2023 Impact Factor
2023 Impact Factor
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Both chronic constipation (CC) and irritable bowel syndrome (IBS) are highly prevalent, heterogeneous functional disorders that affect approximately 10?20% of the North American population.1,2 The global prevalence of IBS ranges from 1% to 45%, and seems to vary by geographic location, diagnostic criteria, age, gender and duration of symptoms.3 Typically, IBS is classified as diarrhea-predominant, constipation-predominant (IBS-C) or mixed type.4 These different IBS phenotypes likely have different pathophysiologies, and it seems reasonable that the approach to treatment should be phenotype-specific. In years past, therapy has been symptom-based, but as researchers’ understanding of the disease advances, more specific therapies are being developed. This article summarizes current and emerging therapies for IBS-C and CC (Table).
The Rome III classification system treats functional constipation (FC) and IBS-C as distinct disorders, the primary distinction involving the presence of abdominal pain as a primary complaint in IBS-C but not in FC. However, the considerable symptom overlap between these 2 disorders has been highlighted in recent studies,18,19 and similar therapeutic strategies are often utilized. Wong et al18 examined the overlap between FC and IBS-C that would result if the requirement that no patient meeting criteria for IBS-C could also be diagnosed with FC was removed. The authors found that among 432 patients, 89.5% of IBC-C cases met criteria for FC, and 43.8% of FC patients fulfilled criteria for IBS-C. Furthermore, by 12 months, 1 in 3 patients with FC transitioned to IBS-C and one-third of IBS-C changed to FC. Thus, these entities are likely to be part of the same condition with patients located along a spectrum of pain severity modulated by serotonin signaling.19 Because of this overlap and transition between diagnoses, it follows that several drugs have been found to be effective for the treatment of symptoms related to both IBS-C and FC.
Traditional IBS-C and CC therapies, such as fiber and laxatives, have tended to focus on the improvement of specific bowel complaints such as stool frequency and stool consistency. Recently, more specific agents, including lubiprostone and linaclotide, are being utilized.
Fiber (either dietary or supplementary) has been long recommended as first-line therapy for functional bowel disease symptoms despite the limited evidence surrounding its use.20 It is apparent from trials identified by systematic reviews that there is a relative paucity of high quality evidence to support this approach, especially for insoluble fiber. When fiber is recommended for functional bowel disease, use of a soluble supplement such as ispaghula/psyllium, is best supported by the available data. Even when used judiciously, fiber can exacerbate abdominal distension, flatulence, constipation and diarrhea.
Although stimulant laxatives such as sodium picosulfate and bisacodyl are routinely used in clinical practice for CC, the evidence surrounding their efficacy has, until recently, been in somewhat short supply. In a recent randomized placebo controlled trial of 468 patients with CC, sodium picosulfate improved stool frequency over 4 weeks.21 The percentage of patients with an increase of 1 or more mean complete spontaneous bowel movements (CSBMs) per week compared to baseline was 65.5% vs. 32.3%, respectively (
Finally, osmotic laxatives such as polyethylene glycol (PEG) 3350 are an established treatment for CC and are often recommended for IBS-C. The 2005 American College of Gastroenterology summary statement gave PEG a grade A recommendation for the treatment of CC,27 a recent meta-analyses found the number needed to treat (NNT) with osmotic laxatives to be 3 (95% CI 2 to 4).28 An RCT demonstrated PEG’s safety and efficacy in 304 subjects, including elderly patients, over 6 months.29 Improvement was seen in 52% of PEG and 11% of placebo subjects (
Lubiprostone is approved for IBS-C in women and for CC in adults. A prostone derived from prostaglandin E1, lubiprostone is a locally-acting, highly selective activator of type-2 chloride channels and cystic fibrosis transmembrane conductance regulator chloride channels, located on the apical aspect enterocytes resulting in the passive paracellular movement of sodium and water (Fig. 1).32 The luminal distension by increased intestinal fluid promotes gastrointestinal (GI) tract motility which in turn increases the intestinal and colonic transit.33 Lubiprostone also enhances and stimulates contraction in colonic as well as gastric muscles through prostaglandin E receptors, suggesting direct effects on GI motility.34,35 This drug has been approved by the Food and Drug Administration (FDA) as a treatment for women and men with chronic constipation at a dose of 24 μg, twice daily, and for women with IBS-C at a dose of 8 μg, twice daily. Lubiprostone is contraindicated in mechanical GI obstruction and is FDA pregnancy category C.
Lubiprostone has been consistently demonstrated to be superior to placebo for increasing the number of SBMs, improving stool consistency, reducing straining, bloating and overall constipation symptoms in several large, multicenter RCTs involving CC and IBS-C.23,36?40 One phase III trial in CC involved 242 patients (average age: 48 years; 89% female; 88% Caucasian) who received either lubiprostone 24 μg twice daily or placebo with food for a period of 4 weeks with a primary efficacy end point of number of SBM at 1 week of treatment.23 Those receiving lubiprostone experienced a significant increase in SBMs compared with placebo at week 1 (5.7 vs. 3.5;
Drossman et al38 evaluated over 1100 IBS-C patients in a placebo-controlled RCT, demonstrating that lubiprostone 8 μg twice daily resulted in significantly higher overall response compared to placebo (17.9% vs. 10.1%,
Linaclotide is an orally administered minimally absorbed 14-amino acid peptide that acts peripherally on the guanylate cyclase-C (GC-C) receptor located on the luminal surface of intestinal epithelial cells. Activation of the GC-C receptor leads to the production of intracellular cyclic guanosine monophosphate (cGMP) which activates the cystic fibrosis transmembrane regulator resulting in active secretion of chloride into the intestinal lumen (Fig. 1).32 As a consequence of this active chloride secretion, there is passive paracellular movement of sodium and water.45 In addition, extracellular cGMP reduces firing of visceral afferent neurons in animal models, suggesting potential benefits of linaclotide for abdominal pain.46 In animal models, linaclotide activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP, inhibiting nociceptors, and thereby reducing nociception.47?49 The activation of GC-C may attenuate the stretch response, dampen stretch-sensitive afferents and normalize afferent sensitization.48,49
The FDA has approved linaclotide for IBS-C at a dose of 290 μg daily and for chronic idiopathic constipation (CIC) at a dose of 145 μg daily. Linaclotide received its first global approval in August 2012 for the treatment of IBS-C and CIC in the US and in September 2013 for approval for the treatment of IBS-C in Europe.50 It is recommended to take linaclotide on an empty stomach at least 30 minutes prior to the first meal of the day, and linaclotide is FDA pregnancy category C.
Two randomized, multicenter, double-blind, dual-dose, placebo-controlled trials of linaclotide have been conducted in patients with CC involving over 1,276 patients.51 Patients received placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more CSBMs per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. For both trials, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, compared with 3.3% and 6.0% of those who received placebo (
Linaclotide has also been studied in patients with IBS-C.52,53 A phase III, 6 month, double-blind, placebo-controlled study found that linaclotide 290 μg daily significantly improved abdominal and bowel symptoms associated with IBS-C in 804 patients.53 One of the prespecified primary end points included the FDA’s recommended composite end point which required improvement of ≥ 30% from baseline in average daily worst abdominal pain score as well as an increase of ≥ 1 CSBM from baseline, both in the same week for ≥ 6/12 weeks. Linaclotide resulted in a response rate of 33.7% vs. 13.9% for placebo-treated patients (
A number of additional analyses of data from phase III IBS-C trials have recently been reported. In a prespecified analysis using the suggested primary endpoint from the European Medicines Agency, Quigley and colleagues54 reported a significantly greater proportion of linaclotide-treated vs. placebo-treated patients were 12-week “degree-of-relief” responders (39.4% vs. 16.6%;
Ileal bile acid transporters located in the terminal ileum normally absorb 97% of luminal bile acids. Bile acids which are not absorbed in the terminal ileum spill over into the proximal colon, where they are deconjugated and dehydroxylated by colonic microbiota to produce secondary bile acids such as deoxycholic acid, which induce colonic secretion.56 There is also considerable evidence that bile acids can modify colonic motility through direct effects on colonic neuromuscular activity independently of secretory effects.57 Recently, a study showed that measurements of individual urinary bile acids were associated with stool characteristics in patients with IBS; these effects were independent of the effects of colonic transit.58 A similar study demonstrated that serum and stool levels of bile acids were increased in diarrhea-predominant IBS patients compared to healthy controls.59 Thus, the modulation of luminal bile acid concentrations represents a novel treatment strategy for patients with bowel disturbances. Specifically, the supplementation of specific bile acid analogues or use of drugs that inhibit ileal bile acid reabsorption may be helpful in treating constipation or IBS-C (Fig. 2).
Bile acids such as chenodeoxycholic acid, previously used for dissolution of gallstones, are known to elicit diarrhea at higher doses in healthy controls and constipated patients.60?63 Rao et al5 showed in a double-blind placebo-controlled study that sodium chenodeoxycholate (CDC), a primary bile acid, accelerated colonic transit and improved bowel function in 36 female patients with IBS-C. Looser stool consistency (
An alternative strategy to providing supplemental bile acids is to inhibit reabsorption of native bile acids in the terminal ileum. Elobixibat (formerly A3309) is a first-in-class selective, minimally absorbed ileal bile acid transporter inhibitor, reducing the active ileal reabsorption of bile acids, resulting in an increased concentration of bile acids entering the colon, which stimulates colonic motility and secretion. Pharmacodynamic studies with elobixibat have demonstrated acceleration of colonic transit, increased stool frequency, improved stool consistency and relief of constipation-related symptoms in CIC patients.64 Elobixibat has been tested in phase II trials involving patients with CIC; the 3 studies published to date report similar results regarding the efficacy and safety of elobixibat compared with placebo, in improving the number of SBMs, stool consistency and in decreasing straining.6?8 There was no consistent amelioration of abdominal pain or bloating, except at the 15 mg daily dose, acknowledging that these studies were conducted in patients with CIC.7,8 Studies in patients with IBS-C (where abdominal pain or cramping is a primary complaint) have not yet been conducted. Further evaluation of elobixibat in phase 3 clinical trials to confirm the most appropriate and well-tolerated treatment dose and the effects of long-term administration are ongoing.
Similar to lincaclotide, plecanatide, an analogue of uroguanylin, activates the GC-C receptor found on GI mucosal epithelial cells, leading to intracellular secretory and extracellular anti-nociceptive effects via a cGMP mediated second messenger pathway (Fig. 1).32,65,66 Plecanatide is a luminally acting drug with little measurable systemic exposure which is being investigated as a treatment for CC and IBS-C.9 Shailubhai et al9 completed a phase IIa trial, demonstrating that plecanatide was safe and well-tolerated in single doses up to 48.6 mg and that dosages of 0.3, 1.0, 3.0 and 9.0 mg once daily for 14 days improved stool frequency, straining and abdominal discomfort in 84 patients with CC. A phase III trial evaluating plecanatide 3 mg per day vs. placebo for 12 weeks in 951 CC patients reported that 21.5% vs. 11.5% (
Three trials (which assessed 620, 641 and 713 patients, respectively) examining the use of prucalopride in CC demonstrated a significant increase in the proportion of patients achieving at least 3 SBMs per week compared with placebo.10?12 Response rates ranged from 19.5% to 31% with 2 mg prucalopride, 24% to 28% with 4 mg prucalopride and 9.6% to 12% with placebo over 12 weeks. Over 85% of study subjects were women. Improvements in disease-specific quality of life were maintained during open-label treatment for up to 18 months.70 Most frequent adverse events resulting in discontinuation were GI events (nausea, abdominal pain and diarrhea [3.3%]) and headache (1.0%). The serious cardiac adverse events (palpitations, myocardial infarction, ventricular fibrillation, torsades de pointes and sudden death) and medication interactions that led to the withdrawal of the less selective serotonergic agonists cisapride and tegaserod have not been observed with prucalopride.71
The comparative effectiveness of prucalopride versus the more commonly recommended osmotic agent PEG was recently evaluated in a single center RCT from Romania.72 Two hundred and forty CIC patients received either PEG 3350 and electrolytes (26 g) or prucalopride (1?2 mg) for 28 days. For the primary endpoint (proportion of patients having ≥ 3 CSBMs during the last treatment week), the treatments were non-inferior in a modified intention-to-treat analysis. Surprisingly, PEG led to significant benefits over prucalopride for most of the prespecified secondary variables (bowel frequency, stool consistency, time to next CSBM, perception of straining and completeness of defecation). No differences in tolerability were observed.
As yet, limited data exist on the impact of prucalopride on motility disorders affecting other parts of the GI tract such as gastroparesis, chronic intestinal pseudo-obstruction, and, most importantly, IBS-C. It is currently approved for use in Europe and Canada, but has not been approved by the FDA for use in the United States. It is indicated for women with CC in whom laxatives have failed to provide adequate relief. The recommended dosage in adults is 2 mg administered orally once daily.
RDX5791 is a first-in-class potent and selective inhibitor of Na+/H+ antiport protein, a sodium transporter on the surface of the intestinal epithelia. The intestinal Na+/H+ antiport protein plays a key role in the uptake of sodium, and thus water, from the intestinal lumen. Animal studies have demonstrated a dose related increase in in fecal water content and transit rate with minimal systemic exposure.76 It is currently in phase II trials for IBS-C.
Pumosetrag, a 5-HT3 receptor partial agonist, is a novel enteroprokinetic compound which stimulates small bowel transit dose dependently.77 A single-blind study showed that pumosetrag 0.5 mg improved bowel motility in 14 patients with CC. In the low bowel motility group, both geometric mean and percent elimination increased after treatment (
Daikenchuto, a Japanese herbal medicine, which consists of an extract powder from dried Sichuan pepper, processed ginger, ginseng and maltose powder, has been used for the treatment of paralytic ileus and radiation-induced enteritis due to its possible prokinetic effects.78?81 A pharmaceutical grade version of daikenchuto, TU-100, has not been widely studied in clinical trials but appears to be safe and well tolerated. TU-100 demonstrated pro-kinetic effects on colonic transit in animal studies but in subsequent human trials, effects on colonic and gastric transit were not statistically significantly different from placebo.15,16
Hemp seed extract is a popular Chinese herbal medicine which is often used to treat FC. Cheng et al17 evaluated 120 patients with FC for 8 weeks. For an endpoint of a mean increase of CSBM ≥ 1/week compared with baseline, hemp seed pill 7.5 g twice daily produced a response in 43.3%, compared to 8.3% with placebo (
Probiotics are known to be generally safe and may offer benefits to patients with functional GI disorders by improving intestinal barrier function, altering epithelial surface glycosylation pattern, increasing mucus production, secreting antimicrobial peptides, modulating the immune system and altering fermentation.82 The role of probiotics in IBS remains unclear, although
Chronic FC and IBS-C are common problems faced by both primary care physicians and gastroenterologists. The Rome III criteria distinguish between these 2 disorders mainly through the presence of abdominal pain or discomfort as a primary and clinically significant complaint in IBS-C but not chronic FC. From a regulatory standpoint, these conditions are treated as separate entities but in clinical practice, the symptoms of IBS-C and chronic FC overlap significantly and oftentimes, their distinction is quite arbitrary. To a certain extent, this suggestion is supported by the current industry model of sequential or even parallel development of novel drugs for chronic FC and IBS-C. Only time will tell if the upcoming Rome IV criteria will uphold the current separation between chronic FC and IBS-C or suggest a paradigm shift which acknowledges the undeniable overlap between these conditions. What is clear is that the current symptom-based diagnostic criteria invite pathophysiological heterogeneity and ensure that “effective” treatments are likely to offer only marginal gains over placebo. Clinicians often take these modest therapeutic gains over placebo to mean that drugs are ineffective. On the contrary, if one considers drugs which target a specific pathophysiologic pathway (for example: serotonin, chloride channels, guanylate cyclase and colonic bile acid concentrations etc.) as biological probes, results from methodologically rigorous RCTs provide insight into the proportion of patients whose symptoms are likely to be related to that pathophysiological abnormality. Future research should focus on not only the development of novel treatments but also bio-markers which provide insights into pathogenesis and treatment response.
Fig. 1. Chloride channel activation in the treatment of constipation. Reprinted from Menees et al with permission from Macmillan Publishers Ltd. ClC-2, type-2 chloride channel; CFTR, cystic fibrosis transmembrane regulator; GC-C, guanylate cyclase-C; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate.
Fig. 2. The use of bile acids to treat constipation. Normally, bile acids are removed from the ileum via transporters to the liver as part of enterohepatic circulation, leading to reduced concentrations of bile acid reaching the colon and decreased colonic motility. Elobixibat inhibits the uptake of bile acids in the terminal ileum, which increases luminal concentration and improves colonic motility. Chenodeoxycholic acid is a bile acid analogue that increases the concentration of bile acid in the gut and promotes colonic motility. Modified from Menees et al with permission from Macmillan Publishers Ltd.
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