Effects of Combined Training Programs in Individuals with Fibromyalgia: A Systematic Review

Fibromyalgia is a rheumatic disease characterised by chronic widespread muscular pain and its treatment is carried out by pharmacological interventions. Physical exercise and a healthy lifestyle act as an important mechanism in reducing the symptoms of the disease. The aims of this study were to analyse and systematise the characteristics of combined training programs (i.e., type and duration of interventions, weekly frequency, duration and structure of training sessions and prescribed intensities) and to analyse their effects on people diagnosed with fibromyalgia. A systematic literature search was performed using the PRISMA method and then randomised controlled trial articles that met the eligibility criteria were selected. The Physiotherapy Evidence Database scale was used to assess the quality and risk of the studies. A total of 230 articles were selected, and in the end, 13 articles met the defined criteria. The results showed different exercise interventions such as: combined training, high-intensity interval training, Tai Chi, aerobic exercise, body balance and strength training. In general, the different interventions were beneficial for decreasing physical symptoms and improving physical fitness and functional capacity. In conclusion, a minimum duration of 14 weeks is recommended for better benefits. Moreover, combined training programs were the most effective for this population, in order to reduce the symptoms of the disease with a duration between 60 and 90 min, three times a week with a light to moderate intensity.


Introduction
Fibromyalgia (FM) is defined as a chronic rheumatic disease and is characterised by chronic widespread pain, muscle stiffness, sleep disturbances and cognitive problems [1][2][3][4]. In addition to these, the following symptoms are also observed: a feeling of fatigue and changes in the psychological state [5]. Moreover, FM can include muscle pain in the tender points, excessive fatigue, muscle strength loss and some psychological problems as mentioned before (i.e., sleep issues, anxiety, depression and reduced levels of satisfaction with life and self-esteem) [6,7]. Most of the time, the diagnosis is quite difficult to perform because there is no accurate (i.e., validated) diagnostic test to identify the disease. Thus, the diagnosis of this disease is carried out through palpation from tender points specific for FM [1].
Studies indicate that FM affects, on average, 2.1% of the world's population and 2.31% of the European population, implying a painful loss of quality of life for the people who suffer from it and high economic costs [8]. The literature also points out that FM is more prevalent in women with values between 2.4% and 6.8% and in urban areas between 0.7% and 11.4% [9]. In Portugal, the prevalence is estimated at 1.7% (1.1% to 2.1%) [10].
Scientifically, the exact cause of the origin of FM remains unknown, so all the treatments of this disease are directed towards the reduction in the signs and symptoms presented [11]. In addition, the clinical control of the patient is carried out mainly through pharmacological interventions [12]. However, this type of treatment is not effective in solving functional problems, namely the loss of mobility and muscle strength and power, which negatively interferes with the quality of life of patients [13,14]. In this sense, some studies have demonstrated the importance of including non-pharmacological treatments in this pathology, mainly the regular practice of physical exercise associated with a healthy lifestyle [5,15].
Physical exercise promotes several benefits on a physical and psychological level. A physical exercise program works as an important mechanism that positively influences this population, attenuating the main symptoms, such as: the feeling of fatigue, depression, anxiety, muscle stiffness and sleep disturbances [16]. In this way, physical exercise has been used as a form of non-pharmacological intervention [17].
The American College of Sports Medicine (ACSM) recommends performing strength exercises (2 to 3 days/week), aerobic exercises (2 to 4 days/week) and flexibility exercises (1 to 3 days/week) to attenuate or reduce the signs and symptoms of FM [18]. In this sense, a combined training program may adjust to the recommendations for this population [19]. due to the fact that it involves aerobic, strength and stretching exercises, simultaneously, inducing several important adaptations in order to cover a greater number of symptoms. Consequently, strength, power, and aerobic capacity and power improvements may occur [20]. This type of training can be performed in the same session or in different sessions [21]. In this sense, aerobic exercise induces adaptations in various functional capacities such as transport, capture and the use of oxygen [22]; strength training becomes essential for increasing muscle strength [23,24]; and stretching exercises are beneficial to reduce the loss of mobility due to its constant immobilisation associated with pain [25].
To better understand the benefits of different types of exercises and physical therapy in FM, a set of studies were reviewed to obtain a comprehensive guideline for the prescription of exercise in this population [26]. The results suggest that individuals with FM have different responses to different types of exercise programs (e.g., aerobic training or strength training), since these same individuals present a great diversity of signs and symptoms. Accordingly, preference should be given to more global exercise protocols that are able to provide positive effects to the greatest number symptoms possible. In this way, it is important to better understand the effects of combined training and recommendations regarding the prescription of physical exercise in individuals diagnosed with FM.
In this way, the objectives of this systematic review were to analyse and systematise the characteristics of combined training programs (i.e., type and duration of interventions, weekly frequency, duration and structure of training sessions and prescribed intensities) and to analyse their effects on people diagnosed with FM.

Materials and Methods
This systematic review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 [27] and the guidelines for performing systematic reviews in sports sciences [28]. The systematic review protocol was a priori registered in the OSF platform with the associated project number osf.io/v37s4.

Eligibility Criteria
The studies included in the present systematic review had the following inclusion criteria: (i) participants ≥ 18 years old with FM and autonomy, without other diseases (e.g., diabetes, hypertension and/or cardiovascular diseases); (ii) studies with combined training programs (aerobic and strength) with duration ≥4 weeks; (iii) exercise training programs supervised by a multidisciplinary team including a fitness exercise professional; (iv) randomised clinical trials; (v) studies written in English because it is the universal language.
The following items were considered the exclusion criteria: (i) participants < 18 years old with other diseases (e.g., diabetes, hypertension and/or cardiovascular diseases); (ii) studies with durations lower than 4 weeks and/or without combined training; (iii) studies written in other languages than English; (iv) other studies than randomised clinical trials.

Information Sources and Search Strategy
A systematic search of three databases (Web of Science, PubMed and EBSCO) was performed until 14 September 2022. Additionally, a manual search on the references of the included articles was also performed.
The search strategy included the Boolean AND/OR and the following keywords: "fibromyalgia" AND "concurrent training" OR "combined training" OR "cross training". The search strategy and their specificities from each database are presented in Table 1.

Specificities of the Databases Search Strategy Number of Articles in Automatic Research
PubMed Search for title and abstract also includes keywords ("fibromyalgia") AND ("concurrent training" OR "combined training" OR "cross training" 280 Web of Science Search for title and abstract also includes keywords ("fibromyalgia") AND ("concurrent training" OR "combined training" OR "cross training" 160 EBSCO Search for title and abstract also includes keywords ("fibromyalgia") AND ("concurrent training" OR "combined training" OR "cross training" 0

Selection and Data Collection Processes
All articles found by the aforementioned search strategy were evaluated by two authors (M.S. and A.D.M.) through titles and their abstracts in order to exclude duplicates and articles that did not meet the inclusion criteria. In addition, the abstracts that did not provide enough information were selected for a complete evaluation of the full article. In a second phase, the two authors evaluated all the articles in full to carry out a second selection according to the inclusion criteria. The lack of consensus between the two investigators was resolved in a meeting with the third investigator (R.O.). Then, M.S. and R.O. extracted the data while J.P.B reviewed the process.

Data Items
The following data were extracted from the selected articles: population characteristics such as sample size, sex, age, years of diagnosed FM, country, body mass index (BMI); intervention: characteristics of combined training programs (i.e., exercises and materials; weekly frequency and duration of training programs; intensity; sets and repetitions); outcomes: instruments/tools (type, manufacturer and questionnaires); aim and main results of the studies.

Study Risk-of-Bias Assessment
The Physiotherapy Evidence Database (PEDro) scale was applied to assess the risk of bias of the included studies. This PEDro scale was previously validated and its reliability confirmed [29]. The PEDro scale rates eleven criteria topics, in which 10 classify the overall score of the article, ranging from 0 (lowest quality) to 10 (highest quality). The classification of the scores was the following: "poor" (<4 points), "fair" (4-5 points), "good" (6-8 points) and "excellent" (9-10 points). Two authors (A.D.M. and R.O.) independently reviewed and rated the included articles, based on the PEDro scale. Then, the same authors shared the scores and discussed them on a point-by-point basis. When a consensus was not reached, a third author (J.P.B) was invited to its classification to make a final decision.

Certainty Assessment
Based on the physiotherapy evidence database scale, Tulder et al.'s [30] criteria were applied to assess the interventions' evidence. Thus, a study with a physiotherapy evidence database score of ≥6 is considered level 1 (high methodological quality) (6-8: good, 9-10: excellent) and a score of 5 or less is considered level 2 (low methodological quality) (4-5: moderate; <4: poor).
Due to the clinical and statistical heterogeneity of the results, a qualitative review was performed, conducting a best-evidence synthesis [31,32]. This classification indicates that if the number of studies displaying the same level of evidence for the same outcome measure or equivalent is lower than 50% of the total number of studies, no evidence can be concluded regarding any of the methods involved in the study.

Study Identification and Selection
A total of 335 articles were found across the three databases. All studies were exported using reference management software (EndNoteTM 20.0.1, Clarivate Analytics, Philadelphia, PA, USA). A total of 105 duplicate articles were recorded and subsequently removed. The remaining 230 articles were analysed by their titles and abstracts, and when insufficient information was available, the article was read in full, resulting in the removal of 288 articles deemed not to be in the scope on this review. Finally, after a complete reading of all articles, 34 more articles were excluded for not meeting the eligibility criteria. Thus, 13 articles were included in this systematic review ( Figure 1).

Study Characteristics
The sample of articles selected for this systematic review included 13 studies published between 2000 and 2020. The studies covered an adult population diagnosed with FM and females with ages ranging from 30 to 59 years. There were different exercise interventions such as combined training, high-intensity interval training, Tai Chi, aerobic exercise, body balance and strength training. Moreover, several instruments/tests were used to assess pain, sleep quality, health status and strength gains in the upper and lower limbs. The characteristics of the articles included in the systematic review are presented in Table 2. Table 3 presents the assessment of risk of bias (PEDro scale). The criteria with lower scores were related to the blinding of all participants and blinding of all persons who administered the training protocols. Moreover, no study was classified with poor methodological quality.

Intervention Characteristics
The characteristics of the interventions exercise programs are presented in Table 4. Regarding the exercises included, only main phases of each training have been reported in the table.

Study characteristics
The sample of articles selected for this systematic review included 13 studies published between 2000 and 2020. The studies covered an adult population diagnosed with FM and females with ages ranging from 30 to 59 years. There were different exercise interventions such as combined training, high-intensity interval training, Tai Chi, aerobic exercise, body balance and strength training. Moreover, several instruments/tests were used to assess pain, sleep quality, health status and strength gains in the upper and lower limbs. The characteristics of the articles included in the systematic review are presented in Table 2.       : eligibility criteria were specified; C2: participants were randomly allocated to groups; C3: allocation was concealed; C4: the groups were similar at baseline regarding the most important prognostic indicators; C5: there was blinding of all participants; C6: there was blinding of all therapists who administered the therapy; C7: there was blinding of all assessors who measured at least one key outcome; C8: measures of at least one key outcome were obtained from more than 85% of the participants initially allocated to groups; C9: all participants for whom outcome measures were available received the treatment or control condition as allocated, or, where this was not the case, data for at least one key outcome were analysed according to "intention to treat"; C10: the results of between-group statistical comparisons are reported for at least one key outcome; C11: the study provides both point measures and measures of variability for at least one key outcome. Note: C1 values do not count for the total score.  In the Exercise + connective tissue massage group, pain, fatigue and sleep problems decreased; health status and quality of life improved (p < 0.05). Exercises with connective tissue massage were superior in improving pain, fatigue, sleep problems and role limitations due to physical health compared to exercise alone. General health perceptions parameters related to quality of life improved in the Exercise group than in the connective tissue massage group (p < 0.05).

Sañudo et al., 2013 [34]
Exercise Group: 10-15 min of AE. This is followed by 15-20 min of ST. Exercise Group + WBV: stood on the platform on both legs, with both knees in isometric 120 • flexion.
Exercises such as unilateral static squats were used.  An improvement from baseline in total FIQ score was observed in the exercise groups (p < 0.002) and it was accompanied by decreases in BDI scores of 8.5 (p < 0.001) and 6.4 (p < 0.001) points in the AE and CE groups, respectively. Relative to non-exercising controls, CE evoked improvements in the SF-36 physical functioning (p = 0.003) and bodily pain (p = 0.003) domains and it was more effective than AE for evoking improvements in the vitality (p = 0.002) and mental health (p = 0.04) domains. Greater improvements were observed in shoulder/hip range of motion and handgrip strength in the CE group.

Intensity Sets (N); Reps (N); Rest Results
Carbonell-Balza et al., 2010 [39] 1st session, pool resistance exercises developed at a slow pace using water and aquatic materials as a means of resistance; 2nd session, pool-balance-oriented activities: position changes, walking backwards, coordination through aquatic exercises and dance exercises; 3rd session: land-based AE and coordination through an exercise circuit and 90 min of psychological follow-up.   Exercise program in a heated pool and included resistance, flexibility, coordination and relaxation exercises. Non-Described Significant differences between the treatment group and the control group were found for the FIQ total score (p = 0.017) and the 6 min walk test (p < 0.001). Significant differences were also found for physical function, grip strength, pain severity, social functioning, psychological distress and quality of life for the treatment group.

Discussion
This systematic review aimed to analyse and systematise the characteristics of combined training programs and their effects in individuals diagnosed with Fibromyalgia. In the studies that were analysed, significant values were found for at least one of the evaluated parameters in all studies: (i) physical fitness tests [1,23,33,36,37,[39][40][41]; (ii) decreased symptoms and impact of FM on participants [1,5,15,17,23,33,36,37,41]; (iii) lower limb strength [1,15,33]. These results are in line with other authors who claim that physical exercise programs are important stimuli with positive influence, attenuating the symptoms of the disease, through changes in the hypothalamic-pituitary-adrenal axis (HPA)-resulting in the release of neurotransmitters due to exercise and controlling and/or reducing localised pain [16,42]. The major findings were the improvement of health-related life quality, pain intensity, stiffness, fatigue, physical function, withdrawals and absence of adverse events [17,[43][44][45]. It is relevant to point out that the thirteen studies in the present review provided moderate-to good-quality evidence for the mental dimension of the SF-36, VAS, FIQ, IPAQ, improvement in %fat, FM, BMI, 6-MWT and decrease in BDI-II, pain, fatigue and sleep. For instance, Bidonde et al. [43], who used a 15% threshold for calculation of the clinically relevant differences between experimental and control groups, reported that eight trials provided low-quality evidence for pain intensity, fatigue, stiffness and physical function, and moderate-quality evidence for withdrawals and HRQL at completion of the intervention (6 to 24 weeks).
Regarding exercise programs, previous research has shown that combined exercise programs have more positive effects compared to single-type exercises in FM [5,46]. Both the aerobic, strength and combined training protocols showed positive effects on the participants as also reported by Bidonde et al. [43]. Results showed that strength training, aerobic training and combined exercise programs resulted in favourable effects on FM symptoms [1,5,15,23,33,35,37,40,41]. Among these, the aerobic and combined interventions presented the highest effects on reducing the FIQ. Flexibility interventions, however, were not significant for reducing it [47][48][49]. Exercise programs lasting between 13 and 24 weeks and training sessions lasting no more than 60 min seemed to be associated with greater improvements in pain relief. Regarding the durations of the exercise programs, it seems that the programs longer than 6 weeks have more positive effects in this population. The association of aerobic exercises and Tai Chi also revealed positive effects on the symptoms presented for this population [5,23]. Aerobic exercises seem to be fundamental stimuli in exercise programs as they induce adaptations in several systems, namely in the cardiovascular, energetic, neuromuscular and neuroendocrine systems [43]. The latter allows an increase in serotonin and norepinephrine concentrations, with a consequent improvement in mood and greater physical well-being [16,47]. The norepinephrine and serotonin are involved in the modulation of arousal and mood and have been related to a variety of affective functions as well as associated clinical dysfunctions [50,51]. The norepinephrine modulates drive and energy and exerts a fine regulation of specific processes including learning, memory, sleep, arousal and adaptation [52]. Further, exercise appears to reduce serotonin transporter expression, increase serotonin levels and increase opioid levels in central inhibitory pathways, suggesting that exercise can reduce pain by utilising our endogenous inhibitory systems [50][51][52].
Regarding studies that evaluated the effects of aerobic exercise combined with Tai Chi exercises, it was found that participants who performed Tai Chi exercises improved in all assessment parameters, such as: impact of Fibromyalgia (FIQ); pain threshold; anxiety and depression (Hospital Anxiety and Depression Scale and BDI-II); and finally, sleep quality (Pittsburgh sleep quality index) compared to participants who performed only aerobic exercise, who had less improvement. It should also be noted that the combined Tai Chi and aerobic exercise groups improved the impact of Fibromyalgia (FIQ) more in the 24-week Tai Chi groups than in the 12-week group [17,36]. In addition to these parameters, there were also enhancements in functional capacity tests, such as sit and reach, and in the 6-MWT, in terms of depression and anxiety [36]. Regarding the type of exercise programs in order to reduce the symptoms of the disease, it appears that combined training programs are the most effective for this population.
Regarding the effects of exercise programs on muscle strength, the studies analysed in this systematic review found that the combined exercise of aerobics and strength promotes higher improvements in strength of concentric extension in the legs compared to the groups that performed only aerobic exercise or strength training [23,34,35,40]. Exercise programs including strength training, endurance and aerobics are accepted as a standard treatment protocol in FM [33,46,53,54]. There is growing evidence and a strong recommendation of using aerobic and strength training together for FM treatment [55].
The studies present different types of exercise, such as aerobics, strength, flexibility and combined interventions, but some studies point to the beneficial effects of using aquatic exercises. The properties of water and the physical activity performed in warm water seem to positively affect FM symptoms [39,41]. Consequently, these physiological changes can help to relax the muscles of the body [56]. In view of the benefits, the practice of physical exercises in water has been indicated to reduce symptoms such as pain, anxiety and depression [1].
As evidenced in the literature, the main symptoms of the disease are pain and constant immobilisation due to this fact [57]. As such, participants, when immobilised in their daily lives, lose muscle strength, which can lead to their disability and reduced quality of life [58]. Therefore, muscle strengthening exercises are essential for gaining muscle mass to generate the strength needed for daily tasks in this population. Nevertheless, it was also verified that a training protocol lasting up to 6 weeks did not generate greater benefits in relation to the evaluated parameters, such as the pain threshold, the impact of FM (FIQ), the functional capacity and the muscle strength gains that were greater between 14 and 24 weeks [15,34,39]. This evidence can be justified by the fact that this type of program is carried out with light to moderate intensity, due to the type of pathology and, as such, the results are not immediately observable, rather in the long term [52]. In addition to these parameters, the distance covered (6-MWT) improved significantly for participants in the exercise groups [14,33,40]. It is relevant to highlight that according to the ACSM [18], light aerobic activity is considered as <40% and moderate is 40 to 59% of the HR reserve.
However, in the study by Atan and Karavelioglu [1], high-intensity interval training (HIIT) plus strengthening and stretching exercises and moderate-intensity continuous training (MICT) plus strengthening and stretching exercises interventions showed significant improvements for FM effect, pain degree, functional capacity and quality of life compared to the control group. HIIT was not superior to MICT, but body composition parameters improved significantly only for the MICT group. It is important to draw attention to the fact that this study was the only one to use an intensity higher than 59% of the HR reserve and, even so, some improvements were not noted.
Light to moderate intensity programs are recommended for this type of population, which could be a reason why the HIIT group has not achieved improvements in pain symptoms [59]. However, it should be noted that when muscle strengthening exercises are combined with flexibility exercises, improvements were observed in the pain threshold, as well as in the participants' quality of life [34,35]. These improvements are justified by the fact that flexibility exercises are used as a way to increase the range of motion of one or more joints, reinforcing once again that these participants lose their mobility due to their constant mobilisation associated with pain [60]. An important point to consider is related to the intensity of strength training, since the protocols were not revealed. One study used six sets [30], while the other used just one set [31]. Even so, the number of repetitions followed the ACSM guidelines [18,61].
Studies that evaluated the effects of aerobic exercise combined with a physical exercise program for muscle strengthening and flexibility and the group that performed only supervised aerobic exercise demonstrated improvements in depression and in the quality of life associated with health in both groups. However, beneficial improvements in quality of life (SF-36) were observed in both exercise groups, with the supervised aerobic exercise group demonstrating improvements in the dimensions of physical and social functioning, while the supervised aerobic exercise group combined with muscle strengthening and flexibility exercises demonstrated improvements in the dimensions of physical functioning, body pain, vitality and mental health [5].
This study reviews the effects of combined training programs in individuals with FM, summarising recent reviews and describing new advances in the research related to progressive exercise regimens (aerobic, strength and flexibility interventions), and other forms of physical activity applied to FM (e.g., Tai Chi, Yoga and Pilates). However, since the population with FM presents heterogeneity, including different years of diagnosis, further investigation with regard to the short-and long-term response patterns to exercise and physical activity prescription may lead to a better customisation program in order to improve exercise adherence and optimise the benefits of exercise and physical activity.
Thus, future research examining the effects of exercise and physical activity for people with FM are needed to elucidate the best dose-response curve for exercise intensity, frequency and duration on symptoms. The assessment of the long-term effects on health in this population and how long the positive effects are sustained should also be studied. Another aspect to consider in future studies is the race description of participants. From the 13 studies included, only one described that information [15]. Finally, when conducting a future systematic review study on this population, a meta-analysis would be interesting to strengthen the results of the same intervention type, which was not possible in the present study.

Conclusions
According to the studies included in this systematic review, it was concluded that the practice of physical exercise is, in general, beneficial and essential for improving the symptoms of the disease, physical fitness and functional capacity and also in terms of anxiety and depression.
Through the analysed studies, the most appropriate training protocol for women diagnosed with FM, with the aim of mitigating the various symptoms of the disease, should contain the following parameters: The results of the present systematic review demonstrate that exercise programs that include aerobic exercises, strength training and stretching exercises are the most beneficial to reduce the symptoms of the disease. Aerobic exercises are essential for the transport and use of oxygen; strength training is essential for gaining muscle mass, generating strength for the patients' daily tasks; and stretching is essential for their mobility.

Future Lines of Research
For future studies, a follow-up of the program is recommended. It would be interesting to evaluate the participants over a year, where several assessments would be carried out at different times regarding their physical fitness and the impact of FM. In this way, it would be possible to collect larger sample data for a better comparison between moments.