Test your medicine knowledge with the MKSAP challenge, in partnership with the American College of Physicians.

A 35-year-old woman is evaluated for constipation. She reports passage of hard stool every 3 to 4 days and associated bloating. Her symptoms have been present for more than 10 years and have progressed gradually. Trials of over-the-counter fiber supplementation and polyethylene glycol worsened the bloating, prompting discontinuation. Senna tea was ineffective. Bisacodyl caused abdominal cramping. She is otherwise healthy and currently takes no medication.

On physical examination, vital signs and other findings are normal.

Which of the following is the most appropriate treatment?

A. Lactulose
B. Linaclotide
C. Methylnaltrexone
D. Rifaximin

MKSAP Answer and Critique

The correct answer is B. Linaclotide.

Linaclotide is the most appropriate treatment for this patient. Linaclotide is a peripherally acting guanylate cyclase-C receptor agonist that is FDA approved for the treatment of chronic idiopathic constipation in adults. Linaclotide increases intracellular and extracellular cyclic guanosine monophosphate, which results in chloride and bicarbonate secretion into intestinal lumen, increasing intestinal fluid content and accelerated transit time. Its superiority to placebo in the treatment of constipation was demonstrated in two 12-week, high-quality randomized controlled trials. Diarrhea occurred in 16% of patients receiving linaclotide (compared to 4.7% in those receiving placebo) in the 12-week clinical trials. The potential for diarrhea can be minimized by taking linaclotide on an empty stomach, ideally 30 minutes before the first meal of the day. Plecanatide is the second guanylate cyclase-C receptor agonist to receive FDA approval for the treatment of chronic idiopathic constipation. Diarrhea was also the most commonly reported side effect of plecanatide therapy in the 12-week clinical trials (5% versus 1% in the placebo group). Lubiprostone, a chloride channel agonist, is a third agent with FDA approval for the treatment of chronic idiopathic constipation. The most common side effects reported in clinical trials were nausea, reported by 29% of patients taking lubiprostone, and diarrhea, reported by 12%. The efficacy and safety of linaclotide, plecanatide, and lubiprostone have not been established in patients aged younger than 18 years nor in pregnant patients.

Because of cost effectiveness, over-the-counter laxatives, such as fiber supplements, polyethylene glycol, and bisacodyl, should be pursued first in patients with constipation, but they were ineffective in this patient.

Osmotic laxatives include magnesium hydroxide, lactulose, sorbitol, and polyethylene glycol (PEG); clinical trials have demonstrated the superiority and safety of PEG. The patient tried over-the-counter PEG, and it was poorly tolerated due to bloating. Substituting another, less effective, osmotic agent (for example, lactulose) will lead to similar adverse effects without relieving constipation.

Methylnaltrexone, an injectable peripheral opioid antagonist that does not cross the blood-brain barrier, is very effective in treating opioid-induced constipation without adversely affecting analgesia. Bowel obstruction is an absolute contraindication to methylnaltrexone. Because this patient does not have opioid-induced constipation, methylnaltrexone is an inappropriate choice.

Rifaximin is a nonabsorbable antibiotic used in the treatment of irritable bowel syndrome predominated by diarrhea, hepatic encephalopathy, and travelers’ diarrhea. It has no proven efficacy in chronic idiopathic constipation and is therefore not indicated in this patient.

Key Point

• Linaclotide is a peripherally acting guanylate cyclase-C receptor agonist that is FDA approved for the treatment of chronic idiopathic constipation in adults with symptoms refractory to first-line therapies.

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