Current Management of Chronic Constipation in Japan
Keywords:
chronic constipation,
treatment
Article ID: 2022-0036-IR
Details
Article ID: 2022-0036-IR
Constipation is a complicated condition. Chronic constipation is diagnosed when constipation occurs for more than 3 months. Chronic constipation is classified using patient symptoms and the pathophysiology. New therapeutic agents to treat chronic constipation have recently been approved in Japan. However, treatments for constipation that is refractory to traditional laxatives have been approved, an algorithm for the treatment of chronic constipation has not yet been developed. The accumulation of knowledge and data is necessary to develop a new algorithm.
Constipation is a complicated condition. It is not simply a decreased number of defecations; constipation also includes hard stool, a sense of incomplete evacuation, and a sense of anorectal blockage. Chronic constipation (CC) is a chronic disorder in which constipation occurs for more than 3 months. The worldwide prevalence of CC among adults is estimated to be approximately 15%.1 Lockdowns associated the Coronavirus disease 2019 pandemic has led to a worldwide reduction of physical activity, resulting in patients with new-onset constipation.2 Functional gastrointestinal disorders (FGIDs), in which patients present with abdominal symptoms without an organic cause, including irritable bowel syndrome (IBS), chronic diarrhea, and functional dyspepsia (FD), affect patients’ health-related quality of life and work productivity. CC is similar to FGIDs in this way.3 However, in contrast to FGIDs, CC is associated with an increased risk of poor survival,4 which may be attributable to the association of CC and increased risks of colon cancer5 and cardiovascular disease (CVD) mortality.6 Straining caused by constipation can increase blood pressure and burden the heart and blood vessels, which can evoke CVD, especially in elderly patients.7 In younger age, the prevalence of CC is higher in females than in males and increases with increasing age, especially after the age of 65 years in both sexes.8 The increased prevalence of CC in elderly patients may be caused by enteric neuronal changes.9 In addition, an association between constipation and enteric glial cell changes (changes in non-neuronal cells in the enteric nervous system) has been suggested.10 Given that an ageing population is a modern-day global issue, therapeutic strategies for CC must be developed. In 2017, a clinical practice guideline for the treatment of CC was published for the first time in Japan.11 This review summarizes the current management of CC in Japan.
CC can be initially classified into known etiology and unknown etiology categories. Etiology-known CC can be caused by organic diseases, systemic disease, and medications. Organic diseases such as colorectal cancer, inflammatory bowel disease, and radiation colitis can cause CC. These causes must be excluded when patients present with alarm symptoms such as bloody stool, weight loss, or an abdominal mass. CC may also be caused by systemic diseases, including metabolic diseases (diabetes mellitus, hypercalcemia, and hypokalemia), endocrine diseases (hypothyroidism and hyperparathyroidism), neuronal diseases (Parkinson’s disease, multiple sclerosis, and myotonic dystrophy), and myopathies (systemic sclerosis and amyloidosis). The use of opioids, anticholinergic agents, antidepressants, antipsychotics, and chemotherapeutic agents also lead to CC.12
CC with unknown etiology can often be attributed to constipation-predominant FGIDs, such as constipation-predominant IBS (IBS-C) and functional constipation (FC). The Bristol stool form scale (BSFS) is widely used to evaluate bowel habits.13 The Rome criteria, which define the diagnostic criteria of FGIDs, can also be used. According to the Rome III criteria, which were proposed in 2006, the main symptom of IBS is abdominal pain or discomfort.14 However, in the Rome IV criteria, proposed in 2016, the term ‘discomfort’ was not included as a main symptom of IBS because of the potential for ambiguous meaning across languages. Given that the Rome criteria are used around the world, vague words with meanings that may differ across languages must be avoided. Therefore, the Rome IV criteria define the main symptom of IBS as abdominal pain only (Fig. 1).15 Therefore, IBS-C and FC may be viewed as painful constipation and painless constipation, respectively. However, the frequency of symptoms is also included in the Rome IV diagnostic criteria. IBS includes at least 1 day of symptoms per week. Patients who experience less frequent symptoms are diagnosed as FC (Fig. 2).15 However, patients often present with varied frequencies of symptoms during long-term follow-up. Depending on the condition and the timeframe, some patients can present with the status of both IBS-C and FC. In effect, these are seamless disorders (Fig. 3).
Diagnostic criteria of irritable bowel syndrome in Rome IV criteria.15
Diagnostic criteria of functional constipation in Rome IV criteria.15
Classification of chronic constipation via symptoms and pathophysiology.
FC can be classified into three categories based on pathophysiology: normal transit constipation (NTC), slow transit constipation (STC), and rectal evacuation disorders. The main causes of NTC and STC are reduced food intake and colonic dysmotility, respectively. Functional tests are needed to distinguish NTC and STC. To evaluate the anorectal function, defecography or anorectal manometry is necessary. However, in Japan, these anorectal functional tests are only conducted in specialized clinics or hospitals. The colonic transit time (CTT) is typically evaluated using radiopaque markers.16 However, because radiopaque markers are not covered by the Japanese health insurance system, this test is rarely available in Japan. Therefore, the BSFS is used to clinically evaluate the CTT in Japan. In addition, several methods of evaluating the CTT using abdominal X-ray have been proposed. Abdominal X-ray imaging is an inexpensive, less invasive method that is widely used. Assessment of the stool burden via abdominal X-ray images was originally proposed by Leech et al.17 This method is recently reported as a surrogate for radiopaque marker studies.18 The combination of unsedated colonoscopy with computed tomographic colonography or barium enema has been proposed for the detection of colonic dysmotility and morphological abnormalities.19 These evaluation methods are alternative options that may be useful in Japan.
An overlap between CC or FC with other FGIDs has been reported. Rome IV diagnostic questionnaires detected that 23% of patients with CC had overlapping symptoms of FD.20 The Japanese version of the Rome III diagnostic questionnaires found that 13.8% of patients with FD had overlapping symptoms of FC.21 The Internet-based survey evaluated overlapping CC and gastroesophageal reflux disease (GERD) in Japan. Among patients with CC, the ratio of patients with overlapping symptoms of CC and GERD was 55.0%–58.8%, depending on the diagnostic criteria used.22 Survey respondents with overlapping symptoms of CC and GERD reported a poorer quality of life and worse GERD symptoms. In Korea, a prospective, nationwide, multi-center, questionnaire study reported that 72 (16.0%) patients with FC had overlapping symptoms with GERD and that 43 (9.5%) patients with FC had overlapping symptoms with FD.23 However, the causal relationships between CC or FC and other FGIDs remain unclear.
In another study, the Athens Insomnia Scale (AIS) score was higher in constipated patients than in non-constipated patients in a Japanese hospital.24 This previous study reported that age, female gender, AIS score, and the use of hypnotics were associated with constipation and suggested an association between insomnia and constipation.
Treatment methods of CC can be classified as non-pharmacological or pharmacological. There are several non-pharmacological treatments for CC. Exercise and fiber intake have been reported as effective treatments for CC.25 In addition, the benefits of abdominal massage have also been reported.26
Laxatives are one form of pharmacological treatment for CC. Laxatives are classified by their mechanism of action. Emollient laxatives increase intestinal fluid and soften stool, whereas stimulant laxatives stimulate colonic motility. In Japan, magnesium oxide and sennoside, which do not always require a prescription, are traditionally used to treat CC. These agents were introduced to Japan by Philipp Franz von Siebold, a German physician, in the nineteenth century.27 Magnesium oxide is an emollient, osmotic laxative that is convenient to administer, inexpensive, and safe. However, the use of magnesium oxide should be monitored by physicians because drug–drug interactions may lead to adverse effects or hypermagnesemia, especially in elderly patients and those with renal impairment.28 A double-blinded, randomized, placebo-controlled trial reported that magnesium oxide and sennoside improved the frequency of bowel movements and quality-of-life score in patients with CC.29
From 2012 to 2022, the Japanese health insurance system approved several new therapeutic agents for CC. Each agent has a unique mechanism of action. In 2012, lubiprostone was approved. Lubiprostone is a type 2 chloride channel (ClC-2) activator. The activation of ClC-2 promotes chloride secretion from epithelial cells and the associated passive transport of sodium and water through the gastrointestinal mucosal epithelium, thereby enhancing fluid secretion into the intestinal lumen and acting as an emollient laxative. The efficacy of lubiprostone for CC was reported in a systematic review and meta-analysis.30 The main adverse effects of lubiprostone include diarrhea, which is more likely in patients aged over 65 years, and nausea, which is more likely in female patients.31 The 24-µg lubiprostone capsule was first approved in Japan, and can be used to administer the standard dose of 48ug daily, which is 24-ug twice daily. For decreasing dose the 24-g capsule can be taken once daily. Because the 12-g lubiprostone capsule was approved in 2018, doses of 36 µg and 12 µg became possible. The incidence of adverse effects is lower when lower doses of lubiprostone are used.32 Lubiprostone has been reported to improve the permeability of the intestine,33 rendering it a novel candidate for the treatment of leaky gut.
In 2017, linaclotide and naldemedine were approved in Japan for the treatment of CC. Linaclotide is a synthetic guanylate cyclase-C (GC-C) agonist. GC-C mediates the production of cyclic guanosine-3′,5′-monophosphate (cGMP). Linaclotide binds to and activates GC-C located on the luminal surface of intestinal epithelial cells, increasing the intracellular and extracellular levels of cGMP to induce fluid secretion. Linaclotide is a type of emollient laxative; additionally, it inhibits colonic nociceptors and relieves abdominal pain via GC-C and extracellular cGMP.34 Based on these effects, linaclotide was first approved for IBS-C in Japan. The optimal dose of linaclotide for IBS-C is 0.5 mg per day.35 Therefore, the daily use of two 0.25-mg linaclotide tablets was approved as the standard dose for IBS-C in Japan. A dose reduction to 0.25 mg linaclotide per day is possible. Linaclotide was effective for the treatment of CC in Japan at doses of 0.0625 mg, 0.125 mg, 0.25 mg, and 0.5 mg.36 The efficacy and safety of 0.5 mg of linaclotide for Japanese patients with CC was demonstrated in a randomized, double-blind, placebo-controlled study.37 In Western countries, doses of 0.145–0.29 mg of linaclotide are approved for the treatment of CC, which is a lower dose range than that used in Japan.12 Therefore, a reduction of the dose of linaclotide used to treat CC may be necessary in Japan.
Opioid-induced constipation is a newly categorized bowel disorder included in the Rome IV criteria.15 Naldemedine is an oral µ-opioid receptor antagonist that has been approved in the United States and Japan for the treatment of opioid-induced constipation. Naldemedine inhibits peripheral µ-opioid receptors in the gastrointestinal tract and has little or no effect on central opioid activity.38 In Japan, medical opioid usage is limited to patients with cancer pain. The optimal dose of naldemedine was reported as 0.2 mg per day for Japanese patients with opioid-induced constipation.39
In 2018, elobixibat and polyethylene glycol with electrolytes were approved as treatments for CC. Elobixibat is an ileal bile acid transporter inhibitor. By inhibiting bile acid reabsorption, elobixibat increases the amount of bile acid reaching the colon, enhancing colonic motility and water secretion. Elobixibat acts as an emollient and stimulant laxative. The optimal dose of elobixibat for Japanese patients with CC is 10 mg per day.40 Therefore, a dose of two 5-mg elobixibat tablets per day was approved as the standard dose for patients with CC in Japan. A dose reduction to 5 mg per day or an increase to 15 mg per day are possible. Because the secretion of bile acids is stimulated by food intake, elobixibat should be taken before a meal. Japan was the first country to approve the use of elobixibat for patients with CC. The median time to bowel movement after the use of elobixibat was 5 h, and elobixibat can be administered before any meal.41
In Europe, the first-line treatment for CC is polyethylene glycol with electrolytes, which is an osmotic, emollient laxative. Previously, in Japan, polyethylene glycol plus electrolytes had been approved only as a bowel preparation before colonoscopy or computed tomographic colonography.42 The efficacy of polyethylene glycol with electrolytes for the treatment of CC was reported in Japan with a randomized, double-blind, placebo-controlled study.43 The initial dose of polyethylene glycol with electrolytes is one or two 6.9-g sachets. The maximum daily dose is six 6.9-g sachets. For convenience, larger double-dose sachets (13.8 g) were approved in Japan in 2022.
In 2019, a crystalline lactulose preparation was approved for the treatment of adult patients with CC in Japan. Lactulose is an osmotic, emollient laxative. Lactulose had been used to treat adults with CC in other countries prior to 2019. However, in Japan, lactulose had only been approved for pediatric patients with CC. A randomized, double-blind, placebo-controlled, dose-finding study determined the optimal dose of lactulose for adult patients to be 26 g per day.44 A dose increase to 39 g per day is permitted.
The Japanese health insurance system does not permit the use of these new laxatives as first-line treatments for patients with CC. These new laxatives can only be prescribed for patients with CC that is refractory to traditional laxatives such as magnesium oxide and sennnoside. However, with the exception of classifying magnesium oxide and sennoside as the first-line treatments, no algorithm for the treatment of CC has been developed in Japan. The change in the frequency of spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs) was similar after the use of linaclotide, elobixibat, or lubiprostone.45 A systematic review and network meta-analysis compared the efficacy of lubiprostone, linaclotide, and elobixibat for CC. The primary end points of the previous study were 3 or more CSBMs per week and an increase of 1 or more CSBMs per week from baseline. No superior drug was identified.46 A systematic review and network meta-analysis compared the efficacy of medications in Japanese patients with CC via the data from six randomized clinical trials, including two regarding linaclotide, three regarding elobixibat, two regarding lubiprostone, and one regarding lactulose. Linaclotide, elobixibat, and lubiprostone were superior to a placebo regarding the changes of SBMs within 1 week. Elobixibat (10 mg) resulted in the greatest increase of SBMs and CSBMs within 1 week and improved the time to the first SBM the most. The use of lubiprostone (48 µg) resulted in the highest proportion of patients with SBM within the first 24 h.47 Although some meta-analyses were conducted, a direct comparison of these new agents is yet to be reported.
With the introduction of new therapeutic agents, the management of CC is changing in Japan. The possible options for treatment for patients with refractory CC have been reported. However, an algorithm for the treatment of CC in Japan is required and must be developed with reference to accumulated data and knowledge regarding the treatment of CC in Japan.
The author thanks Editage (www.editage.jp) for English language editing.
During the past 2 years, TM received service honoraria from EA Pharma.
