Naloxone

Naloxone is a competitive mu-opioid receptor antagonist used to reverse life-threatening opioid respiratory depression. Its action lasts 30 to 90 minutes, which is shorter than most opioids, so recurrent respiratory depression is common and observation is essential.

Class. Opioid receptor antagonist.

Mechanism. Competitive blockade at mu, kappa and delta receptors, rapidly displacing opioid agonists. No agonist effect.

Pharmacokinetics. Intravenous onset 1 to 2 minutes, intramuscular or subcutaneous 2 to 5 minutes, intranasal 3 to 5 minutes. Duration 30 to 90 minutes. Half-life 30 to 81 minutes. Poor oral bioavailability because of first-pass metabolism. Hepatic glucuronidation, renal excretion.

Indications are known or suspected opioid overdose with respiratory depression, reversal of opioid-induced respiratory depression after anaesthesia, and neonatal respiratory depression from maternal opioids (specialist).

Adult opioid overdose

• Intravenous: 0.4 to 2 mg, titrated every 2 to 3 minutes to a respiratory rate of 10 breaths/minute or more and adequate ventilation. In chronic opioid users, start with 0.04 to 0.1 mg increments to avoid abrupt withdrawal.
• Intramuscular or subcutaneous: 0.4 to 2 mg, repeated every 2 to 3 minutes if no response.
• Intranasal: 2 mg (or 4 mg in the high-dose product) in one nostril, repeated after 2 to 3 minutes in the other nostril if needed.
• Maximum bolus dose in practice: 10 mg. If no response to 10 mg, reconsider the diagnosis.
• Infusion: two thirds of the total effective bolus dose given hourly (for example 0.4 to 0.8 mg/hour), titrated, for long-acting opioids or large overdoses.

Postoperative opioid-induced respiratory depression. 40 to 80 micrograms (0.04 to 0.08 mg) intravenously, repeated every 2 minutes until ventilation improves, to avoid reversing analgesia and causing hypertension or pulmonary oedema.

Children

• Intravenous: 10 micrograms/kg, repeated at 2 to 3 minute intervals; up to 100 micrograms/kg (maximum 2 mg) in confirmed severe overdose.
• Intramuscular or intranasal: 0.1 mg/kg to a maximum of 2 mg in overdose.
• Neonates: 10 micrograms/kg intravenously or intramuscularly, repeated as needed; avoid in infants of opioid-dependent mothers because it precipitates seizures and severe withdrawal.

Buprenorphine overdose. Larger doses may be needed (initial 2 mg, repeated, then infusion), because of high receptor affinity.

Contraindications. Hypersensitivity to naloxone. Do not use as a test in patients unlikely to have taken opioids. Use with caution in opioid-dependent patients, in neonates of dependent mothers, and in severe cardiovascular disease.

Boxed-warning-level risks. None formal. Abrupt reversal can cause acute withdrawal, agitation, vomiting, tachycardia, hypertension, arrhythmia, seizures and noncardiogenic pulmonary oedema.

Adverse effects. Common: nausea, vomiting, sweating, tachycardia, agitation, tremor, hypertension. Serious: acute opioid withdrawal, pulmonary oedema, ventricular arrhythmia, seizures (especially with tramadol or pethidine toxicity), return of pain and recurrent respiratory depression when the antagonist wears off.

Interactions. Reverses all opioid agonists. Reduced efficacy against buprenorphine at usual doses. May precipitate seizures with tramadol or pethidine overdose.

Common prescribing errors. Giving a large bolus to an opioid-dependent patient (violent withdrawal); discharging a patient too soon after reversal of a long-acting opioid (methadone, modified-release preparations, patch); giving the same dose to a patient on buprenorphine without repeating it; mistaking the sedation for opioid effect without airway support first.

Special groups

• Pregnancy: use if life-threatening; may cause foetal withdrawal.
• Breastfeeding: compatible.
• Older adults: titrate in small increments.
• Kidney and liver impairment: no dose change for single doses; consider longer observation in liver disease.
• Regional: naloxone for community distribution may be available in some programmes; supply and access vary.

Formulations. Injection 0.4 mg/mL, prefilled syringes, intranasal sprays (2 mg and 4 mg), auto-injectors.

Administration. For infusion, dilute 2 mg in 500 mL of 0.9% sodium chloride or 5% glucose (4 micrograms/mL) and titrate. Airway support and oxygen precede and accompany naloxone. Give intravenously if access is secure; use intramuscular or intranasal otherwise.

Baseline. Respiratory rate, oxygen saturation, level of consciousness, pupil size, the opioid involved (including long-acting forms), and dependence status.

Monitoring. Respiratory rate, oxygen saturation and consciousness every few minutes after each dose. Observe for at least 2 hours after the last naloxone dose for a short-acting opioid, and for much longer (often 6 to 24 hours) for methadone, modified-release preparations, fentanyl patches or large ingestions. Observe for pulmonary oedema and withdrawal.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop the bolus doses once respiratory rate is 10 breaths/minute or more with adequate oxygenation. If an infusion is needed, reduce the rate and stop it only after a monitored period.

Referral and escalation. No response to 10 mg total suggests another cause (hypoxia, co-ingestion, head injury, hypoglycaemia). Recurrent respiratory depression needs repeated doses or infusion and admission. Opioid overdose needs a toxicology review, and overdose from intentional ingestion needs psychiatric review.