Musculoskeletal pain is associated with restless legs syndrome in young adults

The current study is, to our knowledge, the first on the association between MSK pain and RLS in young adults. Most previous studies on this topic have focused on female populations and have often used chronic pain or rehabilitation clinics to recruit their participants [ 15, 16, 26]. In addition, these studies have focused on fibromyalgia, a more specific subset of chronic widespread pain. Our study includes both sexes, is among the first to sample from a general population and involves a more general measure of MSK pain. The questionnaires used covered multiple aspects of MSK pain and therefore provide a thorough assessment of different pain aspects. Lastly, adjustment was made for important potential confounding factors.

The results of this study are consistent with the findings by Stehlik et al. [ 17] in their study of Swedish middle-aged women, where long duration of pain and a high number of pain sites was strongly associated with RLS. A study in Australian twin families by Champion [ 27] also showed significant associations between two or more regional pain sites and RLS. These findings are, together with the results from our study, an extension to the earlier reported associations between RLS and fibromyalgia [ 15, 16].

Psychological distress and sleep quality are important factors in the relationship between pain and RLS. In particular, pain in multiple body areas is often related to depressive symptoms and other mental health problems including anxiety disorders [ 28– 30]. Depression is also linked to altered pain thresholds and a predictor for future pain [ 31]. Several studies have established strong associations between RLS and psychiatric comorbidity including major depressive disorder and anxiety disorders [ 8, 32, 33]. Sleep disruption is a prominent complaint in RLS and is also considered a risk factor for both panic disorder and depression [ 10, 34]. High prevalence of sleep disruption has been reported in chronic MSK pain [ 35] and experimental studies in animals [ 36] and humans [ 37] have shown that sleep disruption can induce musculoskeletal sensitization and lower pain thresholds. In summary, the relationship between pain and sleep can be considered bidirectional [ 38], with an important mediating role for emotional states. In our study, the associations between RLS and MSK pain remained present even after adjusting for psychological distress and sleep quality. This underlines the probability of other shared mechanistic pathways in these conditions, which will be discussed based on the current literature.

The influence of heritable factors in RLS is supported by family studies [ 39, 40] and genome-wide association studies (GWAS) have identified at least six genetic loci in association with RLS [ 41]. Observational studies suggest, at least in part, a genetic basis in chronic pain syndromes including chronic widespread pain and fibromyalgia and pain reporting behavior at multiple MSK pain sites as well [ 42– 44]. In GWAS a number of genes, involved in adrenergic and serotonergic pathways, have been consistently linked to MSK pain [ 45, 46]. Even though specific shared genes between MSK pain and RLS have not been identified thus far, it is evident that with genetic susceptibility being such an important component in the occurrence of both RLS and MSK pain, shared genes (pleiotropy) might be an important factor in the co-existence of these conditions.

The considerable role of dopamine dynamics in RLS is illustrated by the efficacy of dopamine agonists in RLS treatment [ 47] and supported by neuropathological studies [ 48]. Combined with studies establishing the link between brain iron deficiency and RLS [ 49, 50], it is hypothesized that RLS might be seen primarily as an iron insufficiency disorder, with resulting dopaminergic abnormalities [ 18]. Altered dopaminergic responses have been found in brain imaging studies of fibromyalgia patients as well [ 51] and reductions of dopamine metabolism have been found in patients with depression [ 52]. Trials with dopamine agonist pramipexole, frequently used in RLS treatment, have had promising results in both fibromyalgia patients [ 53] and patients with depression [ 54]. It is likely that alterations in dopamine metabolism are an important factor to explain the associations between RLS, MSK pain and depression.

In our study, RLS was not only strongly associated with leg pain, significant associations were also found for shoulder and arm pain, neck pain and lower back pain. An explanation for this finding might be found in the concept of central sensitization of nociception. Central sensitization is characterized by an increase in excitability and synaptic efficacy of neurons in central nociceptive pathways, manifests as pain hypersensitivity, and has been implied as a causal or maintaining factor for pain in a wide range of pathologies including osteoarthritis, temporomandibular disorders, fibromyalgia, tension-type headache, irritable bowel syndrome and low back pain [ 55, 56]. Recently, there has been evidence reported for central sensitization in RLS. In an interesting study by Stiasny-Kolster et al. [ 57] a three- to fourfold increase in sensitivity for pinprick stimuli in untreated RLS-patients was found, along with a reduced tactile sensitivity and paradoxical heat sensation. Treatment with L-Dopa reversed or reduced these symptoms, prompting the authors to conclude that sensory symptoms in RLS are possibly explained by impaired dopaminergic control on spinal nociceptive neurons and central dis-inhibition. The presence of central sensitization or dis-inhibition in RLS sufferers might account for the high comorbidity of multiple site MSK pain.

In summary, we think genetic factors might account for a large part of dysregulation in dopaminergic metabolism, involved in the onset of RLS and MSK pain, but also depression. In turn, the sleep disruption caused by RLS results in lowering of pain thresholds and an increase of depressive symptoms, both related to an increased risk of future pain. The intimate relationship between these conditions requires the clinician to have special attention for comorbid occurrence.

Although we acknowledge the modest response rates (51.4 %) in our study, one needs to bear in mind that the data used for this study were part of an extensive cohort study, involving questionnaires, physical assessments and for most participants also an overnight sleep study [ 20]. In our experience, young adults were a particularly challenging group to recruit for this study. Further, as the sample remains representative of the broader Western Australian population of similarly aged young adults, we are confident the associations found are likely to be true for the population. The RLS-categorization was based on self-reported measures, which might increase prevalence estimates compared to a clinician-based diagnosis. We used the IRLSSG [ 1] screening questions in conjunction with frequency of experiencing symptoms at least 5 times per month as conservative criteria for diagnosis of RLS. Alternate questionnaires for RLS diagnosis, such as the Cambridge-Hopkins questionnaire [ 58], have been suggested as an alternative to the 4 screening questions based on their ability to better differentiate disorders that could mimic RLS [ 59]. However in the large epidemiological Raine Study where participants provided extensive questionnaire datasets, the 4 screening questions were deemed sufficient to make the RLS diagnosis while minimising participant burden. Also the likelihood of common RLS mimics being present in the younger cohort, including conditions as neuropathy, radiculopathy and arthritic pains [ 59], was deemed low. Despite these potential limitations we still found strong, consistent associations. Even though we did not find a statistically significant difference, the RLS prevalence was almost twice as high in females as in males in our samples, consistent with previous reports [ 2, 3, 5]. The 95 % confidence interval for the difference in RLS-prevalence between males and females from our sample was 0 to 3.7 %, in keeping with the known female predominance. Also, the overall prevalence of RLS found in this study is congruent with other large epidemiological surveys [ 2– 6] supporting the representativeness of the Raine cohort and the conservative criteria used for RLS diagnosis. Most known confounders, based on previous literature, were controlled for, but we cannot be certain that all potential confounders were measured. Because of the relatively small group that satisfied the RLS criteria, confidence intervals in our risk estimations were wide. Larger studies are needed if a more accurate estimation of RLS-prevalence risk in MSK pain is sought. Lastly, while we found strong associations between RLS and MSK pain, the cross-sectional nature of our study limits the possibility to make statements on causality. Future studies, particularly prospective studies, are needed to effectively address this causality question.

We have found strong independent associations between MSK pain and RLS in young adults. This finding indicates that there may be an opportunity for early intervention and prompt clinicians to screen for RLS in young adults with MSK pain, and vice versa. Each condition should be regarded in the light of the other. Consideration of the comorbidity of MSK pain and RLS, as well as addressing psychological symptoms such as depression, may be particularly important in determining management needs. In subjects showing an overlap between RLS, multiple pains and depressive symptoms, dopamine agonists such as pramipexole might prove especially effective, as already has been shown for these conditions separately [ 47, 53, 54]. While pharmalogical treatment is the frontline approach for RLS [ 47], in RLS sufferers with comorbid MSK pain non-pharmalogical strategies such as exercise programs [ 60] might be a useful adjunct. Intervention studies are needed to further investigate treatment options in this particular category of patients.