Background
Physical activity and exercise are central to the treatment of rheumatoid arthritis (RA). Health-enhancing physical activity (HEPA) is recommended to the population at large in order to maintain health and prevent comorbidity, including the risk of cardiovascular disease [
1], which is also common in RA and contributes to premature death and poor health in this subgroup of the population.
Recommendations for HEPA include at least 150 min per week of moderate-intensity physical activity and strength training twice weekly [
1]. Previous recommendations are also reflected in the recent European League Against Rheumatism (EULAR) recommendations for physical activity in people with inflammatory arthritis and also highlight that such interventions should include behavioral change techniques and that alternative modes of delivery should be considered [
2].
Individuals with RA have lower levels of physical activity than the population at large [
3] and frequently do not reach recommended HEPA levels [
4‐
6]. In our recent study, 70% of participants with RA reported compliance with HEPA but only 22% had maintained it for at least 6 months [
7].
New drugs and updated treatment recommendations have improved control of inflammation among individuals with RA, but many still have chronic pain, disability, and increased risk of cardiovascular disease [
8,
9]. HEPA might serve as an important complement to pharmacological treatment with few adverse effects [
10]. The promotion of HEPA among individuals with RA offers several benefits, including increased level of physical activity [
11], improved perception of health, and greater muscle strength [
12]. Pain reduction is often observed following physical activity interventions in RA [
13], but the mechanisms behind such effects have not been fully explored.
Several causes of non-inflammatory pain are present; peripheral joint damage induces peripheral sensitization [
13] and central sensitization has been documented [
14,
15]. A generalized increased pain sensitivity (that is, also outside inflamed joints) has previously been reported in patients with RA [
15‐
17]. Pain sensitivity seems to increase with the duration of RA [
14], suggesting progression of central sensitization [
15].
Exercise-induced hypoalgesia (EIH) is a top-down pain inhibitory mechanism normally activated during muscle contraction. In healthy individuals, EIH is reflected as an increase in pressure pain thresholds (PPTs) during muscle contraction [
18]. We have previously reported increased pain sensitivity to threshold and suprathreshold pressure stimuli at rest but a normal function of EIH during muscle contraction among individuals with RA [
16,
17]. Normal EIH was also found among individuals with RA when endogenous pain modulation (the ability of the nervous system to enhance and inhibit the pain experience by different processes) was explored in direct response to submaximal exercise on a bike ergometer [
19]. There is currently strong support for the hypothesis that individuals with RA have increased pain sensitivity but a normal function of EIH.
Exercise for RA results in improvements in pain and function [
20,
21]. Given that previous studies have reported reduced pain sensitivity and more pronounced EIH [
22,
23] among athletes and physically active individuals, it is reasonable to assume that the beneficial effects of long-term HEPA could be mediated by improved top-down pain modulation. We hypothesized that long-term HEPA would reduce pain as well as pain sensitivity by improving the function of endogenous pain modulatory mechanisms, such as EIH. To our knowledge, no previous study has explored the long-term effects of HEPA on pain sensitivity and endogenous pain modulation among individuals with RA.
Discussion
To our knowledge, this is the first study to explore changes in pressure pain sensitivity and activation of pain inhibitory mechanisms among individuals with RA who participated in a long-term HEPA program. The results indicate that 2-year participation in HEPA was associated with clinical improvement, as indicated by a decrease of global pain. However, our hypothesis that HEPA would be associated with reduced pain sensitivity and improved EIH could not be confirmed.
Although we found a statistically significant reduction in pain intensity following HEPA, the magnitude of the pain reduction was small. This would be expected given the participants’ relatively low pain intensity at baseline. However, our participants scored a pain intensity similar to the baseline pain intensities reported in other exercise studies [
34] and this most likely reflect that patients volunteering for exercise studies tend to have a relatively low disease impact.
Our findings that two years of HEPA did not influence pain sensitivity (that is, PPT or moderate suprathreshold pressure pain at rest) indicate that long-term HEPA does not reduce pain sensitivity in RA. They also confirm previous results [
15‐
17] suggesting involvement of central pain mechanisms, including central sensitization, in RA pain as indicated by lower PPTs than healthy controls [
16,
17]. However, these findings are in contrast to the well-established clinical improvement of pain following exercise [
35], which was also confirmed in the present study. Since our results do not favor our hypothesis, pain inhibitory mechanisms other than EIH need to be investigated in order to increase our understanding of the long-term beneficial effects of HEPA on clinical pain among individuals with RA.
There are several possible explanations for the increased sensitivity to strong pressure pain found in the present study. One might be totally unrelated to HEPA but more to previously described continuous sensitization among individuals with RA [
15]. It is reasonable to assume that such a process is first indicated at higher levels of suprathreshold pain since its testing includes a component of temporal summation [
36]. Thus, it might be argued that the HEPA program favorably influenced sensitivity to pressure pain at lower levels since no increase in pressure pain sensitivity was found for these levels over two years.
In our previous study, using baseline data (before intervention) from the present study [
17], we found functioning EIH among both the participants with RA and healthy controls. The present results offer confirmation but also indicate that EIH did not improve significantly during the 2-year HEPA program. One explanation might be that, according to SMS self-reports, the participants did not perform HEPA, particularly circuit training including strengthening exercises, frequently enough. Furthermore, despite clear instructions, they might not have maintained the recommended intensity levels of (the mainly unsupervised) physical activity performed within the study for 2 years. The difficulty to maintain recommended levels of intensity is also supported by our previous study, which found that individuals with RA determine physical activity intensity by standards other than those of health professionals [
37]. Studies of aerobic exercise [
20,
38] and of resistance exercises [
21,
39] indicate that participants with RA seldom maintain high enough levels of physical activity without supervision. This has also been found among individuals with other chronic pain conditions, such as fibromyalgia [
40]. The HEPA support program employed in the present study included behavioral change techniques to support not only adoption but maintenance of physical activity [
24,
41]. Despite major positive outcome and experiences, the results of the main PARA intervention study clearly illustrate the complexity and difficulty of keeping physical activity at a moderate or higher intensity level over time [
29,
42,
43]. A few previous studies on short-term supervised exercise exist but report conflicting results. Two studies including participants with joint pain [
19,
34] reported no change in endogenous pain modulation. One of them [
34] found no change in pressure pain sensitivity, and the other did not assess pain sensitivity [
19]. Another study found a reduction of pressure pain sensitivity after a supervised 12-week exercise program and the authors suggested that this was likely attributed to a high exercise intensity and high adherence to the program [
44]. All together, our present findings may indicate that physical activity on a level that is feasible enough for people with RA to maintain over time outside a health-care context does not correspond to that required for improving endogenous pain modulation and reducing pain sensitivity.
The strengths of our study are the long-term perspective and the fact that the HEPA program was performed in a natural setting with the participants paying their own expenses, thus resembling reality to a great extent. There was a fairly high dropout rate as the result of poor adherence, and there were incomplete data due to an administrative error. Furthermore, since the dropout analysis indicated no major differences between those meeting the inclusion criteria for the present study and those with incomplete data or not meeting the criteria for HEPA for two years (or both), there should be no major influence on external validity. Long-term exercise interventions using multiple assessment methods require comprehensive administrative and methodological procedures, resulting in limited numbers of participants. Thus, although a total sample of 30 participants with RA might be considered a limitation to our study, it resembles the size of samples in previous studies investigating endogenous pain modulation in response to exercise in rheumatic diseases [
19,
34]. The choice of methodology for the present study might have influenced our results. Assessing individual pain-related central mechanisms is complex because several methods measure different aspects. Thus, the long-term effect of HEPA on pain modulation was assessed by segmental and plurisegmental EIH using normalized PPTs during static muscle contraction [
30]. An alternative method would have been conditioned pain modulation, which measures the pain-inhibits-pain mechanism [
19] used to assess endogenous pain modulation. However, although test results obtained with the two methods do not correlate [
45], results from studies using either of the two methods in participants with RA seem to point in the same direction (that is, normally functioning conditioned pain modulation [
15] and EIH [
17]).
The present study explored the influence of long-term HEPA on pain sensitivity and EIH. Future studies should investigate how long-term physical activity with different intensities contributes to changes in EIH among individuals with RA. Furthermore, studies are needed to explore the role of long-term sensitization and the natural long-term course of EIH development among individuals with RA.
Acknowledgments
We gratefully acknowledge the members of the PARA Study Group: physical therapists Christina Eriksson, Annelie Nordström, Eva Prinzell and Malin Wisell, Linköping University Hospital, Linköping; Birgitta Folin, Helena Heldt, Carina Sjöman and Maria Wärfman, Norrköping Hospital, Norrköping; Eva Frykstad, Anna Moberg, Hanna Olsson and Johanna Pettersson, Mälarsjukhuset, Eskilstuna; Anna Hallén and Sofia Sandström, Karolinska University Hospital, Solna; Anna Dahlgren and Åsa Lindkvist, Karolinska University Hospital, Huddinge; Erica Christensen, Elin Löfberg and Sara Stråt, Danderyd University Hospital, Stockholm; Katrin Bylander, Ingrid Larsson and Maria Skogemyr, Östersund Hospital, Östersund; Sofia Blomqvist and Susan Sandberg, Sunderby Hospital, Luleå; Anna Nordin, Winternet, Boden; Emma Swärdh, Karolinska Institutet, Stockholm; and Anne Marie Norén, Stockholm County Council, Stockholm, Sweden.