Naloxone

Indications

• FDA-approved for emergency treatment of known or suspected opioid overdose with respiratory or central nervous system depression, at any age.
• The 4 mg nasal spray moved to over-the-counter status in 2023, followed by a 3 mg over-the-counter product, so no prescription is required.
• Also approved for postoperative reversal of opioid depression and as a diagnostic aid when opioid overdose is suspected but unconfirmed.
• CDC and ASAM advise co-prescribing to patients on 50 morphine milligram equivalents daily or more, on concurrent benzodiazepines, or with any opioid use disorder history.
• Included in buprenorphine-naloxone products purely as an injection deterrent, not for any therapeutic antagonist effect when taken sublingually.
• Give it when overdose is suspected even if the substance is unknown, because naloxone is harmless when no opioid is present.

Mechanism of action

• Competitive antagonist at mu, kappa and delta opioid receptors with highest affinity for mu, displacing agonists from the receptor.
• Reverses opioid-induced respiratory depression, sedation, miosis and hypotension within minutes of reaching the central nervous system.
• Has no intrinsic agonist activity, so it produces no effect at all in a person who has not taken opioids.
• Precipitates acute withdrawal in opioid-dependent patients, which is intensely unpleasant and carries aspiration and agitation risk.
• Oral bioavailability is under 2% because of near-total first-pass metabolism, which is why it must be given by injection or intranasally.

Pharmacokinetics

• Onset is 1-2 min intravenously and 2-5 min by intramuscular or intranasal route, with the 4 mg spray matching roughly 0.4 mg intramuscular exposure.
• Clinical duration is only 30-90 min, far shorter than methadone, extended-release oxycodone or large fentanyl and fentanyl-analogue exposures.
• Elimination half-life is 30-90 min in adults but substantially longer in neonates, in whom it can approach 3 h.
• Metabolized in the liver by glucuronidation to naloxone-3-glucuronide with subsequent renal excretion of conjugated metabolites.
• The short duration relative to most opioids is the single most important pharmacokinetic fact: renarcotization is expected, not exceptional.

Dosing

• Intranasal: 4 mg into one nostril (or 3 mg or 8 mg products), repeated every 2-3 min in alternating nostrils until breathing resumes.
• Intramuscular or subcutaneous: 0.4 mg repeated every 2-3 min; the prefilled 5 mg/0.5 mL syringe is available for high-potency exposures.
• Intravenous in a hospital with a dependent patient: titrate 0.04-0.4 mg to restore adequate respiration, not to restore full consciousness.
• Continuous infusion at roughly two-thirds of the effective bolus dose per hour is appropriate after overdose with methadone or extended-release opioids.
• Pediatric dosing is 0.1 mg/kg IV or IM up to 2 mg; avoid routine use in neonates of opioid-dependent mothers because seizures may follow.
• Always activate emergency services, provide rescue breathing, place the patient on their side and observe for at least 2 h after the last dose.

Adverse effects

• Precipitated withdrawal with nausea, vomiting, diaphoresis, agitation, tachycardia, hypertension and piloerection is the expected effect in dependent patients.
• Vomiting in an obtunded patient carries real aspiration risk, so recovery position and airway attention matter as much as the drug.
• Non-cardiogenic pulmonary edema and ventricular arrhythmias have followed abrupt complete reversal, particularly in postoperative patients.
• Severe uncontrolled pain returns immediately when naloxone is given to a patient receiving opioids for legitimate analgesia.
• Nasal formulations cause nasal dryness, congestion, headache and nasal discomfort, all minor relative to the indication.
• Return of overdose as naloxone wears off is the leading cause of death after apparently successful field reversal.

Monitoring

• Continuous respiratory rate, oxygen saturation and level of consciousness until the patient is reliably breathing on their own.
• Observe at least 2 h after the last dose, and considerably longer after methadone, extended-release opioids or massive fentanyl exposure.
• Anticipate the need for repeat doses or an infusion, and keep additional naloxone immediately available at the bedside.
• Assess and treat precipitated withdrawal symptomatically rather than by giving opioids, which risks a second overdose.
• Use the encounter to offer buprenorphine initiation and direct linkage to ongoing treatment, which reduces subsequent mortality.

Interactions

• Reverses every opioid analgesic and antitussive, so anticipate uncontrolled pain and sympathetic surge in surgical patients.
• Buprenorphine binds mu receptors so tightly that reversal may require larger repeated doses or a continuous naloxone infusion.
• Precipitates withdrawal in patients maintained on methadone or buprenorphine, sometimes lasting hours beyond the naloxone itself.
• Has no meaningful cytochrome P450 interactions and no dose adjustment for concurrent psychotropic medications.
• Does not reverse benzodiazepine, alcohol, stimulant, clonidine or gabapentinoid toxicity, though it is safe to give while sorting that out.

Special populations

• Pregnancy: give it to save the mother, but titrate to restore respiration since abrupt reversal can precipitate fetal distress and preterm labor.
• Lactation: essentially no oral bioavailability in the infant, so naloxone is considered compatible with breastfeeding.
• Pediatric and neonatal use is established at 0.1 mg/kg, with the caution that neonates of dependent mothers may seize on rapid reversal.
• Geriatric patients tolerate reversal less well because the catecholamine surge can provoke arrhythmia or pulmonary edema, so titrate slowly.
• Renal or hepatic impairment requires no dose change in emergency use, although clearance is slower and re-dosing may be needed less often.

Clinical pearls

• Naloxone lasts 30-90 min; fentanyl and methadone last far longer. Call 911 and stay.
• In a dependent patient titrate 0.04-0.4 mg IV to breathing, not to full consciousness.
• The 4 mg nasal spray is over the counter; put it in the hands of everyone on opioids.