Effect of different types of exercise in adult subjects with fibromyalgia: a systematic review and meta-analysis of randomised clinical trials

Exercise has been recommended for fibromyalgia treatment. However, doubts related to exercise benefits remain unclear. The objective of this study was to summarise, through a systematic review with meta-analysis, the available evidence on the effects of aerobic, resistance and stretching exercise on pain, depression, and quality of life. Search was performed using electronic databases Pubmed and Cochrane Library. Studies with interventions based on aerobic exercise, resistance exercise and stretching exercise published until July 2020 and updated in December 2021, were identified. Randomized controlled trials and meta-analyses involving adults with fibromyalgia were also included. Eighteen studies were selected, including a total of 1184 subjects. The effects were summarised using standardised mean differences (95% confidence intervals) by random effect models. In general, aerobic exercise seems to reduce pain perception, depression and improves quality of life; it also improves mental and physical health-related quality of life. Resistance exercise decreases pain perception and improves quality of life and moreover improves the physical dimension of health-related quality of life. It was also observed that resistance exercise appears to have a non-significant positive effect on depression and the mental dimension of health-related quality of life. Studies revealed that stretching exercise reduces the perception and additionally improves quality of life and health-related quality of life. However, a non-significant effect was observed on depression. We conclude that exercise may be a way to reduce depression, and pain and improve the quality of life in adult subjects with fibromyalgia and should be part of the treatment for this pathology.

Fibromyalgia (FM) is a chronic rheumatic disease of unknown cause characterised by generalised musculoskeletal pain, fatigue, anxiety, and depression [1][2][3][4][5] . These symptoms, among others, result in a reduced quality of quality of life in this population 6 . Depression, in particular, has a high prevalence among this population 7 and is of great importance on the overall prevalence of psychiatric comorbidity amongst the FM population compared to the general population 8 .
Currently, FM is treated through both pharmacological and non-pharmacological means 9 . Exercise has been widely applied in the clinical field 10 and is considered a non-pharmacological approach to the treatment of this pathology 3 . In fact, and according to Hagen et al. 11 , there is empirical evidence that exercise reduces the symptoms of most musculoskeletal pathologies, including FM. Indeed, several studies have found that different types of exercise (i.e., aerobic, resistance, and stretching) contribute positively to the quality of life of subjects with FM, enhancing the reduction of pain and depression [12][13][14][15][16] .
However, although systematic reviews and meta-analyses have proliferated in this area, it has been found that the evidence is of low to moderate quality 12 , which led us to question the accuracy and quality of the information provided. Moreover, previous studies failed to report or analyse variables related to the amount of exercise (frequency, volume, or duration) 17 , which may ultimately not provide the most accurate deduction regarding the www.nature.com/scientificreports/ effects of exercise in FM, and may lead to conclusions such as the 'low therapeutic validity of exercise in FM' 18 . For these reasons, clarifying the exercise prescription in this population is essential. Moreover, this information becomes central since adults with FM have a very low rate of adherence to exercise 1 . This occurs not only because of the exacerbation of symptoms, but also because of the contradictory information regarding the exercise these patients receive from the professionals who are part of their treatment team (e.g., rheumatologist, general practitioner, nurse, or physiotherapist) 19 .
In summary, and according to the recommendation of several authors who encourage others to further study this topic 16,20,21 , it was intended to perform a systematic review and meta-analysis to summarise the evidence on the effects of different types of exercise (aerobic exercise-AE, resistance exercise-RE, and stretching exercise-ST) in pain, depression, and quality of life in people with fibromyalgia, in order to contribute to the clarification of the most adequate exercise prescription in this population and to the integration of exercise in the treatment of FM.

Methods
The present study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines 22 .
According to what is recommended by the PRISMA protocol 22 , an exploratory search was carried out and we identified PubMed and Cochrane as fundamental for the completion of the study. From this initial search, the descriptors were also defined for the identification of studies.
The search was performed between May and July 2020, and updated in December 2021, using the terms Fibromyalgia (#1) and Exercise (#2) (#1 And #2) in PubMed (213 references) and in the Cochrane Central Register of Controlled Trials (540 references) in all fields, in English, with no restriction on the date of publication.
Potentially relevant articles were searched in the reference lists of the manuscripts obtained in the search, and other systematic reviews and meta-analyses were included if they contained relevant data.
The present study was registered in the PROSPERO database, under the number CRD42020188457.
Eligibility criteria. The eligibility criteria of the studies were determined according to the PICOS (Population, Intervention, Comparison, Outcomes, and Study Design) strategy, as follows: Population. Subjects aged 18 years old or older, diagnosed with fibromyalgia according to the criteria of American College of Rheumatology 23 .
Intervention. Randomised control trials (RCTs) with interventions based on one of the following types of exercise: aerobic (AE), resistance (RE), or stretching (ST) performed out of water. Interventions that included more than one exercise typology were excluded, as well activities performed in hot water, because the use of hot water causes the reduction of pain and stiffness and relaxes the muscles 24 .
Comparison. All studies included a comparison of at least one type of exercise (i.e., AE, RE, ST), with another type of exercise, with another form of treatment or with groups of subjects who maintained their daily activities without any type of treatment.
Outcomes. All included studies evaluated at least one of the following outcomes: pain; depression, and quality of life, regardless of the instrument used.
Type of study. RCTs comparing AE, RE, or ST, with a control group receiving no treatment or usual care, were included.

Study identification.
After the studies were identified, there was an initial screening based on titles and abstracts, followed by selection through reading of the full text of the manuscripts. The search was carried out by two researchers independently. In case of the conflict, another element was included to achieve a final decision on the inclusion or exclusion of RCTs. Subsequently, all studies were read in full to obtain the final selection of studies.
Data extraction. The following data was extracted from the selected studies: country of origin, authors, design, number of participants, age, gender, type of exercise, intensity, symptoms, adherence, and conclusions of the study.
Quality of study and risk of bias. The quality of the included studies and the issues related to the risk of bias were evaluated, through the Cochrane Collaboration Risk of Bias Tool 25 . Two reviewers assessed the quality of the studies, and differences between both reviewers were resolved by mutual agreement or by a third reviewer. The kappa concordance index Cohen 26 between two reviewers for each of the criteria was determined, Study characteristics. The total sample of individuals consists of a majority of female subjects (97.46% = 1154) with few male subjects (2.53% = 30), in a total of 1,184 subjects over 18 years old. The selected studies were published between 1996 29 and 2019 31 . Most studies were of European origin (50% = nine), six were from Brazil (33.33%), and three were from North America (16.66%). Regarding adherence, the studies revealed that there retention was between 77.77% 32 and 91.66% 33,34 , with an average value of 83.15%. Table 1. Summary of findings table of aerobic exercise intervention for fibromyalgia symptoms in adults. Significant values are in bold. *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% interval confidence). a Large number of studies with high risk of bias. b Heterogeneity present and significant. c Differences in interventions and outcomes measures. d N is under 300. e Asymmetry in the pattern of results.   Full-text arƟcles excluded (33) Design (12) IntervenƟon (14) Outcome (6) PopulaƟon (1)  www.nature.com/scientificreports/ Ten studies reported the use of RE [30][31][32][34][35][36][37][38][39][40] and nine reported the use of AE 29,34,36,37,[41][42][43][44][45] . Intervention with ST was identified in five studies 30,33,35,38,46 .
The interventions had a duration between three weeks (Hooten) and 24 weeks 45 . Regarding to the frequency, twice a week, was the most frequent, varying between daily frequency 34 and five times a week 43 .
Taking into account the different types of training, the intervention protocol is quite varied, with indications regarding the structure of the sessions described in Table 4. Regarding the variables under analysis, pain was analysed, through the MPI (Multidimensional Pain Inventory), PCS (Pain Catastrophizing Scale), VAS (Visual Analogic Scale), the pain subscale of the (Fibromyalgia Impact Questionnaire (FIQ), and the Short Form Health Survey (SF-36). Depression was assessed by the Beck Depression Index (BDI) and by the Hospital Anxiety and Depression Scale (HADS). Quality of life was evaluated using the FIQ and SF-36 questionnaire.
The individual risk of bias assessment is included in Fig. 2, and the risk of bias assessment for all studies is detailed in Fig. 3.

Meta-analysis.
Overall, the results support the conclusion that the three types of exercise have a large and significant effect on pain ( Fig. 4) (i.e., > 0.8; overall effect p < 0.05), and each type off exercise did not differ from each other (p > 0.05).
Regarding depression analysis (Fig. 5), no significant differences between the three types of exercise were found (p > 0.05). However, AE was the only one that had a moderate and significant effect in favour of the experimental group; there was a large but non-significant effect for RE and ST. Heterogeneity. Regarding this point and, according to the Higgins, Thompson, Deeks and Altman 28 guidelines, it was found through a visual inspection of the pain variable that there was considerable heterogeneity in the studies included in the exercise subgroups of AE, RE, and ST; this was also considerable in the subgroup analysis. For depression, the studies included in the three types of exercise were also shown to be heterogeneous, as well as in the subgroup analysis for this outcome. Regarding FM, both studies involved in the subgroup AE and ST did not prove to be heterogeneous, while the studies involved in the subgroup RE showed considerable heterogeneity; the same occurred in the subgroup analysis. For the health-related quality of life (HRQOL), mental dimension, the identified heterogeneity can be considered not important (I 2 < 0.40) in the three types of exercise as well as the subgroup analysis. For the physical dimension of HRQOL, the studies included in relation to AE and ST were found to be homogeneous, with considerable heterogeneity in the RE subgroup.

Discussion
The present paper intended to summarise the evidence on the effects of different types of exercise (i.e., AE, RE, and ST) on pain, depression, and quality of life in people with FM.
Regarding AE, the studies indicate a positive influence on the studied variables, as this was the only type of exercise that had a significant effect on them. Indeed, several studies 2,21,47,48 demonstrated the positive effect of this type of exercise on the major and minor outcomes of FM. For this type of exercise, two perspectives of intervention were observed in the studies: on the one hand, some studies 29,33,35,36,[42][43][44] recorded the heart rate at intervals of moderate intensity, while in other studies 32,40,41 , subjects were asked to increase exercise intensity to a tolerable threshold, with both having a positive and significant effect on outcomes.
This data allows us to conclude that, even if the exercise starts with a lower intensity than that recommended (e.g., American College of Sports Medicine-ACSM), it is likely to produce benefits in this population. This observation is in line with the study by Häuser et al. 48 , in which the authors state that the quantity and intensity of the AE should be adapted according to the physical condition of each individual, and the disease symptoms of each individual subject should determine the beginning and rate of progression of any exercise 43 . Also, Busch et al. 49 concluded that it is necessary to initiate AE slightly below an individual's physical capacity, gradually increasing to moderate levels of intensity, thus avoiding the exacerbation of signs associated with this pathology. In this sense, and according to Bidonde et al. 17 , AE seems to be well tolerated by subjects without increasing pain or other FM symptoms and therefore should be integrated into the treatment programs of FM. Intervention: RE Study participants completed one set of 10 reps at individually specified weight loads where the initial weight loads for the upper and lower extremities generally ranged from 1-3 kg and 3-5 kg, respectively. All individuals were encouraged to increase weight loads by one kg per week during the course of the three-week study period and AE Therefore, the intensity and duration of AE was not advanced using a standardized protocol; rather, study participants were encouraged to gradually increase the intensity and duration of AE to achieve 70% to 75% of maximal heart rate based on age (220 bpm minus age www.nature.com/scientificreports/ In another perspective, the duration of the intervention could also explain the results. Hauser et al. 48 states that AE programs in this population must have a minimum duration of four weeks, which in fact is in line with the studies selected in this analysis, as all of them comply with this minimum duration, except for Hooten's 34 study, which had a duration of three weeks. Regarding RE, this analysis demonstrated a beneficial effect on all the outcomes analysed, although there was a non-significant positive effect for depression. Busch et al. 2 also verified the existence of limited evidence of RE on depression. They warned of the promising effect of this type of exercise on this pathology, recommending the need for more and better-quality studies on this type of exercise 48 . Also, in a meta-analysis on RE, Nelson 20 argues that this type of exercise can be effective and safe in this population, especially when there is a progression from lower intensities. More recently, Vilarino et al. 50 also verified, in a systematic review of the effects of RE training on the mental health of people with FM, that this type of training potentiated mental health, with special emphasis on reducing depression. However, this study´s inclusion criteria included RCTs where subjects could be sedentary or be part of another type of intervention (i.e., AE; ST). However, despite the limitations on this theme Andrade et al. 47 , recommend that the RE protocol in FM should include a reduced initial intensity (40% of 1-RM) and be gradually increased, with the frequency of exercise between two or three times a week, this aligning, in a way, with the guidelines of the ACSM. This association also argues that the initial intensity should be reduced to the level where the subject does not experience pain. This factor is essential in this population, since, according to Larsson et al. 39 , and through Fleck and Kraemer 51 , the estimation of 1-RM is often performed with perceived submaximal efforts, for reasons of health and safety, which, for this population, due to its symptoms, limits the quantification of this measure.
Despite what has been previously described, the majority of the selected RCTs used the prescription recommended by ACSM for RE in this population. But, like AE, the studies of Assumpção et al. 30 , Jones et al. 35 , Bircan et al. 36 , Kayo et al. 37 , and Larsson et al. 39 used different methodologies, where pain tolerance and perceived exertion were taken into account in the progression of intensities. However, both perspectives showed a positive evolution of the studied outcomes.
The relation between RE training and depression, as argued by Vilarino et al. 50 can be influenced by the evaluation methods used in the studies. In fact, although the three RCTs included in this meta-analysis observe a decrease in depression, only the study by Jones et al. 35 study observed a significant decrease (using the BDI to evaluate depression), while the others (Bircan et al. 36 and Ericsson et al. 40 ) evaluated this outcome using the HADS. For ST, despite the low quality of the information obtained, the studies indicate a positive and statistically significant effect on all outcomes, except for depression. For ST, the ACSM recommends for this population a routine of stretching once or twice a week with progression up to five times a week, for all pain-free muscle groups. Initially, the stretching should be maintained between 10 and 30 s, progressing to the maintenance of each position for up to 60 s. However, in the selected studies, only the study by Assumpção et al. 30 indicates the ACSM recommendations. This is rare in general, as is the explanation about the progression of intensities and the care in the selection of muscle groups free of pain.
Thus, despite the evident limitations, there seems to be room for the application of ST in subjects with FM, especially due to the beneficial evolution of the studied outcomes. However, in line with Lorena et al. 16 and Kim et al. 52 , we suggest to further study on this theme, since most of the published papers seem to have low methodological quality and lack exercise standardisation. Although ST appears to be well tolerated, Kim et al. 52 consider the evidence limited, mainly due to the small number of trials and participants, as well as issues related to a high risk of bias.
Therefore, despite the forms adopted for the progression of intensities, it was found that there were positive and significant effects on the main outcomes, except for depression and the mental dimension of health-related quality of life, which obtained a moderate significant effect.  www.nature.com/scientificreports/ Consequently, the studies included in the analysis of both symptoms were investigated for these outcomes, verifying that the study by Jones et al. 3 was the only one in which exercise was performed individually. This point seems fundamental because, according to Busch et al. 53 , subjects in a depressive state with mental health disturbances prefer to practice exercise individually rather than exercise in a group. This can explain the obtained results, and, in our understanding, it should be taken into account in future investigations. Moreover, the symptoms associated with depressive conditions should also be considered since, according to Busch et al. 53 , depression is seen as a significant barrier to exercise.
Still regarding depression, we believe that the difference between observed in the selected studies may also result in the organization of ST sessions. Mainly because the study by Jones et al. 35 , the only one that had a positive and significant effect of ST on depression, the intervention is characterized by 60 min sessions with a 10 min aerobic warm-up (dance) and, on the other hand, in relation to the study by Valim et al. 33 , there is no such   54 , which attests that ST training should be seen as an intervention because this population benefits from its practice, it is considered fundamental that the study of these variables should be continued in order to effectively clarify the possibility of ST in improving mental health.Through this work, the effect of AE, RE and ST training on possible outcomes was analysed, including a subgroup analysis between the three types of exercise. Although there are already several meta-analyses on this topic, some, for example: Bidonde et al. 13 and Kelley et al. 3 studied the effect of exercise on FM without any isolation of the type of exercise, which makes it difficult to identify the real impact that each form of exercise has on the management of this disease.  www.nature.com/scientificreports/ Thus, to produce a clear analysis, RCT's were included if their main intervention was one of the three types of exercise. Studies were excluded if combined interventions (i.e., several types of exercise) were used or if were carried out in the presence of environmental variables that could influence the effect intervention (e.g., hot water).
Initially, the objective was also to collect evidence about exercise prescription in this population and to determine more effective physical exercise methodologies in the management of this pathology. However, due to the huge diversity of forms of exercise prescription, as well as the presence of samples with different characteristics, combined with the lack of pertinent information in some studies, it became difficult to identify methodologies that would facilitate a greater effect of the different types training on the outcomes analysed.
In addition to the previously identified, we believe the heterogeneity should be addressed. According to several authors, i.e. Higgins and Green 55 and Bowden et al. 56 , the heterogeneity reflects clinical variability (i.e., variation between participants), methodological variability (i.e., variation between the designs of the studies), variability in sample characteristics (i.e., age, sex, weight), variations in treatment (variability in the thresholds of diagnostic tests) and, additionally, statistical variability (i.e., variation in measures of effect between different studies due to clinical or methodological factors, or both). In this sense, by considering the information collected through the selected references, it can be seen that there is diverse variability in the samples, measures of evaluation of outcomes and exercise prescription, as well as between the types of exercise (i.e., AE, RE, ST),  www.nature.com/scientificreports/ as different forms of prescription within the same exercise group. Thus, taking into account this considerable variability, the statistical effect model was chosen for the statistical analysis. Even with less statistical power than the fixed effects model, it is more realistic for the integration of effect estimates, since it incorporates possible sources of heterogeneity 55,57 .

Conclusion
Through this systematic review and meta-analysis, was verified that the three types of exercise investigated have a positive effect on pain, depression, and quality of life. The different types of prescription adopted in the analysed studies indicate that exercise is beneficial for this population, especially when considering the principle of individualisation, thereby potentiating a decrease in symptomatology associated with this disease and improving the quality of life in adult subjects with FM. Thus, it is recommended that, when the physical condition of the subjects does not allow the performance of exercise according to the recommendations of generalized international organizations for FM, the physical exercise technicians should adjust the exercise prescription according to individual capacities. However, the heterogeneity observed in studies´ populations, reported outcomes, and intervention components downgraded the certainty of the evidence, and prevents the drawing of firmer conclusions from the evidence provided. In terms of the future research, it is considered pertinent to continue the investigation into the different forms of exercise in this pathology in larger samples to reduce the bias associated to studies in this population. It is also necessary to understand the adherence behaviour of these subjects in the context of the practice, to create indications for maintaining the practice of this population over time.  www.nature.com/scientificreports/ In sum, it seems evident that aerobic, resistance, and stretching exercise have a positive effect on pain, depression, and quality of life in adult subjects with FM. We consider that these types of exercise increase health and quality of life in this population and should be considered as part of the treatment for this pathology.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.