Naltrexone

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Continuing Education Activity

Naltrexone is an FDA-approved opioid antagonist used to treat alcohol use disorder and opioid dependence. Naltrexone blocks the effect of opioids and prevents opioid intoxication and physiologic dependence on opioid users. This medication is a mu-opioid receptor antagonist and also a weaker antagonist of the kappa and delta-opioid receptors. This activity is designed to improve the knowledge of competency of practitioners selecting naltrexone as part of the individualized approach for patients with alcohol or opioid use disorder. Naltrexone's indications, mechanism of action, pharmacokinetics, administration methods, significant adverse effects, contraindications, monitoring, warnings, and toxicity are discussed.

Objectives:

  • Select an individualized approach for planning therapy based on medical history and physical exam findings.

  • Interpret naloxone test results and plan care accordingly.

  • Apply best practices when treating and monitoring patients with opioid or alcohol use disorders with naltrexone alone or in combination with buprenorphine.

  • Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from naltrexone therapy.

Indications

Naltrexone, an opioid antagonist used to treat alcohol use disorder and opioid dependence, 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 receptor antagonist.

  • Naltrexone is FDA-approved for alcohol use disorder.[1] 
  • Naltrexone is also FDA-approved for opioid use disorder.[2] 
  • A fixed-dose combination of naltrexone and bupropion is FDA-approved for obesity.[3]
  • Off-label use includes treating cholestatic pruritus in adults.[4]
  • Researchers are studying its use in patients with stimulant use disorder, particularly 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.[5]

Mechanism of Action

Medications used to treat alcohol and opioid use disorder focus on altering their reinforcing effects on inducing euphoria.[6] Naltrexone (and its active metabolite 6-beta-naltrexone) 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.[7] Endogenous opioids are involved in modulating alcohol and opioids by reinforcing their effects.[8] 

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.[9] Naltrexone competes as an antagonist at opioid receptors and can be used to treat alcohol and opioid use disorders.

Meta-analysis indicated that for preventing heavy drinking, NNT (number needed to treat) is 12 (95% CI, -0.13 to -0.04) with oral naltrexone.[10] In a clinical trial, extended-release naltrexone had a higher rate of opioid-negative urine samples (74% vs 56%, P<0.001) at week 24 compared to counseling and participation in community programs. According to guidelines by the American Society of Addiction Medicine (ASAM), a combination of buprenorphine and low doses of oral naltrexone is effective for opioid use disorder for managing withdrawal.[11][12]

Pharmacokinetics

Absorption: Naltrexone is almost completely absorbed after oral administration but has an extensive first-pass metabolism.

Distribution: Apparent volume of distribution after IV administration is 1350 L, and plasma protein binding is 21%. 

Metabolism: Naltrexone is metabolized to an active metabolite 6β-naltrexone.

Excretion: After oral administration, the half-life is 4 hours, and following an intramuscular injection (IM), the half-life is 5 to 10 days. Naltrexone is excreted primarily by the kidneys as a metabolite and unchanged drug.[13]

Administration

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.[14] The drug should not be administered intravenously (IV), subcutaneously, or into fatty tissue. The IM injection is recommended because many patients with a substance use disorder are non-compliant with the oral formula.[15] Data indicate that outcomes for patients with alcohol dependence who take naltrexone may be more favorable when using the IM formulation.

Note

  • 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 when a patient shows clinical signs or symptoms of opioid withdrawal or when the patient's urine contains opioids.
    • The naloxone test is used by injecting 0.2 mg naloxone IV and observing for 30 seconds for signs or symptoms of opioid withdrawal. If there is 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.
  • Test interpretation: Monitor vital signs and observe the patient for signs and symptoms of opioid withdrawal, such as 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 fasciculations. If signs and 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 is negative, naltrexone hydrochloride therapy could be started if no contraindications are present.
    • In case of any doubt about the test result, hold; don't start naltrexone hydrochloride. 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, 100 mg every other day, 150 mg every 3rd day, or 380 mg injection depot form for monthly administration. 
  • According to ASAM guidelines, extended-release injectable naltrexone 380 mg should be administered by deep IM injection in the gluteal muscle every four weeks.[11]
  • Naltrexone is typically combined with an alpha-2 agonist, which minimizes patient discomfort during withdrawal and shortens 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

  • American Psychiatric Association practice guidelines for alcohol use disorder recommend naltrexone in patients with moderate-to-severe alcohol use disorder.[16]
  • For alcohol use disorder, naltrexone can be given orally 50 mg once daily, 100 mg every other day, 150 mg every third day, or a 380-mg injection depot form for monthly administration. 
  • Studies suggest 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 once per monthly 380 mg injection, especially in individuals with the G-allele of the AII8G polymorphism of the mu-opioid receptor. 

Heroin Use Disorder

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

Specific Patient Populations

Patient with Hepatic Impairment: The AUC of naltrexone increases in liver cirrhosis patients, so the patient's liver function must be considered when dosing the drug in patients with severe hepatic impairment.[16]

Patient with Renal Impairment: Naltrexone and its primary metabolite are excreted mainly in the urine; caution is advised administering naltrexone to patients with renal impairment.

Pregnancy Considerations: 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. If a female treated with naltrexone to treat opioid use disorder becomes pregnant, naltrexone therapy should be stopped if the mother and the physician agree that the risk of relapse is low. According to ACOG, the decision regarding naltrexone treatment during pregnancy requires a risk-benefit analysis considering the possible risk of relapse with naltrexone discontinuation. Methadone or buprenorphine is usually preferred during pregnancy for opioid use disorder.[17]

Breastfeeding Considerations: Naltrexone is also present in breast milk. Considering the importance of treatment for the mother, a decision on whether to discontinue breastfeeding or discontinue the drug needs to be made.[18]

Geriatric Patients: Naltrexone is widely used to treat alcohol use disorder in elderly patients.[19]

Pediatric Patients: The safety of naltrexone in pediatric patients(<18 years) has not been demonstrated.

Adverse Effects

Naltrexone may cause gastrointestinal irritation, such as diarrhea and 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 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. It is safe and associated with few adverse effects, such as headache, nausea, and abdominal pain, when taken chronically for years.

Naltrexone can precipitate a withdrawal syndrome in patients with opioid use disorder characterized by dysphoria, irritability, and 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.[20] Naltrexone-induced drug eruption with urticarial rash and angioedema has been reported.[21]

Drug-Drug Interactions

  • Concurrent administration of bremelanotide with naltrexone is contraindicated due to reduced naltrexone systemic exposure resulting in therapeutic failure.[22]
  • Naltrexone should not be administered with thioridazine due to the risk of lethargy and somnolence.[23]

Mainstreaming Addiction Treatment (MAT) Act

The Mainstreaming Addiction Treatment (MAT) Act provision updates federal guidelines to expand the availability of evidence-based treatment to address the opioid epidemic. The MAT Act empowers all health care providers with a standard controlled substance license to prescribe buprenorphine for opioid use disorder (OUD), just as they prescribe other essential medications. The MAT Act is intended to help destigmatize a standard of care for OUD and integrate substance use disorder treatment across healthcare settings. 

As of December 2022, the MAT Act has eliminated the DATA-Waiver (X-Waiver) program. All DEA-registered practitioners with Schedule III authority may now prescribe buprenorphine for OUD in their practice if applicable state law permits, and SAMHSA encourages them to do so. Prescribers registered as DATA-Waiver prescribers will receive a new DEA registration certificate reflecting this change; no action is needed from registrants.

There are no longer limits on the number of patients with OUD that a practitioner may treat with buprenorphine. Separate tracking of patients treated with buprenorphine or prescriptions written is no longer required. 

Pharmacy staff can now fill buprenorphine prescriptions using the prescribing authority's DEA number and does not need a DATA 2000 waiver from the prescriber. However, depending on the pharmacy, the dispensing software may still require the X-Waiver information to proceed. Practitioners must still comply with applicable state limits regarding treating patients with OUD. Contact information for State Opioid Treatment Authorities can be found here: https://www.samhsa.gov/medicationassisted-treatment/sota.  

Contraindications

Contraindications

  • 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
  • History of seizures: the naltrexone/bupropion fixed dose combination is contraindicated.[24]

Precautions

  • Monitor patients presenting with dyspnea and hypoxia, as a few cases of eosinophilic pneumonia have been reported in the literature.
  • The clinician should discontinue therapy if signs and symptoms of acute hepatitis develop.[25]
  • Patients undergoing surgery while being treated for opioid use disorder should stop oral naltrexone at least 72 hours before the scheduled surgery. In addition, 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 nonopioid medications.

Monitoring

  • Check injection sites for reactions following IM administration.
  • Screen for depression and 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.[26]
  • Clinicians should monitor withdrawal using standardized scales such as COWS (clinical opiate withdrawal scale) or CINA (clinical institute narcotic assessment).[27]

Toxicity

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. Hepatotoxicity is dose-dependent. Reports exist of depression, suicidal ideation, and suicidal attempts. Monitor the patient for symptoms of depression or suicidality.[25] In animal studies, high doses of naltrexone (>1000 mg/kg) produced salivation, reduced activity, depression, tremors, and convulsions. Death in animals was due to clonic-tonic convulsions and respiratory failure.

Treatment of Overdosage

No known antidote for naltrexone exists. Treat patients symptomatically in a closely monitored environment. Clinicians should contact a poison control center for the latest information.[28]

Enhancing Healthcare Team Outcomes

Naltrexone's primary use is to manage alcohol and opioid use disorder. An interprofessional team approach that includes clinicians, pharmacists, and mental health professionals working with patients on naltrexone therapy may improve patient outcomes.[Level 5] The interprofessional team must communicate openly regarding dosing and compliance, be vigilant for signs of opioid withdrawal and adverse events (especially depression and suicidality), and share any notable changes with all team members.

In addition, the following resources and tools can help healthcare members to manage patients better:

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

Healthcare professionals with experience in psychiatry and substance use disorders should prescribe naltrexone. 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 patients with alcohol and opiate use disorder managed with naltrexone need close monitoring but may be monitored as outpatients. Data suggest that naltrexone can help reduce alcohol intake, but its benefits do not occur in everyone.[29][30]

Pharmacists can verify dosing, offer education on interactions and adverse effects, and help monitor the patient as treatment progresses. The patient must always carry a medication safety card to inform the caregiver of the relevant medical management considerations. All team members must use open communication to inform other team members of any concerns or possible changes in patient status. Regarding 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, interprofessional coordination and collaboration among mental health professionals, such as counselors, psychologists, or social workers, as well as physicians, advanced practice practitioners, specialists, pharmacists, nurses, and public health professionals are crucial to optimal patient outcomes.[31]


Details

Updated:

5/30/2023 8:33:31 AM

References


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