Management of Chronic Constipation: A Comprehensive Review

Abstract

Traditionally, the treatment of chronic constipation has focused on lifestyle modification, dietary guidance and therapy, and osmotic and stimulant laxatives. Recently, several drugs with new mechanisms of action have been introduced as treatments for chronic constipation. In Japan, polyethylene glycol and lactulose can now be administered under insurance coverage. The number of treatment options for constipation has increased dramatically. First, lifestyle modifications and dietary therapies must be implemented. If constipation does not improve sufficiently, specialized functional tests are performed to diagnose physiological subgroups. If functional tests are not available, patients are classified as having the “decreased frequency of defecation” type or the “difficult defecation” type based on the patient's symptoms, with treatment applied according to each type. Medical therapy includes osmotic laxatives, secretagogues, bile acid transporter inhibitors, probiotics, prokinetics, and Kampo medicines. The temporary use of stimulant laxatives, suppositories, enemas, and digital evacuation is also recommended. The usefulness of biofeedback is yet to be determined.

Introduction

In the recently published guidelines for chronic constipation in Japan, constipation is defined as “a condition in which a stool that should be evacuated is retained in the colon, resulting in fecal impaction and hard stools, and decreased frequency of bowel movements and/or excessive irritation, residual stool sensation, obstruction of the rectum and difficulty in defecation due to inability to evacuate stool comfortably”, and chronic constipation is defined as “a condition in which patients suffer from chronic constipation that interferes with their daily life and/or may cause various physical problems” (1). The term “chronic” is defined in accordance with the Rome IV criteria (2) as a condition in which “each symptom began more than 6 months ago and has persisted for the last 3 months.” However, in daily practice, whether a patient has nonchronic or chronic constipation is not determined by the period of time that the patient has had constipation but rather left to the judgment of the physician examining the patient.

In general, constipation is diagnosed when patients suffer from decreased frequency of bowel movements (less than three times a week), fragmented hard lumps or hard stools corresponding to Type 1 and Type 2 of the Bristol Stool Form Scale (2), abdominal distention with decreased volume of bowel movements, difficulty in defecation, and residual stools. Chronic constipation is diagnosed when patients report having constipation for some time.

Chronic constipation is a very common disorder (3,4) that reduces the quality of life of patients (5). Furthermore, even in the absence of organic diseases, patients with symptoms of chronic constipation are at an increased risk of a poor survival (6). Chronic constipation itself does not increase a patient's risk for a poor survival; rather, it is known to have many comorbidities (7), and a poor survival may be secondary to these comorbidities.

However, constipation has traditionally not been the focus of much research. When performing a literature search in PubMed using “constipation” as a keyword, 8,974 reports were found during the search period up to 2001, and 34,046 reports were found when the search period was extended to May 2023. When “Japan” was added to the keyword search, 179 and 1,639 reports were found in the earlier and later search periods, respectively. It is evident that the number of research reports on constipation has been rapidly increasing worldwide as well as in Japan.

Traditionally, the treatment of chronic constipation has focused on lifestyle modifications, dietary guidance and therapy, and osmotic and stimulant laxatives (8,9). Since 2002, several drugs with new mechanisms of action have been introduced as treatments for constipation, leading to an increase in the treatment options for constipation, and are now used for constipated patients. This may be the reason for the increase in the number of reports on constipation. Drugs with new mechanisms of action include lubiprostone, linaclotide, prucalopride, and elobixibat (10). Lubiprostone received Food and Drug Administration (FDA) approval in the United States (USA) in 2006, but in Japan, sales began six years later in 2012. Linaclotide received FDA approval in 2012, has been marketed in Japan since 2017, and has been available for chronic constipation since 2018. Elobixibat was first marketed in Japan in April 2018. Prucalopride received FDA approval in 2018, although it is not presently marketed in Japan. In Europe and the USA, polyethylene glycol (PEG) and lactulose formulations are widely used to treat chronic constipation (11). In Japan, however, neither of these drugs was covered by Japanese insurance and could not be used for chronic constipation in adults under medical insurance treatment until recently. The PEG formulation has been covered by Japanese insurance since 2018 and the lactulose preparation since 2019, which may have contributed to an increase in pertinent research reports in Japan.

In the present review, we focus on recent advances in the medical management of constipation, particularly functional constipation.

Diagnostic Algorithm for Chronic Constipation

When a patient arrives at the hospital with constipation, a medical interview is first conducted. It is important to clarify whether the patient has acute or chronic constipation through interviews. Acute constipation can be caused by intestinal obstruction, axis torsion, or stacking. Next, a physical examination, blood tests, and abdominal radiography are conducted to determine whether or not any findings suggest organic disease or a stool evacuation disorder. The patient should be checked for signs and symptoms of organic diseases that may cause constipation, such as abrupt changes in defecation habits, bloody stools, weight loss, a fever, and abnormal physical examination findings, including palpation of an abdominal mass and palpation of a mass or adhesion of blood on a digital rectal examination (1,11,12). If these symptoms are present, colonoscopy and/or magnetic resonance imaging/computed tomography (CT) should be performed, keeping in mind the possibility of constipation due to an organic disease, such as neoplastic or inflammatory disease, that is, organic constipation. In addition, in the interview, it should be determined whether or not the patient is taking any drugs that can cause constipation, i.e. drug-induced constipation, and whether or not the patient has any underlying disease that can cause constipation, i.e. symptomatic constipation. Once organic, drug-induced, and symptomatic constipation have been ruled out, patients may be diagnosed with functional constipation.

Although the Rome IV criteria for functional constipation clearly state that such cases do not meet the diagnostic criteria for irritable bowel syndrome (IBS), Japanese guidelines consider functional constipation and IBS in which constipation is the predominant symptom to fall on a continuous spectrum (1). Therefore, in practice, it is difficult to distinguish between functional constipation and IBS.

Treatment Targets

Chronic constipation symptoms have various effects on daily life and the body, significantly decreasing the physical and mental health-related quality of life (QOL) (5,13,14). Therefore, the goal of treatment for chronic constipation is to achieve a state of complete spontaneous defecation, i.e. defecation without excessive irritation, difficulty in defecation, rectal or anal obstruction, or residual stool; with a frequency of at least three days per week and with neither hard nor soft stools; and maintained continuously to improve the patient's QOL (1).

Treatment Strategies for Functional Constipation

First, lifestyle modifications and dietary therapies must be implemented. If constipation improves with these measures, leading to complete spontaneous defecation and improvement in the QOL, the lifestyle and diet that led to improvement in constipation should be continued without further treatment. If constipation does not improve sufficiently, specialized functional tests, such as the colon transit time test and rectal-anal pressure test, should be performed to diagnose whether the patient has normal-transit constipation, slow-transit constipation, or defecatory or rectal evacuation disorders.

However, in Japan, the colon transit time test is not covered by health insurance and is generally not administered in clinical practice. Furthermore, anorectal manometry, balloon expulsion testing, and defecography are performed only in specialized facilities in Japan. Outside Japan, physicians in many countries are unable to perform these evaluations.

As chronic constipation is a common disease that affects many people, treatment should proceed even if the physiological subgroup cannot be diagnosed. In such cases, it should be confirmed whether the patient has the “decreased frequency of defecation” type or the “difficult defecation” type based on the patient's symptoms, with treatment applied according to each type. In some cases, both types of symptoms are present. In the case of the “difficult defecation” type, a digital rectal examination, rectal echography, and CT of the abdomen are performed to determine whether or not fecal impaction is present in the rectum, and if fecal impaction is indeed present, an enema, suppository, or digital evacuation is performed. Lifestyle modification, dietary therapy, and medical therapy are initiated for patients with both types of symptoms. However, if there is no improvement, the subgroup-specific diagnosis should be made based on various specialized examinations, and treatment should be provided according to the subgroup (1).

Treatments for Functional Constipation

1. Lifestyle modification and dietary therapy

The first step in the treatment of functional constipation is to improve the patient's lifestyle and diet. A lack of exercise, insufficient fiber intake, and inadequate fluid intake are associated with constipation (15-17).

A meta-analysis integrating the results reported in nine articles by Gao et al. (18) showed that exercise significantly improved constipation [relative risk (RR)=1.97 (95% confidence interval (CI): 1.19-3.27; p=0.009; I²=91.3%)]. In particular, a sub-analysis that integrated the results of aerobic exercise research articles revealed an RR of 2.42 (95% CI: 1.34-4.36; p=0.003; I²=88%) (18). However, the articles included in that meta-analysis had a relatively high risk of bias and relatively low methodological quality. Only two of the studies had a low performance risk, and only three studies had a low detection bias. None of the studies described allocation concealment methods; therefore, the risk of allocation bias is unknown. Gao et al. (18) concluded that a more rigorous study is needed to evaluate the effects of exercise therapy on chronic constipation.

A prospective cohort study of 3,327 women showed that the prevalence of constipation tended to decrease with increasing fiber intake (p＜0.0001) (16). Participants were divided into five groups according to the fiber intake. However, the median fiber intake of the highest fiber intake group was 20 g/day, which is less than what is actually considered an adequate fiber intake (25-29 g/day) (19). The median fiber intake for the entire cohort was 12 g/day. Whether or not a fiber intake greater than the cutoff for an adequate intake contributes to a lower prevalence of constipation is unclear, and some reports have indicated that the amount of fiber intake does not correlate with constipation (20,21).

A meta-analysis integrating the results reported in 7 placebo-controlled randomized controlled trials (RCTs) studying the effect of fiber supplements on chronic constipation found that fiber improved constipation compared to placebo (RR of success to respond 1.71, 95% CI: 1.20-2.42, p=0.003), significantly increased stool frequency [standardized mean difference (SMD)=0.39; 95% CI: 0.03-0.76; p=0.03], and significantly softened stool (SMD=0.35; 95% CI 0.04-0.65; p=0.02) (22). However, bloating was reported in three of the studies as an adverse effect; fiber supplementation tended to increase bloating compared to placebo. The fiber supplements used in the seven articles included psyllium, inulin, partially hydrolyzed guar gum (PHGG), resistant maltodextrin, and galacto-oligosaccharides. The amounts ranged from 10 to 22.5 g/day, the duration of treatment ranged from 2 to 8 weeks, and the percentage of women ranged from 64% to 100%. None of the included studies had a low risk of bias (23). Larger and higher-quality RCTs are needed in order to recommend fiber intake for the treatment of constipation, although increasing the fiber intake may help improve constipation when it is inadequate (24).

A cohort study of 13,941 subjects ≥20 years old studying the relationship between fiber intake and constipation without adjustment for confounding factors demonstrated that a lower fiber intake was associated with harder and less frequent stools (25). However, after adjusting for multiple confounding factors, the fiber intake was no longer significantly associated with stool consistency or frequency. When the relationship between the dietary fiber intake and constipation was examined according to the level of physical activity, the study found that increasing dietary fiber intake had no effect on stool hardness in the less active group [odds ratio (OR), 1.02; 95% CI, 0.98-1.05; p=0.407], while increasing dietary fiber intake in the more active group changed stool consistency, with a 3% reduction in the risk of hard stools (OR, 0.97; 95% CI, 0.94-0.99; p=0.020). These results suggest that the benefit of fiber intake for chronic constipation may not be fully realized in less physically active individuals.

Regarding the effect of fluid intake on chronic constipation, studies have reported that a decreased fluid intake leads to constipation (26,27). However, no studies have demonstrated that increased fluid intake is effective as a treatment for chronic constipation in the absence of dehydration (28,29). Among adult patients with functional constipation who were provided approximately 25 g fiber per day with dietary fiber, a higher fluid intake significantly increased the frequency of bowel movements (30). In that study, 117 chronic constipation patients were randomly assigned to the free fluid intake group (Group 1) or the 2-L mineral water intake group (Group 2), and all patients received a diet that supplied sufficient amounts of dietary fiber (25 g) over a 2-month period. The average water intake of Group 1 was 1.1 L, and that of Group 2 was 2.1 L. A significant increase in the frequency of bowel movements was observed in Group 2. Therefore, when functional constipation patients take an appropriate amount of dietary fiber as well as water, higher water intake may improve constipation more than lower water intake (30).

Regarding the type of fiber, psyllium supplement, a soluble fiber, has been shown to increase stool volume and frequency of bowel movements in subjects with chronic constipation as well as in healthy individuals (31,32). The World Gastroenterology Organization Global Guideline lists dietary therapy as both a level 1 treatment and a level 2 treatment (10), and the American Gastroenterological Association-American College of Gastroenterology (AGA-ACG) Clinical Practice Guideline also suggests its efficacy (9). PHGG, a soluble fiber, has also been reported to soften stools in patients with chronic constipation (33) and shorten colonic transit times (34). Another study reported that PHGG significantly reduced the frequency of laxative use, although stool consistency and the frequency of defecation did not change (35). Wheat bran, an insoluble fiber, has also been reported to be effective in improving defecation frequency and colonic transit time (36); however, studies on wheat bran are scarce. Further research is needed to determine which dietary fiber is useful for patients with chronic constipation. In addition, abdominal bloating often occurs when dietary fiber is consumed (9), and countermeasures against abdominal bloating also need to be considered.

2. Osmotic laxatives

Osmotic laxatives are administered if constipation is not sufficiently relieved by dietary therapy. Osmotic laxatives include salt laxatives, such as magnesium (Mg) oxide and PEG formulations, and sugar laxatives, such as lactulose.

Mg oxide has been frequently used in Japan as a treatment for constipation despite the lack of reports providing evidence for its efficacy. Recently, Mori et al. (37) and Morishita et al. (38) reported the results of RCTs showing the benefits of Mg oxide. In their study, Mori et al. compared placebo and 1.5 g/day of Mg oxide, while Morishita et al. compared placebo, 1.5 g/day of magnesium oxide, and 1.0 g/day of senna. Patients with chronic constipation meeting the Rome IV criteria were randomly assigned to one of the treatment groups, and after 28 days of treatment, the effect of each treatment was evaluated. Both reports showed that Mg oxide was more effective for constipation than placebo, and that Mg oxide significantly increased the frequency of spontaneous defecation compared with placebo.

However, some precautions should be considered with regard to the preparation of Mg oxide. First, there is a risk of hypermagnesemia (39). Patients taking Mg oxide for a long time, those with renal impairment, and the elderly are more susceptible than others to hypermagnesemia, especially patients with delayed colonic transit constipation. Indeed, patients with delayed colonic transit constipation may develop hypermagnesemia, even when their renal function is normal (40). Next, attention must be paid to the possibility of drug interaction. Precautions have been advised concerning the concomitant use of new quinolones, bisphosphonates, rosuvastatin, rabeprazole, and several other drugs with Mg oxide, as the concomitant use of Mg oxide reduces the efficacy of many medications. Furthermore, Mg oxide itself may have an altered efficacy when combined with strong acid secretion inhibitors, such as proton pump inhibitors, as Mg oxide is more soluble at a low pH, and its solubility decreases when the pH rises or becomes neutral. When taken orally, Mg oxide is converted to Mg chloride in the acidic stomach, which is then converted to Mg(HCO₃)₂ in the intestinal tract, where it exerts an osmotic effect and draws water into the intestinal tract. If the gastric pH increases, Mg chloride formation does not occur (41). The acidity of the stomach is thus important for ensuring the efficacy of Mg oxide.

Macrogol 4000, a PEG formulation, has only been available for prescription in Japan since 2018, and few reports have provided evidence of the efficacy of PEG formulations in Japanese patients (42). However, many studies that provide evidence supporting the usefulness of PEG formulations have been conducted mainly in Europe and the USA (43-46). A double-blind RCT examined the usefulness and safety of PEG in 304 patients with chronic constipation after 6 months of oral administration of PEG 3,350 or placebo in a 2:1 ratio (43). The results showed that the overall treatment success in the PEG group was 52%, compared to 11% in the placebo group, with a higher percentage of patients achieving significant improvement in the PEG group than in the placebo group (p＜0.001). Super efficacy was defined as a week in which the patient no longer complained of any of the four Rome criteria. 47.3% of the PEG-treated weeks and 14.4% of the placebo-treated weeks were thus considered periods of super efficacy, showing a significant difference between the treatment groups (p＜0.001). Although diarrhea, flatulence, and nausea were observed in the PEG group, the incidence of each symptom in the PEG-treated group did not differ significantly from that in the placebo group. Future studies are expected to demonstrate the efficacy of macrogol 4000 in Japanese patients.

In Japan, lactulose preparations have long been prescribed for the treatment of hyperammonemia, but until recently, they could not be prescribed as a treatment for constipation, except for in children and/or after gynecological surgery. A jelly formulation of lactulose was prescribed for chronic constipation in adults in 2019. In a Phase III study in Japanese subjects, there was a significant dose-dependent increase in spontaneous bowel movement (SBM) at week 1 in the lactulose formulation group compared with the placebo group (p=0.003 for the 26 g/day lactulose group, p＜0.001 for the 39 g/day lactulose group) (47). The secondary endpoints of change from baseline in SBM at Week 2, the percentage of patients experiencing SBM within 24 or 48 h of the first dose, and the time from the first dose of the drug to the first SBM in the study were all significantly better in the lactulose group than in the placebo group. All adverse drug reactions in the lactulose group were mild and resolved or improved with no treatment for drug reactions, discontinuation, or dose reduction.

According to international guidelines, the World Gastroenterology Organization Global Guideline (10) states that Mg preparations are the first drugs to be used for the treatment of constipation. The AGA-ACG Clinical Practice Guideline (9) strongly recommends the use of PEG for chronic constipation and suggest the use of Mg oxide and/or lactulose.

3. Secretagogues and bile acid transporter inhibitors

If constipation improves with osmotic laxatives, the same treatment should be continued. However, if there is no improvement, secretagogues and/or bile acid transporter inhibitors should be administered.

Secretagogues include lubiprostone [a chloride channel (CLC) activator] and linaclotide [a guanylate cyclase C (GC-C) receptor agonist]. Lubiprostone acts primarily in the small intestine and selectively activates CLC-2 in the epithelial apical membrane to increase the translocation of chloride ions to the luminal side of the intestine and promote water secretion into the lumen. Increased water content in the intestinal lumen softens the intestinal contents and enhances intestinal transport capacity (48). In addition, lubiprostone has been reported to repair the barrier function of ischemia-injured porcine ileal mucosa (49). A meta-analysis of RCTs conducted for ≥4 weeks showed that the change from baseline in the weekly average number of SBMs after 4 weeks of administration of lubiprostone was 1.98 (95% CI: 1.17-2.79), and the percentage of patients reporting ≥3 SBMs/week after 4 weeks of administration of lubiprostone was 1.67% (95% CI: 1.36-2.06%), with lubiprostone being significantly more effective than placebo (10). Nausea and diarrhea are the most common side effects of lubiprostone. In an analysis of three 3- and 4-week placebo-controlled studies, three long-term open-label studies, three 12-week placebo-controlled studies, and one 36-week open-label extension study, the incidence of nausea in lubiprostone-treated patients ranged from 11.4% to 31.1%, but the majority of nausea cases were reported to be mild or moderate, especially during the first five days of treatment (50). In dose comparisons, nausea was significantly more common with a 48-μg dose than with placebo, but the incidence of nausea in the lubiprostone group was not significantly different from that in the placebo group at doses ＜48 μg, and the findings were dose-dependent (51,52). The Japanese package insert states that lubiprostone should not be administered to pregnant women or to women who may be pregnant.

Linaclotide increases intracellular cGMP levels via GC-C stimulation. Increased cGMP activates cystic fibrosis transmembrane conductance regulator (CFTR), and activated CFTR increases water secretion into the intestinal lumen and enhances the transport capacity of the small intestine. In addition, cGMP inhibits the activity of submucosal sensory nerves in the intestinal mucosa and suppresses colonic hyperalgesia, which is expected to improve abdominal pain, discomfort, and bowel movement (53). In a meta-analysis of seven RCTs, the number of responders with complete SBM (CSBM) was significantly higher in the linaclotide group than in the placebo group (OR: 3.59; 95% CI: 2.82-4.57; p＜0.001) (54). Diarrhea was the most common side effect, with a risk ratio of 3.10 (95% CI: 2.43-3.95; p＜0.001), but the degree of diarrhea was mild or moderate.

Elobixibat is an inhibitor of the ileal bile acid transporter (IBAT). It increases the amount of bile acid reaching the colon by inhibiting IBAT expression on epithelial cells at the terminal portion of the ileum, thereby suppressing bile acid reabsorption. Bile acids entering the colon bind to the transmembrane G protein-coupled receptor (TGR) 5, resulting in the generation of cAMP and activation of CFTR. Activated CFTR increases water secretion into the intestinal lumen. In addition, bile acids bind to TGR5 of enterochromaffin cells, leading to the release of serotonin on the intestinal wall and thereby promoting colonic motility. This dual action is expected to be effective in a wide range of patients (55). Rectal hyposensitivity has also been associated with constipation (56). Physiological concentrations of rectal chenodeoxycholic acid have been reported to decrease the rectal sensory threshold for rectal balloon distension (57). Elobixibat, which increases the amount of bile acids in the colon, is thought to have the potential to improve rectal hyposensitivity.

In a Phase III study of elobixibat in Japan, the number of SBMs per week during the first week of treatment was least-squares mean 6·4 (95% CI, 5·3-7·6) in the elobixibat group and 1.7 (1.2-2.2) in the placebo group, showing a significant difference (p＜0.001) (58). In a meta-analysis of 3 RCTs, including a Phase 1 study, the mean difference from baseline in the number of SBMs per week between the elobixibat and placebo groups was 5.69 (95% CI, 3.31-8.07), and was significantly greater in the elobixibat group than in the placebo group (59). Abdominal pain and diarrhea were the most common side effects of elobixibat. The overall incidence of side effects was 48% in a 52-week study in which the subjects had taken 5 to 15 mg of elobixibat during the study period (58). The incidence of gastrointestinal side effects was 41%, with 40% being mild, 1% being moderate, and 0% being severe. Abdominal pain occurred in 24% and diarrhea in 15% (58).

4. Stimulant laxatives

Stimulant laxatives include anthraquinone laxatives (senna, sennosides, rhubarb, and aloe) and diphenylmethane laxatives (sodium picosulfate and bisacodyl). Stimulant laxatives increase intestinal motility and inhibit water absorption, thereby producing a laxative effect. Anthraquinone laxatives and sodium picosulfate are not absorbed from the stomach or small intestine but reach the large intestine, where they act after being converted to their active forms, rheinanthrone and diphenyl, respectively, by the action of intestinal bacteria. Bisacodyl is converted into its active form by deacetylase in the small and large intestinal mucosa (60,61). Only one study has provided evidence for the usefulness of senna (38), although senna is often used in clinical practice. In that study, patients with chronic constipation who met the Rome IV criteria were randomly assigned to receive a placebo, Mg oxide, or senna for 28 days to compare their effects on constipation. The numbers of CSBMs and SBMs per week were significantly greater in the senna group than in the placebo group. The constipation QOL was also significantly improved in the senna group compared with the placebo group (38).

A meta-analysis summarizing the results of 2 RCTs in which picosulfate or bisacodyl (1 study each) was used as the treatment showed that the weighted mean difference of weekly CSBMs between the treatment and placebo groups after 4-week treatment was 2.50 (95% CI, 0.93-4.07), with the treatment resulting in a greater number of CSBMs than placebo (62).

The most common side effects of picosulfate and bisacodyl are diarrhea and abdominal pain. The long-term use of anthraquinone laxatives has also been reported to cause melanosis coli and decreased intestinal motility, leading to tolerance and dependence (63-65). However, some reports dispute the idea that stimulant laxatives lead to tolerance or dependence (66,67). Regarding stimulant laxatives, there is insufficient evidence for their efficacy, and the adverse effects of long-term use are not well-defined (67). Temporary use of stimulant laxatives has been suggested in the World Gastroenterology Organization Global Guideline and the Japanese Guidelines for Chronic Consumption (1,10).

5. Probiotics, prokinetics, and Kampo medicine

Probiotics are live microorganisms that have a beneficial effect on humans when taken in appropriate amounts or as products containing such microorganisms. In Japan, probiotics are not covered by insurance for the treatment of chronic constipation, although many studies have reported that probiotics are effective against chronic constipation (68). However, the types of microorganisms used have varied among reports, so further evidence is required to establish their place as a standard treatment.

Most of the prokinetic agents used to treat chronic constipation are 5-HT4 receptor stimulants. Among them, there are many reports on prucalopride, and meta-analyses have shown that it is indeed effective (69); however, it is not marketed in Japan at present. Mosapride, which is marketed in Japan, is not covered by insurance for the treatment of chronic constipation, and there is little evidence that it is actually effective for constipation (70).

Traditional Japanese herbal medicines (Kampo medicines) are made from a combination of several crude drug extracts, and their actions vary depending on the type and combination ratio of the crude drugs contained in the medicine. Crude drugs with hyperkinetic effects include rhubarb and zanthoxylum fruit. Since rhubarb is composed of sennosides, mainly sennoside A, side effects similar to those of stimulant laxatives should be considered (71). Different amounts of rhubarb are found in many Kampo medicines, including Daiokanzoto, Mashiningan, and Junchoto. Zanthoxylum fruit has been found in Daikenchuto. Sal mirabilis (a mineral composed of sodium sulfate) is a crude drug that softens stools via osmotic action. It has been found in Tokakujokito and Bofutsushosan. Mashiningan contains large amounts of fatty oils and thus softens stools (72). The choice of herbal medicine must be determined according to the patient's physical strength, symptoms, and condition. In addition, since glycyrrhiza can cause pseudo-hyperaldosteronism, serum potassium levels should be regularly measured when administering glycyrrhiza-containing Kampo medicine (73).

Although Kampo medicines are used in clinical practice, there are few reports with a high level of evidence, such as RCTs, to prove their effectiveness. Recently, Manabe et al. randomized 63 patients with chronic constipation (including constipated IBS) who met the Rome III criteria to receive Daikenchuto or placebo and treated them for four weeks (74). They reported that the overall improvement was significantly higher in the Daikenchuto group than in the placebo group, and Daikenchuto also significantly improved stool consistency and abdominal distension compared with the placebo group. Further evidence concerning the usefulness of Kampo medicine is expected to be accumulated in the future.

6. Suppositories, enemas and digital evacuation

In patients with the “difficult defecation” type of constipation, enemas, suppositories, and digital evacuation may be successful. Enemas are made of ingredients such as sodium citrate, phosphate, and glycerin; glycerin is generally used in Japan (75,76). Glycerin may induce hemolysis and acute kidney injury if it enters the blood vessels; therefore, glycerin must be injected carefully to avoid damaging the rectal mucosa (76,77). In Japan, suppositories containing sodium bicarbonate, sodium dihydrogen phosphate, and bisacodyl are used, both of which stimulate the colon and rectum and promote defecation (78,79). Enemas and suppositories should not be administered over a long period of time and are often used as rescue therapies (1,80).

7. Biofeedback

Biofeedback is an instrument-based learning process that uses equipment to record or amplify a patient's anorectal activity and provides feedback to the patient and the therapist (81). Biofeedback therapy is effective when the cause of functional defecation disorder is inappropriate action of the pelvic floor muscles when attempting to defecate. A systematic review of 11 studies examining the efficacy of biofeedback therapy in patients with dyssynergic defecation showed that 63% of 725 eligible patients reported clinical improvement with biofeedback therapy (82). A meta-analysis of 6 studies found that although heterogeneity between trials and the overall risk of bias was high, biofeedback treatment was significantly superior to non-biofeedback treatment (OR 3.63, 95% CI 1.10-11.93, p=0.03) (82). Although biofeedback treatment is expected to be useful when properly administered, it is difficult to accurately diagnose dyssynergic defecation in Japan. A standard method of biofeedback treatment has not yet been established, and the number of facilities in Japan that can provide biofeedback therapy is limited.

Implications

With the advent of new medications, more patients with chronic constipation are receiving satisfactory treatment and enjoying an improved QOL than before, but evidence for the effectiveness of each treatment is still insufficient. Although some functional tests are commonly performed in Europe and the U.S., they are generally not available in Japan. We hope that these tests will become available in Japan in the near future. Therefore, it is necessary to conduct research with a high level of evidence to evaluate the effectiveness of each treatment for constipation.

Author’s disclosure of potential Conflicts of Interest (COI).

Akihito Nagahara: Honoraria, Astellas Pharma, EA Pharma, Tsumura and Viatris.