What are the newer medications for treating constipation?

Newer Medications for Constipation

The newer medications for constipation include peripherally acting μ-opioid receptor antagonists (methylnaltrexone, naloxegol, naldemedine), secretagogues (linaclotide, plecanatide, lubiprostone), and selective 5-HT4 receptor agonists (prucalopride), which offer effective treatment options beyond traditional laxatives for various types of constipation. 1

Secretagogues

Linaclotide

• FDA-approved guanylate cyclase-C agonist for treating irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults, and functional constipation in pediatric patients 6-17 years of age 2
• Activates chloride channels in intestinal epithelium, enhancing intestinal fluid secretion and accelerating transit 3, 4
• Recommended adult dosages: 290 mcg daily for IBS-C, 145 mcg or 72 mcg daily for CIC; pediatric dosage (6-17 years): 72 mcg daily 2
• Take on empty stomach at least 30 minutes before meals 2
• Most common side effect is diarrhea, which can be severe in some cases 1, 2
• Has shown effectiveness in improving stool frequency, consistency, and abdominal pain 5, 6

Plecanatide

• pH-dependent guanylate cyclase-C agonist approved for CIC at a dose of 3 mg daily 1
• Also approved for IBS-C at the same dose 1
• May improve stool consistency based on the Bristol Stool Form Scale compared with placebo 1
• Higher risk of diarrhea leading to discontinuation, though absolute risk appears small 1
• Duration of treatment in clinical trials was 4-24 weeks 1

Lubiprostone

• Orally active prostaglandin analog that activates chloride channels to enhance intestinal fluid secretion 1
• FDA-approved for treatment of CIC in adults, OIC in adult patients with chronic non-cancer pain, and IBS-C in women at least 18 years old 7
• Less likely to cause diarrhea than other secretagogues, but nausea is a frequent side effect 1
• Can be used in combination with peripherally acting μ-opioid receptor antagonists such as methylnaltrexone 1

Peripherally Acting μ-Opioid Receptor Antagonists

Methylnaltrexone

• Provides effective relief of opioid-induced constipation (OIC) while preserving opioid-mediated analgesia 1
• Recommended dose: 0.15 mg per kilogram of body weight every other day (no more than once/day) 1
• Should not be used in patients with postoperative ileus or mechanical bowel obstruction 1
• FDA approved for OIC in adults with advanced illness who are receiving palliative care 1

Naloxegol

• Peripherally-acting μ-opioid receptor antagonist for treating OIC in patients receiving chronic opioids for noncancer pain 1
• FDA approved for OIC in adults with chronic noncancer pain, including those with chronic pain related to previous cancer or treatment 1

Naldemedine

• FDA approved for OIC in adults with chronic noncancer pain, including those with chronic pain related to prior cancer or treatment 1
• Works on receptors in the gastrointestinal system to relieve constipation related to opioid therapy 1

Selective 5-HT4 Receptor Agonist

Prucalopride

• Selective, high-affinity 5-HT4 agonist that promotes neurotransmission by enteric neurons, stimulating peristaltic reflex, intestinal secretions, and GI motility 1
• FDA-approved for treatment of chronic idiopathic constipation (CIC) in adults 8
• Recommended dose: 2 mg daily 1
• May be associated with side effects including headache, abdominal pain, nausea, and diarrhea 1
• Strong recommendation for use in adults with CIC who do not respond to over-the-counter agents 1

Treatment Algorithm for Constipation

1. First-line treatments:

   • Traditional laxatives: osmotic (polyethylene glycol) and stimulant laxatives (senna, bisacodyl) 1
   • For opioid-induced constipation: prophylactic treatment with stimulant laxatives 1

2. Second-line treatments (when first-line fails):

   • For chronic idiopathic constipation: secretagogues (linaclotide, plecanatide, lubiprostone) or prucalopride 1
   • For IBS-C: linaclotide (290 mcg), plecanatide (3 mg), or lubiprostone (for women) 1, 2, 7
   • For opioid-induced constipation: peripherally acting μ-opioid receptor antagonists (methylnaltrexone, naloxegol, naldemedine) 1

Important Clinical Considerations

• Before initiating newer medications, assess for and treat other causes of constipation (hypercalcemia, hypokalemia, hypothyroidism, diabetes mellitus) 1
• Rule out impaction or obstruction before starting treatment 1
• Peripherally acting μ-opioid receptor antagonists should not be used in patients with known or suspected mechanical bowel obstruction 1
• Monitor for diarrhea with secretagogues, which can lead to dehydration in some patients, particularly with linaclotide and plecanatide 1, 2
• For patients with refractory constipation, consider combination therapy (e.g., lubiprostone with methylnaltrexone) 1
• The American Gastroenterological Association recommends lubiprostone and linaclotide as treatment options for constipation associated with irritable bowel syndrome 1