Naltrexone
Indications
| Indication | Approved Population | Formulation | Status |
|---|---|---|---|
| Treatment of alcohol dependence | Adults able to abstain from alcohol in an outpatient setting prior to initiation (Vivitrol); adjunct to psychosocial treatment (oral) | Oral 50 mg / Vivitrol 380 mg IM | FDA Approved |
| Blockade of effects of exogenously administered opioids (oral) / Prevention of relapse to opioid dependence following detoxification (Vivitrol) | Adults; must be opioid-free for ≥7–10 days (short-acting opioids) or up to 2 weeks (buprenorphine, methadone) prior to initiation | Oral 50 mg / Vivitrol 380 mg IM | FDA Approved |
Naltrexone is a long-acting opioid receptor antagonist with highest affinity at the μ-opioid receptor and effectively no opioid agonist activity. It was first synthesized in 1963 and approved by the FDA in oral form in 1984 for opioid addiction and in 1994 for alcoholism. Vivitrol — an extended-release intramuscular microsphere formulation — was approved in 2006 for alcohol dependence and in 2010 for prevention of relapse to opioid dependence following opioid detoxification. Together with acamprosate and disulfiram, it is one of the three FDA-approved medications for alcohol use disorder (AUD). For opioid use disorder (OUD), it is the only opioid antagonist alternative to the agonist treatments methadone and buprenorphine.
Both major US guidelines for AUD pharmacotherapy — the APA 2018 practice guideline and the VA/DoD 2021 substance use disorder guideline — recommend naltrexone (oral or extended-release IM) and acamprosate as first-line pharmacotherapies for moderate-to-severe AUD. For OUD, the 2020 ASAM National Practice Guideline endorses extended-release naltrexone as one of three first-line options (alongside methadone and buprenorphine) for patients who have completed detoxification, with the choice individualized based on patient preference, pregnancy status, and treatment access. Naltrexone monotherapy must always be combined with psychosocial treatment to be effective.
Low-dose naltrexone (LDN, 1.5–4.5 mg/day) — Compounded, off-label use for fibromyalgia, multiple sclerosis, Crohn disease, complex regional pain syndrome, and other chronic pain or autoimmune conditions, based on a hypothesised paradoxical immunomodulatory effect at sub-pharmacological μ-receptor doses. Several small randomised studies suggest a possible signal in fibromyalgia and Crohn disease, but the overall evidence base is limited by small sample sizes, short follow-up, and heterogeneous outcomes. Not FDA-approved. Evidence quality: low to very low.
Refractory pruritus — Particularly cholestatic, uraemic, and opioid-induced pruritus; supported by small case series and randomised studies but not FDA-approved. Evidence quality: low.
Self-injurious behavior in autism spectrum disorder and intellectual disability — Limited evidence from older small trials; not FDA-approved. Evidence quality: very low.
Stimulant use disorder, behavioural addictions (gambling, kleptomania, trichotillomania) — Mechanistically plausible; small randomised studies suggest possible benefit, but no FDA approval. Evidence quality: very low.
Note: bupropion + naltrexone (Contrave) is a separate FDA-approved combination product for obesity and is not an off-label use of naltrexone monotherapy.
Dosing
The dosing of naltrexone differs substantially by formulation and indication. The most consequential pre-prescription decision in every case is verifying that the patient has been opioid-free for an adequate interval — a minimum of 7 to 10 days for short-acting opioids (heroin, oxycodone, hydrocodone, morphine, codeine) and up to 14 days for long-acting opioid agonists (methadone, buprenorphine, sustained-release morphine). Failure to do so risks a precipitated opioid withdrawal severe enough to require hospitalisation and, in some reported cases, intensive care admission. Pretreatment with oral naltrexone is not required before Vivitrol; however, an oral test dose (the 25 mg “induction” dose for oral OUD) may help unmask occult opioid dependence in uncertain cases.
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Alcohol use disorder — oral naltrexone | 50 mg PO once daily | 50 mg daily | 50 mg/day (label-evaluated) | Adjunct to psychosocial therapy Pivotal RCTs evaluated 50 mg daily for 12 weeks; longer durations not formally evaluated in registration trials |
| Opioid use disorder — oral naltrexone | 25 mg PO test dose (no withdrawal signs) | 50 mg PO daily | 50 mg/day standard | Confirm opioid-free interval first; consider naloxone challenge if uncertain 50 mg blocks ~25 mg IV heroin for 24 h; 100 mg blocks for 48 h; 150 mg for ~72 h |
| Alternative oral schedules (compliance-supported) | — | 100 mg every other day, OR 50 mg M–F + 100 mg Saturday, OR 150 mg every third day | 150 mg/dose | Useful for directly observed therapy Higher hepatocellular injury risk reported with single doses >50 mg; balance benefit and risk |
| Alcohol or opioid dependence — Vivitrol IM | 380 mg deep IM gluteal injection | 380 mg IM every 4 weeks (monthly) | 380 mg per dose | Alternate buttocks each injection; use only the customised needles supplied (1.5″ or 2″ based on body habitus); pretreatment with oral naltrexone is NOT required Must be opioid-free for ≥7–10 days for short-acting opioids; up to 2 weeks for buprenorphine/methadone |
| Mild renal impairment (CrCl ≥50 mL/min) | No formal dose adjustment | Standard adult dose Naltrexone PK not altered in mild renal insufficiency in population analysis | ||
| Moderate or severe renal impairment | Caution; formal dose recommendation not established | Not formally studied; primary metabolite undergoes active tubular secretion Avoid extended-dose schedules; consider lower starting dose and close monitoring | ||
| Mild–moderate hepatic impairment (Child-Pugh A or B) | No dose adjustment per FDA label | However, oral naltrexone AUC increases ~5× (compensated cirrhosis) and ~10× (decompensated cirrhosis); Vivitrol PK reportedly not altered Recent observational data (VOCAL cohort) support naltrexone safety in compensated cirrhosis | ||
| Severe hepatic impairment (Child-Pugh C) | Not studied (oral); Vivitrol pharmacokinetics not evaluated in severe hepatic impairment | Use cautiously and only after specialist review FDA labels do not list acute hepatitis/liver failure as a contraindication (changed when boxed warning was removed in 2013), but specialist input is appropriate | ||
| Pediatric (<18 years) | Not established | Safety and effectiveness not established for either formulation | ||
| Geriatric (≥65 years) | No specific dose adjustment recommended | Limited data; AUD trials included <3% age >65; Vivitrol OUD trials excluded subjects >65 Monitor renal function; consider lower starting frequency in older adults | ||
The single most consequential prescribing safety check is verifying an adequate opioid-free interval before any naltrexone dose. A minimum of 7–10 days is required for short-acting opioids; up to 14 days for buprenorphine or methadone. Tramadol counts as an opioid for this purpose. A naloxone challenge test is recommended if opioid-free status is uncertain — but be aware that some patients will precipitate withdrawal even with a negative urine screen and a tolerated naloxone challenge, particularly when transitioning from buprenorphine. Always prepare a non-opioid withdrawal management strategy, and never administer Vivitrol in a setting that cannot manage a precipitated withdrawal syndrome severe enough to require hospital admission or ICU-level care.
Patients who have been on naltrexone — particularly Vivitrol — have reduced opioid tolerance compared with their pre-treatment baseline. As the antagonist effect wanes (at the end of the Vivitrol dosing interval, after a missed dose, or after discontinuation of either formulation), even previously tolerated doses of opioids may produce fatal respiratory depression. The current Vivitrol label (revised December 2025) directs prescribers to strongly consider co-prescribing or recommending an opioid overdose reversal agent (naloxone or nalmefene) at every Vivitrol injection, with patient and caregiver education on overdose recognition and naloxone use.
Oral naltrexone is inexpensive, generic, and easy to start or stop, but its real-world effectiveness depends entirely on daily adherence in a population with a high prevalence of treatment ambivalence. Vivitrol guarantees 28-day exposure but requires monthly clinic visits, costs substantially more (typically thousands of dollars per dose without coverage), and forecloses the ability to use opioid analgesics for the full month. The strongest case for Vivitrol is in opioid use disorder, where the X:BOT trial (Lee 2018) showed comparable retention and outcomes to buprenorphine/naloxone among those successfully inducted — but a substantially higher induction failure rate (28% for Vivitrol vs 6% for buprenorphine/naloxone), entirely attributable to the requirement for full opioid detoxification. In alcohol use disorder, both formulations are reasonable first-line options.
Pharmacology of Naltrexone
Mechanism of Action
Naltrexone is a competitive antagonist at all three classical opioid receptors, with highest affinity at the μ-opioid receptor and weaker affinity at κ and δ receptors. It has effectively no opioid agonist activity, no abuse potential, and produces no tolerance or physical dependence. By occupying μ-receptors, naltrexone reversibly blocks the rewarding and respiratory effects of exogenously administered opioids and attenuates the activation of the mesolimbic dopaminergic reward pathway by endogenous opioid peptides. The mechanism by which naltrexone reduces alcohol consumption is incompletely characterised, but is hypothesised to involve blockade of opioid-mediated reinforcement of alcohol drinking — alcohol triggers β-endorphin release, which acts at μ-receptors in the ventral tegmental area to enhance dopaminergic signalling and the rewarding subjective effects of drinking. Naltrexone does not produce a disulfiram-like reaction with alcohol; patients who drink while on naltrexone simply experience less of the rewarding effect.
The major active metabolite, 6β-naltrexol, has substantially weaker μ-receptor binding than the parent compound but accumulates after oral dosing because of its longer half-life and contributes meaningfully to total opioid blockade after repeated oral administration. With Vivitrol, the proportion of 6β-naltrexol relative to naltrexone is much lower than with oral therapy because intramuscular administration bypasses first-pass hepatic metabolism. The clinical blockade duration after a single oral 50 mg dose is approximately 24 hours; doubling the dose extends blockade to ~48 hours, and 150 mg achieves blockade for ~72 hours. A single Vivitrol injection delivers approximately 28 days of effective μ-receptor blockade.
ADME Profile
| Parameter | Oral 50 mg | Vivitrol 380 mg IM |
|---|---|---|
| Absorption | Rapid; ~96% absorbed from GI tract; significant first-pass metabolism limits oral bioavailability to 5–40%; Tmax ~1 h for both naltrexone and 6β-naltrexol | Initial peak ~2 h post-injection (release from microsphere surface); second peak ~2–3 days (release from polymer matrix); slow decline begins ~14 days; measurable levels >1 month |
| Distribution | Vd ~1,350 L (extensive tissue distribution); plasma protein binding ~21% over the therapeutic dose range | Same protein binding (~21%); apparent Vd not separately characterised due to release-rate-limited kinetics |
| Metabolism | Extensive (>98% metabolised); systemic clearance ~3.5 L/min — exceeds liver blood flow, indicating extrahepatic metabolism. Primary pathway is dihydrodiol dehydrogenase (a cytosolic enzyme), not CYP450. Major metabolite: 6β-naltrexol (active); minor: 2-hydroxy-3-methoxy derivatives; conjugation also occurs | Same metabolic pathway; significantly less 6β-naltrexol generated due to bypass of first-pass hepatic metabolism |
| Elimination | Naltrexone t½ ~4 h; 6β-naltrexol t½ ~13 h. Renal excretion 53–79% of total dose (primarily as 6β-naltrexol and conjugates); unchanged naltrexone <2% of urinary excretion. Renal clearance of 6β-naltrexol (230–369 mL/min) suggests active tubular secretion | Apparent t½ for both naltrexone and 6β-naltrexol: 5–10 days (release-rate-limited from polymer matrix). Steady state at end of first dosing interval; minimal accumulation (<15%) with repeated monthly dosing |
Because naltrexone is metabolised almost entirely by dihydrodiol dehydrogenase (a cytosolic, non-CYP enzyme system) and is neither a substrate, inhibitor, nor inducer of major CYP isoforms (1A2, 2A6, 2B6, 2C8/9/19, 2D6, 2E1, 3A4), the kinds of pharmacokinetic interactions that complicate prescribing of CYP-dependent drugs are largely absent. The clinically important interactions are therefore pharmacodynamic: antagonism of opioid analgesics, antitussives, and antidiarrhoeals; potential additive hepatotoxicity with disulfiram or other hepatotoxins; and reported lethargy/somnolence with thioridazine.
Side Effects
The side-effect profiles of oral naltrexone and Vivitrol differ because of the route, the dose-exposure profile, and the local tissue effects of intramuscular microsphere injection. Adverse reactions seen most frequently with oral naltrexone are gastrointestinal (especially nausea), neurological (headache, dizziness), and psychiatric (anxiety, insomnia, fatigue). Vivitrol adds the predictable tier of injection-site reactions, which range from common transient tenderness to rare but serious necrotising lesions requiring surgical debridement. Both formulations carry the dose-related possibility of hepatocellular transaminase elevation that is generally clinically silent, generally reversible, and generally seen at supratherapeutic doses (≥300 mg/day in earlier obesity studies). The FDA black-box warning for hepatotoxicity that was historically attached to naltrexone was removed in 2013 following accumulated evidence that no naltrexone-induced hepatic failure had been documented at recommended doses; the warning now appears in regular Warnings and Precautions, not in a Boxed Warning.
| Adverse Effect | Vivitrol 380 mg / Placebo | Clinical Note |
|---|---|---|
| Any injection-site reaction | 69% / 50% | Includes tenderness 45% (vs 39%), induration 35% (vs 8%), pain 17% (vs 7%); most are mild and self-limiting |
| Nausea | 33% / 11% | Most prominent after first dose; tends to subside within days; less likely with subsequent injections |
| Headache | 25% / 18% | Usually mild and self-limiting |
| Asthenic conditions (fatigue, malaise, lethargy) | 23% / 12% | Usually mild and improves over weeks |
| Insomnia or sleep disturbance | 14% / 12% | Modestly above placebo; consider sleep hygiene before adding hypnotic |
| Anorexia or decreased appetite | 14% / 3% | May contribute to mild weight loss |
| Vomiting | 14% / 6% | Most prominent with first dose |
| Dizziness or syncope | 13% / 4% | Counsel re: driving until tolerance established |
| Diarrhoea | 13% / 10% | Usually transient |
| Pharyngitis | 11% / 11% | Comparable to placebo; included for completeness |
| Abdominal pain | 11% / 8% | Usually mild |
| Anxiety | 12% / 8% | May reflect underlying disorder; consider before attributing to drug |
| Arthralgia, joint stiffness | 12% / 5% | Generally mild |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 10% | Most common reason for oral naltrexone discontinuation |
| Headache | 7% | Usually self-limiting |
| Dizziness | 4% | Counsel re: driving |
| Nervousness or fatigue | 4% each | May overlap with insomnia or sleep disorder (3%) |
| Vomiting | 3% | Often coincident with nausea |
| Anxiety, somnolence | 2% each | Rate similar to placebo in controlled trials in opioid-free patients |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Precipitated opioid withdrawal | High in opioid-dependent patients given naltrexone before adequate opioid-free interval | Within 5 minutes of oral; within hours of Vivitrol; can persist up to 48 h | Manage with non-opioid supportive therapy (clonidine, antiemetics, antidiarrheals, IV fluids); admission may be required; opioids will not reliably reverse antagonist blockade |
| Vulnerability to fatal opioid overdose after discontinuation or dose lapse | Cases of fatal overdose reported | End of Vivitrol dosing interval; missed dose; treatment discontinuation | Strongly consider co-prescribing opioid reversal agent (naloxone, nalmefene) at each Vivitrol injection; counsel patient and caregivers on overdose recognition and reversal use |
| Severe injection-site reaction (Vivitrol) — necrosis, abscess, cellulitis | Uncommon but occur; have required surgical debridement and resulted in significant scarring; primarily in female patients per label | Days to weeks after injection | Use only the customised needles supplied; assess body habitus before each dose; refer for surgical evaluation if abscess, cellulitis, necrosis, or extensive swelling |
| Hepatotoxicity (transaminase elevation, hepatitis, clinically significant liver dysfunction) | Dose-related; 19% transaminase elevation at 300 mg/day in obesity studies; rare at recommended 50 mg/day | Weeks of high-dose exposure | Discontinue if symptoms or signs of acute hepatitis. The FDA boxed warning was removed in 2013; current label retains a regular hepatotoxicity warning and a precaution but does NOT contraindicate use in acute hepatitis or liver failure |
| Depression, suicidal ideation, suicide | Vivitrol AUD trial: depressed mood adverse events 10% vs 5% placebo; suicidal-nature events 1% vs 0% placebo; 2 completed suicides on Vivitrol vs 0 on placebo | Variable; includes post-discontinuation | Monitor at every visit; alert family/caregivers; document a contingency plan for worsening mood. Use the smallest feasible dispensed quantity for oral naltrexone in at-risk patients |
| Eosinophilic pneumonia (Vivitrol) | 1 confirmed + 1 suspected in clinical trials; postmarketing reports | Variable | Consider in any Vivitrol patient with progressive dyspnoea and hypoxaemia not responsive to antibiotics; CT, BAL, treat with corticosteroids |
| Hypersensitivity reactions including anaphylaxis (Vivitrol > oral) | Urticaria, angioedema, anaphylaxis reported in Vivitrol trials and post-marketing | During or soon after injection | Permanently discontinue; treat as standard anaphylaxis. Hypersensitivity to naltrexone, PLG, or carboxymethylcellulose is a labelled contraindication for Vivitrol |
| Inadequate analgesia / unmanageable pain in patients on naltrexone | Predictable pharmacological consequence | Whenever opioid analgesia required | For Vivitrol, blockade lasts ~28 days. Plan elective surgery accordingly; carry a wallet card. For emergencies, use regional anaesthesia, non-opioid analgesia, or — if opioids are absolutely required — administer in an anaesthesia care setting with respiratory monitoring; doses required may be higher and respiratory depression deeper and more prolonged |
| Thrombocytopenia or coagulopathy precipitating injection-site bleeding (Vivitrol) | Predictable risk; small mean platelet decrease seen in Vivitrol AUD trial | Variable | Use Vivitrol with caution in patients with thrombocytopenia or any coagulation disorder (haemophilia, severe hepatic failure) |
Older textbooks, drug-information references, and consumer websites still describe naltrexone as carrying a Black Box Warning for hepatotoxicity and as being contraindicated in acute hepatitis or liver failure. Both statements are out of date. The boxed warning was removed in 2013 (Stoddard & Zummo, J Clin Psychiatry 2015), and acute hepatitis / liver failure are no longer listed as contraindications on the current FDA-approved labels for either oral naltrexone or Vivitrol. The hepatotoxicity warning persists as a regular Warning and Precaution, the recognition that supratherapeutic doses (≥300 mg/day) cause transaminase elevations remains, and clinical caution in patients with active liver disease is still appropriate — but the regulatory architecture is now consistent with accumulated post-marketing data showing that naltrexone at therapeutic doses (50 mg/day oral, 380 mg/month IM) is safe in compensated cirrhosis (VOCAL cohort, JHEP Reports 2024) and has not been associated with documented hepatic failure.
Drug Interactions
Because naltrexone is metabolised through the cytosolic dihydrodiol dehydrogenase pathway and is neither a substrate, inhibitor, nor inducer of major CYP enzymes, the interaction profile is dominated by predictable pharmacodynamic opioid antagonism rather than CYP-mediated PK changes. Three patterns of clinical importance recur: (1) loss of analgesic, antitussive, and antidiarrhoeal effect from any opioid-containing medication; (2) potential for additive hepatotoxicity with disulfiram or other hepatotoxic agents; and (3) the central question — whether the patient has been opioid-free for an adequate interval before naltrexone is given.
Monitoring
The FDA labels do not specify a rigid monitoring schedule, but five domains drive follow-up: confirming and maintaining opioid-free status, surveilling hepatic function, screening for depression and suicidality, assessing injection-site integrity for Vivitrol, and tracking response to therapy with appropriate validated instruments (timeline followback or AUDIT-C for AUD; urine drug screen and self-report for OUD). Because naltrexone has minimal PK drug-drug interactions, routine therapeutic drug monitoring or interaction-driven dose titration is not required.
-
Liver function tests (AST, ALT, bilirubin)
Baseline; every 1–3 months for first 6 months; periodically thereafter
Routine Particularly important in patients with active alcohol use, prior alcoholic liver disease, hepatitis B or C, or concomitant hepatotoxins. Asymptomatic transient elevations are common and rarely require treatment cessation; discontinue if symptoms or signs of acute hepatitis develop. The 2013 boxed warning removal does not eliminate the rationale for periodic LFT surveillance. -
Opioid-free status
Pre-initiation (mandatory); subsequently as clinically indicated
Routine Verify by patient history, urine drug screen, and (when uncertain) naloxone challenge test. Repeat verification before each Vivitrol injection if there has been any concern about interim opioid use. -
Mood and suicidal ideation (PHQ-9 with item 9 review or C-SSRS)
Each visit
Routine Both AUD and OUD populations have elevated baseline suicide risk. The Vivitrol AUD trial showed a small absolute increase in depressed-mood adverse events (10% vs 5%) and suicide-nature events (1% vs 0%) compared with placebo. Document a contingency plan for worsening mood and ensure family/caregivers are alerted to warning signs. -
Injection-site assessment (Vivitrol)
At each monthly visit; alert patient to self-report concerning lesions
Routine Inspect prior injection sites for induration, abscess, cellulitis, or necrosis. Patient-reported worsening lesions or any not improving by 2 weeks should prompt examination. Refer to surgery for suspected abscess, cellulitis, necrosis, or extensive swelling. -
Drinking response (AUD)
Each visit; quarterly objective assessment
Routine Use timeline followback, AUDIT-C, or similar; validate with biomarkers (CDT, GGT, PEth) if useful. Naltrexone reduces heavy drinking days and craving more reliably than it produces complete abstinence; manage patient expectations accordingly. -
Opioid abstinence (OUD)
At each visit
Routine Urine drug screen, self-report, and direct questioning. Patients who relapse on Vivitrol are at high risk of fatal overdose because tolerance has been reduced; reinforce naloxone availability and education at every visit. -
Pregnancy testing
Baseline (women of reproductive potential); periodically as appropriate
Routine Available human data are insufficient to characterise teratogenic risk; pregnancy was a documented reason for Vivitrol discontinuation in the AUD pivotal trial. Discuss the balance of treatment risks vs. risks of untreated AUD/OUD with each pregnant patient. -
Renal function
Baseline; annually or per comorbidity-driven schedule
Routine 6β-naltrexol undergoes active renal tubular secretion. Caution is recommended in moderate–severe impairment; not formally studied. -
Eosinophil count and pulmonary symptoms (Vivitrol)
As clinically indicated
Trigger-based Eosinophilic pneumonia is rare but reported. Investigate any progressive dyspnoea or hypoxaemia not responsive to antibiotics with chest imaging and consider BAL. -
Carrying overdose-reversal documentation
At initiation and periodically reinforced
Routine Patient should carry a wallet card identifying naltrexone use to alert emergency providers. The current Vivitrol label directs prescribers to strongly consider co-prescribing naloxone or nalmefene at every injection.
Contraindications & Cautions
Absolute Contraindications (per FDA Labels — Both Formulations)
- Patients receiving opioid analgesics — naltrexone will block analgesia and may precipitate withdrawal.
- Patients with current physiological opioid dependence, including those on methadone or buprenorphine maintenance therapy. The required opioid-free interval is ≥7–10 days for short-acting opioids and up to 14 days for long-acting opioids before naltrexone can be safely started.
- Patients in acute opioid withdrawal.
- Patients who have failed a naloxone challenge test or have a positive urine screen for opioids.
- Hypersensitivity to naltrexone (oral and Vivitrol) or to PLG (polylactide-co-glycolide), carboxymethylcellulose, or any other component of the Vivitrol diluent.
Important Note on Hepatic Disease — Not a Current Contraindication
Earlier FDA labels for naltrexone listed acute hepatitis or liver failure as absolute contraindications and carried a Boxed Warning for hepatotoxicity. The boxed warning was removed in 2013, and acute hepatitis / liver failure are no longer listed as contraindications on the current oral naltrexone or Vivitrol labels. Hepatotoxicity remains a Warning and Precaution, and patients with active liver disease still warrant additional caution and closer LFT monitoring — but the regulatory architecture is consistent with accumulated post-marketing data showing naltrexone is safe at therapeutic doses, including in compensated cirrhosis. Many secondary references and prescribing tools have not been updated and should be cross-checked against the current FDA label.
Use with Caution / Specialist Input Suggested
- Active or severe hepatic impairment — oral naltrexone AUC increases ~5× in compensated and ~10× in decompensated cirrhosis; Vivitrol PK not formally studied in severe hepatic impairment.
- Moderate–severe renal impairment — naltrexone and 6β-naltrexol are primarily renally cleared; not formally studied in this population.
- History of suicidal ideation or major depression — both AUD and OUD populations have elevated suicide risk; small absolute increases in depressive and suicidal events seen in Vivitrol AUD trial.
- Anticipated need for opioid analgesia in the next 28 days — Vivitrol is an essentially irreversible commitment to no opioid analgesia for the dosing interval; oral therapy is more flexible.
- Thrombocytopenia or coagulopathy — particular concern for Vivitrol IM injection.
- Pregnancy and lactation — Vivitrol uses PLLR-format risk summary; oral generic still labelled Category C. Animal data show increased early fetal loss; human data insufficient. Naltrexone and 6β-naltrexol are present in human milk; effects on breastfed infant unknown. Discuss the balance of treatment vs. untreated AUD/OUD risks.
- Patients unable to ensure psychosocial treatment access — the FDA labels and all major guidelines indicate naltrexone is effective only as part of a comprehensive treatment program.
- Pediatric patients — safety and effectiveness have not been established.
The December 2025 revision of the Vivitrol label added explicit guidance that prescribers should strongly consider recommending or prescribing an opioid overdose reversal agent (naloxone, nalmefene) at the initial Vivitrol injection and at each subsequent injection — because patients are vulnerable to fatal overdose at the end of each dosing interval, after a missed dose, or after discontinuation, when reduced opioid tolerance combined with relapse can be lethal at previously tolerated doses. Educate patients and caregivers on overdose recognition and reversal-agent use; emphasise that reversal agents are temporary and that emergency medical help must always be summoned.
Patient Counselling
Purpose of Therapy
Naltrexone is a medication that blocks the receptors in the brain that opioids use, and that are partly responsible for the rewarding effects of alcohol. It is used as part of a comprehensive treatment programme — including counselling, support groups, and recovery-oriented services — for alcohol use disorder and opioid use disorder. Naltrexone is not addictive, it is not a controlled substance, and it does not cause a “disulfiram-like” reaction if you drink alcohol. It will not get you intoxicated or sedated. It works by reducing cravings and the rewarding effect of drinking; for opioid use disorder, it prevents the high from any opioid use during treatment. The two formulations are oral tablets taken once daily, and Vivitrol — a monthly intramuscular injection given by a healthcare provider that releases medication slowly over 4 weeks.
How to Take It
The oral tablet is taken once daily, with or without food, at the same time each day to support the habit of taking it. Vivitrol is administered by a healthcare provider as a deep intramuscular injection in the buttock muscle every 4 weeks; alternating buttocks each visit. Patients cannot self-administer Vivitrol — it requires specific needles and aseptic technique. If a Vivitrol dose is missed, schedule the next injection as soon as possible and inform the prescriber. Carry a card or wallet identifier indicating you are on naltrexone, so that emergency providers know if you require pain management or surgery.
Sources
- U.S. Food and Drug Administration. VIVITROL (naltrexone for extended-release injectable suspension) prescribing information — current label revised December 2025 (Reference ID 5715866; supplement s061); initial U.S. approval 1984. accessdata.fda.gov Most current Vivitrol label. December 2025 revision adds explicit guidance to co-prescribe an opioid overdose reversal agent at each injection. Primary source for Vivitrol pharmacokinetics, contraindications, AE rates, and dosing.
- DailyMed (NIH). Naltrexone hydrochloride tablet, film coated — current oral naltrexone label (SpecGx LLC, Rev 07/2022; updated 12/07/2023 on DailyMed). dailymed.nlm.nih.gov Authoritative US oral naltrexone label. Note: this label still uses pre-PLLR pregnancy Category C terminology; PK and clinical data herein cited are from this source.
- Stoddard J, Zummo J. Oral and long-acting injectable naltrexone: removal of boxed warning for hepatotoxicity. J Clin Psychiatry. 2015;76(12):1695. doi: 10.4088/JCP.15lr10052 Documents the 2013 FDA action removing the boxed warning for hepatotoxicity from naltrexone labelling.
- Volpicelli JR, Alterman AI, Hayashida M, O’Brien CP. Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry. 1992;49(11):876–880. doi: 10.1001/archpsyc.1992.01820110040006 One of the two pivotal placebo-controlled trials supporting the 1994 FDA approval of oral naltrexone for alcohol dependence.
- O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry. 1992;49(11):881–887. doi: 10.1001/archpsyc.1992.01820110045007 The companion pivotal trial to Volpicelli 1992 supporting the 1994 FDA AUD approval.
- Garbutt JC, Kranzler HR, O’Malley SS, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005;293(13):1617–1625. doi: 10.1001/jama.293.13.1617 Pivotal 24-week, 624-patient, placebo-controlled trial supporting the 2006 Vivitrol approval for alcohol dependence.
- Krupitsky E, Nunes EV, Ling W, Illeperuma A, Gastfriend DR, Silverman BL. Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet. 2011;377(9776):1506–1513. doi: 10.1016/S0140-6736(11)60358-9 Pivotal 24-week, 250-patient, placebo-controlled Russian trial supporting the 2010 Vivitrol approval for opioid relapse prevention.
- Lee JD, Nunes EV, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309–318. doi: 10.1016/S0140-6736(17)32812-X Critical real-world comparative effectiveness trial showing similar outcomes among patients successfully inducted on either Vivitrol or buprenorphine/naloxone, but a substantially higher induction failure rate for Vivitrol (28% vs 6%).
- Ayyala D, Bottyan T, Tien C, et al. Safety of naltrexone in patients with cirrhosis. JHEP Reports. 2024;6(8):101095. doi: 10.1016/j.jhepr.2024.101095 VOCAL-cohort retrospective study supporting safety of naltrexone in compensated and decompensated cirrhosis using RUCAM causality assessment.
- Bolton M, Hodkinson A, Boda S, et al. Serious adverse events reported in placebo randomised controlled trials of oral naltrexone: a systematic review and meta-analysis. BMC Med. 2019;17(1):10. doi: 10.1186/s12916-018-1242-0 Systematic review supporting the safety of oral naltrexone at therapeutic doses across multiple indications and the rationale for the 2013 boxed-warning removal.
- Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients with Alcohol Use Disorder. Am J Psychiatry. 2018;175(1):86–90. doi: 10.1176/appi.ajp.2017.1750101 APA practice guideline; recommends naltrexone (oral or extended-release IM) and acamprosate as first-line pharmacotherapies for moderate-to-severe AUD.
- Crotty K, Freedman KI, Kampman KM. Executive Summary of the American Society of Addiction Medicine (ASAM) National Practice Guideline for the Treatment of Opioid Use Disorder: 2020 Focused Update. J Addict Med. 2020;14(2):99–112. doi: 10.1097/ADM.0000000000000635 ASAM guideline endorsing extended-release naltrexone as one of three first-line OUD pharmacotherapies alongside methadone and buprenorphine.
- U.S. Department of Veterans Affairs / Department of Defense. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders. Version 4.0, 2021. healthquality.va.gov VA/DoD guideline; supports naltrexone for both AUD (oral and IM) and OUD (IM after detoxification).
- McPheeters M, O’Connor EA, Riley S, et al. Pharmacotherapy for Alcohol Use Disorder: A Systematic Review and Meta-analysis. JAMA. 2023;330(17):1653–1665. doi: 10.1001/jama.2023.19761 AHRQ-commissioned 2023 systematic review confirming oral naltrexone reduces return to any drinking and heavy drinking; supports current guideline positioning.
- Crowley TJ, Wagner JE, Zerbe G, Macdonald M. Naltrexone-induced dysphoria in former opioid addicts. Am J Psychiatry. 1985;142(9):1081–1084. doi: 10.1176/ajp.142.9.1081 Foundational characterisation of dysphoric responses to naltrexone in formerly opioid-dependent patients — relevant to depression-related discontinuation patterns observed in modern trials.
- Verebey K. The clinical pharmacology of naltrexone: pharmacology and pharmacodynamics. NIDA Res Monogr. 1981;28:147–158. Classical pharmacological characterisation of oral naltrexone’s μ-receptor binding, half-life, and active metabolite 6β-naltrexol — foundation for current PI pharmacokinetic data.
- Dunbar JL, Turncliff RZ, Dong Q, Silverman BL, Ehrich EW, Lasseter KC. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Alcohol Clin Exp Res. 2006;30(3):480–490. doi: 10.1111/j.1530-0277.2006.00052.x Phase 1 pharmacokinetic study of Vivitrol — establishes the bimodal absorption profile and ~5–10 day apparent half-life that underpins the 28-day dosing interval.