Naltrexone (Vivitrol, ReVia) is a pure opioid antagonist used to prevent relapse in opioid use disorder and to treat alcohol use disorder. It works by competitively blocking mu, kappa, and delta opioid receptors, preventing opioids from producing euphoria and interrupting the endorphin-mediated reward pathway that reinforces alcohol use. Common side effects include nausea, headache, and fatigue. It must never be started in opioid-dependent patients — even a small dose will immediately precipitate severe, painful withdrawal; a minimum opioid-free interval of 7–10 days (longer for methadone) is required before initiating, confirmed by urine drug screen.
Naltrexone
Uses & FDA Indications
Naltrexone is FDA-approved for two distinct indications: prevention of relapse to opioid dependence following opioid detoxification, and treatment of alcohol use disorder (AUD). It is a pure opioid antagonist with no abuse potential of its own.
In opioid use disorder, naltrexone is used as a relapse prevention strategy — it blocks opioid receptors so that using an opioid produces no euphoria or reinforcement, removing the reward that drives compulsive use. The monthly extended-release injectable formulation (Vivitrol) was specifically developed to address the adherence challenge inherent in daily oral regimens. In alcohol use disorder, naltrexone reduces alcohol craving and the pleasurable effects of drinking by interrupting the opioid-mediated reward pathway that alcohol activates.
Naltrexone is not used to manage acute opioid withdrawal or to treat pain. Patients must be fully detoxified from opioids before starting naltrexone — typically requiring 7–10 days free of short-acting opioids and longer for methadone — or initiating treatment will precipitate severe withdrawal.
How It Works
Naltrexone is a competitive antagonist at all three major opioid receptor subtypes — mu (μ), kappa (κ), and delta (δ) — with the highest affinity for the mu receptor, which mediates the euphoric and analgesic effects of opioids. By occupying these receptors without activating them, naltrexone physically blocks exogenous opioids (heroin, oxycodone, fentanyl) from binding and producing their effects.
Its role in alcohol use disorder is more nuanced. Alcohol does not directly bind opioid receptors, but its rewarding effects are partly mediated through release of endogenous opioids (endorphins and enkephalins) that activate the mesolimbic reward pathway. Naltrexone blocks this downstream reward signal, reducing the subjective pleasure of drinking and decreasing craving over time. This is the basis of the "Sinclair Method," which uses naltrexone taken before drinking to progressively extinguish the conditioned reward response to alcohol.
The extended-release injectable naltrexone (Vivitrol) is given once monthly by a healthcare provider. This eliminates the daily adherence problem and the temptation to skip doses in anticipation of opioid use. Patients must carry a medical alert card indicating they are on naltrexone, as emergency opioid analgesia may require higher-than-usual opioid doses that must be carefully managed in an ICU setting.
CRITICAL — PRECIPITATED WITHDRAWAL: Naltrexone must never be started in a patient who is opioid-dependent or has recently used opioids. Even small amounts of naltrexone in an opioid-dependent patient will displace opioids from receptors and trigger immediate, severe withdrawal — including intense pain, vomiting, diarrhea, hypertension, and profound distress. Always confirm opioid-free status with a urine drug screen and/or naloxone challenge before initiating. Minimum opioid-free intervals: 7–10 days for short-acting opioids, at least 10–14 days for methadone.
Side Effects
Common
- Nausea — most common side effect, particularly on initiation of oral naltrexone; usually transient and manageable with food
- Headache — reported in a significant minority of patients; often resolves with continued use
- Fatigue and somnolence — can impair alertness, particularly early in treatment
- Insomnia — sleep disturbance is reported, possibly related to opioid receptor blockade during normal endorphin cycling
- Abdominal pain, decreased appetite
- Injection site reactions (Vivitrol) — pain, tenderness, induration, or nodules at the gluteal injection site; rarely severe tissue reactions requiring surgical intervention
Serious
- Hepatotoxicity — naltrexone carries a warning for liver damage at supratherapeutic doses (doses many times higher than therapeutic). At standard therapeutic doses, clinically significant hepatotoxicity is rare and the drug is considered safe for patients with mild-to-moderate liver disease. Monitor liver function in patients with hepatic impairment.
- Precipitated opioid withdrawal — severe, immediate, and highly distressing; see warning above. Not a dose-dependent side effect — even low doses precipitate withdrawal in opioid-dependent patients.
- Increased opioid sensitivity after discontinuation — blocking effects wear off after stopping; patients may be more sensitive to opioids than before treatment, raising overdose risk if they relapse
- Depression and dysphoria — reported in some patients; may relate to opioid system blockade reducing baseline endorphin tone
Drug Interactions
| Drug / Class | Interaction | Clinical Significance |
|---|---|---|
| Opioid analgesics (morphine, oxycodone, hydrocodone, fentanyl, codeine) | Naltrexone completely blocks opioid receptor access, rendering opioid analgesics ineffective for pain relief. In emergency situations requiring opioid analgesia, very high doses under controlled conditions with respiratory monitoring may be required — a significant clinical challenge. | CONTRAINDICATED in opioid-dependent patients — precipitates withdrawal. Blocks therapeutic opioid effects in all patients. |
| Thioridazine | Combined use may increase lethargy and somnolence. The combination is generally avoided due to additive CNS depression and cardiac concerns with thioridazine itself. | Moderate — avoid combination |
| Disulfiram | Both naltrexone and disulfiram are used in alcohol use disorder. Concurrent use is generally not recommended due to potential hepatotoxic additive effects — both drugs carry liver toxicity warnings, and combining them may compound risk. | Moderate — use with caution; monitor liver function if combined |
| Cough and cold preparations containing opioids (dextromethorphan, codeine) | Naltrexone blocks the effects of opioid-containing antitussives and antidiarrheal agents (loperamide at high doses). Patients may find these medications ineffective. | Low-moderate — clinical awareness; use non-opioid alternatives |
Warnings & Contraindications
Contraindications
- Current physiologic opioid dependence — will precipitate immediate, severe withdrawal
- Acute opioid withdrawal at time of initiation
- Failed naloxone challenge (indicating residual opioid dependence)
- Positive urine screen for opioids without adequate opioid-free washout period
- Hypersensitivity to naltrexone or any component (polylactide-co-glycolide microspheres in Vivitrol)
- Acute hepatitis or liver failure
Emergency Analgesia
Patients on naltrexone who require emergency surgery or acute pain management present a significant clinical challenge. The opioid blockade cannot be rapidly reversed. Anesthesiologists must be informed of naltrexone use before any procedure. In emergencies, non-opioid analgesics should be maximized first; if opioids are absolutely required, they may need to be given in higher doses under close monitoring in an ICU setting, with heightened risk of respiratory depression when naltrexone eventually wears off. Patients should carry a medical alert card or wear identification for this reason.
Opioid Sensitivity After Discontinuation
Following a course of naltrexone treatment, patients who relapse to opioid use may experience dramatically greater sensitivity to opioids than they had before treatment. The dose that was previously tolerated may now cause fatal respiratory depression. This is one of the most critical counseling points for patients discontinuing naltrexone — the "same dose" of an opioid may now be lethal.
Check naltrexone interactions with other medications you may be taking.
Check Drug Interactions →Frequently Asked Questions
Is naltrexone the same as Narcan?
No — naltrexone and Narcan (naloxone) are different drugs with different purposes, though both are opioid antagonists. Naloxone (Narcan) is a short-acting opioid antagonist used as an emergency reversal agent for opioid overdose — it works within minutes but lasts only 30–90 minutes. Naltrexone is a longer-acting opioid antagonist taken orally or by monthly injection for the ongoing treatment of opioid use disorder or alcohol use disorder. Naltrexone is not used for emergency overdose reversal.
How long does naltrexone block opioids?
Oral naltrexone blocks opioid effects for approximately 24–72 hours depending on the dose taken. The extended-release injectable formulation (Vivitrol) provides opioid blockade for approximately 30 days after a single injection. This sustained blockade with Vivitrol is one of its primary advantages — it removes the daily decision of whether to take a pill, improving adherence and reducing the window of vulnerability to relapse that occurs when oral doses are missed.
Does naltrexone help with cravings?
Yes, particularly for alcohol use disorder. Naltrexone reduces alcohol craving and the rewarding effects of drinking by blocking endogenous opioid pathways that normally generate the pleasurable response to alcohol. In opioid use disorder, naltrexone does not directly reduce cravings the same way buprenorphine or methadone do (which activate opioid receptors), but it prevents the reinforcement of opioid use by blocking the euphoric effects — making opioid use unrewarding and thereby reducing relapse. It works best as part of a comprehensive treatment program including counseling.