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 had alcohol abuse or dependence worldwide. Naltrexone is a mu-opioid antagonist. It is FDA-approved for alcohol abuse and opioid dependence treatment.[1] Off-label use includes treatment of cholestatic pruritus in adults. Researchers are studying its use in patients with stimulant addiction, particularly for patients with polydrug dependence on opioids, heroin, and amphetamine.

Another clinical use for naltrexone is for opiate toxicity/addiction. Exogenous opioids include the commonly prescribed pain relievers such as hydrocodone, oxycodone, among others[2] and drugs of abuse such as heroin. Heroin induces euphoria at much higher doses than those prescribed by medical providers to relieve pain. Heroin leads to addiction via the euphoria it induces in its abusers. Opioid overdose can lead to coma and respiratory compromise.  Opioids act mainly via the mu receptor, although they have effects on mu, delta, and kappa-opioid receptors. Synthetic opioid antagonists can modify the action of opioids on these receptors.[3] Naltrexone competes as an antagonist at opioid receptors and can be used to treat alcohol and opioid addiction.

Medications used to treat alcohol and opioid addiction focus on altering their reinforcing effects on inducing euphoria.[4] Naltrexone is pharmacologically effective against alcohol and opioids by blocking the mu-opioid receptor. Endogenous opioids are involved in modulating alcohol and opioids by reinforcing their effects.[5] 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.

Naltrexone is available as an oral tablet (50 mg), and the usual dose for alcohol treatment is 50 to 100 mg.  Naltrexone formulation is also available for depot injection (380 mg). Naltrexone absorption is almost complete after oral administration but has an extensive first-pass effect. Naltrexone excretion is primarily through urine. After oral administration, the half-life is 4 hours, and following an intramuscular injection (IM), the half-life is 5 to 10 days.

The patient first needs detoxification from opioid dependence before starting naltrexone. If there is a possibility of opiate or alcohol withdrawal, the recommended approach is to try a naltrexone challenge test. One should start with 25 mg orally, and if there are no withdrawal symptoms observed, then repeat the test in 1 hour and continue 50 mg, orally, every day. Naltrexone can be given three times a week at doses of 100 to 150 mg or as a 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 commencement 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.

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.

Naltrexone can be given orally with or without food. Administration with food or after meals may minimize adverse gastrointestinal (GI) effects. Advise patients not to self-administer opioids while receiving naltrexone therapy. 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.[6] Do not administer intravenously (IV), subcutaneously, or into fatty tissue. Because many patients with a substance-misuse disorder are non-compliant with the oral formula, the IM injection is a recommendation.[7]  Data indicate that outcomes for patients with alcohol dependence who take naltrexone may be more favorable when using the IM formula.

Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use, but medication adherence is low. Depot injection formulation lasting up to 4 weeks improves 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.

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

Contraindications to naltrexone use are hypersensitivity reactions, including urticaria, angioedema, and anaphylaxis. Opioid dependence or current use of opioid analgesics, including partial agonists, acute opioid withdrawal, and failure to pass a naloxone challenge or positive urine screen for opioids are also contraindications to the use of naltrexone.

Pregnancy Implications

Naltrexone is classified as category C for use during pregnancy, which means that the risk of adverse effects on the fetus 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 being 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. Naltrexone should not be given for the treatment of alcohol use disorder in pregnant women unless needed for the treatment of acute alcohol withdrawal. Other agents are recommended for acute alcohol withdrawal. 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.