Fibromyalgia (FM) is a chronic condition characterized by widespread pain and tenderness. It affects approximately 3% of the general population (5% in women and 1.5% in men) (40). There is no distinct biological marker of FM; to diagnose FM, the American College of Rheumatology criteria require a widespread pain index score of ≥7 combined with a symptom severity scale score of ≥5, or a widespread pain index score of 3–6 and a symptom severity score of ≥9 (66). Beyond the fundamental symptom of pain, patients with FM typically experience a host of additional symptoms, including sleep disturbances, fatigue, cognitive difficulties, depression, and anxiety (31,39,66).
Anxiety, an unpleasant mood characterized by feelings of apprehension and thoughts of worry, has an estimated prevalence of 31% in FM patients (49), compared with 4% in the general population (3). Anxiety can be an appropriate response to stressful events and circumstances (38); however, if the anxiety persists in the absence of and/or when these events and circumstances cease, it can become maladaptive. As a result, maladaptive anxiety may often not be recognized and go untreated in FM patients. This can have a negative effect on treatment outcomes in part because anxious patients can be less likely to adhere to prescribed medical treatments (58).
The presence of anxiety symptoms in FM patients has been directly associated with FM pain (1,19,48), and physical fitness has been inversely associated with anxiety in women with FM (12). The role of exercise in the pathophysiology of FM is not well understood, but research indicates that strength training for FM patients may result in large improvements in pain (4,18,29), physical function (4,18), tender points (37), and anxiety (18). Moderate-intensity aerobic training for FM patients may improve overall well-being (36), physical function (6), depressive symptoms (27), and pain (17). Despite this, FM patients often fear exercise, report exercise as being more painful (11), and are significantly less active compared with sedentary, healthy controls (45). Fear of exercise and the anticipation of symptom exacerbation could serve to blunt the positive effects of exercise training.
Because physical activity levels among FM patients are low (39) and evidence has demonstrated both associations between low physical activity and anxiety (60) and increased anxiety resulting from increased sedentary behavior (15), there has been continued interest in the anxiolytic effects of increased physical activity and exercise training. Meta-analytic reviews have summarized the effect of exercise on anxiety symptoms among patients with FM (26,54), with small, positive effect sizes reported ranging from 0.17 to 0.29 (26,54). However, reviews have not focused on the best available evidence (i.e., randomized control trials) (54). Kelley and Kelley (34) identified the need for a meta-analysis addressing the effects of exercise on anxiety in adults with arthritis and other rheumatic disease, such as FM. Importantly, there also is a critical need to identify potentially important sources of variability in the overall effect of exercise on anxiety to better guide future trial development.
This meta-analysis used the results from randomized controlled trials to evaluate the effects of exercise training on anxiety symptoms in patients with FM. One goal was to estimate the population effect size for exercise effects on anxiety outcomes. A second goal was to examine whether variables of theoretical or practical importance, such as features of the exercise intervention and the method for measuring anxiety, account for significant variation in the estimated population effect.
METHODS
The study was conducted in accordance with the PRISMA statement (46,57).
Data Sources and Searches
Articles published from January 1995 to June 2016 were located by two authors (C.P.M. and M.P.H.) using Google Scholar, MEDLINE, PsycINFO, PubMed, and Web of Science. Keywords used were “exercise,” “physical activity,” “anxiety,” “tension,” “fibromyalgia,” “randomized trial,” and “randomized controlled trial.” Supplemental searches of the articles retrieved were performed manually.
Study Selection
Inclusion criteria included 1) English-language articles, 2) participants with FM (i.e., participants who met American College of Rheumatology criteria for the classification of FM (66,67)), 3) random allocation to either an exercise intervention or a comparison condition that lacked exercise training, and 4) a validated anxiety symptom measure (e.g., State-Trait Anxiety Inventory (59), Fibromyalgia Impact Questionnaire Anxiety subscale (5)) assessed at baseline and after exercise training. Investigations excluded were those that 1) included exercise as one part of a multicomponent intervention but did not include the additional component (e.g., cognitive behavioral therapy) in a comparison condition and 2) compared exercise only with an active treatment (e.g., cognitive behavioral therapy, medication, and another mode of exercise). Figure 1 provides a flowchart of study selection. Table 1 provides an overview of key study characteristics.
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FIGURE 1: Flowchart of study selection.
Data Extraction
Effect size calculation
Hedges’ d effect sizes were calculated to quantify the magnitude of exercise effects on anxiety symptoms. The mean change in the comparison condition was subtracted from the mean change in the exercise condition, and this difference was divided by the pooled standard deviation of baseline scores (25). The effect sizes were adjusted for small sample size bias and calculated such that an improvement in anxiety symptoms resulted in a positive effect size (25).
Study quality assessment
Two authors (CMcD and MPH) independently assessed study quality (scored 0–15), using an expanded version of a widely used method (14), to include research design, randomization methods, control condition, outcome measures, adherence, and reporting of exercise intervention characteristics; higher scores indicated better study quality.
Data synthesis and analysis
Meta-regression was used as the overall analysis of moderator effects. This computes simultaneous estimates of independent effects by multiple moderator variables on the variation in effect size across trials, reducing the probability of type I error. Random effects models were used with macros (SPSS MeanES, MetaReg; SPSS, Inc., Armonk, NY) to aggregate mean effect size delta (Δ) and to test variation in effects according to moderator variables (25,42). Heterogeneity was examined with the Q statistic, percent of observed variance accounted for by sampling error, and I2 (25,28). Heterogeneity was indicated if QTotal reached a significance level of P ≤ 0.05 and the sampling error accounted for less than 75% of the observed variance (25). To assess potential publication bias (i.e., smaller studies showing larger effects), a funnel plot was generated and evaluated. The number of unpublished or unretrieved studies of null effect that would diminish the significance of observed effects of P > 0.05 was estimated as fail-safe N+ (51).
Primary moderators
To provide focused research hypotheses about variation in effect size (53), seven primary moderators were selected on the basis of logical, theoretical, or empirical relations to anxiety and/or exercise effects on anxiety: session frequency, exercise intensity, session duration, program length, comparison type, and anxiety recall time frame.
Primary moderator analysis
Each of the moderators was coded according to planned contrasts (52) (P ≤ 0.05) among its levels. Primary moderators were included in mixed-effects multiple linear regression analysis with maximum likelihood estimation (25,42), adjusting for nonindependence of multiple effects contributed by single studies (53) and whether anxiety was a primary outcome. Tests of the regression model (Q(R)) and its residual error (Q(E)) are reported.
Secondary moderators
Secondary moderators were selected for descriptive, univariate meta-regression analyses (see Table 2). Random effects models were used to calculate mean effect sizes (Δ) and 95% confidence intervals (CI) for continuous and categorical variables (42).
RESULTS
Study characteristics
Twenty-five effects were derived from ten studies composed of 595 patients with FM. Included studies randomized 297 FM patients to exercise training and 298 FM patients to a nonexercise control condition. Primary outcomes of the included trials included the 6-min walk test, pain, total myalgic score, and heart rate variability.
The mean ± SD age was 47.7 ± 3.5 yr. The mean ± SD percentage of women was 97% ± 6%. Exercise training consisted on average of 3 ± 1 sessions per week, 46 ± 3 min per session, and 23 ± 7 wk in duration. The mean ± SD exercise training attendance rate was 72% ± 17%. Attendance was reported for 18 (72%) of 25 of the effects. Compliance with exercise prescription was not reported for any effects. The most frequently used anxiety measures were the anxiety subscale of the Fibromyalgia Impact Questionnaire (k = 11) (7,20,31,44,55,56,61) and State-Trait Anxiety Inventory— State Anxiety subscale (k = 6) (2,21,61).
Twenty-two effects (88.0%) were larger than zero. A forest plot of effects is presented in Figure 2. The mean effect size Δ was 0.28 (95% CI = 0.16–0.40, z = 4.56, P < 0.001). No significant heterogeneity was observed (Q24 = 30.79, P ≥ 0.16, I2 = 25.30%, 95% CI = 3.99%, 41.88%). Sampling error explained 78.7% of variance. The mean quality score was 12.30 ± 1.25. The fail-safe number of effects was 135, and a funnel plot (not shown) revealed a lack of publication bias.
FIGURE 2: Forest plot of the unweighted distribution of Hedges’ d effect sizes.
TABLE 1: Study characteristics.
TABLE 2: Summary of univariate moderator analyses.
Overall meta-regression model of primary moderators
The overall meta-regression model was significantly related to the overall effect size (QR(9) = 22.89, P < 0.01; R2 = 0.74; QE(15) = 7.90, P = 0.93). Program duration (β = 1.44, z = 2.50, P ≤ 0.01) was significantly and independently related to the overall effect of exercise on anxiety symptoms. Significantly larger anxiety improvements resulted from programs lasting greater than 26 wk (Δ = 0.35, 95% CI = 0.05–0.66) compared with those lasting less than 26 wk (Δ = 0.26, 95% CI = 0.13–0.39). Session duration (β = −0.53), frequency (β = −0.25), intensity (β = 0.23), control (β = 0.66), anxiety recall time frame (β = 0.07), and exercise setting (β = 0.45) were not significantly related to effect size (all P ≥ 0.07).
Univariate meta-regression analyses of secondary moderators
Planned contrasts showed a larger effect in studies in which 1) interventions took place in a community facility (Δ = 0.37, 95% CI = 0.24–0.50) compared with a mixed setting (Δ = 0.03, 95% CI = −0.15 to 0.22, z = 3.01, P < 0.01); 2) a no-treatment control was used (Δ = 0.42, 95% CI = 0.24–0.59) compared with the combination of usual care, wait list, and placebo (Δ = 0.20, 95% CI = 0.03–0.38, z = 2.26, P ≤ 0.02) and 3) participants were female (Δ = 0.34, 95% CI = 0.21–0.48) compared with mixed samples (Δ = 0.09, 95% CI = −0.12 to 0.30, z = −2.31, P ≤ 0.02). Definitions for each moderator and associated levels are presented in the Appendix (see Appendix, Supplemental Digital Content 1, Moderator Definitions, https://links.lww.com/MSS/A921).
Effect sizes did not significantly vary according to planned contrasts for author-reported significant improvement in fitness (β = 0.30), author-reported significant improvement in primary outcome (β = 0.04), blinding (β = 0.28), attention-control (β = −0.25), intent-to-treat analysis (β = 0.05), exercise intensity (β = 0.23), exercise mode (β = −0.06), social nature of exercise (β = 0.27), session frequency (β = 0.11), program duration (β = 0.07), session duration (β = −0.26), age (β = −0.05), anxiety reported as a primary outcome (β = 0.02), anxiety recall time frame (β = 0.01), and significant improvement in pain (β = −0.32) (all P ≥ 0.21).
The results of univariate moderator analyses for each primary and secondary moderators are presented in Table 1. For each level of each moderator, the number of effects (k), mean effect size Δ, and 95% CI and the contrast P value are provided.
DISCUSSION
The cumulative evidence suggests that exercise training has a small but statistically significant, positive effect on anxiety symptoms in FM patients. Therefore, in addition to physical benefits of exercise, persons with FM should be encouraged to exercise as an adjuvant for alleviating anxiety symptoms. The magnitude of the overall mean effect (Δ = 0.28) is small by conventional standards (9); however, it may be of clinical significance. The mean effect is comparable with previously reported effects of exercise on anxiety symptoms among FM patients (Δ = 0.29) (26). Meta-analyses of exercise interventions on anxiety outcomes among healthy adults (10), on global well-being (33) and tender points (37) among FM patients, and on depressive symptoms among arthritis patients (35) have also reported comparable mean improvements of 0.22, 0.34, 0.24, and 0.42, respectively.
Exercise program length
Although longer exercise programs often report poorer adherence and may therefore report smaller anxiolytic effects than shorter exercise programs (26), the present findings indicated that larger improvements in anxiety resulted from longer exercise program lengths. One plausible explanation for the present findings is that the mean ± SD attendance for program lengths of ≥26 wk (88% ± 7%) was significantly better (F1,17 = 12.43, P ≤ 0.003) than that for program lengths less than 26 wk (67% ± 14%). In addition, it is notable that significantly larger anxiety reductions resulted from trials in which samples were female-only compared with mixed samples including males and females, given that the six effects (2,61) with programs ≥26 wk were derived from female-only samples, but only 10 of those effects less than 26 wk were derived from female-only samples. These findings highlight the potential importance of promoting long-term adherence to exercise training, particularly among females with FM, to maximize the anxiolytic effects of exercise. However, further research, particularly with an adequate amount of male participants, is needed to more fully test the moderating effects of gender and program length.
Pain
It is plausible that the anxiolytic effect of exercise in FM patients is linked to improvements in pain. Exercise training is safe, well tolerated by most FM patients, and recommended by national and international guidelines for pain management (8,24). Meta-analyses of exercise interventions support treatment guidelines demonstrating meaningful improvements in pain, fatigue, and physical function (22) that are comparable with those achieved by approved drugs. An added benefit for exercise training is improved fitness, an outcome not observed in pharmaceutical trials (23).
Recent research in FM patients suggested that an acute bout of exercise might stimulate central pain regulatory mechanisms resulting in temporary positive changes to both pain perception and brain responses to pain (17). These results for acute exercise suggest a potential mechanism for the efficacy of exercise training as central nervous system adaptations may become more permanent with repeated exposure. Indeed, after prolonged exercise, healthy individuals have demonstrated improved pain tolerance (32) and modulation (16), and increased physical activity among FM patients can result in improved muscle pain ratings (62).
There is overlap among the neuroanatomy thought to be involved in processing pain perception and anxiety (41,64,68), and evidence suggests a reverse causal relationship between anxiety and pain (65). Irritable bowel syndrome-related anxiety significantly enhances a patient's suffering from pain (30,50), and other negative emotions, such as anger and sadness, enhance the experience of pain among female FM patients (63). Further, relaxation techniques (47) and anxiolytic drugs (13), which largely have no analgesic properties, are beneficial for reducing pain in chronic pain patients.
In the present study, 16/20 effects with a pain outcome reported simultaneous improvements in pain and anxiety. When controlling for anxiety measure, effects derived from studies in which pain was also significantly improved reported significantly higher baseline anxiety symptoms (F(1,19) = 5.462, P ≤ 0.032), with greater anxiolytic effects typically seen among those who report higher baseline anxiety symptoms. Despite this, a significant improvement in pain was not significantly related to the anxiolytic effect of exercise (i.e., there was no significant difference in the overall effect size between studies in which pain was significantly improved and studies in which pain was not significantly improved). It is plausible that patient medication use influenced the pain–anxiety relationship. Medication use was reported for just 13/25 effects (20,21,43,44,61) and could not be controlled for or robustly examined in moderator analyses. However, of the studies that reported medication use, 354 patients reported taking 602 separate drugs of which 251 were analgesic and 185 were psychoactive. Other medications included 79 “drugs for FM symptoms,” 45 “other prescription drugs,” and 42 “antidepressants, muscle relaxants, or analgesics,” all of which could influence the anxiolytic effect of exercise and potential moderation of this effect by concurrently improving pain. It is important to note that the purpose of this meta-regression was to examine patient characteristics and features of exercise that may influence, and optimally could be modified to enhance, the effect of exercise on anxiety symptoms among FM patients. The purpose was not to test whether those factors might help to explain the effect of exercise. That purpose would require that trials assess plausible mediators of exercise effects, which was not the case in the included trials.
Future research
Several research needs are suggested by the present findings. Clear and complete information about medication use and patient comorbidities is needed. Comorbidities such as irritable bowel syndrome (43), chronic headache (11), and chronic fatigue syndrome (47) are prevalent among FM patients, yet just 7 or 25 effects (20,21) reported patient comorbidities. Further, most studies reported planned session duration and participant attendance, but compliance with prescribed exercise dose was not reported in any studies. Consequently, the true anxiolytic effect of exercise training among FM patients may be underestimated because of underexposure to exercise. Also needed are well-designed investigations that examine the potential moderating effect of pain-related improvements in FM patients.
CONCLUSIONS
The present results provide evidence for exercise training as a potential low-risk, adjuvant treatment for anxiety symptoms that may develop among FM patients. The findings also suggest that larger anxiety symptom reductions will be achieved by focusing on longer exercise programs while promoting long-term adherence. Finally, anxiety reductions appear to occur regardless of whether pain symptoms improve, providing additional support for FM patients to initiate and/or maintain physical activity.
The authors disclose no conflicts of interest. This study was unfunded. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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