By: Colleagues at the US Food and Drug Administration
Naloxone was first synthesized in 1961 by Jack Fishman and Harold Blumberg and was approved by the US Food and Drug Administration (FDA) in 1971 as a human prescription medication for the reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids (“overdose”) [22]. Naloxone is approved to be administered intravenously (IV), intranasally (IN), or by intramuscular or subcutaneous injection (IM/SC). Naloxone for injection is currently available in the US under many approved generic versions. Additionally, many naloxone-containing drug-device products delivering a range of doses have been approved by the FDA since 2014 (Table S1 of Supplemental Material in S1 File) and are available by prescription or nonprescription. These product approvals have relied upon data derived from healthy subjects, in accordance with the 505(b)(2) pathway outlined in the Federal Food, Drug, and Cosmetic Act of 1938 [23].
The pharmacological action of naloxone [24] is primarily via antagonism at the mu-opioid receptor, with additional antagonist ability at the kappa- and sigma-opioid receptors. Naloxone’s strong attraction to opioid receptors displaces and prevents the binding of opioid agonists such as heroin, fentanyl, and morphine in the central nervous system. Intravenous administration of naloxone leads to rapid redistribution in the body, including crossing the placenta (teratogenicity category C). Naloxone administered intramuscularly and intranasally reach a maximum concentration at 10–30 min and 5–30 min, respectively [25]. The nasal and oral bioavailabilities of naloxone are approximately 50% and 1%, respectively. The serum half-life of naloxone ranges from 30–81 min in adults. Naloxone is primarily excreted via the kidneys after glucuronide conjugation in the liver.
Adolescents (those ≥12 years of age) through adults experiencing opioid overdose can receive an initial dose of 0.4 mg to 2 mg IV, which can be repeated at 2-to-3-minute intervals as needed to reverse respiratory depression; intranasal and IM/SC products follow a similar frequency of dosing. Additional doses may need to be administered every one to two hours or given as an infusion for extended-release opioids or opioids with long durations of action (e.g., methadone, buprenorphine). Caregivers are encouraged to keep patients under surveillance to guard against the chance of renarcotization and return of respiratory depression. There is no maximum dose of naloxone, and very high exposures have been reported in the literature [26]. However, the FDA Prescribing Information cautions clinicians to consider an alternative cause of the patient’s presentation if 10 mg of naloxone has been given IV without an improvement in the patient’s condition [24].
Adults with opioid dependence who receive naloxone can develop an opioid withdrawal syndrome, characterized by body aches, abdominal cramping, nausea, vomiting, diarrhea, rhinorrhea, sneezing, diaphoresis, tremulousness or shivering, anxiety or agitation, piloerection, and yawning. The severity and duration of the precipitated withdrawal is related to the dose of naloxone and to the degree of opioid dependence. Other adverse reactions include tachycardia, increased blood pressure, and rarely, seizures. A rare but serious adverse reaction to naloxone is noncardiogenic pulmonary edema. The risk of naloxone-induced pulmonary edema also appears to be dose-dependent [27].
Naloxone is on the World Health Organization’s List of Essential Medicines [28]. It reverses opioid-induced respiratory depression rapidly but may also precipitate withdrawal in people who have opioid tolerance. Community-based naloxone distribution has become widely accepted in the US as a means of secondary prevention of overdose deaths, albeit with heterogeneity in enabling state governmental laws and policies [29].