Recent advances in understanding and managing chronic constipation

Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease (for example, colon cancer), current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents (such as secretagogues, pro-kinetics, inhibitors of bile acid transporters and ion exchangers). However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents.


Background
Symptoms of constipation are reported by 10% to 20% of adults worldwide 1 . Classically, the term "constipation" refers to infrequent bowel motions or hard feces. However, the disorder is heterogeneous; patients report a variety of symptoms including reduced bowel motion frequency, straining, hard stools, the sensation of incomplete emptying, the sensation of anal blockage, or the use of digitation or positioning to aid defecation (Box 1) 2 . In affected individuals, physical health, mental health, and social functioning are reduced 3,4 . Despite this, only one-fifth of constipated individuals seek health-care advice 5 . Yet, given the high prevalence of this condition, this represents over 8 million health-care visits 6 and $230 million in costs 7 annually in the United States.

Box 1. Diagnostic criteria for functional constipation
Two or more of the following must be present I. Straining during more than one-fourth (25%) of defecations II. Lumpy or hard stools (Bristol Stool Form Scale 1-2) in more than one-fourth (25%) of defecations III. Sensation of incomplete evacuation in more than onefourth (25%) of defecations IV. Sensation of anorectal obstruction/blockage in more than one-fourth (25%) of defecations V. Manual maneuvers to facilitate more than one-fourth (25%) of defecations (for example, digital evacuation and support of the pelvic floor) VI. Fewer than three spontaneous bowel movements per week These criteria must be fulfilled for the previous 3 months. The symptom onset must be at least 6 months prior to diagnosis. In the absence of alarm features, constipation is seldom due to a life-threatening organic disorder (for example, colon cancer) or another disease (for example, hypothyroidism). Hence, guidelines recommend initial empiric therapy for constipated patients rather than investigating for a cause (for example, with colonoscopy) 8,9 . Likewise, although primary constipation generally results from slow colonic transit, impaired rectal evacuation, or both 8 , tests to evaluate these processes are recommended only in patients who do not respond to laxatives.

In addition
Slow colonic transit is associated with hard stools 10 . Consequently, osmotic and stimulant laxatives are the two most commonly prescribed agents 11,12 . Osmotic laxatives (for example, polyethylene glycol or lactulose) retain water in the intestinal lumen, accelerating colonic transit and reducing the consistency of evacuated stool. Stimulant laxatives (for example, senna, bisacodyl, or glycerin) stimulate colonic contractions and the urge to defecate. Although laxatives increase bowel motion frequency 13 , satisfaction is variable 14 . In an internet-based survey of 1,355 patients with self-reported constipation in 10 European countries in 2009, 855 patients were taking laxatives. Of these patients, 28% were very satisfied or satisfied with their treatment, 44% were neutral, and 28% were dissatisfied with therapy. In particular, the symptom of bloating persists 15 . Conceptually, satisfaction may be suboptimal because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. In particular, a substantial proportion of constipated patients have a defecatory disorder that may be associated with normal or slow colonic transit. Defecatory disorders are more appropriately treated with pelvic floor biofeedback therapy than with laxatives [16][17][18] .

Advances in understanding the molecular pathophysiology of constipation
Abnormalities of ion channels within the intestine have been shown to affect secretion, absorption, motility, and sensation, potentially resulting in constipation, diarrhea, and irritable bowel syndrome (IBS) 19 . The presence of these dysfunctional channels may be suggested by a family history of a functional bowel disorder 19 . Documented "channelopathies" include those affecting the voltage-gated sodium channel Na V 1.5, present on smooth muscle cells; the voltage-gated sodium channels Na V 1.7 and Na V 1.9, present on neurons; and ion exchange channels, present on enterocytes 19 . Altered ion channel expression or function occurs because of genetic mutations, posttranslational modification, or accessory protein malfunction.
In particular, the voltage-gated sodium channel Na V 1.5 has been associated with constipation 20 . In one study, mutations, predominantly resulting in loss of function, were found in 7% of patients (4 out of 59) with constipation-predominant IBS (IBS-C) 20 . Further studies are necessary to determine whether these mutations were responsible for the bowel symptoms.
In selected studies, about one in four patients with diarrheapredominant IBS has high concentrations of fecal bile acids 21 .
Conversely, a small fraction (that is, about 6%) of patients with IBS-C have low fecal concentrations of bile acids 22 . It is unclear to what extent these findings represent a primary disturbance (that is, due to reduced secretion or increased reabsorption or both) or are secondary to slow colon transit. Nonetheless, because bile acids stimulate colonic secretion of water and high-amplitude-propagated contractions 23,24 , it is hypothesized that a paucity of colonic bile acids may cause constipation. Indeed, the corollary is also true: excess bile acid administered orally 24 or modification of the enterohepatic recycling pathway 25 can exert a laxative effect.

Normal and abnormal colonic and anal structure and function
Defecation is an intricate viscerosomatic process 26 , and the pathophysiology of defecatory disorders is heterogeneous. A clinical history is insufficient for differentiating the subtypes of constipation 27 . A detailed digital rectal examination 28 may suggest the presence of manometric features of a defecatory disorderpositive predictive value (PPV) of 97% and negative predictive value (NPV) of 37%-but is less useful for predicting an abnormal rectal balloon expulsion test (PPV of 33% and NPV of 65%) 29,30 . Indeed, agreement among anorectal tests is variable, perhaps partly because they assess different aspects of structure or function or both 31,32 . Consequently, the Rome criteria recommend that when standard empiric laxative therapy fails to provide relief for patients with constipation, defecatory disturbances be documented with two tests 32 . However, where manometry or defecography is not available, a digital rectal examination and balloon expulsion test are sufficient for screening.
A detailed rectoanal manometry and rectal balloon expulsion test can provide information regarding rectoanal neuromuscular functions 33 . Relative to water-perfused manometry, highresolution manometry is simpler to perform 34 . However, in clinical practice, the incremental utility of high-resolution manometry above water-perfused manometry is unclear 33 .
In contrast to high-resolution anorectal manometry, highdefinition anorectal manometry provides a three-dimensional evaluation of pressures within the anal canal. To date, relatively small studies suggest that high-resolution and high-definition anorectal manometry have similar performance characteristics for evaluating anorectal disorders 35,36 . In high-definition anorectal manometry, similar to high-resolution anorectal manometry, 70% of healthy individuals exhibit a dyssynergic manometry pattern during simulated evacuation 36 . More recent studies observed that both high-resolution and high-definition anorectal manometry can identify rectoceles, intra-anal intussusception, and rectal prolapse 37-40 . However, whether these techniques will augment or supplant defecography, or fall by the wayside, for diagnosing these conditions has yet to be determined.
Within the colon, high-resolution manometry is better than standard water-perfused manometry for visualizing propagated colonic contractions 41 . While high-resolution colonic manometry remains primarily a research tool, attempts are being made to incorporate these data into clinical practice. For example, among 18 pediatric patients with slow transit constipation and six children with normal transit constipation, manometric findings were predictive of neuropathy with a sensitivity of 100% and a specificity of 86% 42 .
Radiological tests are also useful for evaluating anorectal and colonic functions. Barium defecography is used to exclude or diagnose rectoceles and pelvic organ prolapse causing obstructed defecation. Magnetic resonance imaging (MRI) defecography offers a radiation-free alternative. Furthermore, it provides a comprehensive evaluation of pelvic organ structure and function during defecation without the need to instill radiopaque material into the small bowel, bladder, or vagina. With the exception of internal intussusception 43

Development of novel therapeutic agents for the treatment of constipation
A few medications that selectively target intestinal secretion or motility are available. Serotonin receptor agonists have been used to accelerate intestinal transit. Activation or inhibition of intestinal ionic transporters can increase luminal fluid content and accelerates the rate of colonic transit. Inhibition of ileal bile acid transporters exposes the colon to a greater concentration of these ionic detergents, resulting in the secretion of water into the colonic lumen and accelerated colonic transit.
Prucalopride is a selective, high-affinity, 5-HT (4)  Intestinal chloride channel activators: lubiprostone, linaclotide, and plecanatide The secretion of ions, and thereby fluid, into the intestinal lumen through ion channels can be pharmacologically driven by lubiprostone, linaclotide, and plecanatide. Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) on the apical surface of enterocytes results in chloride secretion into the intestinal lumen, which is followed by a net secretion of sodium and subsequently water 82 .
Linaclotide and plecanatide are uroguanylin analogs that activate cell-surface guanylate cyclase-C receptors on enterocytes, inducing translocation of the CFTR to the apical surface of the cell. Initial studies of linaclotide demonstrated a dose-dependent increase in colonic transit with an associated increase in bowel motion frequency and consistency and reduced straining scores in patients with IBS-C 89 100 . These patients reported a median satisfaction score for treatment of 4.0 (quite satisfied) and were "quite likely" to continue the medication. Animal models suggest that plecanatide, similar to linaclotide, also reduces visceral sensitivity 101 , and phase 3 trials in patients with IBS-C have demonstrated a significant improvement in bowel motion frequency, stool consistency, and abdominal pain above that seen with placebo 102 . Sustained response with the 6 mg dose of plecanatide was seen in 30% of patients in the first study (placebo response 18%, p <0.001) and 24% in the second trial (14% placebo response, p <0.001) 102 . Additional CFTR activators (CFTRact-J027 and its derivatives) have demonstrated efficacy for treating constipation in mouse models 103,104 .
Modifiers of bile acid recycling and synthesis: elobixibat and NGM282 Elobixibat (A3309) is the first-in-class ileal bile acid transporter inhibitor 105 . Inhibiting the absorption of bile acids from the ileum exposes the colonic mucosa to a higher concentration of these ionic detergents. This accelerates colonic transit, increases stool frequency, and potentially relieves the symptoms of constipation 23,24,106 . In a randomized phase 2b trial, 190 patients with chronic constipation received 5, 10, or 15 mg of elobixibat or placebo once daily for 8 weeks. The times to the first spontaneous bowel motion and CSBM were significantly shortened in the 10 and 15 mg groups. Stool frequency and constipation-related symptoms were significantly improved 107 . A phase 3 trial confirmed the efficacy of elobixibat for the treatment of chronic constipation but demonstrated that adverse drug reactions occur in up to half of patients 108 . These are usually mild abdominal pain or diarrhea. Though approved for clinical use in Japan, elobixibat is not currently approved for use by the EMA or the FDA.
In patients with functional constipation, the fibroblast growth factor 19 analog NGM282 accelerated gastric and colonic transit, resulting in an increased number of bowel movements, looser stool form, and increased ease of stool passage 25 . The rationale for this study was the observation that NGM282 induced diarrhea in phase 2 trials relating to type 2 diabetes, primary biliary cholangitis, and non-alcoholic steatohepatitis. However, NGM282 is a potent inhibitor of bile acid synthesis, and in this study, in contrast to the effect of elobixibat, bile acid concentration in stool was reduced. Further physiological studies are needed to elucidate how NGM282 exerts its effects.
Sodium/hydrogen exchanger inhibitors: tenapanor Tenapanor (AZD1722) is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3. It inhibits the absorption of dietary sodium and phosphate, which increases intestinal fluid volume and transit 109 . The effect is more pronounced when tenapanor is administered pre-meal 110 . A phase 2 randomized placebocontrolled trial of 356 patients-87% women, mean ± standard deviation (SD) of 46 ± 13 years-with IBS-C demonstrated a CSBM responder rate of 61% with tenapanor 50 mg twice a day as compared with 34% in the placebo group (p <0.001). Additionally, abdominal pain was significantly reduced in the tenapanor group 111 . The most common adverse events were diarrhea, headache, nausea, urinary tract infection, and abdominal pain. Diarrhea occurred in 9% of patients and resulted in medication cessation in 3%. Of note, data regarding the effect of tenapanor on hyperphosphatemia in patients with chronic kidney disease, which encompassed an older patient cohort (mean ± SD of 59 ± 14 years), demonstrated a similar side effect profile 112 . Thereafter, two phase 3 trials in IBS-C, each with about 600 patients treated for 12 and 26 weeks, have been reported. In the first phase 3 trial, tenapanor met its primary endpoint (combined pain and stool pattern responder rate of 27% versus 19% with placebo, p = 0.02) 113 . Significance was met for the secondary endpoint of abdominal pain relief but not for the CSBM endpoint. In the second study, tenapanor met all primary and secondary endpoints 114 ; the company plans to submit an application to the FDA in the second half of 2018. Tenapanor is not licensed by the EMA.
New but not necessarily better Although these new agents are efficacious, only two studies have directly compared the clinical efficacy of newer and older laxatives. The first study compared polyethylene glycol with tegaserod, which has since been withdrawn from the market, in a randomized open-label, parallel-group study of 237 patients. Polyethylene glycol was better for improving symptoms of constipation. In the second, a randomized, double-blind, double-dummy study of 240 patients with chronic constipation, polyethylene glycol with electrolytes was compared with prucalopride 115 . Polyethylene glycol with electrolytes was noninferior to prucalopride for promoting more than three CSBMs per week and was better tolerated.
Indeed, a network meta-analysis comparing prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, bisacodyl, and sodium picosulfate was undertaken, albeit with limited data for some medications, and observed that these drugs were of comparable efficacy for the endpoints of at least three CSBMs per week or an increase over baseline of at least one CSBM per week. Bisacodyl was superior to the other agents for inducing a greater change from baseline in the number of spontaneous bowel motions per week 116 .
Furthermore, the newer laxatives are much more expensive than the older, over-the-counter agents. In the United States, a 30-day supply of lubiprostone, linaclotide, or plecanatide costs about $450. By comparison, a 30-day supply of psyllium, polyethylene glycol, bisacodyl, or senna costs less than $10, whereas lactulose costs less than $15.

Optimizing therapy and the potential role for individualized treatment of constipation
Consensus guidelines recommend that pelvic floor biofeedback therapy, not laxatives, is the cornerstone for managing defecatory disorders 8 . However, none of the pharmacological studies described above rigorously evaluated anorectal function and excluded patients with defecatory disorders. Therefore, the relative efficacy of these drugs in patients with isolated normal or slow transit constipation is unknown.
Where constipation does not respond to empiric therapy and a defecatory disorder has been excluded, investigation could guide tailored therapy. For example, the 5-HT(4) receptor agonist prucalopride might be a preferential choice for patients with diffusely slow intestinal transit. Ileal bile acid transporter inhibitors could be of benefit for constipated patients with a deficiency of bile acids reaching the colon. A single case report observed that mexiletine normalized bowel functions in a patient with IBS-C and a mutation in the SCN5A gene, which encodes the alpha-subunit of the voltage-gated sodium channel Na V 1.5 20 .
Future studies should evaluate the efficacy of novel and standard laxatives in patients with defined normal or slow transit constipation and the efficacy of targeted therapy (for example, with ileal bile acid transporter inhibitors in constipated patients with a deficiency of bile acids reaching the colon).

Summary and conclusions
Constipation is common, but the underlying pathophysiology remains unclear in many cases. Many patients can be effectively and inexpensively treated with simple laxatives. Newer intestinal secretagogues and promotility agents are more expensive and should be considered in patients who do not respond to simple laxatives. A few new agents are being evaluated in clinical trials. There is a critical need to compare the efficacy of these newer agents relative to established laxatives and also clarify their efficacy in the subtypes of constipation (that is, normal transit, slow transit, and defecatory disorders).

Grant information
This work was supported in part by US Public Health Service National Institutes of Health grant P01 DK68055.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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