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The genetic influence of the brain-derived neurotrophic factor Val66Met polymorphism in chronic low back pain

The genetic influence of the brain-derived neurotrophic factor Val66Met polymorphism in chronic... Background: The Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene is a potential biomarker of vulnerability to pain. Thus, the present study aimed to investigate the association of this polymorphism with clinical and biopsychosocial factors in patients with chronic low back pain (CLBP). Methods: A total of 107 individuals with CLBP answered questionnaires that were validated and adapted for the Brazilian population, including the Brief Inventory of Pain, the Central Sensitization Inventory, the Roland Morris Disability Questionnaire, the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, the Survey of Pain Attitude-Brief, and the Hospital Anxiety and Depression Scale. All of the subjects were genotyped for the BDNF Val66Met polymorphism. Results: The sample showed moderate scores of disability, central sensitization, and kinesiophobia, in addition to mild anxiety, hopelessness, and ruminant thoughts. No significant association was observed between the Val66Met polymorphism and the variables analyzed. Besides, there was no relationship between the BDNF Val66Met polymorphism with CSI, catastrophization, or disabilities that were generated by CLBP. Conclusion: The results showed that the Val66Met polymorphism of the BDNF gene was not associated with clinical and biopsychosocial characteristics of CLBP in the sample studied. Keywords: Central sensitization, Catastrophizing, BDNF, Polymorphism, Single nucleotide polymorphism, Val66Met Background It is well known that the experience of pain is influ- In the populations suffering from chronic pain, low back enced by biological, psychological, and behavioral fac- pain is one of the most prevalent musculoskeletal disor- tors. Among the biological factors, there is a growing ders, affecting 70 to 85% of adults at some point in their interest in the genetic aspects, in an attempt to explain life [1]. Regardless of the primary or secondary path- some of the differences in the pain responses between ology, the consequences of persistent pain include the individuals [4]. Studies have considered that the genetic fear of movement, pain catastrophizing, anxiety, and factors represent more than a 50% susceptibility to central sensitization. These outcomes appear to be the chronic low back pain (CLBP) [5], whereas the variation major contributors of pain and disability under these in the genes that are involved in pain perception and its conditions [2, 3]. modulation, transduction, transmission, and conduction by the nervous system can result in variabilities in the experience of pain [6]. * Correspondence: angelasyamada@gmail.com The brain-derived neurotrophic factor (BDNF) is a Molecular and Cellular Biology Applied to Health, Lutheran University of neurotrophin that is involved in neurogenesis and synap- Brazil (ULBRA), Canoas, Brazil Full list of author information is available at the end of the article tic plasticity in the central nervous system. The © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Yamada et al. Advances in Rheumatology (2021) 61:24 Page 2 of 8 Val66Met polymorphism (c.196G > A, dbSNP: rs6265) of Scale (PCS) [16]; and the Hospital Anxiety and Depres- the BDNF gene represents the replacement of valine sion Scale (HADS) [17]. Afterward, 5 ml of peripheral (Val) with a methionine (Met) at codon 66. This substi- blood was collected using sodium ethylenediaminetetra- tution in the BDNF pro-region changes the intracellular acetic acid (EDTA) as an anticoagulant, and it was then trafficking and packaging of the pro-BDNF, its availabil- frozen. ity in the synaptic cleft, and the deterioration of synaptic plasticity, thus decreasing the BDNF secretion [7]. The Genetic analyses Val66Met polymorphism has been considered as a The total DNA was purified from the blood samples and marker of vulnerability to pain. Individuals with the the Val66Met SNP (rs6265) was genotyped through the Met allele were more likely to have chronic pain when real-time polymerase chain reaction (PCR) when using associated with the presence and severity of chronic TaqMan® SNP Genotyping assays (Thermo Fisher Scien- musculoskeletal pain in multiple sites, in studies that in- tific; catalog 4,351,379, assay ID: C__11592758_10). All vestigated individuals with childhood or recent life stress of the assays were run on a StepOnePlus™ system (Bio- [8], and with an increased risk of chronic postoperative systems Inc., Foster City, USA). pain [9]. However, the studies on the role of BDNF, both in relation to the genotypes, their expression, and the Statistical analyses serum protein levels in chronic pain, still show inconclu- The data was analyzed using descriptive statistics, and sive results. by employing mean, standard deviations, and percent- Most treatment strategies for CLBP are still based on ages through the SAS version 9.4 program. A bivariate the biomedical model, that is, structural-anatomical- analysis was performed to compare the variables under mechanical [10]. However, the biopsychosocial model is study in relation to the genotypes of Val66Met. For the based on a dynamic relationship between the biological qualitative variables, the Chi-square test was applied, changes, psychological status, and social context, empha- and for the quantitative variables, the Mann-Whitney sizing that these factors have different roles in chronic non-parametric test was applied. The allele frequencies pain, disability, and emotional maladjustment [11]. were determined by direct counting of the alleles. The Therefore, the present study aimed to investigate the as- departures from the Hardy-Weinberg equilibrium were sociation of the single nucleotide polymorphism (SNP) evaluated by the Chi-square test. p < 0.05 was considered Val66Met of the BDNF gene with clinical and biopsy- statistically significant. chosocial factors in patients with CLBP. Results Methods The sample was composed of 107 patients (56.5% All of the procedures complied with the requirements of women) with CLBP. The clinical and demographic char- Resolution 466/12 of the National Health Council. The acteristics of the sample are shown in Table 1. Briefly, data collection occurred after the approval by the Re- the mean age was 46.2 ± 14.3 years, the BMI was 26.8 ± search Ethics Committee from the Lutheran University 5.1 kg/m (26.7% with obesity), with a score of 49.6 ± of Brazil (ULBRA), under protocol number 2.254.800. 14.4 in the CSI assessment, presuming central All of the patients gave written informed consent before sensitization, and a score of 15.7 ± 5.3 in the RMDQ, their participation. presuming disabilities. The analysis of the BIP showed that the patients had pain in at least roughly nine body Subjects regions, summing the low back. The Tampa scores were The study was carried out in Palmas (Tocantins, Brazil), considered moderate (45.6 ± 7.8). The PCS scores evi- at the Lutheran University Center of Palmas (CEULP/ denced rumination thoughts. In addition, mild anxiety ULBRA), in the community service center, the Clinical was observed according to the HADS scores. School of Physiotherapy (CSP). The eligibility criteria In the present study, it was observed that 26 (24.3%) were individuals over 18 years of age of both genders, patients were carriers of the Met allele of SNP Val66Met who had CLBP for over 3 months. in the BDNF gene. There were no significant associa- tions between the Val66Met genotypes and either the Procedure quantitative (Table 2) or the qualitative variables studied The individuals with CLBP answered questionnaires that (Table 3). were validated and adapted for the Brazilian population, such as the Brief Inventory of Pain (BIP) [12]; the Cen- Discussion tral Sensitization Inventory (CSI) [13]; the Roland Mor- The present study found no associations between the ris Disability Questionnaire (RMDQ) [14]; the Tampa BDNF Val66Met genotypes and the biopsychosocial Scale for Kinesiophobia [15]; the Pain Catastrophizing phenotypes in patients with CLBP. The Val66Met Yamada et al. Advances in Rheumatology (2021) 61:24 Page 3 of 8 Table 1 Characteristics of the sample studied The averages of the disabilities of the patients in the present study due to CLBP were classified as moderate Variable Mean SD from the RMDQ. It is recommended to consider an as- Age 46.24 14.27 sessment of the multidimensional nature of CLBP in the Subjective assessment of stress 5.84 2.39 management of pain [25]. This could be physical (for ex- BMI 26.82 5.14 ample, disability and body composition), psychological Total CSI score 49.6 14.39 (for example, kinesiophobia, fear-avoidance, pain cata- Total RMDQ score 15.7 5.3 strophizing, pain self-efficacy, depression, anxiety, and BIP pain intensity sleep quality), and/or social (social functioning and work absenteeism) factors. Worst 6.49 2.59 Most of the evaluated patients presented overweight/ Least 3.16 2.45 obesity conditions. Adiposity may modulate pain Average 5.37 2.26 through peripheral sensitization from increased systemic Now 4.56 3.02 inflammation [26]. In addition, it was observed that the BIP interference increased fat infiltration of the paraspinal musculature General activity 5.83 3.34 could be associated with a compromised function of the muscles that control and support the low back [27, 28]. Mood 5.5 3.52 The findings from the BIP data also showed that the Walking 5.41 3.32 worst pain affected the normal work of the patients, Normal work 5.97 3.7 restricting the performance of the activities of daily Relations 3.58 3.34 living. Sleep 5.44 3.46 The individuals in the present study reported being Enjoyment of life 4.48 3.63 physically inactive. The relationship between a cluster of unhealthy lifestyle behaviors (smoking, alcohol drinking, Σ pain-body regions 8.95 6.04 physical activity, weight control, breakfast, snacking, and Total Tampa score 45.61 7.82 sleep) and low back pain (LBP) was investigated in a Total PCS score 2.17 1.2 cross-sectional study of over 400,000 Japanese adults PCS rumination 2.68 1.33 showing an association of this cluster with an increased PCS helplessness 1.53 1.31 risk of LBP, regardless of age and BMI [29]. Moreover, HADS-anxiety 9.04 3.47 chronic pain is at least partly attributed to a sedentary and inactive lifestyle and it could be recognized as a HADS-depression 6.91 3.98 lifestyle-related disease. Physical activity/inactivity may BMI body mass index, BPI the brief inventory of pain, CSI central sensitization inventory, HADS hospital anxiety and depression scale, PCS pain also determine the genetic/epigenetic and neural factors catastrophizing scale, RMDQ Rolland-Morris disability questionnaire, SD encoded in the brain [30]. A single session of exercise standard deviation and regular physical activity induce changes in the genes polymorphism is the most studied in the BNDF gene that regulate the nociceptive processes, the learning of and it has been investigated in several pathological fear, and the stress responses, as well as those that are conditions in humans [18–20]. The Val66Met poly- involved in the pathophysiology of chronic diseases [31]. morphism has also been associated with the methyla- In the current study, the mean of the total scores in tion patterns, and it is being related to the epigenetic Tampa was moderate. Fear can be learned through asso- regulation of the BDNF gene [21]. From a biological ciative learning. Previous study reported that condition- perspective, it is known that the responses of an or- ing to fear was able of inducing a rapid increase in ganism’s experience to the external environment can methylation of the BDNF gene in the hippocampus, and be reflected in the epigenetic changes. Thus, the gene it occurred during the consolidation of fear [32]. It is expression could also be regulated by the epigenetic well known that the fear and the avoidance of particular modifications to the chromatin structure and the pat- movements could add to a disability, but the assessment terns of DNA methylation. These adaptations can and removal of these barriers to movement might, there- modify, among others, neuronal morphology and the fore, reduce the disability [33]. A psychological factor activity to produce changes in behavior [22, 23]. Al- that distinctly predicts changeability in the perception of terations in the chromatin structure represent mecha- pain and the development of moderate kinesiophobia is nisms by which pain can be converted gradually and pain catastrophizing [34]. In the present study, the CLBP progressively into the pathological processes of neuro- patients presented scores that suggested rumination and inflammation, central sensitization, and ultimately, helplessness thoughts, besides mild anxiety and central chronic pain syndromes [24]. sensitization. Anxiety and stress predict chronic pain in Yamada et al. Advances in Rheumatology (2021) 61:24 Page 4 of 8 Table 2 Comparison of the quantitative variables according to the BDNF Val66Met genotypes Variable Val/ Val (n = 81) Val/Met (n = 26) P-value Age 46.2 ± 14.3 46.5 ± 14.6 0.73 Subjective assessment of stress 5.9 ± 2.5 5.8 ± 2.1 0.62 BMI 27.1 ± 5.2 26.4 ± 4.9 0.47 Total CSI score 50.3 ± 14.6 48.0 ± 13.9 0.50 Total RMDQ score 15.6 ± 5.5 15.8 ± 4.8 0.99 BIP pain intensity Worst 6.5 ± 2.5 6.4 ± 2.9 0.97 Least 3.2 ± 2.4 2.8 ± 2.4 0.42 Average 5.4 ± 2.1 5.2 ± 2.8 0.52 Now 4.6 ± 3.0 4.2 ± 3.0 0.45 BIP interference General activity 5.9 ± 3.4 5.4 ± 3.2 0.44 Mood 5.7 ± 3.5 4.9 ± 3.7 0.36 Walking 5.4 ± 3.2 5.3 ± 3.5 0.96 Normal work 6.1 ± 3.8 5.3 ± 3.4 0.16 Relation 3.6 ± 3.4 3.5 ± 3.2 0.92 Sleep 5.4 ± 3.6 5.3 ± 3.2 0.76 Enjoyment of life 4.3 ± 3.7 5.1 ± 3.5 0.34 Summation of pain body regions 9.0 ± 5.0 8.7 ± 8.8 0.07 Total Tampa score 45.6 ± 8.1 45.9 ± 7.2 0.87 Total PCS score 2.2 ± 1.2 1.9 ± 1.1 0.32 PCS rumination 2.8 ± 1.4 2.3 ± 1.1 0.18 PCS helplessness 1.5 ± 1.3 1.4 ± 1.4 0.51 HADS anxiety 9.3 ± 3.5 8.4 ± 3.5 0.52 HADS depression 7.1 ± 3.8 6.6 ± 4.4 0.35 Values are shown as mean ± standard deviation BMI body mass index, BPI the brief inventory of pain, CSI central sensitization inventory, HADS hospital anxiety and depression scale, PCS pain catastrophizing scale, RMDQ Rolland-Morris disability questionnaire P-value for the Mann-Whitney test the long term and they might mediate the vulnerability The importance of behavioral approaches to back pain to pain [35]. Thus, there is plausibility that the extent of management does not preclude the continuing need to central sensitization symptoms in people with non- investigate mechanisms and the potential biological de- specific LBP might be associated with the pre-morbid terminants of non-specific low back pain [40]. The rela- trait anxiety sub-types and the abnormal trait sensory tive importance of the genetic factors in human processing profiles [36, 37]. Moreover, depression and musculoskeletal pain conditions, such as CLBP, painful anxiety are barriers to treatment adherence in various temporomandibular joint disorders, fibromyalgia, and chronic pain conditions, such as low back pain [38]. chronic widespread pain, is becoming clearer. Several Although 74% of the patients in the present study polymorphisms in the genes are contributing to seroto- reported themselves to be active/employed, they de- nergic and adrenergic pathways that are associated with scribed the pain during a month at an intense level musculoskeletal pain [41]. Despite studies demonstrating and with chronicity for up to 13 months. This is im- evidence that the BDNF Val66Met polymorphism influ- portant since CLBP is also considered responsible for ences the cortical processing of experimental electrical absenteeism at work, and with high rates of disability, pain stimuli in an indirect manner [4], or in pain cata- generating high costs for the health system, social se- strophizing [42], the findings in the present study did curity, and society in general [39]. Moreover, non- not show the influence of this polymorphism in chronic opioids were the main medication used, and most of pain complaints. the patients reported a modest relief of the pain with Certain limitations must be considered in the inter- the medication. pretation of the current study’s findings. First, the Yamada et al. Advances in Rheumatology (2021) 61:24 Page 5 of 8 Table 3 Comparison of the qualitative variables according to the BDNF Val66Met genotypes Genotype Val/ Val Val/Met P-value N (%) N (%) Gender Female 45 (55.6) 16 (61.5) 0.59 Male 36 (44.4) 10 (38.6) Civil status Living alone 42 (51.8) 11 (42.3) 0.40 Living with partner 39 (48.2) 15 (57.7) Ethnicity White 14 (18.2) 8 (34.8) Brown 46 (59.7) 13 (56.5) 0.14 Black 17 (22.1) 2 (8.7) Schooling Until high school 63 (77.8) 16 (64.0) 0.17 Complete high school 18 (22.2) 9 (36.0) Have children No 19 (23.5) 6 (23.1) 0.97 Yes 62 (76.5) 20 (76.9) Healthy Good, very good, or great 35 (44.3) 12 (46.1) 0.87 Regular, bad, or lousy 44 (55.7) 14 (53.9) Chronicity pain 3–12 months 21 (25.9) 5 (19.2) 13–60 months 27 (33.3) 13 (50.0) 0.31 > 60 months 33 (40.8) 8 (30.8) Pain intensity Least 8 (9.9) 4 (15.4) Moderate 14 (17.3) 3 (11.5) 0.62 Intense 59 (72.8) 19 (73.1) Pain duration in the month Intermittent 37 (46.2) 15 (65.2) 0.11 Constant 43 (53.8) 8 (34.8) Comorbidities No 46 (56.8) 16 (61.5) 0.67 Yes 35 (43.2) 10 (38.5) Physical activity Inactive 55 (67.9) 18 (69.2) Insufficiently active 8 (9.9) 4 (15.4) 0.80 Moderately active 13 (16.0) 3 (11.5) Vigorously active 5 (6.2) 1 (3.9) Smoking No 68 (91.9) 21 (91.3) 0.93 Yes 6 (8.1) 2 (8.7) Alcoholism No 66 (89.2) 22 (95.7) 0.35 Yes 8 (10.8) 1 (4.3) Yamada et al. Advances in Rheumatology (2021) 61:24 Page 6 of 8 Table 3 Comparison of the qualitative variables according to the BDNF Val66Met genotypes (Continued) Genotype Val/ Val Val/Met P-value N (%) N (%) Satisfaction Unsatisfied or a little satisfied 33 (51.6) 9 (40.9) 0.39 Satisfied or much satisfied 31 (48.4) 13 (59.1) Occupational situation Active/employed 62 (76.5) 18 (69.2) 0.45 Unemployed 19 (23.5) 8 (30.8) Low back pain in family history No 36 (44.4) 12 (46.2) 0.88 Yes 45 (55.6) 14 (53.8) Overweight/obesity No 32 (41.0) 11 (42.3) 0.91 Yes 46 (59.0) 15 (57.7) CSI No 14 (17.3) 4 (15.4) 0.82 Yes 67 (82.7) 22 (84.6) RMDQ No 28 (34.6) 9 (34.6) 0.97 Yes 53 (65.4) 17 (65.4) Medication Non opioid 33 (62.3) 12 (80.0) 0.20 Weak opioid 20 (37.7) 3 (20.0) Medication frequency Every 6 h 35 (66.0) 7 (50.0) 0.27 If there is pain 18 (34.0) 7 (50.0) Start of medication 12 months ago 32 (68.1) 8 (80.0) 13–60 months 7 (14.9) 1 (10.0) 0.75 More than 60 months 8 (17.0) 1 (10.0) Relief of pain with medication 50% relief 32 (62.8) 5 (45.5) 0.29 More than 50% relief 19 (37.2) 6 (54.5) Tampa score Light 7 (8.6) 2 (7.7) Moderate 47 (58.1) 14 (53.8) 0.89 Critical 27 (33.3) 10 (38.5) HADS-anxiety No 34 (42.0) 11 (42.3) 0.98 Yes 47 (58.0) 15 (57.7) HADS-depression No 53 (65.4) 20 (76.9) 0.27 Yes 28 (34.6) 6 (23.1) CSI central sensitization inventory, HADS hospital anxiety and depression scale, RMDQ Rolland-Morris disability questionnaire P-value for the Chi-square test Yamada et al. Advances in Rheumatology (2021) 61:24 Page 7 of 8 statistical power of the sample size that was analyzed Author details Molecular and Cellular Biology Applied to Health, Lutheran University of was limited. Second, this was a cross-sectional study, Brazil (ULBRA), Canoas, Brazil. Human Molecular Genetics Laboratory, which might limit the causality identification of the 3 Lutheran University of Brazil (ULBRA), Canoas, Brazil. Biochemical and demographic and clinical variables that were investi- Molecular Pharmacology from the Federal University of Minas Gerais, Belo Horizonte, Brazil. gated. Third, to have a better understanding of the role of BDNF in CLBP, it would be important to investigate Received: 15 February 2021 Accepted: 27 April 2021 the correlation between the genotypes and the serum levels. References 1. Becker A, Held H, Redaelli M, Strauch K, Chenot JF, Leonhardt C, et al. 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Simon performed the brain-derived neurotrophic factor pathway, life stress, and chronic multi-site statistical analyses. A.S. Yamada, A.H. de Souza, and D. Simon interpreted and musculoskeletal pain. Mol Pain. 2016;12:1744806916646783.https://doi.org/1 discussed the results. A.S. Yamada and D. Simon wrote the paper. A.S. 0.1177/1744806916646783. Yamada, F.T.T. Antunes, C. Ferraz, A.H. de Souza, and D. Simon contributed to 9. Tian Y, Liu X, Jia M, Yu H, Lichtner P, Shi Y, et al. Targeted genotyping the final version of the manuscript. All of the authors have reviewed and identifies susceptibility locus in brain-derived Neurotrophic factor gene for approved the final version of the article, including the authorship list. chronic postsurgical pain. Anesthesiology. 2018;128(3):587–97. https://doi. org/10.1097/ALN.0000000000001977. Funding 10. Desconsi MB, Bartz PT, Fiegenbaum TR, Candotti CT, Vieira A. Treatment of This research was supported by grants from the Brazilian agency patients of nonspecific chronic low back pain by physical therapists: a cross- Coordination for the Improvement of Higher Education Personnel from Brazil sectional study. Fisioter Pesqui. 2019;26(1):15–21. https://doi.org/10.1590/1 (CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; 809-2950/17003626012019. Finance Code 001). The funding source had no involvement in the study 11. Dionísio GH, Salermo VY, Padilha A. Central sensitization and beliefs among design, collection, analysis and interpretation of data, writing of the report, patients with chronic pain in a primary health care unit. BrJP. 2020;3(1):42–7. and the decision to submit the article for publication. https://doi.org/10.5935/2595-0118.20200010. 12. Ferreira KA, Teixeira MJ, Mendonza TR, Cleeland CS. Validation of brief pain Availability of data and materials inventory to Brazilian patients with pain. 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The study was conducted in accordance with the principles of the Declaration of Helsinki. 15. Siqueira FB, Teixeira-Salmela LF, Magalhães LC. Analysis of the psychometric properties of the brazilian version of the Tampa scale for kinesiophobia. Consent for publication Acta Ortop Br. 2007;15(1):19–24. https://doi.org/10.1590/S1413-78522 Not applicable. 16. Junior JS, Nicholas MK, Pereira IA, Pimenta CAM, Asghari A, Cruz RM. Competing interests Validation of the pain-related Catastrophizing thoughts scale. Acta fisiatr. The authors declare that they have no competing interests. 2008;15(1):31–6. Yamada et al. Advances in Rheumatology (2021) 61:24 Page 8 of 8 17. Castro MMC, Quarantini L, Batista-Neves S, Kraychete DC, Daltro C, Miranda- and central sensitization - a pilot observational study. J Bodywork Mov Ther. Scippa A. Validity of the hospital anxiety and depression scale in patients 2018;22(4):909–16. https://doi.org/10.1016/j.jbmt.2017.11.007. with chronic pain. 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The genetic influence of the brain-derived neurotrophic factor Val66Met polymorphism in chronic low back pain

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Abstract

Background: The Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene is a potential biomarker of vulnerability to pain. Thus, the present study aimed to investigate the association of this polymorphism with clinical and biopsychosocial factors in patients with chronic low back pain (CLBP). Methods: A total of 107 individuals with CLBP answered questionnaires that were validated and adapted for the Brazilian population, including the Brief Inventory of Pain, the Central Sensitization Inventory, the Roland Morris Disability Questionnaire, the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, the Survey of Pain Attitude-Brief, and the Hospital Anxiety and Depression Scale. All of the subjects were genotyped for the BDNF Val66Met polymorphism. Results: The sample showed moderate scores of disability, central sensitization, and kinesiophobia, in addition to mild anxiety, hopelessness, and ruminant thoughts. No significant association was observed between the Val66Met polymorphism and the variables analyzed. Besides, there was no relationship between the BDNF Val66Met polymorphism with CSI, catastrophization, or disabilities that were generated by CLBP. Conclusion: The results showed that the Val66Met polymorphism of the BDNF gene was not associated with clinical and biopsychosocial characteristics of CLBP in the sample studied. Keywords: Central sensitization, Catastrophizing, BDNF, Polymorphism, Single nucleotide polymorphism, Val66Met Background It is well known that the experience of pain is influ- In the populations suffering from chronic pain, low back enced by biological, psychological, and behavioral fac- pain is one of the most prevalent musculoskeletal disor- tors. Among the biological factors, there is a growing ders, affecting 70 to 85% of adults at some point in their interest in the genetic aspects, in an attempt to explain life [1]. Regardless of the primary or secondary path- some of the differences in the pain responses between ology, the consequences of persistent pain include the individuals [4]. Studies have considered that the genetic fear of movement, pain catastrophizing, anxiety, and factors represent more than a 50% susceptibility to central sensitization. These outcomes appear to be the chronic low back pain (CLBP) [5], whereas the variation major contributors of pain and disability under these in the genes that are involved in pain perception and its conditions [2, 3]. modulation, transduction, transmission, and conduction by the nervous system can result in variabilities in the experience of pain [6]. * Correspondence: angelasyamada@gmail.com The brain-derived neurotrophic factor (BDNF) is a Molecular and Cellular Biology Applied to Health, Lutheran University of neurotrophin that is involved in neurogenesis and synap- Brazil (ULBRA), Canoas, Brazil Full list of author information is available at the end of the article tic plasticity in the central nervous system. The © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Yamada et al. Advances in Rheumatology (2021) 61:24 Page 2 of 8 Val66Met polymorphism (c.196G > A, dbSNP: rs6265) of Scale (PCS) [16]; and the Hospital Anxiety and Depres- the BDNF gene represents the replacement of valine sion Scale (HADS) [17]. Afterward, 5 ml of peripheral (Val) with a methionine (Met) at codon 66. This substi- blood was collected using sodium ethylenediaminetetra- tution in the BDNF pro-region changes the intracellular acetic acid (EDTA) as an anticoagulant, and it was then trafficking and packaging of the pro-BDNF, its availabil- frozen. ity in the synaptic cleft, and the deterioration of synaptic plasticity, thus decreasing the BDNF secretion [7]. The Genetic analyses Val66Met polymorphism has been considered as a The total DNA was purified from the blood samples and marker of vulnerability to pain. Individuals with the the Val66Met SNP (rs6265) was genotyped through the Met allele were more likely to have chronic pain when real-time polymerase chain reaction (PCR) when using associated with the presence and severity of chronic TaqMan® SNP Genotyping assays (Thermo Fisher Scien- musculoskeletal pain in multiple sites, in studies that in- tific; catalog 4,351,379, assay ID: C__11592758_10). All vestigated individuals with childhood or recent life stress of the assays were run on a StepOnePlus™ system (Bio- [8], and with an increased risk of chronic postoperative systems Inc., Foster City, USA). pain [9]. However, the studies on the role of BDNF, both in relation to the genotypes, their expression, and the Statistical analyses serum protein levels in chronic pain, still show inconclu- The data was analyzed using descriptive statistics, and sive results. by employing mean, standard deviations, and percent- Most treatment strategies for CLBP are still based on ages through the SAS version 9.4 program. A bivariate the biomedical model, that is, structural-anatomical- analysis was performed to compare the variables under mechanical [10]. However, the biopsychosocial model is study in relation to the genotypes of Val66Met. For the based on a dynamic relationship between the biological qualitative variables, the Chi-square test was applied, changes, psychological status, and social context, empha- and for the quantitative variables, the Mann-Whitney sizing that these factors have different roles in chronic non-parametric test was applied. The allele frequencies pain, disability, and emotional maladjustment [11]. were determined by direct counting of the alleles. The Therefore, the present study aimed to investigate the as- departures from the Hardy-Weinberg equilibrium were sociation of the single nucleotide polymorphism (SNP) evaluated by the Chi-square test. p < 0.05 was considered Val66Met of the BDNF gene with clinical and biopsy- statistically significant. chosocial factors in patients with CLBP. Results Methods The sample was composed of 107 patients (56.5% All of the procedures complied with the requirements of women) with CLBP. The clinical and demographic char- Resolution 466/12 of the National Health Council. The acteristics of the sample are shown in Table 1. Briefly, data collection occurred after the approval by the Re- the mean age was 46.2 ± 14.3 years, the BMI was 26.8 ± search Ethics Committee from the Lutheran University 5.1 kg/m (26.7% with obesity), with a score of 49.6 ± of Brazil (ULBRA), under protocol number 2.254.800. 14.4 in the CSI assessment, presuming central All of the patients gave written informed consent before sensitization, and a score of 15.7 ± 5.3 in the RMDQ, their participation. presuming disabilities. The analysis of the BIP showed that the patients had pain in at least roughly nine body Subjects regions, summing the low back. The Tampa scores were The study was carried out in Palmas (Tocantins, Brazil), considered moderate (45.6 ± 7.8). The PCS scores evi- at the Lutheran University Center of Palmas (CEULP/ denced rumination thoughts. In addition, mild anxiety ULBRA), in the community service center, the Clinical was observed according to the HADS scores. School of Physiotherapy (CSP). The eligibility criteria In the present study, it was observed that 26 (24.3%) were individuals over 18 years of age of both genders, patients were carriers of the Met allele of SNP Val66Met who had CLBP for over 3 months. in the BDNF gene. There were no significant associa- tions between the Val66Met genotypes and either the Procedure quantitative (Table 2) or the qualitative variables studied The individuals with CLBP answered questionnaires that (Table 3). were validated and adapted for the Brazilian population, such as the Brief Inventory of Pain (BIP) [12]; the Cen- Discussion tral Sensitization Inventory (CSI) [13]; the Roland Mor- The present study found no associations between the ris Disability Questionnaire (RMDQ) [14]; the Tampa BDNF Val66Met genotypes and the biopsychosocial Scale for Kinesiophobia [15]; the Pain Catastrophizing phenotypes in patients with CLBP. The Val66Met Yamada et al. Advances in Rheumatology (2021) 61:24 Page 3 of 8 Table 1 Characteristics of the sample studied The averages of the disabilities of the patients in the present study due to CLBP were classified as moderate Variable Mean SD from the RMDQ. It is recommended to consider an as- Age 46.24 14.27 sessment of the multidimensional nature of CLBP in the Subjective assessment of stress 5.84 2.39 management of pain [25]. This could be physical (for ex- BMI 26.82 5.14 ample, disability and body composition), psychological Total CSI score 49.6 14.39 (for example, kinesiophobia, fear-avoidance, pain cata- Total RMDQ score 15.7 5.3 strophizing, pain self-efficacy, depression, anxiety, and BIP pain intensity sleep quality), and/or social (social functioning and work absenteeism) factors. Worst 6.49 2.59 Most of the evaluated patients presented overweight/ Least 3.16 2.45 obesity conditions. Adiposity may modulate pain Average 5.37 2.26 through peripheral sensitization from increased systemic Now 4.56 3.02 inflammation [26]. In addition, it was observed that the BIP interference increased fat infiltration of the paraspinal musculature General activity 5.83 3.34 could be associated with a compromised function of the muscles that control and support the low back [27, 28]. Mood 5.5 3.52 The findings from the BIP data also showed that the Walking 5.41 3.32 worst pain affected the normal work of the patients, Normal work 5.97 3.7 restricting the performance of the activities of daily Relations 3.58 3.34 living. Sleep 5.44 3.46 The individuals in the present study reported being Enjoyment of life 4.48 3.63 physically inactive. The relationship between a cluster of unhealthy lifestyle behaviors (smoking, alcohol drinking, Σ pain-body regions 8.95 6.04 physical activity, weight control, breakfast, snacking, and Total Tampa score 45.61 7.82 sleep) and low back pain (LBP) was investigated in a Total PCS score 2.17 1.2 cross-sectional study of over 400,000 Japanese adults PCS rumination 2.68 1.33 showing an association of this cluster with an increased PCS helplessness 1.53 1.31 risk of LBP, regardless of age and BMI [29]. Moreover, HADS-anxiety 9.04 3.47 chronic pain is at least partly attributed to a sedentary and inactive lifestyle and it could be recognized as a HADS-depression 6.91 3.98 lifestyle-related disease. Physical activity/inactivity may BMI body mass index, BPI the brief inventory of pain, CSI central sensitization inventory, HADS hospital anxiety and depression scale, PCS pain also determine the genetic/epigenetic and neural factors catastrophizing scale, RMDQ Rolland-Morris disability questionnaire, SD encoded in the brain [30]. A single session of exercise standard deviation and regular physical activity induce changes in the genes polymorphism is the most studied in the BNDF gene that regulate the nociceptive processes, the learning of and it has been investigated in several pathological fear, and the stress responses, as well as those that are conditions in humans [18–20]. The Val66Met poly- involved in the pathophysiology of chronic diseases [31]. morphism has also been associated with the methyla- In the current study, the mean of the total scores in tion patterns, and it is being related to the epigenetic Tampa was moderate. Fear can be learned through asso- regulation of the BDNF gene [21]. From a biological ciative learning. Previous study reported that condition- perspective, it is known that the responses of an or- ing to fear was able of inducing a rapid increase in ganism’s experience to the external environment can methylation of the BDNF gene in the hippocampus, and be reflected in the epigenetic changes. Thus, the gene it occurred during the consolidation of fear [32]. It is expression could also be regulated by the epigenetic well known that the fear and the avoidance of particular modifications to the chromatin structure and the pat- movements could add to a disability, but the assessment terns of DNA methylation. These adaptations can and removal of these barriers to movement might, there- modify, among others, neuronal morphology and the fore, reduce the disability [33]. A psychological factor activity to produce changes in behavior [22, 23]. Al- that distinctly predicts changeability in the perception of terations in the chromatin structure represent mecha- pain and the development of moderate kinesiophobia is nisms by which pain can be converted gradually and pain catastrophizing [34]. In the present study, the CLBP progressively into the pathological processes of neuro- patients presented scores that suggested rumination and inflammation, central sensitization, and ultimately, helplessness thoughts, besides mild anxiety and central chronic pain syndromes [24]. sensitization. Anxiety and stress predict chronic pain in Yamada et al. Advances in Rheumatology (2021) 61:24 Page 4 of 8 Table 2 Comparison of the quantitative variables according to the BDNF Val66Met genotypes Variable Val/ Val (n = 81) Val/Met (n = 26) P-value Age 46.2 ± 14.3 46.5 ± 14.6 0.73 Subjective assessment of stress 5.9 ± 2.5 5.8 ± 2.1 0.62 BMI 27.1 ± 5.2 26.4 ± 4.9 0.47 Total CSI score 50.3 ± 14.6 48.0 ± 13.9 0.50 Total RMDQ score 15.6 ± 5.5 15.8 ± 4.8 0.99 BIP pain intensity Worst 6.5 ± 2.5 6.4 ± 2.9 0.97 Least 3.2 ± 2.4 2.8 ± 2.4 0.42 Average 5.4 ± 2.1 5.2 ± 2.8 0.52 Now 4.6 ± 3.0 4.2 ± 3.0 0.45 BIP interference General activity 5.9 ± 3.4 5.4 ± 3.2 0.44 Mood 5.7 ± 3.5 4.9 ± 3.7 0.36 Walking 5.4 ± 3.2 5.3 ± 3.5 0.96 Normal work 6.1 ± 3.8 5.3 ± 3.4 0.16 Relation 3.6 ± 3.4 3.5 ± 3.2 0.92 Sleep 5.4 ± 3.6 5.3 ± 3.2 0.76 Enjoyment of life 4.3 ± 3.7 5.1 ± 3.5 0.34 Summation of pain body regions 9.0 ± 5.0 8.7 ± 8.8 0.07 Total Tampa score 45.6 ± 8.1 45.9 ± 7.2 0.87 Total PCS score 2.2 ± 1.2 1.9 ± 1.1 0.32 PCS rumination 2.8 ± 1.4 2.3 ± 1.1 0.18 PCS helplessness 1.5 ± 1.3 1.4 ± 1.4 0.51 HADS anxiety 9.3 ± 3.5 8.4 ± 3.5 0.52 HADS depression 7.1 ± 3.8 6.6 ± 4.4 0.35 Values are shown as mean ± standard deviation BMI body mass index, BPI the brief inventory of pain, CSI central sensitization inventory, HADS hospital anxiety and depression scale, PCS pain catastrophizing scale, RMDQ Rolland-Morris disability questionnaire P-value for the Mann-Whitney test the long term and they might mediate the vulnerability The importance of behavioral approaches to back pain to pain [35]. Thus, there is plausibility that the extent of management does not preclude the continuing need to central sensitization symptoms in people with non- investigate mechanisms and the potential biological de- specific LBP might be associated with the pre-morbid terminants of non-specific low back pain [40]. The rela- trait anxiety sub-types and the abnormal trait sensory tive importance of the genetic factors in human processing profiles [36, 37]. Moreover, depression and musculoskeletal pain conditions, such as CLBP, painful anxiety are barriers to treatment adherence in various temporomandibular joint disorders, fibromyalgia, and chronic pain conditions, such as low back pain [38]. chronic widespread pain, is becoming clearer. Several Although 74% of the patients in the present study polymorphisms in the genes are contributing to seroto- reported themselves to be active/employed, they de- nergic and adrenergic pathways that are associated with scribed the pain during a month at an intense level musculoskeletal pain [41]. Despite studies demonstrating and with chronicity for up to 13 months. This is im- evidence that the BDNF Val66Met polymorphism influ- portant since CLBP is also considered responsible for ences the cortical processing of experimental electrical absenteeism at work, and with high rates of disability, pain stimuli in an indirect manner [4], or in pain cata- generating high costs for the health system, social se- strophizing [42], the findings in the present study did curity, and society in general [39]. Moreover, non- not show the influence of this polymorphism in chronic opioids were the main medication used, and most of pain complaints. the patients reported a modest relief of the pain with Certain limitations must be considered in the inter- the medication. pretation of the current study’s findings. First, the Yamada et al. Advances in Rheumatology (2021) 61:24 Page 5 of 8 Table 3 Comparison of the qualitative variables according to the BDNF Val66Met genotypes Genotype Val/ Val Val/Met P-value N (%) N (%) Gender Female 45 (55.6) 16 (61.5) 0.59 Male 36 (44.4) 10 (38.6) Civil status Living alone 42 (51.8) 11 (42.3) 0.40 Living with partner 39 (48.2) 15 (57.7) Ethnicity White 14 (18.2) 8 (34.8) Brown 46 (59.7) 13 (56.5) 0.14 Black 17 (22.1) 2 (8.7) Schooling Until high school 63 (77.8) 16 (64.0) 0.17 Complete high school 18 (22.2) 9 (36.0) Have children No 19 (23.5) 6 (23.1) 0.97 Yes 62 (76.5) 20 (76.9) Healthy Good, very good, or great 35 (44.3) 12 (46.1) 0.87 Regular, bad, or lousy 44 (55.7) 14 (53.9) Chronicity pain 3–12 months 21 (25.9) 5 (19.2) 13–60 months 27 (33.3) 13 (50.0) 0.31 > 60 months 33 (40.8) 8 (30.8) Pain intensity Least 8 (9.9) 4 (15.4) Moderate 14 (17.3) 3 (11.5) 0.62 Intense 59 (72.8) 19 (73.1) Pain duration in the month Intermittent 37 (46.2) 15 (65.2) 0.11 Constant 43 (53.8) 8 (34.8) Comorbidities No 46 (56.8) 16 (61.5) 0.67 Yes 35 (43.2) 10 (38.5) Physical activity Inactive 55 (67.9) 18 (69.2) Insufficiently active 8 (9.9) 4 (15.4) 0.80 Moderately active 13 (16.0) 3 (11.5) Vigorously active 5 (6.2) 1 (3.9) Smoking No 68 (91.9) 21 (91.3) 0.93 Yes 6 (8.1) 2 (8.7) Alcoholism No 66 (89.2) 22 (95.7) 0.35 Yes 8 (10.8) 1 (4.3) Yamada et al. Advances in Rheumatology (2021) 61:24 Page 6 of 8 Table 3 Comparison of the qualitative variables according to the BDNF Val66Met genotypes (Continued) Genotype Val/ Val Val/Met P-value N (%) N (%) Satisfaction Unsatisfied or a little satisfied 33 (51.6) 9 (40.9) 0.39 Satisfied or much satisfied 31 (48.4) 13 (59.1) Occupational situation Active/employed 62 (76.5) 18 (69.2) 0.45 Unemployed 19 (23.5) 8 (30.8) Low back pain in family history No 36 (44.4) 12 (46.2) 0.88 Yes 45 (55.6) 14 (53.8) Overweight/obesity No 32 (41.0) 11 (42.3) 0.91 Yes 46 (59.0) 15 (57.7) CSI No 14 (17.3) 4 (15.4) 0.82 Yes 67 (82.7) 22 (84.6) RMDQ No 28 (34.6) 9 (34.6) 0.97 Yes 53 (65.4) 17 (65.4) Medication Non opioid 33 (62.3) 12 (80.0) 0.20 Weak opioid 20 (37.7) 3 (20.0) Medication frequency Every 6 h 35 (66.0) 7 (50.0) 0.27 If there is pain 18 (34.0) 7 (50.0) Start of medication 12 months ago 32 (68.1) 8 (80.0) 13–60 months 7 (14.9) 1 (10.0) 0.75 More than 60 months 8 (17.0) 1 (10.0) Relief of pain with medication 50% relief 32 (62.8) 5 (45.5) 0.29 More than 50% relief 19 (37.2) 6 (54.5) Tampa score Light 7 (8.6) 2 (7.7) Moderate 47 (58.1) 14 (53.8) 0.89 Critical 27 (33.3) 10 (38.5) HADS-anxiety No 34 (42.0) 11 (42.3) 0.98 Yes 47 (58.0) 15 (57.7) HADS-depression No 53 (65.4) 20 (76.9) 0.27 Yes 28 (34.6) 6 (23.1) CSI central sensitization inventory, HADS hospital anxiety and depression scale, RMDQ Rolland-Morris disability questionnaire P-value for the Chi-square test Yamada et al. Advances in Rheumatology (2021) 61:24 Page 7 of 8 statistical power of the sample size that was analyzed Author details Molecular and Cellular Biology Applied to Health, Lutheran University of was limited. Second, this was a cross-sectional study, Brazil (ULBRA), Canoas, Brazil. Human Molecular Genetics Laboratory, which might limit the causality identification of the 3 Lutheran University of Brazil (ULBRA), Canoas, Brazil. Biochemical and demographic and clinical variables that were investi- Molecular Pharmacology from the Federal University of Minas Gerais, Belo Horizonte, Brazil. gated. Third, to have a better understanding of the role of BDNF in CLBP, it would be important to investigate Received: 15 February 2021 Accepted: 27 April 2021 the correlation between the genotypes and the serum levels. References 1. Becker A, Held H, Redaelli M, Strauch K, Chenot JF, Leonhardt C, et al. Low Conclusion back pain in primary care: costs of care and prediction of future health care The present study showed no association between the utilization. Spine. 2010;35(18):1714–20. https://doi.org/10.1097/brs.0b013e31 81cd656f. Val66Met BDNF polymorphism with the clinical and 2. Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial biopsychosocial characteristics in patients with CLBP. approach to chronic pain: scientific advances and future directions. Psychol However, further studies are still needed to elucidate if Bull. 2007;133(4):581–624. https://doi.org/10.1037/0033-2909.133.4.581. 3. Siddall PJ, Cousins MJ. Persistent pain as a disease entity: implications for the BDNF Val66Met polymorphism could influence clinical management. Anesth Analg. 2004;99(2):510–20. https://doi.org/1 other distinct subjective pain experience outcomes in 0.1213/01.ANE.0000133383.17666.3A. different samples with CLBP. 4. Vossen H, Kenis G, Rutten B, van Os J, Hermens H, Lousberg R. The genetic influence on the cortical processing of experimental pain and the Abbreviations moderating effect of pain status. PLoS One. 2010;5(10):e13641. https://doi. BDNF: Brain-derived neurotrophic factor; BIP: Brief inventory of pain; org/10.1371/journal.pone.0013641. BMI: Body mass index; CLBP: Chronic low back pain; CSI: Central Sensitization 5. MacGregor AJ, Andrew T, Sambrook PN, Spector TD. Structural, Inventory; CEULP/ULBRA: Lutheran University Center of Palmas; psychological, and genetic influences on low back and neck pain: a study HADS: Hospital anxiety and depression scale; LBP: Low back pain; of adult female twins. Arthritis Rheum. 2004;51(2):160–7. https://doi.org/10.1 Met: Methionine; NAC: Community service center; PCR: Polymerase chain 002/art.20236. reaction; PCS: Pain catastrophizing scale; RMDQ: Roland Morris disability 6. Omair A, Mannion AF, Holden M, Fairbank J, Lie BA, Hägg O, et al. Catechol- questionnaire; SD: Standard deviation; SNP: Single nucleotide polymorphism; O-methyltransferase (COMT) gene polymorphisms are associated with ULBRA: Lutheran University of Brazil; Val: Valine baseline disability but not long-term treatment outcome in patients with chronic low back pain. Eur Spine J. 2015;24(11):2425–31. https://doi.org/10.1 007/s00586-015-3866-5. Acknowledgements 7. Harrisberger F, Smieskova R, Schmidt A, Lenz C, Walter A, Wittfeld K, et al. The authors would like to thank the patients who participated in the study. BDNF Val66Met polymorphism and hippocampal volume in neuropsychiatric disorders: a systematic review and meta-analysis. Neurosci Authors’ contributions Behav Rev. 2015;55:107–1. https://doi.org/10.1016/j.neubiorev.2015.04.017. A.S. Yamada, A.H. de Souza, and D. Simon designed the study. A.S. Yamada 8. Generaal E, Milaneschi Y, Jansen R, Elzinga BM, Dekker J, Penninx BW. The and C. Ferraz collected the data. A.S. Yamada and D. Simon performed the brain-derived neurotrophic factor pathway, life stress, and chronic multi-site statistical analyses. A.S. Yamada, A.H. de Souza, and D. Simon interpreted and musculoskeletal pain. Mol Pain. 2016;12:1744806916646783.https://doi.org/1 discussed the results. A.S. Yamada and D. Simon wrote the paper. A.S. 0.1177/1744806916646783. Yamada, F.T.T. Antunes, C. Ferraz, A.H. de Souza, and D. Simon contributed to 9. Tian Y, Liu X, Jia M, Yu H, Lichtner P, Shi Y, et al. Targeted genotyping the final version of the manuscript. All of the authors have reviewed and identifies susceptibility locus in brain-derived Neurotrophic factor gene for approved the final version of the article, including the authorship list. chronic postsurgical pain. Anesthesiology. 2018;128(3):587–97. https://doi. org/10.1097/ALN.0000000000001977. Funding 10. Desconsi MB, Bartz PT, Fiegenbaum TR, Candotti CT, Vieira A. Treatment of This research was supported by grants from the Brazilian agency patients of nonspecific chronic low back pain by physical therapists: a cross- Coordination for the Improvement of Higher Education Personnel from Brazil sectional study. Fisioter Pesqui. 2019;26(1):15–21. https://doi.org/10.1590/1 (CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; 809-2950/17003626012019. Finance Code 001). The funding source had no involvement in the study 11. Dionísio GH, Salermo VY, Padilha A. Central sensitization and beliefs among design, collection, analysis and interpretation of data, writing of the report, patients with chronic pain in a primary health care unit. BrJP. 2020;3(1):42–7. and the decision to submit the article for publication. https://doi.org/10.5935/2595-0118.20200010. 12. Ferreira KA, Teixeira MJ, Mendonza TR, Cleeland CS. Validation of brief pain Availability of data and materials inventory to Brazilian patients with pain. Support Care Cancer. 2011;19(4): The datasets used and/or analysed during the current study are available 505–11. https://doi.org/10.1007/s00520-010-0844-7. from the corresponding author on reasonable request. 13. Caumo W, Antunes LC, Elkfury JL, et al. The central sensitization inventory validated and adapted for a Brazilian population: psychometric properties Declarations and its relationship with brain-derived neurotrophic factor. J Pain Res. 2017; 10:2109–22. https://doi.org/10.2147/JPR.S131479. Ethics approval and consent to participate 14. Nusbaum L, Natour J, Ferraz MB, Goldenberg J. Translation, adaptation and This study was approved by the Research Ethics Committee of the Lutheran validation of the Roland-Morris questionnaire - Brazil Roland-Morris. Braz J University of Brazil (ULBRA), under protocol number 2.254.800. All subjects Med Biol Res. 2001;34(2):203–10. https://doi.org/10.1590/S0100-879X2001 signed the informed consent form. 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