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Continuing Education Activity

Naltrexone is an opioid antagonist used to treat alcohol use disorder and opioid dependence. It is FDA-approved for alcohol use disorder and opioid dependence treatment. Off-label use includes treatment of cholestatic pruritus in adults. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, monitoring, and toxicity of naltrexone, so providers can direct patient therapy to optimal outcomes when alcohol use disorder and opioid use disorder is an issue.


  • Identify the mechanism of action of naltrexone.
  • Review the approved and off-label indications for naltrexone.
  • Summarize the contraindication and adverse effects of naltrexone.
  • Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from naltrexone therapy.


Naltrexone is an opioid antagonist used to treat alcohol use disorder and opioid dependence. It was developed in 1963 and patented in 1967. In 1984, naltrexone received approval for medical use in the United States. While experimenting with rats at the University of Pennsylvania, Dr. Joseph Volpicelli first recognized naltrexone's potential to treat alcohol use disorder. The World Health Organization (WHO) estimates that over 75 million people have alcohol use disorder or dependence worldwide. Naltrexone is a mu-opioid antagonist.

  • It is FDA-approved for alcohol use disorder.[1] 
  • Naltrexone is also FDA-approved for opioid use disorder.[2] 
  • Off-label use includes treating cholestatic pruritus in adults, and a combination of naltrexone and bupropion is used to treat obesity.[3] 
  • Researchers are studying its use in patients with stimulant use disorder, particularly for patients with polydrug dependence on opioids, heroin, and amphetamine. The drug is part of the current best practices for addressing and treating patients with opioid use disorder.[4]

Mechanism of Action

Medications used to treat alcohol, and opioid use disorder focuses on altering their reinforcing effects on inducing euphoria.[5] Naltrexone (and its active metabolite 6-beta-naltrexol) is pharmacologically effective against alcohol and opioids by blocking the mu-opioid receptor. Naltrexone is also a weaker antagonist of the kappa and delta-opioid receptors.[6] Endogenous opioids are involved in modulating alcohol and opioids by reinforcing their effects.[7] Naltrexone blocks the effect of opioids and prevents opioid intoxication and physiologic dependence on opioid users. Naltrexone also modifies the hypothalamic-pituitary-adrenal axis to suppress ethanol consumption.

Exogenous opioids include the commonly prescribed pain relievers such as hydrocodone, oxycodone, and heroin. Usually, they induce euphoria at much higher doses than those prescribed by medical providers to relieve pain. Opioid overdose can lead to coma and respiratory compromise. Opioids act mainly via the mu receptor, although they affect mu, delta, and kappa-opioid receptors. Synthetic opioid antagonists can modify the action of opioids on these receptors.[8] Naltrexone competes as an antagonist at opioid receptors and can be used to treat alcohol and opioid use disorders.


  • Naltrexone absorption is almost complete after oral administration, but it has an extensive first-pass effect.
  • After oral administration, the half-life is 4 hours, and following an intramuscular injection (IM), the half-life is 5 to 10 days.
  • Naltrexone excretion is primarily through urine.


Oral Dosage

Naltrexone is available as an oral tablet (50 mg), and the usual dose for alcohol treatment is 50 to 100 mg. Dosing should start at 25 mg orally for a single dose and be repeated in an hour if there are no withdrawal signs. Naltrexone can be given orally with or without food. Administration with or after meals may minimize adverse gastrointestinal (GI) effects.

Injection Dosage

Naltrexone is also available in a depot injection (380 mg). The IM form requires injection using provided needles for administration into the upper outer quadrant of the gluteal area; clinicians should avoid injection into the blood vessel.[9] The drug should not be administered intravenously (IV), subcutaneously, or into fatty tissue. Because many patients with a substance use disorder are non-compliant with the oral formula, the IM injection is recommended.[10] Data indicate that outcomes for patients with alcohol dependence who take naltrexone may be more favorable when using the IM formula. 


  • The patient first needs detoxification from opioids before starting naltrexone; the patient must be opioid-free (including tramadol) for at least 7 to 10 days. Advise patients not to self-administer opioids while receiving naltrexone therapy.
  • Since there is a possibility of opioid withdrawal, the recommended approach is to try a naloxone challenge to confirm the appropriateness of the treatment plan. 

Naloxone Challenge 

  • Clinicians understand that there is no completely reliable method to determine if a patient has an adequate opioid-free period to start naltrexone treatment. The naloxone test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal or in a patient whose urine contains opioids.
    • Naloxone test is used by injecting 0.2 mg naloxone IV and observing for 30 seconds for signs or symptoms of opioid withdrawal. If no evidence of opioid withdrawal, inject 0.6 mg of naloxone to observe for an additional 20 minutes. A low dose of 0.1 mg IV has produced a diagnostic response to the naloxone test in some patients.
    • Alternatively, naloxone can be injected subcutaneously with 0.8 mg naloxone to observe the patient for 20 minutes for signs or symptoms of opioid withdrawal.
  • Interpretation of the Test: Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal ( nausea, vomiting, sweating, changes in blood pressure, dysphoria, pupillary dilation, yawning, tearing, craving for opioids, rhinorrhea, stuffy nose, uneasiness, abdominal cramps, poor appetite,  sense of fear, disrupted sleep patterns, skin erythema, fidgeting,  poor ability to focus, mental lapses, muscle aches/cramps,  piloerection, fever, irritability, anxiety, depression, changes in blood pressure, bone or joint pains, backache, tremors, sensations of skin-crawling and/or fasciculations). If signs/symptoms of withdrawal appear, no additional naloxone should be administered.
    • If the test is positive, don't initiate naltrexone hydrochloride therapy. Instead, repeat the challenge test in 24 hours.
    • If the test comes negative, naltrexone hydrochloride therapy could be started if no other contraindications are present.
    • In case of any doubt about the test result, hold, don't start naltrexone hydrochloride and repeat the test in 24 hours.

Opioid Use Disorder

  • For opioid use disorder, naltrexone can be started at a lower dose of 25 mg once daily for a few days and then increased to 50 mg once daily, or 100 mg every other day, or 150 mg every third-day dose or 380 mg injection depot form for monthly administration. 
  • Naltrexone is typically combined with alpha-2 agonist, which minimizes patient discomfort during the withdrawal stage to shorten the duration of opioid withdrawal. Another benefit of rapid opiate detoxification is the reduced time between opioid use and the initiation of sustained naltrexone treatment to prevent relapse. Rapid opiate detoxification completion rates using naltrexone and clonidine range from 75% to 81% compared to 40% for methadone and clonidine alone.

Alcohol Use Disorder

  • For alcohol use disorder, naltrexone can be given orally 50 mg once daily, or 100 mg every other day, or 150 mg every third-day dose, or 380 mg injection depot form for monthly administration. 
  • Studies have suggested that carriers of the G-allele may experience a higher level of craving and a stronger euphoria following alcohol use. Naltrexone, 50 to 150 mg per day orally, appears to shorten subsequent relapses, whether used in the oral form or as once per month 380-mg injection, especially in individuals with the G-allele of the AII8G polymorphism of the mu-opioid receptor.

Heroin Use Disorder

  • Naltrexone maintenance combined with psychosocial therapy effectively reduces heroin use, but medication adherence is low. Depot injection formulation lasting up to 4 weeks improves medication adherence, retention, and drug use markedly.
  • Subcutaneous naltrexone implants in Russia, China, and Australia have doubled treatment retention and reduced relapse to half that of oral naltrexone.

Specific Patient Population

  • Patient with hepatic impairment: AUC of naltrexone increases in patients with liver cirrhosis, so care should be taken when naltrexone is used in patients with severe hepatic impairment.
  • Patient with renal impairment: Naltrexone and its primary metabolite are excreted mainly in the urine, and caution is advised administering naltrexone to patients with renal impairment.

Adverse Effects

Naltrexone may cause gastrointestinal irritation such as diarrhea, abdominal cramps, and in some studies, it shows clinically insignificant increases in blood pressure.

In clinical studies of patients with opioid use disorder, headache, anxiety, low energy, joint and muscle pain, nervousness, abdominal pain/cramps, difficulty sleeping, and nausea and/or vomiting were reported in more than 10% of patients. Less than 10% of incidents reported were loss of appetite, constipation, diarrhea, increased energy, increased thirst, feeling down, dizziness, irritability,  delayed ejaculation, skin rash, and chills. When taken chronically for years, it is safe and associated with few side effects such as headache, nausea, and abdominal pain.

Naltrexone can precipitate a withdrawal syndrome in patients with opioid use disorder characterized by dysphoria, irritability, and having signs of autonomic hyperactivity such as tachycardia, tremor, and sweating. Other rare but potentially serious effects include depression and suicidality.

Piloerection is often associated with opioid withdrawal, especially when stopping the drug suddenly. Clonidine, an alpha2-adrenergic agonist, can aid in detoxification by reducing the signs of autonomic hyperactivity.[11]



  • Failure to pass a naloxone challenge test or positive urine screen for opioids
  • Opioid dependence or current use of opioid analgesics, including partial agonists
  • Acute opioid withdrawal
  • Hypersensitivity reactions, including urticaria, angioedema, and anaphylaxis to naltrexone or any components of the formulation


  • Monitor patients presenting with dyspnea and hypoxia as a few cases of eosinophilic pneumonia reported in the literature.
  • The clinician should discontinue therapy if signs and symptoms of acute hepatitis develop.
  • Patients undergoing surgery while being treated for opioid use disorder should stop oral naltrexone at least 72 hours before the scheduled surgery. The IM naltrexone therapy should be suspended for at least 30 days before surgery.

Switching from Buprenorphine, Buprenorphine/Naloxone, or Methadone to Naltrexone

Patients transitioning from opioid agonists (buprenorphine or methadone) might be at increased risk of precipitation of withdrawal symptoms for approximately 14 days. Therefore, clinicians should be prepared to manage withdrawal symptoms with non-opioid medications.

Pregnancy Implication

Naltrexone is classified as category C for use during pregnancy, which means that the risk to the fetus of adverse effects cannot be ruled out. There is limited research available related to the use of naltrexone during pregnancy. Animal reproduction studies have shown adverse effects. Practice guidelines recommend that if a female treated with naltrexone to treat opioid use disorder becomes pregnant, naltrexone therapy should terminate if the mother and the physician agree that the risk of relapse is low. 

Breastfeeding Women

Naltrexone is also present in breast milk, and considering the importance of treatment of the mother, there needs to be a decision made whether to discontinue breastfeeding or discontinue the drug.[13]


  • Clinicians must monitor for opioid withdrawal.
  • Check injection sites for reactions following IM administration.
  • Screen for depression and/or suicidal thinking.
  • Baseline and periodic liver function tests are necessary. Patients infected with hepatitis B or C can take naltrexone without worsening their liver function. However, most providers refrain from prescribing the medication if liver function tests are 3 to 5 times above normal levels.[14]


There is limited data on naltrexone hydrochloride overdosage in humans. In one study, patients who received 800 mg daily naltrexone hydrochloride for seven days reported no symptoms of toxicity. Cases of hepatitis and liver dysfunction have been observed; transient asymptomatic hepatic transaminase elevations may also occur. Reports exist of depression, suicidal ideation, and suicidal attempts. Monitor the patient for symptoms of depression or suicidality.[15]

In animal studies, high doses of naltrexone ( more than 1000 mg/kg) produced salivation, reduced activity/depression, tremors, and/or convulsions. Death in animals was due to clonic-tonic convulsions and/or respiratory failure.

Treatment of Overdosage

There is no known antidote for naltrexone. Treat patients symptomatically in a closely monitored environment. Clinicians should contact a poison control center for the latest information.

Enhancing Healthcare Team Outcomes

Naltrexone's primary use is to manage alcohol and opioid use disorder. An interprofessional team approach that includes clinicians (MDs, DOs, PAs, and NPs), nursing staff, pharmacists, and mental health professionals working with patients on naltrexone therapy will offer the best chance for optimal patient results. [Level 5] The interprofessional team needs to engage in open communication regarding dosing, compliance, be vigilant for signs of opioid withdrawal, adverse events (especially depression and suicidality), and share any notable changes with all team members. Some resources and tools can help health care members to manage patients better.

  • Clinical opiate withdrawal scale (COWS) to rate common signs/symptoms of opiate withdrawal and monitor symptoms over time.
  • Naltrexone readiness form is used to verify the patient medical history, drug use history, lab information, physical exam, and other pertinent information to check patient readiness.
  • Naltrexone education form ensures to patient's understanding of how naltrexone works,  length of treatment, adverse events.
  • Initial medication management forms and follow-Up medication management forms are used to help patients maintain abstinence.

The drug is best prescribed by healthcare professionals with experience in psychiatry and substance use disorders. The nurses working in outpatient psychiatry must know how this drug should be used and what precautions are necessary to optimize the chances of successful outcomes. Most of the patients with alcohol and opiate use disorder managed with naltrexone need close monitoring but are manageable as outpatients. Data suggest that naltrexone can help reduce alcohol intake, but its benefits do not occur in everyone.[16][17] Pharmacists can verify dosing, offer education on interactions and adverse effects, and help monitor the patient as treatment progresses. A medication safety card must be carried by the patient at all times to inform the caregiver of the relevant medical management considerations. All team members must use open communication lines to inform other team members of any concerns or possible changes in patient status. When it comes to opioid use disorder, naltrexone has been shown to lower the frequency of negative drug tests. Still, relapse rates are high if the patient receives no adjunct behavior therapy; therefore, mental health professionals such as counselors, psychologists, or social workers, are integral members of the interprofessional team for these cases.[18]

Article Details

Article Author

Dharminder Singh

Article Editor:

Abdolreza Saadabadi


6/29/2022 3:58:26 PM

PubMed Link:




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