What is the recommended treatment for constipation refractory to over‑the‑counter agents?

Treatment for Constipation Refractory to Over-the-Counter Medications

For constipation that fails to respond to OTC laxatives, perform anorectal testing to identify defecatory disorders, then escalate to prescription secretagogues (linaclotide, plecanatide) or the prokinetic prucalopride as second-line therapy. 1, 2

Initial Steps Before Escalation

Before advancing treatment, ensure you have:

• Discontinued all constipating medications (opioids, anticholinergics, calcium channel blockers) that can be safely stopped 1
• Ruled out secondary causes through basic laboratory testing: thyroid function, calcium, and glucose to exclude hypothyroidism, hypercalcemia, and diabetes 1
• Performed a digital rectal examination to assess for fecal impaction and signs of pelvic floor dysfunction (paradoxical contraction during straining) 1
• Confirmed an adequate trial of first-line therapy: fiber supplementation and/or osmotic laxatives (polyethylene glycol 17g daily) or stimulant laxatives (bisacodyl, senna) for at least 4-6 weeks 2, 3

Diagnostic Testing for Refractory Cases

Anorectal testing should be performed in all patients who fail first-line laxatives (strong recommendation, high-quality evidence). 1

This diagnostic approach identifies whether the constipation is due to:

• Defecatory disorders (dyssynergic defecation/pelvic floor dysfunction) – present in a substantial proportion of refractory cases 1
• Slow-transit constipation – requires colonic transit studies if anorectal testing is normal 1, 4
• Normal-transit constipation – the most common subtype that may respond to newer agents 5

The testing sequence includes:

• High-resolution anorectal manometry combined with a balloon expulsion test to diagnose pelvic floor dysfunction 1, 3
• Colonic transit study if anorectal testing is normal and symptoms persist 1, 4

Treatment Based on Diagnostic Findings

If Defecatory Disorder is Identified

Pelvic floor retraining by biofeedback therapy is recommended over continued laxative use (strong recommendation, high-quality evidence). 1

• Biofeedback therapy improves symptoms in more than 70% of patients with defecatory disorders 1
• This approach teaches patients to relax pelvic floor muscles during straining and restore normal rectoanal coordination 1
• Refer to a physical therapist experienced in pelvic floor retraining 3

If Normal or Slow-Transit Constipation Without Defecatory Disorder

Escalate to prescription secretagogues or prokinetics as second-line therapy (strong recommendation). 2

The 2023 AGA-ACG guidelines recommend the following second-line agents:

Secretagogues (Guanylate Cyclase-C Agonists)

• Linaclotide 145 mcg or 290 mcg once daily on an empty stomach, 30 minutes before a meal (strong recommendation) 2, 6

  • Stimulates intestinal fluid secretion and accelerates transit 6, 3
  • Trial for at least 4-6 weeks before switching agents 3
  • Common adverse effect is diarrhea; instruct patients to stop and contact you if severe diarrhea or unusual abdominal pain occurs 6

• Plecanatide as an alternative secretagogue (strong recommendation) 2

Prokinetic Agent

• Prucalopride (5-HT4 receptor agonist) accelerates colonic transit (strong recommendation) 2, 5

The choice between linaclotide and prucalopride often depends on insurance coverage and patient co-payment, as both have similar efficacy profiles. 3

If the first agent fails after 4-6 weeks, switch to the alternative class (e.g., from secretagogue to prokinetic or vice versa). 3

Stimulant Laxatives for Short-Term or Rescue Use

• Bisacodyl or sodium picosulfate can be used for short-term (≤4 weeks) or rescue therapy (strong recommendation) 2, 7
• Despite historical concerns, there is little evidence that routine stimulant laxative use causes colonic harm 8

Special Consideration: Opioid-Induced Constipation

If constipation is opioid-related and refractory to laxatives:

• Naldemedine is recommended over no treatment (strong recommendation, high-quality evidence) 1
• Naloxegol is an alternative peripherally-acting μ-opioid receptor antagonist (PAMORA) (strong recommendation, moderate-quality evidence) 1
• Methylnaltrexone 0.15 mg/kg subcutaneously every other day for laxative-refractory opioid-induced constipation 8

Critical caveat: Do NOT use methylnaltrexone or other PAMORAs in patients with mechanical bowel obstruction or postoperative ileus. 9, 6

Surgical Options for Truly Refractory Cases

Surgery is reserved for severe, well-documented slow-transit constipation after failure of aggressive, prolonged trials of all medical therapies (laxatives, fiber, prokinetics). 1

• Total colectomy with ileorectal anastomosis is the definitive surgical treatment 1
• Must exclude coexistent upper GI motility disorders and defecatory disorders before surgery 1
• Only 5% of highly selected cases in tertiary referral centers ultimately require surgery 1, 8
• Patients must understand the procedure treats constipation but may not relieve other symptoms like abdominal pain 1

Common Pitfalls to Avoid

• Do not continue repeating failed first-line therapies (fiber, osmotic laxatives) indefinitely; escalate to prescription agents after an adequate 4-6 week trial 3, 4
• Do not skip anorectal testing in refractory cases, as undiagnosed defecatory disorders will not respond to any laxative or prokinetic 1
• Do not use bulk-forming laxatives in patients with limited mobility or fluid intake due to obstruction risk 8
• Do not prescribe PAMORAs for non-opioid-related constipation or in patients with mechanical obstruction 1, 9