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:

• Until the patient is opioid-free (including tramadol) do not initiate therapy for at least 7 to 10 days as determined by urinalysis.
• The naloxone challenge test can be considered to confirm the patient is opioid-free if there is any suspicion since urinary opioid screen may not be sufficient proof.

Naltrexone Dose in the treatment of alcohol use disorder:

   P/O:

• 50 mg once a day
• some patients may need doses up to 100 mg/day.
• Alternative maintenance regimens may be used and include:
  • 50 mg on weekdays with a 100 mg dose on Saturday; 100 mg every other day; or 150 mg every 3 days (degree of blockade may be reduced with extended dosing interval regimens and doses >50 mg may increase the risk of hepatocellular injury).

IM:

• 380 mg once q 4 weeks

Naltrexone Dose in the treatment of opioid dependence:

 P/O

• Initial: 25 mg
• if no withdrawal signs occur, give 50 mg/day thereafter
• alternative maintenance regimens may be used and include:
  • 50 mg on weekdays with a 100 mg dose on Saturday; 100 mg every other day; or 150 mg every 3 days (degree of blockade may be reduced with extended dosing interval regimens and doses  more than 50 mg may increase risk of hepatocellular injury).

IM:

• 380 mg once q 4 weeks

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

P/O:

• Initial: 12.5 mg once a day
• increase dose by 12.5 mg every 3 to 7 days until clinical benefits are achieved.
• Doses of 50 milligrams daily have been reportedly 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

• Addiction to opioids and alcohol use are linked with adverse outcomes for fetus and obstetrical outcomes.
• There is limited information available about the use of Naltrexone during pregnancy.
• If a woman receiving naltrexone to treat opioid use disorder is pregnant, the physician and patient should discuss the possibility of relapse.
• If the patient is worried about relapse and wishes to continue naltrexone treatment, they should be made aware of the possible risks and obtain consent to continue treatment.
• If naltrexone is discontinued and subsequently the patient relapses, consideration should be given for treatment with methadone or buprenorphine.
• Pregnant women should not use pharmacological drugs to treat alcohol abuse disorder, unless they are required for acute alcohol withdrawal or coexisting disorders.
• Agents other than naltrexone for acute alcohol withdrawal are recommended.

Naltrexone use during breastfeeding:

• Breast milk contains naltrexone and 6-beta-naltrexol, which are both secreted in the metabolite.
• According to the manufacturer, when deciding whether to breastfeed during therapy, you should consider the risks to infants, the benefits to breastfeeding to the infant and the benefits to the mother.
• If you are treating acute alcohol withdrawal or coexisting disorders, you should not use pharmacological agents to treat alcohol abuse disorder in breastfeeding mothers.
• Acute alcohol withdrawal is best managed with an agent other than naltrexone.

Naltrexone Dose in Kidney Disease:

• Mild impairment:

  • Dose adjustment is not necessary.

• Moderate-to-severe impairment:

  • No dosage adjustment provided in the manufacturer’s labeling (has not been studied);
  • Use cautiously since naltrexone and its primary metabolite primarily have urinary excretion.

Naltrexone Dose in Liver disease:

• Mild to moderate impairment:

  • Dose adjustment is not necessary.

• Severe impairment:

  • No dosage adjustment provided in the manufacturer’s labeling (has not been studied);
  • naltrexone AUC increased ~5- and 10-fold in patients with compensated or decompensated hepatic cirrhosis respectively.
  • Not recommended 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:

• Hypersensitivity to naltrexone and any component of the formulation
• Opioid dependence and current opioid analgesic use (including partial opioid antagonists).
• Acute opioid withdrawal
• Negative urine screening for opioids or the Naloxone Challenge.
• Hepatitis acute
• Hepatic failure

Warnings and precautions

• Accidental opioid overdose:

  • Patients who have been prescribed naltrexone might respond to lower doses of opioids than they were previously.
  • This could lead to potentially fatal opioid intoxication.
  • Patients need to be aware of the possibility of being more sensitive to lower opioid doses if naltrexone treatment has been stopped, missed, or at the end of the dosing period.
  • Patients should be aware that any attempt to overcome opioid blocking during naltrexone treatment could lead to fatal opioid overdose.
  • In the presence of large amounts opioids, it is possible to overcome the opioid competitive receptor blockade caused by naltrexone.

• Acute opioid withdrawal

  • Opioid-dependent patients may experience symptoms of acute withdrawal, such as pain, hypertension and sweating.
  • In neonates: Shouting, inability to feed

• Eosinophilic pneumonia:

  • Eosinophilic pneumonia cases have been reported. This should be considered for patients with dyspnea and progressive hypoxia.

• Hepatocellular injury:

  • It is possible to sustain hepatocellular damage due to dose-related effects.
  • The margin of safety between the seemingly safe and the hepatotoxic doses seems to be =5-fold.
  • If you develop signs/symptoms that indicate acute hepatitis, discontinue treatment.
  • Clinicians should note that elevated transaminases could be due to pre-existing liver disease, hepatitis B or C infection, concomitant use other hepatotoxic medications, and abrupt opioid withdrawals may lead to acute liver injury.

• Hypersensitivity reactions

  • Reports of hypersensitivity include angioedema and urticaria.

• Injection site reactions:

  • Severe injection site reactions, such as cellulitis, hematomas, abscess, necrosis, and induration have all been reported.
  • Females are at greater risk.
  • Any injection site pain, swelling or bruising should be reported to the doctor immediately.
  • Use IM only in the gluteal muscles
  • Don't inject IV, SubQ or into fatty tissues
  • Incorrect administration can increase the chance of injectable reactions.

• Suicidal thoughts/depression

  • Postmarketing reports have shown that suicide attempts, suicidal thoughts and depression were common.
  • Pay attention.

• Bleeding disorders:

  • Patients with thrombocytopenia, hemophilia or severe hepatic impairment should not use IM injection.
  • Administration of IM may cause bleeding/hematoma.

• Hepatic impairment

  • In acute hepatitis and hepatic failure, it is not recommended to use.

• Renal impairment

  • Patients with severe or moderate renal impairment should be cautious (has not been tested).

Naltrexone: Drug Interaction

Monitoring parameters:

• Liver function tests (baseline and periodic)
• Monitor for opioid withdrawal
• Injection site reactions with IM administration
• Depression and/or suicidal thinking

How to administer Naltrexone (Vivitrol)?

P/O:

• May be administered with or without food.
• Administration with food or after meals may minimize adverse gastrointestinal effects.
• Patients should be advised not to self-administer opioids while receiving naltrexone therapy.

Intramuscular: Vivitrol:

• Administer IM into the upper outer quadrant of the gluteal area; must inject dose using one of the provided needles for administration.
• Use either the 1.5-inch needle (for very lean patients) or the 2-inch needle (for patients with a larger amount of subcutaneous tissue overlying the gluteal muscle).
• Either needle may be used for patients with average body habitus.
• Avoid inadvertent injection into a blood vessel
• Do not administer IV, SubQ, or into fatty tissue (the risk of serious injection site reaction is increased if given incorrectly as a SubQ injection or into fatty tissue instead of the gluteal muscle).
• The 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 a cyclopropyl derivative oxymorphone that has a structure similar to naloxone or nalorphine (a derivative of morphine).
• It is a competitive antagonist of opioid receptor sites and has the highest affinity to mu receptors.
• Endogenous opioids play a role in modulating alcohol's reinforcing effect.
• Naltrexone also modifies the hypothalamic-pituitary-adrenal axis to suppress alcohol consumption.

Duration: P/O:

• 50 mg: 24 hours
• 100 mg: 48 hours
• 150 mg: 72 hours

IM:

• 4 weeks

Absorption: P/O:

• Almost complete

Distribution:

• Widely throughout the body but considerable interindividual variation exists

Metabolism

• Extensively metabolized via noncytochrome-mediated dehydrogenase conversion to 6-beta-naltrexol (primary metabolite) and related minor metabolites
• Glucuronide conjugates are also formed from naltrexone and its metabolites

P/O:

• Extensive first-pass effect

Protein binding:

• 21%

Bioavailability: P/O:

• Variable range (5% to 40%)

Half-life elimination:

• Oral: 4 hours
• 6-beta-naltrexol: 13 hours
• IM: naltrexone and 6-betanaltrexol: 5 to 10 days (dependent upon erosion of polymer)

Time to peak serum concentration:

• Oral: ~60 minutes
• IM: Biphasic: ~2 hours (first peak), ~2 to 3 days (second peak)

Excretion:

• Primarily urine (as metabolites and small amounts of the 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: