Current Gastroenterology Reports

, Volume 14, Issue 4, pp 306–312

Recent Advances in the Management of Difficult Constipation

Authors

    • Division of Gastroenterology & HepatologyDartmouth-Hitchcock Medical Center
  • John Levenick
    • Division of Gastroenterology & HepatologyDartmouth-Hitchcock Medical Center
  • Michael Crowell
    • Division of GastroenterologyMayo Clinic Scottsdale
Neuromuscular Disorders of the Gastrointestinal Tract (A Foxx-Orenstein, Section Editor)

DOI: 10.1007/s11894-012-0269-1

Cite this article as:
Lacy, B.E., Levenick, J. & Crowell, M. Curr Gastroenterol Rep (2012) 14: 306. doi:10.1007/s11894-012-0269-1

Abstract

Constipation is a highly prevalent disorder. Some patients suffer from acute, intermittent episodes of constipation. Others, however, suffer from chronic constipation, a term that refers to those patients with symptoms of constipation for more than 6 months. In clinical practice, chronic constipation is often used interchangeably with the term functional constipation, which is currently defined using the Rome III criteria. Symptoms can be burdensome, leading to a reduction in patients’ quality of life. In addition, chronic constipation is important because it imposes a significant economic impact to the health care system. Some patients with chronic constipation have persistent symptoms despite implementing lifestyle changes and using either over-the-counter agents or prescription medications. These patients may be categorized as having difficult constipation. This report will focus on recent advances in the management of difficult constipation, and include a discussion of new and upcoming medications as well as new diagnostic tests and procedures.

Keywords

Anorectal manometryConstipationDefecographyGuanylate cyclaseLinaclotidePrucaloprideRome criteriaSacral nerve stimulationWireless motility capsule

Introduction

Many patients are occasionally troubled by symptoms of mild, acute constipation, meaning that they may skip a day without having a bowel movement or have symptoms of hard stool or excess straining. These patients rarely come to the attention of the medical community and generally self-medicate with changes in diet, lifestyle and/or the use of over-the-counter agents. Other patients, however, have chronic symptoms of constipation, meaning symptoms that have been persistent for more than 3 months and that developed at least 6 months earlier. These patients fall into a completely different category, as chronic constipation has been shown to significantly affect patients’ lives. A recent study estimated the prevalence of chronic constipation in the US to be approximately 15 % [1]. Although considered to be nothing more than a nuisance by some providers, chronic constipation is an important health care issue because multiple studies have demonstrated that chronic constipation reduces patients’ quality of life and imposes a significant economic burden to the health care system [28,9•]. The significant economic costs associated with treating chronic constipation arise due to both direct costs, as well as indirect costs (e.g., absenteeism and presenteeism). One large survey study found that annual health care costs for patients with chronic constipation were $7,522—nearly 50 % higher than for patients with IBS ($5,049; [10]). A recent study found that direct medical costs of patients with chronic constipation were double those of controls over a 15-year period ($63,591 vs. $24,529; [11]).

Chronic and Difficult Constipation Defined

Although the definition is not new, it is important to mention the current Rome criteria for chronic (functional) constipation [12]. The Rome III criteria defines functional constipation as active symptoms within the last 3 months with symptom onset at least 6 months previously, in addition to the presence of at least 2 other symptoms during 25 % of defecations (e.g., stool frequency of < 3 per week, straining at stool, feelings of incomplete evacuation, the need for digital manipulation, and rectal pressure or pain). As well, patients cannot meet Rome III criteria for IBS.

Although the term “difficult constipation” is frequently used by clinicians and researchers, a formal definition does not exist. For the sake of this article, we will define the patient with difficult constipation as one who has persistent symptoms of chronic (functional) constipation despite appropriate lifestyle changes and medical management. We will review new diagnostic tests for the evaluation of the patient with difficult constipation and also review new and upcoming treatment options. In the interest of space, management of the difficult to treat IBS with constipation patient will not be reviewed.

New Diagnostic Tests

The FDA approved the wireless motility capsule (SmartPill Corporation, Buffalo NY) in 2006. The wireless motility capsule is similar in size to a video capsule (27 × 12 mm). This single-use capsule contains sensors to measure temperature (range of 25–49 degrees C), pH (range of 0.05 to 9.0 pH units), and pressure (range of 0–350 mm Hg). Transit time throughout the entire gastrointestinal tract (GI) tract can be measured (also called whole gut transit time), as can individual components of whole gut transit, including gastric emptying, small bowel transit, and colonic transit. Two recent studies involving the wireless motility capsule are worth mentioning. The first study compared the wireless motility capsule to radiopaque markers (ROMs) in the evaluation of regional and colonic transit time (CTT) in healthy volunteers (n = 87) and patients with constipation (Rome II criteria; n = 78). After an overnight fast, patients ingested a standard nutrient bar, followed by a single Sitzmark capsule (containing 24 markers) followed by a wireless motility capsule. Rao and colleagues found that the correlation coefficient between CTT using the wireless motility capsule and the ROM test on day 5 was r = 0.59 for the entire group [13]. It was somewhat better in constipated subjects (r = 0.69) and worse in healthy volunteers (r = 0.40). The sensitivity and specificity for identifying abnormal colonic transit in patients with constipation was 0.46 and 0.95 respectively. A second prospective, multicenter trial compared colonic transit measurements using radiopaque markers to the wireless motility capsule [14•]. This study involved 158 patients (87 % women; mean age = 43 years) with symptomatic constipation, and was designed to demonstrate equivalence between the two different tests. The authors reported that the percent positive agreement between the two studies (both with evidence of delayed transit) was 80 %. The percent negative agreement between the two studies (both studies showed no evidence of impaired colonic transit) was 91 %.

In summary, these two studies demonstrate that the wireless motility capsule provides a reliable measure of both colonic and whole gut transit. It appears to be as good as the radiopaque marker study, though it is more expensive and requires specialized technology that is available currently at only a small number of medical centers. Future research is needed to assess the clinical utility of this new technique in patients with difficult constipation.

High Resolution Anorectal Manometry

High-resolution anorectal manometry (HRAM) is a new diagnostic technique used to evaluate anorectal function and physiology. The catheters are similar in many respects to High-resolution esophageal manometry catheters, meaning that each catheter contains multiple radial sensors (12–36 on average, spaced 1 cm apart); for the HRAM catheter, a rectal balloon is also present. During the study, multiple sensors are positioned across the anal canal, while two are contained within the rectal balloon. Standard measurements can be taken at rest, during voluntary contraction, during straining, and during rectal balloon distensions. Although published several years ago, one study is worth mentioning because it compared simultaneous standard water perfused anorectal manometry to HRAM [15•]. In this study of 29 patients referred for anorectal manometry, HRAM provided greater resolution of intraluminal pressures compared to standard manometry.

Recently, a new technology has become available that provides dynamic vector analysis of the anal canal using a novel 3-D high-resolution anorectal manometry system (Motility Visualization System v.2.2, Sierra Scientific). The system uses 256 circumferential arrayed pressure sensors arranged longitudinally along the length of a rigid carrier that provides assessment of anal pressure profiles topographically in three dimensions. Future studies are needed to determine whether HRAM should become the standard of care in all motility laboratories for patients with persistent symptoms of constipation thought to have a pelvic floor disorder.

Magnetic Resonance Defecography

Over the last several years magnetic resonance (MR) defecography has gradually supplanted barium defecography as the test of choice to evaluate both anatomical and functional anorectal function. MR defecography has the added benefits of not exposing patients to radiation, provides better images of perineal descent (since bony landmarks are not obscured with barium), and provides some information on the anatomy of the bladder and vagina [16]. Two recent studies evaluated the clinical usefulness of MR defecography. The first study involved 48 patients with symptoms of constipation who were subdivided into those with dyssynergic defecation (n = 18; 9 women; mean age = 46 years) and those without dyssynergic defecation (n = 30; 5 men; mean age 56 years; [17•]). Two separate radiologists independently read all images. Images were measured and scored with regard to evacuation ability, changes in the anorectal angle, the presence of paradoxical sphincter contraction (marked impression of the puborectalis on the posterior rectal wall identified), time to initiate evacuation, and time of evacuation. A priori the presence of impaired evacuation ability was defined as the inability to expel any rectal contrast, or less than two-thirds of the rectal contrast, within 60 seconds. The authors found that impaired evacuation of rectal contrast was present in 100 % of patients with dyssynergic defecation, compared to 77 % of those without (p = 0.04). In those patients with dyssynergic defecation that could evacuate some contrast, evacuation time was prolonged (> 60 seconds) in all patients, compared to 73 % of the control (non-dyssynergic) group (p < 0.001). Lastly, paradoxical sphincter contraction was observed in 83 % of the dyssynergic defecation group, compared to 13 % of the control (non-dyssynergic) group (p < 0.0001). Although the study was limited by its size, it is important in that it demonstrates that MR defecography can identify key functional and structural abnormalities in patients with dyssynergic defection, and that these abnormalities are more prevalent in patients with dyssynergic compared to those patients with functional constipation without dyssynergia.

The second study involved a retrospective review of 83 patients (72 women; mean age = 53 years) who underwent dynamic MR defecography with the specific goal of determining whether evaluation of the defecation phase added any additional benefit compared to the rest, squeeze, and strain phases [18]. Images were performed with an open-configuration MRI system; a previously published grading system was used to assess images at rest, and during squeezing, straining, and defecation. The authors reported that defecation phase images provided new information that aided in the identification of abnormal rectal descent in 12.9 % of cases, in abnormal vaginal descent in 61.2 % of cases, and in abnormal bladder descent in 50.6 % of cases. Although defecation phase images are standard in most MR suites, this is the first study to specifically evaluate this portion of the study and determine its clinical usefulness.

New and Upcoming Treatment Options

Prucalopride

Prucalopride warrants mention because it is now approved for use in the European Union and there is interest in obtaining approval for use in the United States. Prucalopride is an orally administered dihydrobenzofurancarboxamide derivative shown to be a potent, selective, high-affinity agonist at 5-HT4 receptors. The safety and efficacy of prucalopride has been evaluated in three large studies [19,20,21•]. All 3 studies were 12 weeks in duration and were similar in design—multi-center, randomized, double-blind, placebo-controlled, and parallel group. Patients entered the study if they had symptoms of chronic constipation (e.g., two or fewer complete spontaneous bowel movements (CSBM) each week for a minimum of 6-months before the screening visit, as well as very hard or hard stools, or straining with at least 25 % of bowel movements). Although not strictly defined as having difficult constipation, nearly all likely did, given that most if not all had failed standard therapy. Patients were randomized to once daily prucalopride (2 or 4 mg) or placebo and the primary efficacy endpoint was the proportion of patients having three or more spontaneous, complete bowel movements per week, averaged over the 12-week period. The data are summarized in Table 1. In the Camilleri study [19] the primary endpoint (3 or more CSBM/week) was reached by 31 % of those on 2 mg of prucalopride, 28 % of those on 4 mg, and 12 % of those on placebo (p < 0.001 for both study groups). In the Tack study [20], patients treated with prucalopride were more likely to rate their treatment as quite effective or extremely effective (35—36 %), compared to placebo (19 %; p < 0.001). The third study was a multicenter trial involving 41 sites (20). Patients treated with prucalopride were more likely to rate their treatment as effective compared to those treated with placebo (37–39 % vs. 20 %; p < 0.001). Adverse events were what is expected in a constipation trial, primarily that of diarrhea.
Table 1

Summary of prucalopride phase III clinical trials

 

Dose

Camilleri [19]

Tack [20]

Quigley [21•]

% Women

 

88 %

90.8 %

86.6 %

Mean age (years)

 

48.3

43.9

47.9

Mean duration of symptoms (years)

 

21.1

17.5

22.0

Total Randomized

 

628

720

651

Total Completed

 

534 (85 %)

597 (83 %)

567 (89 %)

Total Evaluated

 

620

713

641

 

Placebo

209

240

212

 

2 mg

207

236

214

 

4 mg

204

237

215

Mean CSBM/week (at baseline)

 

0.4 - 0.5

0.4-0.5

0.4-0.5

> 3 CSBM/week

Placebo

12 %

9.6 %

12.1 %

 

2 mg

30.9 %^

19.5 %#

23.9 %#

 

4 mg

28.4 %^

23.6 %^

23.5 %#

Increase in >1

Placebo

25.8 %

20.9 %

27.5 %

CSBM/week

2 mg

47.3 %^

38.1 %^

42.6 %^

 

4 mg

46.6 %^

44.1 %^

46.6 %^

Median time

Placebo

12.6

20.5

13.0

To 1st CSBM

2 mg

1.3^

4.7^

2.3

(in days)

4 mg

1.0^

2.1^

1.9

Note: *p < 0.05; #p < 0.01; ^p < 0.001

In the study by Camilleri and colleagues [19] no patient in the placebo group stopped the medication due to diarrhea, although 1.5 %–4.4 % of prucalopride patients discontinued the medication due to diarrhea (2 mg and 4 mg doses, respectively). In the Tack study, discontinuation of the study medication due to AEs) was reported in 6.7 % of placebo-treated patients, compared to 6.3 % of patients treated with 2 mg of prucalopride and 15.1 % treated with 4 mg of prucalopride [20]. None of the studies found any differences among the three groups with respect to serum chemistries, urinalyses, vital signs, EKG findings, or hematologic findings [19,20,21•].

In summary, prucalopride improves symptoms of constipation and appears to be safe. It remains to be seen whether the FDA will approve this medication, given its mechanism of action, and the FDA’s concern about cardiovascular safety in 5-HT4 agonists. However, a just published comprehensive review on the safety of 5-HT4 agonists should be reassuring [22••].

Linaclotide

Linaclotide is a 14-amino acid peptide that stimulates intestinal guanylate cyclase type-C (GC-C) receptors (see Fig. 1; [23]). Linaclotide is acid stable and protease resistant with low bioavailability; it is undetectable in the systemic circulation at therapeutic doses. Activation of GC-C stimulates the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), which then increases the flow of electrolytes (HCO3- and Cl-) and water into the lumen of the GI tract (see Fig. 1). This is associated with faster GI transit. Stimulation of the GC-C receptor on intestinal epithelial cells and release of cGMP into the serosa leads to a reduction in visceral hyperalgesia [23].
https://static-content.springer.com/image/art%3A10.1007%2Fs11894-012-0269-1/MediaObjects/11894_2012_269_Fig1_HTML.gif
Fig. 1

Proposed mechanism of action of linaclotide

Johnston and colleagues were the first to investigate the safety, tolerability, and efficacy of linaclotide in patients with CC who met modified Rome II criteria [24]. This multicenter, placebo-controlled pilot study published in 2009, showed that there was a trend towards a dose-dependent increase in the frequency of weekly spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs). Stool consistency, straining, and patient reported outcomes also improved in all dosing groups.

These promising results led to a larger multicenter, placebo-controlled study involving 310 CC patients defined by modified Rome II criteria [25]. Patients were randomized to one of four linaclotide dosages (75, 150, 300, or 600 μg) or placebo once daily for 4 weeks. The primary end point was the change in mean weekly SBM frequency from the 14-day pre-treatment period to the 4-week treatment period. Patients were also analyzed using a responder definition of a weekly SBM > 3 and an increase of > 1 relative to baseline, for 3 of the 4 treatment weeks. Secondary endpoints included changes in stool consistency, straining, abdominal discomfort, and bloating (see Table 2). Lembo and colleagues noted that the frequency of weekly SBMs increased significantly in a linear response to increasing dosages of linaclotide (2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 μg, respectively), compared to 1.5 for placebo (p < 0.05 for each linaclotide dosage group compared to placebo). The median time to first SBM, mean number of CSBMs, stool consistency, and severity of straining also demonstrated a significantly improved dose-dependent relationship compared to placebo. No rebound effect occurred during a 14-day post-treatment surveillance period. Adverse events were reported in 33.8 % of patients receiving the study drug and 31.9 % of placebo (n.s.). The most commonly reported AEs were GI related, of which diarrhea was the most frequent, 5.1 %–14.3 %, versus 2.9 % of placebo patients. Only two cases of diarrhea were graded as severe, both were in the 600 μg group and both resulted in cessation of treatment.
Table 2

Summary of linaclotide clinical trials in chronic constipation

 

Lembo 2010 [25]

Lembo 2011 [26••]

 

Trial 01*

Trial 303*

% Female

92 %

90 %

87 %

Mean age (years)

47

48

Total Randomized

310

630

642

Total analyzed

307

630

642

Mean CSBM/week (baseline)

0.4

0.3

0.3

Mean SBM/week (baseline)

2.3

1.9

2.0

CSBM/week

Placebo 0.5

Placebo 0.6

0.5

75 μg 1.5

145 μg 2.0c

1.9c

150 μg 1.6a

290 μg 2.7c

2.0c

300 μg 1.8b

  

600 μg 2.3a

  

SBM/week

Placebo 1.5

Placebo 1.1c

1.1c

75 μg 2.6a

145 μg 3.4c

3.0c

150 μg 3.3a

290 μg 3.7c

3.0c

300 μg 3.6b

  

600 μg 4.3b

  

ap ≤0.01; bp ≤ 0.001; cp < 0.0001; * 12 week data

note that SBM & CSBM frequency is reported as a change from the 14-day baseline

The most recent report on linaclotide describes data from two parallel, randomized, placebo-controlled, double-blinded trials using either 145 μg or 290 μg linaclotide or placebo over 12-weeks in 1272 patients with CC [26••]. Trial 01 consisted of 630 patients while trial 303 consisted of 642 patients (median age 48; 89 % female). The primary endpoint of both trials was defined a priori as both three or more CSBMs/week and an increase of at least one CSBM/week from baseline for at least 9 out of the 12 weeks. Secondary endpoints included measurements of stool frequency, stool consistency, severity of straining, abdominal discomfort, bloating, and overall constipation severity. The authors reported that once daily linaclotide produced early and sustained improvement in bowel and abdominal symptoms, SBMs, and CSBMs within the first week of treatment. For the 12-week study period the primary end point (12-week CSBM overall responder for ≥ 9 of 12 weeks) was met in both trial 01 (16.0 %, 21.3 % vs. 6.0 % for placebo, p = 0.0012 and p < 0.0001) and 303 (21.2 % and 19.4 % vs. 3.3 %, p < 0.0001). These benefits remained when the data were pooled and analyzed for weeks 1 through week 12. Secondary endpoints including CSBMs/week, SBMs/week, stool consistency, straining, constipation severity, abdominal discomfort, and bloating were superior to placebo and statistically significant in both studies for each dose of linaclotide (see Table 2). Trial 303 included a randomized 4-week withdrawal study that included 538 of the 642 patients. A rebound effect was not found during the withdrawal period, and patients initially treated with placebo and then randomized to linaclotide noted results similar to those initially treated with linaclotide. Quality of life assessments, using the PAC-QOL instrument, showed an improvement in patients treated with linaclotide compared to those treated with placebo (p < 0.01). The authors reported one death in this study—it occurred due to an overdose of fentanyl and was not thought related to the study drug. Discontinuation rates due to AEs were 4.2 % in placebo-treated patients, compared to 7.9 % in patients treated with 145 ug linaclotide and 7.3 % in those treated with 290 ug of linaclotide. Discontinuation of the study medication and AEs were primarily GI—related (e.g., diarrhea, flatulence, and abdominal pain). No clinically significant differences were found among the 3 groups with regard to EKG results, vital signs, blood chemistries, urinalysis, or hematologic findings. Although the strict definition for entrance into these studies was chronic constipation, using modified Rome II criteria, it is reasonable to assume that many of these patients had difficult constipation, and thus these findings are relevant for that population.

A3309

A3309 is a novel oral agent that inhibits the ileal bile acid transporter and consequently increases the flow of bile into the colon. It increases colonic transit, as demonstrated in a small study (Phase 1b) of patients with chronic constipation [27]. In a double-blind, placebo controlled study of 36 women with chronic constipation; 14 days of treatment with 20 mg of A3309 improved colonic transit at 24 hours and improved stool consistency [28]. Colonic transit at 48 hours was accelerated using both a 15 mg and 20 mg dose, compared to placebo (p = 0.002 and p < 0.001, respectively). Patients reported improvements in stool consistency and straining. Gastric emptying in patients treated with A3309 appeared to be slightly delayed compared to placebo, though this was not statistically significant. Adverse events including lower abdominal cramping and pain in 36–50 % of patients treated with A3309. Further trials are warranted to determine whether the efficacy can be maintained over a prolonged period of time, whether side effects are short-lived and/or tolerable, and whether this is another treatment option for patients with difficult constipation.

Sacral Nerve Stimulation

The first report of electrical stimulation to improve colonic motility was published in 1995 [29]. Since then, sacral nerve stimulation has been shown to induce pan-colonic antegrade propagating sequences and increase stool frequency in patients with both slow transit constipation and those with normal transit constipation resistant to standard therapy (i.e., the difficult constipation patient; [30,31]). In the multi-center prospective study by Kamm and colleagues, 45 of 62 patients (89 % women) noted a 50 % improvement in symptoms with a 3-week trial of stimulation, and then went on to chronic stimulation [31]. Of these patients, 39 (87 %) were considered to have a successful response (improvement in stool frequency, straining, and ease of evacuation) during a median follow-up period of 28 weeks. These encouraging results led Govaert and colleagues [32•] to review data gathered from two prospective studies performed at two tertiary care centers in Europe involving 117 patients with persistent symptoms of constipation who had failed dietary changes, medications, and biofeedback (90 % women; mean age = 45). The authors reported that 68 patients (58 %) had successful percutaneous nerve evaluation (PNE) during a 3-week trial period and progressed to the second part of the study, which involved an implantable sacral nerve modulator (SNM). Patients with normal colonic transit had a better response to percutaneous nerve stimulation than those with slow transit (76 % vs. 52 %; p = 0.048), and younger patients seemed to respond better than older patients. At one-year follow-up after placement of an SNM, 61 patients (52 %) of those initially evaluated continued to use SNM. Using the Wexner constipation score (0–30), these patients appeared to have an overall improvement in global constipation symptoms (Wexner score of approximately 9; n = 29) compared to baseline (Wexner score of approximately 18; n = 80). However, since Wexner scores were not obtained in those who failed PNE, and also not obtained in those who had the stimulator removed (n = 6), it is difficult to assess efficacy. This most recent study on the use of sacral nerve stimulation (or modulation) is intriguing, although larger, multi-center studies with clearly defined endpoints are needed to determine if this is a safe and efficacious therapy for the patient with difficult constipation.

Conclusion

Gastroenterologists and other specialists are frequently asked to consult on the patient with difficult constipation. The results from both medical and surgical research studies published over the last 1–2 years provide some hope that patients will find relief from their symptoms. Data from three large Phase III studies involving nearly 2,000 patients has clearly demonstrated that prucalopride improves symptoms of chronic constipation. This data, combined with recent studies that demonstrated the cardiovascular safety of 5-HT4 agonists, may ultimately lead to its approval in the US. The data from the linaclotide trials is exciting; it is currently under FDA review and should be available for use in the US in late 2012. Linaclotide’s mechanism of action is unique and the prospective, multicenter trials published to date show that it is efficacious at treating the multiple symptoms of constipation. Other medications hold promise; however, it will likely be several years before the results of large, prospective studies are available for review. Finally, sacral nerve stimulation and colonic stimulation may hold promise for those patients who fail medical therapy. These therapies are currently investigational only and need to be subjected to rigorous testing before they can be recommended for the patient with difficult constipation.

Disclosure

M. Crowell has been a board member for the American Journal of Gastroenterology, and a consultant for Ethicon, Inc and EndoStim, Inc; B Lacy is on the Scientific Advisory Board for Takeda and Salix; J Levenick reported no potential conflicts of interest relevant to this article.

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© Springer Science+Business Media, LLC 2012