Chronic Constipation

Abstract

Background: Chronic constipation is a common condition seen in family practice among the elderly and women. There is no consensus regarding its exact definition, and it may be interpreted differently by physicians and patients. Physicians prescribe various treatments, and patients often adopt different over-the-counter remedies. Chronic constipation is either caused by slow colonic transit or pelvic floor dysfunction, and treatment differs accordingly.
Methods: To update our knowledge of chronic constipation and its etiology and best-evidence treatment, information was synthesized from articles published in PubMed, EMBASE, and Cochrane Database of Systematic Reviews. Levels of evidence and recommendations were made according to the Strength of Recommendation taxonomy.
Results: The standard advice of increasing dietary fibers, fluids, and exercise for relieving chronic constipation will only benefit patients with true deficiency. Biofeedback works best for constipation caused by pelvic floor dysfunction. Pharmacological agents increase bulk or water content in the bowel lumen or aim to stimulate bowel movements. Novel classes of compounds have emerged for treating chronic constipation, with promising clinical trial data. Finally, the link between senna abuse and colon cancer remains unsupported.
Conclusions: Chronic constipation should be managed according to its etiology and guided by the best evidence-based treatment.

Introduction

The word "constipation" has varied meanings for different individuals. Although medical personnel define constipation as <3 bowel="bowel" movements="movements" per="per" style="font-size: 0.85em; line-height: 0;" sup="sup" week="week">[1,2]

 patients often equate constipation with stool consistency, feelings of incomplete emptying, straining, and urge for defecation.^[3,4] Furthermore, the normalcy of bowel habit ranges widely from 3 bowel movements per day to 3 per week,^[5] with a tendency to underestimate while self-reporting;^[6] hence, using defecation frequency alone may not be diagnostic of constipation. The Rome Foundation was established in 1991 by Drossman et al, primarily to standardize consensus-derived criteria of functional gastrointestinal disorder, and released the Rome III criteria in 2006 for constipation as having at least 2 of the following: (1) straining during ≥25% defecation; (2) lumpy or hard stools in ≥25% of defecation; (3) sensation of incomplete evacuation in ≥25% of defecation; (4) sensation of anorectal obstruction/blockage in ≥25% of defecation; (5) need for manual maneuvers to facilitate in ≥25% of defecation; and (6) fewer than 3 defecations per week.^[7,8] Also, patients should rarely have loose stools without laxatives and be distinct from having irritable bowel syndrome.^[8,9] For constipation to be defined as chronic, a patient must be symptomatic for at least 6 months with applicable criteria for the previous 3 months.^[3,9] Although the validity of the Rome III criteria for constipation has been recently questioned,^[10] with a known disparity between self-reported and criteria-based definitions,^[11] the use of colonic transit time^[12,13] and anorectal function tests^[14] as diagnostic tools is still controversial. In general, the prevalence of constipation among the general population in North America has been quoted as 1.9% to 27.2%,^[15,16] with 50% to 74% of the institutionalized elderly reporting daily use of laxatives.^[17,18] Women are 2 to 3 times more likely to have constipation than men in terms of prevalence^{[3,15,19–21]} and physical symptoms.^[15,20] Possible reasons include higher risk of injury to the pelvic floor from childbirth^[22] and the general willingness of women to report their symptoms and respond to surveys.^[23] Advanced age is also a risk factor for chronic constipation, with the largest increase in prevalence after the age of 70 years.^[15] This can be due to effects of medication, immobility, and blunted urge to defecate. In the United States, constipation accounts for 7 million physician visits per year^[24] and is among the top 5 outpatient gastrointestinal diagnoses.^[25] Annually, diagnostic workup for constipation averages US$3000 per patient,^[26] and it takes another US$4500 per person to provide treatment.^[27] In general, constipation has a significant impact on quality-of-life indicators irrespective of culture and nationalities,^[28] especially on the elderly.^[29] A recent systematic review showed that impairment caused by constipation as measured by Health-Related Quality of Life scores predominates in the mental health domains and is comparable to that caused by serious chronic conditions such as osteoarthritis and diabetes.^[30]

Etiology of Chronic Constipation

Extrinsic Factors Low fiber intake, inadequate hydration, reduced mobility as the result of general functional decline and institutionalization, reduced sensation of thirst, electrolyte disturbances (hypercalcemia, hypokalemia, hypermagnesemia), endocrine and metabolic disorders (eg, diabetes mellitus, hyperparathyroidism, hypothyroidism, chronic renal failure), neurological disorders (eg, dementia, Parkinson disease, neuropathies, multiple sclerosis, spinal cord injuries, cauda equine syndrome), psychological comorbidities (eg, depression, distress, personality disorders, or history of abuse), and concurrent medications (eg, anticholinergics, diuretics, β-blockers, opiates, iron supplements, calcium channel blockers, antidepressants, acetaminophen, aspirin and NSAIDs) all are said to contribute to chronic constipation, especially in the elderly.^[17,31–36] Among them, the trio of insufficient dietary fiber, fluids, and exercise has been widely ascribed,^[37] but in fact the evidence behind these 3 factors is inconsistent and of low to medium quality.^[38] (See Notes section: Diagnostic Approach for Chronic Constipation.) The association between smoking, alcohol, and body mass index with chronic constipation L131(BMI) is inconclusive.^[36,39]

Intrinsic Factors Normal defecation requires a series of orchestrated actions, starting with relaxation of the puborectalis muscles, descent of the pelvic floor with straightening of the anorectal angle, inhibition of segmental colonic peristalsis, contraction of the abdominal wall muscles, and finally, relaxation of the external anal sphincter with expulsion of feces. Intrinsic factors leading to chronic constipation can be broadly classified into 2 categories: pelvic floor dysfunction (PFD) and slow colon transit time (STC). A retrospective study reported the prevalence of PFD as 37% and STC as 23%,^[40] based on physiologic tests. However, a clear distinction between the two is often impossible, with an overlap of up to 55%.^[40,41]

Anorectal/PFD involves laxity of the pelvic floor muscles, impaired rectal sensation, and decreased luminal pressure in the anal canal and have been documented as causes for chronic constipation in the elderly, especially in women.^[42–44] On the contrary, paradoxical contraction of the puborectalis and external anal sphincter during defecation can lead to incomplete emptying^[45,46] or even functional outlet obstruction. Finally, anatomic anomalies (such as rectal wall prolapse or rectocele) or perineal damage (from traumatic childbirth or sacral nerve injury) can also distort the normal functions of the anorectal/pelvic floor unit.

STC is a poorly understood condition thought to be a cause of intractable constipation in children^[47] and young women.^[48] It is characterized by reduced high-amplitude propagated contractions^[49,50] in the colon, leading to slow transit of feces, bloating, abdominal discomfort, and infrequent defecation.^[51] The protracted time in the colon also renders the feces hard and small and fails to mount sufficient rectal pressure to trigger the defecation reflex.^[52] Often, the pressure required is found to be higher than in subjects with normal colonic transit.^[53]Various physiologic and histobiochemical findings have been postulated to explain the phenomenon of slow colonic transit: reduced cholinergic^[54,55] and enhanced adrenergic responses;^[55] mitigated gastrocolic reflex;^[56]dysynergy of rectosigmoid colonic activities;^[57,58] enteric neurodegeneration^[59] of both the myenteric plexus ganglia^[60,61] and the interstitial cells of Cajal;^[61,62] and abnormalities of enteric neurotransmitters such as substance P,^[63–65] vasoactive intestinal peptides,^[63,64] and nitric oxide.^[63,66]

Complications of Chronic Constipation

(1) Fecal incontinence: Overflow incontinence caused by fresh fecal matter bypassing the inssipated obstructing bolus^[67] may confuse the diagnosis of chronic constipation unless a rectal examination is performed. The odds ratio for developing fecal incontinence with chronic constipation is 1.7.^[68]

(2) Hemorrhoids: Prolonged straining and increase of intra-abdominal pressure raises the venous pressure in the plexus and ateriovenous anastomoses of the anorectal junction.^[69] The relative risk for development of hemorrhoids with constipation is up to 4.1.^[70]

(3) Anal fissure: Trauma and sudden tear of the anal mucosa during evacuation of hard stool is usually an initiating event, but spasm of the internal anal sphincter leading to relative ischemia is thought to be the perpetuating factor.^[69] It is estimated that anal fissure is 5 times more likely to develop with chronic constipation.^[70,71]

(4) Organ prolapse: Chronic constipation is a known risk for prolapse of pelvic organs such as the uterus, rectum, urinary bladder, and vagina^[72] and their recurrence.^[73] The odds ratio for having rectal prolapse is quoted as 2.3.^[68]

(5) Fecal impaction and bowel obstruction: Prolonged stasis of fecal matter leads to impaction and giant fecolith obstructing the large bowel, necessitating surgery.^[74,75] Retrospective analysis revealed a 5- to 6-times increased risk of fecal impaction resulting from chronic constipation.^[68,70,71]

(6) Bowel perforation and stercoral peritonitis: Extremely impacted feces (fecaloma) can compress the colonic wall, causing an ischemic ulcer^[76] and subsequent perforation,^[77,78] culminating in stercoral peritonitis^[78,79] and sometimes death.^[79] It is not a common condition; fewer than 90 cases have been reported in the medical literature from 1894 to 2006.^[80]

Diagnostic Approach and Investigations

It is important to conduct a detailed history and physical examination before proceeding with investigations. It is imperative to understand the patient's views and definitions of chronic constipation, which may often differ from medical criteria. The clinician should also weigh the cost-benefits of investigations and only order those that help diagnose the etiology of chronic constipation and affect the treatment and prognosis in such patients. A brief outline of the diagnostic approach for chronic constipation is given in the Notes section: Diagnostic Approach for Chronic Constipation. It must be emphasized that these investigations are not indicated as routine studies except for differentiating between slow colon transit time and pelvic floor dysfunction, in which treatment would differ. Moreover, contrast studies and colonoscopy should be considered if the patient has a positive family history of colon cancer or inflammatory bowel disease and presents with alarming complaints of rectal bleeding, abrupt weight loss, anemia, or change in bowel habits.

Evidence-based Management of Chronic Constipation

Methods A literature search of published medical reports in all languages was performed from PUBMED, EMBASE, and the Cochrane Database of Systematic Reviews from inception to October 2010 using the OVID Portal of Queen's University, Kingston, Ontario. Abstracts were initially obtained using key words of "chronic constipation," "treatment," and "trials." Manual searches of references and review articles supplemented the computerized search, and only full-length articles were considered. Two reviewers (L.L. and T.R.) worked independently and went over the initial search for abstracts that satisfied the key words as mentioned. They then adopted a simple form to select studies that satisfied the following 2 inclusion criteria: (1) involving human subjects over the age of 18 years and (2) describing at least 1 form of treatment for chronic constipation. Evaluation of selected studies was performed by each reviewer (L.L. and T.R.) regarding their quality and evidence according to the Strength of Recommendations Taxonomy (SORT),^[81] with levels of evidence from I to III and recommendations from A to C. Any disagreement was discussed and resolved among the reviewers to reach mutual consensus.

Results One hundred forty-five abstracts were identified by using key words of "chronic constipation" AND "treatment" AND "trials." Duplicates were removed, and, after imposing the selection criteria, only 62 relevant full-text articles were then retrieved for potential inclusion.^{[9,34,46,82–141]} They were deemed eligible on which mutual consensus was reached between the two reviewers (LL and TR). Additional consultation with the other two coauthors (WR and JK) was sought as required. The studies were then rated according to the SORT as below and summarized in the Notes section: Senna, Melanosis Coli, and Colon Cancer: Fact or Myth?

Lifestyle Modifications

Despite the fact that chronic constipation had been observed with deficiency in dietary fiber, fluids, or exercise, lifestyle modification to prevent or treat chronic constipation is still unsubstantiated.^[82,142] (See Notes section: Lack of Dietary Fiber, Fluid, and Exercises Will Cause Constipation: How True Is This?) However, such principles are widely disseminated to the public through pamphlets^[37] and practice guidelines (http://www.worldgastroenterology.org/assets/downloads/en/pdf/guidelines/05_constipation.pdf). Studies only report benefits if there is a lack of any of the three. Physicians and allied medical professionals should be aware of the evidence when advising their patients.

Biofeedback

For the PFD type of chronic constipation, biofeedback provides a retraining of the sensation and control of the anorectum and pelvic floor, thereby eliminating paradoxical contractions during the process of defecation. Its value has been shown both in uncontrolled trials^[93] and in recent randomized, controlled trials (RCTs)^[46,92,94] for improving both psychological and clinical outcome measures. There have been no reports of adverse effects for using biofeedback. As a result, the level of evidence and recommendation in using biofeedback for PFD type of chronic constipation is good except for the diversity of protocols and heterogeneity of trial designs.

Pharmacological Treatment

Medications for chronic constipation can be categorized into bulk-forming agents, stool softeners and emollients, osmotic agents, stimulants, chloride channel activators, 5-HT₄ receptor agonists, and guanylate cyclase-c receptor agonist.

Bulk-Forming Agents Bulk-forming agents are fiber supplements that expand with water to increase bulk of the stool and enhance bowel movements. Commercially available preparations include psyllium (ispaghula husks), calcium polycarbophil, methycellulose, and bran. Adequate fluid intake is a must for bulk-forming agents to work; lack of water enhances bloating and may paradoxically predispose to bowel obstruction. Among them, psyllium has superior efficacy in treating constipation, with at least 3 RCTs demonstrating benefits over placebo in improving colonic transit time and stool consistency.^[98–100] Two controlled trials reported the benefits of bran in reducing the use of laxatives in the elderly.^[102,103] In comparison, there is only 1 controlled trial for methylcellulose^[104] and a case series for polycarbophil^[105] supporting their clinical use. Bulk-forming agents are considered as first-line agents for chronic constipation, especially in patients with dietary fiber deficiency.

Stool Softeners and Emollients Docusate sodium is a commonly prescribed stool softener that has a detergent effect. Although there is no known study comparing its stand-alone efficacy against placebo, one double-blind randomized trial found docusate to be inferior to psyllium in chronic constipation.^[98] Another systematic review did show a small effect of docusate in increasing stool frequency in the chronically ill, but overall quality of evidence was poor. Hence, the recommendation for use of docusate sodium is only moderate. Mineral oil is an emollient used for its lubricating effect on stool, but no placebo-controlled, randomized trial has been reported. Aspiration and lipoid pneumonia is a known risk of using mineral oil in children^[143] and the elderly.^[144] The level of evidence for use of mineral oil is hence moderate. Stool softeners are often prescribed when bulk-forming agents do not work or are not preferred.

Osmotic Agents Agents such as polyethylene glycol (PEG), lactulose, sorbitol, and magnesium hydroxide adsorb and retain water as the result of their hyperosmolar nature and enhance stool passage. PEG has the best evidence of use, with at least 3 well-designed RCTs demonstrating significant benefits of PEG over placebo^[106–108] in increasing stool frequency and softness. However, PEG can cause nausea, flatulence, and diarrhea, especially in the elderly, and the dosage should be titrated upward according to response.^[19] In fact, some studies also reported efficacy at a low dosage of PEG.^[145–147] For lactulose, at least 2 systematic reviews reported RCTs showing efficacy over placebo,^[109,110] and the evidence is considered superior. No randomized, placebo-controlled trials have been conducted with sorbitol, but at least 1 double-blind, randomized, crossover study showed no difference in efficacy when compared with lactulose.^[111] Similarly, the use of magnesium hydroxide for chronic constipation is not supported by any placebo-controlled trials, with only 1 report of severe hypermagnesia requiring hemodialysis after chronic use.^[112] Osmotic agents are useful when first-line bulk-forming agents or stool softeners do not work.

Stimulants Senna and bisacodyl are the most commonly used stimulants. They act on the myenteric plexus of the colon and stimulate peristaltic contractions,^[148,149] which decreases transit time.^[150,151] They also decrease water absorption from the lumen. For bisacodyl, there is a double-blind, randomized, placebo-controlled trial showing efficacy and safety over placebo^[114] and another open-labeled, randomized study showing comparable benefits with sodium picosulphate.^[113] The level and recommendation for using bisacodyl is superior. Surprisingly, despite the widespread use of senna for more than a century, there is no well-designed RCT comparing its efficacy with placebo. However, at least 3 controlled trials compared the effects of senna with another laxative in treating chronic constipation. It was found that senna was a better choice,^[115] or, senna enhanced the effects when given in combination.^[116,117] Even so, the recommendation for senna is only considered moderate. There has been intense debate as to the potential risk of colonic carcinoma as the result long-term use of senna, based on the observation that senna use leads to Melanosis coli, an alleged risk for cancer of the colon. (See Notes section: Senna, Melanosis Coli, and Colon Cancer: Fact or Myth?)

Chloride Channel Activators Chloride channel activators are bicyclic fatty acids that increase intestinal fluid secretion by selectively activating type 2 chloride channels (CIC-2) in the apical membrane of the gastrointestinal epithelium. Lubiprostone is a representative that was licensed in 2004^[152] and approved in 2006^[153] by the Food and Drug Administration (FDA) for long-term treatment of chronic constipation. At least 3 double blind, randomized, placebo-controlled trials^[118–120] have shown efficacy of lubiprostone in increasing spontaneous bowel movements and improving self-reported symptoms of chronic constipation. Known adverse effects include headache, nausea, and diarrhea but are well tolerated. Long-term use of lubiprostone also appears to be safe.^[154]Evidence and recommendation for use of lubiprostone is hence excellent.

5-Hydroxytryptamine Receptor Subtype 4 Agonists 5-Hydroxytryptamine receptor subtype 4 (5-HT₄) receptors are found in the primary afferent neurons, smooth muscle cells, enterochromaffin cells, and the myenteric plexus of the colon.^[155] They mediate the release of other neurotransmitters that initiate peristaltic action in the bowel.^[155,156] Tegaserod, a 5-HT₄ partial agonist, was approved by the FDA for use in 2002 both for constipation the dominant type of irritable bowel syndrome and also for idiopathic constipation in patients under the age of 65 years. Despite its efficacy shown by multiple randomized, placebo-controlled, clinical trials from different countries,^[121–124] the FDA disapproved marketing of tegaserod in 2007 because of a small increased risk in cardiovascular events, which led to its final withdrawal in 2008. This led to public criticisms against the FDA for being paternalistic and counterproductive.^[125,126] Research interest in tegaserod still continues,^[127] and 2 recent cohort studies have specifically shown a lack of association of cardiovascular events with tegaserod.^[128,129]Whether tegaserod will be relaunched in the future remains to be seen. Prucalopride is a highly selective 5-HT₄agonist stimulating prokinetic activity of the colon in in vitro and in vivo studies of humans and animals.^[157]Clinically, it significantly improved bowel movements and other reported symptoms in patients with chronic constipation,^[130] especially in severe cases,^[131–134] with no significant cardiovascular adverse events.^[135] The level of evidence and recommendation for using prucalopride to treat chronic constipation is therefore superior, but it is only available in the European market.

Guanylate Cyclase-c Receptor Agonist Linaclotide is a 14–amino acid peptide that acts on guanylate cyclase-c receptors of the colonic epithelium and induces intestinal fluid secretion and reduces colonic transit time. Its clinical efficacy and safety have been tested in randomized, double-blind, placebo-controlled trials,^[158,159] with promising results thus far. Recommendation and level of evidence for prucalotide will not be forthcoming because of its experimental nature.

Other Treatments

Bacteriotherapy (Probiotics) Lactobacillus and Bifidobacterium are recognized symbiotic flora in the large intestine that compete with harmful pathogens in binding to the surface of enterocytes and confer mucosal health. Both flora had been reported at low levels in patients with chronic constipation,^[160] which supports the use of these probiotic bacteria for treating chronic constipation and other inflammatory bowel conditions.^[161] One prospective study showed that Bifidobacterium supplementation can relieve constipation in hypocaloric dieting,^[95]whereas another prospective trial reported efficacy of Lactobacillus in improving chronic constipation in nursing home residents.^[96] However, survival and viability of these probiotic bacteria as consumed in commercial form has yet to be standardized for such treatment to be officially endorsed.^[97] Because of the lack of properly controlled trials, evidence and recommendation is poor.

Traditional Chinese Medicine Chronic constipation was described in the ancient texts of Chinese medicine in 200 AD. It is treated by a combination of herbs and acupuncture, depending on the symptomatology. At least 2 RCTs have shown efficacy of a particular formula (Yun-Chang capsule; aka Hemp Seed Pill) in treating the functional type of chronic constipation.^[136,137] However, the overall quality of studies using traditional Chinese medicine for chronic constipation is heterogenous.^[138]

Surgery

Patients with intractable chronic constipation caused by slow colon transit who fail pharmacological treatments may be considered for surgery. Possible operations include total colectomy or partial colectomy. A recent systematic review based on case reports and case series concluded that such surgical operations can improve defecatory frequencies and decrease postoperative use of laxatives; however, there is heterogeneity in design among the studies, resulting in variable quality of evidence.^[139] For the anismus type of PFD, at least 2 RCTs have shown benefits of partial division of puborectalis as compared with biofeedback^[140] or Botulinum toxin injection.^[140,141]

http://www.medscape.com/viewarticle/746570