Background

Chronic constipation is a disorder characterized by unsatisfactory defecation that results from infrequent stools, difficult stool passage, or both over a time period of at least 12 weeks.¹ The diagnosis is primarily symptom-based, relying on the patient's self report of symptoms; however, the description of constipation symptoms varies significantly among patients. Common symptoms may include infrequent bowel movement, hard stool, too small stool, difficulties with stool expulsion (need for excessive straining), feeling of incomplete evacuation or simply a patient description of "a feeling of being constipated" without any of these constipation-related symptoms. While physicians traditionally defined constipation as fewer than three bowel movements per week,² more specific diagnostic criteria have been developed to better specify the nature and duration of symptoms (Table 1).¹

Table 1

Symptom-based criteria for chronic functional constipation.

Chronic constipation appears to be very common in the general population although its prevalence varies depending on the diagnostic criteria used. Estimates suggest that 2% to 28% of the US population suffers from chronic constipation,^{3, 4} with most estimates in the range of 12% to 19%.² Chronic constipation disproportionately affects women compared with men (2.2:1), and the prevalence increases with age.² Although symptoms may be benign, chronic constipation can significantly reduce quality of life, and, if left untreated, can result in fecal impaction, incontinence, and, very rarely, bowel perforation.⁵ Approximately 2.5 million US physician visits are attributed to constipation each year;³ assuming an average cost of approximately $3,000 per patient (in 2007 dollars),⁶ the cost of diagnosing and treating constipation is roughly $7.5 billion annually.

Irritable Bowel Syndrome (IBS) is the most common and best studied functional gastrointestinal (GI) disorder. Epidemiological studies show that 8% to 23% of adults in the Western world have IBS of varying severity.^{7, 8}

IBS symptoms are heterogeneous in their expression. The typifying clinical presentation is abdominal pain or discomfort associated with altered bowel habits (e.g., diarrhea, constipation, or a combination of both at times) and with a change in the consistency or frequency of stools. Other associated symptoms may include bloating, urgency, and/or a feeling of incomplete evacuation. Although symptoms tend to occur in clusters, individual symptoms may also occur sequentially and they may vary in type, location, and severity over time. IBS is classified as diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or mixed—a combination of both (IBS-M), depending on the most prevalent bowel pattern. This sub-classification is determined by stool frequency, form, and passage. However, because the predominant symptom often changes over time, it is not uncommon for a patient to alternate between these IBS subgroups or between different functional bowel disorders such as IBS-C or IBS-D and functional constipation or functional diarrhea.^{7, 8}

There are no biological markers or specific tests for the diagnosis of IBS. The diagnosis is therefore based on identifying a cluster of clinical symptoms that are consistent with the disorder and excluding other conditions by looking for clinical alert signs and performing limited diagnostic testing.

Since the pathophysiological mechanisms underlying the disorder are not known, the current approach to management is based primarily on the patients' predominant symptoms and overall wellbeing rather than on a specific underlying etiological mechanism. The specific treatment is determined by whether pain, diarrhea, or constipation is predominant and the targeted symptom is treated using the same medications as in other conditions. For example, symptom/s of constipation associated with IBS (i.e., IBS-C) are treated in the same way as in functional constipation and symptom/s of diarrhea associated with IBS (i.e., IBS-D) are treated in the same way as in functional diarrhea. Since the treatment of constipation symptoms is similar in the two conditions, we reviewed and included clinical trials related to constipation symptoms in these two conditions (IBS-C and chronic constipation).

Functional constipation is considered one of a group of five functional bowel disorders defined by the Rome III classification system (developed by multinational working teams known as the Rome Committees).⁸ As a functional disorder, constipation can stand on its own as a distinct diagnosis of functional constipation or be part of another functional bowel disorder of IBS. IBS is the most common functional gastrointestinal disorder. It is defined as a combination of chronic or recurrent gastrointestinal symptoms, not explained by structural or biochemical abnormalities. The diagnosis is based on identifying typifying symptoms, using of symptom-based diagnostic criteria, and limited diagnostic tests to exclude other conditions.

In order to meet the criteria patients must have abdominal pain or discomfort associated with alterations in stool frequency, form, and passage. IBS is sub-classified as diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or mixed (combination of both), depending on the most prevalent bowel pattern. However, because the predominant symptom often changes over time, it is not uncommon for a patient to alternate between these IBS subgroups.⁹ This report focuses on functional constipation and does not cover other IBS associated symptoms such as abdominal pain/discomfort, diarrhea, and bloating.

Etiology

There are many causes for constipation. The disorder may be secondary to systemic diseases (e.g., hypothyroidism, hyperparathyroidism, diabetes mellitus), gastrointestinal diseases (e.g., mechanical obstruction due to colon or rectal cancer), neurological disorders (e.g., autonomic neuropathy, Parkinson's disease, multiple sclerosis). Another common etiology is the use of prescription or over the counter (OTC) medications that slow down the intestinal transit (Table 2).

Table 2

Medications associated with constipation.

Chronic primary or idiopathic constipation is primarily a diagnosis of exclusion which is made when the other possible etiologies have been ruled out. Once primary idiopathic constipation has been diagnosed and "red flags" suggesting other serious diseases such as colon or rectal cancer have been eliminated, empiric treatment may be started with an appropriate follow-up to assess the response.

Approach to Management

III. Pharmacologic treatments for chronic constipation

Pharmacologic treatments for chronic constipation (Table 3) include several groups of medications with different mechanism/mode of action.

Table 3

Medications associated with constipation.

Bulk-forming agents are organic polymers that absorb water. These agents increase stool mass and water content thereby making it bulkier, softer and easier to pass. Examples include bran, psyllium and methylcellulose. These agents are often used as the first line treatment of constipation.

Stool softeners, like docusate sodium and docusate calcium, are surface-active agents that facilitate water interacting with the stool in order to soften the stool, make it more slippery, and easier to pass. These agents are often used as OTC medications for constipation.

Osmotic laxatives are poorly absorbed ions or molecules that create an osmotic gradient within the intestinal lumen, drawing water into the lumen and making stools soft and loose. Examples of this group of agents include poorly absorbed electrolytes such as milk of magnesia, magnesium citrate, and sodium phosphate; poorly absorbed disaccharides such as lactulose and sorbitol; and polyethylene glycol 3350 (PEG). These agents are usually used for short-term treatment of constipation or for intermittent use in chronic constipation. The PEG solution is also used for intestinal purges in preparation for diagnostic procedures (e.g., colonoscopy) or surgery.

Stimulant laxatives increase peristalsis in the large bowel and fluid and electrolyte secretion in the distal small bowel and colon. These agents include anthraquinones (senna, cascara, danthron), diphenylmethanes (bisacodyl and phenolphthalein) and castor oil. They are available in different OTC forms and are usually used for intermittent and short term treatment of constipation.

Secretory agents – this group is currently represented by Lubiprostone, a new agent that was recently approved by the US Food and Drug Administration (FDA) for the treatment of chronic idiopathic constipation in adults. It works by activating chloride channels on the small intestinal mucosa and thereby leading to chloride rich intestinal fluid secretion that increases luminal water content and stool hydration.

Prokinetic agents – These agents act by increasing intestinal motility and thereby accelerating intestinal transit. Tegaserod maleate is a 5-HT4 pre-synaptic receptor agonist that enhances the peristaltic reflex, increases colonic motility, decreases visceral hypersensitivity, and facilitates secretion into the colonic lumen. Note that marketing of tegaserod in the US and Canada was suspended in March of 2007 (more than halfway through this review) because of concern regarding serious cardiovascular events.¹² Detailed information regarding these cardiovascular adverse events and the US Food and Drug Administration (FDA) decision regarding the suspension of tegaserod is provided in Key Question 3 (General Risk of Harms) below.

With the exception of lubiprostone and lactulose (and previously, tegaserod maleate), drugs for chronic constipation are available without a prescription (i.e., OTC). They are given once to three times daily and typically work within 12 hours to 1 week. Table 4 summarizes the most common products available in the US and Canada.

Table 4

Drugs for constipation: product information and directions for administration.

Scope and Key Questions

In this report, we review the general and comparative effectiveness, safety, and tolerability of drugs for chronic constipation. Our review covers the use of the following in adults and children with chronic constipation and IBS-C: docusate calcium, docusate sodium, lactulose, lubiprostone, polyethylene glycol 3350, psyllium, and tegaserod. Our review does not include drugs for intermittent or short-term constipation, such as stimulant laxatives.

In March 2007 the FDA issued a public health advisory to inform patients and health care professionals that the sponsor of tegaserod (Zelnorm®) agreed to stop selling the medication because a recent analysis of data from 29 RCTs including 11,614 patients treated with tegaserod found an increased risk of heart attack, stroke, and unstable angina in patients taking the medication.¹² The FDA reported that in clinical studies 0.1% (n = 13) of patients treated with tegaserod experienced serious and life-threatening cardiovascular adverse events, compared with 0.01% (n = 1) of patients on placebo. Of the 13 patients taking tegaserod having these events, four had a heart attack (1 died), six had unstable angina, and three had a stroke. The average age of subjects in these studies was 43 years and 88% were women.

The FDA has agreed to allow access to the medication through a special program when the benefits outweigh the risks of series adverse events or for patients with no other treatment options. The FDA also indicated that it will consider limited re-introduction of the medication at a later date.

The RTI-UNC Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project (DERP). The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

1. What is the general effectiveness of drugs used to treat chronic constipation and chronic constipation associated with Irritable Bowel Syndrome? Given general effectiveness, what is the comparative effectiveness of drugs used to treat chronic constipation and chronic constipation associated with Irritable Bowel Syndrome?
2. Does treatment duration influence the effectiveness of drugs used to treat chronic constipation and chronic constipation associated with Irritable Bowel Syndrome? When should treatments be switched in patients not responding to a given drug?
3. What is the comparative tolerability and safety of drugs used to treat chronic constipation and chronic constipation associated with Irritable Bowel Syndrome?
4. Are there subgroups of patients based on demographics (age, racial or ethnic groups, and gender), other medications, or co-morbidities, including Irritable Bowel Syndrome, for which one symptomatic treatment is more effective or associated with fewer adverse events?