section name header

Introduction

AHFS Class:

Generic Name(s):

Naltrexone is an opioid antagonist.1,  2

Uses

Opioid Use Disorder

Naltrexone is used in the management of opioid use disorder as part of a comprehensive management program that includes psychosocial support.1,  2,  14,  28,  29,  30,  35,  66,  143,  147,  158,  160,  164,  165,  166,  170,  372 The drug has been shown to produce complete blockade of the euphoric effects of opioids and reduce cravings to prevent relapse to opioid use in patients who have undergone detoxification.1,  2,  27,  102,  158,  190,  191,  372 Naltrexone hydrochloride has been designated an orphan drug by FDA for the blockade of the pharmacological effects of exogenously administered opioids as an adjunct to the maintenance of the opioid-free state in detoxified formerly opioid-dependent individuals.3

Naltrexone is commercially available as an extended-release injectable suspension and as oral tablets (as the hydrochloride salt) for use in the management of opioid use disorder.1,  2 However, the current evidence does not support the use of oral naltrexone as an effective treatment for opioid use disorder, except in specific situations (e.g., highly motivated patients who are able to adhere to daily dosing).29,  372,  760 Oral naltrexone has not been shown in clinical studies to be superior to placebo or to no pharmacologic treatment with regard to prevention of relapse in patients with opioid dependence.29 The treatment benefits of oral naltrexone are often limited by poor patient adherence to daily dosing.372

Prior to initiating naltrexone treatment, patients should be adequately withdrawn from opioids (free from opioids including tramadol) and should no longer be physically dependent.372 Naltrexone can precipitate severe withdrawal symptoms in patients who have not been adequately withdrawn from opioids.372 In general, patients should be free of opioids for at least 7-10 days before starting naltrexone.1,  2,  372 A naloxone challenge test can be used if it is uncertain whether the patient is no longer physically dependent on opioids; however, in some cases, patients may experience precipitated withdrawal despite having a negative urine screen or tolerating a naloxone challenge test.1,  372

Opioid antagonists (e.g., naltrexone, naloxone) have been used for rapid or ultrarapid detoxification in the management of opioid withdrawal in both inpatient and outpatient settings.246 Rapid opioid detoxification involves the administration of an opioid antagonist such as naltrexone and/or naloxone to shorten the time period of detoxification, and ultrarapid detoxification involves the administration of an opioid antagonist (i.e., naltrexone, naloxone) while the patient is sedated or under general anesthesia.246 The risk of adverse respiratory and cardiovascular effects associated with ultrarapid detoxification must be considered as well as the costs of general anesthesia and hospitalization.246 Due to the high risk for adverse events or death, opioid withdrawal management using ultrarapid opioid detoxification is currently not recommended.372 Naltrexone-facilitated opioid withdrawal can be a safe and effective approach, but should only be administered by experienced clinicians and in cases where anesthesia or conscious sedation are not employed.372

Clinical Experience

Efficacy of extended-release injectable naltrexone was evaluated in a 24-week, placebo-controlled, double-blind randomized study in outpatients who were completing or had recently completed detoxification.1 Patients received IM injections of naltrexone 380 mg or placebo every 4 weeks.1 A higher percentage of patients receiving naltrexone were opioid-free than those receiving placebo in this study.1,  1 Complete opioid abstinence was achieved by 23% of patients in the placebo group compared with 36% of patients in the naltrexone group from weeks 5 to 24.28

Clinical Perspective

Medications used in the treatment of opioid use disorder have been associated with reduced risk of overdose and deaths.760 Evidence-based treatment with these drugs should be offered to all patients who meet criteria for opioid use disorder.372,  760 FDA-approved medications for the treatment of opioid use disorder include methadone (a full opioid agonist), buprenorphine (an opioid partial agonist), and naltrexone (an opioid antagonist).760 These treatments differ based on the evidence supporting their use, requirement for withdrawal from opioids prior to treatment initiation, and treatment setting (e.g., opioid treatment program, office-based or home-based setting).760 While methadone and buprenorphine are more widely used than naltrexone, do not require full withdrawal from opioids, and have stronger evidence for better outcomes, naltrexone can be an option for highly motivated persons who have completed or are able to complete withdrawal.760 Naltrexone can be prescribed in any setting by any healthcare provider with prescribing authority.372 When determining whether to use methadone, buprenorphine, or naltrexone, clinicians should consider the patient's preferences, past treatment history, current clinical condition, and treatment setting.372,  760 Compared with the other treatments, naltrexone is a long-acting opioid antagonist that does not produce euphoria and does not have addictive properties; however, adherence rates with naltrexone treatment are historically low.29,  372,  760 Additionally, oral naltrexone has not been shown to be superior to placebo or no pharmacologic treatment with regard to prevention of relapse in patients with opioid dependence.29 The American Society of Addiction Medicine (ASAM) and the Centers for Disease Control and Prevention (CDC) do not recommend the use of oral naltrexone except under very limited circumstances.372,  760 Examples include highly compliant and motivated patients such as individuals in safety sensitive positions (e.g., police, firefighters, healthcare professionals) or other individuals with high levels of monitoring and knowledge of negative consequences for nonadherence; patients who wish to take an opioid receptor antagonist but are unable to take extended-release naltrexone; and patients who may benefit from medication to prevent return to illicit drug use but cannot or will not take extended-release naltrexone and do not wish to be treated with (or do not have access to) opioid agonists.372 Extended-release injectable naltrexone has been shown to be more effective than placebo or no pharmacologic therapy, and as effective as buprenorphine-naloxone therapy in preventing return to illicit opioid use and is considered an effective treatment for patients who are able to give consent, are fully withdrawn from opioids, and have no contraindications to therapy.1,  28,  30,  372

Alcohol Use Disorder

Naltrexone is used in the management of alcohol use disorder as part of a comprehensive program that includes counseling and other psychosocial support.1,  2,  5 The drug blocks opiate receptors that are involved in the rewarding effects of drinking and craving for alcohol.5

Behavior modification is an integral component in maintaining alcohol cessation; naltrexone has not been shown to provide any therapeutic benefit except as part of an appropriate plan of addiction management.2,  5,  232,  238,  239,  245,  250 Although psychosocial programs alone (i.e., without drug therapy) may be associated with moderate improvement in complete cessation rates232,  238,  239 and substantial initial rates of alcohol cessation, long-term cessation rates are low, with 50% of patients undergoing intensive inpatient and/or outpatient behavior modification usually relapsing within the first 3 months.232,  238,  239 When pharmacologic therapy (e.g., naltrexone) is used with a comprehensive management program, benefits of such programs may be prolonged.238

When used in conjunction with a comprehensive management program including behavior modification, naltrexone has been reported to decrease alcohol craving, reduce alcohol consumption, decrease the number of drinking days, maintain abstinence from alcohol ingestion, and prevent relapse.2,  231,  232,  233,  235,  236,  238,  239 However, improvements may be modest and not consistently effective for all patients.2,  232,  233,  244,  245

Naltrexone is commercially available as an extended-release injectable suspension and as oral tablets (as the hydrochloride salt) for use in the management of alcohol use disorder.1,  2 The oral formulation is indicated for the treatment of alcohol dependence, and the injectable formulation is indicated for the treatment of alcohol dependence in patients who are able to abstain from alcohol in an outpatient setting.1,  2 Oral naltrexone is most effective when prescribed for patients who are highly motivated and/or supported with observed daily dosing and who are abstinent at the time of treatment initiation.5 Extended-release injectable naltrexone is also most effective when prescribed to patients who are abstinent at treatment initiation.5 Both formulations have the greatest benefit in patients who can discontinue drinking on their own for several days before treatment initiation; naltrexone has not been shown to be effective in patients who are drinking at treatment initiation.5

Clinical Experience

Efficacy of oral naltrexone therapy for the treatment of alcohol dependence has been evaluated in several double-blind, placebo-controlled studies.2,  231,  232,  233,  236,  238,  239,  244,  245 In one of these studies, reported abstinence rates for naltrexone (50 mg orally once daily for 12 weeks) compared with placebo in alcohol-dependent patients were 51 versus 23%, while relapse occurred in 31 versus 60% of patients, respectively.2 Further analysis of data indicated that the rates of abstinence for naltrexone versus placebo were 61 versus 19% in patients receiving supportive therapy in addition to naltrexone or placebo, respectively, while in patients undergoing coping skills training, abstinence rates were 28 versus 21% in those receiving additional naltrexone or placebo therapy, respectively.233

In another 12-week placebo-controlled study in alcohol-dependent patients that evaluated oral naltrexone as an adjunct to treatment following alcohol detoxification, rates of abstinence for naltrexone versus placebo were 54 versus 43%, respectively.232 Although relapse (defined as drinking during 5 or more days within 1 week, having 5 or more drinks per drinking occasion, or having an alcohol blood concentration exceeding 100 mg/dL) in this study was reported in 23 or 54% of patients receiving naltrexone hydrochloride (50 mg orally once daily for 12 weeks) or placebo, respectively,232,  238 reanalysis by the manufacturer found relapse rates of 21 or 41% in patients receiving the drug or placebo, respectively.2 In patients who reportedly had consumed at least one drink while participating in the study, relapse occurred in 50 or 95% of patients receiving naltrexone or placebo, respectively.232,  236,  238,  239 Results of this study also indicated that patients receiving naltrexone experienced less pleasure after alcohol ingestion and had fewer drinking days and less alcohol craving than those receiving placebo.2,  232,  235,  236,  239 In an uncontrolled, large multicenter study in patients with alcohol dependence, including those with psychiatric conditions, those physically dependent on other substances, and those with human immunodeficiency virus (HIV) infection, abstinence and relapse rates were similar to those in the controlled studies.2

In a study in 627 US veterans (almost all men) with chronic, severe alcoholism (history of heavy drinking at least twice in a week during the previous 30 days and a DSM-IV diagnosis of alcohol dependence but who were sober for at least 5 days prior to study entry), oral naltrexone hydrochloride therapy (50 mg daily) was not effective as an adjunct to standard psychosocial therapy in the management of alcohol dependence as evidenced by no apparent benefit after 13 weeks on days to relapse (mean: 72.3 vs 62.4 days for naltrexone and placebo, respectively) nor at 52 weeks on the percentage of days on which drinking occurred or the number of drinks per drinking day.244,  245 As a result, it was concluded that the use of adjunctive naltrexone therapy could not be supported in men with chronic, severe alcoholism.244,  245 Whether these findings can be extrapolated to patients with less severe or less chronic alcoholism or to women or non-veterans remains to be established.244,  245 Patients in this study relative to other studies typically were older, had been drinking for longer periods, and were less likely to be married or living with a partner; although employment data were not reported, about one-third were receiving disability pensions, which may have negatively affected their motivation to stop drinking.244,  245

A large randomized controlled study was conducted to evaluate the effects of medication, behavioral therapies, and their combinations for treatment of alcohol dependence.12 Results showed that intensive counseling delivered by treatment specialists (combined behavioral intervention [CBI]) alone, naltrexone alone, and the combination of CBI and naltrexone all produced similar outcomes (e.g., abstinence rates) when used in the context of medical management (scheduled visits with a licensed healthcare professional to educate, counsel, and follow-up with patients).12 These findings suggest that naltrexone can be effective when used in the context of medical management without the need for specialist care.12

Efficacy of the injectable extended-release formulation of naltrexone was established in a 6-month study in individuals with alcohol dependence.1,  248 Adults were randomized to receive naltrexone 380 mg, naltrexone 190 mg, or placebo administered IM monthly in conjunction with 12 sessions of psychosocial intervention.1,  248 Treatment with 380 mg of naltrexone was associated with a greater reduction in days of heavy drinking (defined as 5 or more alcohol-containing drinks per day for male patients and 4 or more alcohol-containing drinks per day for female patients) than treatment with placebo.1,  248 Individuals receiving 380 mg of naltrexone reported a 25% greater reduction in the rate of heavy drinking relative to placebo-treated individuals.248 Treatment with 190 mg of naltrexone generally was not associated with a substantial reduction in the rate of heavy drinking.248 Subgroup analyses suggested that the treatment effects were greater in male patients than in female patients, and were also greater in individuals with lead-in abstinence (about 8% of the study population) than in those who were actively drinking during the lead-in phase.1,  248 Patients who abstained from drinking prior to treatment initiation had severalfold higher rates of abstinence with naltrexone therapy compared with placebo.16 In this subgroup of patients, the median time to first drink was 41 days in the naltrexone group compared with 12 days in the placebo group.16

Clinical Perspective

FDA-approved medications for the management of alcohol use disorder include disulfiram, acamprosate, and naltrexone.5 Clinicians should consider prescribing one of these agents for patients who are dependent on alcohol or who have stopped drinking but continue to experience cravings or relapses, particularly in those with moderate or severe alcohol use disorder.5 When selecting a particular treatment, clinicians should consider the patient's preferences, past treatment history, level of motivation for abstinence, clinical condition, contraindications, and history of medication adherence.5 Patients who are seeking treatment for both alcohol use disorder and concurrent opioid use disorder may benefit from naltrexone.5 There is some evidence suggesting that patients with a family history of alcohol problems may benefit more from treatment with naltrexone than patients who do not have such a history.5 There is also some evidence suggesting that individuals with intense craving for alcohol may derive greater benefit from naltrexone treatment than those with low levels of craving.5

Dosage and Administration

General

Pretreatment Screening

Cautions

Contraindications

Warnings/Precautions

Vulnerability to Opioid Overdose

After opioid detoxification, patients are likely to have reduced tolerance to opioids.1,  2 As the blockade of exogenous opioids produced by naltrexone decreases and eventually dissipates completely, patients who have been treated with naltrexone may respond to lower doses of opioids than previously used.1,  2 This could result in potentially life-threatening opioid overdose (e.g., respiratory compromise or arrest, circulatory collapse) if the patient uses previously tolerated doses of opioids.1,  2 Cases of overdosage with fatal outcomes have been reported after patients discontinued treatment with naltrexone.1,  2

The possibility also exists that patients who are treated with naltrexone could overcome the potent opioid blockade effect of naltrexone; the plasma concentration of exogenous opioids attained immediately following their acute administration may be sufficient to overcome the competitive receptor blockade.1,  2 This poses a potential risk to individuals who attempt, on their own, to overcome the blockade by administering large amounts of exogenous opioids.1,  2 Any attempts by a patient to overcome the antagonistic activity of naltrexone is especially dangerous and may lead to life-threatening opioid intoxication or fatal overdose.1,  2

Inform patients that they may be more sensitive to opioids, even at lower doses, after naltrexone treatment is discontinued.1,  2 It is important that patients inform family members and the people closest to the patient of this increased sensitivity to opioids and the risk of overdose.1,  2 Also inform patients of the serious consequences of trying to overcome the opioid blockade.1,  2

Because of the risks for opioid overdose, discuss with the patient and caregiver the importance of having access to naloxone for the emergency treatment of opioid overdose.1 Educate patients and caregivers on how to recognize the signs and symptoms of an opioid overdose and how to treat with naloxone.1 Emphasize the importance of calling 911 or seeking emergency medical help in all cases of known or suspected opioid overdose, even if naloxone is administered.1

Precipitated Opioid Withdrawal

Administration of naltrexone, an opioid antagonist, may precipitate opioid withdrawal severe enough to require hospitalization in patients physically dependent on opioids.1,  2 To prevent the risk of precipitating signs and symptoms of withdrawal, opioid-dependent individuals who are candidates for naltrexone therapy should remain free of opioids for a minimum of 7-10 days for patients previously dependent on short-acting opioids; up to 14 days may be required for those transitioning from methadone or buprenorphine.1,  2

Monitor patients closely in an appropriate medical setting where precipitated withdrawal can be managed if a decision is made by the healthcare provider for a more rapid transition from agonist to antagonist therapy.1,  2

Because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period, the healthcare provider should always be prepared to manage withdrawal.1,  2 A naloxone challenge test may be helpful; however, patients may sometimes experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment).1,  2

Patients treated for alcohol dependence with naltrexone should also be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment.1,  2 Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids.1,  2

Hepatotoxicity

Hepatitis and clinically significant liver dysfunction have been reported with the use of naltrexone in clinical studies and during the postmarketing period.1,  2 Transient, asymptomatic hepatic transaminase elevations also have been observed.1,  2 Patients with elevated transaminases were often found to have other potential causative or contributory etiologies, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant use of other potentially hepatotoxic drugs.1,  2 Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury.1,  2

Advise patients of the risk of hepatic injury and to seek medical attention if they experience symptoms of acute hepatitis.1,  2 Use of naltrexone should be discontinued if signs and/or symptoms of hepatotoxicity occur.1,  2 Some experts recommend against the use of naltrexone in patients with serum aminotransferase concentrations greater than 5 times the upper limit of normal (ULN) unless the benefits outweigh the risks.5 Liver function tests should be conducted prior to and during therapy in patients with preexisting hepatic impairment.372

Depression and Suicidality

Depression, suicidal ideation, attempted suicide, and completed suicides have been reported in patients receiving oral or injectable naltrexone for opioid dependence.1,  2 No causal relationship has been demonstrated, but endogenous opioids may be a contributing factor.1,  2

In adults with alcohol dependence, adverse events of a suicidal nature (suicidal ideation, suicide attempts, completed suicides) were more common in patients treated with injectable naltrexone than in those treated with placebo, although these events were infrequent overall.1

Monitor patients taking naltrexone for the development of depression or suicidal thinking.2 Families and caregivers of patients being treated with naltrexone should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient's healthcare provider.2

Ultrarapid Opioid Withdrawal

Safe use of naltrexone in ultrarapid opioid detoxification programs has not been established and is not recommended.2,  372

Injection Site Reactions

Injection-site reactions including pain, tenderness, induration, swelling, erythema, bruising, or pruritus, have occurred after administration of naltrexone extended-release injections and in some cases, the reaction was severe.1 Cases of injection-site reactions with features including induration, cellulitis, hematoma, abscess, sterile abscess, and necrosis have been reported in patients receiving the drug in the postmarketing setting, primarily in female patients; some cases required surgical intervention and/or resulted in significant scarring.1

Naltrexone extended-release injectable suspension must be prepared and administered by a healthcare professional.1 Injections must only be administered as a deep IM gluteal injection.1 Inadvertent subcutaneous injections may increase the likelihood of severe injection site reactions.1 Healthcare providers should ensure that the injection is given correctly, and should consider alternate treatment for those patients whose body habitus precludes an intramuscular gluteal injection with one of the manufacturer-provided needles.1 If signs of abscess, cellulitis, necrosis, or extensive swelling occurs, the patient should be evaluated by a physician to determine if referral to a surgeon is warranted.1

Reversal of Naltrexone Blockade for Pain Management

In an emergency situation in patients receiving naltrexone, options for pain management include regional analgesia, or use of non-opioid analgesics.1,  2 If opioid therapy is required as part of anesthesia or analgesia, patients should be continuously monitored in an anesthesia care setting by persons not involved in the conduct of the surgical or diagnostic procedure.1 This care should be provided by individuals specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, specifically the establishment and maintenance of a patent airway and assisted ventilation.1 Irrespective of the drug chosen to reverse the blockade, the patient should be monitored closely by appropriately trained personnel in a setting equipped and staffed for cardiopulmonary resuscitation.1,  2

Eosinophilic Pneumonia

In clinical studies of naltrexone extended-release injectable suspension, one diagnosed case and one suspected case of eosinophilic pneumonia were reported; both cases required hospitalization and resolved with antibiotic and corticosteroid treatment.1 If dyspnea and hypoxemia develops during naltrexone therapy, consider the diagnosis of eosinophilic pneumonia, particularly in patients who do not respond to antibiotics.1 Advise patients of the risk of eosinophilic pneumonia and to seek medical attention if they develop symptoms of pneumonia.1

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., urticaria, angioedema, anaphylaxis) have been reported with the use of naltrexone extended-release injectable suspension in clinical trials and in the postmarketing setting.1

Advise patients of the risk of hypersensitivity reactions, including anaphylaxis.1 If a hypersensitivity reaction occurs, patients should seek immediate medical attention in a healthcare setting prepared to treat anaphylaxis; naltrexone therapy should be discontinued.1

Administration Precautions

Administer IM injections of naltrexone extended-release suspension with caution to patients with thrombocytopenia or any coagulation disorder (e.g., hemophilia, severe hepatic failure).1

Alcohol Withdrawal

Use of naltrexone does not eliminate nor diminish alcohol withdrawal symptoms.1

Laboratory Test Interferences

Naltrexone may be cross-reactive with certain immunoassay methods for the detection of drugs of abuse (specifically opioids) in urine.1 For further information, refer to the specific immunoassay instructions.1

Specific Populations

Pregnancy

In reproduction studies in rats and rabbits, oral naltrexone increased the incidence of early fetal loss.1,  2 There are no adequate and well-controlled studies of oral naltrexone use in pregnant women.2 Available data from published case series of naltrexone extended-release injectable suspension are insufficient to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.1 Naltrexone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.2

Untreated opioid addiction in pregnancy is associated with adverse obstetrical outcomes, such as low birth weight, preterm birth, and fetal death, and often results in continued or relapsing illicit opioid use.1 Published studies have demonstrated that alcohol is associated with fetal harm, including growth restriction, facial abnormalities, CNS abnormalities, behavioral disorders, and impaired intellectual development.1

Lactation

Naltrexone and its major metabolite, 6β-naltrexol, are present in human milk.1 There are no data on the effects of the drug on the breastfed infant or on milk production.1,  2 Consider the developmental health benefits of breastfeeding along with the mother's clinical need for naltrexone and any potential adverse effects on the breastfed infant from naltrexone or the underlying maternal condition.1

Pediatric Use

The safety and efficacy of naltrexone have not been established in pediatric patients younger than 18 years of age.1,  2

Geriatric Use

Clinical studies of naltrexone extended-release injectable suspension did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients.1 In trials of alcohol-dependent patients, 2.6% of patients were over 65 years of age, and one patient was over 75 years of age.1 No individuals older than 65 years of age were included in studies of opioid dependency.1

The pharmacokinetics of naltrexone have not been evaluated in the geriatric population.1 This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function.1 Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function in this population.1

Hepatic Impairment

Patients with severe hepatic impairment have not been adequately studied.1,  2 The pharmacokinetics of naltrexone in patients with mild to moderate hepatic impairment are not altered; dosage adjustments of naltrexone extended-release injection are not required. 1 The manufacturer of naltrexone oral tablets makes no specific dosage recommendations for patients with hepatic impairment.2

Patients with compensated and decompensated liver cirrhosis have been reported to have approximately 5- and 10-fold higher naltrexone AUC, respectively, compared with patients with normal liver function.2 Alterations in naltrexone bioavailability may be related to liver disease severity.2

Renal Impairment

Caution is recommended when naltrexone is used patients with renal impairment as the drug and its main metabolite are excreted primarily in the urine.1,  2

Patients with severe renal impairment have not been adequately studied.2

Common Adverse Effects

The most common adverse effects in patients with opioid use disorder receiving naltrexone extended-release injectable suspension (incidence 2% and at least twice as frequent as with placebo) include hepatic enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache.1

The most common adverse effects in patients with opioid use disorder receiving naltrexone oral tablets (incidence 10%) include difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy, joint and muscle pain, and headache.2

The most common adverse effects in patients with alcohol use disorder receiving naltrexone extended-release injectable suspension (incidence 5% and at least twice as frequent as with placebo) include nausea, vomiting, injection site reactions (including induration, pruritus, nodules and swelling), muscle cramps, dizziness or syncope, somnolence or sedation, anorexia, and decreased appetite or other appetite disorders.1

The most common adverse effects in patients with alcohol use disorder receiving naltrexone oral tablets (incidence 2%) include depression, nausea, headache, dizziness, nervousness, fatigue, insomnia, vomiting, anxiety, and somnolence.2

Drug Interactions

The manufacturer states that concomitant administration of naltrexone with drugs other than opioid agonists has not been studied; therefore, naltrexone should be used with caution in patients receiving other drugs.2

Naltrexone is not metabolized by the cytochrome P-450 (CYP) isoenzyme system.1

Naltrexone does not inhibit or induce major CYP enzymes.1

Glyburide

Glyburide may increase serum concentrations of naltrexone.372 If used concomitantly, monitor for adverse effects of naltrexone.372

Opioid Agonists

Patients receiving naltrexone may not benefit therapeutically from opioid-containing preparations, including those used for the management of cough and cold, diarrhea, and pain.1,  2 Use of these preparations should generally be avoided during naltrexone therapy, except in an emergency situation as the amount of opioid required may be greater than usual and cause respiratory depression to be deeper and more prolonged.1,  2

To prevent precipitation of withdrawal, avoid use of naltrexone in patients receiving opiates or in nondetoxified patients physically dependent on opiates.1,  2

Peripherally Acting Opioid Antagonists

Naltrexone should not be used concomitantly with methylnaltrexone or naloxegol.372

Disulfiram

The safety and efficacy of concomitant use of naltrexone and disulfiram currently are not known but both drugs are potentially hepatotoxic.2 The manufacturer recommends that the drugs be used together only if the potential benefits justify the possible risks to the patient.2

Phenothiazines

Increased lethargy and somnolence have been reported following doses of naltrexone and thioridazine.2

Laboratory Tests

Naltrexone reportedly does not interfere with the determination of urinary morphine, methadone, or quinine using thin-layer (TLC), gas-liquid (GLC), or high-pressure liquid (HPLC) chromatography.2 However, naltrexone may interfere with some other immunoassay or enzymatic methods used for the detection of urinary opiates; the manufacturer of the test should be consulted for specific details.1,  2

Other Information

Description

Naltrexone is an opioid antagonist and generally has little or no agonist activity.1,  2 Naltrexone acts as a competitive antagonist at µ, κ, and δ receptors in the CNS;1,  2,  5,  10 the drug appears to have the highest affinity for the µ receptor.1 The major metabolite of naltrexone, 6β-naltrexol, is also an opioid antagonist and may contribute to the antagonist activity of the drug.1,  2 Naltrexone does not produce physical or psychologic dependence, and tolerance to the drug's opioid antagonist activity reportedly does not develop.1

In patients who have received single or repeated large doses of opioid agonists, naltrexone attenuates or produces a complete but reversible block of the pharmacologic effects (e.g., physical dependence, analgesia, euphoria, tolerance) of the opiate.1,  2 Naltrexone may precipitate mild to potentially severe withdrawal in individuals physically dependent on opiates.1 By blocking the effects of opioids by competitive binding at opioid receptors, it makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of opioids may result in non-opioid receptor-mediated symptoms such as histamine release.1,  2 However, in usual doses in patients who have not recently received opiates, naloxone exerts little or no pharmacologic effect, but may produce pupillary constriction by an unknown mechanism.1,  2 Naltrexone does not produce physical or psychologic dependence, and tolerance to the drug's opioid antagonist activity reportedly does not develop.2

The mechanism of action of naltrexone in alcohol dependence is not entirely known, but is thought to involve the endogenous opioid system.1,  2 Evidence from studies in animals suggests that alcohol ingestion stimulates release of endogenous opioid agonists, which may increase some of the rewarding effects associated with alcohol ingestion through agonist activity at opiate (e.g., µ) receptors.2,  10 In animals and humans, opiate antagonists (e.g., naltrexone) that competitively bind to opiate receptors may reduce alcohol consumption by blocking the effects of endogenous opiates and thus making alcohol ingestion less pleasurable.2,  8 Naltrexone also has been found in humans to augment plasma cortisol and adrenocorticotropic hormone (ACTH) levels through activation of the hypothalamic-pituitary-adrenal (HPA)-axis, which is found to be related to reduced urge and amount of alcohol drinking.8 In addition, naltrexone appears to decrease substantially the subjective alcohol “high”2 and this may reduce alcohol drinking behaviors.8,  10 Naltrexone does not cause disulfiram-like reactions following ingestion of alcohol.1,  2

Naltrexone is rapidly and almost completely (about 96%) absorbed following oral administration with peak plasma concentrations of both naltrexone and the primary metabolite, 6β-naltrexol, occurring within 1 hour of oral dosing.2 After IM administration of extended-release injection, plasma concentration time profile characterized by a transient initial peak approximately 2 hours after injection, followed by a second peak observed approximately 2-3 days later.1 Then, beginning approximately 14 days after dosing, concentrations slowly decline, with measurable levels beyond 1 month.1 Less 6β-naltrexol is generated following IM administration compared with oral administration due to a reduction in first-pass hepatic metabolism.1

Plasma protein binding is low (21%) over the therapeutic range of naltrexone.1 The cytochrome P-450 (CYP) system is not involved in naltrexone metabolism.1 Naltrexone and its metabolites are excreted primarily in the urine, with minimal unchanged drug.1 The elimination half- life of extended-release injectable suspension is 5-10 days and is dependent on the erosion of the polymer.1 Elimination half-life of 6β-naltrexol following extended-release injectable suspension administration is 5-10 days.1 The mean elimination half-life after oral administration for naltrexone and 6β-naltrexol are 4 hours and 13 hours, respectively.1

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Naltrexone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injectable suspension, extended-release, for IM use

380 mg

Vivitrol® (available as a dose pack containing a single-dose vial of naltrexone microspheres, diluent, needles, and syringe)

Alkemes

Naltrexone Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

50 mg*

Naltrexone Hydrochloride Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Copyright

AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions July 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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