Naltrexone for Opioid Antagonism

Naltrexone is a long-acting competitive opioid receptor antagonist used to prevent relapse in opioid dependence after detoxification and to reduce relapse in alcohol dependence. It blocks the effects of opioid analgesics and of illicit opioids, so it is also a perioperative and emergency pain-management hazard. It does not treat withdrawal and will precipitate it in anyone still physically dependent on opioids.

Class. Opioid receptor antagonist (pure, competitive, mu preference).

Mechanism. Competitive blockade at mu, kappa and delta receptors, preventing agonist binding. Chronic use may upregulate opioid receptors, so tolerance falls and the risk of overdose rises if opioids are taken after a lapse or after stopping.

Pharmacokinetics. Oral bioavailability 5 to 40% because of extensive first-pass metabolism. Peak within 1 hour. Half-life about 4 hours for naltrexone and about 13 hours for the active metabolite 6-beta-naltrexol. Opioid blockade after 50 mg lasts 24 hours, after 100 mg 48 hours and after 150 mg 72 hours. The extended-release injection gives therapeutic concentrations for about 4 weeks. Metabolised by dihydrodiol dehydrogenase (not by cytochrome P450), with renal excretion of metabolites.

Indications are relapse prevention after opioid detoxification (as part of a supervised programme with psychosocial support) and relapse prevention in alcohol dependence. It has no role in acute opioid overdose, for which naloxone is used.

Before starting (opioid dependence)

• Patient must be opioid-free: at least 7 to 10 days after short-acting opioids and at least 10 to 14 days after long-acting opioids (methadone, buprenorphine). Confirm with a negative urine drug screen and no withdrawal signs.
• Where doubt remains, a naloxone challenge (0.2 mg intravenously, observe for 30 seconds, then 0.6 mg if no reaction) may be used by a specialist; any withdrawal response delays the start.

Adults

• Oral: test dose 25 mg, observe for 1 hour for withdrawal; if none, continue 50 mg once daily. No loading dose.
• Supervised alternatives to improve adherence: 100 mg on alternate days, or 150 mg every third day.
• Extended-release intramuscular injection: 380 mg into the gluteal muscle every 4 weeks, alternating buttocks, after tolerating oral naltrexone.
• Alcohol dependence: 50 mg once daily. Duration is usually 3 months, extended as needed for benefit.
• Maximum 150 mg orally in any single dose.

Children. Not established under 18 years.

Contraindications. Current opioid dependence or use (including opioid analgesics, cough preparations and diarrhoea preparations containing opioids); positive urine opioid screen; acute opioid withdrawal; failed naloxone challenge; acute hepatitis or liver failure; hypersensitivity.

Boxed-warning-level risks. Hepatocellular injury has been described at high doses, although the formal boxed warning has been removed in some regions. Overdose from attempts to overcome the blockade, and overdose after loss of tolerance following missed doses or discontinuation, can be fatal.

Adverse effects. Common: nausea, vomiting, abdominal pain, headache, dizziness, insomnia, anxiety, fatigue, joint and muscle pain. Serious: hepatitis, injection-site reactions (induration, necrosis requiring surgery), eosinophilic pneumonia, depression and suicidal ideation (causal link uncertain), precipitated withdrawal and overdose after relapse.

Interactions. Opioid agonists (analgesics, antitussives, antidiarrhoeals) are blocked, and large doses to overcome the blockade are dangerous. Disulfiram adds hepatotoxicity. Thioridazine with naltrexone has caused lethargy and sedation.

Common prescribing errors. Starting before the opioid-free interval has elapsed (precipitated withdrawal); omitting liver tests; giving opioid analgesia to a patient on naltrexone without recognising the blockade; not warning about reduced tolerance; failing to stop it before elective surgery.

Perioperative points. Stop oral naltrexone at least 72 hours before elective surgery likely to need opioids, and plan the extended-release injection so that surgery falls at least 30 days after the last dose. In emergencies, use non-opioid analgesia (paracetamol, an NSAID, ketamine), regional anaesthesia and local anaesthetics; opioid doses large enough to overcome blockade carry a risk of delayed respiratory depression when blockade wears off.

Special groups

• Pregnancy: limited data; use only if benefit clearly outweighs risk.
• Breastfeeding: small amounts enter milk; short-term use may be acceptable with infant observation.
• Older adults: no adjustment, but reduce the dose if kidney or liver function is poor.
• Kidney impairment: caution with creatinine clearance under 50 mL/min; avoid in severe impairment.
• Liver impairment: avoid in acute hepatitis and decompensated liver disease; caution in mild to moderate disease, with liver tests.
• Regional: availability varies and many programmes use methadone or buprenorphine instead; check supply before starting.

Formulations. Tablets 50 mg, extended-release injectable suspension 380 mg.

Administration. Oral doses with or without food (with food if nausea). Reconstitute the extended-release injection exactly as labelled, using the supplied needle and a deep gluteal injection, never intravenously or subcutaneously.

Baseline. Liver function (ALT, AST, bilirubin), hepatitis B and C status, renal function, urine opioid screen, pregnancy test, opioid-free interval and mental state.

Monitoring. Liver tests monthly for 3 months, then every 3 months. Mental state and mood. Adherence. Withdrawal signs after the first dose. Injection sites.

Therapeutic drug monitoring. Not used.

Dose reduction and stopping thresholds. Stop for ALT or AST over 3 times the upper limit of normal with symptoms, jaundice, severe injection-site reaction or eosinophilic pneumonia. Warn the patient about the loss of opioid tolerance after stopping.

Referral and escalation. Overdose after relapse, precipitated withdrawal, suicidal ideation or hepatitis needs urgent assessment. Treatment is run by or with an addiction or psychiatric service.