Update on the Management of Adults With Chronic Idiopathic Constipation

Associate Professor of Medicine, Uniformed Services University of the Health Sciences; Chief, Division of Gastroenterology, National Naval Medical Center, Bethesda, Maryland

Professor of Medicine, David Geffen School of Medicine at UCLA; Director, Women’s Digestive Health Center, UCLA Center for Neurovisceral Sciences & Women’s Health, Los Angeles, California

Program Activity Director; Professor of Medicine, Rush University Medical Center, Chicago, Illinois

Medical Writer; Vice President, Digestive Diseases Education Company, Fishers, Indiana

Constipation is a common, multisymptom gastrointestinal (GI) disorder that affects up to 27% of the North American population—twice as many women as men—and, although reported among all age-groups, tends to be associated with increasing age.^1,2 In the United States alone, constipation accounts for an estimated 2.5 million patient visits to physicians annually³ and an overall annual cost of $29 billion.⁴ About $400 million is spent annually on over-the-counter (OTC) laxatives, with 5 million laxative prescriptions being written each year.^4,5 Most patients with constipation are seen by family physicians (31%), internists (20%), or obstetricians/gynecologists (9%).³ Conversely, gastroenterologists treat only 4% of patients with constipation; these are usually the most severe cases. Tertiary care evaluation is estimated to average $2752 per patient.⁶ Furthermore, epidemiologic data suggest that patients with constipation have diminished health-related quality of life compared with that of nonconstipated individuals,^4,7,8 and that constipation has a substantial direct (ie, health care utilization) and indirect (ie, work absenteeism and decreased productivity) socioeconomic impact.^4,9

Lifestyle interventions (eg, increased fluid, fiber, exercise) represent the basis of nonpharmacologic therapy for constipation and are regarded as good behaviors to promote, especially for patients with mild symptoms. When lifestyle interventions do not provide adequate relief, numerous OTC medications usually constitute the next step, particularly for patients with mild-to-moderate symptoms.¹ Prescription agents are generally reserved for patients with more severe symptoms or for individuals whose symptoms are chronic or recurrent.

This article aims to offer primary care physicians (PCPs) a comprehensive review of the pathophysiology and diagnosis of chronic constipation (CC), and to provide a timely update on treatment modalities. Its content is derived, in part, from the proceedings of IMPACT^™ (Improving Medical Practice by Advancing Clinical Therapeutics), a series of free-standing symposia produced by Digestive Diseases Education Company and held during the fall of 2006 throughout the United States.

 

Definition of Chronic Constipation

In recently published expert recommendations, the American College of Gastroenterology (ACG) Chronic Constipation Task Force characterized CC as “unsatisfactory defecation that results from infrequent stool, difficult stool passage, or both.”¹⁰ However, patients, physicians, and clinical investigators often differ in their definitions of constipation. Infrequency of defecation or dyschezia (difficulty with stool expulsion) is often included in the definition, but the criteria used remain controversial and vary across studies.

Rome Criteria for Functional Bowel Disorders

In an effort to standardize the definition of CC for research purposes, the Rome Committees have developed 3 iterations of consensus definitions. The Rome III criteria for functional bowel disorders are used in research and, to a lesser extent, in clinical practice (TABLE 1).¹¹ These criteria include signs and symptoms that patients frequently describe, such as straining (a sense of incomplete or ineffective defecation), lumpy or hard stools, incomplete evacuation, anorectal obstruction or blockage, and the use of manual maneuvers to facilitate evacuation, in addition to infrequency (ie, <3 defecations per week).

Rome III Diagnostic Criteria

The Bristol Stool Form Scale*

	Type 1		Separate hard lumps, like nuts (difficult to pass)
	Type 2		Sausage-shaped but lumpy
	Type 3		Like a sausage but with cracks in its surface
	Type 4		Like a sausage or snake, smooth and soft
	Type 5		Soft blobs with clear-cut edges (passed easily)
	Type 6		Fluffy pieces with ragged edges; a mushy stool
	Type 7		Watery, no solid pieces, entirely liquid
*Stool form correlates with intestinal transit time.
h, hours
Heaton KW, et al. Gut. 1992;33:818-824.29 O’Donnell LJ, et al. BMJ. 1990;300:439-440.15

According to this definition, patients with CC must neither have loose stools—in the absence of laxative use—nor meet the criteria for irritable bowel syndrome (IBS).¹¹ The Rome III criteria define IBS as “a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit, and with features of disordered defecation.”¹¹ About 10% to 20% of the world’s adults and adolescents describe symptoms consistent with IBS, with most North American studies reporting a predominance among women.^12,13 Patients with IBS typically suffer from diarrhea-predominant IBS, constipation-predominant IBS (IBS-C), or “mixed” IBS with alternating bowel patterns.^11,14 Because stool form (from watery to hard) reflects intestinal transit time, PCPs should consider using the Bristol Stool Form Scale (TABLE 2), developed at the Bristol Royal Infirmary in England,¹⁵ to identify constipation as types 1 and 2 and diarrhea as types 6 and 7.

Physician Versus Patient Definition of Constipation

Because the term “constipation” has a popular meaning independent of any scientific definition, patients who call themselves constipated often have symptoms that vary from scientific definitions. This discrepancy may result in significant misunderstandings between patients and clinicians.

In a randomized study of 531 family practice patients, 27% used a frequency definition for constipation and considered themselves constipated if they defecated less often than every other day (ie, an average of <3.5 bowel movements per week), whereas 25% defined constipation simply as passing hard stools.¹⁶ Treating physicians who were asked the same question defined constipation as defecation less than every 3 or 4 days, sometimes in combination with hard stools.

A landmark epidemiologic study, the Epidemiology of Constipation (EPOC) study, which surveyed more than 10,000 American adults, indicated that only 26% of patients fulfilling CC symptom-based criteria, similar to the Rome criteria, actually had fewer than 3 bowel movements per week.¹⁷ In the EPOC study, patients reported other symptoms (ie, bloating, abdominal fullness, unsuccessful defecation, and blockage) at rates similar to those of defecatory infrequency. Other epidemiologic studies also have shown that patients with CC cite straining and hard or lumpy stools, rather than infrequency, as their most bothersome symptoms.^18-20 The description of CC and its estimated prevalence also may be complicated by the poor reliability of patient reports. For instance, 51% of a cohort of patients who considered themselves constipated and who orally reported 3 or fewer bowel movements per week for more than 6 months actually passed an average of 6 stools per week, as documented by diary records.¹⁵

Finally, ethnic- and gender-specific standards may be required for the accurate diagnosis of constipated patients who exhibit patterns of bowel movements that vary from those of the overall population with this disorder.¹⁸ Primary care physicians (PCPs) should consider patient definitions of constipation in addition to validated, scientific definitions, such as the Rome criteria. Clinicians are responsible for understanding their patients’ meaning of constipation to avoid any unnecessary test or inappropriate treatment.

 

Pathophysiology of Chronic Constipation

Constipation is a symptom of many diseases. When constipation is due to another disease, it is referred to as “secondary.” Secondary CC may result from endocrine and metabolic diseases (ie, diabetes, hypothyroidism, hypercalcemia, and hypokalemia), neurologic disorders (ie, peripheral or autonomic neuropathy, multiple sclerosis, and chronic pseudo-obstruction), and collagen-vascular diseases (eg, progressive systemic sclerosis).²¹ Long-term use of specific drugs also may lead to secondary CC (TABLE 3).²²

When there is no known underlying disorder, CC is termed “primary” or “idiopathic.” The pathophysiology of idiopathic CC is thought to involve behavioral, endocrine, and neurogenic processes.²³ Although idiopathic CC has many potential causes, it is usually classified into 3 categories based on differences in pathophysiology: normal-transit constipation, dyssynergic defecation, and slow-transit constipation.^24,25

Medications Associated With Secondary Constipation

Normal-Transit Constipation

Normal-transit constipation, or functional constipation, is the most common form of idiopathic CC, with an estimated prevalence of 59%. In patients with normal-transit constipation, stool passes through the colon at a normal pace and defecation frequency is normal; however, patients believe they are constipated. The patient perceives difficulty with evacuation or the presence of hard stools.²⁴ Stool texture is not abnormally hard in patients with CC when tested objectively; thus, the complaint of “hard stools” most likely reflects the patient’s difficulty in evacuating stools.²⁶ As testing becomes more sophisticated, many patients may be reclassified as having dyssynergic defecation.

Dyssynergic Constipation

Dyssynergic constipation affects about 25% of patients with idiopathic CC and is commonly due to a failure of the pelvic floor or external anal sphincter to relax when one attempts to defecate.²⁷ This may result from anal pain associated with the passage of hard stool, anal fissure, hemorrhoids, incorrect toilet training, or psychosexual troubles.²⁴ Abnormal defecation may also result from transient intra-anal intussusceptions, anterior wall rectal ulcer syndrome, and perineal descent.

Slow-Transit Constipation

Slow-transit constipation accounts for about 13% of idiopathic CC cases and is characterized by the delayed emptying of the proximal colon with fewer high-amplitude peristaltic contractions.^24,27 It may also be associated with cultural factors, loss of neurons from the enteric nervous system, and chronic outlet obstruction.²⁴ Delayed colon transit, which is considerd the hallmark of constipation, exists in about 50% of patients with CC refractory to fiber supplements and is not related to pelvic-floor dyssynergia.²⁵

 

Evaluation of Chronic Constipation

Patient’s Medical History

Because of the frequent discrepancy between patients’ and clinicians’ definitions of CC, a complete medical history should be taken and should include relevant age-, gender-, lifestyle-, and disease-related risk factors.^10,28 Bowel movement infrequency is only 1 component of CC, and it may not be the primary symptom patients consider in decribing themselves as constipated.¹⁷ It is important that PCPs understand the symptom-based criteria for CC and their patients’ complaints and descriptors of their condition.

Patients should be asked how they define constipation and how the onset, severity, and duration of each symptom relate to their normal bowel habits.²⁸ In addition to medical and surgical histories, a complete history for CC should include the description of bowel patterns, identification of social and environmental factors that may affect bowel habits, evaluation of cognitive and functional abilities, cultural beliefs and expectations regarding bowel patterns, and review of diet and fluid intake.²⁸ Clinicians should pay particular attention to patients’ use of prescription and OTC medications known to increase the risk of constipation (TABLE 3).²²

Objective measures can facilitate the diagnosis of CC by providing a common framework for physicians’ and patients’ understanding of the symptoms. The best example is the previously discussed Bristol Stool Form Scale (TABLE 2), which allows patients to indicate which of 7 stool forms any given bowel movement has produced.¹⁵ When used as part of a defecation diary, the Bristol Scale has been validated as being correlated with fecal output and straining/urgency.²⁹ This assessment of stool form can be used to estimate colonic transit time, because very loose or hard stools are correlated with rapid or slow colonic transit, respectively. Other objective instruments with research and clinical value include the Constipation Assessment Scale and the Elderly Bowel Symptom Questionnaire.²⁸

Physical Examination

A medical history and a thorough digital rectal examination should be performed in every patient with CC. The digital rectal examination can reveal whether fecal impactions, anal strictures, or rectal masses are present.²⁴ It can also assess anal sphincter tone and strength, puborectalis muscle tenderness or spasm, and the ability of patients to open the rectal outlet during simulated defecation.

Laboratory, Imaging, and Physiological Testing

In the absence of alarm signs or symptoms (ie, fever, nausea, vomiting, weight loss ≥10 lb, anorexia, blood in the stools, anemia, family history of inflammatory bowel disease or colon cancer, onset of constipation after age 50, or acute onset in the elderly population), data are insufficient to support routine diagnostic testing of constipated patients.¹⁰ The ACG recommends empiric therapy as the first course of action.

Conversely, in constipated patients with alarm signs or symptoms or in persons with signs or symptoms of an organic disorder, laboratory tests (ie, complete blood count, thyroid function tests, urinalysis, and measurements of serum calcium, glucose and electrolytes), as well as flexible sigmoidoscopy, colonoscopy, or barium enema are indicated.¹⁰ The ACG guidelines also recommend routine colon cancer screening in all patients aged 50 years and older, whether or not they are constipated.

Diagnostic studies evaluating physiologic dysfunction use balloon expulsion, defecography, anorectal manometry, and colonic-transit testing, all of which have inadequate experimental support to justify routine clinical use.³⁰ However, because these tests may reveal correctable anomalies, they may be considered in patients with refractory symptoms who do not have a secondary cause of constipation or in whom a high-fiber diet and laxative treatment have proved ineffective.^24,30

 

Treatment of Chronic Constipation

Lifestyle, Diet, and Therapeutic Modifications

Initial management of patients with CC should include education about the physiologic basis and characteristics of normal bowel patterns, diet and lifestyle evaluation, consideration of medical options, and review of concurrent therapy for other conditions that may predispose them to constipation.^21,28,31-33 Patients should be counseled to avoid postponing defecation and to monitor bowel habits with a daily diary of bowel frequency and characteristics along with any emerging abdominal symptoms. Dietary patterns, a sedentary lifestyle, and inadequate fluid intake may promote constipation, especially in elderly patients. Modest exercise may be helpful, although increased exercise and fluid intake may not relieve CC, except in cases of dehydration. When possible, another drug should be substituted for those that may cause constipation.

Phosphate enemas are sometimes used in clinical practice to relieve constipation. However, compelling evidence does not exist to support their clinical effectiveness rather than other medications in the management of CC.³⁴ A number of infrequently reported, but detrimental, complications (eg, hyperphosphatemia, hypernatremia, hypocalcemia, and severe dehydration) associated with enemas limits their use, especially in elders.

Laxatives

Many clinicians and patients consider laxatives as the first-line therapy for constipation.^1,10 These include dietary fiber and other bulking materials, lubricating substances, stimulants, and osmotic agents and are among the most commonly used OTC drugs in the United States.^1,28,32,33 Because most patients are likely to take 1 or more of these agents before seeking medical attention, self-medication is an important part of a patient’s history.²¹

Some patients consume relatively low levels of fiber, which may contribute to the prevalence of CC in the United States.^28,33 Dietary fiber forms viscous gels in the intestine, allowing water retention in the stools and intraluminal volume to increase. This stimulates motility and reduces colonic transit time. Fiber also facilitates defecation by softening stool consistency. Current dietary guidelines recommend 20 to 35 g of fiber per day for adults. Patients with normal-transit constipation may derive the most benefit from increased dietary fiber, but the condition of persons with dyssynergic defecation or slow-transit constipation may not improve and may worsen with more fiber.²¹ Indeed, fiber may increase stool volume, while related bloating and flatulence deter fiber use by some patients.

Bulking laxatives are approved by the US Food and Drug Administration (FDA) for the short-term (up to 2 weeks) treatment of occasional constipation.^1,10,28 However, all randomized controlled trials (RCTs) evaluating these agents have shown suboptimal study design (eg, small population sample, short study duration) and have met few of the Rome criteria.¹⁰ Psyllium increases stool frequency in patients with CC, but insufficient data are available to make a definite recommendation about the efficacy of calcium polycarbophil, methylcellulose, and bran. Patients whose symptoms are refractory to bulking agents or whose disease characteristics preclude their use may benefit from other types of laxatives.²¹

Stimulant laxatives promote colonic motility and alter electrolyte transport across the intestinal mucosa, usually within a few hours after administration.^21,28,32,33 Docusates are surface-active agents that modestly reduce fluid absorption by the colon, thereby increasing stool water and softening stools. Castor oil, which shares the same properties and stimulates intestinal motility, is more potent. Diphenyl-methane derivatives (eg, bisacodyl) inhibit water absorption from the small and large bowels by affecting prostaglandins and other eicosanoids, kinins, and the sodium-potassium ion pump. Anthraquinones (eg, aloe, cascara sagrada, senna) are metabolized to an active form by intestinal bacteria and may enhance motility to a greater extent than their effects on fluid transport. Stimulant laxatives are approved by the FDA for the short-term treatment of occasional constipation.^1,10,28 However, the ACG has concluded that clinical evidence is lacking to make a recommendation regarding the sustained efficacy of stimulant laxatives in patients with CC.^1,10 There is also a concern about their side effects.^21,28,32,33 Some patients may have abdominal discomfort or cramps, while others may suffer from fecal incontinence, loose stools, hypokalemia, or protein-losing enteropathy.

Osmotic laxatives include saline agents, poorly absorbed sugars (eg, lactulose), and polyethylene glycol (PEG). Saline laxatives are salts of magnesium (eg, milk of magnesia) or of poorly absorbed anions (eg, phosphate, potassium, sulfate), which promote excretion of water into the intestinal lumen to maintain an iso-osmotic balance with plasma due to their poor absorbability from the bowel.^32,33 These agents usually take effect in 30 minutes to 3 hours after administration. Because lactulose cannot be absorbed in humans, it promotes water retention intraluminally.^32,33 It also can be fermented by colonic bacteria, producing short-chain fatty acids that have osmotic effects and stimulate intestinal motility. Similar effects result from poorly absorbed sugar alcohols (eg, mannitol, sorbitol), which have also been used in the treatment of CC. High-molecular-weight PEG (ie, PEG-3350) is an inert polymer with an anomalously high osmotic activity that sequesters water in the intestinal lumen. Low doses of PEG-3350 (eg, 17 g daily) are moderately effective and may take up to 2 weeks to yield any significant effect, whereas a single high dose (eg, 68 g) provides overnight improvement of constipation.^28,32,33 Osmotic laxatives are FDA-approved for the short-term treatment of occasional constipation.^1,10,28 (PEG-3350 is available as an OTC medication in the United States.) The ACG guidelines support the use of lactulose and PEG-3350 for improving stool frequency and consistency in patients with CC but do not recommend milk of magnesia based on insufficient evidence.^1,10 Potential side effects of these agents, often resulting from their overuse, include transient flatulence, colic, abdominal cramps and diarrhea, and, in patients with cardiac or renal dysfunction, excessive absorption of magnesium, phosphate, or sodium may lead to electrolyte imbalance and volume overload.^1,32

Neuromuscular Agents

The neuromuscular circuitry of the enteric and extrinsic neural input to the gut provides several targets for pharmacologic intervention for the treatment of CC. Acetylcholine release onto the intestinal musculature is critical to colonic peristalsis.³⁴ Some patients with colonic inertia may have decreased cholinergic nerve activity, either from cholinergic dysfunction within the enteric nervous system or from concomitant therapy with anticholinergic agents (eg, tricyclic antidepressants). Bethanechol, a cholinergic agonist, may yield good results in patients using drugs with peripheral anticholinergic activity.²¹ Neostigmine, a cholinesterase inhibitor, has shown effectiveness in 90% of patients with acute colonic pseudo-obstruction. The side effects of these agents, which include bradycardia, excess salivation, abdominal pain and cramping, and vomiting, can be usually managed with careful dose titration.

The intestinal cholinergic nerve terminals are regulated by other neurotransmitters, most notably serotonin (5-HT).³⁵ Several 5-HT₄ receptor agonists (ie, cisapride, norcisapride, prucalopride, and tegaserod) have been evaluated in patients with CC; none are available in the United States. Tegaserod, which had been approved by the FDA for the treatment of women with IBS-C and CC in adults aged younger than 65 years, was withdrawn from the US market on March 30, 2007, owing to an increased risk of serious cardiovascular (CV) adverse events.³⁶ A retrospective analysis of 29 RCTs revealed a statistically significant imbalance in the incidence of CV ischemic events (ie, myocardial infarction [MI], stroke, and unstable angina pectoris) in patients taking tegaserod (n=11,614) compared with persons receiving placebo (n=7031).³⁷ These events occurred in 13 (0.11%) patients treated with tegaserod compared with 1 (0.01%) placebo-treated patient. All affected patients had preexisting CV disease and/or risk factors. The FDA has requested that:³⁶

• Patients being treated with tegaserod contact their physician to discuss alternative treatments

• Patients taking tegaserod seek immediate emergency medical care should they have severe chest pain, shortness of breath, dizziness, sudden onset of weakness, difficulty walking or talking, or any other symptoms of MI or stroke

• Physicians who have been prescribing tegaserod transition their patients to other therapies adapted to their condition.

The FDA is evaluating whether to allow the limited rein-troduction of tegaserod if an appropriate patient population can be identified in whom the agent’s GI benefits outweigh the CV risks.^36,37

Two other drugs have also been shown to affect colonic neuromuscular activity. Colchicine, a plant alkaloid used to treat gout and known to induce diarrhea as a side effect, increases stool frequency and reduces the need for rescue laxatives in about 10% of CC-affected patients.^21,38 Misoprostol, a prostaglandin analogue with diarrhea as a common side effect when used to treat acid-peptic disorders, increases the rate of intestinal transit in about 25% of patients with severe or refractory CC when titrated to just below the threshold for severe abdominal cramping, a frequent side effect.^21,39,40 Because misoprostol can potentially stimulate uterine contractions, it must not be used during pregnancy or in women who may become pregnant.

Chloride-Channel Activator

Lubiprostone, a targeted bicyclic fatty acid, is the only FDA-ap-proved prescription medication for the treatment of long-term (up to 12 weeks) idiopathic CC in adults.^41,42 This agent locally activates the type-2 chloride channels located in the apical intestinal membrane, thereby increasing intestinal fluid secretion without modifying serum electrolyte concentrations. In RCTs, lubiprostone, 24 μg twice daily, significantly increased spontaneous bowel movements compared with placebo (FIGURE).^43,44 In addition, lubiprostone significantly improved straining and stool consistently during the 4-week treatment period compared with placebo (P<0.001). Adverse events associated with lubiprostone included nausea (31%), diarrhea (13%), headache (13%), and abdominal distention (7%).⁴²

Nonpharmacologic Therapies

Biofeedback has been used in patients with intractable constipation caused by pelvic-floor dyssynergia or functional outlet obstruction.^24,27 This therapy aims to condition the pelvic-floor muscles to relax during defecation by practicing defecation of an intrarectal balloon while monitoring pelvic floor muscle-activity via electromyography. This technique has significantly greater benefit for patients with pelvic-floor dyssynergia than for patients with slow-transit constipation.⁴⁵ Because no published RCTs exist of biofeedback in CC patients, the ACG could not recommend its efficacy or safety.¹ The practice guidelines of the Rehabilitation Nursing Foundation stress that its success may depend on concurrent use of other behavioral management techniques, diet modification, and physical therapy.²⁸

Surgery (ie, total colectomy; partial colectomy with ileorectal, cecorectal, or ileosigmoid anastomosis; segmental resection) has also been used for patients with severe, intractable CC.^46,47 Despite improvement in defecation frequency, some patients continue to experience abdominal pain and require laxatives and enemas.⁴⁶ Long-term follow-up of CC patients who have undergone surgery has revealed a high rate of complications (eg, small-bowel obstruction).⁴⁷

 

Conclusions

Chronic constipation is a highly prevalent, multisymptom GI condition that is associated with significant morbidity, reduced quality of life, and substantial effects on socioeconomics. Because of the common discrepancy between patients’ and clinicians’ definitions of CC, it is important for PCPs to appreciate both the objective diagnostic criteria for CC and patient-centered subjective complaints. To avoid misunderstandings, a comprehensive medical history must include the patient’s meaning of constipation and his or her own bowel patterns.

Although most patients with CC try traditional therapies before consulting a physician, dissatisfaction with lifestyle interventions and OTC medications prompt them to seek medical help. Improved understanding of pathophysiologic mechanisms associated with CC have led to the development of novel therapeutic agents that may improve clinical outcomes, particularly in patients with more severe or refractory idiopathic CC.

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