Constipation in Emergency Medicine Medication

The mainstay of treatment of constipation is a high-fiber diet. Bulking agents usually are the next line of treatment. Enemas can be used to assist in complete stool evacuation. Avoid irritant or peristaltic stimulants (eg, senna). Chronic use has been reported to induce damage to the myenteric plexus, which may eventually impair bowel motility. A number of newer agents have been developed and can be added to the armamentarium for treatment of this potentially debilitating disease such as prucalopride, a 5HT4 receptor agonist, and lubiprostone, a chloride channel activator.^[6]

Class Summary

These agents are used to increase fecal mass, which stimulates peristalsis.

Psyllium (Metamucil, Fiberall)

Promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

Methylcellulose (Citrucel)

Promotes bowel evacuation by forming a viscous liquid and promoting peristalsis.

Class Summary

These agents act by retaining fluid in the bowel, osmosis, or altering the pattern of water distribution in feces.

Magnesium hydroxide (Phillips' Milk of Magnesia)

Causes osmotic retention of fluid, which distends colon and increases peristaltic activity. This in turn promotes emptying of the bowel.

Sodium phosphate (Fleet enema)

Through osmotic effects, these agents draw water from the intestine into the lumen of the gut, producing distention and promoting bowel emptying.

Polyethylene glycol solution (MiraLax)

For treatment of occasional constipation. In theory, less risk of dehydration or electrolyte imbalance with isotonic polyethylene glycol compared with hypertonic sugar solutions. Laxative effect generated because polyethylene glycol is not absorbed and continues to hold water by osmotic action through small bowel and colon, resulting in mechanical cleansing.

Supplied with measuring cap marked to contain 17 g of laxative powder when filled to indicated line. May require 2-4 d (48-96 h) to produce bowel movement.

Lactulose (Cephulac, Cholac, Constilac)

Produces an osmotic effect in the colon, resulting in distention and promoting peristalsis. Action may take up to 48 h.

Class Summary

Lower surface tension of stool and allow mixing of aqueous and fatty substances, thereby softening stool.

Docusate sodium (Colace, Surfak)

Allows the incorporation of water and fat into stool causing softening of stool.

Class Summary

Emollient stool softeners cause stool to soften. Stimulants increase peristaltic activity in the GI.

Docusate sodium and casanthranol combination (Peri-Colace, Diocto C, Silace-C)

Docusate sodium allows incorporation of water and fat into stool causing stool to soften.

Casanthranol is an anthraquinone stimulant hydrolyzed by colonic bacteria into active compound. Usually produce action 8-12 h after administration.

Class Summary

In a randomized, placebo-controlled, parallel-group, phase-3 multicenter trial, patients with severe chronic constipation received placebo or 2 mg or 4 mg of prucalopride once daily for 12 weeks. The primary measure of efficacy in the clinical trials is 3 or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week. Twelve weeks of treatment with prucalopride 2 mg and 4 mg once daily resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint than with placebo. There was also significantly improved bowel habit and associated symptoms and patient satisfaction with bowel habit and treatment.^[7]

Prucalopride

Not available in the US. Selective, high-affinity 5-hydroxytryptamine 4 receptor agonist. Serotonin-4 receptors are involved in initiating peristalsis in the intestines.

Class Summary

These agents may stimulate peristaltic activity by partially activating serotonin type 4 receptors.

Tegaserod was temporarily withdrawn from the US market in March 2007 at the request of the FDA; tegaserod marketing was suspended because of a meta-analysis of safety data pooled from 29 clinical trials that involved more than 18,000 patients. The results showed an excess number of serious cardiovascular adverse events, including angina, myocardial infarction, and stroke, in those taking tegaserod compared with placebo.

In each study, patients were assigned at random to either tegaserod or placebo. Tegaserod was taken by 11,614 patients, and placebo was taken by 7,031 patients. The average age of patients in these studies was 43 years, and most patients (ie, 88%) were women. Serious and life-threatening cardiovascular adverse effects occurred in 13 patients (0.1%) treated with tegaserod; among these, 4 patients had a heart attack (1 died), 6 had unstable angina, and 3 had a stroke. Among the patients taking placebo, only 1 (0.01%) had symptoms suggesting the beginning of a stroke that went away without complication.

On July 27, 2007, restricted use of tegaserod was permitted via a treatment investigational new drug (IND) protocol. The treatment IND will allow tegaserod treatment of irritable bowel syndrome with constipation (IBS-C) or chronic idiopathic constipation (CIC) in women younger than 55 years who meet specific guidelines. Its use was further restricted to those in critical need who have no known or preexisting heart disease.

Novartis, the manufacturer of tegaserod (Zelnorm), voluntarily withdrew the product from the market in April 2008. Novartis has agreed to produce the drug for use in only emergency situations. Requests for use in this situation should be made to the FDA, which, in turn, will authorize shipment of the drug by the manufacturer. For more information, see the FDA Med Watch Product Safety Alert.

Tegaserod (Zelnorm)

Available in US for emergency use. An emergency situation is defined as one that is immediately life-threatening or serious enough to qualify for hospitalization. Serotonin type 4 (5-HT4) receptor partial agonist with no affinity for 5-HT3 receptors. May trigger peristaltic reflex via 5-HT4 activation, which enhances basal motor activity and normalizes impaired GI motility. Research studies have shown inhibitory activity of the drug on visceral activity in the GI tract.

Class Summary

Two peripherally active opioid antagonists, methylnaltrexone bromide and alvimopan, have been approved by the FDA. They do not affect the central effects of analgesia. Both agents have been shown to improve opioid-induced increased gastrointestinal transit time and constipation when compared with placebo.^{[8, 9]}

Methylnaltrexone bromide (Relistor)

It is a derivative of naltrexone and does not cross the blood-brain barrier. It acts as a selective antagonist at peripheral opioid receptors without blocking the central analgesic effects. Opioids cause smooth muscle relaxation and consequently impair normal intestinal contractility. Methylnaltrexone bromide blocks the opioid receptors on the intestinal muscle cells, thus permitting the bowels to function normally.

Alvimopan (Entereg)

In May 2008, the FDA approved the drug for the treatment of opioid-induced constipation and postoperative ileus. Alvimopan is a peripherally acting mu-opioid receptor antagonist. The drug does not impact the central effects of analgesia.

Class Summary

These agents may assist in increasing GI motility.

Lubiprostone is indicated for treatment of irritable bowel syndrome with constipation (IBS-C) in women ≥18 years and received approval by the FDA in April 2008. In the same year, it was the focus of a study by Sweetser et al on colonic sensory and motor function.^[10] No overall effects of lubiprostone were noted on the end points of compliance, fasting tone, motility indexes, or sensation. However, a treatment-by-sex interaction for compliance was noted in women (P = 0.02). Lubiprostone induced a decreased fasting compliance in women (P = 0.06) and an overall decreased colonic tone contraction after a standard meal relative to fasting tone (P = 0.014), with greater effect in women (P < 0.01). Sweetser et al concluded that lubiprostone did not increase colonic motor function.

In 2008, Johanson et al also did work to assess the efficacy and safety of lubiprostone in adults with chronic constipation.^[11] The study had 242 patients who received oral lubiprostone 24 mcg or placebo twice daily for 4 weeks. The primary efficacy end point was the number of spontaneous bowel movements (SBMs) as well as BM characteristics, constipation severity, abdominal bloating/discomfort, global treatment effectiveness rating, and safety assessments. Their results showed that lubiprostone-treated patients reported a greater mean number of SBMs compared with placebo-treated patients (5.69 vs 3.46, P = 0.0001).

In 2010, Barish et al also looked at lubiprostone versus placebo to assess efficacy in patients with chronic constipation.^[12] They also demonstrated a significantly greater number of SBMs in the lubiprostone group when compared with placebo. The lubiprostone-treated patients also reported significant improvement in stool consistency, straining, and constipation severity at all weeks and abdominal bloating at week 1.

An investigational drug, linaclotide, has just been put through a phase 3 clinical trial to assess its efficacy and safety in patients with chronic constipation.^[13] Data suggest that linaclotide statistically improved each of the constipation and abdominal symptoms measured for each of the 2 doses studied (133 mcg or 266 mcg oral once-daily dosing) over the 12-week study period. In a phase 2b study in patients with chronic constipation, linaclotide showed statistically significant reduced abdominal pain, abdominal discomfort, bloating and severity of straining, and increased CSBMs frequency throughout the 12-week treatment period versus placebo for all doses studied (75, 150, 300, and 600 mcg oral once-daily dosing). The most common and only dose-related adverse event was diarrhea.^[14]

Linaclotide (Investigational Drug)

A first-in-class compound, linaclotide is an agonist of guanylate cyclase type-c (a receptor found in the lining of the intestine.) Activation of these receptors lead to an increase in cyclic guanosine monophosphate, anion secretion, fluid secretion, and intestinal transit.

Lubiprostone (Amitiza)

A gastrointestinal system-targeted bicyclic functional fatty acid that acts as a chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum. Specifically activates C1C-2, an apical membrane in the human intestine. Increases intestinal fluid secretion to assist in GI motility and the transit of stool in the gut, thereby decreasing symptoms of chronic idiopathic constipation (eg, abdominal pain, bloating, straining, hard stools).