The diagnostic criteria for functional constipation: This criteria is cited from “Mearin et al. ”.
Chronic constipation, a common condition, can have remarkably negative effects on a patient’s quality of life. Recent research has identified factors that may influence the prognosis of chronic constipation and suggests the need for adequate therapy. However, the major obstacles in this field were: (1) a small number of therapeutic options, (2) no clear diagnostic criteria, and (3) no effective method to collect information form the patients. These were due to the fact that bowel movement patterns vary widely among individuals, and also the functional constipation, including irritable bowel syndrome, is difficult to be distinguished from the chronic constipation. Recently, it has been demonstrated that the Rome IV diagnostic criteria of functional constipation and the Bristol stool form scale are useful for the objective evaluation and recording of stool. Based on these developments, and the increase of newly developed medicines the therapy for the constipation is significantly changing and therefore, if conventional therapy for chronic constipation is ineffective, switching of medicines is possible. Therefore, clinicians should update the information of these newly developed drugs available in clinics and diagnostic criteria. For this purpose, in this chapter, we have summarized the perspective on the current paradigm of treatment for chronic constipation focusing on recently introduced therapeutic drugs.
- chronic constipation
- Rome IV diagnostic criteria
Many reports describe a high prevalence of constipation worldwide. For example, a survey conducted in North America by Higgins et al. reported prevalence rates of 12–19%, particularly among older populations . Generally, research suggests that constipation reduces the patient’s quality of life (QOL) to a level comparable with the negative effects of allergy or inflammatory bowel disease . Despite these negative characteristics, however, a clear overview of chronic constipation has not yet been established.
The Rome IV diagnostic criteria, which were revised in 2016, are often used to evaluate functional constipation. However, these diagnostic criteria exclude irritable bowel syndrome (IBS), a prevalent condition (7–21%) that exists on a continuous spectrum with functional constipation. Notably, IBS and functional constipation may be associated with predominant symptoms such as abdominal pain or bloating, which are not necessarily predominant in all cases of constipation . This suggests that IBS and functional constipation often overlap in real-world scenarios . Furthermore, the diagnosis of chronic constipation, which often involves the appraisal of symptoms (including QOL measures), and associated therapies appear to be incomplete.
In addition to the lack of diagnostic and treatment methodology, the Japan Collaborative Cohort Study found evidence suggesting that a low bowel movement frequency increases the risks of cardiovascular disease (CVD), such as stroke and ischemic myocardial infarction, and of related mortality. The same study also found a high incidence of CVD among laxative users in Japan [5, 6]. Therefore, the effect of constipation indicates an increasingly poor prognosis. In this chapter, we review the present clinical practices targeting constipation and discuss newly introduced therapeutic drugs for constipation, such as secretagogues, which have recently yielded medical advances. With this review, we aim to prevent a perspective on the future treatment of chronic constipation.
2. Definition of constipation
Individual bowel movement patterns (including constipation) vary widely and are easily affected by many factors, including changes in the diet, living environment, mental status, and time course [7, 8]. Additionally, physicians and patients may hold different understandings of constipation. Consequently, the term “constipation” may encompass a broad spectrum of symptoms and situations. Despite these differences, constipation can be adequately defined as a status in which comfortable defecation is impossible, in accordance with many international clinical practice guidelines and review articles, as well as the Rome IV criteria [4, 9, 10].
3. Chronic constipation, including chronic functional constipation and IBS
Constipation can be roughly classified as acute or chronic, each of which can be further divided according to an organized or functional pathogenic mechanism. However, this chapter will discuss specifically chronic functional constipation in adult patients and its deleterious effects on the long-term QOL. Previously, the Rome III criteria were used to diagnose chronic functional constipation when a stringent definition is required for research purposes. In May 2016, however, the revised Rome IV criteria were published  (Table 1). Notably, these updated criteria include the requirement of other symptoms associated with difficulty of defecation and incompleteness of evacuation, as well as symptoms associated with constipation, and do not diagnose chronic functional constipation based on the frequency of bowel movements alone. Of note, these criteria require the exclusion of IBS prior to a diagnosis of chronic functional constipation (Table 2). However, this condition overlaps with IBS in many clinical cases. Accordingly, we recommend that in actual clinical settings, cases in which a patient’s continued inability to defecate comfortably that has deleterious effects on daily life should be managed as chronic constipation, even if the Rome IV criteria are not fulfilled . Later, we discuss the diagnosis and management of chronic constipation, including chronic functional constipation and IBS.
|Diagnostic criteriaa for functional constipation (FC)|
|Diagnostic criteriaa for irritable bowel syndrome|
|Recurrent abdominal pain, on average, at least a day per week in the last 3 months, associated with 2 or more of the following criteria:
3.1. Alarming symptoms associated with chronic constipation
Particular attention should be given to the management of constipation associated with alarming symptoms, which may correlate with a poor outcome due to the required therapy for an underlying disease or surgically treated condition. Patients with alarming symptoms should be further scrutinized and subjected to additional diagnostic testing before treatment is administered for constipation. Potentially alarming symptoms may include a change in stool caliber, heme-positive stool, iron-deficiency anemia, obstructive symptoms, an age of >50 years with no history of colon cancer screening, recent onset of constipation, rectal bleeding, rectal prolapse, and weight loss [9, 10, 11]. Such symptoms should be considered an indication for colonoscopy.
3.2. Secondary constipation
Secondary constipation should be excluded prior to a diagnosis of functional or chronic constipation due to IBS, as underlying high-risk diseases and etiologies must be identified [4, 10, 11]. Secondary constipation can be subdivided coarsely into drug-induced and symptomatic cases. Consequently, a diagnostic interview for chronic constipation should inquire about the time of onset, duration of disease, frequency of bowel movements, consistency of stool, symptoms associated with constipation, and the presence of concrete situations of dyschezia (e.g., abdominal pain and/or bloating, sensation of incomplete evacuation, need for manual maneuvers to facilitate defecation, and evacuation time). A clinical history, including lifestyle factors and dietary fiber and fluid intake, should also be taken. A systemic physical examination that includes a digital rectal examination (palpation for gastrointestinal mass, anorectal inspection to assess fecal impaction, stricture, rectal prolapse, rectocele, paradoxical or nonrelaxing puborectalis activity, and rectal mass), laboratory analyses (complete blood counts, biochemical profile, calcium and glucose levels, and thyroid function tests) and colonoscopy is also required to exclude secondary constipation. In summary, underlying diseases and drug-affected constipation should be considered in an evaluation of chronic constipation.
3.2.1. Underlying diseases
The diagnosis and treatment of underlying diseases is very important in the management of chronic constipation. Underlying diseases that may cause chronic constipation are listed below :
3.2.2. Drug-induced constipation
When evaluating a case of chronic constipation, the patient’s current profile of medicine use must be understood precisely and considered during further treatment. A list of drugs that may cause chronic constipation is provided below .
4. Diagnostic approaches to the treatment of chronic constipation
An interview based on the diagnostic criteria (Table 1) for functional constipation is useful when planning treatment for chronic constipation. The simple and objective Bristol stool form scale, which is used worldwide, is particularly useful for enabling an evaluation and record of the stool form and thus elucidating an individual patient’s defecation status [12, 13]. When possible, the patient should maintain a stool diary that includes the number of bowel movements per day and stool consistency (Bristol stool form types 1–7, Figure 1) for approximately 1 week. This record is also useful for evaluating symptoms and sensations (e.g., sensation of incomplete evacuation, abdominal pain, and/or bloating) after evacuation .
The Bristol scale can also be used to estimate the colonic transit time. Currently, cases of functional constipation are categorized as normal-transit, slow-transit, or defecatory rectal evacuation disorder . A previous histological analysis reported that slow-transit constipation results from a reduction in Cajal cells , suggesting that this type is caused by a decrease in the statuses of lower postprandial phasic responses (e.g., the disappearance of bowel peristalsis) . Other research indicates that defecatory rectal evacuation disorders are caused by functional failures (e.g., pelvic floor line coordination disturbance) . Although Bristol stool form types 1 and 2 can be attributed to slower transit constipation and types 6 and 7 are characteristic of rapid transit constipation , patients who meet the diagnostic criteria for functional constipation often exhibit characteristics of slow colonic transit constipation . Still, the diagnosis of defecatory rectal evacuation disorders does not require diagnostic colonic and anorectal testing .
An improved QOL is among the most important goals of treatment for chronic constipation. Accordingly, various questionnaires are useful during the processes of diagnosis and treatment (see Section 5). If initial conservative medical management does not cure chronic constipation, additional measures such as the balloon expulsion test [8, 20, 21], manometric assessment , defecography , and radio-opaque marker testing of the whole-gut transit time should be considered . Additional tests may also be performed, although the availability may be limited to certain medical centers or countries. Accordingly, interinstitutional cooperation is important.
5. Self-reported questionnaires for diagnostic purposes
Questionnaire-based self-report measures can be classified by the type of QOL evaluation and type of constipation severity quantitation. Various methods are currently advocated, although further progress in this area is needed . The questionnaires most frequently mentioned in a literature search via the PubMed database are shown below.
5.1. Evaluation of severity of constipation
5.2. QOL evaluation tool
6. Practical treatment
In this section, we aim to provide an overview of the various available treatments for chronic constipation for which the details have been published. Patient education is a very important first step in the therapeutic management of chronic constipation . Patients should be instructed to consume an adequate quantity of dietary fiber (total fiber intake: 20–30 g/day), set a routine of regular toilet time after mealtimes, and take an on-defecation position involving elevation of the lower limbs. If such measures are ineffective, an oral fiber supplement, such as psyllium (up to 30 mg/day in divided doses) may be attempted .
Drug therapy should be initiated if the above-described lifestyle modifications fail to treat chronic constipation, and this should be accompanied by an assessment of bowel movements every 2–4 weeks to determine the therapeutic effects. Generally, osmotic laxatives (e.g., lactulose, lactitol, mannitol, and sorbitol) are administered initially as these are cost-effective and have few adverse effects [18, 30]. Although saline laxatives (e.g., magnesium sulfate) are frequently administered in Japan, these drugs are not widely accepted worldwide and have only been evaluated clinically in small-scale randomized controlled trials (RCTs) . Furthermore, patients with renal failure face the risk of serious hypermagnesemia consequent to the use of magnesium sulfate . However, this drug should be considered, given its low cost and abundant use in Japan. Polyethylene glycol laxatives (17–34 g/day) should also be considered, as many RCTs have indicated that these agents are more effective than lactulose [33, 34].
If chronic constipation remains unresolved by the above therapies, newer medicines should be considered. Recent years have seen the rapid development of novel agents such as secretagogues (e.g., lubiprostone and linaclotide). However, as the availability and indications of these new drugs for chronic constipation vary among countries, all medical treatment for chronic constipation should comply with national clinical practice guidelines or guiding principle. Finally, surgical or biofeedback treatment should be considered for cases of chronic constipation that cannot be resolved with medication and patients with defecatory rectal evacuation disorders [35, 36].
7. New therapeutic drugs for chronic constipation
The extensive development of novel drugs for chronic constipation has led to variability in the potential applications among countries. For example, neither secretagogues (e.g., plecanatide) nor serotonergic enterokinetic agents (e.g., prucalopride and selective 5-hydroxytryptamine receptor agonists) have been approved for use in Japan. Below, we comment mainly on the new therapeutic drugs for chronic constipation that have been authorized for use in Japan.
Various studies have analyzed lubiprostone, the most well-developed one of the newer class of drugs. The mechanism of action of this constipation-targeting drug is interesting. Lubiprostone is a selective type-2 chloride channel (ClC-2 channel) activator. This biogenic bicyclic fatty acid was developed by Cuppoletti and Ueno for the treatment of chronic constipation and has been approved for use worldwide after the initial authorization for manufacturing and marketing in the US and Japan. [37, 38] Lubiprostone is the first clinically applied secretagogue, and accordingly, a broad range of clinical experience is associated with this drug. Moreover, the mechanism of action of this drug has been analyzed in much greater detail relative to secretagogues introduced subsequently. Specifically, this drug activates ClC-2 channels expressed in the apical membranes of intestinal epithelial cells and exerts its laxative function by inducing the secretion of intestinal fluids. The ability of lubiprostone to improve constipation symptoms has been validated through RCTs , which reported the maintenance of efficacy throughout a 48-week administration period with no significant side effects .
No currently available therapeutic drug can improve abnormal intestinal tract permeability in humans. However, Moeser et al. revealed that lubiprostone not only promotes the secretion of intestinal fluid by activating ClC-2 channels but also protects and restores injured small intestinal mucosa . The mechanism underlying the restoration of tight junctions in the mucosa remains unknown, although the ClC-2 channel was found to play an important role in restoring the tight-junction structure and barrier function in a mouse model of colitis . Furthermore, Kato et al. demonstrated that lubiprostone could improve intestinal permeability in humans . Although these research findings require validation, lubiprostone appears to be a promising treatment for leaky gut syndrome.
Linaclotide is a newly developed therapeutic drug for chronic constipation and constipation-predominant IBS. This drug is absorbed at low levels and has few adverse effects, of which the main complaint is diarrhea . This peptide drug comprises 14 amino acids and acts by binding to the guanylate cyclase C (GC-C) receptor expressed on intestinal epithelial cells, which promotes the secretion of fluids into the intestinal lumen. The GC-C receptor is associated with bodily fluid and ionic homeostasis, bowel movements, and relief from afferent pain signaling and is thus considered a therapeutic target for chronic constipation and constipation-predominant IBS .
When compared with placebo, linaclotide yielded excellent results in terms of the reduction in abdominal pain and increase in complete SBMs at 12 weeks after the initial first administration . Furthermore, linaclotide was associated with a significant increase in the average QOL score relative to placebo in a questionnaire-based survey . A cost-effectiveness analysis study revealed that the less expensive linaclotide yielded equivalent patient satisfaction to that achieved with lubiprostone . As chronic constipation overlaps partially with constipation-predominant IBS, linaclotide may greatly expand the treatment options for constipation. Although linaclotide has been prescribed widely at our hospital at an appropriate once-daily dosage of 0.5 mg, we presume that many physicians may initiate this drug at a daily dosage of 0.25 mg to avoid adverse effects.
Bile acids are synthesized from cholesterol in the liver and secreted to the duodenum, where they play an essential role in lipid digestion and absorption. Upon reaching the terminal ileum, bile acids are absorbed solely by the ileal bile acid transporter (IBAT) expressed only in the terminal ileum . Here, 95% of the bile acids are reabsorbed through the portal system and are reconjugated and reexcreted into bile by hepatocytes in an enterohepatic cycle that occurs 2–15 times daily. Unabsorbed bile acids are transported to the colon, where they encourage the secretion of water into the large bowel lumen and thus promote large bowel movement [61, 62]. Accordingly, the administration of ursodeoxycholic acid or the occurrence of ileal diseases that enable the transport of excess amounts of bile acids to the large bowel can cause diarrhea .
The drug elobixibat specifically inhibits the IBAT required for bile acid reabsorption and is thus commercially available as the first IBAT inhibitor. Through its inhibitory actions, elobixibat increases the entry of bile acids into the large bowel and thus promotes evacuation. When administered orally, this drug is absorbed at low levels; accordingly, it has few adverse effects and is considered safe . In Japan, elobixibat is administered orally at a once-daily dosage of 10 mg before a meal. However, the usage of this drug may vary among countries and should be confirmed carefully. To date, elobixibat has been used in only seven cases at our hospital in the short time since it has been licensed. Although only two patients have used this drug continuously for at least 2 months, all treated patients have achieved complete SBM. Elobixbat appears to act simultaneously as a stool softener and laxative stimulant. We expect that the use of this drug will increase.
Naldemedine, a peripherally acting μ-opioid receptor antagonist, was developed as a therapeutic drug for opioid-induced constipation and is approved in the US and Japan . This new class medication showed important therapeutic effect in improving opioid-induced constipation without reducing the efficacy of opioid drugs because it selectively targets the peripheral μ-opioid receptor as demonstrated in two-phase 3 trials [65, 66]. Therefore, although opioid-induced constipation has been initially treated with conventional laxatives, however, based on these evidences, naldemedine is expected to become a leading therapy for cases using opioids. Recently, we are switching to naldemedine to manage the constipation in cases using opioid, and approximately one-third of patients using opioids have been treated with naldemedine and showed the safe and effective bowel movement (manuscript in preparation).
To improve the QOL in the cases suffered with chronic constipation, the appropriate therapeutic intervention is essential. With the rise in the therapeutic options and its real world data, and the objective assessment methods, its treatment is dramatically changing. It is obvious that the correct diagnosis excluding the emergent situation is essential; however, the physicians need to update the information for these newly developed medicines useful for constipation and switch from the conventional agents for better QOL.
As the appropriate use of these new agents under various conditions remains uncertain, therefore, the accumulation of the clinical information, real-world data are necessary. For this purpose, this review overviewed the symptoms, diagnosis, and medicines available to date. We hope that these informations are useful for physicians treating patients and that various pathophysiological studies will elucidate the correct use of these new anticonstipation agents.
Furthermore, we hope that the development of a more ideal questionnaire will enable effective decisions regarding the most effective treatment for chronic constipation.
Conflict of interest
The authors declare that they have no current financial arrangement or affiliation with any organization that may have a direct influence on their work.
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