To examine the association between leisure time physical exercise, body mass index (BMI), and risk of fibromyalgia (FM).
To examine the association between leisure time physical exercise, body mass index (BMI), and risk of fibromyalgia (FM).
A longitudinal study with baseline assessment of physical exercise (frequency, duration, and intensity) and BMI was used to explore the risk of having FM at 11-year followup in a large, unselected female population (n = 15,990) without FM or physical impairments at baseline.
At followup, 380 cases of incident FM were reported. A weak dose-response association was found between level of physical exercise and risk of FM (for trend, P = 0.13) where women who reported the highest exercise level had a relative risk (RR) of 0.77 (95% confidence interval [95% CI] 0.55–1.07). BMI was an independent risk factor for FM (for trend, P < 0.001), and overweight or obese women (BMI ≥25.0 kg/m2) had a 60–70% higher risk compared with women with normal weight (BMI 18.5–24.9 kg/m2). Overweight or obese women who exercised ≥1 hour per week had an RR of 1.72 (95% CI 1.07–2.76) compared with normal-weight women with a similar activity level, whereas the risk was >2-fold higher for overweight or obese women who were either inactive (RR 2.09, 95% CI 1.36–3.21) or exercised <1 hour per week (RR 2.19, 95% CI 1.39–3.46).
Being overweight or obese was associated with an increased risk of FM, especially among women who also reported low levels of physical exercise. Community-based measures aimed at reducing the incidence of FM should emphasize the importance of regular exercise and the maintenance of normal body weight.
Fibromyalgia (FM) is a chronic pain syndrome defined by widespread pain that includes all 4 body quadrants, reduced pressure pain threshold at a minimum of 11 of 18 anatomically defined tender point sites, and pain duration >3 months (1). Associated features often include undue fatigue, sleep disturbances, headache, cognitive difficulty, and mood disturbances (2). The prevalence of FM increases with age and is considerably higher among women than men (3). Although the etiology of FM is poorly understood, many authors have suggested that a dysfunctional autonomic nervous system involving deficiencies in the hypothalamic–pituitary–adrenal (HPA) axis and sympathetic nervous system contribute to the development of FM by altering pain perception and endogenous pain inhibition (4–8).
It is well established that regular physical exercise has a primary preventive effect on several chronic diseases, such as cardiovascular diseases (9), hypertension (10), and type 2 diabetes mellitus (11). For localized musculoskeletal disorders, prospective studies have provided evidence that regular physical exercise can prevent the development of symptoms in the neck/shoulder (12–14) and low back (15, 16). Moreover, longitudinal studies have shown that physical exercise is associated with less musculoskeletal pain (17, 18) and stiff or painful joints (19) among aging women. Studies investigating the primary preventive effect of physical exercise on FM are scarce. However, a recent study showed that physical exercise had a preventive effect on the development of FM in men suffering from posttraumatic stress disorder (20).
Several studies have reported lower physical fitness among patients with FM compared with healthy controls in terms of aerobic capacity (21), strength capacity (22), and flexibility (23). Moreover, high body mass index (BMI), which may indicate poor physical fitness, has been associated with a decreased pressure pain threshold among patients with FM (24). At present, it is unknown whether poor physical fitness is a contributing factor to the development of FM, or whether it is a consequence of the illness.
The main objective of the present study was to investigate whether an inverse association exists between the level of leisure time physical exercise and the future development of FM in a large, unselected population (n = 15,990) of adult women. Participation in recreational physical exercise and body mass is intimately linked (25), and high BMI has been associated with increased prevalence of widespread musculoskeletal pain in cross-sectional studies (26–28). A second objective was therefore to investigate whether being overweight/obese represents an independent risk factor for the future development of FM.
In Nord-Trøndelag County in Norway, all inhabitants ≥20 years of age were invited to participate in 2 waves of a large health survey called the Nord-Trøndelag Health (HUNT) Study, the first in 1984–1986 (HUNT 1) and the second in 1995–1997 (HUNT 2). The HUNT study is a collaboration between the HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology), the Nord-Trøndelag County Council, and The Norwegian Institute of Public Health.
Among 42,568 eligible women, 38,274 (89.9%) accepted the invitation to HUNT 1. The women filled out a questionnaire that was included with the invitation. At the examination, body height and weight were measured and the women were given a second questionnaire to complete at home and return in a prestamped envelope. Detailed information about the HUNT 1 and HUNT 2 studies are described elsewhere (online at www.hunt.ntnu.no/).
At HUNT 2 in 1995–1997, 46,709 women were invited to participate and 34,518 (73.9%) accepted the invitation. The procedures were similar to those described for HUNT 1, although both the questionnaires and the clinical examination were more comprehensive.
For the purpose of the present study, we selected all 24,357 women who had participated in both surveys. We excluded 1,825 women who reported to be physically impaired at HUNT 1 and 850 women with FM at HUNT 2 who reported musculoskeletal pain that had lasted for ≥10 years. Additionally, 3,238 women failed to return the second questionnaire in HUNT 1 that included information on leisure time physical exercise, and 2,454 did not answer the questions related to FM and musculoskeletal pain in HUNT 2. As a result, this study is based on 15,990 women with information on relevant variables at both surveys who reported no FM or physical impairment at HUNT 1. The study was approved by the Regional Committee for Ethics in Medical Research and carried out according to the Declaration of Helsinki.
At baseline (HUNT 1), the participants were asked to complete a questionnaire that included questions on the frequency, duration, and intensity of leisure time physical exercise per week (i.e., walking, skiing, swimming, or other sports). The frequency question allowed 5 response options (0, <1, 1, 2–3, and ≥4 times per week; coded 1–5). Participants who reported exercising at least once a week were also asked about the average duration per session (<15, 15–30, 31–60, and >60 minutes; coded 1–4) and the average intensity of the activity (light, moderate, and vigorous; coded 1–3). The questionnaire has been validated against measurement of maximal oxygen consumption and found to perform well (29); however, this validation was only performed on a random sample of men.
Among women who exercised once a week or more, a summary score of frequency, duration, and intensity was constructed. The score summarizes each participant's responses by giving equal weight to each measure according to the following equation: 1/5 × frequency + 1/4 × duration + 1/3 × intensity. This approach gives a maximum value of 1.0 for each of the 3 components of the summary score. The resulting summary scores ranged from 1.18 to 3.00 and, based on the distribution of the summary scores, the participants were classified into 3 exercise dose groups (thirds), using 1.63 and 2.02 as cutoff values.
Additionally, based on information on frequency and duration, we calculated the average number of hours spent on exercise during a week. In the calculation, the response option 2–3 times per week was counted as 2.5 times, and ≥4 times per week was counted as 5 times. For duration, the response option <15 minutes was counted as 10 minutes, 15–30 minutes was counted as 25 minutes, 31–60 minutes was counted as 45 minutes, and >60 minutes was counted as 75 minutes.
Standardized measurements of body height (to the nearest centimeter) and mass (to the nearest half kilogram) obtained at the baseline clinical examination at HUNT 1 were used to calculate BMI as the body mass divided by the squared value of the height (kg/m2). Participants were then classified into 4 BMI groups according to the cut points suggested by the World Health Organization (30), i.e., underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25.0–29.9 kg/m2), and obese (BMI ≥30.0 kg/m2).
In the questionnaire at HUNT 2, the participants were asked to report physician-diagnosed FM and duration of musculoskeletal pain. The diagnosis of FM was confirmed (yes/no) by the question: “Has a doctor ever said that you have fibromyalgia (fibrositis/chronic pain syndrome)?” However, no information about the time of diagnosis was collected. To ensure that only cases with incident FM (i.e., FM diagnosed after HUNT 1) were included in the analysis, we used information about the duration of musculoskeletal pain, and excluded cases of FM who reported that their musculoskeletal pain had lasted for ≥10 years. The first question concerning duration was: “During the last year, have you had pain and/or stiffness in your muscles and limbs that lasted for at least 3 consecutive months?” If their answer was yes, the subjects were required to indicate the duration of symptoms, i.e., the number of months if symptoms had lasted <1 year and the number of years if symptoms had lasted >1 year.
A generalized linear model for the binomial family was used to estimate relative risk (RR) of FM, in which women who reported different levels of exercise were compared with the reference group of inactive women, i.e., those who reported to exercise less than once per week. The RR for FM between categories of BMI was estimated in similar models. The precision of the estimated RRs was assessed by 95% confidence intervals (95% CIs), and trend tests across categories of exercise level and BMI were calculated by treating the categories as ordinal variables in the regression model.
Our basic models were adjusted for age in 10-year categories (20–29 years, 30–39 years, 40–49 years, 50–59 years, 60–69 years, and ≥70 years). In multivariable models, we controlled for potential confounding with smoking status (never, former, current, and unknown) and education (<10 years, 10–12 years, ≥13 years, and unknown), as well as confounding with BMI (<18.5 kg/m2, 18.5–24.9 kg/m2, 25.0–29.9 kg/m2, and ≥30.0 kg/m2) in the analysis of exercise, and frequency of exercise (inactive, 1 time per week, 2–3 times per week, and ≥4 times per week) in the analysis of BMI. In additional models, we also adjusted for a measure of psychological well-being at baseline (coded as depressed, somewhat happy, and happy).
In a supplementary analysis, we examined the combined effect of different BMI and exercise levels on the reference category of women who were of normal weight and reported to exercise ≥1 hour per week. To assess potential statistical interaction between exercise and BMI, we conducted a likelihood ratio test after including the product term of these 2 factors in the regression model.
All statistical tests were 2-sided, and all statistical analyses were performed using Stata for Windows, version 10.0 (StataCorp).
The characteristics of the study population are presented in Table 1. During the ∼11 years from HUNT 1 (1984–1986) to HUNT 2 (1995–1997), 380 cases of incident FM were reported among the 15,990 women.
|Characteristic||Inactive†||1 session||2–3 sessions||≥4 sessions|
|Age, mean ± SD years||42.0 ± 13.2||41.9 ± 13.2||43.8 ± 14.2||49.6 ± 15.3|
|BMI, mean ± SD kg/m2||24.5 ± 4.4||24.1 ± 3.8||24.3 ± 3.8||24.5 ± 4.0|
|Overweight or obese‡||37.8||32.8||35.2||38.8|
Table 2 gives the age-adjusted and multivariably adjusted associations for the BMI categories and each measure of physical exercise with the risk for FM. Analysis of BMI showed that women who were classified as overweight (25.0–29.9 kg/m2) or obese (≥30.0 kg/m2) had a higher risk of FM compared with women who were normal weight; RRs were 1.70 (95% CI 1.35–2.13) and 1.64 (95% CI 1.16–2.33), respectively (for trend, P < 0.001).
|Women, no.||Cases, no.||Age-adjusted RR†||Multi-adjusted RR (95% CI)‡||P for trend|
|BMI categories (kg/m2)§|
|Underweight (<18.5)||322||8||1.15||1.06 (0.53–2.13)|
|Normal weight (18.5–24.9)||9,942||211||1.00||1.00 (reference)|
|Overweight (25.0–29.9)||4,245||123||1.72||1.70 (1.35–2.13)|
|Obese (≥30.0)||1,481||38||1.69||1.64 (1.16–2.33)||< 0.001|
|Exercise sessions per week, no.|
|Exercise per week, hours|
|Summary score of exercise#|
Overall, there was weak evidence of a dose-response effect for the different measures of physical activity (for trend, P = 0.13–0.16) (Table 2). More specifically, women who reported exercising ≥4 times per week had a 29% lower risk of FM (adjusted RR 0.71, 95% CI 0.46–1.09) compared with inactive women. Analysis of exercise hours per week showed that women who reported exercising ≥2 hours had an RR of 0.77 (95% CI 0.52–1.15) compared with inactive women. Similar results were found in the analysis of the summary score combining information on frequency, duration, and intensity of exercise; women with the highest exercise level had a somewhat lower risk than inactive women (RR 0.77, 95% CI 0.55–1.07).
We examined the combined effect of exercise and BMI on the risk of FM (Table 3). Although there was no evidence of statistical interaction between BMI and exercise (from likelihood ratio test, P = 0.84), we observed that overweight or obese women who exercised ≥1 hour per week had an RR of 1.72 (95% CI 1.07–2.76) compared with normal-weight women with a similar activity level, whereas the risk was >2-fold higher for overweight or obese women who were either inactive (RR 2.09, 95% CI 1.36–3.21) or who reported exercising ≤1 hour per week (RR 2.19, 95% CI 1.39–3.46). Among normal-weight women, we found no clear association between exercise and the risk of FM; inactive women had an RR of 1.18 (95% CI 0.84–1.64) compared with the most physically active women.
|BMI and exercise categories||Women, no.||Cases, no.||Age-adjusted RR†||Multi-adjusted RR (95% CI)‡|
|Normal weight (18.5–24.9 kg/m2)|
|≥1 hour per week||3,362||57||1.00||1.00 (reference)|
|0.1–0.9 hour per week||2,860||60||1.15||1.10 (0.77–1.58)|
|Overweight or obese (≥25.0 kg/m2)|
|≥1 hour per week||1,846||39||1.63||1.72 (1.07–2.76)|
|0.1–0.9 hour per week||1,494||46||2.19||2.19 (1.39–3.46)|
The main objective of the present study was to investigate the association between levels of leisure time physical exercise and future risk of FM and, second, whether being overweight/obese represents an independent risk factor for future development of FM. We found a weak inverse dose-response association between level of exercise at baseline and incidence of FM at the 11-year followup, and a high BMI (i.e., BMI ≥25 kg/m2) represented an independent risk factor for the future development of FM. When examining the combined effect of BMI and physical exercise, we found the highest risk among overweight and obese women who reported low exercise levels, and a somewhat lower risk in overweight and obese women who exercised ≥1 hour per week. To the best of our knowledge, this is the first study to document BMI and level of leisure time physical exercise as risk factors for future development of FM.
The current study shows that a high BMI (i.e., being overweight or obese) is a strong and independent risk factor for future development of FM. Moreover, the higher RRs for the combined effect of being overweight/obese and inactive, relative to being overweight/obese alone, point to a further disadvantage for overweight women who do not exercise. Several studies have shown an association between obesity and widespread musculoskeletal pain, including nonweight-bearing body sites (26–28); however, the causality between high body mass and pain is undecided due to the cross-sectional nature of these studies. There are currently no known mechanisms that can explain a causal relationship between being overweight/obese and widespread pain in FM, although FM and obesity do seem to share some etiologic factors that may explain this relationship.
First, elevated serum levels of proinflammatory cytokines have been observed in both subjects with FM (31) and obese subjects (32). Proinflammatory cytokines have previously been shown to induce or facilitate both inflammatory and neuropathic pain as well as hyperalgesia (33). A recent longitudinal study reported an elevated baseline level of the proinflammatory cytokine interleukin-8 (IL-8) in patients with FM compared with healthy controls (31). IL-8 level was significantly reduced among patients with FM after 6 months of multidisciplinary treatment, but was still higher than in controls. Another study, including only patients with FM, reported a moderate association (i.e., ∼27% explained variance) between the level of IL-6 and BMI in patients with FM (34). Therefore, proinflammatory cytokines seem to play a role in FM and in the relationship between FM and obesity, but further studies are needed to elucidate the exact mechanism.
Second, dysregulation of the HPA axis has been observed in both FM (5) and obesity (35). A recent study reported increased norepinephrine/cortisol and norepinephrine/epinephrine secretion ratios, as well as higher waist-to-hip ratio in patients with FM compared with healthy controls (36). The relative increase in norepinephrine secretion among patients with FM lends support to the notion that FM is maintained by chronic hyperactivity of the sympathetic nervous system (7).
Finally, increased sympathetic tonus and reduced sympathetic reactivity, as recorded by heart rate variability, has been observed in patients with FM (37) as well as in overweight and obese subjects (38). An autonomic dysfunction may therefore contribute to enhanced pain and other symptoms associated with FM (e.g., disturbed sleep, fatigue) by alterations of the physiologic responses required for adequate stress management and pain inhibition (39). Of interest is the observation that weight loss is associated with reduced symptoms in patients with FM. A pilot study investigating the effect of a 20-week weight loss program in overweight and obese women with FM reported that an average weight reduction of 4.4% was associated with a significant reduction in FM symptoms and pain interference (40). Another study found that overweight and obese women with FM who underwent bariatric surgery reported significantly less FM symptoms at followup 6–12 months after surgery (41). Together with the findings in the current study, the abovementioned studies indicate that maintenance of normal body weight is important in both primary and secondary prevention of FM. However, prospective studies are required to elucidate whether a disturbed autonomic regulation is a risk factor for both obesity and FM or whether it develops secondary to these pathologic states.
The pathogenesis of FM is only partially understood, but a hallmark is altered pain processing, indicated by increased sensitivity to painful stimuli (hyperalgesia) and lowered pain threshold (allodynia). Therefore, the potential preventive effect of physical exercise on the development of FM may in particular relate to the preservation or enhancement of the endogenous pain inhibitory capacity. It is well known that aerobic exercise provides temporary pain relief, often named exercised-induced analgesia (42). This effect likely involves the endogenous opioid system, although the precise mechanism is still unclear. There is some evidence that temporary pain relief after exercise can accumulate and translate to a more persistent buffer against pain development. One study showed that pregnant women who performed regular aerobic exercise had consistently higher plasma levels of β-endorphin and less labor pain compared with pregnant women who did not exercise (43). A recent study showed that rats systematically bred to have high aerobic capacity had a higher pain threshold and a shorter postexercise period with hyperalgesia than rats bred to have low aerobic capacity (44). Therefore, regular exercise seems to be directly associated with reduction in pain perception, possibly due to an elevated tonic activation of the endogenous opioid system.
The beneficial effect of exercise on pain perception has also been demonstrated in studies with sleep deprivation. Both total sleep deprivation and selective stage 4 (slow wave sleep) interruption in healthy subjects has been associated with development of similar symptoms as observed in patients with FM, i.e., reduced pain threshold to mechanical pressure at multiple body sites (45–47). Conversely, selective stage 4 interruptions in a small group of well-trained long-distance runners did not induce the same symptoms (45). This may indicate that regular physical exercise and improved aerobic fitness can enhance the endogenous pain inhibitory capacity (48). Therefore, the findings in the current study, together with the findings in the abovementioned studies, indicate that regular physical exercise, and thereby improved physical fitness, may serve as a buffer against the perpetuation of musculoskeletal symptoms that eventually lead to the development of FM. However, the results of this study do not indicate a strong effect of physical exercise on the prevention of FM.
Despite the obvious strengths of the current study, such as the prospective design and the large, population-based sample size, some limitations should be considered in the interpretation of the results. First, incident cases of FM were assessed at the followup survey (i.e., HUNT 2) among those who were able to and chose to participate in both studies. Hence, if women who were overweight/obese or physically inactive at baseline were less likely to participate at the followup survey, the estimated RR may be underestimated. Second, misclassification of leisure time physical exercise cannot be ruled out. Physical exercise was assessed by a single baseline measure without followup information, and the questionnaire-based nature of the data allows for subjective interpretation of the questions and individual perception of the activity (49). It should also be noted that the HUNT data do not allow assessment of the relative importance of different exercise types or fitness components (e.g., cardiorespiratory fitness, strength, and flexibility) in preventing development of FM. However, validation studies have shown that questionnaires may be useful in classifying people into broad categories of physical exercise (e.g., low, moderate, or highly active) but less appropriate for quantifying energy expenditure (50). Nonetheless, biased estimates due to confounding by unmeasured or unknown factors cannot be ruled out in this type of study. Adjustments for variables commonly associated with FM, such as genetic predisposition, sociopsychological factors, adverse life events, and occupational exposures (e.g., work stress), could be of importance.
To summarize, BMI was identified as an independent risk factor for the development of FM 11 years later. A weak inverse dose-response association was indicated between level of leisure time physical exercise and future risk of FM. Being overweight or obese was associated with an increased risk of FM, especially among women who also reported low levels of leisure time physical exercise. Therefore, community-based measures aimed at reducing the incidence of FM should emphasize the importance of regular physical exercise and maintenance of normal body weight.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Mork had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Mork, Vasseljen, Nilsen.
Analysis and interpretation of data. Mork, Vasseljen, Nilsen.