DDW: Chronic Constipation Treatments: A Review of the Evidence

WASHINGTON, May 23 -- Anorectal biofeedback, probiotics, and the type-2 chloride channel activator lubiprostone all seem to be effective therapeutic options in chronic constipation. PEG 3550 is only for short-term use.
So said panelists who presented the latest evidence-based approaches for treating chronic constipation at an industry-sponsored symposium held here in conjunction with Digestive Disease Week.

They also reviewed the status of tegaserod and other 5-HT agonists.

Looking first at biofeedback, Nicholas J. Talley, M.D., Ph.D., of the Mayo Clinic in Rochester, Minn., noted that a randomized controlled trial published online this year by the journal Diseases of the Colon and Rectum confirmed the efficacy of the technique in chronic constipation.

In the study, biofeedback patients had significantly more unassisted bowel movements after three months than those on placebo, Dr. Talley said. About 65% of patients said they were satisfied with the treatment, compared with less than 40% of the placebo group (P=0.017).

He also referred to a study published last year in Gastroenterology that showed that biofeedback compared favorably to the osmotive laxative PEG 3550. Nearly 80% of the biofeedback-treated patients reported major improvement in symptoms, compared with less than 30% of the patients treated with PEG 3550 (P<0.01), Dr. Talley said.

However, noted Brooks D. Cash, M.D., of the Uniformed Services University of the Health Sciences, in Bethesda, Md., the laxative PEG 3550 is indicated only for short-term (no more than two weeks) treatment of constipation, not for long-term treatment. For that indication, the drug is supported by a series of well-designed studies, and it has a "grade A" recommendation from the American College of Gastroenterology task force, he said.

The drug became available in a non-prescription, over-the-counter form in March of this year, Dr. Cash said, noting that the non-prescription formulation should be used for no more than seven days.

Dr. Cash also reviewed recent events surrounding 5-HT agonists. Tegaserod was withdrawn from the market on March 30, 2007, because of reports of serious cardiovascular adverse events, including myocardial infarction, he said. The 5-HT agonist pergolide was withdrawn at about the same time because of similar concerns, he added.

The 5-HT agonist alosetron was suspended from the market in November 2000 because of reports of ischemic colitis and severe constipation. However, Dr. Cash said, the drug was re-introduced with a risk management program in April of 2002. It's indicated for women with severe irritable bowel syndrome.

In contrast, probiotics are getting increasing attention among gastroenterologists, Dr. Cash said. In a recent parallel, double-blind study of 72 healthy adult volunteers, the daily ingestion of fermented milk containing Bifidobacterium animalis decreased total colonic transit time by 21% and sigmoid transit time by 39%, he noted. The study suggests that regular intake of probiotics may help achieve a more regular intestinal transit, he said.

The type-2 chloride channel activator lubiprostone, approved by the FDA in January 2006 for the treatment of chronic idiopathic constipation in adults, is also proving to be an effective option, said Eugene Chang, M.D., of the University of Chicago, Ill.

In a two-week, randomized, placebo-controlled trial published last year, lubiprostone demonstrated slowed gastric emptying but accelerated small intestinal and colonic transit times in healthy subjects, Dr. Chang said.

Chloride and bicarbonate secretion are important to normal physical functioning of the gastrointestinal tract because they provide an aqueous phase for digestion and absorption of food, hydrate mucus, and purge intestinal pathogens and noxious agents, Dr. Chang said.

Studies published in the American Journal of Gastroenterology in 2005 found that, compared with placebo, lubiprostone increased the number of spontaneous bowel movements after four weeks and was associated with the onset of a first spontaneous bowel movement in 61% of treated patients compared with 31% of placebo-treated patients (P<0.0001), added Dr. Cash.

Lubiprostone has been shown to be well-tolerated with short-term (four weeks) and long-term (six to 12 months) use, he said. The most common adverse events associated with this medication included nausea, diarrhea, and headache, he said, adding that nausea can be decreased if the drug is taken with food.

Arnold Wald, M.D., of the University of Wisconsin at Madison, reviewed the diagnostic tests most commonly used identify constipation. These include colonoscopy, colon transit studies, the balloon expulsion test, and anorectal manometry, he said.

While the clinical evidence supporting the latter three was good, Dr. Wald noted, the evidence that colonoscopy is useful for diagnosing constipation is poor. It simply has a "low yield" in detecting chronic constipation, he said.

Chronic constipation is a multi-symptom disorder that leads to an estimated 2.5 million office visits and between 30,000 and 90,000 hospitalizations per year, the presenters noted.

DDW: Lubiprostone Effective in Irritable Bowel Syndrome

WASHINGTON, May 22 -- A drug approved for chronic constipation also appears to be effective to treat the condition when it is associated with irritable bowel syndrome (IBS-C), a researcher said here.But the benefit can be achieved with a dose of lubiprostone (Amitiza) that is a third of that needed to treat chronic constipation, according to Douglas Drossman, M.D., of the University of North Carolina in Chapel Hill.
The finding emerged from two industry-supported studies, involving 1,167 patients in 130 centers, Dr. Drossman said during Digestive Disease Week sessions.
The report came after Novartis halted sales on March 30 of tegaserod (Zelnorm), its agent for irritable bowel syndrome and constipation, following suggestions of a small increase in ischemic events, including angina and stroke, in those taking the drug.
Lubiprostone, a type-2 chloride channel activator, improved symptoms in phase II studies of patients with IBS-C, Dr. Drossman said.
He and colleagues conducted a parallel randomized, double-blind, placebo-controlled studies whose endpoint was significant or moderate improvement on a seven-point scale.
Patients were randomized to placebo or 8 mcg of lubiprostone twice daily. The recommended dose for chronic constipation is 24 mcg twice daily.
The combined studies found that patients getting lubiprostone were nearly twice as likely to achieve overall response. It was 17% for the medication, compared with 10.1% for placebo - a difference that was significant at P=0.001.
Individually, each study also showed a significant benefit for lubiprostone, at P=0.009 and P=0.031.
The drug was well-tolerated, Dr. Drossman said, with a similar rate of serious adverse events in treatment and placebo arms. The most common treatment-related adverse effects were nausea (8% for lubiprostone versus 4% for placebo) and diarrhea (6% versus 4%, respectively).
The findings suggest "we can get benefit for pain in the lower dose, while still achieving benefit in terms of constipation" Dr. Drossman said.
The studies add to the weapons a doctor can deploy to aid patients with the condition, commented Maria Abreu, M.D., of Mount Sinai in New York, who moderated a press conference where they were discussed.
"It's a big group of people and a group of people who are miserable," said Dr. Abreu, who was not involved in the research.
IBS-C poses "very vexing problems," Dr. Abreu said, because the most unpleasant symptom is pain, which is hard to quantify.
In this study, she said, "the absolute difference between placebo and response seems very small but you have to take into account that there's no objective criteria for pain."
The bottom line, Dr. Abreu said, is "I would use it as first-line therapy for some patients with constipation-predominant IBS, on the basis of these studies."

DDW: Popcorn and Nuts Exonerated in Diverticulosis

WASHINGTON, May 21 -- Forget that time-honored advice to diverticulosis patients to shun hard-to-digest foods like nuts and popcorn, said investigators here. Indeed, evidence from a large cohort of health professionals suggests that popcorn may even have a protective effect against the complications of diverticulosis, Lisa Strate, M.D., of the University of Washington in Seattle, said during Digestive Disease Week sessions.
Those complications -- infection, inflammation, and bleeding -- affect between 10% and 30% of patients with diverticulosis, she said, and can require hospitalization.
To avoid that, doctors have warned patients to stay away from nuts, corn, and popcorn, even though some of those foods -- nuts in particular -- are known to have health benefits.
"The recommendation has evolved over the past 60 or 70 years," Dr. Strate said. "It simply stems from a theory that trauma was one of the causes of diverticular complications and that these foods would be more likely to traumatize the colon wall."
To test the theory, Dr. Strate and colleagues turned to the long-running Health Professionals Follow-up Study, which enrolled more than 50,000 men between the ages of 40 and 75.
Starting in 1986, men with newly diagnosed diverticular disease or complications were sent supplemental questionnaires asking of details of treatment and diagnosis. Dr. Strate said.
The records have been collected since 1986 but no one looked at them until now, Dr. Strate said.
Analyzing the 47,454 men who were free of diverticular disease at baseline she and colleagues found there were 383 new cases of diverticular bleeding and 801 new cases of diverticulitis after 18 years of follow-up.
Using the 131-item dietary questionnaires filled out by participants every two years, they divided the cohort into those who ate nuts, corn or popcorn frequently (two or more times a week) and those who did so rarely (less then once a month).
A multivariate analysis showed that:
Eating nuts frequently was associated with a 20% reduction in the risk of diverticular complications (no tests of statistical significance were provided).
Men with the highest popcorn intake (at least two times per week) had a hazards ratio for diverticular complications of 0.71 (95% CI 0.56-0.90; P for trend 0.18) when compared to men with the lowest popcorn intake (less than once per month).
And there was no association between any of the three foods and diverticular bleeding.
For doctors, the take-home message is that patients who enjoy nuts and popcorn should keep on eating them, she said, although she said it's probably too early to recommend popcorn as a protection again the disease.
The finding is good news for patients who like popcorn, said Maria Abreu, M.D., of Mount Sinai in New York, who moderated a press conference where Dr. Strate discussed her findings.
A significant proportion of older Americans has diverticulosis "and they've all been told by their doctors to strictly avoid nuts and corn and popcorn," said Dr. Abreu, a gastroenterologist who was not involved in the research.
"When patients come in who've eaten any of those foods any time in the past year, their episode of diverticulitis or bleeding is blamed on the popcorn," she said.