Naltrexone

Indications

• FDA-approved for alcohol use disorder in adults, cutting heavy drinking days and relapse risk; oral 50 mg/day or extended-release 380 mg IM monthly.
• FDA-approved for blockade of exogenous opioid effects and prevention of relapse to opioid dependence in adults after complete opioid detoxification.
• Extended-release injectable naltrexone matched buprenorphine-naloxone on relapse in the X:BOT trial once induction succeeded, but induction failed far more often.
• Off-label with bupropion for methamphetamine use disorder, the regimen tested in ADAPT-2; response rates are modest but clearly exceed placebo.
• Off-label for gambling disorder, kleptomania, trichotillomania and self-injurious behavior in intellectual disability, on small-trial evidence only.
• Marketed with bupropion as Contrave for chronic weight management; naltrexone alone is not indicated for obesity or for smoking cessation.

Mechanism of action

• Competitive antagonist at mu-opioid receptors with weaker kappa and delta blockade, abolishing euphoria and analgesia from full opioid agonists.
• In alcohol use disorder it blunts the endogenous opioid surge triggered by drinking, reducing alcohol-induced reward and cue-driven craving.
• The effect falls mainly on heavy drinking days and drinks per occasion rather than on total abstinence, so patients can drink through it.
• No agonist activity at any dose, so there is no euphoria, no tolerance, no physical dependence and no withdrawal syndrome on stopping.
• OPRM1 A118G genotype may predict a stronger response to naltrexone, but pharmacogenetic testing is not part of routine practice.

Pharmacokinetics

• Oral absorption is nearly complete but heavy first-pass metabolism leaves roughly 5-40% bioavailability; food does not require a dose change.
• Metabolized by hepatic dihydrodiol dehydrogenase rather than CYP450 to the active metabolite 6-beta-naltrexol, which circulates far longer.
• Plasma half-life is about 4 h for naltrexone and 13 h for 6-beta-naltrexol; a 50 mg oral dose blocks opioid receptors for roughly 24 h.
• The intramuscular suspension peaks at 2 h and again at 2-3 days, then delivers sustained exposure with an apparent half-life of 5-10 days.
• Excreted renally as metabolites; compensated cirrhosis raises exposure several-fold, and there are no data in severe renal impairment.

Dosing

• Confirm the patient is opioid-free for 7-10 days (10-14 days after methadone) and consider a naloxone challenge or urine screen before dose one.
• Oral: start 25 mg once daily for one to two days to test tolerability, then 50 mg daily; alternate-day 100 mg dosing can support observed therapy.
• Extended-release: 380 mg IM into the gluteal muscle every 4 weeks, alternating sides, using only the supplied needle, diluent and technique.
• For alcohol use disorder treatment may begin while the patient is still drinking; abstinence is not required before the first dose.
• No taper is needed on discontinuation, but opioid tolerance is lost during treatment, so counsel on overdose risk and dispense take-home naloxone.
• No adjustment for mild to moderate hepatic or renal impairment; avoid in acute hepatitis or hepatic failure and use caution in severe renal disease.

Adverse effects

• Nausea in roughly 10-33%, plus headache, dizziness, fatigue, insomnia and anxiety, are the usual early complaints and fade over one to two weeks.
• Injection-site reactions affect up to 50% of depot recipients; induration, cellulitis, sterile abscess and rare necrosis need prompt evaluation.
• Dose-related transaminase elevation occurs; the old hepatotoxicity boxed warning was removed in 2013, but liver monitoring remains prudent.
• Opioid analgesia is blocked, so emergency pain control requires regional anesthesia, non-opioid agents or titrated opioids with airway monitoring.
• Precipitated withdrawal follows dosing in an opioid-dependent patient and is prolonged and severe with the depot because it cannot be removed.
• Depressed mood and suicidal ideation have been reported; monitor mood, recognizing that untreated substance use disorder itself carries this risk.

Monitoring

• Baseline liver function tests and periodic transaminases, especially with hepatitis C, alcohol-related liver disease or other hepatotoxic drugs.
• Urine drug screen covering opioids, oxycodone, methadone and buprenorphine before initiation and before each depot injection.
• Pregnancy test in people of childbearing potential, a baseline renal panel, and inspection of injection sites at every depot visit.
• Track drinking days, heavy drinking days and craving using the timeline followback, AUDIT-C or the Penn Alcohol Craving Scale.
• Reassess at 3 months; if heavy drinking persists despite adherence, consider acamprosate, disulfiram or off-label topiramate.

Interactions

• Contraindicated with any full opioid agonist, including methadone, buprenorphine, codeine-containing cough syrups and antidiarrheals such as loperamide.
• Blocks opioid analgesics and antitussives; flag naltrexone status before elective surgery and stop the oral drug at least 72 h beforehand.
• Additive hepatic risk with high-dose acetaminophen, isoniazid, methotrexate or continued heavy alcohol use warrants closer transaminase checks.
• The bupropion combination lowers seizure threshold; avoid in seizure disorder, bulimia, anorexia nervosa and abrupt sedative or alcohol withdrawal.
• No clinically significant CYP450 interactions, which makes naltrexone easy to combine with antidepressants, antipsychotics and mood stabilizers.

Special populations

• Pregnancy: human data are limited; methadone or buprenorphine remains preferred for opioid use disorder, though stable patients may continue naltrexone.
• Lactation: small amounts enter milk and the depot is less preferred; monitor the infant for sedation and poor feeding if treatment continues.
• Pediatric safety and effectiveness are not established; adolescent use for alcohol or opioid use disorder is off-label and supported by small series.
• Geriatric data are sparse; use standard doses but screen for hepatic and renal impairment, sedation and fall risk before starting the depot.
• Hepatic: contraindicated in acute hepatitis or hepatic failure; compensated cirrhosis substantially raises exposure and calls for closer follow-up.

Clinical pearls

• Opioid tolerance is lost on naltrexone, so overdose risk spikes after stopping; send naloxone home.
• The depot cannot be removed, so document 7-10 days opioid-free before the first injection.
• It reduces heavy drinking more than it produces abstinence; continue it through a lapse.