRS), from 0 (no pain) to 10 (the worst imaginable pain) over the last 4 weeks. Age and sex of each participant was recorded. Each subject was weighed and their body mass index (BMI) was calculated. Patients were asked in an interview if they were employed, if they used alcohol excessively  and if they had sleep disturbances (in “yes” or “no” format) caused by pain that prevented them from falling asleep or staying asleep during the night.https://www.pridedallas.com/questionnaires [The CSI-Pol can be found in Appendix A  and IBM SPSS Statistics, version 22.0 . Qualitative variables were characterized by the number of important cases (n) and the percentage of the total (%). Categorical comparison of groups was made using two-way tables and chi square test or Fisher exact test. The normality of continuous variables was determined using Kolmogorov–Smirnov. Lilliefors and Shapiro–Wilk tests were used to assess the homogeneity of dispersion from normal distribution.p values or by Mann–Whitney U-test (two-way variables). Effect sizes and power analyses were performed using the G*Power 3.1.9.7 tool. Categorical variables were compared between groups using chi2 test or Fisher exact tests. Spearman’s correlation coefficients were used to examine the associations between the Polish version of the Central Sensitization Inventory (CSI-Pol) scores and pain intensity (NRS), NDI and ODI. Correlations were evaluated using the Spearman rank correlation test. The correlation strength was presented according to the Guilford classification [Poor when the correlation coefficient r = 0.1 < │r│ ≤ 0.3Moderate when 0.3 < │r│ ≤ 0.5High (strong) when 0.5 < │r│ ≤ 0.7Very high (very strong) when 0.7 < │r│ ≤ 0.9Nearly full when 0.9 < │r│ < 1Full when │r│ = 1Variables that were normally distributed were presented as a mean and standard deviation and compared between groups by one-way analyses of variance (more than 3 groups) with post-hoc analysis using Neuman-Keulus test or by student t test (2 groups). A Brown–Forsythe test was used to evaluate the homogeneity of variance (significance < 0.05). Variables that were not normally distributed, or for which the criterion of homogeneity of variance was not completed, were presented as a median and interquartile range (IQR) and compared between groups with Kruskal–Wallis analysis of variance (ANOVAs) (more than 3 groups) with post-hoc testing using Mann–Whitney U-tests with Bonferroni correction of fication :Poor whep < 0.05. Data were given as means (M) with standard deviations (SD). Construct validity and factor structure were determined through the use of questionnaire principal component analysis with Maximum Likelihood Extraction (MLE), with the requirements for extraction being the satisfaction of all three points: scree plot inflection point, Eigen value > 1.0 and accounting for > 10% of variance [The criterion for significant differences was variance . The recAdditionally, the original 4-factor model suggested by Mayer et al. was tested via confirmatory factor analysis (CFA) with ordinal data . In the Internal consistency of the scale items was determined from Cronbach’s α coefficients . Reliabip < 0.001). This indicated that the correlation matrix was unlikely to be an identity matrix and, therefore, was suitable for MLE. The factor analysis revealed a satisfactory percentage of total variance explained by the one factor at 39.3%. The CSI-Pol unidimensional was supported by visual inspection of the scree plot, as shown in Fig. p < 0.000).The correlation matrix for the CSI-Pol was determined suitable from the Kaiser-Meyer-Oklin values 0.916) and Barlett’s Test of Sphericity . Loadings for the single items were identical to those for the 4-factor model (Table The rest of the fit indicators suggested that the 1-factor model fit the data satisfactorily (root mean square error of approximation (RMSEA) = 0.08; 90% confidence interval (CI) 0.08 to 0.09). However, the 4-factor model fit the data better than the 1-factor model (RMSEA = 0.07 90% CI 0.07 to 0.08). Standardized factor loadings for the 4-factor model ranged from 0.349 (for item 25) to 0.801 (for item 16). The 4 factors were highly and significantly correlated  with an individual item range from 0.917 to 0.948. The internal consistency for items in each of the individual factors was somewhat lower. Factor 1 (Cronbach’s α = 0.874), Factor 2 (Cronbach’s α = 0.855) and Factor 3 (Cronbach’s α = 0.734) were acceptable, but Factor 4 (Cronbach’s α = 0.574) was poor.90, being at 0.99 and 2.31%, respectively. Detailed results are in Table All patients performed a retest after 7 ± 1 days. The test–retest reliability was high at (ICC = 0.96) with an individual range from 0.74 to 0.91. Measurement error was determined from SEM 0.99 and MDCp < 0.001) and sex (women = 80.1% vs. 53.3%) (p < 0.001).The mean age of the patient population and control sample was 55.7 +/− 14.1 and 42.0 +/− 12.6 respectively. The majority of patients were women (80.1%). The patients differed significantly from controls in age . The most frequent self-reported previously diagnosed CS-related disorder in the patient population, as measured on CSI B, were migraine or tension headaches ; neck injury, including whiplash  and depression . In the control sample, migraine  and irritable bowel syndrome  were the most frequently reported comorbidities on CSI B.The CSI-Pol scores varied from 0 to 83 points in the total sample, including controls. The total mean CSI-Pol score for all patients and controls combined was 32.8 (SD 16.6). The median was 31.0 (IQR 22.0). The CSI-Pol mean score in the patient sample (35.27 ± 17.25) was significantly different than in the control sample (23.3 ± 8.9). The proportion of patients in each CSI-Pol severity subgroup were: subclinical = 59 (39.1%), mild = 35 (23.2%), moderate = 29 (19.2%), severe = 13 (8.6%) and extreme = 15 (9.9%) [The results of ANOVAs showed that the patients scored significantly higher than the controls on all 4 factors, as shown in Table p < 0.03). Patients with both spinal locations were also significantly more likely to score above the 40-point CSI-Pol cutoff score (p < 0.03). Mean scores on the NRS pain severity, BMI scale, sleep disturbances, and alcohol use did not differ among the three patient subgroups.The comparison of demographic and clinical variables among three patient subgroups  is provided in Table In Table A statistically significant relationship was found between the CSI-Pol and the level of depressive symptoms Table . A positA statistically significant relationship was found between the CSI-Pol and the perception of overall support measured by Berlin Social Support Scales, as well as the perceived emotional and instrumental support and support seeking with received support and protective buffering. The direction of the correlations were negative. The values of the correlation coefficients are presented in Table In 23.17% of patients with a CSI-Pol with chronic spinal pain scores above 40 - widespread, non-neuroanatomical pain was observed, alsoaccording to Nijs et al. guidelines, a disproportion in spinal pain experience was seen .The differences in quantitative sensory testing are shown in Fig. The CSI was developed to screen patients for symptoms related to CS and Central Sensitivity Syndromes so that proper identification and treatment planning can be made. As stated previously, a Polish version of the CSI was published in 2019 (CSI-Pol), but it was not psychometrically validated . TherefoThere are a number of classification algorithms to differentiate nociceptive and neuropathic pain from CS or nociplastic pain, but problems with nosology have been identified . Polish Our results showed that the CSI-Pol had excellent internal consistency and test-retest reliability, as well as significant positive associations with functional scales used for CNP and CLBP assessment. The CSI-Pol demonstrated high test–retest reliability in the present study (ICC = 0.96), indicating that it is a reliable instrument. These results are comparable with previous test–retest results of the English , Dutch, Significant differences were identified between mean CSI-Pol total scores in the patient population and the control group. The CSI score of 40 out of 100 has previously been shown to be a reasonable cutoff for distinguishing between CSs patients and control subjects. The prevalence of patients in the present study with CSI-Pol scores above 40 was quite high (57 out of 151–38%). Approximately 19% subjects scored in moderate, 9% in severe and 10% in extreme CSI-Pol ranges. We observed significant positive correlations between CSI-Pol scores and self-reported disability, as measured by the ODI and the NDI. Most of our patients who scored below the 40-point cut-off had mild to moderate disability with predominance of minimal disability in ODI and NDI scales. Most patients who scored over 40 reported moderate to severe disability. The correlation between the CSI-Pol and NDI was strong and with the ODI was moderate.Previous studies with different clinical samples have reported a wide range of scores above 40. For example, in a Japanese study, 11% of musculoskeletal pain patients  scored above 40 , compareA large majority of the patients in the present study were women, which is consistent with previous studies on CS-related chronic pain populations , 25. CarWe divided our patient sample into those with CNP and CLBP. In one recent study the median CSI score was 39 in a CNP cohort , which wCentral sensitization is often associated with mental disorders such as anxiety and depression, and a relationship between chronic pain and depression has validated in several epidemiological studies . Higher We found a statistically significant relationship between CSI-Pol scores and perceived social support on several items of the Berlin Social Support Scales. As far as we know, no previous studies have investigated the relationship between the CSI and Berlin Social Support Scales. Higher perceived social support in our patients was related to lower CSI-Pol scores. Social support is very important to reduce suffering. It can reduce the feelings of loneliness in difficult situations, which can significantly improve mood and well-being . The infThe biopsychosocial model assumes that the perception of pain is influences by cognitive, behavioral, emotional, and social components. In this model, it is important to take into account both the biological and social context. For instance, the present study takes into account social support and the aspects of the perception of emotional states affecting the perception and maintenance of pain. These findings in the present study suggest that the experience of symptoms associated with chronic pain and Central Sensitivity Syndromes are multimodal, and require a broader conceptualization than the biomedical model. It is very important that pain physicians not rely on pharmacological interventions alone, but should also utilize biopsychosocial approaches in the treatment o f CS-related symptomology and chronic pain. Available evidence indicates that CS is present in a subgroups especially of the CLBP population and in those patients require intervention targeted at the central nervous system rather than the lower back region. That’s why it’s important to stratify patients into groups with predominantly nociceptive, neuropathic or central sensitization pain in order to schedule the target intervention.strategies properly. We believe that CSI-Pol will help in this procedure. The main goal of chronic pain treatment should be education to improve the patient’s pain following exercises or daily physical activity. Therefore, pain neuroscience education should be one of the basic therapeutic factors to become not only knowledge for neuroscientists but also for patients to understand their pain. It is important to create a new therapeutic procedures in Poland that would be reimbursed by the state rather than physical therapy procedures.The current study was performed in one group of chronic spinal pain patients in two neurological and orthopedic outpatient clinics in Poland, so these results may not generalize to other populations.This study determined evidence of reliability and validity of the CSI-Pol, suggesting that it may be a useful tool for assessing CS-related symptomology in Polish patients with spinal pain, which may help clinicians in assessment and treatment planning.Additional file 1. CSI-Pol. The polish Central Sensitization Inventory (CSI-Pol) version part A and part B. New corrected version of item 24. Also available at: https://www.pridedallas.com/questionnaires.Additional file 2. CSI-Eng. Original version of Central Sensitization Inventory. Also available at: https://www.pridedallas.com/questionnaires.


Results: Primary or revision posterior arthrodesis was performed on 1931 consecutive adults  for deformity and degenerative pathologies. At surgery, females were older than males , had slightly more comorbidities , and were more likely to undergo deformity correction . Females described more pre-op pain  and lower pre-op function . By 3 months post-op, there was no significant gender difference in VAS or ODI scores. Similar pain and function scores between males and females continued through 6 months and 12 months. Conclusion: Although females have more pain and dysfunction before undergoing spinal surgery, the differences in these values do not reach the Minimum Clinically Important Difference (MCID). Post-operatively, there is no difference in pain and function scores among males and females at 3, 6, and 12 months.Background: To analyze gender differences regarding the recovery experience  after spinal arthrodesis surgery. Methods: Pre-operative and post-operative gender-based differences in patient-reported outcomes for open posterior spinal arthrodesis at 6 weeks, 3 months, 6 months, and 1 year were studied, including age, comorbidities, body mass index (BMI), diagnosis, number of vertebrae fused, type of surgery, primary vs. revision surgery, and complications. Statistical analysis included the use of Student’s  Historically, common stereotypes exist regarding the differences in how males and females perceive pain. Females have been reported to describe higher levels of pain when presented with equal amounts of thermal stimuli compared to males . FemalesHowever, in the setting of low back pain, much is unknown regarding gender perceived differences in pain and functional outcomes. Chenot et al. found that females had a lower pain threshold and lower functional capacity than males with chronic low back pain . On the Specifically, gender differences in pain perception and function after spinal fusion surgery have not been studied in the setting of lumbar degenerative disease or thoracolumbar deformity. Consequently, gender-based outcome differences remain unclear in patients undergoing spinal surgery for these conditions. The purpose of this study is therefore to analyze how a patient’s gender impacts self-reported pain and functional recovery after spinal arthrodesis surgery for thoracolumbar deformity and lumbar degenerative disease.This was a retrospective cohort study utilizing patient data from a single center’s prospectively collected surgical database that received IRB exemption. Only adult patients (>18 years old) undergoing open posterior instrumented arthrodesis were included in this study. Included were both primary and revision surgeries of any length, with or without interbody fusions, for lumbar degenerative conditions and thoracolumbar deformity. Patients without a minimum 1 year of clinical and radiographic follow-up data were excluded. Trauma, tumor, and infection cases were additional grounds for exclusion. All surgeries were performed by 5 fellowship trained spine surgeons.A similar strategy for post-operative pain management and limited narcotic use was used throughout this study, with an effort to have all patients off opiate analgesics by 3 months post-op. Post-operative bracing was optional and provided at the request of individual patients. Post-operative physical therapy was typically instituted at 8–12 weeks post-op, and continued for 4 weeks. All patients were placed on a home exercise program after formal physical therapy was completed.All patient demographic information and baseline characteristics including comorbidities, smoking status, body mass index (BMI), and indication for surgery were noted. Surgical factors were additionally collected.Clinical outcome measurements included the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI). These scores were collected pre-operatively, at 6 weeks, 3 months, 6 months, and 1 year after surgery. Radiographic data were additionally collected at similar time points. Radiographic evidence of fusion included no implant–bone interface lucency, apparent bridging bone either posterolaterally or through the interspace, and no motion on flexion-extension radiographs at the 1 year post-operative follow-up. All peri-operative complications were noted.t-test was used to compare gender differences in age at the time of surgery. Spearman’s rho analysis was used to determine the strength of association between either VAS or ODI scores and a patient’s gender, BMI, and age. A Chi-Square test was used to determine potential gender differences in the presence of complications, type of diagnosis (degenerative vs. deformity), and number of comorbidities. Linear regression models were used to estimate and compare the differential effects of a patient’s gender, diagnosis (degenerative vs. deformity), age, number of comorbidities, BMI, levels of fusion, revision status, and presence of complications on ODI and VAS scores over time. Statistical significance was set at p < 0.01. All statistical analyses were conducted with IBM SPSS Statistics for Windows .Mann–Whitney U test, was employed to determine potential gender differences in ODI and VAS scores. Student’s p < 0.01) and were more likely to require surgery for degenerative disease compared to other diagnoses  (p < 0.01). In general, females had a greater number of comorbidities compared to males .A total of 1931 consecutive patients  met inclusion criteria. Mean follow-up was 84 months; range, 12–192 months) . Males h < 0.01) . FemalesA total of 1045 patients (54.1%) underwent primary fusion . There wp < 0.01). At 6 weeks post-op, females continued to describe marginally more pain than males . By 3 months, there was no gender-based difference in pain scores . Furthermore, there was no significant gender difference in pain scores at 6 months (p > 0.01), or 1 year post-operatively (p > 0.01). Both male and female patients demonstrated significant clinical improvement in pain scores by 1 year follow-up . Functional improvements in both genders were significant at 1 year (p < 0.01). At one year, there was no gender difference in ODI scores noted (p > 0.01). Females experienced a slightly greater mean overall improvement in ODI by 1 year .Females reported lower pre-op dysfunction scores  interpreted as the estimated change in VAS or ODI for a unit change in the respective factor. As can be seen in Predictors of pain and function were estimated through a linear regression model of 1 year post-operative VAS scores Table 7) and ODI scores , respect and ODI Numerous studies suggest certain patient characteristics and comorbidities affect outcomes after spinal fusion ,10,11,12In 2002, Gehrchen et al. conducted a retrospective review including 112 patients with degenerative disc disease (DDD) and spondylolisthesis that showed female gender to be an independent risk factor for a nonoptimal outcome after lumbar fusion . In 1984However, the results of our study align more closely to those of Triebel et al. and Pochon et al. ,6. TriebOur study shows that while females reported slightly more pain and worse function than males at the time of surgery, by 3 months and beyond, no further gender differences in post-operative pain or function existed. Our findings support the ultimate conclusions of gender outcome equality by Triebel et al. and Pochon et al. However, our study further expands their findings to the realm of deformity surgery ,6.p < 0.01) and disability  that females present with prior to undergoing spinal arthrodesis is not clinically relevant.An important aspect to acknowledge when reviewing the results of our study is the MCID for VAS back pain and ODI score. Previous studies have suggested that the MCID for VAS and ODI are 2.1 and 14.9, respectively . Both MCp < 0.01). As far as we are aware, why females wait longer and endure more pain before undergoing spine or total joint surgery has not been well studied. Possible explanations for this phenomenon include that (1) females are more reluctant to choose surgical intervention [Similar results have been echoed in the total joint arthroplasty literature. For instance, Holtzman and Katz showed that females have more pain and dysfunction prior to undergoing total joint arthroplasty. However, they found that females do not recover as well post-operatively compared to their male counterparts ,17. Anotrvention , 2) femrvention , and (3) femrventrvention . Anotherrvention ,10,12,13Given the higher comorbidity burden of females, it is surprising that they ultimately achieved similar outcomes to males. There are several potential explanations. Physical therapy use has been associated with improved outcomes after lumbar fusion , and curThere are several limitations to this study. First, this study was retrospective in nature. All patients underwent open posterior spinal arthrodesis and results may differ for other approaches or decompression without fusion. Furthermore, patient-reported pain and functional scores are individually subjective. Additionally, although our analyses accounted for many variables, possible confounding variables that we were unable to account for include patient expectations, the operating surgeon, physical therapy effort by the patient, psychosocial factors, living environment, and psychological background. Additionally, this study focused on general VAS scores for pain and did not distinguish between back pain and leg pain. Additionally, the findings here are limited to a single center’s experience and may not be broadly applicable.Although females have more pain and dysfunction before undergoing spinal arthrodesis for thoracolumbar deformity and lumbar degenerative disease, the differences in these values do not reach the Minimum Clinically Important Difference (MCID). Post-operatively, there is no difference in pain and function scores among males and females at 3, 6, and 12 months.


Although pain is a frequent complaint of patients with chronic kidney disease who undergo hemodialysis, few studies have assessed the functional interference of pain in activities of daily living (ADLs). Hence, the aim of this study was to evaluate the prevalence, location, intensity, and functional interference of pain in ADLs of chronic kidney disease patients undergoing hemodialysis and to estimate the association of specific pain sites with severe functional interference by pain in ADLs. This cross-sectional study included patients with chronic kidney disease undergoing hemodialysis. The prevalence, intensity, and functional interference of pain in ADLs were assessed using the brief pain inventory. Poisson regression was used to calculate the prevalence ratio. A total of 65 patients participated in the study. The overall prevalence of pain was 89.23%; the prevalence of headache was 18.46% and that of pain in the trunk was 55.38%, upper limbs was 35.38%, and lower limbs was 60.00%. The prevalence of moderate and severe pain at the time of hemodialysis was 13.85% and 21.54%, respectively. A high prevalence of severe functional interference of pain in general activity (61.54%), mobility (56.92%), and disposition (55.38%) was observed. Pain is a frequent complaint in patients undergoing hemodialysis, mainly musculoskeletal and intradialytic, and it interferes with ADLs and incapacitates the patient. Pain was highly prevalent in the upper and lower limbs and the trunk. Furthermore, a higher prevalence of severe pain at the time of hemodialysis and functional interference of pain, mainly in general activity, mobility, and disposition, were observed. Chronic kidney disease (CKD) is a public health problem  with a gPatients with end-stage renal disease may present with pain related to renal bone disease , osteoarthritis, calcific uremic arteriolopathy, and peripheral neuropathy. In addition, comorbidities such as ischemic peripheral artery disease, diabetic neuropathy, osteopenia/osteoporosis  result in different types of pain. Furthermore, primary kidney disease as well as hemodialysis or peritoneal dialysis are important causes of pain . Pain inAlthough pain is a frequent complaint of CKD patients undergoing HD, few studies in the literature have analyzed the presence of pain, especially how it interferes with the activities of daily living (ADLs) ,15,16. TThis cross-sectional study was performed with data of patients at a Nephrology Clinic in the Midwest region of Brazil, which serves patients through the Sistema Único de Saúde or SUS . A total of 85 patients were interviewed. Data were collected from June to September 2018. This research with human subjects was conducted in compliance with the Helsinki Declaration. This research was approved in October 2016 by the Ethics Committee of the Hospital das Clínicas of the Federal University of Goiás , CAAE 59756416.1.0000.5083; with the protocol number 1,782,067.Adult patients aged over 18 years, with end-stage renal disease, undergoing HD for 6 months or more, and with no other known disease were included. Patients with any type of disability that could interfere with data collection, patients with cancer, HIV, and/or neurological diseases, and patients who did not undergo treatment at the service during data collection were excluded.Sociodemographic, lifestyle, economic, family, and social profile data were collected using a standardized questionnaire that was prepared by the authors and was previously tested. Sociodemographic and lifestyle variables were age, sex, marital status, education, and physical activities (yes/no). In the assessment of economic profile, whether the patient’s spouse worked outside the home, whether he/she had his/her own home, whether he/she was paid for his/her work, and the salary range were enquired . While eThe brief pain inventory (BPI) was used to assess the prevalence, intensity, location, and functional interference of pain in the ADLs of CKD patients undergoing HD. The BPI is an instrument developed by Daut et al. at the University of Wisconsin in 1983 to assess pain and its impact on the daily activities of cancer patients . In 2004The BPI assesses the location of pain , pain during HD, pain intensity in the past week, and the functional interference of pain in ADLs. The pain location  was determined via a diagram representing the human body, and the pain intensity was measured using a numerical rating scale from 0 to 10. Pain intensity in patients with HD was classified as no pain (score = 0), mild pain (score ≤ 3), moderate pain (scores between 4 and 6), and severe pain (score ≥ 7) .Functional interference of pain was assessed on a scale of 0–10, where 0 implied “it did not interfere” and 10 implied “it completely interfered”. Functional interference was scored according to the scores for seven BPI questions, comprising the domains of physical interference  and affective interference  . PatientThe seven items that assessed the functional interference of pain in the patients’ ADLs were considered independent variables. In addition, four outcomes were considered: headache (yes/no) or trunk (yes/no), upper limb (yes/no), or lower limb (yes/no) pain. All data were collected by the main researcher (PRS), during the HD of patients with CKD. Responses to the questionnaire were recorded in 20–35 min, and no difficulty was observed.® version 3.1 program. The statistical package Stata version 16.0  was used for the analyses. Statistical significance was established at p < 0.05. Descriptive variables are presented in absolute numbers (n) and relative frequencies (%), with means and standard deviations. The Chi-square test (χ2) or Fisher’s exact test was used in the bivariate analysis of functional interference of pain in ADLs. Poisson regression was used to calculate the prevalence ratio (PR) and 95% confidence interval (CI) for the variable functional interference of pain in ADLs. Variables with p < 0.20 in the bivariate analysis were included in the multiple hierarchical Poisson regression analyses, with robust variance based on a hierarchical model [n < 10 in all strata) [The database was built using the EPI DATAal model . Indepen strata) .n = 17) patients underwent treatment for 6–24 months, 29.2% (n = 19) for 25–48 months, 21.5% (n = 14) for 49–72 months, and 23.1% (n = 15) for >73 months. In our sample, all patients had nephropathy, 80.0% (n = 52) had hypertension, 60.0% (n = 39) were diabetic, 4.6% (n = 3) had polycystic kidney disease, 13.8% (n = 9) had nephrosclerosis, and 56.9% (n = 37) had a musculoskeletal disease. Sixty-two patients (95.4%) received family support for HD treatment. The demographic and economic profiles are presented in Of the 85 interviewed patients, 20 were excluded (12 who did not consent to participate and eight who had difficulties in understanding and answering the questionnaires). Thus, 65 patients with CKD undergoing HD participated in this research, of which 33 (50.8%) were men and 32 (49.2%) were women. The participants were aged between 24 and 85 years with a mean age of 55 ± 1.83 years. The mean time for the patients were undergoing HD was 54.51 ± 6.04 months, and 26.2% (n = 58) patients experienced some type of pain. The prevalence of headache was 18.5% (n = 12), that of trunk pain was 55.4% (n = 36), that of pain in the upper limbs was 35.4% (n = 23), and that of pain in the lower limbs was 60% (n = 39). In the past week, 73.8% (n = 48) patients experienced pain, whereas 26.5% (n = 17) had no pain. Of the 48 patients with pain, 38.5% (n = 25) patients had mild pain, 29.2% (n = 19) had moderate pain, and 6.2% (n = 4) had severe pain. The average maximum pain intensity in the past week was 6.11 ± 0.42 on the numerical rating scale, and the average minimum pain intensity was 2.77 ± 0.30. Pain intensity at the time of HD was mild in 6.2% (n = 4), moderate in 13.8% (n = 9), and severe in 21.5% (n = 14) patients. Most importantly, of the total number of patients, 26.2% (n = 17) had severe pain , with longer dialysis time associated with higher pain prevalence. The presence of pre-existing musculoskeletal disease was associated with the presence of pain (p = 0.016). These patients continuously used analgesics prescribed by a physician and did not use opioids. Pain at the time of dialysis was present in 41.5% (n = 27) of patients.Of the investigated patients, 89.2% (n = 16) could not perform ADLs independently. Functional interference of pain in the ADLs of patients with CKD undergoing HD was assessed using seven BPI variables, as shown in Of the total number of patients, 24.6% (p = 0.003). The prevalence and Poisson regression analysis for the association of pain sites with severe functional interference of pain in ADLs are shown in p = 0.446), ability to walk , and relationships with other people .Poisson regression analysis revealed a significant association of severe functional interference of pain in the ability to walk with pain in the upper limb (This research focused on investigating the prevalence, location, intensity, and functional interference of pain in ADLs of patients with CKD undergoing HD. Furthermore, to the best of our knowledge, this is the first study to investigate the association of pain sites with severe functional interference in ADLs. The results of this study indicate that patients with CKD show a high prevalence of pain, especially in the upper and lower limbs and the trunk. The prevalence of pain of severe intensity at the time of HD and severe functional interference of pain, primarily in general activity, mobility, and disposition, was high. In addition, a significant association was observed between pain in the upper limb and its functional interference on the ability to walk.Our findings of high prevalence of pain are consistent with other studies that have evaluated patients with CKD undergoing HD ,29,30,31In this study, a higher prevalence of severe pain was reported at the time of HD. This result is in line with other studies, as indicated by a systematic review . In addiA high prevalence of severe functional interference of pain was reported, primarily in general activity, mobility, and disposition. Other studies performed in Spain, Brazil, Switzerland, Argentina, and China have also investigated the interference of pain in ADLs ,16,33,35Chronic and acute pain are common in patients undergoing HD, especially during puncture. Bone and abdominal pain may appear with high intensity and discomfort that interfere with sleep quality and ADLs ,29,36,37A significant association was observed between the functional interference of pain in the ability to walk and pain in the upper limb. We hypothesized that pain in patients undergoing HD could be limiting and disabling, ultimately affecting patient mobility. A recent systematic review suggests that acute and chronic pain is a prevalent complaint in adults and elderly people on HD and that the higher frequency of moderate and severe pain in different parts of the body interfered with daily activities . These fPain management in patients with end-stage renal disease is a complex and challenging task, and effective pain and symptom control improves quality of life. Pain history assessment is the initial step in pain management, followed by the involvement of palliative care, patient and family counseling, discussion of treatment options, and correction of reversible causes. The first line of treatment should be conservative management, with exercises, physical therapy, acupuncture, meditation, music therapy, and cognitive behavioral therapy. If pain control is not optimal, replacement/addition of opioid analgesics is recommended. However, complex pain syndrome requires an analgesic regimen composed of polypharmacy with opioids, non-opioids, and adjuvant medications, which must be individualized to the patient to obtain adequate pain control .Family support based on social care for the patient, considering their individual needs and coping possibilities, can help health teams with pain assessment and management in the family environment, helping to control and improve this symptom in patients undergoing HD . With reThe strengths of this study are the inclusion of patients undergoing HD and assessment of severe functional interference of pain in ADLs, which is a novelty of this study. However, it also has some limitations that must be considered. First, as the study design was cross-sectional, a temporal relationship and inference of causality between variables could not be established. Second, the sample size was small, but representative, considering that they are patients undergoing HD. Third, the adoption of convenience sampling restricted the applicability of the survey results to the population. Fourth, data collection was carried out at a single HD service center in Brazil, which may limit the applicability of the findings to different HD centers, especially those that treat patients with high comorbidities. Despite these limitations, the results are clinically important, mainly because the high prevalence of pain and the non-use of opioids found in this study reveal the possible failure in adequate pain assessment of patients with CKD and, consequently, the possibility of inappropriate and ineffective prescription of medications. Further research, with a larger sample size, is needed to validate our findings. Furthermore, it is important that future studies investigate the causes of pain in patients with end-stage renal disease, influence of musculoskeletal diseases, amyloidosis, diabetic neuropathy, and physical activity, and use of medications. We encourage further studies on this topic in large HD centers.We highlight the importance of adequate pain assessment in HD patients, as well as the inclusion of professionals who specialize in pain management in the multidisciplinary team. The adoption of pharmacological or non-pharmacological therapeutic approaches, such as the use of opioids and physiotherapy, can improve the symptoms of pain in HD patients and, consequently, have significant improvements in the quality of life of these patients.This study showed that CKD patients undergoing HD have a high prevalence of pain, mainly musculoskeletal and intradialytic pain. A high prevalence of pain was also observed in the upper and lower limbs and the trunk. Furthermore, a higher prevalence of severe pain at the time of HD and functional interference of pain, mainly in general activity, mobility, and disposition, were observed. In addition, severe functional interference of pain in the ability to walk was associated with pain in the upper limb. These results indicate that pain in patients undergoing HD is limiting and disabling.


To assess the efficacy of PBMT on reducing postoperative pain scores in patients submitted to third molar extractions. A randomized controlled trial (ReBEC:RBR-94BCKZ) was designed according to the SPIRIT and followed the CONSORT. Patients were randomly allocated according to control or PBMT groups. PBMT consisted of the application of GaAlAs laser  applied in six points  after extraction. Pain scores were assessed using the Visual Analogue Scale (VAS) in millimeters evaluated after 6 (T6), 24 (T24), and 48 (T48) hours. The Wilcoxon Mann–Whitney test was used to check for possible associations between VAS scores and treatment groups.p<0.001). The same statistically significant effect on the reduction of postoperative pain was observed at T24  and T48 . A total of 101 third molar extractions were performed in 44 patients. The mean age was 28 years old(SD±11.54). Comparing control and intervention, PBMT group showed a significant effect on the reduction of postoperative pain at T6 compared to control ( PBMT significantly reduce the postoperative pain scores when assessed 6, 24, and 48 hours after third molar extractions. Key words:Controlled clinical trial, gallium aluminium arsenide lasers, third molar. Third molars extraction is a common dental procedure both in private practice and hospital settings. This type of procedure often requires a considerable involvement of the surrounding connective tissues and, depending on tooth position, it might be necessary to conduct bone removal or tooth sectioning, which could increase invasiveness, surgical time, and are often related to increased morbidity, that could result in impairment of daily activities during the postoperative period, due to reported discomfort, swelling, trismus, and postoperative pain ,2.The standard therapeutic approach to pain management is the administration of analgesic drugs, corticosteroids, or nonsteroidal anti-inflammatory drugs (NSAIDs) . PreviouIn this perspective, several alternatives have been reported aiming to reduce postoperative pain, such as cryotherapy, use of Platelet-Rich Fibrin (PRF), and photobiomodulation therapy (PBMT) -10. The The decision-making process in healthcare procedures must consider high-quality evidence studies to guide the interventions, and randomized clinical trials are one of the greatest levels of evidence considering the hierarchical pyramid of evidence . Thus, tMaterial and methods- Study DesignThis prospective equivalence randomized controlled trial with parallel-groups blinded to the evaluators was designed following the SPIRIT statement and is reported following CONSORT guidelines. The protocol was approved by the institutional ethics committee (Protocol 3.699.947) and the trial was registered prior its beginning (ReBEC TRIAL: RBR-94BCKZ). The study was conducted from June 2017 to January 2020.- Eligibility criteriaThe inclusion criteria were: 1) Young adults; 2) Indication for third molar removal; 3) Good general health, which allows for surgical removal; 4) Signed informed consent form for participation and permission to use obtained data or research purposes.Exclusion criteria: 1) Systemic disease that prevents surgery; 2) Continuous use of any medication. Also, patients that reported the use of analgesic after surgery, both in control or experimental group, were excluded of the study.- Randomization and allocation concealmentPatients were randomly allocated according to the type of intervention  that were performed considering the tooth as unit; the randomization process was performed using the Random Allocator software© in blocks of 6. To ensure concealment of randomization, consecutively numbered brown envelopes were used, with the following intervention draws: CONTROL and PBMT and only one researcher was involved in this process. The surgeon only became aware of the type of intervention at the time of surgery when the envelope was opened by a blinded researcher.- Clinical proceduresAll surgeries were carried out by the same surgeon (T.M.P.I) which is specialist in oral maxillofacial surgery. All patients were orally premedicated with 2g of amoxicillin 1 hour prior to the surgery and were prescribed to take 500mg of amoxicillin every 8 hours for 7 days . Local a- Study groups1) ControlThe tooth extraction was performed according to the specificities of each clinical case. After tooth removal, the surgical area was cleansed with 0.9% saline solution and sutures were performed.2) PBMT groupPBMT [Gallium Aluminum Arsenide Diode (GaAlAs)]  in continuous mode was applied in six points in contact with the soft tissue  after the sutures. The application points were divided into two points in the labial region ; two points in the lingual region ; and two points in the previous occlusal direction, resulting in a total dose of 66 J. This PBMT protocol was applied only in the tooth extraction and is based on a previous study ,17.- Sample size calculationThe sample size was calculated using an earlier study that assessed different interventions to relief postoperative pain after third molar extractions using visual analog scale (VAS) . The sam- Primary outcome – Postoperative painThe primary outcome was the evaluation of pain level using a Visual Analogue Pain Scale (VAS), ranging from zero (no pain) to 10 (worst possible pain) . The fol- Statistical AnalysesDescriptive analyses with mean values and standard deviation (SD) or frequency distribution (%) were calculated for each variable. Statistical analysis was performed using Stata Software 16.0 . Comparison between control and PBMT group between characteristics of tooth extraction were performed through the chi-square test. Data were tested for normality by means of a Shapiro-Wilk test and found to not be normally distributed. The Wilcoxon Mann–Whitney test was used to check for possible associations between VAS scores and treatment groups. Statistical significance was set at the alpha level of 0.05.The CONSORT flow diagram with the enrollment characteristics of this study is presented in Fig. A total of 101 third molar extractions were performed in 44 patients according to the randomization process. The sample was composed in its majority by females (n=28 / 63.6%), and most of the patients did not have hypertension (93.2%), smoking habits (100%), and diabetes (100%). The mean age of the sample was 28 years old (SD ± 11.54). The characteristics of the sample regarding the patients and extracted teeth are presented in p<0.001) on the reduction of postoperative pain at T6 where PBMT VAS mean score was 0.9 (0.63–1.16) compared to a mean VAS score of 2.5 (2.11–2.88) in the control group. The same statistically significant effect on the reduction of postoperative pain was observed at T24  and T48 .When considering the whole sample, the average VAS pain scores were 1.69 at the first assessment (T6), increased a little 24 hours after the intervention [1.78] and then reduced slightly in the last assessment (1.74 at T48). p<0.001) compared to the control group. According to the classification, the PBMT demonstrated a statistical significance compared to the control group at Class I (p=0.02) and Class II (p<0.001) at T6, T24, and T48.This clinical trial evaluated the PBMT  effectiveness on reducing postoperative pain scores in patients submitted to third molar extractions. As previously mentioned, third molar extractions are among the most frequent oral surgery procedures, which is also commonly associated with postoperative pain, resulting in impaired quality of life during the postoperative course. In the literature, there is still a lack of evidence regarding PBMT effectiveness in reducing third molar extraction postoperative pain, where previous studies presented positive and others no difference compared to a control group -22. AlsoIn the last decade, different PBMT specs and protocols have been studied for different outcomes, among them the reduction of pain related to orthodontic treatments, temporomandibular disorders, and recently dental implant stability and peri-implant alterations .The Gallium and Aluminum Arsenide Diode (GaAlAs) laser that was used in the present study has a continuous emission and a wavelength of 620 to 830 nanometers (nm), which is suggested to improve bone healing and analgesic induction through endogenous opioid release . Right ap<0.001). The same statistically significant effect could be observed at 24 and 48 hours on the reduction of postoperative pain.A previous systematic review of clinical trials revealed that the PBMT could have positive effects on pain after tooth extraction . In our Pain relief is an important outcome associated with the quality of life of subjects submitted to oral surgeries and these consequences could impair daily activities of these subjects including psychological, physical, and social aspects . AlthougCompared to previous studies on the topic, the present randomized controlled trial has a bigger sample size (n=101 teeth), which provides higher statistical power to the analyses, increasing the possibility of external validation of the data. On the other hand, the use of a VAS to assess pain outcomes on the same patient in different third molar extractions could affect in some way the patient's responses and the study design did not prevent any self-medication by the patients.Photobiomodulation (PBMT) therapy presented a statistically significant reduction of postoperative pain scores when assessed 6, 24, and 48 hours after third molar extractions.


Somatosensory testing could be useful in stratifying pain patients and improving pain treatment guidelines. Bedside-suitable techniques are searched for application in daily clinical practice. This study aimed to characterize chronic unilateral lumbosacral radiculopathy (LSR) patients with radicular pain using multimodal bedside-suitable somatosensory testing.We evaluated 50 chronic unilateral LSR patients with radicular pain (LSR group) and 24 controls (Control group). Sensory testing was performed using a battery of bedside sensory tests . Participants had to rate their sensory perceptions on both legs at multiple test points within L3 to S2 dermatomes. Characteristics of the testing process and sensory disturbances were analyzed.p < 0.001) in the LSR group (29.3 ± 6.5 minutes per patient) than in the Control group (20.5 ± 5.2). Nine sensory phenotypes were detected in the LSR group according to individual sensory disturbances within 5 superficial tests.LSR group showed sensory disturbances in 82% of patients. The Control group showed no sensory disturbances. Sensory testing took longer (The applied multimodal bedside-suitable somatosensory testing battery is suitable for sensory evaluation and characterization of LSR patients. Grouping of allied sensory phenotypes revealed some tendencies in pain intensity characteristics. Low back pain (LBP) is a leading cause of disability defined by the global all-age years lived with disability (YLDs) index in 2017 . There iAlso, for the application of comprehensive QST in patients with radiculopathy, there is uncertainty regarding site selection for sensory testing. Low back pain with radiculopathy could manifest with the pain of different mechanisms – nociceptive, referred, neuropathic, or a mix of any of these. Pain is usually related to patients’ posture, activity, and some other factors . TherefoWe hypothesized that a bedside-suitable sensory testing battery describing qualitative characteristics could demonstrate the variability of sensory disturbances in LSR patients with radicular pain and could be applicable for sensory phenotyping.The presented study is a prospective diagnostic study aimed to explore the feasibility of bedside-suitable multimodal somatosensory testing for the evaluation of LSR patients with radicular pain. The objectives of this study were: to assess the capability of selected testing battery to detect sensory disturbances in LSR patients, also to evaluated the time needed to perform sensory testing and patient cooperation issues. The secondary aim of this study was to characterize typical sensory disturbances in LSR patients with radicular pain. The main study group was collected of chronic painful unilateral LSR patients (LSR group). The Control group consisted of chronic pain patients without LSR but with pain syndromes anatomically unrelated to the body region being explored by sensory testing, i.e., pain syndromes not involving the lower waist and legs. The decision to form the Control group of pain patients  was made because sensory testing is a psychophysical testing type. Therefore, subjects free of pain would have a different psychophysical background.The Vilnius Regional Biomedical Research Ethics Committee approved this study protocol (#158200-15-772-289). All participants were informed about the goal and the study process and gave their informed consent to participate.The study was carried out from 2015 to 2018. The patients were recruited from those who were referred to the Pain Medicine Centre at the Vilnius University Hospital Santaros Klinikos  on a scheduled basis. During the screening, all consecutive patients meeting inclusion criteria for the LSR or Control group were invited.The inclusion criteria for the LSR group were chronic painful unilateral LSR patients complaining of leg pain (with or without low back pain) and pain duration of >3 months. Criteria for painful LSR were typical radiating segmental pain with at least one sign of neurological impairment of corresponding spinal segments (positive straight leg raise (SLR) test at an interval of 0–70° or sensory impairment at testing with a standard neurological pin or motor function impairment less than 5th-grade muscle strength according to Lovett’s scale or impairment of deep tendon reflexes). The results of the radiological examination had to be compatible with clinical symptoms.The Control group was formed of chronic pain patients (pain duration of >3 months) without LSR and with pain syndromes anatomically unrelated to the lower waist and legs. The age limits for both groups were 18 to 85 years.Exclusion criteria for both groups are presented in Pain evaluation consisted of: pain intensity evaluated separately for low back and leg (Brief Pain Inventory short form (BPI-SF) Pain items, numeric rating scale 0 to 10 points (NRS 0-10)), pain impact on functioning , anxiety and depression evaluation  score), screening for neuropathic pain component (painDETECT Questionnaire (PD-Q) score). Assessment of magnetic resonance imaging (MRI) and/or computed tomography (CT) of the lumbosacral spine not older than 6 months were collected and analyzed. Sensory testing was performed on all patients, collecting data on sensory disturbances, testing duration, and any test completion problems.Bonica’s Management of Pain [A single investigator performed sensory testing. Dermatomes L3, L4, L5, S1, and S2, according to the dermatomal distribution map from  of Pain  were tesIf the perception in the radiculopathy-affected leg was rated as being normally sensitive at all points examined, the tested modality was qualified as normal. If the sensory perception in any of the tested dermatomes was rated as hyposensitive or hypersensitive in at least two adjacent test points along the dermatome, then the tested modality was qualified as hyposensitive or hypersensitive, respectively. The dermatomes with sensory disturbances had to correspond to the segments defined in the clinical diagnosis of radiculopathy. Noncompliance with radiculopathy-affected segments was qualified as an exclusion criterion.The full sensory testing battery consisted of 6 tests , as listed in p-value less than 0.05 was considered significant. Statistical analysis was performed using the statistical analysis software (SAS) package version 9.2. We used descriptive statistics such as frequency tables and means (with standard deviation) to describe quantitative and qualitative data, respectively. The normality of the distribution was assessed using the Kolmogorov–Smirnov test. Differences between the two independent quantitative normally distributed, nonnormally distributed, and qualitative groups were evaluated by the Student’s t-test, Mann–Whitney U test, and the chi-square test, respectively. A Kruskal–Wallis one-way ANOVA was used to assess the mean differences in more than 2 groups. The Bonferroni correction was used for pairwise comparisons. A two-tailed A total of 362 patients were screened for enrollment into the LSR group. 56 patients were enrolled into the LSR group, and 50 of them completed it . Twenty-p = 0.017) and body mass index , which is consistent with data confirming association of higher weight with LBP [Fifty LSR patients  and 24 control group patients  completed this study. Post hoc analysis showed both groups to be age- and sex-matched. The groups differed reliably in weight . Low back pain was present in 88% of the LSR patients. Detailed pain and related characteristics of the LSR group are presented in Other complaints concomitant to pain were reported: paresthesia/numbness – 72%, muscle cramps – 22%, feeling of cold in the leg – 12%, and leg swelling – 4%.p = 0.029 and p = 0.023, respectively, but this was treated as indeterminant for comparative sensory testing results.Pain characteristics in the Control group were: pain duration 43.6 ± 70.2 months, range 3–312, pain intensity as average during last week 5.3 ± 1.16 points on NRS 0-10, range 3–7. These variables differed from the LSR group with statistical significance of The distribution of nerve root impairment according to LSR diagnosis is shown in Sensory impairment by testing with a standard neurological pin was detected in 76% of patients, impairment of deep tendon reflexes was detected in 64% of patients, and motor function impairment was detected in 72% of patients. Positive SLR test was detected in 88% of patients with 39° ±16° (range 15° –70° ). Eight percent of patients without any neurologic deficit were diagnosed with LSR based on typical segmental radicular pain distribution with a positive SLR test present. Neurogenic claudication was reported by 38% of patients.The sole selective radiologic finding corresponding to spinal nerve involvement of LSR diagnosis was detected in 54% of cases. All other patients (46%) could be defined as having diffuse/multiple degenerative changes compatible with LSR diagnosis, though it is difficult to determine the exact anatomical site of spinal nerve impingement.p < 0.001.Sensory testing took significantly longer in the LSR group (29.3 ± 6.5 minutes per patient) than in the Control group (20.5 ± 5.2 minutes per patient), Patients from the Control group showed no sensory impairment or asymmetry between the left and right legs to all tested sensory modalities.In the LSR group, 82% of the patients showed sensory disturbances. The full spectrum of disturbances is presented in p < 0.001), to pinprick testing , to cold testing , and to warmth testing .The frequency of hyposensitivity to the tactile dynamic test was much rarer compared to other types of superficial sensory tests. Statistical comparison of proportions showed that the percentage frequency of hyposensitivity and other sensory types  differed significantly in tactile dynamic testing (28% and 72%) if to compare to tactile static testing  have been tested. As patient groups in different phenotypes were small, the following grouping of allied phenotypes has been applied. The following groups were formed : “NormalThirteen (9.3%) of 140 excluded patients were categorized with “inability to understand study instructions or documentation properly. ” This group consisted of patients with insufficient cognitive function or language knowledge . Additionally, four (7.1%) of 56 patients enrolled in the trial were excluded due to inconsistent or inconclusive sensory testing.Qualitative type sensory testing is relatively uncommon in clinical trials as comprehensive automated QST still reigns as the gold standard. In contrast to QST, qualitative sensory testing tools create a fixed-intensity stimulus. They allow classification of sensory perception as either normal or not if compared to an intact reference testing site without determining the degree of sensory dysfunction. Like QST, qualitative sensory testing provides information on the perception of stimulation to different types of receptors and their nerve fibers. The duration of the full testing battery was 29.3 ± 6.5 minutes per patient. Such duration seems quite adequate and corresponds to an intended 30 minutes for at least one test point of the standardized QST protocol by the German Research Network on Neuropathic Pain . During Exceptional attention was paid to patient selection (inclusion/exclusion criteria) to avoid any factors that might misrepresent sensory function and testing. Therefore, screening for patients with pure unilateral LSR and excluding any patients with diseases, conditions, or factors that could affect sensations in the areas of the body being studied was critical. A significant list of exclusion criteria considerably reduced the number of patients screened for inclusion, with 140 (68%) of 206 study candidates excluded. This is the primary limiting factor for this type of sensory testing to be used in clinical practice.Also, good patient cooperation is essential to ensure the effective use of sensory testing. The patient cooperation level in our study was acceptable. The overall withdrawal rate due to inconsistent contact or linguistic issues was 8% (17 patients of 206).All sensory testing instruments were easy to handle; no technical problems occurred. The price of the whole set of testing instruments was approximately 2000 euros. This is about 10 times less than comprehensive automated QST systems.In our study, nine (18%) of the 50 subjects did not report any superficial disturbances . Normal sensations were found in 18% to 58% if the different tests were assessed separately. Intact sensory function or a relatively low degree of sensory impairment difficult to distinguish from the unaffected side of the body are among possible explanations. Qualitative type of sensory testing in patient populations with unilateral sciatica , in lumbThe dominant impairment type detected in our study is hyposensitivity. This conforms with all other radiculopathy studies. Hyposensitivity to most superficial tests (to 4 or 5 tests) dominated across the study population and accounted for 31 (62%) of the 50 study patients.Patients with hypersensitivity are another specific group. Five of the 50 patients showed hypersensitivity to all superficial tests. Another four patients showed isolated hypersensitivity to one modality (brush or cold perception), with hyposensitive responses to all other tests. While hypersensitivity phenomena were common in one report with qualitative type testing study , some otBrush testing (200–400 mN) for tactile dynamic perception showed statistically significantly the smallest portion of hyposensitivity cases than other sensory modalities. This resembles findings of sensory testing with cotton swab stroke in atypical odontalgia patients . Deep tissue sensitivity testing was performed with a nonstandardized instrument. The results of this test exhibited a relatively high percentage of hypersensitivity  and the presence of mixed hypo- and hypersensitivity together in the same patient at different tested points (16% of patients). The most reliable explanation of such intraindividual mixed type disturbances could be the different underlying tissues  at various testing sites, which could be of great importance when testing the lower limb . A mechaThe unexpected finding was the neuropathic scores obtained with PD-Q. In general, PD-Q scores in LSR group were low (9.5 ± 3.8) with 81% of patients qualified as ‘unlikely neuropathic pain’, 17% as ‘uncertain’, and only 2% as ‘likely neuropathic pain’. Given that study population consisted of carefully selected LSR patients, the results appear to be in line with publications on this subject .We did not intend to measure the reliability of testing techniques. The use of nonstandardized testing instruments has already been investigated in atypical odontalgia patients  and exhiData from QST studies usually report sensory function in group averages of quantitative indicators. However, individual variability remains unclear. Our study revealed considerable variability of sensory disturbances – nine sensory phenotypes were distinguished according to individual sensory profiles. This was also reported with QST in cervical radiculopathy . The varThe applied multimodal bedside-suitable somatosensory testing battery is suitable for sensory evaluation, characterization and phenotyping of LSR patients with radicular pain. Tactile static testing with a 10g monofilament showed the highest sensitivity to detect superficial sensory disturbances. It could be recommended as the most sensitive single testing instrument. Tactile dynamic testing with 200–400 mN brush detected sensory impairments significantly less frequently than any other modalities, therefore not recommended for the screening of LSR patients. The detected sensory phenotypes should be explored for the relation with treatment effects.