In this study, we evaluated pain perception through BPI and KPPS in two different cohorts of PD subjects, respectively with and without constipation, with the aim of exploring a possible connection between these frequent and disabling non-motor disturbances. We found that PD patients with constipation compared to those without- scored significantly higher in BPI-severity, BPI-interference and KPPS total. Our analysis suggests that constipation is significantly associated with pain in PD.

Interestingly, previous studies revealed a significant association between constipation and pain severity among patients with chronic pain (Shiro et al. 2017; Arai et al. 2018; Frazzitta et al. 2019). These studies investigated potential mechanistic links contributing to the association between constipation and pain severity, highlighting the significance of physical activity level, and endogenous pain modulatory mechanisms as key factors. Constipation correlates with inadequate levels of physical activity and an excess of sedentary behavior (Alves Silva et al. 2020). Conversely, reduced physical activity, has been associated with impaired gastrointestinal motility and increased risk of constipation (Peters et al. 2001). Likewise, physical inactivity could lead to increased pain sensitivity due to changes in musculoskeletal health (Law and Sluka 2017). It is extensively recognized that individuals with PD exhibit lower levels of physical activity in comparison to healthy individuals (von Rosen et al. 2021). Thus, despite constipation in PD basically reflects the degeneration of the enteric nervous system by the Lewy Body pathology (Grillo et al. 2022), physical inactivity may contribute to it. Constipation may long precede the onset of motor symptoms, suggesting that, at least in some cases, neurodegeneration may proceed bottom-up, from the enteric or peripheral autonomic nervous system to the brain (the so called “body-first” hypothesis) (Horsager et al. 2022). Recent works showed that the “body first” PD subtype with prodromal constipation displays more severe clinical burden in motor or cognitive domains (Picillo et al. 2021; Grillo et al. 2022). Here, we show that constipation may also be associated with other non-motor symptoms, i.e. pain, and therefore it should be considered a clinical marker of greater frailty in PD.

Our analysis shows that patients with constipation had a significantly longer disease duration. This is in line with the progressive nature of PD. However, the multivariate analysis, shows a significant difference in KPPS total scores and BPI independently from disease duration. Thus, the association of pain with constipation may not reflect a “more severe” PD due to progression of neurodegeneration. Instead, it may reflect an interplay between the two conditions (pain and constipation), or overlapping, and still poorly understood mechanisms, that account for the correlation that we have found.

Nociception is a complex process that involves multiple neural structures including nociceptors, dorsal horn of spinal cord, spinothalamic system, and cortical regions. Neurodegenerative changes in PD can potentially alter this process at both central and peripheral level, thus generating different subtypes of pain that often coexist in the same subject (Antonini et al. 2018; Rukavina et al. 2019). Indeed, pain related to PD may be primary (i.e. nociplastic, that is a maladaptive pain processing within the central nervous system), or secondary to musculoskeletal or visceral conditions, or neuropathic in origin (Mylius et al. 2021). Pain is exacerbated by dopamine fluctuations in PD patients, supporting the idea that dopamine depletion has an underlying role in pain hypersensitivity in PD, although the exact mechanism is still unclear. Moreover, there is increasing evidence that a hypodopaminergic tone characterizes chronic pain states (Taylor et al. 2016). PD patients in the off-phase display lower pain thresholds and tolerance compared to healthy controls, underpinning increased spinal nociceptive activity, and decreased descending inhibition (Gerdelat-Mas et al. 2007; Mylius et al. 2009). Pain thresholds are partially restored, but not completely normalised, during on-states after dopamine medication, suggesting that additional mechanisms are likely to contribute to pain hypersensitivity in PD (Thompson et al. 2017). Recently, it has been suggested that noradrenaline dysfunction may also contribute to alter the pain endogenous modulation in PD (Ray Chaudhuri et al. 2023) Indeed, in healthy individuals, pain descending pathways inhibit spinal nociceptive activity through the actions of noradrenaline at α2-adrenoceptors, whereas spinal noradrenergic activity is impaired in chronic pain states (Bannister and Dickenson 2017). It is also likely that noradrenergic transmission is negatively involved in dysautonomic symptoms in PD (Titova et al. 2017).

From a pathophysiological point of view, there may be other overlaps in the in the genesis of pain, constipation, and PD. Indeed, the three conditions have been individually associated with gut microbial dysbiosis (Wallen et al. 2020; Pan et al. 2022).

Gut microbiome alterations can drive maladaptive neuroplasticity in pain processing pathways by inducing immune cells to release pro-inflammatory factors and ultimately amplify dorsal root ganglion and dorsal horn neuronal excitability (Liu et al. 2023), Moreover, gut microbiome is necessary for absorption and production of the amino acid tryptophan, which is the precursor of serotonin (5-HT), a neurotransmitter involved in pain modulation (Bannister and Dickenson 2017), as well as in the regulation of mood and cognition (Cryan and Leonard 2000), which are often impaired in chronic pain states and in PD. Widespread chronic pain correlates to reduced 5-HT levels, and reduced tryptophan absorption (Lattanzio 2017). Likewise, the dysfunction of the serotonergic system is involved in many aspects of PD (Hsam and Kohl 2023). Furthermore, 5-HT is involved in the local regulation of gut movements (Mawe and Hoffman 2013) and its depletion may contribute to the alteration of gut motility in PD.

Thus, the degeneration of dopaminergic and non-dopaminergic pathways in the brain, characteristic of PD, may impact the intricate balance of neurotransmitters involved in pain modulation and gut functionality (Maiti et al. 2017) and impair central nociceptive processing and modulation, playing an important role in pain pathogenesis in PD (Fil et al. 2013; Buhmann et al. 2017; Antonini et al. 2018; Blanchet and Brefel-Courbon 2018). Dopamine fluctuations worsen pain perception in PD (Mylius et al. 2009). Our findings indicate that PD patients with constipation are more prone to fluctuation-related and nocturnal pain which may be consequent to an insufficient bioavailability of dopaminergic drugs.

It is well known that an altered gastrointestinal motility and changes in the microbiota composition can alter levodopa pharmacokinetics (Zhong et al. 2023). A stable gut microbiota, indeed, contributes to the regulation of multiple neuro-chemical and neuro-metabolic pathways that guarantee a normal gut physiology and proper transmission along the gut-brain axis. By contrast, ever-increasing evidence demonstrates that imbalance within gut microbiome may be involved in PD pathogenesis, gastrointestinal disorders, and pain processing alterations (Bravo et al. 2012; Shiro et al. 2017; Freidin et al. 2021; Chen et al. 2021; Warnecke et al. 2022). In the complex interplay of constipation, impaired levodopa absorption and likely intestinal dysbiosis and impaired pain processing, the relationship between constipation and increased pain occurrence is not surprising. Constipation-related fluctuations in levodopa absorption may worsen motor complications in PD patients and levodopa-fluctuations related dyskinesia and dystonia may also result in painful sensations (Stocchi and Torti 2017).

Despite PD was initially described as a motor syndrome associated to dopamine deficiency, it is now well recognized that NMS have a greater impact on Health-related quality of life (HRQOL) than motor symptoms (Barone et al. 2009). However, furthers subanalysis of single NMS domains suggest that neither pain nor constipation primarily contributes to HRQoL, despite these finding are not uniform. Inconclusive results may depend on lack of specific and shared definitions and scoring systems for pain and constipation in PD. If not carefully investigated, pain in PD may be neglected during routine visits. In fact, patients often do not report spontaneously on pain (Buhmann et al. 2020). The awareness that PD patients with constipation are at higher risk of experiencing pain, should lead clinicians to perform a more careful assessment of pain in this group of patients; furthermore, it should prompt efforts to restore gastrointestinal motility and levodopa absorption as an important step to manage pain in this population, with hope-for reducing painkiller and NSAID overuse. In addition, patients should be educated to modify their fiber and water intake and to change sedentary habits in order to manage constipation (Astarloa et al. 1992; Alwardat et al. 2019). We should recognize that the relationship between pain and constipation likely involves a complex interplay of multiple factors, also including phycological aspects. Thus, actions aiming at restoring well-being in a patient-centered proactive strategy, by promoting physical activity, dietary habits, and by managing anxiety and depression, may all potentially affect HRQoL, reducing psychosocial distress (Schirinzi et al. 2019, 2020; Pontone et al. 2023). These are all recognised factors that deserve further exploration in future studies.

There are several limitations to be acknowledged in this study. First, the sample size is limited to the number of patients who fulfilled the inclusion criteria from a previous database that was created for different purposes. Therefore, these data should be confirmed in an ad-hoc powered study. Second, the retrospective nature of the study and the absence of long-term follow-up could affect the ability to determine the temporal relationship between constipation and pain severity in PD. A longitudinal study design would be more appropriate to assess the long-term relationship between these variables. Third, we did not consider that levodopa is a possible cause of constipation and related gastrointestinal disorders, therefore, patients on OFF-medication state should be included in future studies.