Naloxone is a medication used to rapidly reverse opioid overdose. It works by binding to the same receptors in the brain that opioids bind to, effectively blocking the effects of opioids and reversing their effects, such as respiratory depression, which can be fatal if not treated promptly. Naloxone is often administered via injection or nasal spray and is considered a critical tool in harm reduction efforts to prevent opioid-related deaths. It's typically used by emergency medical personnel, but there are also efforts to make it more widely available to bystanders and family members of individuals at risk of overdose.

Naloxone (Narcan) is a pure opioid receptor antagonist that is used to treat opioid overdose. It is also combined with opioids to reduce the risks of opioid misuse.

Naloxone (Narcan) Uses:

• Opioid overdose:
  •  Used for the complete or partial reversal of opioid depression (including respiratory depression) induced by natural and synthetic opioids (eg, propoxyphene, methadone, nalbuphine, butorphanol, pentazocine).
  • Naloxone is also indicated for the diagnosis of suspected or known acute opioid overdosage.
• Evzio (IM, SubQ) intranasal:
  • Used for the emergency treatment of known or suspected opioid overdose as manifested by respiratory and/or CNS depression.
  • Intended for immediate administration as emergency therapy in settings where opioids may be present.
  • Not a Substitute for emergency medical care.
• Off Label Use of Naloxone in Adults:
  • Opioid-induced pruritus

Naloxone (Narcan) Dose in Adults

• Naloxone is a medicine that quickly reverses the effects of opioid overdose.
• It works by blocking the opioid receptors in the brain, which helps restore normal breathing and prevents death from overdose.
• Naloxone can be given through an injection into a vein (preferred), a muscle, under the skin, or sprayed into the nose.
• Sometimes it's used off-label with a nebulizer or injected into the bone marrow in emergencies.
• Giving it directly into the windpipe is not ideal and is only done if nothing else is available.

Naloxone Dose in the treatment of Opioid overdose:

• IV, IM, SubQ:
  • Initial: 0.4 to 2 mg; may repeat every 2 to 3 minutes.
  • Consider lower initial dose (0.1 to 0.2 mg) for opioid-dependent patients.
  • Endotracheal administration (off-label): 2 to 2.5 times initial IV dose.
• IM, SubQ (Evzio auto-injector):
  • Single dose: 0.4 mg or 2 mg (contents of 1 auto-injector); may repeat every 2 to 3 minutes.
• Continuous Infusion (off-label):
  • IV: Calculate dosage based on effective intermittent dose or use two-thirds of initial effective naloxone bolus on an hourly basis.
• Inhalation via Nebulization (off-label):
  • 2 mg per nebulization; may repeat. Switch to IV or IM administration when possible.
• Intranasal:
  • Onset slightly delayed compared to IM or IV routes.
  • Single dose: 4 mg (nasal spray) or 2 mg (injectable solution); may repeat every 2 to 3 minutes or in alternating nostrils.

Naloxone Dose in the treatment of Reversal of respiratory depression with therapeutic opioid doses:

• IV:
  • Initial: 0.02 to 0.2 mg; titrate to avoid withdrawal, seizures, arrhythmias, or severe pain.
  • Endotracheal administration (off-label): 2 to 2.5 times initial IV dose.
• Continuous Infusion (off-label):
  • IV: Calculate dosage based on effective intermittent dose or use two-thirds of initial effective naloxone bolus on an hourly basis.
  • Readminister half of initial bolus dose 15 minutes after starting infusion.
  • Adjust infusion rate to maintain ventilation and prevent withdrawal symptoms.

Naloxone Dose in the treatment of Opioid-dependent patients being treated for cancer pain (off-label dosing): 

• IV:
  • Dilute 0.4 mg/mL ampule into 9 mL of normal saline to achieve a 0.04 mg/mL concentration.
  • For initial treatment:
    • Option 1: 0.02 mg (20 mcg) IV push; administer every 2 minutes until improvement in symptoms.
    • Option 2: 0.04 to 0.08 mg (40 to 80 mcg) slow IV push; administer every 30 to 60 seconds until improvement in symptoms.
    • If no response after total naloxone dose of 1 mg, consider other causes of respiratory depression.
  • Continuous infusion (off-label) for long-acting opioids: Start at 66% of total bolus dose (or 0.2 mg per hour) to reverse opioid toxicity.

Postoperative Reversal:

• IV: 0.1 to 0.2 mg every 2 to 3 minutes until desired response (adequate ventilation and alertness without significant pain).
• Repeat doses may be needed within 1 to 2 hour intervals depending on type, dose, and timing of the last dose of opioid administered.

Naloxone Dose in the treatment of Opioid-induced pruritus (off-label):

IV Infusion:

• Start at 0.25 mcg/kg/hour (Gan 1997).
• Doses up to approximately 3 mcg/kg/hour have been used (Kendrick 1996).
• However, doses exceeding 2 mcg/kg/hour are more likely to reverse analgesia and are not recommended (Kjellberg 2001; Miller 2011).
• Monitor pain control closely and ensure naloxone isn't reversing analgesia.

Naloxone (Narcan) Dose in Childrens

Naloxone Dose in the treatment of Opioid intoxication and overdose (full reversal):

• IV (preferred), Intraosseous:
  • Infants and Children <5 years or ≤20 kg:
    • Initial: 0.1 mg/kg/dose; repeat every 2 to 3 minutes if needed.
  • Children ≥5 years or >20 kg and Adolescents:
    • Initial: 2 mg/dose; repeat every 2 to 3 minutes if needed.
• E.T.:
  • Infants, Children, and Adolescents: 2 to 3 times the IV dose.
• IM, SubQ (Parenteral formulation):
  • Infants and Children <5 years or <20 kg:
    • Initial: 0.1 mg/kg/dose; repeat every 2 to 3 minutes if needed.
  • Children ≥5 years or ≥20 kg and Adolescents:
    • Initial: 2 mg/dose; repeat every 2 to 3 minutes if needed.
• Auto-injector (Evzio):
  • Infants, Children, and Adolescents: 0.4 mg or 2 mg (contents of 1 auto-injector) as a single dose; may repeat every 2 to 3 minutes if needed until emergency medical assistance becomes available.
• Intranasal (Narcan Nasal Spray):
  • Infants, Children, and Adolescents: 4 mg (contents of 1 nasal spray) as a single dose; may repeat every 2 to 3 minutes in alternating nostrils if needed until medical assistance becomes available.
• Alternate dosing for Intranasal (Parenteral formulation):
  • Adolescents ≥13 years: 2 mg (1 mg per nostril).
• Continuous IV infusion:
  • Infants, Children, and Adolescents: Initial dosage/hour based on effective intermittent dose or two-thirds of the initial effective naloxone bolus given as the hourly infusion; titrate dose accordingly; closely monitor the patient for recurrence of opioid-induced respiratory depression.

Naloxone Dose in the treatment of Reversal of respiratory depression from therapeutic opioid dosing:

Infants, Children, and Adolescents

• IV:
  • Range: 0.001 to 0.005 mg/kg/dose (PALS [Kleinman 2010]).
  • AAP recommends wider dosage range: 0.001 to 0.015 mg/kg/dose (Hegenbarth 2008).
  • Manufacturer's labeling suggests repeat doses may be given every 2 to 3 minutes as needed based on response.

Naloxone Dose in the Opioid-induced pruritus:

• Prevention:
  • Children ≥6 years and Adolescents ≤17 years:
    • Continuous IV infusion: 0.25 mcg/kg/hour.
    • Used in a double-blind, prospective, randomized, placebo-controlled study (n=20) showing lower incidence and severity of opioid-induced side effects (pruritus, nausea) without loss of pain control (Maxwell 2005).
• Treatment:
  • Children ≥3 years and Adolescents:
    • Continuous IV infusion: Initial dose of 2 mcg/kg/hour.
    • If pruritus continues, may titrate by 0.5 mcg/kg/hour every few hours.
    • Based on a retrospective study (n=30, age range: 3 to 20 years) with a reported mean (±SD) dose of 2.3 ± 0.68 mcg/kg/hour (Vrchoticky 2000).
    • Monitor closely; doses ≥3 mcg/kg/hour may increase the risk for loss of pain control, and patients may require an increase in opioid dose.

Naloxone Pregnancy Risk Category: C

• Naloxone can cross the placenta, potentially causing opioid withdrawal in the fetus.
• It's usually not recommended for pregnant women with opioid use disorder except in life-threatening overdose situations.
• Using naloxone to diagnose opioid dependence during pregnancy is not advised.
• Generally, when giving antidotes to pregnant women, it's crucial to consider the mother's health and prognosis.
• Antidotes should be given if there's a clear need, without holding back due to concerns about birth defects.
• Pregnant women with mild to moderate hypertension during labor should be cautious with naloxone, as it might lead to severe hypertension.

Naloxone use during breastfeeding:

• It's uncertain if naloxone appears in breast milk, but its absorption after oral use is generally low, meaning exposure to a breastfeeding baby would likely be minimal.
• However, because naloxone reverses opioids, it's essential to think about the opioid levels in breast milk and the possibility of them transferring to the baby.
• The decision to breastfeed while using naloxone should weigh the risks of infant exposure, the advantages of breastfeeding for the baby, and the benefits of treatment for the mother.

Naloxone Dose in Kidney Disease:

• The manufacturer's labeling doesn't include specific dosage adjustments for individuals with renal impairment.

Naloxone Dose in Liver disease:

• The manufacturer's labeling doesn't specify dosage adjustments for individuals with hepatic impairment.

Side effects of Naloxone (Narcan)

• Cardiovascular:
  • Flushing (Parenteral)
  • Hypertension
  • Hypotension
  • Tachycardia
  • Ventricular Fibrillation
  • Ventricular Tachycardia
• Central Nervous System:
  • Agitation
  • Body Pain
  • Brain Disease
  • Coma
  • Confusion (Parenteral)
  • Disorientation (Parenteral)
  • Dizziness (Parenteral)
  • Excessive Crying (Neonates)
  • Hallucination (Parenteral)
  • Headache (Nasal)
  • Hyperreflexia (Neonates)
  • Irritability
  • Nervousness
  • Outbursts Of Anger (Parenteral)
  • Paresthesia (Parenteral)
  • Restlessness
  • Seizure (Neonates)
  • Shivering
  • Tonicclonic Seizures (Parenteral)
  • Withdrawal Syndrome
  • Yawning
• Dermatologic:
  • Diaphoresis
  • Piloerection
  • Xeroderma (Nasal)
• Endocrine & Metabolic:
  • Hot Flash (Parenteral)
• Gastrointestinal:
  • Abdominal Cramps
  • Constipation (Nasal)
  • Diarrhea
  • Nausea
  • Toothache (Nasal)
  • Vomiting
• Local:
  • Erythema At Injection Site (Parenteral)
  • Injection Site Reaction
• Neuromuscular & Skeletal:
  • Muscle Spasm (Nasal)
  • Musculoskeletal Pain (Nasal)
  • Tremor
  • Weakness
• Respiratory:
  • Dry Nose (Nasal)
  • Dyspnea
  • Hypoxia (Parenteral)
  • Nasal Congestion (Nasal)
  • Nasal Discomfort (Pain; Nasal)
  • Nasal Mucosa Swelling (Nasal)
  • Pulmonary Edema
  • Respiratory Depression (Parenteral)
  • Rhinitis (Nasal)
  • Rhinorrhea
  • Sneezing
• Miscellaneous:
  • Fever

Contraindications to Naloxone (Narcan):

• Individuals who have a hypersensitivity reaction to naloxone or any component of the naloxone formulation should not use naloxone.
• If there's a known allergy or sensitivity to naloxone or any ingredient in the formulation, it's crucial to seek alternative treatments and inform healthcare providers to avoid any adverse reactions.

Warnings and precautions

Acute opioid withdrawal

• Administering naloxone can trigger acute opioid withdrawal by releasing catecholamines, which might reveal pain or precipitate withdrawal symptoms in regular opioid users.
• These symptoms can include pain, rapid heartbeat, high blood pressure, fever, sweating, stomach cramps, diarrhea, nausea, vomiting, restlessness, and irritability.
• In newborns born to mothers with opioid dependence, withdrawal symptoms can be life-threatening, leading to excessive crying, a high-pitched cry, feeding difficulties, seizures, and exaggerated reflexes.
• When using naloxone outside of acute opioid overdose situations, like in postoperative patients, it's important to carefully adjust the dose to reverse breathing problems without fully waking the patient or reversing pain relief.
• A lower nasal dose of 2 mg is less likely to cause severe withdrawal than 4 mg, but it may not be strong enough for patients who've overdosed on potent opioids.

Cardiovascular disease

• Naloxone should be used cautiously in patients with cardiovascular disease or those taking medications that could negatively affect the cardiovascular system, such as those that may cause low blood pressure, fluid buildup in the lungs, or irregular heart rhythms.
• Abrupt reversal with opioid antagonists like naloxone has been linked to complications like pulmonary edema and cardiovascular instability, including potentially dangerous heart rhythms like ventricular fibrillation.
• It's important to monitor patients closely and be prepared to manage any cardiovascular complications that may arise when using naloxone.

Seizures:

• Naloxone should be used cautiously in patients with a history of seizures.
• It's important to be aware of this history and monitor patients closely for any signs of seizure activity when administering naloxone.
• Additionally, naloxone should not be used to treat seizures induced by meperidine, as it may not be effective and could potentially worsen the situation.
• If naloxone is needed in patients with a history of seizures, it should be used with caution and under close medical supervision.

Naloxone: Drug Interaction

Monitoring parameters:

• Respiratory Rate: Keep track of how often the person breathes per minute.
• Heart Rate: Monitor the number of heartbeats per minute.
• Blood Pressure: Check the force of blood against artery walls regularly.
• Temperature: Keep an eye on body temperature to detect any fever or hypothermia.
• Level of Consciousness: Observe the person's awareness and responsiveness.
• ABGs or Pulse Oximetry: Measure oxygen and carbon dioxide levels in the blood or use a pulse oximeter to monitor oxygen saturation.

How to administer Naloxone/ Narcan?

• IV Push:
  • Administer over 30 seconds as undiluted preparation or dilute 0.4 mg (1 mL) ampule with 9 mL of normal saline for a total volume of 10 mL to achieve a concentration of 0.04 mg/mL.
• IV Continuous Infusion:
  • Dilute to 4 mcg/mL in D W or normal saline.
• IM, SubQ:
  • Administer if unable to obtain IV access.
• Auto-Injector (IM or SubQ):
  • Intended for buddy administration; administer into the anterolateral aspect of the thigh. Seek emergency medical assistance after the first dose. Repeat doses may be required.
• Endotracheal (off-label):
  • Dilute to 1 to 2 mL with normal saline, flush with 5 mL of saline, and administer 5 ventilations.
• Inhalation via Nebulization (off-label):
  • Dilute 2 mg of naloxone with 3 mL of normal saline and administer via nebulizer face mask.
• Intranasal:
  • Administer in alternating nostrils. Each container contains a single intranasal spray; do not reuse. If repeat administration is necessary, use a new container.
  • Alternate intranasal administration: Administer total dose equally divided into each nostril using a mucosal atomization device (MAD). If a MAD is not available, spray into the nares without a MAD, but expect some drug loss.

Mechanism of action of Naloxone (Narcan):

• Naloxone is a pure opioid antagonist that competes with and displaces opioids at opioid receptor sites.
• It effectively blocks the effects of opioids by binding to opioid receptors in the brain and preventing opioids from attaching to these receptors.
• This action quickly reverses the effects of opioids, such as respiratory depression and sedation, making naloxone a crucial medication for treating opioid overdose.

Onset of Action:

• Endotracheal, IM, SubQ: 2 to 5 minutes
• Inhalation via nebulization: Approximately 5 minutes
• Intranasal: Approximately 8 to 13 minutes
• IV: Approximately 2 minutes

Duration:

• Approximately 30 to 120 minutes depending on the route of administration. IV has a shorter duration than IM.
• Repeated doses are often necessary due to naloxone's shorter action compared to most opioids.

Absorption:

• Intranasal, IM, SubQ: Absorption in pediatric patients may be erratic or delayed.

Protein Binding:

• Relatively weak, primarily to albumin and other plasma constituents.

Metabolism:

• Primarily hepatic via glucuronidation.

Bioavailability:

• Nasal: 43% to 54% compared to 0.4 mg IM dose.

Time to Peak:

• IM, SubQ: 15 minutes
• Intranasal: 19.8 to 30 minutes

Half-life Elimination:

• Neonates: Mean 3.1 ± 0.5 hours
• Adults: IM, IV, or SubQ: 0.5 to 1.5 hours
• Intranasal: Approximately 2 hours

Excretion:

• Primarily through urine as metabolites.

International Brands of Naloxone:

• Evzio
• Narcan
• O.S. Naloxone Hydrochloride
• Feng Du
• Intrenon
• Jin Er Lun
• Mapin
• Min-I-Jet Naloxone
• N-Xone
• Nalone
• Naloxon
• Naloxone Hydrochlorid
• Naloxonum Hydrochloricum
• Naloxonum Prolongatum
• Narcan
• Narcanti
• Narcotan
• Narlox
• Narxona
• Naxone
• Nex
• Nexodal
• Opaxon
• Oxogina
• Prenoxad
• Resuerix
• Xeropium
• Zynox

Naloxone Brand Names in Pakistan: