Update on constipation: One treatment does not fit all
ABSTRACTConstipation is a common clinical problem that can be difficult to manage. It has a variety of identifiable causes, but even idiopathic constipation has different possible mechanisms. Often, the key to improvement and patient satisfaction is to understand the mechanism and the patient.
KEY POINTS
- A high-fiber diet often improves functional constipation, but it may worsen slow-transit constipation or dyssynergia (a failure of the pelvic floor muscles to relax). Nevertheless, fiber remains a mainstay of treatment for its ability to provide homogeneous stool consistency.
- Drugs approved for treating constipation increase fluid in the lumen, speed intestinal transit, and improve stool consistency, while tegaserod (Zelnorm) additionally acts as a serotonin agonist.
- Colonoscopy and other tests are reserved for patients with refractory constipation and those with symptoms suggesting colon cancer.
- Prebiotics (short-chain carbohydrates that stimulate activity of beneficial colonic bacterial flora) and probiotics (live bacterial preparations) are under evaluation as treatments for chronic constipation.
LUBIPROSTONE
Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.66 It is approved for treating chronic constipation in adults.
In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.67–69
More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.70
The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.68 Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.71 However, adverse events may cause up to 20% of patients to stop taking the drug.69 When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.72
Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.73
OTHER PROMOTILITY AGENTS
Several promotility agents have been studied for treating chronic idiopathic constipation.
Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.77
Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.78 Renzapride has been studied in patients with this condition,78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.
EMERGING TREATMENTS
New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.
Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.82 In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.83
Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.
Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.86 Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.86
Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.88 Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al89 showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.
PROBIOTICS AND PREBIOTICS
The bacteria of the colon influence peristalsis of the colon.90 Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.91,92
Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,93,94Lactobacillus,95 and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.96
Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.97 In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.98
Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.99 A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.100
Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.91 They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.46 Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.91 Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.91,92
