Current Treatment Practices for Adult Patients with Constipation in Japan

Constipation is a disease that increases the risk of death. Many medical textbooks in Japan describe chronic constipation as “a disease that decreases the quality of life (QOL) but does not affect life prognosis.” However, recent epidemiological studies in Japan and overseas have reported that patients with chronic constipation have a poor prognosis, and the situation is different than previously described. At 15 years, the survival rate of patients with chronic constipation is 20% worse than that of patients without chronic constipation [1]. Chronic constipation is a fatal disease that must be addressed by medical professionals. This study summarizes the recent findings regarding constipation treatment practices in Japan.

There are many reasons for the poor prognosis in patients with chronic constipation; however, cardiovascular events are the most important [2]. The pressure required to expel hard stools during defecation (straining) causes a sudden increase in blood pressure, which in turn can lead to cardiovascular events. Reports from Japan have shown that chronic constipation is a risk factor for cardiovascular events [3]. It is also a risk factor for stroke, subarachnoid hemorrhage, and rupture of aneurysms [3]. To prevent cardiovascular events from occurring during defecation, patients should be proactively asked if they have constipation and treated accordingly. Although blood pressure treatment, especially pharmacotherapy, is now effective and blood pressure can be controlled strictly, physicians must be aware that if constipation is left untreated, a sudden transient rise in blood pressure during defecation can cause various events. Furthermore, recent overseas studies have reported the risk of venous thrombosis in patients with chronic constipation [4].

Regarding non-cardiovascular diseases, recent epidemiological studies have revealed that chronic constipation is a risk factor for chronic kidney disease (CKD). Kakuda et al. [5] compared the incidence of CKD in 3.5 million veterans with and without constipation in the USA. After approximately 8 years of observation, the incidence of CKD was observed to be significantly higher in patients with constipation than in patients without constipation. Although hypertension and the use of non-steroidal anti-inflammatory drugs are well-known risk factors for CKD, constipation may also be considered a risk factor. Chronic respiratory diseases should also be considered a risk factor, as defecation is the most likely cause of hypoxia in these patients [6].

As per the previous discussion, constipation may be related to survival and QOL. Therefore, it is important to manage constipation in daily practice. Although constipation is thought to be more common in women, there is no difference between the sexes among older adults with constipation. Constipation is a disease of older adults. Textbooks state that the need for constipation treatment in older adult patients is necessary to address the decreased QOL. A comparison of the QOL of patients with constipation and patients with other diseases showed that their physical and mental QOL was reduced, as were those with inflammatory bowel disease, depression, cardiac disease, and other conditions [7]. Constipation often causes people to refrain from going out or traveling, and not feeling refreshed itself is a significant loss of health.

However, from a medical perspective, as mentioned earlier, constipation is a risk factor for the development of cardiovascular events and CKD; thus, it is indeed a disease that must be treated. Furthermore, in older patients, constipation causes a decline in dietary intake, which in turn causes deterioration of nutritional status, resulting in a vicious cycle of sarcopenia and frailty [8], there by accelerating aging. Additionally, the risk of gastrointestinal obstruction, rectal ulcers, and gastrointestinal perforation due to constipation must be considered. In the past, it was considered that constipation could cause intestinal perforations; in a super-aging society, we need to be more careful because of the possibility of such events occurring. Constipation can lead to serious complications if it is underestimated. Therefore, patients should be actively asked whether they have constipation, and therapeutic interventions should be provided as early as possible.

Factors contributing to constipation in adult patients include the normal ganglion phenomenon between the intestinal muscular layers, changes in the number of nerve cells, pelvic floor dysfunction, and neural changes involved in intestinal motility, including a decrease in the rectal sensory threshold. Additionally, changes in the living environment, including decreased physical activity and changes in the diet, can cause constipation in older individuals [9]. Another cause is the longer transit time of the large intestine in older people than in younger people [10].

Under normal conditions, when feces stored in the sigmoid colon move into the rectum by means of strong peristalsis, the rectal wall stretches, and this stimulus is transmitted to the cerebral cortex, causing a defecation desire. Stretching of the rectal wall triggers the rectoanal excitatory and inhibitory reflexes that facilitate defecation. Although the defecation desire is important for defecation, the rectal sensory threshold is higher in older than in younger patients [11]. In a Japanese study, approximately half of the patients with chronic constipation receiving therapeutic drugs were not satisfied with their treatment, and the rate of loss of defecation desire was higher in the group of patients with chronic constipation than in the control group of patients with non-chronic constipation [12].

Chronic constipation due to fecal retention (reducing rectal responsiveness) results in decreased defecation desire. In addition, unpleasant experiences, including pain during defecation, may lead to avoidance of defecation, exacerbating constipation. Therefore, a loss of defecation desire may be a factor in the vicious cycle of constipation.

In addition, the importance of drug-induced constipation, especially opioid-induced constipation (OIC), is increasing with the aging of the population and an increase in the number of patients with cancer. Approximately 80% of μ-opioid receptors are centrally located and provide pain relief. However, 20% are located in the intestinal tract; opioids bind to μ-opioid receptors in the intestinal tract and result in decreased secretion of digestive fluids, decreased peristalsis, and decreased tension of the anal sphincter muscle, leading to OIC [13]. While OIC is well-known in the field of palliative care, other drug-induced constipation is more frequent due to the anticholinergic effects of antipsychotics, which are frequently used in the psychiatric field, and paralytic ileus caused by the long-term use of these drugs.

In Japan and abroad, constipation is defined objectively. The “Guidelines for the Diagnosis and Treatment of Chronic Constipation 2017 [9],” which is the basis of constipation treatment in Japan, defines constipation as “a state of inability to comfortably evacuate the bowel.”

In contrast, the Rome IV criteria published in 2016 [14] define C2 functional constipation as a symptomatic functional bowel disorder with dyspareunia, infrequent defecation, or incomplete defecation. OIC is classified as C6 and diagnosed based on the difficulty of defecation, such as straining, hard stools, and incomplete evacuation, or a decrease of bowel movements at the time of opioid initiation or dosage increase. How can OIC be easily diagnosed in patients with chronic constipation? Two important factors in the treatment of chronic constipation are to differentiate patients who really need treatment from those who complain that “I am constipated” and to actively ask patients if they have chronic constipation when they are at a risk of cardiovascular or other problems, even if they do not complain about it.

Abdominal ultrasound has long been studied for its usefulness in diagnosing constipation [15, 16]. However, abdominal ultrasonography systems are large and heavy, and the procedure is difficult to perform and learn, making it a modality only certain physicians can perform. However, in recent years, advances in medical equipment have led manufacturers to develop portable smartphone-sized handheld ultrasound devices with Bluetooth connectivity. The possibility of diagnosing constipation with ultrasonography was agreed upon at the 22nd Annual Meeting of the Japanese Neurogastroenterological Association Consensus Meeting “Assessment of Chronic Constipation by Ultrasonography,” and the best practices for observing rectal fecal impaction by echo were published [17]. In practice, the probe is placed in a transverse maneuver over the pubic symphysis, and the ultrasound beam is tilted caudally from 10° to 30° to visualize the bladder.

The bladder is placed in an acoustic shadow, and the rectum is visualized deeper than the bladder. The definition of constipation based on rectal ultrasonography was summarized by Tanaka et al. [18]. In the absence of hypoechoic areas with the total correction or obvious hyperechoic findings, the diagnosis is not of fecal impaction. Fecal impaction is diagnosed when there is a semilunar echogenic region with acoustic shadows and a crescent-shaped echogenic region. Hard stool impaction is diagnosed when there is a crescent-shaped echogenic region. The flowchart for the diagnosis of constipation by ultrasound confirms the presence of rectal fecal impaction in patients suspected of having constipation and, if present, confirms the presence of hard stool. The presence, nature, location, and amount of rectal fecal impaction should be confirmed during treatment and care selection.

The performance of handled ultrasonography for diagnosing constipation was compared with that of computed tomography (CT) and digital rectal examination (DRE) in 134 patients who were referred to the palliative care team during hospitalization for constipation. The results were consistent with the portable ultrasonography findings in 96% of patients diagnosed with fecal impaction by CT and 92% of patients diagnosed with fecal impaction by DRE. These results indicate that ultrasonography is non-inferior to CT or DRE for the diagnosis of constipation. However, there are some points to be aware of regarding CT, including mobility and risk of exposure, and DRE, including photophobia, positional change, and vagal reflex; if the diagnosis of rectal constipation can be performed by ultrasonography, it may reduce patient burden and risk [19].

The current treatments for chronic constipation are limited to administering laxatives and checking whether stools are produced, which are of extremely poor quality. Clear defecation begins with type 4 of the Bristol Stool Shape Scale (BSFS), where a type-4 banana shape is associated with the best Patient Assessment of Constipation Quality of Life (PAC-QOL) [20]. In addition, BSFS 3–5 stools are considered normal overseas, while Asians consider BSFS 4 banana-shaped stools as normal. Mammals are said to defecate within 12 s, and the risk of cardiovascular events is lowered because of the short time required for a clear bowel movement. Hard stools are more difficult to defecate and cause irritation and higher blood pressure elevation during defecation. In addition, hard stools are not defecated in one lump due to rectal contractions during defecation but are divided into separate stools, leading to patient complaints of a strong sensation of residual stools. In contrast, watery or muddy stools have the highest prescription discontinuation rate because patients fear fecal incontinence. A survey conducted in Japan on the fecal shape of patients receiving treatment for chronic constipation at medical institutions showed that half of them had hard stools (BSFS 1–2), 20% had muddy or watery stools (BSFS 6–7), and only 10–20% had (BSFS 4) normal stools. This indicates that constipation treatment in Japan remains unsatisfactory. The goal of treatment is not only to have stools but also to achieve type 4 normal stools, aiming for defecation without residual stools or complete defecation, which is the first step toward improving patient satisfaction and, ultimately, life expectancy.

Dietary fiber is often considered beneficial for constipation. However, a few reports have indicated that there is not necessarily a correlation between improvement in constipation and the amount of dietary fiber ingested [21]. Dietary fiber is not digested in the digestive tract and reaches the large intestine, where it binds with water and increases the volume of stools. Therefore, it is necessary to ensure a certain amount of dietary fiber intake. According to the Dietary Reference Intakes for Japanese 2020 edition [22], the target amount of dietary fiber is 17.8 g for women aged 50–64 years, 17.4 g for those aged 65–74 years, and 16.5 g for those aged 75 years and older. According to the 2028 National Health and Nutrition Survey, the median fiber intake for women was 16.1 g for those aged 0–59 years, 19.1 g for those aged 60–69 years, and 19.5 g for those aged 70–79 years. Therefore, postmenopausal women should consume close to or slightly more than the target amount of dietary fiber.

Studies have also reported the effectiveness of exercise in treating constipation. However, the level of evidence is low. Decreased physical activity and exercise may be associated with the onset or exacerbation of chronic constipation. Studies have reported that vigorous exercise prevents constipation [23, 24], suggesting that moderate exercise is desirable for relieving constipation. In addition, randomized trials have reported that abdominal wall massage for 15 min a day, 5 times a week, is effective in improving the symptoms of chronic constipation [25]. Posture is also important. In the crouching position, the pubic bone and rectum are close to each other, and the recto-anal angle is close to a straight line; thus, it is important to keep the posture at 35°. It is also important to use footrests in Western-style toilets.

Basic drug therapy is based on the use of non-stimulant and stimulant laxatives. In patients who have not defecated for a while, the initial treatment is highly effective if a glycerin enema is administered to an outpatient or if a stimulant laxative is used only for the first time to induce defecation. Enemas are especially effective when a fecal bolus is observed in the rectum on DRE. In general, the treatment effect and patient satisfaction are high if stimulant laxatives are not prescribed to any constipated patient by themselves but only when they are inadequate (e.g., exacerbation of constipation due to business trips or travel) after continuous prescription of other non-stimulant laxatives for maintenance. In particular, the use of laxatives until they are sufficiently effective for initial treatment and until the normalization of fecal characteristics contributes to an increase in the rate of prescription continuation.

Conventional laxatives include osmotic laxatives and stimulants; new intestinal secretagogues, ileal bile acid transporter inhibitors, and osmotic laxatives have emerged in recent years. The characteristics of each drug are summarized in Table 1. Regarding the mechanism of action, drugs for constipation can be divided into three categories: those that induce intestinal water secretion, those that stimulate the large intestine, and those that recover a loss of defecation desire. Osmotic and secretory laxatives induce intestinal water secretion, whereas stimulant laxatives and herbal remedies stimulate the colon. Elobixibat is a distinct agent that combines all three actions by inhibiting bile acid reabsorption in the terminal ileum and increasing bile acid influx into the colon.

Osmotic laxatives increase stool frequency by inducing intestinal water secretion. Magnesium oxide (MgO) is a common osmotic laxative. Although the drug is inexpensive and long-term administration has been reported, electrolyte abnormalities and overdoses can be problematic in patients with renal and cardiac failure and can cause dehydration and bradycardia [26]. Oral MgO increases serum magnesium in patients with renal failure [27], and the “Guidelines for Safe Pharmacotherapy of the Elderly 2015” published by the Japanese Geriatrics Society recommend that older patients with renal dysfunction should not receive MgO because of the increased risk of hypermagnesemia [28].

Reported risk factors for hypermagnesemia include age ≥68 years, renal dysfunction, MgO dosage >1,650 mg/day, and administration of MgO for >36 days [29]. In addition, MgO is converted into magnesium salts by gastric juices, and water is transferred to the intestinal tract. Therefore, its effectiveness is reduced by less than half in patients who have undergone total gastrectomy or are taking acid-secretion inhibitors [30]. When MgO is administered in daily practice, care should be taken regarding surgical and medical histories, especially regarding proton pump inhibitors and histamine 2 blockers. It is also characterized by a large number of concomitant medications that should be used with caution and that reduce the effect of concomitant medications, including acid secretion inhibitors, bisphosphonates, non-steroidal anti-inflammatory drugs, and antiepileptic drugs, by inhibiting their absorption. Although it is widely used today, the above points require caution when using it, and it should be ensured that renal function is not impaired, in which case the dose of magnesium should be reduced regularly. The osmotic effect of polyethylene glycol promotes water secretion into the intestinal tract and exerts a laxative effect [31].

Stimulant laxatives include anthraquinones, including sennosides and aloe, and diphenyls, including sodium picosulfate. Both are hydrolyzed to their active forms by intestinal bacteria and enzymes in the digestive tract, which then act on the colon’s intermuscular plexus to promote high-amplitude colonic contraction waves, inhibit water absorption from the intestinal tract, and produce purgative effects. As anthraquinones can cause intractable constipation owing to the emergence of tolerance after long-term continuous use, they should be used only when necessary and not for a long period without any intention.

Lubiprostone and linaclotide are also available for use. Lubiprostone activates the CIC-2 chloride channel on the luminal side of the small intestine and stimulates osmotic water secretion into the intestinal tract, softening stool and promoting defecation [32]; side effects include nausea and diarrhea. Also, lubiprostone significantly improved the symptoms of OIC and was well tolerated in patients with chronic noncancer pain [33]. Linaclotide improves gastrointestinal tract hypersensitivity by increasing cyclic guanosine monophosphate levels in intestinal epithelial cells, promoting intestinal fluid secretion and defecation. Therefore, linaclotide can treat constipation-type irritable bowel syndrome [34].

Elobixibat inhibits bile acid transporters expressed on epithelial cells in the terminal portion of the ileum, increasing the amount of bile acid entering the colon, which, in turn, increases water and electrolyte secretion into the intestinal tract, enhances intestinal peristalsis, and promotes defecation [35]. Regarding constipation in cancer patients, an increase in the frequency of spontaneous bowel movements has also been observed, and furthermore, treatment with elobixibat has been shown to be unaffected by the amount of food consumed. Therefore, it is suggested that elobixibat may be used in cancer patients regardless of dietary intake [36]. The decrease in rectal sensory thresholds due to the increase in bile acids has restorative effects on defecation desire [37]. Thus, besides promoting water secretion and intestinal peristalsis, it also recovers loss of defecation desire and has a triple-action effect.

Lactulose reaches the lower gastrointestinal tract without being digested or absorbed, increases the osmotic pressure of intestinal contents to promote water secretion, and is decomposed by intestinal bacteria to produce organic acids, which increase intestinal peristalsis and have a laxative effect. In Japan, a randomized, double-blind, placebo-controlled study in patients with chronic constipation has been done, and significant effectiveness has been reported [38].

Naldemedine, which is one of the peripherally acting μ-opioid receptor antagonists, is a constipation medication covered by insurance only for OIC in Japan [39]. OIC is caused by decreased water retention, decreased intestinal peristalsis, and contraction of the anal sphincter, and the mechanism of naldemedine suggests that it can ameliorate these effects. Until now, MgO has been mainly used for the treatment of OIC; however, in a randomized controlled trial in which MgO or naldemedine was administered simultaneously with opioid initiation as a prophylactic treatment for OIC, naldemedine showed no worsening of PAC-QOL after 2 weeks compared with MgO; additionally, complete spontaneous bowel movements were significantly higher, and the incidence of nausea was significantly lower [40]. We also investigated the changes in defecation frequency and QOL after administering various laxatives to patients with OIC to determine which laxatives are effective in treating OIC. The results showed no difference in defecation frequency among conventional laxatives, novel laxatives, or naldemedine. However, compared with conventional laxatives, naldemedine and the novel laxatives elobixibat and lubiprostone significantly improved defecation-related QOL; additionally, naldemedine and elobixibat improved defecation-related symptoms [41]. The prevention and treatment of OIC, previously dominated by MgO, are expected to transition with the advent of naldemedine.

The number of currently available laxatives has increased, and many options are available for different situations. Because new laxatives cost more than twice as much as conventional drugs, it is generally preferable to use stimulant laxatives on an ad hoc basis, mainly conventional osmotic laxatives such as MgO, when considering cost-effectiveness. However, the risk of hypermagnesemia must be considered in cases of inadequate efficacy in patients with constipation, long-term MgO administration, or impaired renal function. In addition, patients taking acid secretion inhibitors, multiple medications, or who have undergone total gastrectomy should consider switching to a new constipation drug if MgO is not effective, which is important to use according to the patient’s preference (timing, compliance, dosage form). Nardimedine for OIC, linaclotide or polycarbofil for constipation with abdominal pain, such as in patients with irritable bowel disorder-constipation, and elobixibat for patients with loss of defecation desire would be good options (Fig. 1).

Several challenges remain regarding the treatment of constipation. Dealing with patients who habitually use stimulant laxatives, treating loss of defecation desire, and diagnosing and treating fecal impaction seem to be the most pressing issues. Handheld ultrasound devices may provide a breakthrough regarding fecal impaction. We believe its use in clinical practice and accumulation of relevant evidence are important. In addition, it is important to raise awareness regarding constipation among medical professionals, as some of them still believe that constipation is not an important disease.

The authors thank Editage (www.editage.com) for the English language editing.

Atsushi Nakajima received grants and research support from Gilead, Mylan EPD, EA Pharma, Kowa, Taisho, and Biofermin. A.N. is also a consultant for Gilead Sciences, Boehringer Ingelheim, Bristol Myers Squibb, Kowa, Astellas Pharma, EA Pharma, and Mylan EPD. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conceptualization: T.K. and A.N.; writing – original draft preparation: T.K. and N.M.; writing – review and editing and supervision: H.O. and A.N. All authors have read and agreed to the published version of the manuscript.