Chronic Constipation: an Evidence-Based Review

Home , Bisacodyl, Cathartic, Linaclotide

J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from

CLINICAL REVIEW Chronic Constipation: An Evidence-Based Review

Lawrence Leung, MBBChir, FRACGP, FRCGP, Taylor Riutta, MD, Jyoti Kotecha, MPA, MRSC, and Walter Rosser MD, MRCGP, FCFP

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.(J Am Board Fam Med 2011;24:436–451.) copyright.

Keywords: Chronic Constipation, Clinical Review, Evidence-Based Medicine, Family Medicine, Gastrointestinal Problems, Systematic Review

The word “constipation” has varied meanings for was established in 1991 by Drossman et al, primar- different individuals. Although medical personnel ily to standardize consensus-derived criteria of define constipation as Ͻ3 bowel movements per functional gastrointestinal disorder, and released http://www.jabfm.org/ week,1,2 patients often equate constipation with the Rome III criteria in 2006 for constipation as stool consistency, feelings of incomplete emptying, having at least 2 of the following: (1) straining 3,4 straining, and urge for defecation. Furthermore, during Ն25% defecation; (2) lumpy or hard stools the normalcy of bowel habit ranges widely from 3 in Ն25% of defecation; (3) sensation of incomplete 5 bowel movements per day to 3 per week, with a evacuation in Ն25% of defecation; (4) sensation of tendency to underestimate while self-reporting6; Ն anorectal obstruction/blockage in 25% of defe- on 29 September 2021 by guest. Protected hence, using defecation frequency alone may not be cation; (5) need for manual maneuvers to facilitate diagnostic of constipation. The Rome Foundation in Ն25% of defecation; and (6) fewer than 3 defe- cations per week.7,8 Also, patients should rarely have loose stools without laxatives and be distinct This article was externally peer reviewed. 8,9 Submitted 13 November 2010; revised 20 February 2011; from having irritable bowel syndrome. For con- accepted 7 March 2011. stipation to be defined as chronic, a patient must be From the Department of Family Medicine (LL, TR, WR) and the Centre of Studies in Primary Care (LL, JK, WR), symptomatic for at least 6 months with applicable Queen’s University, Kingston, Ontario, Canada. criteria for the previous 3 months.3,9 Although the Funding: none. Conflict of interest: none declared. validity of the Rome III criteria for constipation has Corresponding author: Lawrence Leung, Department of been recently questioned,10 with a known disparity Family Medicine, Queen’s University, 220 Bagot Street, Kingston, Ontario, Canada K7L 5E9 (E-mail: leungl@ between self-reported and criteria-based defini- queensu.ca). tions,11 the use of colonic transit time12,13 and

436 JABFM July-August 2011 Vol. 24 No. 4 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from anorectal function tests14 as diagnostic tools is still rly.17,31–36 Among them, the trio of insufficient controversial. In general, the prevalence of consti- dietary fiber, fluids, and exercise has been widely pation among the general population in North ascribed,37 but in fact the evidence behind these 3 America has been quoted as 1.9% to 27.2%,15,16 factors is inconsistent and of low to medium qual- with 50% to 74% of the institutionalized elderly ity.38 (See Notes section: Diagnostic Approach for reporting daily use of laxatives.17,18 Women are 2 Chronic Constipation.) The association between to 3 times more likely to have constipation than smoking, alcohol, and body mass index with men in terms of prevalence3,15,19–21 and physical chronic constipation L131(BMI) is inconclu- symptoms.15,20 Possible reasons include higher risk sive.36,39 of injury to the pelvic floor from childbirth22 and the general willingness of women to report their Intrinsic Factors symptoms and respond to surveys.23 Advanced age Normal defecation requires a series of orchestrated is also a risk factor for chronic constipation, with actions, starting with relaxation of the puborectalis the largest increase in prevalence after the age of 70 muscles, descent of the pelvic floor with straight- years.15 This can be due to effects of medication, ening of the anorectal angle, inhibition of segmen- immobility, and blunted urge to defecate. In the tal colonic peristalsis, contraction of the abdominal United States, constipation accounts for 7 million wall muscles, and finally, relaxation of the external physician visits per year24 and is among the top 5 anal sphincter with expulsion of feces. Intrinsic outpatient gastrointestinal diagnoses.25 Annually, factors leading to chronic constipation can be diagnostic workup for constipation averages broadly classified into 2 categories: pelvic floor dys- US$3000 per patient,26 and it takes another function (PFD) and slow colon transit time (STC). US$4500 per person to provide treatment.27 In A retrospective study reported the prevalence of general, constipation has a significant impact on PFD as 37% and STC as 23%,40 based on physi- quality-of-life indicators irrespective of culture and ologic tests. However, a clear distinction between nationalities,28 especially on the elderly.29 A recent the two is often impossible, with an overlap of copyright. systematic review showed that impairment caused up to 55%.40,41 by constipation as measured by Health-Related Anorectal/PFD involves laxity of the pelvic floor Quality of Life scores predominates in the mental muscles, impaired rectal sensation, and decreased health domains and is comparable to that caused by luminal pressure in the anal canal and have been serious chronic conditions such as osteoarthritis documented as causes for chronic constipation in and diabetes.30 the elderly, especially in women.42–44 On the con-

trary, paradoxical contraction of the puborectalis http://www.jabfm.org/ Etiology of Chronic Constipation and external anal sphincter during defecation can Extrinsic Factors lead to incomplete emptying45,46 or even functional Low fiber intake, inadequate hydration, reduced outlet obstruction. Finally, anatomic anomalies mobility as the result of general functional decline (such as rectal wall prolapse or rectocele) or peri- and institutionalization, reduced sensation of thirst, neal damage (from traumatic childbirth or sacral electrolyte disturbances (hypercalcemia, hypokale- nerve injury) can also distort the normal functions mia, hypermagnesemia), endocrine and metabolic of the anorectal/pelvic floor unit. on 29 September 2021 by guest. Protected disorders (eg, diabetes mellitus, hyperparathyroid- STC is a poorly understood condition thought ism, hypothyroidism, chronic renal failure), neuro- to be a cause of intractable constipation in chil- logical disorders (eg, dementia, Parkinson disease, dren47 and young women.48 It is characterized by neuropathies, multiple sclerosis, spinal cord inju- reduced high-amplitude propagated contrac- ries, cauda equine syndrome), psychological co- tions49,50 in the colon, leading to slow transit of morbidities (eg, depression, distress, personality feces, bloating, abdominal discomfort, and infre- disorders, or history of abuse), and concurrent quent defecation.51 The protracted time in the co- medications (eg, anticholinergics, diuretics, lon also renders the feces hard and small and fails to ␤-blockers, opiates, iron supplements, calcium mount sufficient rectal pressure to trigger the def- channel blockers, antidepressants, acetaminophen, ecation reflex.52 Often, the pressure required is aspirin and NSAIDs) all are said to contribute to found to be higher than in subjects with normal chronic constipation, especially in the elde- colonic transit.53 Various physiologic and histobio- doi: 10.3122/jabfm.2011.04.100272 Chronic Constipation 437 J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from chemical findings have been postulated to explain Diagnostic Approach and Investigations the phenomenon of slow colonic transit: reduced It is important to conduct a detailed history and cholinergic54,55 and enhanced adrenergic respon- physical examination before proceeding with in- ses55; mitigated gastrocolic reflex56; dysynergy of vestigations. It is imperative to understand the rectosigmoid colonic activities57,58; enteric neuro- patient’s views and definitions of chronic consti- degeneration59 of both the myenteric plexus gan- pation, which may often differ from medical cri- glia60,61 and the interstitial cells of Cajal61,62; and teria. The clinician should also weigh the cost- abnormalities of enteric neurotransmitters such as benefits of investigations and only order those substance P,63–65 vasoactive intestinal peptides,63,64 that help diagnose the etiology of chronic con- and nitric oxide.63,66 stipation and affect the treatment and prognosis in such patients. A brief outline of the diagnostic approach for chronic constipation is given in the Complications of Chronic Constipation Notes section: Diagnostic Approach for Chronic (1) Fecal incontinence: Overflow incontinence caused Constipation. It must be emphasized that these by fresh fecal matter bypassing the inssipated ob- investigations are not indicated as routine studies structing bolus67 may confuse the diagnosis of except for differentiating between slow colon tran- chronic constipation unless a rectal examination is sit time and pelvic floor dysfunction, in which performed. The odds ratio for developing fecal in- treatment would differ. Moreover, contrast studies continence with chronic constipation is 1.7.68 and colonoscopy should be considered if the pa- (2) Hemorrhoids: Prolonged straining and in- tient has a positive family history of colon cancer or crease of intra-abdominal pressure raises the ve- inflammatory bowel disease and presents with nous pressure in the plexus and ateriovenous anas- alarming complaints of rectal bleeding, abrupt tomoses of the anorectal junction.69 The relative weight loss, anemia, or change in bowel habits. risk for development of hemorrhoids with constipation is up to 4.1.70 copyright. (3) Anal fissure: Trauma and sudden tear of the Evidence-Based Management of Chronic anal mucosa during evacuation of hard stool is Constipation usually an initiating event, but spasm of the internal Methods anal sphincter leading to relative ischemia is A literature search of published medical reports in thought to be the perpetuating factor.69 It is esti- all languages was performed from PUBMED, mated that anal fissure is 5 times more likely to EMBASE, and the Cochrane Database of System- 70,71

develop with chronic constipation. atic Reviews from inception to October 2010 using http://www.jabfm.org/ (4) Organ prolapse: Chronic constipation is a the OVID Portal of Queen’s University, Kingston, known risk for prolapse of pelvic organs such as the Ontario. Abstracts were initially obtained using key uterus, rectum, urinary bladder, and vagina72 and words of “chronic constipation,” “treatment,” and their recurrence.73 The odds ratio for having rectal “trials.” Manual searches of references and review prolapse is quoted as 2.3.68 articles supplemented the computerized search, (5) Fecal impaction and bowel obstruction: Pro- and only full-length articles were considered. Two longed stasis of fecal matter leads to impaction and reviewers (L.L. and T.R.) worked independently on 29 September 2021 by guest. Protected giant fecolith obstructing the large bowel, necessi- and went over the initial search for abstracts that tating surgery.74,75 Retrospective analysis revealed satisﬁed the key words as mentioned. They then a 5- to 6-times increased risk of fecal impaction adopted a simple form to select studies that satisﬁed resulting from chronic constipation.68,70,71 the following 2 inclusion criteria: (1) involving hu- (6) Bowel perforation and stercoral peritonitis: man subjects over the age of 18 years and (2) de- Extremely impacted feces (fecaloma) can compress scribing at least 1 form of treatment for chronic the colonic wall, causing an ischemic ulcer76 and constipation. Evaluation of selected studies was subsequent perforation,77,78 culminating in sterc- performed by each reviewer (L.L. and T.R.) re- oral peritonitis78,79 and sometimes death.79 It is not garding their quality and evidence according a common condition; fewer than 90 cases have been to the Strength of Recommendations Taxonomy reported in the medical literature from 1894 to (SORT),81 with levels of evidence from I to III and 2006.80 recommendations from A to C. Any disagreement

438 JABFM July-August 2011 Vol. 24 No. 4 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from was discussed and resolved among the reviewers to Pharmacological Treatment reach mutual consensus. Medications for chronic constipation can be cate- gorized into bulk-forming agents, stool softeners Results and emollients, osmotic agents, stimulants, chlo- One hundred forty-five abstracts were identified by ride channel activators, 5-HT4 receptor agonists, using key words of “chronic constipation” AND and guanylate cyclase-c receptor agonist. “treatment” AND “trials.” Duplicates were re- moved, and, after imposing the selection criteria, only 62 relevant full-text articles were then re- Bulk-Forming Agents trieved for potential inclusion.9,34,46,82–141 They Bulk-forming agents are fiber supplements that ex- were deemed eligible on which mutual consensus pand with water to increase bulk of the stool and was reached between the two reviewers (LL and enhance bowel movements. Commercially avail- TR). Additional consultation with the other two able preparations include psyllium (ispaghula coauthors (WR and JK) was sought as required. husks), calcium polycarbophil, methycellulose, and The studies were then rated according to the bran. Adequate fluid intake is a must for bulk- SORT as below and summarized in the Notes sec- forming agents to work; lack of water enhances tion: Senna, Melanosis Coli, and Colon Cancer: Fact bloating and may paradoxically predispose to bowel or Myth? obstruction. Among them, psyllium has superior efficacy in treating constipation, with at least 3 Lifestyle Modifications RCTs demonstrating benefits over placebo in im- Despite the fact that chronic constipation had been proving colonic transit time and stool consiste- 98–100 observed with deficiency in dietary fiber, fluids, or ncy. Two controlled trials reported the ben- exercise, lifestyle modification to prevent or treat efits of bran in reducing the use of laxatives in the 82,142 102,103 chronic constipation is still unsubstantiated. elderly. In comparison, there is only 1 con- copyright. 104 (See Notes section: Lack of Dietary Fiber, Fluid, trolled trial for methylcellulose and a case series 105 and Exercises Will Cause Constipation: How True for polycarbophil supporting their clinical use. Is This?) However, such principles are widely dis- Bulk-forming agents are considered as first-line seminated to the public through pamphlets37 and agents for chronic constipation, especially in pa- practice guidelines (http://www.worldgastroenterology. tients with dietary fiber deficiency. 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 Stool Softeners and Emollients http://www.jabfm.org/ allied medical professionals should be aware of the Docusate sodium is a commonly prescribed stool evidence when advising their patients. softener that has a detergent effect. Although there is no known study comparing its stand-alone effi- Biofeedback cacy against placebo, one double-blind randomized For the PFD type of chronic constipation, biofeed- trial found docusate to be inferior to psyllium in 98 back provides a retraining of the sensation and chronic constipation. Another systematic review on 29 September 2021 by guest. Protected control of the anorectum and pelvic floor, thereby did show a small effect of docusate in increasing eliminating paradoxical contractions during the stool frequency in the chronically ill, but overall process of defecation. Its value has been shown quality of evidence was poor. Hence, the recom- both in uncontrolled trials93 and in recent random- mendation for use of docusate sodium is only mod- ized, controlled trials (RCTs)46,92,94 for improving erate. Mineral oil is an emollient used for its lubri- both psychological and clinical outcome measures. cating effect on stool, but no placebo-controlled, There have been no reports of adverse effects for randomized trial has been reported. Aspiration and using biofeedback. As a result, the level of evidence lipoid pneumonia is a known risk of using mineral and recommendation in using biofeedback for PFD oil in children143 and the elderly.144 The level of type of chronic constipation is good except for the evidence for use of mineral oil is hence moderate. diversity of protocols and heterogeneity of trial Stool softeners are often prescribed when bulk- designs. forming agents do not work or are not preferred. doi: 10.3122/jabfm.2011.04.100272 Chronic Constipation 439 J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from

Osmotic Agents based on the observation that senna use leads to Agents such as polyethylene glycol (PEG), lactu- Melanosis coli, an alleged risk for cancer of the colon. lose, sorbitol, and magnesium hydroxide adsorb (See Notes section: Senna, Melanosis Coli, and Co- and retain water as the result of their hyperosmolar lon Cancer: Fact or Myth?) nature and enhance stool passage. PEG has the best evidence of use, with at least 3 well-designed RCTs Chloride Channel Activators demonstrating significant benefits of PEG over Chloride channel activators are bicyclic fatty acids placebo106–108 in increasing stool frequency and that increase intestinal fluid secretion by selectively softness. However, PEG can cause nausea, flatu- activating type 2 chloride channels (CIC-2) in the lence, and diarrhea, especially in the elderly, and apical membrane of the gastrointestinal epithelium. the dosage should be titrated upward according to Lubiprostone is a representative that was licensed response.19 In fact, some studies also reported ef- in 2004152 and approved in 2006153 by the Food ficacy at a low dosage of PEG.145–147 For lactulose, and Drug Administration (FDA) for long-term at least 2 systematic reviews reported RCTs show- treatment of chronic constipation. At least 3 double ing efficacy over placebo,109,110 and the evidence is blind, randomized, placebo-controlled trials118–120 considered superior. No randomized, placebo-con- have shown efficacy of lubiprostone in increasing trolled trials have been conducted with sorbitol, but spontaneous bowel movements and improving self- at least 1 double-blind, randomized, crossover reported symptoms of chronic constipation. study showed no difference in efficacy when com- Known adverse effects include headache, nausea, pared with lactulose.111 Similarly, the use of mag- and diarrhea but are well tolerated. Long-term use nesium hydroxide for chronic constipation is not of lubiprostone also appears to be safe.154 Evidence supported by any placebo-controlled trials, with and recommendation for use of lubiprostone is only 1 report of severe hypermagnesia requiring hence excellent. hemodialysis after chronic use.112 Osmotic agents are useful when first-line bulk-forming agents or 5-Hydroxytryptamine Receptor Subtype 4 Agonists copyright. stool softeners do not work. 5-Hydroxytryptamine receptor subtype 4 (5-HT4) receptors are found in the primary afferent neu- rons, smooth muscle cells, enterochromaffin cells, Stimulants and the myenteric plexus of the colon.155 They Senna and bisacodyl are the most commonly used mediate the release of other neurotransmitters that stimulants. They act on the myenteric plexus of the initiate peristaltic action in the bowel.155,156 Tega- 148,149 colon and stimulate peristaltic contractions, serod, a 5-HT4 partial agonist, was approved by the http://www.jabfm.org/ which decreases transit time.150,151 They also de- FDA for use in 2002 both for constipation the crease water absorption from the lumen. For bi- dominant type of irritable bowel syndrome and also sacodyl, there is a double-blind, randomized, pla- for idiopathic constipation in patients under the cebo-controlled trial showing efficacy and safety age of 65 years. Despite its efficacy shown by mul- over placebo114 and another open-labeled, random- tiple randomized, placebo-controlled, clinical trials ized study showing comparable benefits with so- from different countries,121–124 the FDA disap- dium picosulphate.113 The level and recommenda- proved marketing of tegaserod in 2007 because of a on 29 September 2021 by guest. Protected tion for using bisacodyl is superior. Surprisingly, small increased risk in cardiovascular events, which despite the widespread use of senna for more than led to its final withdrawal in 2008. This led to a century, there is no well-designed RCT compar- public criticisms against the FDA for being pater- ing its efficacy with placebo. However, at least 3 nalistic and counterproductive.125,126 Research in- controlled trials compared the effects of senna with terest in tegaserod still continues,127 and 2 recent another laxative in treating chronic constipation. It cohort studies have specifically shown a lack of was found that senna was a better choice,115 or, association of cardiovascular events with tegas- senna enhanced the effects when given in combi- erod.128,129 Whether tegaserod will be relaunched nation.116,117 Even so, the recommendation for in the future remains to be seen. Prucalopride is a senna is only considered moderate. There has been highly selective 5-HT4 agonist stimulating proki- intense debate as to the potential risk of colonic netic activity of the colon in in vitro and in vivo carcinoma as the result long-term use of senna, studies of humans and animals.157 Clinically, it sig-

440 JABFM July-August 2011 Vol. 24 No. 4 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from nificantly improved bowel movements and other tional Chinese medicine for chronic constipation is reported symptoms in patients with chronic consti- heterogenous.138 pation,130 especially in severe cases,131–134 with no significant cardiovascular adverse events.135 The level of evidence and recommendation for using Surgery prucalopride to treat chronic constipation is there- Patients with intractable chronic constipation fore superior, but it is only available in the Euro- caused by slow colon transit who fail pharmacolog- pean market. ical treatments may be considered for surgery. Pos- sible operations include total colectomy or partial Guanylate Cyclase-c Receptor Agonist colectomy. A recent systematic review based on Linaclotide is a 14–amino acid peptide that acts on case reports and case series concluded that such guanylate cyclase-c receptors of the colonic epithe- surgical operations can improve defecatory fre- lium and induces intestinal fluid secretion and re- quencies and decrease postoperative use of laxa- duces colonic transit time. Its clinical efficacy and tives; however, there is heterogeneity in design safety have been tested in randomized, double- among the studies, resulting in variable quality of blind, placebo-controlled trials,158,159 with promis- evidence.139 For the anismus type of PFD, at least ing results thus far. Recommendation and level of 2 RCTs have shown benefits of partial division of evidence for prucalotide will not be forthcoming puborectalis as compared with biofeedback140 or because of its experimental nature. Botulinum toxin injection.140,141 Other Treatments Bacteriotherapy (Probiotics) Lactobacillus and Bifidobacterium are recognized Conclusions symbiotic flora in the large intestine that compete It is indeed surprising that as a common condition with harmful pathogens in binding to the surface of found in at least one quarter of patients, chronic copyright. enterocytes and confer mucosal health. Both flora constipation is treated in a wide variety of ways, had been reported at low levels in patients with with relatively little evidence-based data, especially 160 chronic constipation, which supports the use of regarding dietary fiber, fluids and exercise. As with these probiotic bacteria for treating chronic consti- any other condition, a thorough history and phys- pation and other inflammatory bowel condi- ical examination is mandatory, with additional 161 tions. One prospective study showed that Bifido- blood and special tests to confirm the diagnosis of bacterium supplementation can relieve constipation chronic constipation and its subtypes. A practical http://www.jabfm.org/ 95 in hypocaloric dieting, whereas another prospec- triage approach is summarized in Figure 1), and the tive trial reported efficacy of Lactobacillus in im- various evidence-based options for managing proving chronic constipation in nursing home res- chronic constipation are listed in the order of their idents.96 However, survival and viability of these level of recommendation in Table 1. In summary, probiotic bacteria as consumed in commercial form family physicians should look for pelvic floor dys- has yet to be standardized for such treatment to be

function as a cause of chronic constipation, which is on 29 September 2021 by guest. Protected officially endorsed.97 Because of the lack of prop- best treated by biofeedback. The classic triad of erly controlled trials, evidence and recommendation is poor. increasing dietary fiber, exercise, and fluids will benefit patients with actual deficiencies. The best Traditional Chinese Medicine pharmacological treatment for chronic constipa- Chronic constipation was described in the ancient tion caused by slow colonic transit time is to start texts of Chinese medicine in 200 AD. It is treated with a bulk-forming agent (psyllium or bran) and by a combination of herbs and acupuncture, de- with a stool softener/osmotic agent (lactulose, pending on the symptomatology. At least 2 RCTs PEG, or docusate), then add in stimulants (bisaco- have shown efficacy of a particular formula (Yun- dyl or senna) and finally the newer agents for severe Chang capsule; aka Hemp Seed Pill) in treating the or resistant cases (chloride channel activators or 136,137 functional type of chronic constipation. 5-HT4 agonist). In recalcitrant cases, surgical treat- However, the overall quality of studies using tradi- ment may be considered. doi: 10.3122/jabfm.2011.04.100272 Chronic Constipation 441 J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from

Figure 1. Flow diagram for management of chronic constipation.

History and full physical examination

Fulfilling Rome III criteria for chronic constipation?

Yes No Consider other diagnoses Any correctable causes, e.g., due to medications, Correct as co-morbid medical, Yes appropriate surgical or psychiatric conditions ?

No Tests for Pelvic Floor Dysfunction (PFD) Normal Investigations for colonic colonic transit time transit PFD confirmed NO PFD

Slow Colonic transit Biofeedback copyright. Adequate dietary Increase dietary Lack of dietary fibers, fluids or fibers, fluids or fibers, fluids or Partial division exercise exercise exercise of puborectalis

Start with bulk Add in stool softener forming agent like like docusate sodium psyllium or bran http://www.jabfm.org/

Consider osmotic agents Consider stimulants like like polyethylene glycol bisacodyl and senna (PEG)-lactulose or sorbitol

Consider chloride channel activators, Colectomy / 5-HT antagonist and guanylate cyclase-c 4 Hemicolectomy receptor agonist on 29 September 2021 by guest. Protected

Notes lifestyle enquiry regarding the level of fluid intake, Diagnostic Approach for Chronic Constipation dietary fiber consumption, and daily exercise. History includes (1) duration of complaint; (2) pa- Physical examination includes (1) previous sur- tient’s definition of constipation; (3) defecatory fre- gical scars; (2) abdominal distension and bowel quency; (4) stool consistency; (5) concurrent med- sounds; (3) palpable mass (fecoliths); (4) inspection ication (eg, anticholinergics, diuretics, ␤-blockers, of anus for skin tags, hemorrhoids, fissures, hema- opiates, iron supplements, calcium channel block- tomas, and prolapse; (5) rectal examination to assess ers, antidepressants, acetaminophen, aspirin, and anal reflex, sphincter tone, tenderness, out-pouch- NSAIDs); (6) comorbidities (Parkinson, hypothy- ing (rectocele), or mass in the rectum; (6) gyneco- roidism); (7) use of supplements or laxatives; and (8) logical examination to exclude cystoceles or vagi-

442 JABFM July-August 2011 Vol. 24 No. 4 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from

Table 1. Summary of Various Management Options for Chronic Constipation According to the Strength of Recommendations Taxonomy (SORT)81

Level of Treatment Recommendation Comments Reference

Nonpharmacological Increasing dietary fiber C No RCTs, data from multiple observational studies, results 34,82–87 conflicting. More likely to be beneficial in people with fibers deficiency. Increasing exercise B Two small RCTs with opposite results and 2 other cohorts 9,83,88,89 showing benefits. More likely to be beneficial in people with lack of exercise. Increasing fluids C One observational study and 1 controlled trial, the latter 90,91 showing benefits of increased fluids only in presence of sufficient fiber intake. Biofeedback B Useful in pelvic function disorder type of chronic 46,92–94 constipation. Benefits reported with both uncontrolled trials and RCTs. However, protocols of biofeedback vary and are heterogeneous in nature; hence recommendation is not standardized. Bacteriotherapy (probiotics) C One prospective study of bifidobacterium and one 95–97 uncontrolled trial of Lactobacillus; viability of preparation when consumed is questionable. Surgery (colectomy/ B One systematic review reported benefits based on case 139 hemicolectomy) reports and no RCT; quality of studies was heterogeneous. Surgery (partial division of B Two RCTs randomizing patients to surgical and 140,141 puborectalis) nonsurgical treatments (biofeedback or Botulinum toxin injection). Pharmacological Psyllium A At least 3 well-designed RCTs showing benefits over 98–101 copyright. placebo.

Bran B Two controlled trials showed benefits in reducing use of 102,103 laxatives. Methylcellulose B Only 1 controlled trial of medium quality. 104 Polycarbophil B Only 1 case series of medium quality. 105 Polyethylene glycol A At least 3 RCTs showing benefits over placebo. 106–108 Lactulose A Two systematic reviews of RCTs with benefits over 109,110 placebos. http://www.jabfm.org/ Sorbitol B One double-blind RCT showing comparable efficacy of 111 sorbitol with lactulose, not placebo. Magnesium hydroxide (milk of C No evidence of benefits from any studies, with 1 adverse 112 magnesia) report of overuse. Senna A At least 3 controlled trials showing benefits over placebo. 115–117 Docusate sodium B One double-blind RCT comparing with psyllium. 98

Bisacodyl A One double-blind RCT with 1 open-labelled controlled 113,114 on 29 September 2021 by guest. Protected trial. Lubiprostone A At least 3 double-blind RCTs showing benefits over 118–120 placebo. Tegaserod – At least 3 RCTs from different centers showed benefits 121–129 over placebo. Withdrawn from market by FDA because of concern; 2 recent cohorts claim no association with cardiovascular risks. Prucalopride A At least 3 RCTs showing benefits over placebo, including 130–135 severe chronic constipation. At present only marketed in Europe. Traditional Chinese medicine B Two RCTs showing benefits of a particular formula, yet 136–138 overall quality of studies are heterogeneous.

RCT indicates randomized, controlled trial; FDA, Food and Drug Administration.

doi: 10.3122/jabfm.2011.04.100272 Chronic Constipation 443 J Am Board Fam Med: first published as 10.3122/jabfm.2011.04.100272 on 7 July 2011. Downloaded from nal/uterine prolapse; and (7) full neurological the self-reported symptoms in women.9,83 Evi- examination to exclude neurological causes. dence is Level 2C. Investigations include (1) blood tests such as complete blood count, serum glucose, and thyroid Fluids and renal functions maybe useful despite limited A 3-month, prospective study of 21 012 nursing evidence.162,163 (2) Colon transit time: Radiograph home residents age Ͼ65 years found a link between study with the Sitz marker has been a standard test insufficient fluid intake and constipation.90 One in distinguishing prolonged transit from normal controlled trial showed that higher fluid intake transit but is unreliable in measuring segmental improved chronic constipation in the presence of transit.164 Scintigraphy with radioisotope is more a high-fiber diet.91 Other than that there have accurate in measuring transit in different segments been no known trials looking at the effects of of the colon165 but is more expensive and limited to increased fluids on chronic constipation. Evi- centers with access to radioisotopes. (3) Anorectal dence is hence 2C. manometry: Pressure exerted by the anal sphincter at rest (normal Ͼ80 mm Hg) and with defecatory Senna, Melanosis Coli, and Colon Cancer: Fact or attempt (normal Ͼ180 mm Hg) is measured with a Myth? balloon catheter in the anal canal.166 (4) Balloon Senna belongs to the genera of anthroquinone- expulsion test: Patient is asked to expel a 50 mL containing herbal laxatives that also embrace aloe, rectal balloon (filled with air or water) within 60 cascara, frangula, and rhubarb. The active ingredi- seconds; failure to do so suggests pelvic floor dys- ents include sennoside A and B. Melanosis coli is a function.14 (5) Defecography: Serial radiographs of brownish-black discoloration of the colonic epithe- the anorectum are taken when the patient is asked lium found with chronic use of anthraquinone lax- to expel thick barium paste from the rectum. Move- atives,168 with an association of 73% to 95%.147,169 ment of the pelvic floor and anorectal angle is Histologically, there is accumulation of lipofuscin- measured with reference to the sacro-coccygeal containing macrophages in the lamina propria of copyright. line.14 (6) Dynamic pelvic MRI gives better visual- the colonic mucosa.170 Lipofuscin is thought to ization of the pelvic floor dynamics than does con- derive from apoptotic bodies generated by anthro- ventional barium defecography and also reveals quinone-induced apoptosis of the colonic epithelial other anatomic defects contributing to impaired cells.168,171 Melanosis coli can resolve after discon- defecation.167 tinuation of anthraquinone laxatives.169 In the last three decades, induction of aberrant crypt foci

(ACF) in rat colon has been widely accepted as the http://www.jabfm.org/ Lack of Dietary Fiber, Fluid, and Exercises Will pre-neoplastic lesions for modeling colorectal can- Cause Constipation: How True Is This? cer.172–177 Although 2 studies showed that senna Dietary Fiber promoted formation of carcinogen-induced ACF in A prospective cohort of 3327 women found that rat colon when given at high doses,178,179 other higher daily ﬁber intake (20 g/d versus 7 g/d) sig- studies failed to show any effects of senna in initi- niﬁcantly reduces the likelihood of self-reported 180,181 83 ating ACF per se or promoting existing ACF.

constipation. However, other studies have found on 29 September 2021 by guest. Protected In fact, one study even demonstrated a reduction of no such association.34,84,85 Increasing daily dietary ACF in rat colon after long-term usage of senna.182 fiber intake may help constipation caused by fiber Similar data in humans are lacking, except for one deficiency,34,84,86 but one should not assume that study that showed increased ACF after a single high fiber deficiency is the main or sole cause.82,87 Evi- dose of senna colonic lavage.183 A prospective study dence is Level 2C. of 1095 patients reported an increased relative risk of 3.04 for colorectal cancer as a result of anthraquinone Exercise laxative abuse.184 Similarly, a retrospective study of One small, nonplacebo RCT reported that regular 3049 patients who underwent colonoscopy revealed a exercise decreases constipation as per Rome I cri- higher incidence of Melanosis coli in patients diagnosed teria,88 whereas another even smaller study did not with colonic adenomas184(which are not necessarily show any benefit.89 Two other cohort studies malignant). However, subsequent studies failed to showed that physical activity significantly decreased demonstrate an association of anthraquinone laxatives

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