Peripheral Opioid Receptor Antagonists for Constipation

Peripherally acting mu opioid receptor antagonists block opioid effects in the gut without reversing central analgesia. They treat opioid-induced constipation that has not responded to laxatives.

Pharmacokinetics. Methylnaltrexone is a quaternary compound with poor central penetration. Naloxegol and naldemedine are substrates of P glycoprotein, which limits brain entry. Naloxegol is cleared by CYP3A4.

• Methylnaltrexone subcutaneously, every other day as needed (not more than one dose in 24 hours): 8 mg for 38 to under 62 kg; 12 mg for 62 to 114 kg; 0.15 mg/kg for other weights. Oral 450 mg once daily.
• Naloxegol 25 mg orally once daily in the morning on an empty stomach; 12.5 mg if creatinine clearance is under 60 mL/min or with moderate CYP3A4 inhibitors.
• Naldemedine 200 microgram orally once daily.
• Alvimopan for postoperative ileus after bowel resection, in hospital only.

Differences. Methylnaltrexone is useful when swallowing is impaired. Naloxegol has important CYP3A4 interactions.

• Opioid-induced constipation after inadequate response to a stimulant plus an osmotic laxative.
• Stop other laxatives when starting the antagonist, then add them back if needed.

Selection. Evidence is stronger in non-cancer pain; palliative use is established. Cost and availability are limited in many East African settings.

Contraindications. Known or suspected gastrointestinal obstruction. Recent gastrointestinal surgery. Risk of perforation: active diverticular disease, peptic ulcer, Crohn disease, colorectal cancer or peritoneal metastases. Naloxegol with strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir).

Adverse effects. Abdominal pain, diarrhoea, flatulence, nausea, opioid withdrawal syndrome, and gastrointestinal perforation.

Interactions. Strong CYP3A4 inhibitors raise naloxegol levels; inducers such as rifampicin lower them. Other opioid antagonists give additive withdrawal.

Special groups.

• Kidney impairment: methylnaltrexone subcutaneous dose halved when creatinine clearance is under 30 mL/min; naloxegol 12.5 mg when under 60 mL/min.
• Liver impairment: avoid naloxegol in severe impairment; limited data for the others.
• Pregnancy: avoid; precipitated withdrawal in the foetus.
• Breastfeeding: limited data; avoid.
• Older adults: no adjustment, but check kidney function.

Monitoring. Bowel function, abdominal pain and signs of withdrawal.

Referral and escalation. Severe, persistent or worsening abdominal pain, vomiting or distension needs urgent assessment for perforation or obstruction.