PHILADELPHIA, April 7 - New drug therapies are coming on the market to treat chronic constipation, but it is instructive to examine some of the older approaches and therapies to see what works and what doesn't.
John Johanson, M.D., M.Sc., a clinical associate professor of medicine at the University of Illinois College of Medicine and a member of Rockford Gastroenterology Associates in Rockford, Ill., reviewed the field for a symposium titled, "When the Going Gets Tough: Managing Patients with Chronic Constipation," held in conjunction with the annual meeting of the American College of Physicians here.
Action Points
- For chronic constipation, doctors might first try lifestyle measures such as hydration, increased fiber intake, exercise, and a dedicated time to have a bowel movement. These measures are inexpensive, safe, easy, and involve the patient in their own care.
Dr. Johanson said the goal of therapy for constipation is to improve symptoms that are of concern to the patient. To achieve patient satisfaction, he said the physician must be sure to understand what the patient means by constipation, e.g., whether frequency of bowel movements, straining, or something else.
The first approach is usually lifestyle measures such as hydration, increased fiber intake, exercise, and a dedicated time to have a bowel movement. These measures are inexpensive, safe, easy, and involve the patient in their own care.
If necessary, the next steps would be fiber supplements, followed by laxatives, stool softeners, and enemas. The different kinds of laxatives are bulking agents, osmotic agents, stimulants, lubricants, and stool softeners. Combinations of laxatives may be helpful to take advantage of different mechanisms of action.
The Data
Dr. Johanson said there are no data to indicate that fluid intake or exercise works for chronic constipation. They work in normal people to increase stool frequency and produce softer stools, but about 95% of patients with chronic constipation find no benefit. Nonetheless, he recommends these measures because they are benign and may help 5% of his chronic constipation patients.
Little data exist that confirm that laxatives work for patients with chronic constipation. In a meta-analysis of 11 studies involving 375 patients on various laxatives and 174 individuals on placebo, there was some immediate benefit in the number of bowel movements but no benefit past four weeks, something of no help in chronic constipation.
Laxatives did nothing for straining, which was patients' most common complaint. Depending on the specific class of laxative, they may aggravate nausea, abdominal pain, bloating, flatulence, and cause esophageal or colonic obstruction, metabolic disturbances, hypovolemia, and allergic or even anaphylactic reactions.
Stimulant laxatives may be abused, osmotic laxatives take several days to work, and with many the response is unpredictable, making them inconvenient for patients. A task force of the American College of Gastroenterology in 2005 gave positive recommendations to three laxative classes -- psyllium to increase stool frequency; stool softeners; and polyethylene glycol and lactulose to improve stool frequency and consistency.
New Drugs
Two newer treatment options for chronic constipation have been approved by the Food and Drug administration: Zelnorm (tegaserod, Novartis), a 5-HT4 agonist, and Amitiza (lubiprostone, Takeda), a chloride channel activator. Still under investigation are opioid antagonists, 5-HT4 and 5-HT3 combination drugs, and neurotrophic factors.
Zelnorm is similar in structure to serotonin and is indicated for irritable bowel syndrome for limited times for women only at any age, and for chronic constipation in men and women under 65 years of age. Given at 6 mg orally twice a day, the drug can be used for chronic constipation without time limits. The drug binds serotonin receptors in the gut, stimulates peristalsis, and accelerates oral-cecal transit. A bowel movement occurs for most people within 48 hours, and Zelnorm is the first drug to show benefits on straining.
Amitiza is a gastrointestinal-targeted bicyclic fatty acid that selectively activates the ClC-2 chloride channel. As chloride ions pass into the lumen, sodium follows, followed by water. The result is an enhancement of intestinal fluid secretion.
Dr. Johanson conducted a four-week clinical trial that showed an increase of bowel movements from less than two per week at baseline to five to six per week in the Amitiza group, compared with three per week for the placebo group (P<0.002 for all weekly time points vs. placebo). The proportion of responders at each time point was statistically superior to placebo.
The drug produced a spontaneous bowel movement within 24 hours of the first dose for 61.3% of the people, compared with 31.4% in the placebo group. Therefore the drug worked quickly and predictably. There were no serious adverse effects at the recommended 24 microgram twice-daily dose, no evidence of rebound after discontinuation, and no altered electrolyte levels. This drug also relieved multiple constipation symptoms, including straining, hard stools, and frequency.
Experimental emerging therapies include two drugs that are 5-HT4 agonists/5-HT3 antagonists: renzapride and mosapride. They have a similar mechanism of action and produce clinically significant dose-related acceleration of transit in patients with irritable bowel syndrome but have not yet been studied in chronic constipation. "We don't think there would be any reason why it wouldn't work in those patients," Dr. Johanson said.
Alvimopan is a peripheral mu-opioid antagonist. It has been used in the treatment of acute postoperative ileus and for reversal of delayed colonic transit caused by opioid therapy. Because it does not cross the blood-brain barrier, it did not interfere with analgesia. Treatment-related adverse effects were mild to moderate, mostly bowel related, and occurred during the first week of treatment.
Neurotrophin-3 is a subcutaneous injection, and getting patients to inject themselves for chronic constipation may be a problem, Dr. Johanson believes. At weeks seven to eight, a dose of 9 mg three times weekly was associated with an increase in bowel movement frequency (P<0.0003 vs. placebo), as well as dose-related softening of stool, more rapid colonic transport, and improved constipation symptoms. Adverse effects were mostly mild to moderate with some injection site reactions and upper respiratory infections.
"The interesting thing about a neurotrophic factor is that if it really does cause regrowth of enteric nerves -- and that's one of the things that potentially might be causing constipation -- if this really worked in that manner, it could actually cure constipation rather than treat the symptoms," Dr. Johanson speculated.