Lubiprostone Safe, Effective for Chronic Constipation in Adults

First Agent Indicated for Elderly Patients

The recently approved lubiprostone (Amitiza; Sucampo/Take da) is only the second nonlaxative prescription medication that is now indicated for the treatment of chronic idiopathic constipation.

Tegaserod maleate (Zelnorm), which initially had been approved for the treatment of constipation-predominant irritable bowel syndrome (IBS) in women, received a new indication for the treatment of chronic constipation in men and women in 2004. But unlike lubiprostone, which can be used in all adults aged ≥18 years, tegaserod is restricted to use in adults under the age of 65. Yet older adults are often the ones more susceptible to this condition.

"What often gets missed in a primary care setting is that chronic constipation is common, and that it actually has an impact on a patient's quality of life," says Anthony J. Lembo, MD, assistant professor of medicine, Harvard Medical School.

Estimates suggest that constipation affects from 12% to 19% of Americans, with women outnumbering men by more than 2 to 1 (Am J Gastroenterol. 2004; 99:750-759). Prevalence increases with age, especially after the age of 65.

Constipation can interfere with daily activities and significantly interfere with work. In the elderly, constipation can diminish physical functioning and inhibit socialization.

The Centers for Disease Control and Prevention reports that constipation is responsible for 2.5 million physician visits each year, half of which are in primary care offices. Thus, says Dr Lembo, "constipation needs to be considered in all patients the primary care physician is seeing."

Diagnostic Criteria

Evaluation begins with ruling out warning signs of serious underlying disease, including unintended weight loss, nighttime pain, rectal bleeding, pelvic pain with defecation, and abnormal physical examination or laboratory findings. Other red flags are a family history of gastrointestinal (GI) cancer or IBS.

The Rome III criteria for the diagnosis of functional constipation in adults include the rare occurrence of loose stools, the exclusion of IBS, plus ≥2 of these for the last 3 months:

? Straining during ≥25% of bowel movements

? Lumpy or hard stools for ≥25% of bowel movements

? Sensation of incomplete evacuation or of anorectal blockage for ≥25% of bowel movements

? Manual maneuvers to facilitate ≥25% of bowel movements (eg, digital evacuation or pelvic floor support)

? <3 bowel movements weekly.

Treatment Challenges

Challenges to the management of chronic constipation in the primary care setting "are not that dissimilar to challenges in the tertiary care setting," Dr Lembo says. "The biggest challenge is getting patients to have a satisfactory bowel movement and finding the right therapy or therapies that will be able to achieve that."

Before seeing a doctor, he says, "Most people with symptoms of chronic constipation have tried 1 or more over-the-counter [OTC] therapies." The Consumer Healthcare Products Association estimates that Americans spent $690 million on OTC laxatives in 2005. Dr Lembo adds that "at least 1 study suggests that about half of them are not completely satisfied with most of the OTC preparations they have tried" (Am J Gastroenterol. 2004; 99:S234).

In a review article published before lubiprostone and tegaserod were approved for the treatment of chronic constipation (N Engl J Med. 2003; 349:1360-1368), Dr Lembo and his coauthor recommended beginning treatment with fiber, then, if needed, an osmotic laxative (eg, saline, magnesium, polyethylene glycol, lactulose), and finally a stimulant laxative (eg, bisacodyl, senna).

He said that while his advice today would be slightly different, "I think you should still begin the therapy with fiber for just about every patient with chronic constipation," with a few exceptions.

"Not giving enough fiber or increasing the dose of the fiber too quickly is probably the biggest pitfall I've seen in the primary care setting," he says, noting that this can happen because most patients do not follow their physician's recommendations for fiber therapy because they have side effects, such as gas or bloating.

One way to improve compliance is to tell patients to increase their intake of dietary fiber gradually over 1 to 2 weeks, beginning with such fiber-rich foods as fruits and vegetables, before turning to commercial fiber supplements. "There are people, especially those with mild constipation, who may improve if they can get the proper dose of fiber," which he defined as at least 12 to 15 g of added fiber per day.

A second choice after fiber is an osmotic laxative, he says. If that does not help, "I would consider tegaserod or lubiprostone after that, depending on the patient, of course, before turning to a stimulant laxative." He suggests that "tegaserod and lubiprostone probably offer better satisfaction with bowel movements than most stimulant laxatives, which often cause cramps and sometimes diarrhea."

Lubiprostone versus Tegaserod

Lubiprostone represents a new class of agents called chloride channel openers. "It increases secretions in the gut by opening chloride channels," Dr Lembo says. This increased intestinal fluid enhances intestinal motility, facilitating the passage of stool.

"Tegaserod is a promotility agent that enhances peristaltic reflexes by stimulating the 5HT4 receptor," he adds. This mimics the serotonin effects, normalizing motility in the GI tract. Tegaserod also inhibits visceral sensitivity and stimulates intestinal secretion.

Based on mechanism of action alone, "It's unclear whether you can a priori pick out a patient who may respond better to one versus the other."

Since there have been no head-to-head studies, "you can't make direct comparisons between the 2 products." Both agents have shown efficacy in long-term, 12-month, open-label studies. In shorter-term, placebo-controlled trials, improvements in symptoms of straining, abdominal distension/bloating, abdominal discomfort/pain, as well as in stool consistency and frequency, have been reported with both drugs. "They both have long-term data, and that's why they both have long-term indications for the treatment of chronic constipation," he points out.

Both agents have a low potential for important drug?drug interactions. The biggest difference is "that tegaserod is approved only for people between the ages of 18 and 65, whereas lubiprostone is approved for ages 18 and beyond" (Table).

The package insert for tegaserod includes a precaution about reports of ischemic colitis, but Dr Lembo speculates that the higher rate of ischemic colitis in people with irritable bowel symptoms who were included in the trials "may account for some of those postmarketing reports."

He says, "I couldn't say if one is better than the other." But when it comes to patients >65 years, he notes that for those with IBS symptoms, tegaserod may be preferred, noting that "there is an overlap between IBS and chronic constipation."

Hospitalization, Quality of Life

"Often primary care physicians do not consider constipation to be a significant issue for patients. I think there is more awareness now that constipation is an issue that needs to be dealt with. Although it may not have significant mortality, it does have significant morbidity," Dr Lembo notes.

He emphasizes that mortality and morbidity are serious issues in the elderly, who are often hospitalized because of constipation (Figure). "But even for the average healthy person, she may not have to be hospitalized, but it certainly can have an impact on her overall quality of life."