Chronic constipation: Update on management
ABSTRACT
Managing chronic constipation involves identifying and treating secondary causes, instituting lifestyle changes, prescribing pharmacologic and nonpharmacologic therapies, and, occasionally, referring for surgery. Several new drugs have been approved, and others are in the pipeline.
KEY POINTS
- Although newer drugs are available, lifestyle modifications and laxatives continue to be the treatments of choice for chronic constipation, as they have high response rates and few adverse effects and are relatively affordable.
- Chronic constipation requires different management approaches depending on whether colonic transit time is normal or prolonged and whether outlet function is abnormal.
- Surgical treatments for constipation are reserved for patients whose symptoms persist despite maximal medical therapy.
STOOL SOFTENERS: LITTLE EVIDENCE
Stool softeners enhance the interaction of stool and water, leading to softer stool and easier evacuation. Docusate sodium and docusate calcium are thought to facilitate the mixing of aqueous and fatty substances, thereby softening the stool.
However, there is little evidence to support the use of docusate for constipation in hospitalized adults or in ambulatory care. A recent review reported that docusate was no better than placebo in diminishing symptoms of constipation.36
INTESTINAL SECRETAGOGUES
The secretagogues include lubiprostone, linaclotide, and plecanatide. These medications are preferred therapy for patients with normal- or slow-transit constipation once conservative therapies have failed. Even though there is no current consensus, lifestyle measures and conservative treatment options should be tried for about 8 weeks.
Lubiprostone and linaclotide are approved by the US Food and Drug Administration (FDA) for both constipation and constipation-predominant irritable bowel syndrome. They activate chloride channels on the apical surface of enterocytes, increasing intestinal secretion of chloride, which in turn increases luminal sodium efflux to maintain electroneutrality, leading to secretion of water into the intestinal lumen. This eventually facilitates intestinal transit and increases the passage of stool.
Lubiprostone
Lubiprostone, a prostaglandin E1 derivative, is approved for treating chronic constipation, constipation-predominant irritable bowel syndrome in women, and opioid-induced constipation in patients with chronic noncancer pain.
Adverse effects in clinical trials were nausea (up to 30%) and headache.37,38
Linaclotide
Linaclotide, a minimally absorbed 14-amino acid peptide, increases intestinal secretion of chloride and bicarbonate, increasing intestinal fluid and promoting intestinal transit.39 It also decreases the firing rate of the visceral afferent pain fibers and helps reduce visceral pain, especially in patients with constipation-predominant irritable bowel syndrome.40 It is approved for chronic constipation and constipation-predominant irritable bowel syndrome.41–43
Dosage starts at 145 μg/day for chronic constipation, and can be titrated up to 290 μg if there is no response or if a diagnosis of constipation-predominant irritable bowel syndrome is under consideration. Linaclotide should be taken 30 to 60 minutes before breakfast to reduce the likelihood of diarrhea.44
Adverse effects. Diarrhea led to treatment discontinuation in 4.5% of patients in one study.42
Plecanatide
Plecanatide is a guanylate cyclase-c agonist with a mode of action similar to that of linaclotide. It was recently approved by the FDA for chronic idiopathic constipation in adults. The recommended dose is 3 mg once daily.
Data from phase 2 trials in chronic constipation showed improvement in straining, abdominal discomfort, and stool frequency after 14 days of treatment.45
A phase 3 trial showed that plecanatide was more effective than placebo when used for 12 weeks in 951 patients with chronic constipation (P = .009).46 The most common adverse effect reported was diarrhea.
SEROTONIN RECEPTOR AGONISTS
Activation of serotonin 5-HT4 receptors in the gut leads to release of acetylcholine, which in turn induces mucosal secretion by activating submucosal neurons and increasing gut motility.47
Two 5-HT4 receptor agonists were withdrawn from the market (cisapride in 2000 and tegaserod in 2007) due to serious cardiovascular adverse events (fatal arrhythmias, heart attacks, and strokes) resulting from their affinity for hERG-K+ cardiac channels.
The newer agents prucalopride,48 velusetrag, and naronapride are highly selective 5-HT4 agonists with low affinity for hERG-K+ receptors and do not have proarrhythmic properties, based on extensive assessment in clinical trials.
Prucalopride
Prucalopride has been shown to accelerate gastrointestinal and colonic transit in patients with chronic constipation, with improvement in bowel movements, symptoms of chronic constipation, and quality of life.49–52
Adverse effects reported with its use have been headache, nausea, abdominal pain, and cramps.
Prucalopride is approved in Europe and Canada for chronic constipation in women but is not yet approved in the United States.
Dosage is 2 mg orally once daily. Caution is advised in elderly patients, in whom the preferred maximum dose is 1 mg daily, as there are only limited data available on the safety of this medication in the elderly.
Velusetrag
Velusetrag has been shown to increase colonic motility and improve symptoms of chronic constipation. In a phase 2 trial,53 the most effective dose was 15 mg once daily. Higher doses were associated with a higher incidence of adverse effects such as diarrhea, headache, nausea, and vomiting.
Naronapride
Naronapride (ATI-7505) is in phase 2 trials for chronic constipation. Reported adverse effects were headache, diarrhea, nausea, and vomiting.54
BILE SALT ABSORPTION INHIBITORS
Bile acids exert prosecretory and prokinetic effects by increasing colonic secretion of water and electrolytes through the activation of adenylate cyclase. This happens as a result of their deconjugation after passage into the colon.
Elobixibat is an ileal bile acid transporter inhibitor that prevents absorption of nonconjugated bile salts in the distal ileum. It has few side effects because its systemic absorption is minimal. Phase 3 trials are under way. Dosage is 5 to 20 mg daily. Adverse effects are few because systemic absorption is minimal, but include abdominal pain and diarrhea.55,56
