Naltrexone is a medication primarily used in the management of alcohol dependence and opioid dependence. It works by blocking the effects of opioids in the brain, thereby reducing cravings and the rewarding effects of alcohol and opioids.

In the treatment of alcohol dependence, naltrexone can be taken in pill form on a daily basis or as an extended-release injection administered once a month. When used for opioid dependence, it's typically administered as a daily pill or as a monthly injection.

While naltrexone can be an effective component of a comprehensive treatment plan for addiction, it's often most successful when combined with counseling, support groups, and other therapies aimed at addressing the underlying factors contributing to substance use disorder.

Naltrexone (Revia, Vivitrol) is an opioid antagonist that is available as an oral and injectable formulation for the treatment of alcohol and opioid dependence after proper detoxification.

Naltrexone Uses:

• Alcohol use disorder:
  • Used in the treatment of alcohol use disorder.
• Opioid dependence:
  • Used For the blockade of the effects of exogenously administered opioids.
• Off Label Use of Naltrexone in Adults:
  • Cholestatic pruritus
  • Pathological gambling disorder

Naltrexone Dose in Adults

Note:

• Before starting treatment with naltrexone, it's crucial that the patient hasn't used opioids, including tramadol, for at least 7 to 10 days, as confirmed by a urine test.
• If there's any doubt, a naloxone challenge test might be necessary to ensure the patient is opioid-free, as regular urine tests might not be enough.

Naltrexone Dose in the treatment of alcohol use disorder:

• The typical dose of naltrexone for treating alcohol use disorder when taken orally is 50 mg daily, although some patients may need doses up to 100 mg per day.
• Alternative maintenance schedules can also be considered, such as taking 50 mg on weekdays with a 100 mg dose on Saturdays, taking 100 mg every other day, or taking 150 mg every three days.
• It's important to note that extended dosing intervals and doses exceeding 50 mg may decrease the effectiveness of the medication and increase the risk of liver injury.
• Alternatively, naltrexone can be administered as an injection, with a dose of 380 mg given once every four weeks.

Naltrexone Dose in the treatment of opioid dependence:

• For opioid dependence treatment, the usual starting dose of naltrexone taken orally is 25 mg, followed by 50 mg per day if there are no signs of withdrawal.
• Alternative maintenance plans can be considered, such as taking 50 mg on weekdays with a 100 mg dose on Saturdays, taking 100 mg every other day, or taking 150 mg every three days.
• It's essential to be cautious with extended dosing intervals and doses over 50 mg, as they may reduce the medication's effectiveness and increase the risk of liver injury.
• Another option is an injection of 380 mg once every four weeks.

Naltrexone Dose in the treatment of Cholestatic pruritus (off-label):

• In the treatment of cholestatic pruritus, which is an off-label use of naltrexone, the typical starting dose taken orally is 12.5 mg once daily.
• This dose can be gradually increased by 12.5 mg every 3 to 7 days until the desired clinical benefits are observed.
• Some reports suggest doses of 50 mg daily have been used for up to 28 weeks.

Naltrexone dose in children:

Not established in opioid dependence. In other conditions like Crohn's disease and autism, the dose ranged from 0.1 - 2 mg/kg/day [Ref]

Pregnancy Risk Category: C

• Using naltrexone during pregnancy is a topic where information is limited.
• Clinical guidelines suggest that if a woman taking naltrexone for opioid use disorder becomes pregnant, discontinuing the medication may be considered if both the patient and physician agree that the risk of relapse is low.
• However, if the patient prefers to continue naltrexone, they should be informed about the potential risks, and their consent for ongoing treatment should be obtained.
• If naltrexone is stopped and the patient relapses, other medications like methadone or buprenorphine may be considered.
• It's important to note that pharmacological agents, including naltrexone, aren't typically recommended for treating alcohol use disorder in pregnant women, unless necessary for acute alcohol withdrawal or a coexisting disorder.
• Other medications are usually preferred for managing acute alcohol withdrawal.

Naltrexone use during breastfeeding:

• Naltrexone and its metabolite, 6-beta-naltrexol, have been detected in breast milk according to a study by Chan in 2004.
• The decision whether to breastfeed while undergoing naltrexone therapy should carefully weigh the potential risk of infant exposure against the benefits of breastfeeding for the baby and the benefits of treatment for the mother.
• Generally, pharmacological agents, including naltrexone, aren't typically recommended for treating alcohol use disorder in breastfeeding women, unless necessary for acute alcohol withdrawal or a coexisting disorder.
• Other medications are usually preferred for managing acute alcohol withdrawal in breastfeeding mothers.

Naltrexone Dose in Kidney Disease:

• For individuals with mild impairment, no adjustment in naltrexone dosage is typically required.

• For those with moderate-to-severe impairment, there's no specific dosage adjustment provided in the manufacturer's labeling as it hasn't been extensively studied in this population. Caution is advised when prescribing naltrexone in these cases because both naltrexone and its main metabolite are mainly excreted through urine.

Naltrexone Dose in Liver disease:

• For individuals with mild to moderate impairment, no adjustment in naltrexone dosage is typically necessary.
• For those with severe impairment, there's no specific dosage adjustment provided in the manufacturer's labeling as it hasn't been extensively studied in this population. It's important to note that naltrexone's exposure in the bloodstream (AUC) can increase significantly in patients with compensated or decompensated hepatic cirrhosis, by approximately 5- and 10-fold respectively. Therefore, caution is advised in such cases. Additionally, naltrexone is not recommended for use in acute hepatitis or hepatic failure.

• Combined reporting of adverse events from oral and injectable formulations.

Common Side Effects of Naltrexone:

• Cardiovascular:
  • Syncope
• Central Nervous System:
  • Headache
  • Insomnia
  • Dizziness
  • Anxiety
  • Decreased Energy
  • Nervousness
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Decreased Appetite
  • Diarrhea
  • Abdominal Pain
  • Abdominal Cramps
• Hepatic:
  • Increased Serum ALT
• Local:
  • Injection Site Reaction
• Neuromuscular & Skeletal:
  • Increased Creatine Phosphokinase
  • Arthralgia
  • Myalgia
• Respiratory:
  • Pharyngitis

Less Common Side Effects Of Naltrexone:

• Cardiovascular:
  • Hypertension
• Central Nervous System:
  • Suicidal Ideation
  • Delayed Ejaculation
  • Depression
  • Drowsiness
  • Fatigue
  • Chills
  • Depressed Mood
  • Increased Energy
  • Irritability
• Dermatologic:
  • Skin Rash
• Endocrine & Metabolic:
  • Increased Gamma-Glutamyl Transferase
  • Increased Thirst
  • Polydipsia
• Gastrointestinal:
  • Xerostomia
  • Toothache
  • Constipation
• Genitourinary:
  • Impotence
• Hepatic:
  • Increased Serum AST
• Infection:
  • Influenza
• Neuromuscular & Skeletal:
  • Muscle Cramps
  • Back Pain

Contraindications to Naltrexone:

• Naltrexone is contraindicated in individuals with hypersensitivity to naltrexone or any component of the formulation, those with opioid dependence or current use of opioid analgesics (including partial opioid agonists), and those experiencing acute opioid withdrawal or who fail a naloxone challenge or have a positive urine screen for opioids.
• In Canada, additional contraindications not listed in US labeling include acute hepatitis and hepatic failure.

Warnings and precautions

Accidental opioid overdose:

• Patients who have been treated with naltrexone may experience increased sensitivity to lower doses of opioids than they were previously accustomed to.
• This heightened sensitivity could potentially lead to dangerous opioid intoxication.
• It's crucial to inform patients that they may be more susceptible to lower doses of opioids after stopping naltrexone treatment, missing a dose, or nearing the end of the dosing interval.
• Additionally, patients should be warned that attempting to overcome the opioid blockade during naltrexone therapy could result in fatal opioid overdose.
• The competitive receptor blockade produced by naltrexone can potentially be overcome in the presence of large amounts of opioids, posing a significant risk.

Acute opioid withdrawal

• The abrupt discontinuation of naltrexone treatment may induce symptoms of acute opioid withdrawal in individuals who are dependent on opioids.
• These symptoms can include pain, hypertension, sweating, agitation, and irritability in adults.
• In neonates born to mothers who were using opioids and taking naltrexone during pregnancy, symptoms of withdrawal may manifest as a shrill cry and failure to feed.

Eosinophilic pneumonia:

• Cases of eosinophilic pneumonia have been reported in individuals taking naltrexone, and healthcare providers should be aware of this potential adverse reaction.
• Patients presenting with progressive hypoxia and dyspnea should be evaluated for eosinophilic pneumonia, particularly if they are receiving naltrexone treatment.
• This underscores the importance of monitoring patients closely for respiratory symptoms while they are on naltrexone therapy and promptly addressing any concerning signs or symptoms.

Hepatocellular injury:

• There is a risk of dose-related hepatocellular injury with naltrexone, and this risk increases when the dosage exceeds safe levels by more than fivefold.
• It's essential to discontinue therapy if signs or symptoms of acute hepatitis develop.
• Clinicians should be aware that elevated liver enzymes may be caused by pre-existing conditions like alcoholic liver disease, hepatitis B and/or C infection, or the concurrent use of other drugs known to be harmful to the liver.
• Additionally, abrupt opioid withdrawal can also contribute to acute liver injury.
• Regular monitoring of liver function is crucial during naltrexone therapy to detect any signs of hepatotoxicity early.

Hypersensitivity reactions

• Hypersensitivity reactions, such as urticaria (hives), angioedema (swelling under the skin), and anaphylaxis (severe allergic reaction), have been reported in individuals taking naltrexone.

Injection site reactions:

• Serious injection site reactions, such as cellulitis, induration (hardening of tissue), hematoma (localized swelling filled with blood), abscess (collection of pus), and necrosis (tissue death), have been reported with the use of naltrexone injection.
• Severe cases may even require surgical intervention.
• Females seem to be at a higher risk for these reactions.
• Patients should be instructed to report any symptoms such as pain, swelling, bruising, itching, or redness at the injection site that does not improve or worsens over time.
• It's essential to administer naltrexone injection only into the gluteal muscle and not into veins, subcutaneous tissue, or fatty areas, as incorrect administration can increase the risk of injection site reactions.

Suicidal thoughts/depression

• Suicidal thoughts, attempted suicide, and depression have been reported in individuals taking naltrexone, particularly in the postmarketing phase.
• Healthcare providers should closely monitor patients for signs of depression or suicidal ideation during treatment with naltrexone.
• It's important to promptly address any concerning symptoms and provide appropriate support and intervention as needed.

Bleeding disorders:

• Caution should be exercised when using intramuscular (IM) injection of naltrexone in patients with thrombocytopenia (low platelet count), bleeding disorders (including hemophilia), severe hepatic failure, or those receiving anticoagulant therapy.
• There is a risk of bleeding or hematoma formation at the injection site.

Hepatic impairment

• Naltrexone use is not recommended in individuals with acute hepatitis or hepatic failure, according to the American Psychiatric Association guidelines.
• This caution is due to the potential for exacerbating liver dysfunction or causing further harm in patients with compromised liver function.

Renal impairment

• Naltrexone should be used cautiously in patients with moderate to severe renal impairment, as it has not been extensively studied in this population.

Naltrexone: Drug Interaction

Monitoring parameters:

• Liver Function Tests: Your doctor will check your liver function before starting naltrexone and regularly while you're on the medication.
• Watch for Opioid Withdrawal: Be aware of signs like feeling unwell or anxious, as these could indicate opioid withdrawal, especially if you've recently stopped using opioids.
• Injection Site Reactions: If you're getting naltrexone injections, keep an eye out for any unusual reactions at the injection site, like pain, swelling, or bruising.
• Be Mindful of Your Mood: Pay attention to your feelings and thoughts.

How to administer Naltrexone (Vivitrol)?

Oral Administration:

• Naltrexone can be taken with or without food.
• Taking it with food or after meals might help reduce stomach-related side effects.
• Patients should avoid self-administering opioids while on naltrexone therapy.

IM Administration (Vivitrol):

• Inject into the upper outer quadrant of the gluteal area.
• Use the provided needles for administration: either the 1.5-inch needle for lean patients or the 2-inch needle for those with more subcutaneous tissue.
• Avoid injecting into a blood vessel.
• Do not administer intravenously (IV), subcutaneously (SubQ), or into fatty tissue.
• Injection should alternate between the two buttocks.
• Do not substitute any components of the dose-pack.

Mechanism of action of Naltrexone:

• Naltrexone, a pure opioid antagonist, is derived from oxymorphone, much like naloxone and nalorphine, which are also morphine derivatives.
• It works by competitively blocking opioid receptor sites, particularly the mu receptors, where it has the highest affinity.
• Endogenous opioids play a role in influencing the rewarding effects of alcohol, and naltrexone helps modulate this expression, reducing the reinforcing effects of alcohol consumption.
• Additionally, naltrexone affects the hypothalamic-pituitary-adrenal axis, leading to a suppression of alcohol intake.

Duration:

• Oral: 50 mg lasts 24 hours; 100 mg lasts 48 hours; 150 mg lasts 72 hours.
• IM: Lasts for 4 weeks.

Absorption:

• Oral: Almost complete.

Distribution:

• Volume of Distribution (V): Approximately 1350 L.
• Naltrexone is distributed widely throughout the body, but there's significant variation among individuals.

Metabolism:

• Extensively metabolized via noncytochrome-mediated dehydrogenase conversion to 6-beta-naltrexol (primary metabolite) and minor metabolites.
• Glucuronide conjugates are also formed from naltrexone and its metabolites.
• Oral: Experiences an extensive first-pass effect.

Protein Binding:

• Approximately 21%.

Bioavailability:

• Oral: Variable range from 5% to 40%.

Half-life elimination:

• Oral: 4 hours.
• 6-beta-naltrexol: 13 hours.
• IM: Naltrexone and 6-beta-naltrexol: 5 to 10 days, depending on the erosion of the polymer.

Time to Peak, Serum:

• Oral: Around 60 minutes.
• IM: Biphasic, with the first peak occurring around 2 hours and the second peak around 2 to 3 days.

Excretion:

• Primarily through urine as metabolites and small amounts of unchanged drug.

International Brand Names of Naltrexone:

• ReVia
• Vivitrol
• APO-Naltrexone
• Abernil
• Adepend
• Adinot
• Anarcol
• Antaxon
• Antaxone
• Arrop
• Morfblock
• Nalerona
• Nalorex
• Naltox
• Naltrax
• Naltrexin
• Narpan
• Nemexin
• Nodict
• Nuo Xin Shejg
• Nutrexon
• Opizone
• Phaltrexia
• Re-Via
• Regental
• Revez
• ReVia
• Revia
• Trexan
• Uninaltrex

Naltrexone Brand Names in Pakistan: