Background
Achilles tendinopathy is a difficult to manage musculoskeletal (MSK) condition with an incompletely understood pathophysiology [
1,
2] that adversely affects quality of life [
3]. While typically associated with running, this painful condition also affects up to 6% of the non-athletic general population [
4]. The sympathetic nervous system (SNS), insulin resistance, type 2 diabetes mellitus (T2DM), dyslipidaemia, and visceral adiposity have been identified as potential contributors to MSK pain, including tendinopathy [
5‐
7]. There is evidence that the SNS could underpin these metabolic features associated with MSK and tendon pain [
8].
Recently, SNS function in painful tendons has been investigated in a small number of studies. A systematic review of microscopy studies has revealed increased markers of catecholamines synthesis (e.g. tyrosine hydroxylase) and adrenoreceptors in the paratendinous tissue, as well as increased adrenoreceptor like substances on abnormal tenocytes within the tendon proper, in biopsies from painful tendons [
9]. In addition, upregulation of the SNS contributes to chronic pain [
10]. Among individuals with tendon pain, SNS activity is higher in people with longer symptom duration and correlates with poorer tendon structure [
11]. Together, these observations raise the possibility that the SNS plays a role in the chronicity of tendinopathy and structural change within the tendon.
Polycystic ovarian syndrome (PCOS) is a common clinical disorder among women that presents as a combination of hyperandrogenism, ovulatory dysfunction, and polycystic ovaries [
12]. Other clinical features include insulin resistance, T2DM, infertility, and visceral obesity [
13]. PCOS has also been associated with increased sympathetic activity, independent of other metabolic factors [
13,
14].
Only one study has examined in vivo sympathetic drive in tendinopathy, and this was in a metabolically-normal population with clinical symptoms of tendon pain [
11]. A double-blinded randomised controlled trial of moxonidine (a sympatholytic medication) to treat the symptoms of PCOS (Clinical Trial registration NCT01504321) [
15] provided a unique opportunity to document the change in tendon and MSK symptoms in response to sympathetic nervous inhibition in a metabolically diverse population.
As moxonidine is a centrally acting imidazoline 1 (and to a lesser extent adrenoreceptor type-2) agonist which has been shown to reduce both sympathetic drive and insulin resistance [
15], it was hypothesised that this may improve MSK and Achilles tendon pain, which both have links to increased SNS drive and metabolic dysfunction. Therefore, the aim of this paper was to examine the effects of moxonidine on Achilles and general MSK pain (primary outcome) and on Achilles tendon structure (secondary outcome) in women with a diagnosis of PCOS.
Discussion
Findings
In this study of women with PCOS, we examined the effect modulating the SNS had on MSK pain, Achilles pain and Achilles structure. It follows on from previous work which examined the involvement of muscle sympathetic nerve activity in people with Achilles tendinopathy, notably those with increased duration of symptoms [
11].
We did not demonstrate a significant change in either group post intervention with regards to Achilles tendon or musculoskeletal symptoms. Given structural tendon changes are not always associated with pain and symptoms [
28,
29], analysis of the effect moxonidine had on UTC data was of benefit in this population with few symptoms. Percentage of aligned fibrillar structure appeared to be similar to (if not slightly worse than) previous measures in elite Australian footballers [
22], however tendon structure was not significantly changed by the 12-week intervention in either group. These findings suggest there is currently no evidence that blocking SNS activity with moxonidine for 12 weeks provides benefit for MSK or Achilles tendon pain, nor for Achilles tendon structure. This is of particular note in this population of women with PCOS, as this MSK pain may prevent women from undertaking physical activity as a vital part of their disease management [
30‐
32].
Limitations
This study has a number of key limitations that must be taken into consideration. The study has a small sample size due to it being a secondary analysis as part of a larger project investigating the effects of moxonidine in PCOS. The smaller sample size in comparison to the parent RCT was due purely to the premature end of access to resources for measuring MSK and Achilles data, so selection bias is minimised. However, this renders it underpowered in properly examining the effects of moxonidine on MSK and Achilles tendon pain, and definitive conclusions cannot be drawn from this paper.
Moreover, as recruitment in this study was based on a diagnosis of PCOS and not on Achilles tendon symptoms, a small number of participants began the study with pre-existing tendinopathy and the chances of significant change in either group was limited by this ceiling effect. Additionally, physical activity data were not measured, where differences among participants could plausibly affect tendon pain and structure measures.
Furthermore, the analysis of the MSNA data showed that while the moxonidine group had a lower sympathetic drive at baseline, there was no difference when comparing the effect of interventions between groups. Previous reports have shown that moxonidine is associated with reduced blood pressure and MSNA even in young normotensive subjects [
33], yet systolic and diastolic blood pressure were also unaffected. It is possible that the intervention group were not compliant with their moxonidine dosages, although this did not seem to be a major issue as per the original RCT [
15]. Moxonidine’s effect may also be changed in those with PCOS due to differences in adrenoreceptor expression [
34], as one would expect moxonidine to reduce overall sympathetic drive and blood pressure. Regardless, the lack of significant change in sympathetic drive may provide another reason as to why the active intervention did not change tendon/MSK outcomes.
Therefore, while no changes in MSK or Achilles symptoms were found, it must be considered that this study was a secondary project to the original RCT and its role in the literature is predominantly descriptive and should guide future research in the area.
Conclusion
This study of women with PCOS found no change in Achilles tendon pain, Achilles tendon structure or other MSK symptoms as a result of the sympatholytic medication. It was limited by its small sample size and inadequate modulation of SNS drive. While this study was the first to investigate the effect of blocking the SNS on MSK and Achilles tendon pain in a population with metabolic disease, there should be further studies of higher power, which recruit based on both tendon symptoms and metabolic disease, to investigate its true potential.
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