What is naltrexone, its mechanism of action, available formulations, indications for opioid dependence relapse prevention and alcohol‑use disorder, dosing regimens, common adverse effects, contraindications, and alternative pharmacologic options?

What is Naltrexone?

Naltrexone is a pure opioid receptor antagonist approved by the FDA for treating both alcohol dependence and opioid use disorder by competitively blocking mu, kappa, and delta opioid receptors, thereby preventing the euphoric effects of opioids and reducing alcohol cravings. 1, 2, 1

Mechanism of Action

• Naltrexone functions as a competitive antagonist at opioid receptors, blocking the subjective and objective effects of exogenously administered opioids for extended periods. 1, 2
• A single 50 mg dose blocks the pharmacologic effects of 25 mg intravenously administered heroin for up to 24 hours; doubling the dose provides 48-hour blockade, and tripling provides approximately 72-hour blockade. 1, 2
• For alcohol dependence, naltrexone blocks endogenous opioid receptors, dampening activation of the reward pathway by alcohol and reducing both craving and the reinforcing "high" from drinking. 3, 4
• The medication does not produce tolerance, dependence, or aversive reactions (unlike disulfiram), and has minimal intrinsic pharmacologic actions beyond opioid blockade. 1, 2

Available Formulations and Dosing

Oral Naltrexone

• Available as 50 mg tablets for daily administration, or alternatively 100 mg on Mondays and Wednesdays with 150 mg on Fridays. 3
• Standard dosing begins with 25 mg on day 1 to assess tolerability, then 50 mg daily for 3-12 months. 5
• Oral bioavailability ranges from 5-40% due to significant first-pass metabolism, with peak plasma levels occurring within one hour. 1, 2

Injectable Extended-Release Naltrexone (Vivitrol)

• FDA-approved 380 mg intramuscular injection administered once monthly for both alcohol and opioid dependence. 3, 1
• Injectable formulation may be preferred when medication adherence is a concern, as it eliminates daily dosing requirements. 3

FDA-Approved Indications

• Alcohol dependence: Reduces relapse to heavy drinking and decreases alcohol craving when combined with psychosocial treatment. 1, 6
• Opioid use disorder: Maintains abstinence in detoxified patients, particularly highly motivated individuals who prefer opioid-free treatment over methadone or buprenorphine maintenance. 3, 1
• Naltrexone provides no therapeutic benefit except as part of an appropriate comprehensive addiction management plan. 1

Critical Pre-Treatment Requirements

Opioid-Free Period

• Patients must be completely opioid-free for 7-10 days before starting naltrexone to avoid precipitating severe withdrawal syndrome. 3, 5
• Verify opioid-free status through urine drug screening or naloxone challenge test before first dose. 7
• In subjects physically dependent on opioids, naltrexone will precipitate hyperacute withdrawal symptomatology. 1, 2

Alcohol Withdrawal Management

• Naltrexone is contraindicated during acute alcohol withdrawal and should only be initiated 3-7 days after last alcohol consumption, once withdrawal symptoms have completely resolved. 5
• Benzodiazepines remain the gold standard for managing alcohol withdrawal syndrome; naltrexone provides no benefit for withdrawal symptoms. 5

Efficacy and Clinical Outcomes

Alcohol Use Disorder

• Meta-analyses demonstrate modest effect size (0.15-0.2 range) in reducing relapse to heavy drinking, with number needed to treat approximately 20. 6, 5
• More effective at reducing heavy drinking days than achieving complete abstinence. 6
• Clinical trials show reduction in relapse rates from 54-60% to 23-31% when combined with psychosocial treatment. 5

Opioid Use Disorder

• In non-comparative trials, 23-62% of patients remained in treatment after 3-4 weeks, with 32-58% of continuing patients remaining opioid-free 6-12 months after stopping naltrexone. 8
• Most beneficial for highly motivated patients such as healthcare professionals, those with strong family support, or criminal justice populations. 3, 9
• Represents a second-line option after buprenorphine or methadone maintenance therapy, which demonstrate superior retention and outcomes. 10

Common Adverse Effects

• Gastrointestinal effects (particularly nausea) are the most commonly reported side effects. 8, 4
• May cause or worsen depression, anxiety, and insomnia; screen for these conditions before initiation. 3
• Produces some pupillary constriction by an unknown mechanism. 1, 2
• Overall low incidence of side effects at standard 50 mg daily dosing. 8

Contraindications and Safety Concerns

Absolute Contraindications

• Current opioid dependence or use (will precipitate withdrawal). 3, 1, 2
• Acute hepatitis or decompensated cirrhosis. 5
• Patients requiring opioid analgesics for pain management (blocks therapeutic opioid effects). 3, 10
• Pregnancy (offer buprenorphine or methadone instead for pregnant women with opioid use disorder). 10

Hepatotoxicity Monitoring

• Liver function tests should be obtained at baseline and every 3-6 months during treatment. 3, 5
• Hepatotoxicity occurs at supratherapeutic doses but has not emerged as a clinical problem at standard 50 mg daily dosing. 3, 6
• Not recommended for patients with alcoholic liver disease; consider baclofen or acamprosate as safer alternatives. 5

Renal Impairment

• Patients with moderate-to-severe renal impairment should have total daily dose reduced by half (25 mg daily). 3
• Renal clearance ranges from 30-127 mL/min, suggesting elimination primarily by glomerular filtration. 1, 2

Critical Safety Warning: Post-Discontinuation Overdose Risk

• Patients who discontinue naltrexone have markedly decreased opioid tolerance and face significantly increased risk of overdose and death if they return to previous opioid use. 3, 10
• Provide opioid overdose education and naloxone to all patients on naltrexone therapy. 3, 10
• This represents the most serious mortality risk associated with naltrexone treatment. 3

Perioperative Management

• For elective procedures requiring opioid analgesia, hold oral naltrexone 2-3 days prior to surgery. 3
• Extended-release injectable naltrexone requires 24-30 days after last injection before elective procedures. 3, 10
• Overcoming naltrexone blockade with high-dose opioids has resulted in excessive histamine release and adverse outcomes in experimental subjects. 1, 2

Alternative Pharmacologic Options

For Opioid Use Disorder

• Buprenorphine or methadone maintenance therapy combined with behavioral interventions represent first-line treatment, demonstrating superior retention and outcomes compared to naltrexone. 10
• Buprenorphine is most accessible for office-based treatment without requiring specialized clinic enrollment. 10
• Methadone requires enrollment in SAMHSA-certified opioid treatment program with supervised dosing. 10

For Alcohol Use Disorder

• Acamprosate reduces withdrawal effects and alcohol craving, with similar efficacy to naltrexone. 5
• Baclofen is the only alcohol pharmacotherapy proven safe in cirrhotic patients and should be considered for those with liver disease. 5

Essential Implementation Requirements

• Naltrexone is only effective when combined with comprehensive psychosocial treatment including counseling, group therapy, and mutual support programs. 3, 1, 9
• Can be prescribed from office-based practices without specialized clinic enrollment, unlike methadone. 3
• Treatment duration typically ranges from 3-12 months, though optimal duration has not been well-established. 5, 6
• Any licensed physician can prescribe naltrexone as it is unscheduled under the Controlled Substances Act. 9

Common Pitfalls to Avoid

• Never initiate naltrexone during active opioid use or alcohol withdrawal—this precipitates severe withdrawal and provides no therapeutic benefit. 5, 1, 2
• Do not use naltrexone as monotherapy; it requires integration with psychosocial interventions to be effective. 1, 9
• Avoid dismissing patients with substance use disorder from practice, as this represents patient abandonment and compromises safety. 10
• Do not fail to educate patients about increased overdose risk after discontinuation due to decreased opioid tolerance. 3, 10