Short and Long-Term Effects of Balneotherapy on Musculoskeletal Pain and Fatigue Associated with Stress

Short and Long-Term Effects of Balneotherapy on Musculoskeletal Pain and Fatigue Associated with Stress | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Short and Long-Term Effects of Balneotherapy on Musculoskeletal Pain and Fatigue Associated with Stress Lolita Rapoliené, Lolita Rapolienė, Giedrė Taletavičienė, Arvydas Martinkėnas, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5989141/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jun, 2025 Read the published version in International Journal of Biometeorology → Version 1 posted 4 You are reading this latest preprint version Abstract Background Balneotherapy has emerged as a promising therapeutic approach for managing musculoskeletal diseases (MSDs), offering evidence-based benefits in reducing pain, enhancing mobility, and improving quality of life. Objective This study aims to evaluate the effects of balneotherapy on musculoskeletal pain, fatigue, and associated symptoms in individuals experiencing stress. Methods A six-month randomized controlled parallel-group study was conducted at six medical spa centers in Lithuania, involving 373 patients with stress levels ≥ 3. Participants underwent 6–11 days outpatient or inpatient balneotherapy programs, with MSDs-related outcomes assessed at a six-month follow-up. Statistical analyses were performed using SPSS Version 28. Results Balneotherapy led to significant improvements in multiple parameters. Pain frequency and intensity decreased, with effect sizes ranging from small to large, accompanied by notable reductions in muscle spasms and tension. Spine mobility improved, pain medication use decreased, and hand strength increased following the 11-days medical spa treatment. Fatigue levels declined, while sleep quality and overall quality of life improved significantly, with effect sizes ranging from medium to large. Long-term benefits in muscle tension, spine mobility, fatigue, and quality of life were observed for up to six months. Comparative analysis indicated that balneotherapy was more effective than both non-treatment and nature-based therapy alone. Conclusion Balneotherapy, particularly when combined with nature-based interventions or inpatient approaches, effectively improves musculoskeletal health, with benefits lasting up to six months. balneotherapy fatigue musculoskeletal pain peloidotherapy spa therapy sleep Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Musculoskeletal disorders (MSDs) encompass a diverse group of over 150 conditions affecting the joints, muscles, bones, ligaments and tendons, often leading to temporary or permanent impairments in function (WHO 2022 ). In 2021, MSDs accounted for 367.2 million incident cases and 1.69 billion prevalent cases globally, with disability-adjusted life years (DALYs) increasing significantly between 1990 and 2021. These conditions substantially impact quality of life, contribute to high healthcare costs, and are a leading cause of disability (Liu et al. 2022 ). MSDs are among the most common reasons for seeking healthcare, presenting with symptoms such as musculoskeletal (MSK) pain, stiffness, joint noises, reduced mobility, fatigue, numbness, and instability (Villa-Forte 2024 ). They are closely associated with functional disability (Koechlin et al. 2019 ; Raja et al. 2020 ), emotional distress, mood and anxiety disorders, depressive conditions, and reduced quality of life (Heikkinen et al. 2019 ). The relationship between stress and MSK pain is complex, involving physiological, neurological, and psychological interactions (Wyns et al. 2023 ; Bonanno et al. 2024 ). Given the multifactorial nature of MSDs, management strategies focus on pain relief, improving mobility and function, reducing inflammation, preventing disease progression, strengthening muscles, and enhancing overall quality of life (El-Tallawy et al 2021 ). In recent years, balneotherapy (BT), also referred to as spa therapy (ST), has gained prominence in several countries, including European nations, Turkey, Israel, China, and Japan. While the terms are often used interchangeably, clear distinctions are necessary for scientific research and systematic reviews (Fioravanti et al. 2017 ; Gutenbrunner et al. 2010 ). BT primarily involves the therapeutic use of natural thermal mineral waters, additive baths, peloids, and various environmental elements. It is considered the core intervention within ST, which also encompasses non-balneological treatments (Karagülle et al. 2021; Rat et al. 2020). An increasing body of scientific evidence supports the benefits of BT beyond its traditional applications. Studies have highlighted its effectiveness in treating conditions such as obesity, metabolic disorders, sleep disturbances, mental health conditions, long-COVID, and cancer rehabilitation (Fioravanti et al. 2024 ; Koçak et al. 2020 ; Manica et al. 2024 ; Clark-Kennedy et al. 2021 ; Yang et al. 2018 ; Rapolienė et al. 2016 ; Maccarone et al. 2021; Reger et al. 2022 ). In the context of MSDs, BT has been shown to reduce pain, improve mobility, and enhance quality of life (Bai et al. 2019 ; Fioravanti et al. 2020; Bernetti et al. 2020 ; Facchini et al. 2023 ). These therapeutic benefits are attributed to the mineral composition, temperature, and mechanical properties of thermal waters, along with the spa environment, which collectively exert anti-inflammatory, antioxidant, immunomodulatory, and regenerative effects (Antonelli et al. 2018a; Gálvez et al. 2024 ; Silva et al. 2023 ). Recognized by organizations such as the World Health Organization (WHO) and the Osteoarthritis Research Society International (OARSI), BT is increasingly regarded as a valuable complementary approach to conventional treatments (Bernetti et al. 2020 ; WHO 2022 ). While BT is well-established for MSDs management, its effects on individuals experiencing moderate stress remain underexplored. The relationship between stress and MSK pain, particularly in individuals without diagnosed rheumatological conditions, is not fully understood, limiting the development of targeted therapeutic approaches (Abousha et al. 2024). This study aims to investigate the role of BT in alleviating MSD-related symptoms in individuals experiencing stress, assessing whether stress contributes to MSK health outcomes. By comparing different BT modalities and their effects on MSK pain and associated symptoms, this research seeks to advance personalized treatment strategies that address both the physical and emotional aspects of MSDs. In particular, the objective of this study was to evaluate the effects of BT on MSK pain, fatigue, and associated symptoms in individuals experiencing stress. By examining these outcomes, the research aims to provide scientific insights into the efficacy of BT as a complementary therapy for managing stress-related MSK issues and enhancing overall well-being. Materials and methods Study Design and Setting This research employed a multicenter, randomized controlled, single-blind (for researchers) parallel group design. The study was conducted from December 2022 to August 2023, with treatment provided between January and February 2023. It was carried out across two clusters—Klaipeda and Druskininkai—at six medical spa centers in Lithuania: Gradiali (Palanga), Atostogų Parkas (Kretingos region), Egle (Druskininkai), Draugystė (Druskininkai), Tulpė (Birštonas), and Versmė (Birštonas). The research adhered to the Declaration of Helsinki guidelines and received approval from the Kaunas Regional Research Ethics Committee (approval code BE-2-87, date 28/11/2022). The study was registered on ClinicalTrials.gov (Identifier: NCT06018649, registration date: 30/08/2023). Informed consent was obtained from all participants prior to enrollment. BT was administered, and the entire study was conducted in accordance with the principles of good clinical practice. Study participants, randomization, and group allocation A probabilistic nested (cluster) sampling method was used, with participants selected through a multi-stage, criterion-based process. Inclusion criteria included individuals aged 18–65 years with moderate stress intensity (above 3 points on a 10-point Visual Analog Scale (VAS)), pain of at least 1 point on Numerical Rating Scale (NRS), and residency near selected medical spa centers or the ability to travel to the service centers. Exclusion criteria included exacerbated or uncontrolled chronic diseases, active infections, malignant tumors, recent surgery or major trauma within the past year, prior BT within the last 3 months, pregnancy or lactation, bleeding disorders, severe mental conditions, and difficulties accessing the study area. All participants provided written informed consent before participation, which outlined the study's purpose, terms, and procedures. In total, 1137 individuals were assessed for eligibility, with 194 participants from Klaipeda and 179 from Druskininkai meeting the inclusion criteria. Participants who met eligibility criteria were coded and assigned to one of the study clusters in Klaipeda or Druskininkai, and then randomized into different treatment groups (1–6) using the SPSS function "Random Sample of Cases‘ which allows for the selection of a subset of cases based on an approximate percentage or an exact number. This process ensured unbiased distribution across the study arms. Group composition was evaluated for age, gender, and baseline stress levels. TreatmentGroups The study included multiple parallel intervention groups, which were named according to the abbreviations of the treatment modalities: 6ABT: 6 days of outpatient BT in Medical Spa; 11ABT: 11 days of outpatient BT in Medical Spa; 11ABTNT: 11 days of outpatient BT in Medical Spa with self-guided Nature Therapy (NT) procedures; 11BTS: 11 days of inpatient BT in Medical Spa (residential treatment); 11NT: 11 days of outpatient self-guided Nature therapy (NT) procedures; 11C: 11 days control group (no treatment). All BT groups, except for the 11BTS group, received outpatient BT treatment in the medical spa while maintaining their usual work and daily routines. Participants in the 11BTS group stayed at the medical spa for the entire treatment period and underwent all procedures as inpatients, without receiving any additional treatment. Participants in the 11NT group received initial education during the first session guided by a specialist, along with written instructions for subsequent self-guided nature therapy. They also received daily Short Message Service (SMS) reminders to perform the prescribed NT procedures. Treatment Protocols The BT treatments included a 20-minute session in 29–31°C tap water pools with light activities, a 20-minute bath in mineral water at 36–38°C, a 20-minute sapropel wrap at 38–40°C, and a 25-minute salt therapy session (either inhalation or a salt chamber). Instructions for each BT procedure were provided before the start of the sessions. Following each treatment, participants were given a 20-minute rest period for relaxation. NT, developed by researchers with a focus on physiotherapy, green therapy, and mindfulness, consisted of a 45-minute walk in nature, strength exercises, sensory experiences, aromatherapy, and mindfulness activities. The mineral waters used in the treatments had total mineralization levels ranging from 17 to 82 g/L and were rich in chloride, sodium, calcium, magnesium, and sulfates, with pH values between 5.71 and 7.54. However, the gas content was low. In three research centers, the mineral water was diluted with freshwater. The specific baths used included: "Versmė" (22.2 g/L, high mineralization), "Tulpė" (21.6 g/L, high mineralization), "Atostogų parkas" (82.4 g/L, brine), "Draugystė" (27 g/L, high mineralization), "Eglė" (12 g/L, medium mineralization), and "Gradiali" (8.3 g/L, medium mineralization). The peloids (peat or sapropel) used in the treatments consisted of 60–80% reed-origin material, with pH values ranging from 6.4 to 7.0, moisture content between 76% and 95%, and ash content ranging from 8–86%. Organic matter content varied from 14–91%, with the presence of humic and fulvic acids. The peloids were rich in calcium, magnesium, chloride, and bicarbonates, while heavy metal concentrations remained below the limits set by soil regulations. Detailed characteristics of the resources are provided in Online Resource 1. Study outcomes and instruments The primary outcomes of the study were MSK pain and fatigue. Secondary outcomes included muscle tension, spinal mobility, hand strength, frequency of muscle spasms (defined as sudden, involuntary muscle contractions), use of pain medications, sleep quality, and overall quality of life. Pain intensity was assessed using the Numerical Rating Scale (NRS), where participants rated their pain from 0 (no pain) to 10 (worst pain) (Delgado et al., 2018 ). Participants reported their current pain level. Pain frequency, muscle spasms, pain medication (acetaminophen, NSAIDs, etc.) use, and quality of life were evaluated using 4- and 5-point Likert scales (Joshi et al., 2015 ). The response categories for pain frequency and muscle spasms were: 1 – "never," 2 – "rarely," 3 – "frequently," and 4 – "always“. Pain medication use use (acetaminophen, NSAIDs [ibuprofen, naproxen, diclofenac, etc.], gabapentinoids [gabapentin, pregabalin], opioids, and their combinations) was rated on a scale from 1 – "never" to 5 – "daily". Quality of life was assessed on a scale from 1 – "excellent" to 5 – "very poor." Muscle tension was evaluated through palpation of the neck and shoulder area ( m.trapezius ), lower back (lumbar extensor muscles), and thighs (posterior thigh muscles), rated on a scale from 0 (low tone) to 4 (rigid/stiff muscles). Hand strength was measured using a dynamometer, a standardized method for assessing muscle strength (Quattrocchi, 2024). Spinal mobility was assessed using the Fingertip-to-Floor Distance (FFD) test, measured with a metal ruler, where lower values indicated better mobility (Guo, 2023). Fatigue was assessed using the Fatigue Assessment Scale (FAS), a 10-item scale measuring physical and mental exhaustion, with responses ranging from 1 ("never") to 5 ("always") (Michielsen, 2003). The total FAS score ranged from 10 (lowest fatigue) to 50 (highest fatigue), with scores of 22–34 indicating mild to moderate fatigue. Sleep quality was evaluated using the Single item Sleep Scale (SQS), where responses ranged from 0 ("terrible") to 10 ("excellent") (Snyder, 2018). Written consent for the scale's use was obtained, and the scale was validated through double translation and expert review. Side effect frequencies were determined during the study based on information reported by trial participants through prospective assessments (prespecified symptom inventories), which offer greater sensitivity and consistency in detecting side effects of specific treatments (Katz NP, 2012 ). The therapy safety survey asked participants to review a list of symptoms and potential side effects related to their treatments. They rated any unwanted effects from mineral water, mud, or salt therapies, including their frequency, severity (on a Likert scale from 1–5), and duration (from brief to lasting after treatment). Overall safety was assessed on a 5-point scale, ranging from "extremely safe" to "not safe." Assessment periods The study's observation periods were divided into baseline (T0: January 27–29), post-treatment (T1: February 5 and 11–12), 3-month follow-up (T2: May 6 and 13–14), and 6-month follow-up (T3: August 5 and 12–13) assessments. Statistical Analysis Sample size for statistically significant comparisons was calculated using the G*Power program based on previous studies (Rapoliene et al., 2016). For an effect size of 0.4, 55 participants per group were planned. Descriptive statistics (means, SDs, 95% CIs) were calculated, and t-tests were used for continuous variables, while chi-square tests were applied for categorical data. ANOVA with Tukey’s HSD assessed group differences, and paired t-tests compared baseline and post-treatment values. Long-term effects were analyzed using general linear model (GLM) Repeated Measures, with Bonferroni tests for mean differences. Non-parametric tests were used for non-normally distributed data (Friedman test, Mann-Whitney U, Kruskal-Wallis test Friedman). Effect size was estimated using Cohen’s d ( d ) and r (small: 0.2, medium: 0.5, large: 0.8), and correlations were assessed with Spearman’s and Kendall’s tau. Significance was set at p ≤ 0.05, using SPSS Version 28. Results The flow diagram of study is showen in Fig. 1 . After the treatment period, data from 340 participants were included in the analysis. For the 6-month follow-up analysis, data from 235 participants who participated in all examinations, were analyzed. The characteristics of the study participants are detailed in Table 1. Table 1 . The characteristics of participants in study groups. Parameters/groups 6ABT 11ABT 11ABTNT 11BTS 11NT 11C P, χ 2, No of participants 59 63 63 61 43 51 340 Age, y, N(SD) 45.53 (9.96) 48.81 (11.49) 46.57 (9.92) 48.77 (10.69) 44.74 (12.93) 45.77 (10.99) 0.209* Gender Men, N (%) 13 (22.8) 7 (12.7) 20 (33.33) 17 (27.42) 7 (16.67) 12 (24.49) 0.147 Women, N (%) 44 (77.2) 48 (87.3) 40 (67.2) 45 (72.58) 35 (83.33) 37 (75.51) Marital status Married, N (%) 44 (77.2) 36 (65.5) 41 (68.3) 35 (59.3) 26 (66.7) 37 (75.5) 0.246 Single, N (%) 5 (8.8) 9 (16.4) 4 (6.7) 6 (10.2) 3 (7.7) 8 (16.3) Divorced, N (%) 7 (12.3) 7 (12.7) 11 (8.3) 15 (25.4) 6 (15.4) 3 (6.1) Widow, N (%) 1 (1.8) 3 (5.5) 4 (6.7) 3 (5.1) 4 (10.3) 1 (2) Education Incomplete secondary (%) 0.085 Secondary (%) 3 (5.3) 8 (14.5) 10 (16.7) 2 (3.3) 0 (0.0) 8 (16.3) Higher (%) 5 (8.8) 7 (12.7) 7 (11.7) 8 (13.3) 2 (5.0) 3 (6.1) College (%) 10 (17.5) 7 (12.7) 15 (25.0) 13 (21.7) 8 (20.0) 5 (10.2) University, N (%) 39 (68.4) 33 (60.0) 28 (46.7) 37 (61.7) 30 (75.0) 33 (67.3) Work sector Farming, N (%) 1 (1.8) 1 (1.9) 1 (1.7) 1 (1.7) 0 (0.0) 2 (4.1) 0.528 Industry, N (%) 6 (10.5) 2 (3.7) 5 (8.3) 7 (11.7) 2 (5.0) 3 (6.1) Clerk, N (%) 29 (50.9) 25 (46.3) 27 (45.0) 35 (58.3) 22 (55.0) 22 (44.9) Service, N (%) 16 (28.1) 20 (37.0) 21 (35.0) 12 (20.0) 15 (37.5) 21 (42.9) Studying, N (%) 1 (1.8) 3 (5.6) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.0) Housewife, N (%) 2 (3.5) 0 (0.0) 2 (3.3) 1 (1.7) 0 (0.0) 0 (0.0) Pensioner, N (%) 2 (3.5) 3 (5.6) 3 (5.0) 4 (6.7) 1 (2.5) 0 (0.0) Unemployed, N (%) 0 (0.0) 0 (0.0) 1 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) Work style Sedentary, N(%) 31 (54.4) 23 (41.8) 28 (48.3) 30 (51.7) 22 (55.0) 18 (37.5) 0.897 Sedentary with some physical, N (%) 14 (24.6) 20 (36.4) 19 (32.8) 18 (31.0) 10 (25.0) 19 (39.6) Physical, N(%) 8 (14.0) 10 (18.2) 8 (13.8) 9 (15.5) 7 (17.5) 9 (18.8) Intense physical, N (%) 4 (7.0) 2 (3.6) 3 (5.2) 1 (1.7) 1 (2.5) 2 (4.2) Body mass index (BMI) BMI 26,64 (5,26) 26,31 (4,95) 26,67 (5,5) 27,10 (4,48) 25,62 (4,5) 26,98 (5,54) 0.475 * Co-morbidities Cardiovascular, N (%) 9 (2.6) 9 (2.6) 9 (2.6) 11 (3.2) 4,0 (1.2) 10,0 (2.9) N/A Musculoskeletal, N (%) 4 (1.2) 6 (1.8) 5 (1.5) 9 (2.6) 3 (0.9) 10 (2.9) Gastrointestival, N (%) 3 (0.9) 4 (1.2) 3 (0.9) 5 (1.5) - 2 (0.6) Nervous, N (%) 5 (1.5) 4 (1.2) 4 (1.2) 1 (0.3) 2 (0.6) 5 (1.5) Endocrine, N (%) 5 (1.5) 8 (2.4) 5 (1.5) 8 (2.4) 3 (0.9) 6 (1.8) Pulmonary, N (%) 1 (0.3) 2 (0.6) 2 (0.6) 4 (1.2) 2 (0.6) 2 (0.6) Skin, N (%) 2 (0.6) 5 (1.5) 8 (2.4) 3 (0.9) 1 (0.3) 7 (2.0) Urogenital, N (%) 2 (0.6) 2 (0.6) 4 (1.2) 2 (0.6) 3 (0.9) 2 (0.6) Allergy, N (%) 2 (0.6) 7 (2.0) 8 (2.4) 4 (1.2) 3 (0.9) 1 (0.3) Abbreviations: 6ABT- 6-days outpatient BT group, 11ABT- 11-days outpatient BT group, 11ABTNT- 11-days outpatient BT combined with NT group, 11BTS- 11-days inpatient BT group, 11NT- 11-days NT group, 11C- 11-days control group; p- the significance of baseline difference between groups (2-sided)s; χ 2,- Pearson chi-square, N/A- not applicable because of small number of cases; *ANOVA. There were no significant differences between groups in terms of sociodemographic and clinical characteristics. No differences in MSK pain were observed between the groups in the post-treatment and follow-up analyses (p = 0.687 and p = 0.680, respectively, according to the Kruskal-Wallis test). 1. The short-term effect of BT 1.1. The impact of BT on MSK pain At T0, mean pain frequency scores ranged from 2.29 to 2.53 (Online Resource 2). After treatment (T1), BT groups showed significant reductions (1.83–2.27), with the largest improvement (28%) in the 6-days BT group ( r = 0.9, p 0.05). Pain intensity significantly decreased in all BT groups ( p < 0.001), with reductions of 45–68% and the largest effect in 11-days BT with NT group. Mean differences ranged from 1.36 to 2.32 points (NRS). 1.2. The impact of BT on MSK- associated symptoms Muscle spasms decreased by 18–29% in BT groups ( p < 0.005, r = 0.4–0.8), with the largest reduction in the 11-days inpatient BT group (Online Resource 2). Muscle tension in the m. trapezius decreased by 17–34% across all BT groups, with large effects in all 11-days BT groups. The greatest reduction (mean difference of 0.9) was observed in the 11-days inpatient BT group ( p < 0.001). Lower back tension decreased by 29–36%, with the greatest improvement (0.7 points) in the inpatient BT group. Thigh tension reductions ranged from 26–47%, with the inpatient BT group showing the largest effect ( d = 1.1). Spinal mobility increased by 18–48% across all BT groups ( d = 0.4–0.7), with the 6-days BT and 11-days BT with NT showing the best results. Inpatient BT treatment improved mobility by 2.3 cm. Hand strength improved by 4–5% after 11-days outpatient and inpatient treatments ( p = 0.003–0.023), with right-hand gains of 1.5–1.7 kg and left-hand gains of 1.2–1.5 kg, though with small effect sizes. Pain medication use decreased by 21–38% in BT groups ( p < 0.01, d = 0.4–0.7), with outpatient groups showing greater reductions. 1.3. Impact of BT on fatigue, sleep, and life quality Before the study, mild fatigue levels ranged from 23.59 to 28.40, lowest in the control group. At T1, fatigue significantly decreased in all BT groups, with the 11-days outpatient BT group reaching normal levels ( p < 0.001). Reductions ranged from 14–18%, with medium to large effect sizes ( d = 0.57–0.82). The greatest improvements were seen in the 11-days BT with NT and inpatient groups (Fig. 2). Sleep quality improved significantly in all BT groups ( p < 0.001), increasing from T0 (4.55–6.33) to T1 (6.47–7.82). All BT groups reached "good" sleep quality. Improvements ranged from 25–50%, with medium to large effect sizes ( d = 0.68–1.47). The 11-days inpatient BT group showed the largest effect size (-1.5) (Fig.3). At T0, mean scores ranged from 2.16 to 2.72. By T1, BT groups showed 15–25% improvements ( d = 0.5–1.0), with the largest effects in 6-days outpatient and 11-days inpatient BT. No significant changes were observed in the NT alone or the control groups. (Fig. 4). 1.4. Differences in short-time BT between groups Pairwise comparisons (T1, N=340, Mann-Whitney U) revealed significant differences between the treatment and control groups after the intervention (Online Resource 3). MSK pain frequency decreased in the 6-days BT, 11-days BT with NT, and inpatient groups compared to controls ( r= 0.2). Pain intensity was significantly lower in the 11-days BT groups ( r= 0.3–0.4) compared to controls, with BT with NT being more effective than NT alone ( r= 0.3). Muscle spasm was reduced more in the 6-days outpatient BT and 11-days inpatient groups compared to controls ( r= 0.2). Muscle tension was significantly reduced in all BT groups ( r= 0.4–0.8), with lower back muscle tension notably lower in the NT group than in controls. Hand strength increased more in the 6-days BT group compared to the 11-days outpatient BT group ( r= 0.2), and left-hand strength was higher in the 11-days inpatient group than in 11-days outpatient BT and control groups ( r= 0.2). Fatigue decreased more in the 11-days outpatient and inpatient BT groups than in controls ( r= 0.3). Sleep quality improved in the 6-days and 11-days outpatient BT with NT, and 11-days inpatient groups compared to controls ( r= 0.3–0.4), with BT with NT more effective than NT alone. In the 11-days outpatient group, sleep quality was better than in the inpatient group ( r= 0.3). Quality of life was significantly improved in the 11-days inpatient group compared to controls ( r= 0.2). 2. Long-term effect on study outcomes During follow-up (GLM, N=235), no consistent changes in pain frequency or intensity were observed in any group (Online resource 4). However, the occurrence of muscle spasm decreased by 18% from baseline for up to six months in the 11-days inpatient BT group. A long-term reduction in muscle tension in the m. trapezius region was observed in all BT groups for up to six months, with reductions of up to 32% from baseline. In the lower back region, this effect was noted in the 6-days and 11-days outpatient BT groups, with reductions of up to 33% from baseline. In the thigh region, muscle tension decreased by up to 37% from baseline for up to three months in the 11-days outpatient BT combined with NT and inpatient BT groups. Spinal mobility improved for up to six months in the 11-days BT with NT (by 65% from baseline) and inpatient (by 45%) groups, with an increase of up to 2.2 cm. Hand strength increased for up to three months in the 11-days outpatient BT (right hand: up to 1.7 kg), BT with NT (left hand: up to 2.6 kg), and control (up to 2.0 kg) groups. The use of pain medications decreased for up to six months in the 11-days outpatient BT group (by up to 27%) and for up to three months in the 6-days BT group (by up to 40%). Fatigue was consistently reduced by 15–18% for up to six months in the 11-days outpatient BT with NT and inpatient groups. Sleep quality improved for up to six months in all BT groups, with improvements ranging from 17% to 68%. 11-days inpatient treatment yielded the greatest improvements in sleep quality, with a mean increase of 2.9 points at three months ( p < 0.001) and 3.1 points at six months ( p < 0.001). The control group exhibited the lowest improvement, with only slight improvements in sleep quality observed at three months. An improvement in quality of life, exceeding baseline assessments by 15–18%, was observed for up to six months in the 6-days outpatient BT and 11-days inpatient BT groups. These findings highlight treatment-specific differences in MSK outcomes over time. 2.1. Differences in long-term treatment effects among study groups Post hoc pairwise comparisons using GLM (N=235) revealed several significant differences between study groups in the long term (Online resource 5). At 3 months, both 6-days and 11-days outpatient BT, with or without NT, significantly reduced muscle tension in the m. trapezius and thigh regions compared to the control group (p<0.05). At 6 months, these effects persisted: 6-days BT was more effective than control in reducing pain intensity (p=0.025) and tension in the m. trapezius region (p<0.05), while 11-days outpatient BT reduced lower back muscle tension more effectively than both NT alone (p=0.018) and controls (p=0.015). However, no significant differences were observed between the groups during follow-up for pain, muscle spasm, spinal mobility, hand strength, fatigue, sleep, and life quality. 3. The relations of stress and MSK associated symptoms Stress was positively correlated with fatigue (r = 0.417), physical (r = 0.449) and mental health (r = 0.549), quality of life (r = 0.519), MSK pain frequency (r = 0.294), pain intensity (r = 0.267), and pain medication use (r = 0.314), indicating that higher stress is linked to more pain and MSK related symptoms. MSK pain frequency showed moderate correlations with fatigue (r = 0.119), physical health (r = 0.273), mental health (r = 0.116), and quality of life (r = 0.255), with stronger links to pain intensity (r = 0.570), muscle spasm (r = 0.411), and pain medication use. Pain intensity correlated with physical health (r = 0.156), quality of life (r = 0.199), and muscle spasm (r = 0.172), with a strong link to MSK pain frequency (r = 0.570) (Online Resource 6). Stress, pain frequency, and pain intensity were all interrelated, suggesting stress plays a significant role in MSK pain development and severity. 4. Pain and fatigue gender differences To investigate potential gender-based differences in pain intensity and fatigue levels, we compared pain and fatigue before and after treatment within the study groups (Online Resource 7). The results indicated that, overall, there were no significant differences in pain intensity or fatigue levels between male and female participants. Within the individual study groups, pain intensity did not vary by gender. However, prior to treatment, women in the 11ABT group exhibited higher fatigue levels, which could have been influenced by the substantially larger number of women in this group (47 vs. 7). Therefore, it can be concluded that gender did not significantly affect pain intensity or fatigue levels. 5. Safety of BT treatment Adverse reaction (AR) incidence varied by BT type: mineral water (13.8–31.3%), peloid therapy (8.6–14.1%), and salt therapy (3.3–21.9%). ARs differed significantly between groups for mineral water ( p = 0.005) and salt therapy ( p < 0.001) but not for peloid therapy ( p = 0.553). The highest AR rates occurred after 11-days course of mineral water (inpatient/outpatient) and salt therapy (outpatient), while the lowest were in 6-days BT group. Common ARs—drowsiness, fatigue, skin irritation, thirst, and redness—were mostly temporary. Mud and salt therapy ARs were linked to initial blood pressure, while mineral water and mud therapy ARs were associated with initial skin conditions. One participant (0.3%) discontinued due to heat intolerance. 87% of participants rated BT as very safe, with no significant safety differences between groups. Discussion This study investigated the short- and long-term effects of balneotherapy on musculoskeletal pain and associated symptoms, as well as differences across treatment protocols. The findings confirm the immediate benefits of BT, with the magnitude of change varying by treatment type. Long-term effects were sustained for most parameters, except MSK pain, with improvements persisting up to six months. Notably, differences between BT groups diminished over time, emphasizing the importance of personalized interventions. The results demonstrate significant short-term improvements across all BT groups in pain frequency and intensity, frequency of muscle spasms, muscle tension in different regions, spinal mobility, use of pain medications (analgesic), fatigue, sleep quality, and quality of life. These improvements ranged from 4% to 68% from baseline, depending on the variable, with effect sizes ranging from small to large. The most pronounced changes were observed following the 11-daysoutpatient BT combined with NT and inpatient treatment. According to our findings, gender did not have a significant effect on pain intensity or fatigue levels. Additionally, we found that pain intensity and frequency were closely linked to physical and mental health, fatigue, and quality of life. The effects of multi-faceted BT, supported by the project's findings, confirmed that distress intensity was significantly reduced across various treatment modalities utilizing different natural resources, regardless of treatment duration, composition, or season (mean difference 1–3.5 points, VAS, Cohen's d 0.4–1.3). This reduction in distress was further supported by a significant decrease in salivary cortisol levels, which dropped by up to 0.87 nmol/L in the BT plus nature therapy (NT) group (Cohen's d = 0.4, small effect), indicating a physiological response to the intervention (Rapolienė et al. 2025). Long-term benefits were sustained for most parameters, except for MSK pain, with improvements lasting up to six months. The magnitude of change ranged from 15% to 65% from baseline across most BT groups. BT, particularly 11-days regimens with NT or inpatient care, showed superior outcomes over the control and NT alone, with small to medium effect sizes. Differences between BT groups were minimal, except for reduced pain frequency and intensity in the 11-days BT groups, improved left-hand strength in inpatients, and better sleep quality in the 11-days outpatient BT group. At the 6-month follow-up, BT benefits persisted, especially in muscle relaxation. The study aligns with previous research showing that short-term of ST, including BT, effectively manages MSK pain, joint swelling, and low back pain, often outperforming or matching control treatments in the short and long term (Fioravanti et al. 2003, 2015; Karagülle et al. 2015; Ortega et al. 2017; Rapoliene et al. 2020; Bestaş et al. 2022). Greater reductions in some groups are likely due to higher baseline pain levels. The greatest improvement was observed in the combined BT and NT group, supporting their synergistic effects in chronic pain management (Jimenez et al. 2021; Smith et al. 2024). Effect sizes ranged from 0.7 to 1.8, with pain reductions between 1.4 and 2.3 points on the NRS, higher than typical aquatic exercise interventions (0.19–0.32) (Verhagen et al., 2012), land exercises (Eversden et al 2007), and similar to ST treatments (Maccarone et al., 2023). A study on elderly osteoarthritis patients reported even greater pain reductions after BT sessions, along with a significant decrease in non steroidal anti-inflammatory drugs (NSAIDs) use (Gaál et al. 2008). Our findings are consistent with previous studies on mineral water baths, where higher concentrations led to greater pain (3.4 VAS) and fatigue reductions (Rapoliene et al. 2016), while lower (20-60 g/l) provided smaller, short-term benefits on pain and spine mobility, and three month-lasting sleep quality improvements (Rapoliene et al. 2020). The stronger effects in this study likely result from the integration of multiple BT modalities. Reduction in muscle spasms and tension aligns with previous research showing the positive effects of bath in mineral water and curative mud baths on MSK pain and muscle tension, supporting their use as drug-free interventions for mild MSK issues (Tuulik et al. 2022). While hand strength improvements were small after 2-week BT treatment, these changes suggest BT may contribute to functional muscle strength improvements. A Romanian study reported similar findings, with improved grip strength in sarcopenia patients after 10 daily sessions of sapropelic mud and salt water therapy, along with significant pain reduction (VAS 4, p < 0.0001) (Stanciu et al. 2023). Our findings on the positive changes in MSK symptoms are in agreement with with previous studies and systematic reviews, which highlight the beneficial effects of BT and ST using various resources. These interventions have been shown to improve pain, decrease the number of tender points, enhance joint and spinal mobility, and support motor and functional recovery, along with other investigated symptoms and signs (Bai et al. 2019; Balogh et al. 2005; Cantista et al. 2020; Dilekçi et al. 2020; Gáti et al. 2018; Haji et al. 2021; Manica et al. 2024; Ozkuk et al. 2019; Santos et al. 2016; Protano et al. 2023; Popławska et al. 2024). BT significantly reduced fatigue, improved sleep, and enhanced quality of life with medium-to-large effect, supporting its broad benefits for individuals with MSDs. These findings align with evidence that 2-week BT interventions positively impact sleep, mood, and well-being with the effect of 0.581 to 0.980 (Koçak et al. 2020; Maccarone et al. 2023; Silva et al. 2023; Castelli et al. 2022; Yang B et al. 2018). ST studies also show similar benefits, reducing fatigue, pain, and post-COVID-19 limitations while improving physical (+72%) and emotional (+66%) function (Costantino et al., 2024). BT was linked to better functional status, mental health, and quality of life in chronic low back pain patients (Terzić Marković et al. 2024). Our study confirms the interconnection between pain, fatigue, and overall well-being, with the inpatient BT group showing the greatest stress reduction (mean difference of 2.4 VAS, p < 0.001), lasting up to three months (Rapolienė et al. 2024). BT’s positive effects stem from its ability to reduce muscle spasms and joint load while enhancing pain tolerance, circulation, and connective tissue elasticity. BT has been shown to positively influence inflammation, oxidative stress, cartilage health, and immune function in individuals with chronic MSK conditions. Research using animal models of osteoarthritis and rheumatoid arthritis suggests that various BT treatments help alleviate pain, reduce inflammation, and improve mobility while lowering oxidative stress and inhibiting enzymes that degrade joint tissues. Additionally, in vitro studies indicate that mineral water and its components exhibit anti-inflammatory, antioxidant, and cartilage-protective effects on joint and bone cell cultures (Cheleschi et al. 2021; Masiero et al. 2020; Silva et al. 2023; Gálvez et al. 2024). Determining the most effective BT modality for MSK health remains challenging, as all treatment protocols showed improvements. Similarly, other treatments vary in effectiveness—a review of 137 studies found effect sizes ranging from 0.63 (hyaluronic acid) to 0.18 (acetaminophen) for osteoarthritis, with NSAIDs offering short-term relief (Bannuru et al. 2015; da Costa et al. 2021). The optimal BT duration remains debated, with evidence supporting programs ranging from three days to three weeks (Noriega et al. 2020; Gebretsadik et al. 2021; Maraver et al. 2020; Karagülle et al. 2017; 2021; Özkuk et bal. 2019). The development of guidelines for BT treatment methodology, ensuring both efficacy and practicality for clinicians, is crucial. Further research is needed to establish standardized guidelines tailored to predominant specific symptoms, as well as to compare the short- and long-term effects of pharmacological and non-pharmacological interventions. Given the rising burden of chronic MSK conditions (WHO 2022; Hacker 2024), effective, non-invasive pain management strategies are critical. BT, particularly in combination with NT, presents a promising complementary therapy alongside pharmacological and rehabilitation interventions (Groven et al. 2020). While randomized controlled trials support BT’s role in multidisciplinary treatment (Maier et al. 2024), further research is needed to refine standardized guidelines for optimal intervention protocols. Large-scale trials comparing BT with pharmacological and non-pharmacological treatments will be essential for integrating BT into modern clinical practice (Fioravanti et al. 2020). Limitation of study This study has several limitations. It focused on patients with moderate stress and nonspecific MSK pain. Participant dropout during follow-up reduced the sample size for long-term analysis. Managing multiple groups and parameters led to poor compliance and challenges in follow-up attendance. Clustering of participants before randomization introduced inconsistencies in the sample. The use of multiple research centers limited conclusions about individual spa treatment components, and variability in treatment settings highlighted the need for standardized approaches. Finally, broader challenges in balneology research, such as small sample sizes, short follow-up, and lack of standardization, hinder definitive conclusions and emphasize the need for larger, rigorous studies. Conclusions This study demonstrates the positive effects of balneotherapy on musculoskeletal pain, mobility, muscle strength, cramps, tension, fatigue, sleep, and quality of life, with varying efficacy depending on the treatment regimen. Significant short-term improvements were observed, with some long-term benefits lasting up to six months. BT, especially when combined with nature-based interventions or inpatient care, can lead to sustained improvements in MSDs, although periodic treatments may be necessary. Future studies with larger sample sizes and longer follow-up are needed to explore the long-term impact of BT and optimize treatment protocols for different MSK conditions. Abbreviations 6ABT: 6 days of Ambulatory BT/outpatient (1-week) 11ABT: 11 days of Ambulatory BT/outpatient (2-weeks) 11ABTNT: 11 days of Ambulatory BT with Nature Therapy (NT)/outpatient (2-weeks) 11BTS: 11 days of BT Stationary/inpatient (2-weeks) 11NT: 11 days of Nature therapy/outpatient (2-weeks). 11C: control group (no treatment) (2-weeks). AIOS- arizona integrative outcomes scale BT balneotherapy FAS- fatigue assessment scale GLM- general linear model Repeated Measures MSDs- musculoskeletal disorders MSK- musculoskeletal SQS- single- item sleep quality scale ST- spa therapy QoL- quality of life T0- baseline examination T1- after treatment examination T2- after 3- month follow-up T3- after 6- month follow-up Declarations Disclosure The authors report no conflicts of interest in this work. Author Contributions: Conceptualization, L.R. and A.F.; methodology, L.R and A.F.; software, A.M. and V.K.; validation, L.R., A.M., and V.K.; formal analysis, A.M. and V.K..; investigation, L.R, G.T.; resources, L.R.; data curation, L.R, and A.M..; writing—original draft preparation, L.R.; writing—review and editing, A.F.; visualization, L.R., and G.T.; supervision, A.F.; project administration, L.R..; funding acquisition, L.R. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Research Council of Lithuania and the Ministry of Economy and Innovation (P roject "Effectiveness and safety of the use of Lithuania's unique natural resources for improving the mental and physical health of the organism experiencing stress" (LUGISES) grant number S-REP-22-6). Ethics approval : The study was conducted following the Declaration of Helsinki, approved by the Kaunas Regional Research Ethics Committee (permission code BE-2-87 and date of approval 28 of November 2022), and registered in ClinicalTrial.gov (Identifier: NCT06018649) (30/08/2023). Informed Consent Statement: Informed consent was obtained from all subjects included in the study. Data Availability Statement: The raw data supporting the conclusions of this article will be made available by the authors on reasonable request. Acknowledgments : We are grateful to the chief executives and staff of the research centers at Gradiali, Eglė, Draugystė, Tulpė, Versmė, and Atostogų Parkas, as well as our colleagues at Klaipeda University, who contributed to the execution of this large-scale research. Special thanks to Dr. Aelita Bredelyte for her contributions to the investigation, data curation, and resource management. Conflicts of Interest: The authors declare no conflicts of interest. 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Quattrocchi A, Garufi G, Gugliandolo G, De Marchis C, Collufio D, Cardali S M, Donato N (2024) Handgrip Strength in Health Applications: A Review of the Measurement Methodologies and Influencing Factors. Sensors , 24 (16), 5100. https://doi.org/10.3390/s24165100 Popławska NA, Woźniak K, Śliz J, Skorupska M, Czeczotka MJ. The Beneficial Effect of Balneotherapy on Osteoarthritis. Med Og Nauk Zdr. 2024; 30(3): 192–196. doi: 10.26444/monz/190328 Protano C, Fontana M, De Giorgi A, Marotta D, Cocomello N, Crucianelli S, Del Cimmuto A, & Vitali M (2023). Balneotherapy for osteoarthritis: a systematic review. Rheumatology international , 43 (9), 1597–1610. https://doi.org/10.1007/s00296-023-05358-7 RajaSN, CarrDB, Cohen M, FinnerupNB, FlorH, GibsonS, KeefeFJ, MogilSJ, Ringkamp M, SlukaKA, SongXJ, Stevens B,Sullivan MD, Tutelman PR, Ushida T,Vader K (2020) The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 161(9):1976-1982. doi: 10.1097/j.pain.0000000000001939. Rapolienė L, Razbadauskas A, Sąlyga J, Martinkėnas A (2016) Stress and Fatigue Management Using Balneotherapy in a Short-Time Randomized Controlled Trial. Evidence-Based Complementary and Alternative Medicine (4):1-10. DOI:10.1155/2016/9631684 Rapolienė L, Razbadauskas A, Mockevičienė D, Varžaitytė L, & Skarbalienė A. (2020). Balneotherapy for musculoskeletal pain: does the mineral content matter?. International journal of biometeorology , 64 (6), 965–979. https://doi.org/10.1007/s00484-019-01800-3 Rapolienė L., Rapolis D., Bredelytė A., Taletavičienė G., Fioravanti A., & Martinkėnas A. (2025). Balneotherapy as a Complementary Intervention for Stress and Cortisol Reduction: Findings from a Randomized Controlled Trial. Brain Sciences , 15 (2), 165. https://doi.org/10.3390/brainsci15020165. Rat AC, Loeuille D, Vallata A, Bernard L, Spitz E, Desvignes A, Boulange M, Paysant J, Guillemin F, Chary-Valckenaere I (2020) Spa therapy with physical rehabilitation is an alternative to usual spa therapy protocol in symptomatic knee osteoarthritis. Sci Rep 10:11004. https://doi.org/10.1038/s41598-020-67436-1 Reger M, Kutschan S, Freuding M et al (2022) Water therapies (hydro­therapy, balneotherapy or aqua therapy) for patients with cancer: a systematic review. J Cancer Res Clin Oncol 148:1277–1297. https://doi.org/10.1007/s00432-022-03947-w Santos I, Cantista P, Vasconcelos C (2016) Balneotherapy in rheumatoid arthritis-a systematic review. Int. J. Biometeorol 60:1287–1301. doi: 10.1007/s00484-015-1108-5. Silva J, Martins J, Nicomédio C, Goncalves C, Palito C, Goncalves R, Fernandes PO, Nunes A, Alves MJ (2023) A Novel Approach to Assess Balneotherapy effects on Musculoskeletal Diseases-An Open Interventional Trial combining physiological indicators, biomarkers, and patients’ Health Perception. Geriatrics 8 (3):55. https://doi.org/10.3390/geriatrics8030055 Smith A, Wyles KJ, Hernandez SM, Clarke S, Schofield P, Hughes S W (2024) Harnessing the therapeutic effects of nature for chronic Pain: A role for immersive virtual reality? A narrative review. European Journal of Pain 29(2):e4727. https://doi. org/10.1002/ejp.4727 Snyder E, Cai B, DeMuro C, Morrison MF, Ball W (2018) A New Single-Item Sleep Quality Scale: Results of Psychometric Evaluation in Patients With Chronic Primary Insomnia and Depression. J Clin Sleep Med 14(11):1849-1857. doi:10.5664/jcsm.7478 Stanciu LE, Iliescu MG, Oprea C, Ionescu EV, Petcu A, Ciortea VM, Petcu LC, Apostol S, Nedelcu AD, Motoașcă I, Irsay L (2023) The Impact of Complex Rehabilitation Treatment on Sarcopenia-Pathology with an Endocrine Morphological Substrate and Musculoskeletal Implications. Medicina (Kaunas, Lithuania), 59(7): 1238. https://doi.org/10.3390/medicina59071238. Terzic Markovic D, Kocic S, Bradic J, Jurisic-Skevin A, Jakovljevic B., Majstorovi, B, Dimoski Z, Stojanovic G, Maksimovic V, Pavlovic Jugovic K, Dabic M, Jezdimirovic D, & Zivanovic S. (2024). Novel Insight into the Association between Balneotherapy and Functional State and Health Perception in Chronic Low Back Pain: A Cross-Sectional Study. Journal of clinical medicine , 13 (17), 5248. https://doi.org/10.3390/jcm13175248 Tuulik V R, Kumm M, Tuulik V, Veraksitš A, Päll T (2022) The therapeutic effect of Värska mud and Värska mineral water baths on the overuse pain and muscle tension syndromes in the working age population. Environmental geochemistry and health 44(7):2101–2110. https://doi.org/10.1007/s10653-021-00951-w Verhagen AP, Cardoso JR, Bierma-Zeinstra SM (2012) Aquatic exercise & balneotherapy in musculoskeletal conditions. Best Pract Res Clin Rheumatol 26(3):335-43. doi: 10.1016/j.berh.2012.05.008. Villa-Forte A (2024) Evaluation of the patient with Joint symptoms. MSD Manual Proffesional Version. https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/approach-to-the-patient-with-joint-symptoms/evaluation-of-the-patient-with-joint-symptoms. WHO (2022). Musculoskeletal health. 14 July 2022. https://www.who.int/news-room/fact-sheets/detail/musculoskeletal-conditions Wyns A, Hendrix J, Lahousse A, De Bruyne E, Nijs J, Godderis L, Polli A (2023) The Biology of Stress Intolerance in Patients with Chronic Pain - State of the Art and Future Directions. Journal of Clinical Medicine . 12 (6):2245. https://doi.org/10.3390/jcm12062245 Cite Share Download PDF Status: Published Journal Publication published 07 Jun, 2025 Read the published version in International Journal of Biometeorology → Version 1 posted Reviewers agreed at journal 02 Apr, 2025 Reviewers invited by journal 02 Apr, 2025 Editor assigned by journal 31 Mar, 2025 First submitted to journal 31 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5989141","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":437592333,"identity":"eab779fc-b42c-4308-8cf4-95ca056cb45d","order_by":0,"name":"Lolita Rapoliené","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/klEQVRIiWNgGAWjYBACPgbmhgNQNuOBBCDJz8zABuLJ4NLCxsDYcACmB6xFshmihYcHjxYGuBYQYXCAkBb2xsbDH2oY8vlnNx848KDijpzxcd5jDz62MfDY49LCcxDosGMMljPuHEs4kHDmmbHZYb50wxln8NgikQjUwsZgwHAjx+BAYtvhxG2HecykeSoIafnHYCAP1vLvcP3mZpAWAwJaDrYxGBiAtTQcTjBgJmQLyC9n+yQMDMF+OXbYcMZhHnOgXyR4eA5g18LP3nz4Q8U3GwO5280HH/6oOSzP33/GDBhiNnLsDTisgQAJMEITIQiIUTMKRsEoGAUjEwAAouJbtPRqzOcAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-5089-4095","institution":"Klaipedos universitetas","correspondingAuthor":true,"prefix":"","firstName":"Lolita","middleName":"","lastName":"Rapoliené","suffix":""},{"id":437592334,"identity":"50d4d72b-e8f1-497c-a062-d4114c93babb","order_by":1,"name":"Lolita Rapolienė","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Lolita","middleName":"","lastName":"Rapolienė","suffix":""},{"id":437592335,"identity":"0128e24b-c84d-4257-b44f-ab51130a67c7","order_by":2,"name":"Giedrė Taletavičienė","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Giedrė","middleName":"","lastName":"Taletavičienė","suffix":""},{"id":437592336,"identity":"9b280c36-5916-4832-8522-e6c1d9e223f5","order_by":3,"name":"Arvydas Martinkėnas","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Arvydas","middleName":"","lastName":"Martinkėnas","suffix":""},{"id":437592337,"identity":"c1b1f1d5-70a6-4b36-b939-82cf98ca0c21","order_by":4,"name":"Vytė Kontautienė","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Vytė","middleName":"","lastName":"Kontautienė","suffix":""},{"id":437592338,"identity":"a08ceaec-1ce6-4f61-b9e2-40de907b1eb8","order_by":5,"name":"Antonella Fioravanti","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"","lastName":"Fioravanti","suffix":""},{"id":437592339,"identity":"1e34fbb9-6463-44d1-a342-34801a05bed4","order_by":6,"name":"Arvydas Balčius","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Arvydas","middleName":"","lastName":"Balčius","suffix":""}],"badges":[],"createdAt":"2025-02-08 17:24:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5989141/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5989141/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00484-025-02936-1","type":"published","date":"2025-06-07T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":80049735,"identity":"afadc73b-733c-4c64-a583-64b4f5bfb1a4","added_by":"auto","created_at":"2025-04-07 10:13:41","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85438,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe study flow diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5989141/v1/614cfada095391f6a9a2c31b.jpg"},{"id":80050641,"identity":"43b14e70-78f9-456a-85cf-bd0408f4e058","added_by":"auto","created_at":"2025-04-07 10:21:41","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":35670,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFatigue Changes Measured by Fatigue Assessment Scale Across Study Groups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e* significant changes, \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05. Abbreviations: 6ABT- 6-days outpatient BT group, 11ABT- 11-days outpatient BT group, 11ABTNT- 11-days outpatient BT combined with NT group, 11BTS- 11-days inpatient BT group, 11NT- 11-days NT group, 11C- 11-days control group.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5989141/v1/e47e3dd70b3a82809246ad9c.jpg"},{"id":80052159,"identity":"0213984e-3896-4e17-91b1-003a467703fa","added_by":"auto","created_at":"2025-04-07 10:37:41","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":35191,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSleep Quality Measured by Single-Item Sleep Quality Scale: Changes Across Study Groups.\u003c/strong\u003e * significant changes, \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05. Abbreviations: 6ABT- 6-days outpatient BT group, 11ABT- 11-days outpatient BT group, 11ABTNT- 11-days outpatient BT combined with NT group, 11BTS- 11-days inpatient BT group, 11NT- 11-days NT group, 11C- 11-days control group.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5989141/v1/5dd07083a41b0ac8f636d535.jpg"},{"id":80051719,"identity":"0233c7f1-a48a-473c-b072-5e72135cd9c4","added_by":"auto","created_at":"2025-04-07 10:29:41","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":35078,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in quality of life across study groups\u003c/strong\u003e. * significant changes, \u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.05. Abbreviations: 6ABT- 6-days outpatient BT group, 11ABT- 11-days outpatient BT group, 11ABTNT- 11-days outpatient BT combined with NT group, 11BTS- 11-days inpatient BT group, 11NT- 11-days NT group, 11C- 11-days control group.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5989141/v1/c3e625a0397ec66102be821a.jpg"},{"id":84242522,"identity":"b5ff8ff5-915f-424c-a758-d6a46e3f7823","added_by":"auto","created_at":"2025-06-09 16:09:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1472898,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5989141/v1/e6b0595a-74d8-47ae-8ed3-5f4742fc9991.pdf"}],"financialInterests":"","formattedTitle":"Short and Long-Term Effects of Balneotherapy on Musculoskeletal Pain and Fatigue Associated with Stress","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMusculoskeletal disorders (MSDs) encompass a diverse group of over 150 conditions affecting the joints, muscles, bones, ligaments and tendons, often leading to temporary or permanent impairments in function (WHO \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). In 2021, MSDs accounted for 367.2\u0026nbsp;million incident cases and 1.69\u0026nbsp;billion prevalent cases globally, with disability-adjusted life years (DALYs) increasing significantly between 1990 and 2021. These conditions substantially impact quality of life, contribute to high healthcare costs, and are a leading cause of disability (Liu et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). MSDs are among the most common reasons for seeking healthcare, presenting with symptoms such as musculoskeletal (MSK) pain, stiffness, joint noises, reduced mobility, fatigue, numbness, and instability (Villa-Forte \u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). They are closely associated with functional disability (Koechlin et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Raja et al. \u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e2020\u003c/span\u003e), emotional distress, mood and anxiety disorders, depressive conditions, and reduced quality of life (Heikkinen et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The relationship between stress and MSK pain is complex, involving physiological, neurological, and psychological interactions (Wyns et al. \u003cspan citationid=\"CR79\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Bonanno et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGiven the multifactorial nature of MSDs, management strategies focus on pain relief, improving mobility and function, reducing inflammation, preventing disease progression, strengthening muscles, and enhancing overall quality of life (El-Tallawy et al \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In recent years, balneotherapy (BT), also referred to as spa therapy (ST), has gained prominence in several countries, including European nations, Turkey, Israel, China, and Japan. While the terms are often used interchangeably, clear distinctions are necessary for scientific research and systematic reviews (Fioravanti et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Gutenbrunner et al. \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2010\u003c/span\u003e). BT primarily involves the therapeutic use of natural thermal mineral waters, additive baths, peloids, and various environmental elements. It is considered the core intervention within ST, which also encompasses non-balneological treatments (Karag\u0026uuml;lle et al. 2021; Rat et al. 2020).\u003c/p\u003e \u003cp\u003eAn increasing body of scientific evidence supports the benefits of BT beyond its traditional applications. Studies have highlighted its effectiveness in treating conditions such as obesity, metabolic disorders, sleep disturbances, mental health conditions, long-COVID, and cancer rehabilitation (Fioravanti et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Ko\u0026ccedil;ak et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Manica et al. \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Clark-Kennedy et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Yang et al. \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Rapolienė et al. \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Maccarone et al. 2021; Reger et al. \u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). In the context of MSDs, BT has been shown to reduce pain, improve mobility, and enhance quality of life (Bai et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Fioravanti et al. 2020; Bernetti et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Facchini et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). These therapeutic benefits are attributed to the mineral composition, temperature, and mechanical properties of thermal waters, along with the spa environment, which collectively exert anti-inflammatory, antioxidant, immunomodulatory, and regenerative effects (Antonelli et al. 2018a; G\u0026aacute;lvez et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Silva et al. \u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Recognized by organizations such as the World Health Organization (WHO) and the Osteoarthritis Research Society International (OARSI), BT is increasingly regarded as a valuable complementary approach to conventional treatments (Bernetti et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; WHO \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWhile BT is well-established for MSDs management, its effects on individuals experiencing moderate stress remain underexplored. The relationship between stress and MSK pain, particularly in individuals without diagnosed rheumatological conditions, is not fully understood, limiting the development of targeted therapeutic approaches (Abousha et al. 2024). This study aims to investigate the role of BT in alleviating MSD-related symptoms in individuals experiencing stress, assessing whether stress contributes to MSK health outcomes. By comparing different BT modalities and their effects on MSK pain and associated symptoms, this research seeks to advance personalized treatment strategies that address both the physical and emotional aspects of MSDs.\u003c/p\u003e \u003cp\u003eIn particular, the objective of this study was to evaluate the effects of BT on MSK pain, fatigue, and associated symptoms in individuals experiencing stress. By examining these outcomes, the research aims to provide scientific insights into the efficacy of BT as a complementary therapy for managing stress-related MSK issues and enhancing overall well-being.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Setting\u003c/h2\u003e \u003cp\u003eThis research employed a multicenter, randomized controlled, single-blind (for researchers) parallel group design. The study was conducted from December 2022 to August 2023, with treatment provided between January and February 2023. It was carried out across two clusters\u0026mdash;Klaipeda and Druskininkai\u0026mdash;at six medical spa centers in Lithuania: Gradiali (Palanga), Atostogų Parkas (Kretingos region), Egle (Druskininkai), Draugystė (Druskininkai), Tulpė (Birštonas), and Versmė (Birštonas). The research adhered to the Declaration of Helsinki guidelines and received approval from the Kaunas Regional Research Ethics Committee (approval code BE-2-87, date 28/11/2022). The study was registered on ClinicalTrials.gov (Identifier: NCT06018649, registration date: 30/08/2023). Informed consent was obtained from all participants prior to enrollment. BT was administered, and the entire study was conducted in accordance with the principles of good clinical practice.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy participants, randomization, and group allocation\u003c/h3\u003e\n\u003cp\u003eA probabilistic nested (cluster) sampling method was used, with participants selected through a multi-stage, criterion-based process. Inclusion criteria included individuals aged 18\u0026ndash;65 years with moderate stress intensity (above 3 points on a 10-point Visual Analog Scale (VAS)), pain of at least 1 point on Numerical Rating Scale (NRS), and residency near selected medical spa centers or the ability to travel to the service centers. Exclusion criteria included exacerbated or uncontrolled chronic diseases, active infections, malignant tumors, recent surgery or major trauma within the past year, prior BT within the last 3 months, pregnancy or lactation, bleeding disorders, severe mental conditions, and difficulties accessing the study area. All participants provided written informed consent before participation, which outlined the study's purpose, terms, and procedures.\u003c/p\u003e \u003cp\u003eIn total, 1137 individuals were assessed for eligibility, with 194 participants from Klaipeda and 179 from Druskininkai meeting the inclusion criteria. Participants who met eligibility criteria were coded and assigned to one of the study clusters in Klaipeda or Druskininkai, and then randomized into different treatment groups (1\u0026ndash;6) using the SPSS function \"Random Sample of Cases\u0026lsquo; which allows for the selection of a subset of cases based on an approximate percentage or an exact number. This process ensured unbiased distribution across the study arms. Group composition was evaluated for age, gender, and baseline stress levels.\u003c/p\u003e\n\u003ch3\u003eTreatmentGroups\u003c/h3\u003e\n\u003cp\u003eThe study included multiple parallel intervention groups, which were named according to the abbreviations of the treatment modalities:\u003c/p\u003e \u003cp\u003e6ABT: 6 days of outpatient BT in Medical Spa; 11ABT: 11 days of outpatient BT in Medical Spa; 11ABTNT: 11 days of outpatient BT in Medical Spa with self-guided Nature Therapy (NT) procedures; 11BTS: 11 days of inpatient BT in Medical Spa (residential treatment); 11NT: 11 days of outpatient self-guided Nature therapy (NT) procedures; 11C: 11 days control group (no treatment).\u003c/p\u003e \u003cp\u003eAll BT groups, except for the 11BTS group, received outpatient BT treatment in the medical spa while maintaining their usual work and daily routines. Participants in the 11BTS group stayed at the medical spa for the entire treatment period and underwent all procedures as inpatients, without receiving any additional treatment. Participants in the 11NT group received initial education during the first session guided by a specialist, along with written instructions for subsequent self-guided nature therapy. They also received daily Short Message Service (SMS) reminders to perform the prescribed NT procedures.\u003c/p\u003e\n\u003ch3\u003eTreatment Protocols\u003c/h3\u003e\n\u003cp\u003eThe BT treatments included a 20-minute session in 29\u0026ndash;31\u0026deg;C tap water pools with light activities, a 20-minute bath in mineral water at 36\u0026ndash;38\u0026deg;C, a 20-minute sapropel wrap at 38\u0026ndash;40\u0026deg;C, and a 25-minute salt therapy session (either inhalation or a salt chamber). Instructions for each BT procedure were provided before the start of the sessions. Following each treatment, participants were given a 20-minute rest period for relaxation. NT, developed by researchers with a focus on physiotherapy, green therapy, and mindfulness, consisted of a 45-minute walk in nature, strength exercises, sensory experiences, aromatherapy, and mindfulness activities.\u003c/p\u003e \u003cp\u003eThe mineral waters used in the treatments had total mineralization levels ranging from 17 to 82 g/L and were rich in chloride, sodium, calcium, magnesium, and sulfates, with pH values between 5.71 and 7.54. However, the gas content was low. In three research centers, the mineral water was diluted with freshwater. The specific baths used included: \"Versmė\" (22.2 g/L, high mineralization), \"Tulpė\" (21.6 g/L, high mineralization), \"Atostogų parkas\" (82.4 g/L, brine), \"Draugystė\" (27 g/L, high mineralization), \"Eglė\" (12 g/L, medium mineralization), and \"Gradiali\" (8.3 g/L, medium mineralization). The peloids (peat or sapropel) used in the treatments consisted of 60\u0026ndash;80% reed-origin material, with pH values ranging from 6.4 to 7.0, moisture content between 76% and 95%, and ash content ranging from 8\u0026ndash;86%. Organic matter content varied from 14\u0026ndash;91%, with the presence of humic and fulvic acids. The peloids were rich in calcium, magnesium, chloride, and bicarbonates, while heavy metal concentrations remained below the limits set by soil regulations. Detailed characteristics of the resources are provided in Online Resource 1.\u003c/p\u003e\n\u003ch3\u003eStudy outcomes and instruments\u003c/h3\u003e\n\u003cp\u003eThe primary outcomes of the study were MSK pain and fatigue. Secondary outcomes included muscle tension, spinal mobility, hand strength, frequency of muscle spasms (defined as sudden, involuntary muscle contractions), use of pain medications, sleep quality, and overall quality of life.\u003c/p\u003e \u003cp\u003ePain intensity was assessed using the Numerical Rating Scale (NRS), where participants rated their pain from 0 (no pain) to 10 (worst pain) (Delgado et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Participants reported their current pain level. Pain frequency, muscle spasms, pain medication (acetaminophen, NSAIDs, etc.) use, and quality of life were evaluated using 4- and 5-point Likert scales (Joshi et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The response categories for pain frequency and muscle spasms were: 1 \u0026ndash; \"never,\" 2 \u0026ndash; \"rarely,\" 3 \u0026ndash; \"frequently,\" and 4 \u0026ndash; \"always\u0026ldquo;. Pain medication use use (acetaminophen, NSAIDs [ibuprofen, naproxen, diclofenac, etc.], gabapentinoids [gabapentin, pregabalin], opioids, and their combinations) was rated on a scale from 1 \u0026ndash; \"never\" to 5 \u0026ndash; \"daily\". Quality of life was assessed on a scale from 1 \u0026ndash; \"excellent\" to 5 \u0026ndash; \"very poor.\"\u003c/p\u003e \u003cp\u003eMuscle tension was evaluated through palpation of the neck and shoulder area (\u003cem\u003em.trapezius\u003c/em\u003e), lower back (lumbar extensor muscles), and thighs (posterior thigh muscles), rated on a scale from 0 (low tone) to 4 (rigid/stiff muscles). Hand strength was measured using a dynamometer, a standardized method for assessing muscle strength (Quattrocchi, 2024). Spinal mobility was assessed using the Fingertip-to-Floor Distance (FFD) test, measured with a metal ruler, where lower values indicated better mobility (Guo, 2023).\u003c/p\u003e \u003cp\u003eFatigue was assessed using the Fatigue Assessment Scale (FAS), a 10-item scale measuring physical and mental exhaustion, with responses ranging from 1 (\"never\") to 5 (\"always\") (Michielsen, 2003). The total FAS score ranged from 10 (lowest fatigue) to 50 (highest fatigue), with scores of 22\u0026ndash;34 indicating mild to moderate fatigue. Sleep quality was evaluated using the Single item Sleep Scale (SQS), where responses ranged from 0 (\"terrible\") to 10 (\"excellent\") (Snyder, 2018). Written consent for the scale's use was obtained, and the scale was validated through double translation and expert review.\u003c/p\u003e \u003cp\u003eSide effect frequencies were determined during the study based on information reported by trial participants through prospective assessments (prespecified symptom inventories), which offer greater sensitivity and consistency in detecting side effects of specific treatments (Katz NP, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). The therapy safety survey asked participants to review a list of symptoms and potential side effects related to their treatments. They rated any unwanted effects from mineral water, mud, or salt therapies, including their frequency, severity (on a Likert scale from 1\u0026ndash;5), and duration (from brief to lasting after treatment). Overall safety was assessed on a 5-point scale, ranging from \"extremely safe\" to \"not safe.\"\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAssessment periods\u003c/h2\u003e \u003cp\u003eThe study's observation periods were divided into baseline (T0: January 27\u0026ndash;29), post-treatment (T1: February 5 and 11\u0026ndash;12), 3-month follow-up (T2: May 6 and 13\u0026ndash;14), and 6-month follow-up (T3: August 5 and 12\u0026ndash;13) assessments.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eSample size for statistically significant comparisons was calculated using the G*Power program based on previous studies (Rapoliene et al., 2016). For an effect size of 0.4, 55 participants per group were planned. Descriptive statistics (means, SDs, 95% CIs) were calculated, and t-tests were used for continuous variables, while chi-square tests were applied for categorical data. ANOVA with Tukey\u0026rsquo;s HSD assessed group differences, and paired t-tests compared baseline and post-treatment values. Long-term effects were analyzed using general linear model (GLM) Repeated Measures, with Bonferroni tests for mean differences. Non-parametric tests were used for non-normally distributed data (Friedman test, Mann-Whitney U, Kruskal-Wallis test Friedman). Effect size was estimated using Cohen\u0026rsquo;s \u003cem\u003ed\u003c/em\u003e (\u003cem\u003ed\u003c/em\u003e) and \u003cem\u003er\u003c/em\u003e (small: 0.2, medium: 0.5, large: 0.8), and correlations were assessed with Spearman\u0026rsquo;s and Kendall\u0026rsquo;s tau. Significance was set at p\u0026thinsp;\u0026le;\u0026thinsp;0.05, using SPSS Version 28.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe flow diagram of study is showen in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter the treatment period, data from 340 participants were included in the analysis. For the 6-month follow-up analysis, data from 235 participants who participated in all examinations, were analyzed. The characteristics of the study participants are detailed in Table\u0026nbsp;1.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e. The characteristics of participants in study groups.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"642\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eParameters/groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6ABT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11ABT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11ABTNT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11BTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11NT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e11C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP,\u0026nbsp;\u003c/strong\u003e\u003cem\u003e\u0026chi;\u003c/em\u003e\u003csup\u003e2,\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNo of participants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e59\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e63\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e63\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e61\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e43\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e51\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e340\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eAge, y, N(SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e45.53 (9.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e48.81 (11.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e46.57 (9.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e48.77 (10.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e44.74 (12.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e45.77 (10.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.209*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMen, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e13 (22.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e20 (33.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e17 (27.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (16.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e12 (24.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.147\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eWomen, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e44 (77.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e48 (87.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e40 (67.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e45 (72.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35 (83.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e37 (75.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMarital status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eMarried, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e44 (77.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e36 (65.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e41 (68.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e35 (59.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e26 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e37 (75.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.246\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSingle, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDivorced, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e11 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e15 (25.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eWidow, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (5.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEducation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eIncomplete secondary (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"5\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eSecondary (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e10 (16.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eHigher (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e7 (11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCollege (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e15 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e13 (21.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eUniversity, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e39 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e33 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e28 (46.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e37 (61.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e33 (67.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWork sector\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eFarming, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"8\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.528\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eIndustry, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (11.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (6.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eClerk, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e29 (50.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e25 (46.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e27 (45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e35 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e22 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e22 (44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eService, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e16 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e20 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e21 (35.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e12 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e15 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e21 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eStudying, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHousewife, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePensioner, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eUnemployed, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWork style\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSedentary, N(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e31 (54.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e23 (41.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e28 (48.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e30 (51.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e22 (55.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e18 (37.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.897\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSedentary with some physical, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e14 (24.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e20 (36.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e19 (32.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e18 (31.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e19 (39.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePhysical, N(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e8 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (17.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003eIntense physical, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBody mass index (BMI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e26,64 (5,26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e26,31 (4,95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e26,67 (5,5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e27,10 (4,48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e25,62 (4,5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e26,98 (5,54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.475\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" valign=\"bottom\" style=\"width: 642px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCo-morbidities\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eCardiovascular, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e9 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11 (3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4,0 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10,0 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"9\" style=\"width: 66px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eMusculoskeletal, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e9 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eGastrointestival, \u0026nbsp;N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eNervous, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eEndocrine, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003ePulmonary, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eSkin, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e8 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eUrogenital, \u0026nbsp;N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eAllergy, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e8 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e1 (0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations:\u0026nbsp;6ABT- 6-days outpatient BT group, 11ABT- 11-days outpatient BT group, 11ABTNT- 11-days outpatient BT combined with NT group, 11BTS- 11-days inpatient BT group, 11NT- 11-days NT group, 11C- 11-days control group; p- the significance of\u0026nbsp;baseline difference between groups (2-sided)s; \u003cem\u003e\u0026chi;\u003c/em\u003e\u003csup\u003e2,-\u0026nbsp;\u003c/sup\u003ePearson chi-square, N/A- not applicable because of small number of cases; *ANOVA.\u003c/p\u003e\n\u003cp\u003eThere were no significant differences between groups in terms of sociodemographic and clinical characteristics. No differences in MSK pain were observed between the groups in the post-treatment and follow-up analyses (p = 0.687 and p = 0.680, respectively, according to the Kruskal-Wallis test).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe short-term effect of BT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1.1. \u003cstrong\u003eThe impact of BT on MSK pain\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt T0, mean pain frequency scores ranged from 2.29 to 2.53 (Online Resource 2). After treatment (T1), BT\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003egroups showed significant reductions (1.83\u0026ndash;2.27), with the largest improvement (28%) in the 6-days BT group (\u003cem\u003er\u0026nbsp;\u003c/em\u003e= 0.9, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). No significant changes were found in NT-only or control groups (\u003cem\u003ep\u003c/em\u003e \u0026gt; 0.05). Pain intensity significantly decreased in all BT groups (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), with reductions of 45\u0026ndash;68% and the largest effect in 11-days BT with NT group. Mean differences ranged from 1.36 to 2.32 points (NRS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe impact of BT on MSK- associated symptoms\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMuscle spasms decreased by 18\u0026ndash;29% in BT groups (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.005, \u003cem\u003er\u003c/em\u003e = 0.4\u0026ndash;0.8), with the largest reduction in the 11-days inpatient BT group\u0026nbsp;(Online Resource 2).\u003c/p\u003e\n\u003cp\u003eMuscle tension in the \u003cem\u003em. trapezius\u003c/em\u003e decreased by 17\u0026ndash;34% across all BT groups, with large effects in all 11-days BT groups. The greatest reduction (mean difference of 0.9) was observed in the 11-days inpatient BT group (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). Lower back tension decreased by 29\u0026ndash;36%, with the greatest improvement (0.7 points) in the inpatient BT group. Thigh tension reductions ranged from 26\u0026ndash;47%, with the inpatient BT group showing the largest effect (\u003cem\u003ed\u003c/em\u003e = 1.1).\u003c/p\u003e\n\u003cp\u003eSpinal mobility increased by 18\u0026ndash;48% across all BT groups\u0026nbsp;(\u003cem\u003ed\u003c/em\u003e = 0.4\u0026ndash;0.7), with the 6-days\u0026nbsp;BT and 11-days BT with NT showing the best results. Inpatient BT treatment improved mobility by 2.3 cm.\u003c/p\u003e\n\u003cp\u003eHand strength improved by 4\u0026ndash;5% after 11-days\u0026nbsp;outpatient and inpatient treatments (\u003cem\u003ep\u003c/em\u003e = 0.003\u0026ndash;0.023), with right-hand gains of 1.5\u0026ndash;1.7 kg and left-hand gains of 1.2\u0026ndash;1.5 kg, though with small effect sizes.\u003c/p\u003e\n\u003cp\u003ePain medication use decreased by 21\u0026ndash;38% in BT groups (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01, \u003cem\u003ed\u003c/em\u003e = 0.4\u0026ndash;0.7), with outpatient groups showing greater reductions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eImpact of BT on fatigue, sleep, and life quality\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore the study, mild fatigue levels ranged from 23.59 to 28.40, lowest in the control group. At T1, fatigue significantly decreased in all BT groups, with the 11-days outpatient BT group reaching normal levels (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001).\u0026nbsp;Reductions ranged from\u0026nbsp;14\u0026ndash;18%,\u0026nbsp;with\u0026nbsp;medium to large effect sizes (\u003cem\u003ed\u003c/em\u003e = 0.57\u0026ndash;0.82).\u0026nbsp;The\u0026nbsp;greatest improvements\u0026nbsp;were seen in the 11-days\u0026nbsp;BT with NT\u0026nbsp;and\u0026nbsp;inpatient groups (Fig. 2).\u003c/p\u003e\n\u003cp\u003eSleep quality\u0026nbsp;improved significantly in all\u0026nbsp;BT groups\u0026nbsp;(\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), increasing from\u0026nbsp;T0 (4.55\u0026ndash;6.33) to T1 (6.47\u0026ndash;7.82).\u0026nbsp;All BT groups reached \u0026quot;good\u0026quot; sleep quality.\u0026nbsp;Improvements ranged from\u0026nbsp;25\u0026ndash;50%,\u0026nbsp;with\u0026nbsp;medium to large effect sizes (\u003cem\u003ed\u003c/em\u003e = 0.68\u0026ndash;1.47).\u0026nbsp;The\u0026nbsp;11-days\u0026nbsp;inpatient BT group\u0026nbsp;showed the\u0026nbsp;largest effect size (-1.5) (Fig.3).\u003c/p\u003e\n\u003cp\u003eAt T0, mean scores ranged from 2.16 to 2.72. By T1, BT groups showed 15\u0026ndash;25% improvements (\u003cem\u003ed\u003c/em\u003e = 0.5\u0026ndash;1.0), with the largest effects in 6-days outpatient and 11-days inpatient BT. No significant changes were observed in the NT alone or the control groups. (Fig. 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.4.\u0026nbsp;Differences in short-time BT between groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePairwise comparisons (T1, N=340, Mann-Whitney U) revealed significant differences between the treatment and control groups after the intervention (Online Resource 3). MSK pain frequency decreased in the 6-days BT, 11-days BT with NT, and inpatient groups compared to controls (\u003cem\u003er=\u003c/em\u003e 0.2). Pain intensity was significantly lower in the 11-days\u0026nbsp;BT groups (\u003cem\u003er=\u003c/em\u003e 0.3\u0026ndash;0.4) compared to controls, with BT with NT being more effective than NT alone (\u003cem\u003er=\u003c/em\u003e 0.3). Muscle spasm was reduced more in the 6-days\u0026nbsp;outpatient BT\u0026nbsp;and\u0026nbsp;11-days\u0026nbsp;inpatient groups compared to controls (\u003cem\u003er=\u003c/em\u003e 0.2). Muscle tension was significantly reduced in all BT groups (\u003cem\u003er=\u003c/em\u003e 0.4\u0026ndash;0.8), with\u0026nbsp;lower back muscle tension notably lower in the NT group than in controls. Hand strength increased more in the 6-days\u0026nbsp;BT group compared to the 11-days\u0026nbsp;outpatient BT group (\u003cem\u003er=\u003c/em\u003e 0.2), and left-hand strength was higher in the 11-days inpatient group than in 11-days outpatient BT and control groups (\u003cem\u003er=\u003c/em\u003e 0.2). Fatigue decreased more in the 11-days\u0026nbsp;outpatient and inpatient BT groups than in controls (\u003cem\u003er=\u003c/em\u003e 0.3). Sleep quality improved in the 6-days\u0026nbsp;and \u0026nbsp;11-days outpatient\u0026nbsp;BT with NT, and 11-days inpatient groups compared to controls (\u003cem\u003er=\u003c/em\u003e 0.3\u0026ndash;0.4), with BT with NT more effective than NT alone. In the 11-days\u0026nbsp;outpatient group, sleep quality was better than in the inpatient group (\u003cem\u003er=\u003c/em\u003e 0.3). Quality of life was significantly improved in the 11-days inpatient group compared to controls (\u003cem\u003er=\u003c/em\u003e 0.2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eLong-term effect on study outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring follow-up (GLM, N=235), no consistent changes in pain frequency or intensity were observed in any group (Online resource 4). However, the occurrence of muscle spasm decreased by 18% from baseline for up to six months in the 11-days inpatient BT group. A long-term reduction in muscle tension in the \u003cem\u003em. trapezius\u003c/em\u003e region was observed in all BT groups for up to six months, with reductions of up to 32% from baseline.\u0026nbsp;In the\u0026nbsp;lower back region, this effect was noted in the 6-days and 11-days outpatient BT groups, with reductions of up to 33% from baseline.\u0026nbsp;In the\u0026nbsp;thigh region, muscle tension decreased by up to 37% from baseline for up to three months in the 11-days outpatient BT combined with NT\u0026nbsp;and\u0026nbsp;inpatient BT groups.\u003c/p\u003e\n\u003cp\u003eSpinal mobility improved for up to six months in the 11-days BT with NT\u0026nbsp;\u0026nbsp;(by\u0026nbsp;65% from baseline)\u0026nbsp;and\u0026nbsp;inpatient (by\u0026nbsp;45%) groups, with an increase of up to\u0026nbsp;2.2 cm. Hand strength increased for up to three months in the 11-days outpatient BT\u0026nbsp;(right hand: up to 1.7 kg),\u0026nbsp;BT with NT\u0026nbsp;(left hand: up to 2.6 kg), and control\u0026nbsp;(up to 2.0 kg) groups. The use of pain medications decreased for up to six months in the 11-days\u0026nbsp;outpatient BT group (by up to 27%) and for up to three months in the 6-days BT group (by up to 40%).\u003c/p\u003e\n\u003cp\u003eFatigue was consistently reduced by 15\u0026ndash;18% for up to six months in the 11-days\u0026nbsp;outpatient BT with NT\u0026nbsp;and\u0026nbsp;inpatient groups. Sleep quality improved for up to six months in all BT groups, with improvements ranging from 17% to 68%. 11-days\u0026nbsp;inpatient treatment yielded the greatest improvements in sleep quality,\u0026nbsp;with a mean increase of 2.9 points at three months (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) and 3.1 points at six months (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). The control group exhibited the lowest improvement, with only slight improvements in sleep quality observed at three months.\u003c/p\u003e\n\u003cp\u003eAn improvement in quality of life, exceeding baseline assessments by 15\u0026ndash;18%, was observed for up to six months in the 6-days outpatient BT and 11-days inpatient BT groups. These findings highlight treatment-specific differences in MSK outcomes over time.\u003c/p\u003e\n\u003cp\u003e2.1. \u003cstrong\u003eDifferences in long-term treatment effects among study groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePost hoc pairwise comparisons using GLM (N=235) revealed several significant differences between study groups in the long term (Online resource 5). At 3 months, both 6-days and 11-days outpatient BT, with or without NT, significantly reduced muscle tension in the \u003cem\u003em. trapezius\u003c/em\u003e and thigh regions compared to the control group (p\u0026lt;0.05). At 6 months, these effects persisted: 6-days BT was more effective than control in reducing pain intensity (p=0.025) and tension in the \u003cem\u003em. trapezius\u003c/em\u003e region (p\u0026lt;0.05), while 11-days outpatient BT reduced lower back muscle tension more effectively than both NT alone (p=0.018) and controls (p=0.015). However, no significant differences were observed between the groups during follow-up for pain, muscle spasm, spinal mobility, hand strength, fatigue, sleep, and life quality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eThe relations of stress and MSK associated symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStress was positively correlated with fatigue (r = 0.417), physical (r = 0.449) and mental health (r = 0.549), quality of life (r = 0.519), MSK pain frequency (r = 0.294), pain intensity (r = 0.267), and pain medication use (r = 0.314), indicating that higher stress is linked to more pain and MSK related symptoms. MSK pain frequency showed moderate correlations with fatigue (r = 0.119), physical health (r = 0.273), mental health (r = 0.116), and quality of life (r = 0.255), with stronger links to pain intensity (r = 0.570), muscle spasm (r = 0.411), and pain medication use. Pain intensity correlated with physical health (r = 0.156), quality of life (r = 0.199), and muscle spasm (r = 0.172), with a strong link to MSK pain frequency (r = 0.570) (Online Resource 6).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStress, pain frequency, and pain intensity were all interrelated, suggesting stress plays a significant role in MSK pain development and severity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp; \u0026nbsp; \u0026nbsp;Pain and fatigue gender differences\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate potential gender-based differences in pain intensity and fatigue levels, we compared pain and fatigue before and after treatment within the study groups (Online Resource 7). The results indicated that, overall, there were no significant differences in pain intensity or fatigue levels between male and female participants. Within the individual study groups, pain intensity did not vary by gender. However, prior to treatment, women in the 11ABT group exhibited higher fatigue levels, which could have been influenced by the substantially larger number of women in this group (47 vs. 7). Therefore, it can be concluded that gender did not significantly affect pain intensity or fatigue\u0026nbsp;levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eSafety of BT treatment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse reaction (AR) incidence varied by BT type: mineral water (13.8\u0026ndash;31.3%), peloid therapy (8.6\u0026ndash;14.1%), and salt therapy (3.3\u0026ndash;21.9%). ARs differed significantly between groups for mineral water \u003cem\u003e(\u003cem\u003ep\u003c/em\u003e =\u003c/em\u003e 0.005) and salt therapy \u003cem\u003e(\u003cem\u003ep\u003c/em\u003e \u0026lt;\u003c/em\u003e 0.001) but not for peloid therapy \u003cem\u003e(\u003cem\u003ep\u003c/em\u003e =\u003c/em\u003e 0.553). The highest AR rates occurred after 11-days course of mineral water (inpatient/outpatient) and salt therapy (outpatient), while the lowest were in 6-days BT group. Common ARs\u0026mdash;drowsiness, fatigue, skin irritation, thirst, and redness\u0026mdash;were mostly temporary. Mud and salt therapy ARs were linked to initial blood pressure, while mineral water and mud therapy ARs were associated with initial skin conditions. One participant (0.3%) discontinued due to heat intolerance. 87% of participants rated BT as very safe, with no significant safety differences between groups.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study investigated the short- and long-term effects of balneotherapy on musculoskeletal pain and associated symptoms, as well as differences across treatment protocols. The findings confirm the immediate benefits of BT, with the magnitude of change varying by treatment type. Long-term effects were sustained for most parameters, except MSK pain, with improvements persisting up to six months. Notably, differences between BT groups diminished over time, emphasizing the importance of personalized interventions.\u003c/p\u003e\n\u003cp\u003eThe results demonstrate significant short-term improvements across all BT groups in pain frequency and intensity, frequency of muscle spasms, muscle tension in different regions, spinal mobility, use of pain medications (analgesic), fatigue, sleep quality, and quality of life. These improvements ranged from 4% to 68% from baseline, depending on the variable, with effect sizes ranging from small to large. The most pronounced changes were observed following the 11-daysoutpatient BT combined with NT and inpatient treatment. According to our findings, gender did not have a significant effect on pain intensity or fatigue levels. Additionally, we found that pain intensity and frequency were closely linked to physical and mental health, fatigue, and quality of life. The effects of multi-faceted BT, supported by the project\u0026apos;s findings, confirmed that distress intensity was significantly reduced across various treatment modalities utilizing different natural resources, regardless of treatment duration, composition, or season (mean difference 1\u0026ndash;3.5 points, VAS, Cohen\u0026apos;s d 0.4\u0026ndash;1.3). This reduction in distress was further supported by a significant decrease in salivary cortisol levels, which dropped by up to 0.87 nmol/L in the BT plus nature therapy (NT) group (Cohen\u0026apos;s d = 0.4, small effect), indicating a physiological response to the intervention (Rapolienė et al. 2025).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLong-term benefits were sustained for most parameters, except for MSK pain, with improvements lasting up to six months. The magnitude of change ranged from 15% to 65% from baseline across most BT groups. BT, particularly 11-days regimens with NT or inpatient care, showed superior outcomes over the control and NT alone, with small to medium effect sizes. Differences between BT groups were minimal, except for reduced pain frequency and intensity in the 11-days BT groups, improved left-hand strength in inpatients, and better sleep quality in the 11-days outpatient BT group. At the 6-month follow-up, BT benefits persisted, especially in muscle relaxation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study aligns with previous research showing that short-term of ST, including BT, effectively manages MSK pain, joint swelling, and low back pain, often outperforming or matching control treatments in the short and long term (Fioravanti et al. 2003, 2015; Karag\u0026uuml;lle et al. 2015; Ortega et al. 2017; Rapoliene et al. 2020; Bestaş et al. 2022). Greater reductions in some groups are likely due to higher baseline pain levels. The greatest improvement was observed in the combined BT and NT group, supporting their synergistic effects in chronic pain management (Jimenez et al. 2021; Smith et al. 2024). Effect sizes ranged from 0.7 to 1.8, with pain reductions between 1.4 and 2.3 points on the NRS, higher than typical aquatic exercise interventions (0.19\u0026ndash;0.32) (Verhagen et al., 2012), land exercises (Eversden et al 2007), and similar to ST treatments (Maccarone et al., 2023). A study on elderly osteoarthritis patients reported even greater pain reductions after BT sessions, along with a significant decrease in non steroidal anti-inflammatory drugs (NSAIDs) use (Ga\u0026aacute;l et al. 2008). Our findings are consistent with previous studies on mineral water baths, where higher concentrations led to greater pain (3.4 VAS) and fatigue reductions (Rapoliene et al. 2016), while lower (20-60 g/l) provided smaller, short-term benefits on pain and spine mobility, and three month-lasting sleep quality improvements (Rapoliene et al. 2020). The stronger effects in this study likely result from the integration of multiple BT modalities.\u003c/p\u003e\n\u003cp\u003eReduction in muscle spasms and tension aligns with previous research showing the positive effects of bath in mineral water and curative mud baths on MSK pain and muscle tension, supporting their use as drug-free interventions for mild MSK issues (Tuulik et al. 2022). While hand strength improvements were small after 2-week BT treatment, these changes suggest BT may contribute to functional muscle strength improvements. A Romanian study reported similar findings, with improved grip strength in sarcopenia patients after 10 daily sessions of sapropelic mud and salt water therapy, along with significant pain reduction (VAS 4, p \u0026lt; 0.0001) (Stanciu et al. 2023).\u003c/p\u003e\n\u003cp\u003eOur findings on the positive changes in MSK symptoms are in agreement with with previous studies and systematic reviews, which highlight the beneficial effects of BT and ST using various resources. These interventions have been shown to improve pain, decrease the number of tender points, enhance joint and spinal mobility, and support motor and functional recovery, along with other investigated symptoms and signs (Bai et al. 2019; Balogh et al. 2005; Cantista et al. 2020; Dilek\u0026ccedil;i et al. 2020; G\u0026aacute;ti et al. 2018; Haji et al. 2021; Manica et al. 2024; Ozkuk et al. 2019; Santos et al. 2016; Protano et al. 2023; Popławska et al. 2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBT significantly reduced fatigue, improved sleep, and enhanced quality of life with medium-to-large effect, supporting its broad benefits for individuals with MSDs. These findings align with evidence that 2-week BT interventions positively impact sleep, mood, and well-being with the effect of 0.581 to 0.980 (Ko\u0026ccedil;ak et al. 2020; Maccarone et al. 2023; Silva et al. 2023; Castelli et al. 2022; Yang B et al. 2018). ST studies also show similar benefits, reducing fatigue, pain, and post-COVID-19 limitations while improving physical (+72%) and emotional (+66%) function (Costantino et al., 2024). BT was linked to better functional status, mental health, and quality of life in chronic low back pain patients (Terzić Marković et al. 2024). Our study confirms the interconnection between pain, fatigue, and overall well-being, with the inpatient BT group showing the greatest stress reduction (mean difference of 2.4 VAS, p \u0026lt; 0.001), lasting up to three months (Rapolienė et al. 2024).\u003c/p\u003e\n\u003cp\u003eBT\u0026rsquo;s positive effects stem from its ability to reduce muscle spasms and joint load while enhancing pain tolerance, circulation, and connective tissue elasticity. BT has been shown to positively influence inflammation, oxidative stress, cartilage health, and immune function in individuals with chronic MSK conditions. Research using animal models of osteoarthritis and rheumatoid arthritis suggests that various BT treatments help alleviate pain, reduce inflammation, and improve mobility while lowering oxidative stress and inhibiting enzymes that degrade joint tissues. Additionally, in vitro studies indicate that mineral water and its components exhibit anti-inflammatory, antioxidant, and cartilage-protective effects on joint and bone cell cultures (Cheleschi et al. 2021; Masiero et al. 2020; Silva et al. 2023; G\u0026aacute;lvez et al. 2024).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDetermining the most effective BT modality for MSK health remains challenging, as all treatment protocols showed improvements. Similarly, other treatments vary in effectiveness\u0026mdash;a review of 137 studies found effect sizes ranging from 0.63 (hyaluronic acid) to 0.18 (acetaminophen) for osteoarthritis, with NSAIDs offering short-term relief (Bannuru et al. 2015; da Costa et al. 2021).\u003c/p\u003e\n\u003cp\u003eThe optimal BT duration remains debated, with evidence supporting programs ranging from three days to three weeks (Noriega et al. 2020; Gebretsadik\u0026nbsp;et al. 2021;\u0026nbsp;Maraver et al. 2020; Karag\u0026uuml;lle et al. 2017; 2021; \u0026Ouml;zkuk et bal. 2019). The development of guidelines for BT treatment methodology, ensuring both efficacy and practicality for clinicians, is crucial. Further research is needed to establish standardized guidelines tailored to predominant specific symptoms, as well as to compare the short- and long-term effects of pharmacological and non-pharmacological interventions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the rising burden of chronic MSK conditions (WHO 2022; Hacker 2024), effective, non-invasive pain management strategies are critical. BT, particularly in combination with NT, presents a promising complementary therapy alongside pharmacological and rehabilitation interventions (Groven et al. 2020). While randomized controlled trials support BT\u0026rsquo;s role in multidisciplinary treatment (Maier et al. 2024), further research is needed to refine standardized guidelines for optimal intervention protocols. Large-scale trials comparing BT with pharmacological and non-pharmacological treatments will be essential for integrating BT into modern clinical practice (Fioravanti et al. 2020).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitation of study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. It focused on patients with moderate stress and nonspecific MSK pain. Participant dropout during follow-up reduced the sample size for long-term analysis. Managing multiple groups and parameters led to poor compliance and challenges in follow-up attendance. Clustering of participants before randomization introduced inconsistencies in the sample. The use of multiple research centers limited conclusions about individual spa treatment components, and variability in treatment settings highlighted the need for standardized approaches. Finally, broader challenges in balneology research, such as small sample sizes, short follow-up, and lack of standardization, hinder definitive conclusions and emphasize the need for larger, rigorous studies.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study demonstrates the positive effects of balneotherapy on musculoskeletal pain, mobility, muscle strength, cramps, tension, fatigue, sleep, and quality of life, with varying efficacy depending on the treatment regimen. Significant short-term improvements were observed, with some long-term benefits lasting up to six months. BT, especially when combined with nature-based interventions or inpatient care, can lead to sustained improvements in MSDs, although periodic treatments may be necessary. Future studies with larger sample sizes and longer follow-up are needed to explore the long-term impact of BT and optimize treatment protocols for different MSK conditions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e6ABT: 6 days of Ambulatory BT/outpatient (1-week)\u003c/p\u003e\n\u003cp\u003e11ABT: 11 days of Ambulatory BT/outpatient (2-weeks)\u003c/p\u003e\n\u003cp\u003e11ABTNT: 11 days of Ambulatory BT with Nature Therapy (NT)/outpatient (2-weeks)\u003c/p\u003e\n\u003cp\u003e11BTS: 11 days of BT Stationary/inpatient (2-weeks)\u003c/p\u003e\n\u003cp\u003e11NT: 11 days of Nature therapy/outpatient (2-weeks).\u003c/p\u003e\n\u003cp\u003e11C: control group (no treatment) (2-weeks).\u003c/p\u003e\n\u003cp\u003eAIOS- arizona integrative outcomes scale\u003c/p\u003e\n\u003cp\u003eBT balneotherapy\u003c/p\u003e\n\u003cp\u003eFAS- fatigue assessment scale\u003c/p\u003e\n\u003cp\u003eGLM- general linear model Repeated Measures\u003c/p\u003e\n\u003cp\u003eMSDs- \u0026nbsp;musculoskeletal disorders\u003c/p\u003e\n\u003cp\u003eMSK- musculoskeletal\u003c/p\u003e\n\u003cp\u003eSQS- single- item sleep quality scale\u003c/p\u003e\n\u003cp\u003eST- spa therapy\u003c/p\u003e\n\u003cp\u003eQoL- quality of life\u003c/p\u003e\n\u003cp\u003eT0- baseline examination\u003c/p\u003e\n\u003cp\u003eT1- after treatment examination\u003c/p\u003e\n\u003cp\u003eT2- after 3- month follow-up\u003c/p\u003e\n\u003cp\u003eT3- after 6- month follow-up\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e The authors report no conflicts of interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Conceptualization, L.R. and A.F.; methodology, L.R and A.F.; software, A.M. and V.K.; validation, L.R., A.M., and V.K.; formal analysis, A.M. and V.K..; investigation, L.R, G.T.; resources, L.R.; data curation, L.R, and A.M..; writing\u0026mdash;original draft preparation, L.R.; writing\u0026mdash;review and editing, A.F.; visualization, L.R., and G.T.; supervision, A.F.; project administration, L.R..; funding acquisition, L.R. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research was funded by the\u0026nbsp;\u003cstrong\u003eResearch Council of Lithuania and\u003c/strong\u003e the Ministry of Economy and Innovation\u0026nbsp;(P\u003cstrong\u003eroject \u0026quot;Effectiveness and safety of the use of Lithuania\u0026apos;s unique natural resources for improving the mental and physical health of the organism experiencing stress\u0026quot; (LUGISES) grant number S-REP-22-6).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThe study was conducted following the Declaration of Helsinki, approved by the Kaunas Regional Research Ethics Committee (permission code BE-2-87 and date of approval 28 of November 2022), and registered in ClinicalTrial.gov (Identifier: NCT06018649) (30/08/2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from all subjects included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e The raw data supporting the conclusions of this article will be made available by the authors on\u0026nbsp;\u003cstrong\u003ereasonable\u0026nbsp;\u003c/strong\u003erequest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e: We are grateful to the chief executives and staff of the research centers at Gradiali, Eglė, Draugystė, Tulpė, Versmė, and Atostogų Parkas, as well as our colleagues at Klaipeda University, who contributed to the execution of this large-scale research. Special thanks to Dr. Aelita Bredelyte for her contributions to the investigation, data curation, and resource management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analysis, or interpretation of data; or in the writing of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAboushaar N, Serrano N. The mutually reinforcing dynamics between pain and stress: mechanisms, impacts and management strategies. Front Pain Res (Lausanne). 2024 Nov 18;5:1445280. doi: 10.3389/fpain.2024.1445280. PMID: 39624230; PMCID: PMC11609167\u003c/li\u003e\n\u003cli\u003eAntonelli M, Donelli D (2018b) Effects of balneotherapy and spa therapy on levels of cortisol as a stress biomarker: a systematic review. 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European Journal of Pain 29(2):e4727. https://doi. org/10.1002/ejp.4727 \u003c/li\u003e\n\u003cli\u003eSnyder E, Cai B, DeMuro C, Morrison MF, Ball W (2018) A New Single-Item Sleep Quality Scale: Results of Psychometric Evaluation in Patients With Chronic Primary Insomnia and Depression. J Clin Sleep Med 14(11):1849-1857. doi:10.5664/jcsm.7478\u003c/li\u003e\n\u003cli\u003eStanciu LE, Iliescu MG, Oprea C, Ionescu EV, Petcu A, Ciortea VM, Petcu LC, Apostol S, Nedelcu AD, Motoașcă I, Irsay L (2023) The Impact of Complex Rehabilitation Treatment on Sarcopenia-Pathology with an Endocrine Morphological Substrate and Musculoskeletal Implications. Medicina (Kaunas, Lithuania), 59(7): 1238. https://doi.org/10.3390/medicina59071238.\u003c/li\u003e\n\u003cli\u003eTerzic Markovic D, Kocic S, Bradic J, Jurisic-Skevin A, Jakovljevic B., Majstorovi, B, Dimoski Z, Stojanovic G, Maksimovic V, Pavlovic Jugovic K, Dabic M, Jezdimirovic D, \u0026amp; Zivanovic S. (2024). 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Best Pract Res Clin Rheumatol 26(3):335-43. doi: 10.1016/j.berh.2012.05.008.\u003c/li\u003e\n\u003cli\u003eVilla-Forte A (2024) Evaluation of the patient with Joint symptoms. MSD Manual Proffesional Version. https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/approach-to-the-patient-with-joint-symptoms/evaluation-of-the-patient-with-joint-symptoms.\u003c/li\u003e\n\u003cli\u003eWHO (2022). Musculoskeletal health. 14 July 2022. https://www.who.int/news-room/fact-sheets/detail/musculoskeletal-conditions\u003c/li\u003e\n\u003cli\u003eWyns A, Hendrix J, Lahousse A, De Bruyne E, Nijs J, Godderis L, Polli A (2023) The Biology of Stress Intolerance in Patients with Chronic Pain - State of the Art and Future Directions. \u003cem\u003eJournal of Clinical Medicine\u003c/em\u003e\u003cem\u003e.\u003c/em\u003e \u003cem\u003e12\u003c/em\u003e(6):2245. https://doi.org/10.3390/jcm12062245\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-biometeorology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbm","sideBox":"Learn more about [International Journal of Biometeorology](http://link.springer.com/journal/484)","snPcode":"484","submissionUrl":"https://www.editorialmanager.com/ijbm/default2.aspx","title":"International Journal of Biometeorology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"balneotherapy, fatigue, musculoskeletal pain, peloidotherapy, spa therapy, sleep","lastPublishedDoi":"10.21203/rs.3.rs-5989141/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5989141/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eBalneotherapy has emerged as a promising therapeutic approach for managing musculoskeletal diseases (MSDs), offering evidence-based benefits in reducing pain, enhancing mobility, and improving quality of life.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aims to evaluate the effects of balneotherapy on musculoskeletal pain, fatigue, and associated symptoms in individuals experiencing stress.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA six-month randomized controlled parallel-group study was conducted at six medical spa centers in Lithuania, involving 373 patients with stress levels\u0026thinsp;\u0026ge;\u0026thinsp;3. Participants underwent 6\u0026ndash;11 days outpatient or inpatient balneotherapy programs, with MSDs-related outcomes assessed at a six-month follow-up. Statistical analyses were performed using SPSS Version 28.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBalneotherapy led to significant improvements in multiple parameters. Pain frequency and intensity decreased, with effect sizes ranging from small to large, accompanied by notable reductions in muscle spasms and tension. Spine mobility improved, pain medication use decreased, and hand strength increased following the 11-days medical spa treatment. Fatigue levels declined, while sleep quality and overall quality of life improved significantly, with effect sizes ranging from medium to large. Long-term benefits in muscle tension, spine mobility, fatigue, and quality of life were observed for up to six months. Comparative analysis indicated that balneotherapy was more effective than both non-treatment and nature-based therapy alone.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBalneotherapy, particularly when combined with nature-based interventions or inpatient approaches, effectively improves musculoskeletal health, with benefits lasting up to six months.\u003c/p\u003e","manuscriptTitle":"Short and Long-Term Effects of Balneotherapy on Musculoskeletal Pain and Fatigue Associated with Stress","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-07 10:13:36","doi":"10.21203/rs.3.rs-5989141/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-04-02T18:38:25+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-02T18:30:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-01T01:45:11+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Biometeorology","date":"2025-03-31T15:40:39+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-biometeorology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijbm","sideBox":"Learn more about [International Journal of Biometeorology](http://link.springer.com/journal/484)","snPcode":"484","submissionUrl":"https://www.editorialmanager.com/ijbm/default2.aspx","title":"International Journal of Biometeorology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"129e1735-2477-4ebf-b67c-851dcf997438","owner":[],"postedDate":"April 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-06-09T16:00:33+00:00","versionOfRecord":{"articleIdentity":"rs-5989141","link":"https://doi.org/10.1007/s00484-025-02936-1","journal":{"identity":"international-journal-of-biometeorology","isVorOnly":false,"title":"International Journal of Biometeorology"},"publishedOn":"2025-06-07 15:57:12","publishedOnDateReadable":"June 7th, 2025"},"versionCreatedAt":"2025-04-07 10:13:36","video":"","vorDoi":"10.1007/s00484-025-02936-1","vorDoiUrl":"https://doi.org/10.1007/s00484-025-02936-1","workflowStages":[]},"version":"v1","identity":"rs-5989141","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5989141","identity":"rs-5989141","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}