The management of constipation-related functional gastrointestinal disorder (constipation-predominant irritable bowel syndrome)

The terminology constipation-related functional gastrointestinal disorders was applied to embrace two conditions - constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation - because of the similarity in the etiology between the two conditions. The cardinal symptoms of IBS-C are abdominal pain or discomfort associated with constipation. The current symptom-based Rome III criteria are used to confirm the diagnosis. Many patients with IBS-C initially treat their symptoms with lifestyle modifications and exclusion diets, together with treatment of symptoms such as constipation by using fiber supplements, over-the-counter laxatives, or probiotics. Less commonly, the patients may also undergo various forms of psychotherapy. Despite these therapeutic modalities, many IBS patients are disappointed with their symptomatic response. There are several drugs that are being proposed for its treatment in the future, one of which is linaclotide, a 14-amino acid synthetic peptide that improves stool frequency and consistency and intestinal transit. Four-week treatment with Bifidobacterium lactis showed superior results when compared with placebo in decreasing the abdominal distention and improving orocecal and colonic transit.


Introduction
Th e terminology constipation-related functional gastrointestinal (GI) disorders was applied to embrace two conditions -constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation (CC) -because of the similarity in the etiology between the two conditions as seen by the common underlying causes and presenting symptoms between IBS-C and CC. Moreover, the vast majority of published literature treats each IBS-C and CC case as a separate condition.

Shared factors between constipation-predominant irritable bowel syndrome and chronic constipation Decreased bowel motility
Several studies have documented decreased rectal, colonic, and small bowel motility in IBS-C [1]. Th ese abnormalities are best described in the subset of CC identifi ed as colonic inertia, a condition recognized by a slow colon transit time [2].

Pelvic fl oor dysfunction
Pelvic fl oor dysfunction is described as the inability to organize the sequence of events that result in the normal evacuation of stool. Th is involves the inability to contract abdominal wall musculature, impaired relaxation of puborectalis muscle, defective rectal contraction, paradoxical anal contraction, and/or defective anal relaxation [3].
Although recently recognized as a contributor to symptoms in a subset of IBS-C [4], this mechanism has also been identifi ed as a primary etiology of symptoms in a subset of patients with CC [5].

Visceral hypersensitivity
Visceral hypersensitivity, representing a lower pain threshold of the digestive tract, is not only a well-defi ned pathophysiologic mechanism underlying IBS-C but is also proposed by others to be a biomarker of the condition [6][7][8].

Psychological stress
Psychological stress may be responsible for the development of symptoms in IBS-C [9] and may worsen symptoms. In contrast, psychological stress has a smaller role in CC but may promote dyssynergic defecation in some cases [3].

The management of constipation-related functional gastrointestinal disorder (constipation-predominant irritable bowel syndrome)
Amal F. Radwan, Nagwa R. Ahmed, Eman A. Sultan a The terminology constipation-related functional gastrointestinal disorders was applied to embrace two conditions -constipation-predominant irritable bowel syndrome ( IBS-C) and chronic constipation -because of the similarity in the etiology between the two conditions. The cardinal symptoms of IBS-C are abdominal pain or discomfort associated with constipation. The current symptom-based Rome III criteria are used to confi rm the diagnosis. Many patients with IBS-C initially treat their symptoms with lifestyle modifi cations and exclusion diets, together with treatment of symptoms such as constipation by using fi ber supplements, over-the-counter laxatives, or probiotics. Less commonly, the patients may also undergo various forms of psychotherapy. Despite these therapeutic modalities, many IBS patients are disappointed with their symptomatic response. There are several drugs that are being proposed for its treatment in the future, one of which is linaclotide, a 14-amino acid synthetic peptide that improves stool frequency and consistency and intestinal transit. Four-week treatment with Bifi dobacterium lactis showed superior results when compared with placebo in decreasing the abdominal distention and improving orocecal and colonic transit.

Altered bowel fl ora
Th ere is emerging proof to propose a role for altered bowel fl ora in the occurrence of symptoms of IBS-C, and possibly CC [10].

Diet
Th e strong association between a low-fi ber diet and CC is better described in CC than in IBS-C [11].
It is essential to be aware that none of these individual pathophysiologic mechanisms are universally documented in either IBS-C or CC.

Constipation-predominant irritable bowel syndrome to irritable bowel syndrome (IBS) subgroups
Patients with IBS are subtyped according to bowel symptoms into those with predominant constipation (IBS-C), those with predominant diarrhea ( IBS-D), or those with a mixture of both symptoms ( IBS-M) [12][13][14]. Th e defi nition of IBS has progressed over time; at present it is based on symptom-based criteria, such as Rome III, and the accurate use of preferred diagnostic tests to exclude organic disease [15,16].

Epidemiology and demographic
Th e incidence of IBS relies upon the diagnostic criteria used and the characteristics of the studied population (primary care or specialty clinic). Th e epidemiology of IBS in North America was studied in 2002, before the introduction of Rome II criteria, and ranged from 3 to 20% [17]. A recent study carried out in the USA and Canada, using the Rome criteria, reported that the prevalence of IBS was 5-12% according to age [18]. Using the Rome III criteria, the incidence of IBS has been estimated to range from 10 to 18% in the general population of western countries [19,20], where there is also a female predominance [17,[21][22][23]. In contrast, a female predominance has not been consistently documented in Asia. Broadly IBS is more likely to aff ect younger persons, although individuals of all ages can suff er from this condition [17,[21][22][23]. In general, the prevalence of IBS has shown similarity between the White and the Black population; however, there are some data proposing that it may be lower in Hispanics than in non-Hispanic Whites in the USA [24].
IBS is a chronic condition; in about half of the patients symptoms are relatively stable over time. Moreover, a signifi cant proportion of patients with IBS will experience a more dynamic clinical course with improvement or change in their symptoms seen when followed up for a prolonged period of time. Patients with IBS can be aff ected physically, psychologically, socially, and economically [14]. Mental symptoms are associated with disturbance in sexuality, mood, and anxiety [25]. Although in addition to the physical criteria used to evaluate the IBS health-related quality of life (e.g. stool frequency, stool characteristics), global symptom severity should be addressed, including psychological status and symptom-related fears, which might lead to a low health-related quality of life score [26].

Clinical features of irritable bowel syndrome with predominant constipation
Th e cardinal symptoms of IBS-C are abdominal pain or discomfort associated with constipation. Th e current symptom-based (Rome III) criteria [14] consist of recurrent abdominal pain or discomfort for at least 3 days a month in the last 3 months, which is associated with 2 or more of the following: (1) Improvement with defecation.
(2) Change in the frequency of stool.
(3) Change in the appearance of stool.
Th ese criteria should be fulfi lled for at least 3 months with symptom onset at least 6 months before diagnosis. Th e cardinal symptom of IBS is always abdominal pain associated with changing bowel function. However, bloating is most common, especially in women, and is documented by a third of patients and considered an essential reason for consulting a physician. Moreover bloating is associated with decreased energy, poor quality of life, and excessive use of medications [27].
Defi ciency of biomarkers makes the diagnosis of IBS-C greatly reliant on the fulfi llment of symptombased criteria (Rome III). However, overlap with other functional disorders such as CC and functional dyspepsia may occur [14,28,29]. In addition, organic diseases can present with symptoms similar to those of IBS-C, which can lead to more tests, increasing costs, but without diagnostic yields such as complete blood count and full metabolic panel [16].
Th e specifi city of the Rome criteria was raised when alarm symptoms manifested along with the GI symptoms [30,31]. On average, patients with IBS documented at least 1.65 red fl ag symptoms such as blood passing per rectum, unintentional weight loss, iron defi ciency anemia, nocturnal symptoms, or a signifi cant change in symptoms after a stable pattern over several years [32]; such patients may require further investigation. A family history of colorectal cancer, infl ammatory bowel disease, or celiac sprue is also considered an alarm feature. Unfortunately, the discriminatory value of these alarm symptoms is discouraged. Colonoscopy is indicated in patients with late-onset symptoms [33,34], and in patients older than 50 years with new symptoms. Testing is needed in patients who have not shown an improvement despite symptom-based treatment.

The current management and therapies
Many patients with IBS-C initially treat their symptoms with lifestyle modifi cations such as exercise and exclusion diets together with treatment of symptoms such as constipation with fi ber supplements, over-the-counter laxatives, or probiotics. Less commonly, they may also undergo various forms of psychotherapy such as relaxation, stress management, cognitive behavior therapy, and hypnosis. Despite these forms of therapy, many IBS patients are disappointed with their symptomatic response. Th e traditional approach to therapy in IBS-C patients has extensively depended on a patient's predominant or most bothersome symptom -for example, laxatives for constipation and smooth-muscle relaxants for abdominal pain. However, this approach has its limitations and is typically without impact on the natural history of the disorder [35]. Th e interpretation of the response to any treatment is complicated and there is a powerful placebo eff ect (up to 46%) during the fi rst few weeks of therapy [34].
In clinical practice, the principle of treating patients with IBS-C are as follows: the most evidence-based treatment for patients with IBS are those that control function of bowel. Patients with IBS-C with delayed transit usually have greater distension and bloating compared with those with normal transit. Drugs that stimulate transit can be expected to improve this problem.
Secretagogues increase small bowel and colonic transit and relieve abdominal symptoms and bowel dysfunction.
Despite meta-analyses of the benefi t of use of antidepressants in IBS, evidence from pharmacodynamic and clinical trials is limited in IBS-C.
Probiotics contribute to relieving bloating, fl atulence, and possibly pain in IBS, but more research is needed.

Bulking agents
Soluble fi ber such as psyllium (12-20 g/day) is considered the fi rst-line treatment for constipation associated with IBS-C. Despite its extensive use in clinical practice, evidence on the role of bulking agents in IBS is limited [34,36]. However, many researchers have reported that insoluble fi ber (bran) can aggravate symptoms such as bloating [37]. Th e eff ect of fi ber supplementation in clinical trials has been assessed in many systematic reviews with somewhat diff ering conclusions.

Osmotic and stimulant laxatives
Osmotic laxatives are often the alternative fi rst-line therapy for IBS-C. A study has evaluated the eff ect of polyethylene glycol in 27 postpubertal adolescents with IBS-C, and has found that it accelerates the number of bowel movements per week without any eff ect on abdominal pain intensity [38]. Despite a defi ciency of proof, stimulant laxatives are frequently prescribed by clinicians as a treatment for IBS-C. Although these agents increase the colonic transit, it is unknown whether stimulants off er any benefi ts for abdominal pain in IBS-C patients.

Antispasmodics
Th e cardinal features of IBS are abdominal pain or discomfort, which are thought to be symptoms related to alterations in the intestinal or colonic smooth-muscle motility and/or visceral hypersensitivity. Because of their eff ects on smooth-muscle contractile activity, antispasmodics are a therapeutic modality for the symptoms of IBS-C [38]. Moreover, the liability of these agents to promote constipation makes them relatively contraindicated in patients with IBS-C [39].

Prokinetic agents Serotonergic agents
Tegaserod was the only 5-HT4 receptor agonist available for the treatment of women with IBS-C from 2002, and its withdrawal from the market in 2009 due to unexplained raised the incidence of cardiovascular and cerebrovascular events in the treatment group in comparison with the placebo group.

Intestinal secretagogues
Lubiprostone is an activator of a chloride channel with FDA approval for the management of IBS-C. Lubiprostone is available as an 8-μg, twice-daily, oral treatment for women with IBS-C. It is an oral bicyclic fatty acid (FA) derivative of prostaglandin E1 that specially activates the chloride channel (type 2) located in the apical membrane of human intestinal epithelial cells, thereby increasing chloride-rich fl uid secretion into the GI tract. Activation of the chloride channel increased passive paracellular movement of sodium and water and a resultant net increase in fl uid secretion into the intestine lumen [40], softening of feces, and increase in stool biomass with secondary eff ects on peristalsis and transit [41,42]. Th e most frequent treatment-related side eff ects were nausea (8%), diarrhea (6%), and abdominal pain (5%). In addition to these side eff ects, dyspnea has been occasionally reported. However, the mechanism of dyspnea is uncertain, but it typically occurs within 30-60 min of taking the fi rst dose and is generally improved in a few hours' time. Occasionally, dyspnea returns with subsequent dosing. Lubiprostone has a pregnancy category C rating because of the increased fetal demise observed in guinea pig research.

Low-dose antidepressants
Antidepressants (tricyclic antidepressants or selective serotonin reuptake inhibitors) can be indicated in cases with abdominal pain that does not respond to medication primarily aimed at improving bowel function. Antidepressants were found to be adequate for the global symptoms of IBS in a recent meta-analysis. Few studies of antidepressants have focused on IBS-C patients. One randomized, controlled trial involving 44 patients with IBS-C reported that the selective serotonin reuptake inhibitor fl uoxetine improved global and individual symptoms [43]. It is essential to keep in mind that tricyclic agents can aggravate constipation-related complaints because of their anticholinergic properties.

A future therapy for constipation-predominant irritable bowel syndrome
Linaclotide is a 14-amino acid synthetic peptide that specifi cally binds to and activates guanylate cyclase C receptor on the luminal surface of the intestinal epithelium, resulting in production of cyclic guanosine monophosphate [44]. Intracellular cyclic guanosine monophosphate results in activation of the cystic fi brosis transmembrane regulator leading to increased active secretion of chloride and passive paracellular movement of sodium and water into the intestinal lumen leading to improvement of stool frequency, consistency, and intestinal transit. Linaclotide is orally administered and minimally absorbed. All primary and secondary endpoints were achieved and effi cacy was maintained for 26 weeks [45]. Combining the phase 3 data showed improved quality of life, as measured by the IBS-QOL scale, in seven of eight domains in the patients treated with linaclotide [46].
Th ere was no evidence of rebound or worsening of abdominal pain or bowel symptoms during the randomized withdrawal period [47]. Linaclotide was commonly well tolerated. Th e most common adverse eff ect was diarrhea (4 vs. 0.2% for linaclotide and placebo, respectively) [45].

Bile acid modulators
Bile acids can produce alteration in intestinal and colonic motility and secretion. Recent research has investigated the role of specifi c bile acid analogs or drugs that alter bile acid reabsorption as innovative therapies for IBS-C. Many studies have evaluated the eff ects of chenodeoxycholic acid on colonic transit, and clinical parameters in female patients with IBS-C were recently reported. Chenodeoxycholic acid signifi cantly increases overall colonic transit and improves clinical outcomes in IBS patients, including stool frequency and stool consistency, and facilitates the passage of stool. Its most frequent side eff ect was abdominal cramping/pain, which was documented by over 40% of patients compared with none in the placebo group [48].

Complementary and alternative medicines
In general, there is a defi ciency of extensive, high-quality studies supporting the effi cacy of complementary and alternative medicines therapies for IBS-C. A single-center, randomized, double-blind trial on 34 women with IBS-C compared the probiotic Bifi dobacterium lactis with placebo [49], in this study 4 weeks of B. lactis (125 g of yogurt containing B. lactis ingested daily) treatment gave superior results to placebo in decreasing abdominal distention and improving orocecal and colonic transit.
A Cochrane review of herbal medicines (e.g. Padma Lax) for use in the treatment of IBS-C. Many welldesigned clinical studies showed improvement of IBS symptoms [50]. It has been proposed that a combination of certain herbs may act in a coordinated manner on serotonin and acetylcholine receptors in isolated human intestine, but this requires further investigation.

Financial support and sponsorship
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Confl icts of interest
Th ere are no confl icts of interest.