Authors previously reported that the stool consistency was associated with pain perception in healthy subjects. Specifically, the more watery their stool was, the more sensitive were the healthy subjects to painful stimuli (3). In contrast to healthy subjects, in the current study, patients with chronic pain showed that constipation was significantly and positively associated with the pain severity of the total patients and patients with low back and/or lower limb, and whole body pain. However, there were no significant associations between the stool consistency and the pain severity.
Constipation is associated with the GM composition. For example, the patients with constipation rigorously reduced abundance in Prevotella and increased representation in several genera of Firmicutes compared with the controls (8). Khalif et al. (16), reported lower amount of Lactobacillus and Bifidobacteria species in the stool sample of adults with chronic constipation. Moreover, short-chain fatty acids generated from the enteric bacterial fermentation of undigested carbohydrates may contribute to the pathophysiology of constipation (9).
The GM has an influence on autism, major depression, and Parkinson disease (17). In a study on healthy volunteers, those who took specific probiotics (Lactobacillus belveticus and Bifidobacterium longum) displayed less anxiety and depression (18). The GM contributes to the modulation of multiple neurochemical and neuro-metabolic pathways (11, 12). These pathways involve the hypothalamic-pituitary-adrenal axis, chemokines and cytokines, and autonomic nervous and enteric nervous systems, which constitute the microbiota-gut-brain axis (10). Also, brain function and psychological makeup are considered to have a reciprocal relationship with GM. Furthermore, GM can release neuroactive molecules (such as acetylcholine, catecholamine, γ-aminobutyric acid, histamine melatonin, and 5-hydroxytryptramine (5-HT) similar to the host that may induce neuropeptide production in the brain, and increase gut-blood barrier and blood-brain barrier (BBB) permeability (19, 20). The 5-HT plays an important role in the regulation of peristalsis (21), pain perception (21, 22), mood, and cognition (23). Despite its well-known role in the central nervous system, while only 5% out of the whole human body 5-HT is found in the brain, the gut contains 95% of 5-HT (24). Since 5-HT is synthesized from essential amino acid tryptophan, the increasing microbiota deterioration reduces the functionality of the tryptophan absorption in the gut, thereby reducing 5-HT biosynthesis (25).
The endogenous pain modulatory mechanisms, involving both opioid and 5-HT signaling, are impaired in patients with chronic pain (26). The dysfunction of endogenous pain modulatory mechanisms is observed in patients with whole body pain (e g, widespread pain, fibromyalgia) rather than local pain (27). Previous research suggested that patients with fibromyalgia reduced 5-HT levels, and reduced tryptophan absorption (25). Low tryptophan absorption induces low 5-HT synthesis that causes fibromyalgia symptoms (25). The current study results indicated an association between constipation and pain severity in patients with chronic pain, especially in patients with whole body, low back and/or lower limb pain. Based on the current study results, it was thus postulated that dysbiosis might have disrupted pain-modulation systems, thereby leading to a vicious cycle in which biological factors could have aggravated the pain intensity of patients with low back and/or lower limb, and whole body pain.
The constipation was associated with insufficient physical activity and excessive sedentary behavior. The mild to moderate physical activity showed positive effects on constipation (28, 29). Also, it is well known that inactivity is a risk factor for development of chronic pain (30). Moreover, increase in physical activity attenuates the severity of symptoms in patients with chronic pain (31). One of the mechanisms by which the exercise induced hypoalgesia is thought to involve the endogenous pain modulatory system (32). Additionally, it is reported that the regular exercise influences the composition and function of human GM (33). Therefore, it is suspected that the physical activity, GM, and the endogenous pain modulatory function are correlated with patients with chronic pain.
The stool consistency and constipation may be affected by age, gender, and BMI (29, 34), but CCCS had no correlation with these factors. Although the BSFS was correlated with age and BMI, the correlation coefficients were small (rs = -0.116, -0.174). In addition, BSFS and CCCS did not show gender differences. Thus, it was thought that stool consistency and constipation had little influence on age, gender, and degree of obesity.
The pain severity was correlated with CCCS, but was not correlated with BSFS. There may be a relationship with CCCS and BSFS, since they had negative correlation. However, the correlation coefficient was small. Constipation does not necessary mean a hard stool. Furthermore, BSFS is a graded scale from 1 to 7. Therefore, it was thought that BSFS did not have a significant association with the pain severity. On the other hand, authors previously reported that BSFS was associated with the pain perception in healthy subjects (3). One of the reasons might be that the subjects of the authors’ previous study were younger than the subjects of the current study. Another reason might be that although BSFS was associated with pain perception in healthy subjects, the pain perception was induced by painful external stimuli. Therefore, further studies are necessary to investigate the difference between healthy subjects and patients with chronic pain.
Medication has several side effects, especially gastrointestinal effect. Although opioid, pregabalin, and antidepressant out of the drugs listed in the current study are known to cause constipation (35-38), there were some differences of the prescribed ratio only in acetaminophen. Furthermore, there were no significant differences in BSFS and CCCS among medications. It was thus postulated that medication would hardly have influenced the current study findings.
There were several limitations to the current study due to the inclusion of elements of a qualitative study. First, the study did not measure GM composition and richness, and blood levels of substances such as short-chain fatty acids. There is growing evidence that microbiota diversity can change variations in short-chain fatty acids (39). Secondly, authors’ previous study showed that stool form consistency was associated with pain perception (3), which was not consistent with the current study results. Authors’ previous study was conducted on young healthy subjects and, in contrast, the current study was conducted on older patients with chronic pain; therefore, these results could be inconsistent. Further studies should evaluate the relationship between GM and pain perception in older adults and patients with chronic pain using 16S rRNA analysis or by measuring short-chain fatty acids. Thirdly, the intensity of pain was affected by the dosage of the prescribed medications. Fourthly, the patients were classified into five groups based on the anatomical part of the body in which the patients felt pain. Even if the part with pain was the same, it included various diseases. Further studies are needed to investigate the influence of the dosage of the prescribed medications and the underlying disease. Finally, the current study did not evaluate the effects of endogenous pain modulatory molecules including the 5-HT.
4.1. Conclusions
The results of the current study showed that constipation was significantly and positively associated with the pain severity in the total patients and patients with low back and/or lower limb, and whole body pain.
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