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INTRODUCTION

There is increasing recognition of the similarities in the etiology of constipation predominant irritable bowel syndrome (IBS-C) and chronic constipation (CC), and a more inclusive terminology is emerging of constipation-related functional gastrointestinal (GI) disorders, which embraces both conditions. This is partly driven by the increasing appreciation that IBS-C and CC share a number of common underlying causes and presenting symptoms, which are described below.

However, the vast majority of published literature treats IBS-C and CC as separate entities, and therefore, this article will integrate the pathophysiology of IBS-C and CC, but in the light of the available data, these conditions will then be discussed individually.

In the final section a case scenario is provided, which aims to bring together some of the emerging considerations about integrating the management of IBS-C and CC.

In IBS-C and CC, a variety of pathophysiologic mechanisms have been reported, and there is considerable overlap in the symptoms for which a number of common pathophysiologic mechanisms have been proposed. This section highlights the similarities and differences in the possible etiologies of IBS-C and CC.

Shared factors include decreased bowel motility, pelvic floor dysfunction, visceral hypersensitivity, psychological stressors, altered bowel flora, and diet. There has been a long-standing belief that altered GI motor function exists in some cases of IBS-C and CC, specifically decreased motility and delayed bowel transit. Studies have shown decreased rectal, colonic, and small bowel motility in IBS-C (Quigley, 2005). These abnormalities are best exemplified in the subset of CC known as colonic inertia, a condition defined by a slow colon transit time (Stivland et al, 1991). Pelvic floor dysfunction or dyssynergic defecation is characterized by the inability to coordinate the sequence of events that result in normal evacuation of stool. This includes some combination of the inability to contract the abdominal wall musculature, deficient relaxation of the puborectalis muscle, impaired rectal contraction, paradoxical anal contraction, and/or inadequate anal relaxation (Rao et al, 1998). Although recently identified as a contributor to symptoms in a subset of IBS-C (Prott et al, 2010), this mechanism has also been recognized as a primary etiology of symptoms in a subset of patients with CC (Lembo, Camilleri, 2003).

Visceral hypersensitivity, reflecting a lower pain threshold for the digestive tract, is not only a well-defined pathophysiologic mechanism underlying IBS-C, but also suggested by some to be a biomarker of the condition (Mertz et al, 1995; Bouin et al, 2002; Lawal, 2006). Visceral hypersensitivity results from altered interactions between the central nervous system and enteric nervous system, commonly known as the brain-gut axis (Drossman, 1999). The nociceptive pathways that may be involved in the brain-gut axis have provided, and continue to provide, potential therapeutic targets for the treatment of IBS-C. On the other hand, according to the Rome III definition, abdominal pain plays a much smaller role in CC, as does visceral hypersensitivity (Longstreth et al, 2006^a). Psychological stress may be responsible for symptom development in IBS (O'Malley et al, 2011) and may worsen symptoms. In contrast, psychological stress appears to play a smaller role in CC, but is believed to promote dyssynergic defecation in some cases (Rao, 2007).

There is emerging evidence to suggest a role for altered bowel flora in the development of symptoms in IBS-C, and possibly CC (Attaluri et al, 2010). A long-held connection between low-fiber diet and CC is better defined in CC than for IBS-C (Trowell, 1976).

It is important to understand that none of these individual pathophysiologic mechanisms are universally reported in either IBS-C or CC. More often than not, it is a combination of 2 or more of these etiologic factors that are responsible for symptoms of IBS-C and CC.

PART 1: IRRITABLE BOWEL SYNDROME WITH PREDOMINANT CONSTIPATION

IBS Subgroups

IBS is a common GI functional disorder, characterized by symptoms of abdominal pain or discomfort directly associated with disturbances in defecation that are not explained by identifiable structural or biochemical abnormalities (Drossman et al, 2002; Longstreth et al, 2006^b). Patients with IBS are subtyped based on bowel symptoms into those with predominant constipation (IBS-C) predominant diarrhea (IBC-D), or a mixture of both symptoms (IBS-M) (Longstreth, 2005; Thompson WG, 1993; Longstreth et al, 2006^a). The definition of IBS has evolved over time, now relying upon the use of symptom-based criteria, such as Rome III and the judicious use of selected diagnostic testing to exclude organic disease (Longstreth et al, 2006^a; Furman, Cash , 2011).

One systematic review reported that population-based studies from the US (based on Manning criteria) found similar distributions between IBS-C, IBS-D and mixed IBS (IBS-M) (Guilera et al, 2005). However, based on a survey of 249 IBS patients, 18% of patients with IBS had constipation-predominant symptoms, 36% had diarrhea-predominant symptoms and 46% have a mixed pattern of symptoms (Ersryd et al, 2007). Potential explanations for the variance between publications include differences in geography, gender, demographics, and criteria applied to the populations studied.

Unfortunately, much of the literature concerning IBS epidemiology does not differentiate the study populations into these specific sub-types, and addresses the condition as a whole. Where possible, this article will draw these subgroup distinctions and will focus specifically on data relating to IBS-C.

Epidemiology and Demographics

The prevalence of IBS depends on the diagnostic criteria used and the characteristics of the population studied (primary care vs specialty clinic). In a comprehensive review of IBS epidemiology in North America in 2002, prior to Rome II, the prevalence estimates ranged from 3% to 20% (Saito et al, 2002). In a more recent study in the United States and Canada, using Rome II criteria, the IBS prevalence was reported as 5% to 12%, according to age (Talley et al, 1992^a). Finally, based on Rome III, the prevalence of IBS has been estimated to range from 10% to 18% in the general population of Western countries (Jung et al, 2007; Olafsdottir et al, 2010).

In Western studies there is a predominance of females with IBS (pooled odds ratio [OR] 1.46; (% CI 1.13‒1.88) (Andrews et al, 2005; Hungin et al, 2005; Minocha et al, 2006; Saito et al, 2002). However, across Asia, a female predominance has not been consistently reported. Generally, younger persons are more likely to be affected with IBS. However, patients of all ages can suffer with this condition. For example, Talley et al showed that the prevalence of IBS increases with age from 8% among those aged 65 to 74 years to more than 12% for those older than 85 years of age (Talley et al, 1992^a). Several studies have shown an inverse relationship between IBS prevalence and annual income (Andrews et al, 2005; Minocha et al, 2006; Saito et al, 2002; Hungin et al, 2005).

The prevalence of IBS is generally similar in white and black populations, although some data have suggested it may be lower in Hispanics than in non-Hispanic whites in the United States (Talley, 2010).

IBS is the digestive disorder most often diagnosed by gastroenterologists, accounting for 28% of all patients, and between 30% and 50% of referrals to gastroenterologists. IBS also accounts for 12% of diagnoses made by primary care physicians. (Drossman et al, 2002). Indeed, the National Diseases and Therapeutic Index (NDTI) shows that the condition accounts for 2.6 million office-based visits and 3.5 million all-location visits (Sandler 1990). However, despite this large number, only a limited proportion of sufferers seek medical attention, and the actual number of patients with IBS is probably larger than that reported (Drossman et al, 2002).

IBS is a chronic disorder that may wax and wane for years. In a 1-year study in which Talley et al surveyed a population twice over a 12- to 20-month period, the prevalence of IBS was similar on both occasions (Talley et al, 1992^b). However, about 9% of people with symptoms on the first survey did not have symptoms on the second survey, and about 38% of those with IBS reported that their symptoms had disappeared during the period between the 2 surveys. In a systematic review of the natural history of physician-diagnosed IBS, ~30% to ~50% of patients had unchanged symptoms with longitudinal follow-up (El-Serag et al, 2004). These data suggest that IBS is a chronic condition with symptoms relatively stable over time in up to half the patients. However, a significant proportion of IBS patients will experience a more dynamic clinical course with resolution or a change in their symptoms when followed over prolonged periods of time.

IBS is not associated with an increase in mortality. In a recent study from Olmsted County, which involved 4,176 respondents from randomly selected residents, there was no association between survival and IBS detected in more than 30,000 person-years of follow-up (Chang et al, 2010).

IBS can affect patients physically, psychologically, socially, and economically, and in the past 2 decades, the condition has gained considerable attention in the healthcare field due to its high prevalence (Longstreth et al, 2006^a).

Typically, IBS symptoms are chronic and episodic, causing debilitating symptoms over years. This is illustrated in a survey of 1597 patients with IBS; 50% said that they had experienced symptoms for > 10 years, 57% experienced symptoms daily, 25% weekly and 14% monthly. Moreover, only 4% of patients rated their symptoms as mild. This is in line with the results of a survey conducted by the International Foundation for Functional Gastrointestinal Disorders (IFFGD) in 2002, when 39% of respondents rated their IBS symptoms as extremely or very severe (Hulisz, 2004).

Studies have shown that the duration of symptom flares and the presence of abdominal pain (as opposed to abdominal discomfort) is associated with an impact on the physical component of HRQOL in IBS (Spiegel et al, 2004^b). Mental symptoms are associated with abnormalities in sexuality, mood, and anxiety (Spiegel et al, 2004^b). These symptoms are associated with feelings of chronic stress, exhaustion, and sleep difficulties and also have an impact on social integration and activities (Spiegel et al, 2004^b). Moreover, data consistently show that patients with IBS score lower on all 8 domains of the SF-36 HRQOL questionnaire, compared with a normal non-IBS cohort. Indeed, IBS patients have a similar physical HRQOL as patients with diabetes and a lower score than patients with depression or gastroesophageal reflux disease (GERD). Also, the mental SF-36 scores were lower in patients with IBS than those with chronic renal failure and similar to Class 3 congestive heart failure (CHF) and rheumatoid arthritis (Spiegel, 2009^b). IBS unquestionably has a negative impact on HRQOL, and failing to recognize this could undermine the physician-patient relationship and lead to dissatisfaction with care. These findings suggest that in addition to the physical criteria used to judge IBS HRQOL (eg, stool frequency, stool characteristics), global symptom severity should also be addressed, including psychological status and symptom-related fears that might contribute to the low HRQOL score (Agarwal et al, 2011).

Administering a full HRQOL instrument is not likely to be practical in the busy clinic setting. To assist with this, a short questionnaire has been developed specifically for use in everyday clinical practice. Administered in the waiting room, a nurse can quickly score the results and provide this to the doctor ahead of the consultation. This questionnaire is called the BEST score because the 4 questions spell out BEST (Speigel et al, 2006):

• How Bad are your bowel symptoms?
• Can you still Enjoy the things you used to enjoy?
• Do you feel like your bowel symptoms mean there's something Seriously wrong?
• Do your bowel symptoms make you feel Tense?

It is important that healthcare professionals (HCPs) are aware of the negative impact of IBS on patients; if their symptoms are not satisfactorily controlled, they tend to visit their doctors more, consume more diagnostic resources, take more medications, miss more workdays, and have a lower work productivity. Moreover, they are hospitalized more frequently and consume more direct costs than those without IBS. Resource utilization is highest in patients with severe symptoms and poor HRQOL (Spiegel et al, 2009^b).

The annual costs of IBS treatment in the United States has been estimated to be over $20 billion in both direct ($1.6 billion) and indirect ($19.2 billion) expenditures (Shih et al. 2002), which is staggering considering the proportion of those with IBS who do not seek medical attention (Talley et al, 1997). This is driven by the associated absenteeism, more frequent healthcare visits, and the presence of more long-standing comorbid conditions such as back pain, tingling, headaches, temporomandibular joint pain and muscle aches. The investigation of these conditions and the treatment of symptoms lead to patients with IBS consuming over 50% more healthcare resources than matched controls without IBS (Talley et al, 1995; Longstreth et al, 2003). Thus, the costs associated with IBS are impacted by the high prevalence of the disease and the disproportionate use of resources.

Clinical Features of IBS With Predominant Constipation

The cardinal symptoms of IBS-C are abdominal pain or discomfort associated with constipation. The current symptom-based (Rome III) criteria are (Longstreth et al, 2006^a)

• Recurrent abdominal pain or discomfort for at least 3 days per month in the last 3 months, which is associated with 2 or more of the following:
  • Improvement with defecation
  • Onset associated with a change in frequency of stool
  • Onset associated with a change in form (appearance) of stool
• Supportive symptoms include
  • Abnormal stool frequency (< 3 per week)
  • Abnormal stool form (lumpy-hard)
  • Straining
  • Urgency
  • A feeling of incomplete evacuation
  • Passing mucus and gas

These criteria should be fulfilled for at least 3 months with symptom onset at least 6 months before diagnosis.

Abdominal pain associated with changed bowel function is always cited as the cardinal symptom of IBS. However, bloating is very common, especially in women, and is reported by a third of patients as the most important reason for consulting a physician. Bloating is associated with decreased energy, decreased quality of life, and increased use of medications and healthcare utilization (Ringel et al, 2009). Therefore, effective management of these symptoms is important to ensure patient satisfaction and improved quality of life. Indeed, treatment of IBS should be initiated when the symptoms are found to reduce functional status and diminish overall HRQOL and the information provided across HRQOL domains could be useful to develop personalized therapy.

Patients with IBS often experience other GI- and non-GI‒related comorbidities (Table 1) (Whitehead et al, 2002).

Table 1. Comorbidities in Patients With IBS

Patients also experience a wide range of non-GI symptoms such as:

• Headache: 23%-45%
• Back pain: 27%-81%
• Fatigue: 36%-63%
• Myalgia: 29%-36%
• Dyspareunia 9%-42%
• Urinary frequency: 21%-61%
• Dizziness: 11%-27%

As a result, IBS patients make more healthcare visits and incur more healthcare costs than non-IBS patients. More than half of these are due to non-GI concerns (Whitehead et al, 2002). Moreover, IBS patients with comorbid somatic disorders report more severe IBS symptoms and lower HRQOL (Whitehead et al, 2002).

No criteria have been established to determine severity of IBS, mainly due to the large number of factors that influence severity and the wide gap between patient and physician perceptions of severity. Patients tend to rate severity on multiple symptoms including abdominal pain and discomfort (pain, bloating); defecation-related symptoms (straining); illness-related anxiety (something serious is wrong with me) (Lembo et al, 2005). Therefore, factors that are important to consider when assessing severity include (Lembo et al, 2005; Drossman et al, 2000):

• HRQOL
• Psychosocial factors
• Healthcare use behavior
• Disability
• Overall impact of IBS on the patient's life

Gender Issues

As discussed above, more women have IBS than men, except in Asian countries. Women with IBS tend to report greater overall IBS symptom severity, intensity of abdominal pain and bloating, and impact of symptoms on daily life, and a lower HRQOL (Xiong et al, 2004; Lau et al, 2002). Women also report more extraintestinal symptoms, including nausea, urinary urgency, and dyspareunia and are more likely to report constipation and bloating (Ho et al, 1998; Kwan et al, 2002; Danivat et al, 1988; Masud et al, 2001; Rajendra, Alahuddin, 2004). Symptoms vary according to the menstrual cycle, with increased reporting of GI symptoms (eg, looser stools and rectal sensitivity) in the late luteal and menses phases when compared with the mid-follicular phase (Ghoshal et al, 2008; Han et al, 2006).

Given the lack of biomarkers, the diagnosis of IBS-C is largely based on the fulfillment of symptom-based criteria (Rome III).

However, the overlap with other functional disorders includes CC and functional dyspepsia (Longstreth et al, 2006^a; Thompson et al, 1992; Thompson et al, 1999). Organic diseases can present with similar symptoms to those in IBS-C, which can lead to additional tests increasing costs, but not diagnostic yield (eg, complete blood count, full metabolic panel (Furman, Cash, 2011). Using a case vignette for IBS-C, Spiegel showed that the approach to IBS as a disease of exclusion meant that non-IBS experts used 1.3 times more tests and spent $212 per person more in diagnostic expenditure (Spiegel et al, 2010). These results confirm that the likelihood of identifying organic disease with routine laboratory tests is no greater in patients with IBS (without alarm features) than in the general population.

The specificity of the Rome criteria increases when alarm symptoms are included with the GI symptoms (Ford et al, 2008^a;Jellema et al, 2009). On average, IBS patients report at least 1.65 red flag symptoms (Whitehead et al, 2006), and those that may mandate further investigation include blood passed per rectum, unintentional weight loss, iron deficiency anemia, nocturnal symptoms, or a significant change in symptoms after a stable pattern over several years. A family history of colorectal cancer, IBD, or celiac sprue also constitutes an alarm feature. Unfortunately, the discriminatory value of these alarm symptoms is disappointing. In these cases, and in patients with late-onset symptoms, a colonoscopy is indicated. It is interesting to note that, in community-based surveys, up to 50% of patients with IBS undergo colonoscopy in the course of their diagnostic evaluation (Talley et al, 1995).

The Rome III guidelines encourage clinicians to make a positive diagnosis of IBS-C on the basis of symptom complexes and emphasize that IBS-C is not a diagnosis of exclusion (Longstreth et al, 2006^a).

In making an accurate and quick symptom-led diagnosis, it is essential that the HCP and the patient communicate effectively, but there are several barriers to achieving this. For the patient, there is the embarrassment of discussing intimate bowel symptoms and a feeling of inadequacy. For the HCP, there needs to be empathy with the patient's anxieties and conveying a sense of engagement with their condition. Achievable management goals need to be set that are subsequently reviewed in order for the patient to take a sense of responsibility for their condition (Lacy et al, 2007). In addition, the lag time to make a diagnosis of IBS needs to be reduced. The average time from experiencing symptoms to having a formal diagnosis of IBS is 5 years (International Foundation for Functional GI Disorders).

A validated Patient Daily Diary used on a regular basis would provide an objective log of the patient's symptoms in the lead up to their consultation. Such a diary is provided by the International Foundation for Functional Gastrointestinal Disorders.

There are several scenarios in which diagnostic testing is recommended (Speigel et al, 2004^a; Brandt et al, 2009):

• Colonoscopy in patients aged > 50 years with new symptoms
• Testing in patients who have not improved despite symptom-based treatment

Thus, the available evidence supports the application of validated symptom-based clinical criteria along with the judicious use of selected high-yield laboratory and endoscopic testing in selected patients.

Patient Dissatisfaction With Current Management and Therapies

Many IBS-C patients initially treat their symptoms with lifestyle modifications such as exercise and exclusion diets together with remedies directed at the symptoms of constipation, including fiber supplements, over-the-counter (OTC) laxatives, and probiotics. Less frequently, they may also pursue various forms of psychotherapy such as relaxation, stress management, cognitive behavior therapy, and hypnosis. Despite these forms of therapy, many IBS patients are dissatisfied with their symptomatic response. This dissatisfaction leads to increased physician consultations, many drug therapies, and multiple changes and adjustments in treatment strategies. .

A recent survey of 657 members of the Intestinal Disease Foundation (IDF), including 420 with IBS, 97% of IBS respondents had required 2 or more healthcare professional consults (visits and telephone) and approximately 75% had made 4 or more such visits/calls in the preceding 3 months (Hulisz, 2004). Many patients try multiple traditional medications in an attempt to find symptom relief. In addition, in the Truth in IBS (T-IBS) Survey more than 50% of IBS sufferers (n = 318) reported that IBS symptoms had a substantial impact on their social activities (eg, going shopping, going out to eat), and 52% reported that IBS negatively affected their sex life or physical relationships (Hungin et al, 2005).

This overall level of patient dissatisfaction is shown in a recent study comparing the patients' ideal expectations vs their actual experience when visiting a physician about their IBS (Table 2) (Halpert et al, 2010).

Table 2. Patient Expectation vs Actual Experience

Thus, there is room for improvement and for physicians to provide the type of care that their IBS-C patients are seeking. The patients' concerns often relate to their misconceptions about the etiology of IBS-C, and this further amplifies the burden of the disease and health-related fears and concerns. For instance, in a survey of 261 patients with IBS, 80.5% believed it results from anxiety, 75.1% believed that it is caused by dietary factors, and 63.5% believed it to be caused by depression. Moreover, 1 in 7 patients believed that IBS-C can progress to cancer, increases the chances of developing IBD, and shortens lifespan. When asked about prescription medications, only 66.7% felt they were effective. Thus, there remains an unmet need for those patients who fail to improve with currently available therapies.

The traditional approach to therapy for IBS-C has largely focused on a patient's predominant or most bothersome symptom(s) (eg, laxatives for constipation and smooth-muscle relaxants for abdominal pain). This approach has its limitations and typically has no impact on the natural history of the disorder (Camilleri et al, 2009^b). Complicating the interpretation of response to any treatment, there is a powerful placebo effect (up to 46%) during the first few weeks of therapy (Brandt et al, 2009).

The principles of treating IBS-C in clinical practice are as follows: The most "evidence-based" treatments for IBS are those that influence bowel function. IBS-C patients with delayed transit tend to have greater distension and bloating than those with normal transit. Therefore, drugs that accelerate transit can be expected to improve this troublesome problem

• Secretagogues accelerate small bowel and colonic transit and relieve abdominal symptoms as well as bowel dysfunction
• Despite meta-analyses of antidepressant benefit in IBS overall, the pharmacodynamic and clinical trial evidence is limited in IBS-C
• Probiotics tend to relieve bloating, flatulence, and possibly, pain in IBS, but more data are needed

Bulking agents. Soluble fiber such as psyllium (12-20 g/day) is typically regarded as the first-line treatment for constipation associated with IBS-C. Although commonly used in clinical practice, the evidence for the role of bulking agents in IBS is limited (Brandt et al, 2009; Ford et al, 2008^b). Indeed, several studies have shown that insoluble fiber (bran) can aggravate symptoms such as bloating (Miller et al, 2006).

The clinical trials assessing fiber supplements have been evaluated collectively in several systematic reviews with somewhat differing conclusions. The American College of Gastroenterology (ACG) Task Force recently reported their findings from an evidence-based review on the effectiveness of fiber supplements in the management of IBS-C and concluded that psyllium hydrophilic mucilloid (ispaghula husk) is moderately effective at increasing stool frequency and consistency and can be given a conditional recommendation (Grade 2C). However, wheat or corn bran cannot be recommended (Lee, 2010). A recent Cochrane review of 11 studies did not find fiber supplements more effective than placebo in the treatment of IBS (Ruepert et al, 2011).

Osmotic and stimulant laxatives. Osmotic laxatives are often the alternative first line therapy for IBS-C. No placebo-controlled, randomized studies of osmotic laxatives have been published, and most of these agents have been studied only in CC patients. A small study was published that assessed polyethylene glycol (PEG) in 27 postpubertal adolescents with IBS-C, and although it increased the number of bowel movements per week, it had no effect on abdominal pain intensity (Whitehead et al, 1990).

Despite a lack of evidence, stimulant laxatives are commonly recommended by clinicians as a treatment for IBS-C. Although these agents accelerate colonic transit, an important unknown is whether stimulants offer any benefits for abdominal pain in IBS-C patients. There are currently no high-quality studies that have assessed the long-term safety of osmotic or stimulant laxatives in IBS-C patients.

Antispasmodics. Abdominal pain or discomfort are cardinal features of IBS and are thought to be symptoms that are related to alterations in intestinal or colonic smooth-muscle motility and/or visceral hypersensitivity. Because of their effects on smooth-muscle contractile activity, antispasmodics are a mainstay of therapy for the symptoms of IBS-C.

Antispasmodics include antimuscarinics, calcium channel blockers, and anticholinergics. Of these only 4 specific anticholinergics are available in the United States: hyoscine, dicyclomine, belladonna, and propantheline. Hyoscine and peppermint oil are the most effective agents in this class (Whitehead et al, 1990).The clinical utility of these drugs is limited by their side effects (including dry mouth, dizziness, blurry vision, urinary retention, and confusion in the elderly). Moreover, the propensity of these agents to promote constipation makes them relatively contraindicated in patients with IBS-C. (Saad, 2011)

Prokinetic Agents

Serotonergic agents. Tegaserod was the only 5-HT4 receptor agonist available for the treatment of women with IBS-C from 2002 until its voluntarily withdrawal from the market in 2009 due to an unexplained increased incidence of cardiovascular and cerebrovascular events in the treatment group compared to the placebo group. Although tegaserod's efficacy and tolerability in the treatment of women with IBS-C was readily demonstrated in 3 multicenter, double-blind, placebo-controlled trials involving more than 3000 patients (Muller-Lissner et al, 2001; Novick et al, 2002; Lefkowitz et al, 2000), the 13 cardiovascular ischemic events (3 myocardial infarctions, 1 sudden cardiac death, 6 cases of unstable angina, and 3 cerebrovascular accidents) in 11,614 patients treated with tegaserod compared with 1 event in the 7031 patients receiving placebo in a pooled analysis of all the clinical trials (P = .02) could not be explained, leading to its withdrawal from the US and Canadian markets for safety concerns (Thompson, 2007).

Intestinal secretagogues. Lubiprostone is a chloride channel activator 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 derivative of prostaglandin E1 that selectively activates the type-2 chloride channel located on the apical membrane of human intestinal epithelial cells (Cuppoletti et al, 2004), thereby increasing chloride-rich fluid secretion into the GI tract. Activation increases passive paracellular movement of sodium ions and water and a resultant net increase in fluid secretion into the lumen of the intestine (Cuppoletti et al, 2004) , softening the feces and increasing stool biomass with attendant secondary effects on peristalsis and transit (Lang et al, 2008; Owen, 2008).

The efficacy and tolerability of lubiprostone for the treatment of IBS-C have been assessed in large, high-quality phase 3 randomized, controlled trials (RCTs). Two phase 3, 12-week, multicenter, double-blind, randomized, placebo-controlled trials evaluated lubiprostone in 1171 patients (92% female) meeting the Rome II criteria for IBS-C (Drossman et al, 2009). In these trials, participants were randomized in a 2:1 fashion to receive lubiprostone 8 μg twice a day. The studies used a rigorous and previously untested primary endpoint. A 7-point Likert scale was employed to answer the following question: "How would you rate your relief of IBS symptoms (abdominal pain/discomfort, bowel habits, and other IBS symptoms) over the past week compared with how you felt before you entered the study?" Those reporting at least moderate relief in 4 of 4 weeks or significant relief in 2 of 4 weeks were considered monthly responders. An overall responder had to be a monthly responder in 2 of the 3 months of the clinical trial. This rigorous endpoint was designed to minimize the placebo effect. In these phase 3 trials, patients randomized to lubiprostone were nearly twice as likely to be responders as those on placebo (18% vs 10%, P =.001). Lubiprostone was also superior to placebo in improving individual IBS symptoms, including abdominal discomfort/pain, stool consistency, straining, constipation severity, and QOL. Lubiprostone 8 μg bid was well tolerated in these trials. The most common treatment-related side effects were nausea (8%), diarrhea (6%), and abdominal pain (5%). There was no difference in serious side effects between those taking lubiprostone or placebo (1% in both groups). The results of the phase 3 clinical trials led the FDA to approve lubiprostone for the treatment of women aged 18 years and older suffering from IBS-C in 2008. An evidence-based systematic review performed by the ACG IBS Task Force concluded that "Lubiprostone in a dose of 8 μg twice daily is more effective than placebo in relieving global IBS symptoms in women with IBC-S (Grade 1B rating)."

A recently published extension study reported a similar safety profile over a period of up to 52 weeks of open-label treatment with lubiprostone (Chey et al, 2012). It was concluded that lubiprostone at a dose of 8 μg bid was safe and well tolerated over 9 to 13 months of treatments. In addition to the side effects already mentioned, there have been rare reports of dyspnea. The mechanism of dyspnea is unclear but it typically occurs within 30 to 60 minutes of taking the first dose, generally resolving in a few hours' time. Occasionally, dyspnea recurs with subsequent dosing.

Lubiprostone carries a pregnancy category C rating because of increased fetal demise in guinea pig studies. The product label recommends documentation of a negative pregnancy test before initiation of therapy and the use of contraception while taking lubiprostone in women with the potential of childbearing.

Low-Dose Antidepressants

Antidepressants (tricyclic antidepressants [TCAs] or selective serotonin reuptake inhibitors [SSRIs]) can be considered if abdominal pain does not respond to therapies primarily aimed at improving bowel function. Theoretically, they should provide benefits in IBS by both central and peripheral mechanisms. A recent meta-analysis found that antidepressants as a class were efficacious for the global symptoms of IBS. Few studies of antidepressants have focused on IBS-C patients. One randomized, controlled trial found that the SSRI fluoxetine improved global and individual symptoms in 44 patients with IBS-C (Vahedi et al, 2005). It is important to remember that tricyclic agents can aggravate constipation-related complaints because of their anticholinergic properties.

What to Expect From Future Therapies for IBS-C?

Linaclotide. Linaclotide is a 14-amino acid synthetic peptide that selectively binds to and activates the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium, resulting in the production of cyclic guanosine monophosphate (cGMP) (Bryant et al, 2010). Intracellular cGMP results in activation of the cystic fibrosis transmembrane regulator (CFTR) leading to increased active secretion of chloride and passive paracellular movement of sodium and water into the intestinal lumen leading to improvements in stool frequency, consistency, and intestinal transit. Based upon studies in animals, it has been suggested that extracellular cGMP may reduce visceral hyperalgesia by reducing firing of visceral afferent nerve fibers (Bharucha, Linden, 2010).

Linaclotide is minimally absorbed and orally administered qd. The results of the phase 3, IBS-C, randomized, double-blind, placebo-controlled trials with up to 26 weeks of treatment were presented at Digestive Diseases Week 2011 (Rao et al, 2011; Chey et al, 2011^a; Carson et al, 2011). The phase 3 trials in IBS-C (as defined by modified Rome II criteria) utilized the rigorous interim primary endpoint developed by the FDA for treatment trials in IBS-C. In addition to the FDA interim endpoint, 3 additional primary and 10 secondary endpoints were studied over 12 to 26 weeks (Johnston, Schneier, 2012). Some of the key endpoints assessed in these trials included

• FDA interim endpoint: a responder was defined as a patient who had a ≥ 30% reduction from baseline in abdominal pain at its worst and an increase in complete spontaneous bowel movements (CSBMs) of ≥ 1 per week in the same week, for at least 6 of 12 weeks of treatment
• Abdominal pain responder endpoint: a responder had a ≥ 30% reduction from baseline in abdominal pain for at least 9 or 12 weeks of treatment
• CSBM responder endpoint: a responder has ≥ 3 CSBMS per week with an increase in CSBMs of ≥ 1 per week for at least 9 of 12 weeks of treatment