What is the recommended medication regimen for opioid‑induced constipation in a patient on chronic opioid therapy?

Medication for Opioid-Induced Constipation

Start a stimulant laxative (senna 2 tablets each morning or bisacodyl 5–15 mg daily) immediately with the first opioid dose, escalate to osmotic laxatives (polyethylene glycol 17 g twice daily) if constipation persists, and reserve peripherally acting μ-opioid receptor antagonists (PAMORAs)—specifically naldemedine 0.2 mg daily—for laxative-refractory cases. 1

First-Line: Prophylactic Stimulant Laxatives

• Begin senna 2 tablets each morning or bisacodyl 5–15 mg daily simultaneously with the first opioid dose—never delay prophylaxis, as up to 80% of patients develop opioid-induced constipation and tolerance to this side effect does not develop. 1

• Increase the laxative dose proportionally whenever the opioid dose is escalated to maintain bowel function. 1

• The therapeutic goal is one soft, non-forced bowel movement every 1–2 days without straining. 1

• Do not add docusate (stool softener) to senna—it provides no additional benefit and is less effective than senna alone. 1

• Avoid supplemental fiber (psyllium, Metamucil)—it is ineffective for opioid-induced constipation and may worsen symptoms. 1

• Maintain adequate fluid intake to support laxative effectiveness. 1

Second-Line: Osmotic Laxatives

• Before escalating therapy, rule out bowel obstruction or fecal impaction with abdominal examination and consider digital rectal exam—escalation in the presence of obstruction risks perforation. 1

• If constipation persists on standard stimulant dosing, increase bisacodyl to 10–15 mg two to three times daily. 1

• Add an osmotic laxative when stimulant therapy alone is insufficient:

  • Polyethylene glycol (PEG) 17 g in 8 oz water twice daily (preferred for safety profile), or 1
  • Lactulose 30–60 mL daily, or 1
  • Magnesium hydroxide or citrate 30–60 mL daily (use cautiously in renal impairment due to hypermagnesemia risk). 1

• Rectal interventions (bisacodyl or glycerin suppositories) may be used if oral agents fail, but avoid in patients with thrombocytopenia or neutropenia. 1

Third-Line: Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs)

Reserve PAMORAs for patients who have failed adequate trials of both stimulant and osmotic laxatives and whose constipation is clearly opioid-related. 1

PAMORA Selection (in order of recommendation strength):

• Naldemedine 0.2 mg orally once daily—strongest recommendation with high-quality evidence for laxative-refractory opioid-induced constipation. 1

• Naloxegol 12.5–25 mg orally once daily—strong recommendation with moderate-quality evidence. 1

• Methylnaltrexone 0.15 mg/kg subcutaneously every other day (maximum once daily)—conditional recommendation with lower-quality evidence, though some network meta-analyses suggest possible superiority; FDA-approved for advanced illness patients requiring palliative care. 1, 2

• PAMORAs block peripheral opioid receptors in the gut without crossing the blood-brain barrier, thus preserving central analgesia. 1

PAMORA Dosing Adjustments:

• Renal impairment (creatinine clearance <60 mL/min): Reduce naldemedine to 150 mg daily (tablets) or methylnaltrexone to 6 mg daily (injection); for methylnaltrexone in advanced illness, use 0.075 mg/kg every other day. 2

• Severe hepatic impairment (Child-Pugh Class C): Reduce naldemedine to 150 mg daily or methylnaltrexone to 6 mg daily. 2

Alternative Strategies for Refractory Cases

• Opioid rotation to fentanyl or methadone may lessen constipating effects when opioid-induced constipation persists despite maximal laxative therapy. 1

• Lubiprostone 24 mcg twice daily (intestinal secretagogue) may be considered, though evidence is more limited compared with PAMORAs. 1

• If gastroparesis is suspected, add metoclopramide 10–20 mg orally four times daily, with caution in elderly patients due to tardive dyskinesia risk. 1

Critical Pitfalls to Avoid

• Never delay prophylactic laxatives—they must start with the first opioid dose, as 80–95% of patients develop constipation and tolerance does not develop. 1

• Do not use stool softeners (docusate) alone without a stimulant laxative—they are ineffective for opioid-induced constipation. 1

• Always exclude bowel obstruction or impaction before escalating stimulant doses or adding PAMORAs—failure to do so risks perforation. 1

• Do not rely on dietary fiber as a preventive or therapeutic measure for opioid-induced constipation. 1

• Avoid magnesium-based laxatives in patients with renal impairment due to hypermagnesemia risk. 1

• Discontinue all maintenance laxative therapy prior to initiating PAMORAs in chronic non-cancer pain patients; laxatives can be used as needed if suboptimal response after three days. 2

• Patients must be within close proximity to toilet facilities once PAMORAs are administered. 2