Methylnaltrexone

Methylnaltrexone is a quaternary derivative of naltrexone that acts as a peripherally acting mu-opioid receptor antagonist. It does not cross the intact blood brain barrier, so it relieves opioid-induced constipation without reversing analgesia. It is available as a subcutaneous injection and an oral tablet.

Classification. Peripherally acting mu-opioid receptor antagonist.

Mechanism. Binds mu-opioid receptors in the gut to counter opioid-induced reduction in motility and secretion. The positive charge of the quaternary ammonium group limits entry into the brain.

Pharmacodynamics. After a subcutaneous dose, laxation occurs within 4 hours in about half of patients, and often within 30 to 60 minutes.

Pharmacokinetics. Subcutaneous bioavailability about 82%. Half-life about 8 hours. Oral bioavailability is low (about 11%), hence the 450 mg tablet dose. About half is excreted unchanged in urine and faeces.

Metabolism. Minor conversion to methyl-6-naltrexol isomers. Little cytochrome P450 involvement.

Adult doses.

Opioid-induced constipation in advanced illness (including palliative care), when response to laxatives has been inadequate.

• Subcutaneous injection every other day as needed; maximum one dose in 24 hours.

• Dose by body weight:

- Under 38 kg: 0.15 mg/kg.

- 38 to under 62 kg: 8 mg.

- 62 to 114 kg: 12 mg.

- Over 114 kg: 0.15 mg/kg.

• Stop other laxatives while assessing the response.

Opioid-induced constipation in chronic non-cancer pain.

• Subcutaneous: 12 mg once daily.

• Oral: 450 mg once daily in the morning.

Dose adjustments.

• Subcutaneous, advanced illness, CrCl under 30 mL/min: reduce the dose by 50% (4 mg for 38 to under 62 kg; 6 mg for 62 to 114 kg; 0.075 mg/kg for other weights).

• Subcutaneous, chronic non-cancer pain, CrCl under 60 mL/min: 6 mg once daily.

• Oral, CrCl under 60 mL/min: 150 mg once daily.

• Oral, moderate to severe liver impairment: 150 mg once daily.

Children. Not established.

Contraindications. Known or suspected mechanical gastrointestinal obstruction; hypersensitivity.

Common adverse effects. Abdominal pain, flatulence, nausea, diarrhoea, dizziness, sweating and injection site reaction.

Serious adverse effects.

• Gastrointestinal perforation, particularly with peptic ulcer, diverticulitis, malignancy or Ogilvie syndrome; stop for severe, persistent or worsening abdominal pain.

• Opioid withdrawal symptoms, more likely when the blood brain barrier is disrupted.

• Severe or persistent diarrhoea.

• Hypersensitivity reactions.

Major interactions.

• Other opioid antagonists: avoid.

• Other laxatives: stop maintenance laxatives before starting.

• Minimal cytochrome P450 interactions.

• Drugs that slow gastric emptying may delay oral absorption.

Special groups.

• Pregnancy: avoid; limited data and risk of opioid withdrawal in the foetus.

• Breastfeeding: avoid; unknown.

• Children: not established.

• Older adults: no adjustment.

• Kidney impairment: reduce the subcutaneous and oral doses when CrCl is under 30 mL/min (advanced illness) or under 60 mL/min (chronic non-cancer pain).

• Liver impairment: reduce the oral dose in moderate to severe impairment.

• Regional: limited availability and high cost in East Africa.

Formulations. Injection 12 mg in 0.6 mL (20 mg/mL) vial or prefilled syringe; tablets 150 mg.

Subcutaneous administration.

• Inject into the upper arm, abdomen or thigh; rotate sites.

• Do not inject into the same site repeatedly or into tender, bruised or scarred skin.

• No dilution is needed.

• Protect vials from light and store at room temperature.

• Do not give intravenously.

Oral administration. Take in the morning on an empty stomach, at least 30 minutes before the first meal; swallow whole.

Baseline. Exclude obstruction and perforation risk; kidney function; liver function for oral dosing.

Monitoring.

• Bowel response within 4 hours of the first dose.

• Abdominal pain and diarrhoea.

• Opioid withdrawal symptoms and pain control.

• Kidney function.

Therapeutic drug monitoring. Not applicable.

Stopping. No taper is needed. Stop for severe abdominal pain, perforation, withdrawal or when the opioid is stopped.

Referral and escalation. Urgent imaging and surgical review for severe abdominal pain, fever or peritonism. Palliative care or pain specialist input if analgesia is affected.