What are the alternatives to prucalopride (Resolor) for treating chronic constipation?

Alternatives to Prucalopride for Chronic Constipation

For patients with chronic constipation who cannot use prucalopride (Resolor), the best alternatives are linaclotide and plecanatide, which are both strongly recommended with moderate certainty of evidence by current guidelines. 1

First-Line Options (Before Prescription Medications)

Before considering prescription alternatives to prucalopride, patients should try over-the-counter (OTC) options:

• Osmotic laxatives: Polyethylene glycol (PEG), lactulose, or magnesium salts increase water in the large bowel 1
• Stimulant laxatives: Senna is suggested with low certainty of evidence, starting at a lower dose and increasing if needed 1
  • Common side effects include abdominal pain and cramping at higher doses 1

Prescription Alternatives to Prucalopride

Strongly Recommended Options (Moderate Evidence)

1. Linaclotide

   • Mechanism: Guanylate cyclase-C agonist that increases intestinal fluid secretion 1
   • Dosing: Taken daily, trials conducted for 12 weeks 1
   • Side effects: May cause diarrhea leading to treatment discontinuation 1
   • Can be used as replacement for or adjunct to OTC agents 1

2. Plecanatide

   • Mechanism: pH-dependent guanylate cyclase-C agonist 1
   • Dosing: 3 mg daily taken with or without food 1
   • Efficacy: Increases complete spontaneous bowel movements (CSBMs) and improves stool consistency 1
   • Side effects: Higher risk of diarrhea leading to discontinuation, though absolute risk is small 1
   • May have beneficial effects on abdominal pain based on IBS-C trial data 1

Conditionally Recommended Option (Low Evidence)

Lubiprostone

• Recommendation strength: Conditional with low certainty of evidence 1
• Implementation: Can replace or supplement OTC agents 1
• Duration: Trials lasted 4 weeks, but no limit in drug labeling 1
• Side effect management: Nausea risk is dose-dependent and reduced when taken with food and water 1

Comparing Mechanisms of Action

Understanding the different mechanisms can help select the most appropriate alternative:

• Prucalopride: Selective 5-HT4 receptor agonist that promotes enteric neurotransmission, stimulating peristaltic reflex, intestinal secretions, and GI motility 1, 2
• Linaclotide/Plecanatide: Guanylate cyclase-C agonists that increase intestinal fluid secretion 1
• Lubiprostone: Chloride channel activator 1

Special Considerations

• Efficacy comparison: Prucalopride directly stimulates colonic motility, differentiating it from other medications approved for chronic constipation in the last decade, which are exclusively osmotic or chloride secretagogues 2
• Cardiovascular safety: Unlike earlier 5-HT4 agonists (cisapride, tegaserod), prucalopride does not interact with cardiac hERG potassium channels or other serotonergic receptors in blood vessels 2
• Elderly patients: Limited data on differences in outcomes related to age with plecanatide 1, while prucalopride efficacy in persons 65 years and older is comparable to the overall population 1

Treatment Algorithm

1. Start with OTC agents (osmotic laxatives like PEG)
2. If inadequate response, add stimulant laxative (senna)
3. If still inadequate, choose one prescription medication based on:
   • Linaclotide or Plecanatide: First choice alternatives (strong recommendations)
   • Lubiprostone: Consider if other options contraindicated or unavailable

Monitoring and Expectations

• Most common side effects with prescription alternatives are gastrointestinal (diarrhea, nausea, abdominal pain) 1
• Improvement should be assessed by:
  • Increase in complete spontaneous bowel movements
  • Improved stool consistency
  • Patient-reported satisfaction and quality of life 3

Pitfalls to Avoid

• Failing to try adequate doses of OTC agents before moving to prescription alternatives 1
• Not warning patients about potential initial side effects that may resolve with continued treatment 1
• Using older 5-HT4 agonists (cisapride, tegaserod) that have cardiovascular safety concerns 2
• Not considering the patient's specific constipation subtype when selecting alternatives 4