Naloxone

Introduction

• Opioid use disorder affects more than 2.1 million Americans. Opioid-induced respiratory depression (ORID) may present as a slowed or absent respiratory rate, low oxygen saturation levels, and a rise in end tidal carbon dioxide.^1,2
• Naloxone is a μ-opioid receptor antagonist developed in the 1960s to combat ORID.³
• Excessive opioid overdose without prompt naloxone administration may eventually lead to cardiovascular arrest.²
• The FDA has approved multiple naloxone formulations for use in the United States, with Narcan being the most widely recognized brand.¹
• Narcan can be administered through a variety of routes including intravenous (IV), intramuscular, subcutaneous, intranasal, and via inhalation for intubated patients.⁴

Physical Properties

• Naloxone, 17-allyl-4,5-alpha-epoxy-3,14-dihydroxymorphinan-6-one, is a synthetic morphinane alkaloid.³
• To create naloxone, an enone double bond was reduced to a single bond, a hydrogen at position 14 was replaced by a hydroxy group, and the methyl group attached to nitrogen was switched out by an allyl group³ (Figure 1).

Mechanism of Action

• Naloxone competitively binds and antagonizes the μ-opioid receptor with a binding affinity of about 1 nM. This process allows active displacement of opioid drugs from their receptor and reversal of symptoms.^2,3
• Naloxone also competitively binds kappa and delta opioid receptors in the central nervous system, but at a lower affinity than the μ-receptor.⁵
• It can cross the blood-brain barrier and has rapid receptor association/dissociation kinetics.³

Metabolism/Excretion

• Naloxone undergoes hepatic metabolism and is conjugated to naloxone 3-glucuronide, N-dealkylated, and reduced metabolites.⁴
• About 60-65% of naloxone is excreted by the kidneys after an IV bolus is metabolized.⁴
• The serum half-life of IV naloxone is approximately 60 minutes, 1.24 hours for intramuscular, and 1.85-2.08 hours for intranasal.^4,5
• An IV bolus of naloxone has a volume of distribution of 200L and a metabolic clearance of 2500 L/d.⁴

Bioavailability

• Intranasal formulations of naloxone typically reach peak plasma concentrations within 20-30 minutes.³
• Intranasal administration has a bioavailability of 50% and a latency time of 15 minutes, while intramuscular administration has a bioavailability of 98% and a latency time of 8 minutes.¹
• IV route has 100% bioavailability and a 2-minute latency to effect.¹
• Due to the low oral (1-2%) and rectal (15%) bioavailability of naloxone, these routes are unsuitable for emergency situations.³

Dosing Recommendations

• Naloxone is a rapid-onset, short-duration drug that may require additional doses if the desired opioid reversal level is not achieved.⁴
• Type of drug, drug dose, use behaviors, opioid tolerance, and age must all be taken into account when administering this drug.⁶
• Apneic patients should receive an initial dose of 0.2-1mg naloxone.⁷
• For patients in cardiorespiratory arrest due to opioid overdose, an initial dose of 2 mg should be administered at minimum.⁷
• In patients with spontaneous ventilation, an initial dose of 0.04mg IV may be administered and then titrated upwards until adequate ventilation is secured.⁷
• Depending on the duration of opioid action, a naloxone infusion may be used as an alternative to repeated dosing by determining the total initial dose required to reinstate breathing and delivering two-thirds of that dose every hour.⁷
• The FDA-approved OTC intranasal spray, Narcan, delivers an initial dose of 4mg that can be re-dosed every 2-3 minutes by alternating nostrils if needed.⁵
• If a clinician “overshoots’ or provides too much naloxone, manage the symptoms expectantly and not with additional opioids.⁷

Clinical Use

• Naloxone is indicated for the reversal of ORID and is frequently used by anesthesia providers in the perioperative setting.^5,8
• Common substances that may require naloxone intervention include heroin, fentanyl, carfentanil, hydrocodone, oxycodone, and methadone.⁵
• Without timely naloxone administration, opioid overdose can result in inadequate ventilation, hypercarbia, and even death.⁴
• Prepackaged OTC naloxone, Narcan, can be used by laypeople on individuals suffering from suspected opioid overdose.¹
• Chronic opioid users who receive naloxone should be monitored for 6–12 hours after ingestion of long-acting opioids. If a patient requires IV naloxone doses of more than 5 mg, they should be admitted for observation.⁵
• If a patient’s respiratory rate is completely reversed with 0.4-2mg of naloxone, they should be observed for 2-4 hours and discharged if no complications arise.⁵
• Over a 13-year period, postoperative naloxone administration occurred in 0.1% of approximately 450,000 cases at a major tertiary institution.⁸

Adverse Effects

• The main risk of excessive naloxone administration includes naloxone-induced withdrawal symptoms for individuals who are highly opioid dependent.¹
• Common symptoms include severe pain, agitation, muscle cramps, vomiting, aggression, diarrhea, abdominal pain, rhinorrhea, and nausea.^1,5
• Naloxone, in rare cases, can cause an allergic reaction that includes hives, difficulty breathing, and swelling of the face, ears, nose, and throat.¹
• Noncardiogenic pulmonary edema is also associated with naloxone use and has an incidence of 0.2%-3.6% in patients who received the drug and are transported to the emergency department.⁵
• Naloxone is also listed as part of the key potentially inappropriate drugs in pediatrics, with an increased risk of seizure in pediatric populations.⁵

Contraindications

• In an emergency, there are no contraindications to naloxone administration.⁵
• Individuals with a known hypersensitivity reaction to naloxone may be relatively contraindicated.⁵

Special Considerations

• Automated alerts may improve naloxone co-prescription in individuals at risk of opioid overdose.⁹
• There is a low liability risk for medical providers who prescribe naloxone.¹⁰
• Naloxone should be stored at room temperature.⁵
• Overdose education and increased naloxone distribution within communities are associated with reduced overdose rates.¹⁰
• Naloxone can also be used off-label for the naloxone challenge test to determine opioid physiological dependence.⁵