Opioid Antagonists

Opioid antagonists bind opioid receptors with high affinity and no intrinsic activity, displacing agonists and reversing their effects. They are used to treat opioid-induced respiratory depression and overdose, opioid-induced constipation and, for naltrexone, relapse prevention in opioid and alcohol use disorder.

Mechanism. Competitive antagonism at mu, delta and kappa receptors. Naloxone is short-acting and parenteral. Naltrexone is long-acting and oral or depot. Methylnaltrexone and naloxegol are peripherally restricted and do not reverse central analgesia.

Pharmacokinetics. Naloxone: onset within 2 minutes intravenously, 5 minutes intramuscularly; duration 30 to 90 minutes, shorter than most opioids; extensive first-pass metabolism, so not given orally. Naltrexone: oral half-life 4 hours, active 6-beta-naltrexol 13 hours; depot lasts 4 weeks.

Naloxone.

• Opioid overdose with respiratory depression, adult: 0.4 to 2 mg intravenously, repeated every 2 to 3 minutes, to a total of about 10 mg; intramuscular or subcutaneous 0.4 to 2 mg; intranasal 4 mg.
• Postoperative or analgesic reversal: dilute 400 micrograms in 10 mL and give 40 to 100 micrograms every 2 minutes until respiration is adequate, to preserve analgesia.
• Infusion after reversal: two thirds of the effective bolus dose each hour.
• Child: 10 micrograms/kg intravenously, repeated; 100 micrograms/kg may be used if there is no response.

Naltrexone. Oral 25 mg test dose, then 50 mg daily; depot 380 mg intramuscularly every 4 weeks. Start only after 7 to 10 days opioid-free, confirmed by a negative naloxone challenge; contraindicated with opioid analgesics.

Methylnaltrexone. Subcutaneous 8 mg (38 to 61 kg) or 12 mg (62 to 114 kg) on alternate days; 0.15 mg/kg outside this weight range; halve the dose if CrCl is under 30 mL/min.

Naloxegol and naldemedine. Naloxegol 25 mg orally daily (12.5 mg with renal impairment or CYP3A4 inhibitors); naldemedine 200 micrograms daily.

Alvimopan. Hospital use to speed bowel recovery after bowel resection.

• First-line. Naloxone for life-threatening opioid-induced respiratory depression or opioid poisoning.
• Alternative. Methylnaltrexone, naloxegol or naldemedine for opioid-induced constipation unresponsive to two laxatives; naltrexone for relapse prevention in opioid or alcohol dependence.
• Specialist. Naloxone infusion for long-acting opioids; naloxone for neuraxial opioid pruritus.
• Emergency. Naloxone for suspected opioid poisoning, including with unknown agents when respiration is under 8 breaths/minute or the patient is comatose with pinpoint pupils.

Principles. In overdose, the aim is adequate breathing, not full consciousness. Support ventilation with a bag-valve-mask before and during naloxone. Observe for at least 2 hours after the last dose, and longer after long-acting opioids (methadone, modified-release preparations, buprenorphine, fentanyl patches).

Buprenorphine. Reversal needs larger doses (2 mg or more) and an infusion; respiratory support is the priority.

Contraindications. Naloxone: hypersensitivity only. Naltrexone: current opioid use, acute hepatitis, liver failure. Peripheral antagonists: known or suspected gastrointestinal obstruction.

Serious adverse effects.

• Naloxone: acute opioid withdrawal with agitation and vomiting; pulmonary oedema, arrhythmia, hypertension and seizures after large or abrupt reversal; return of respiratory depression when the opioid outlasts naloxone.
• Naltrexone: hepatotoxicity (boxed-warning-level), injection-site reactions, loss of opioid tolerance and risk of fatal overdose after relapse.
• Methylnaltrexone: abdominal pain and gastrointestinal perforation.

Major interactions. Naloxone and naltrexone abolish opioid analgesia and precipitate withdrawal in dependent patients; naloxegol with strong CYP3A4 inhibitors (avoid) and moderate inhibitors (reduce dose).

Common prescribing errors.

• Giving full overdose doses to postoperative patients, reversing analgesia.
• Too little or no repeat after reversal of long-acting opioids.
• Discharge after a single naloxone dose.
• Starting naltrexone too early.
• Ignoring airway support.

Special groups.

• Pregnancy: naloxone is used when needed; it may precipitate foetal withdrawal in dependent mothers.
• Breastfeeding: compatible.
• Children: 10 micrograms/kg intravenously, repeated; neonates of opioid-dependent mothers need cautious dosing because of withdrawal seizures.
• Older adults: titrate gently.
• Kidney: halve methylnaltrexone and naloxegol.
• Liver: avoid naltrexone in acute hepatitis.
• East Africa: naloxone supply and opioid-dependence services vary between facilities and may be limited: confirm naloxone stock wherever opioids are given, because supply varies between facilities.

Monitoring. Respiratory rate, saturation and sedation continuously until stable and for at least 2 hours after the last dose; repeat dosing if respiration falls; liver enzymes at baseline and monthly for 3 months on naltrexone.

Referral and escalation. Admission for monitored care after long-acting opioid poisoning, repeated naloxone doses or infusion; intensive care for persistent hypoventilation, aspiration or pulmonary oedema; addiction services for all opioid overdoses.

Comparison with alternative classes. Antagonists are the only specific reversal agents for opioids; supportive ventilation is the alternative when antagonists are unavailable or contraindicated. Peripheral antagonists preserve analgesia but need laxatives to have failed first.