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Naloxone
Naloxone is a synthetic opioid antagonist1 of the morphinan chemical class,2 derived from oxymorphone.2 It reverses opioid effects, including the suppression of breathing during an overdose,3 but does not reverse the effects of non-opioid drugs. It can trigger withdrawal in opioid-dependent individuals.4 Its short action allows respiratory depression to return when longer-lasting opioids remain active.5 Heart problems have occurred in people with pre-existing heart disease or those taking medications that adversely affect the heart.
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Duration
Subjective Effects
Pharmacology
Pharmacodynamics
In vitro evidence suggests that naloxone antagonizes opioid effects by competing for opiate receptor sites,1 with its strongest affinity at μ-opioid receptors, followed by δ-opioid and κ-opioid receptors. This prevents opioids from activating these receptors and reverses opioid-induced depression of breathing and central nervous system activity.6 Inverse agonist activity at μ-opioid receptors is also reported.7 Naloxone blocks endogenous opioid signaling, including endorphin-mediated pain relief and some placebo analgesic responses, while otherwise having little effect in the absence of opioids. Its opioid receptor activity resides in the (−)-enantiomer.
Pharmacokinetics
Naloxone has low oral systemic bioavailability because of hepatic first-pass metabolism, although it can block opioid receptors in the intestine. Sublingual absorption is also poor. It distributes rapidly into tissues, crosses the blood-brain barrier and placenta, and is excreted in small amounts in breast milk. Its volume of distribution is 200 L; approximately 45% binds to albumin, with additional binding to other proteins. Hepatic metabolism primarily involves glucuronidation, with additional N-dealkylation and reduction of the 6-keto group. It is listed as a substrate of UGT1A1, CYP2C18, CYP2C19, CYP3A, CYP3A4, and P-glycoprotein, and as an inhibitor of CYP3A and CYP3A4 with unspecified inhibitory strength. Intranasal bioavailability is 42-47%. An 8 mg intranasal dose produced peak plasma concentrations of 12.3-12.8 ng/mL and an AUC of 16.7-19.0 h·ng/mL; a 0.4 mg intramuscular dose produced corresponding values of 0.876-0.910 ng/mL and 1.94-1.95 h·ng/mL. A 2 mg intravenous dose produced a peak concentration of 26.2 ng/mL and an AUC of 12.8 h·ng/mL. Reported mean elimination half-lives are 1.8-2.7 hours intranasally, 1.4 hours intramuscularly, and 1.2 hours intravenously; another report gives a serum half-life of 30-81 minutes following parenteral administration. The mean half-life in neonates is 3.1 ± 0.5 hours.6 Clearance is 2500 L/day. Following oral or intravenous administration, urinary elimination accounts for 25-40% within 6 hours, 50% within 24 hours, and 60-70% within 72 hours, with metabolites detected in urine. Reduced liver and kidney function in older people may increase naloxone levels. Intramuscular and subcutaneous absorption can be unpredictable in children.
Interactions
An unlisted combination is an unknown one, not a safe one. Check a dedicated combination chart before mixing.
Tolerance
Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.
Harm Potential
Addiction & Dependence
Psychological
Extremely LowNaloxone is considered non-habit-forming.1
Physical
Naloxone can precipitate rapid opioid withdrawal in people using opioids; this reflects opioid dependence rather than dependence on naloxone. The July 2017 guidelines describe vomiting, agitation, shivering, sweating, and tachycardia as unpleasant effects of acute opioid withdrawal that may lead to aggression or refusal to accept further treatment.9
Toxicity
The oral LD50 in mice and rats exceeds 1 g/kg.
LD50 Data
| Species | Route | Value |
|---|---|---|
| mouse | oral | g/kg |
| rat | oral | g/kg |
| mouse | intraperitoneal | 80 mg/kg |
| rat | intraperitoneal | 239 mg/kg |
| mouse | subcutaneous | 286 mg/kg |
| rat | subcutaneous | 500 mg/kg |
Naloxone has rarely been associated with abnormal heart rhythms in people with opioids in their system.10
Naloxone has rarely been associated with pulmonary edema in people with opioids in their system.11
Naloxone can precipitate withdrawal in neonates following exposure during pregnancy in women taking opioids.
Psychosis Risk
Psychosis may occur as part of opioid withdrawal precipitated by naloxone.
Seizure Risk
Seizures have rarely been reported after naloxone administration, but their relationship to naloxone is unclear.12
History & Culture
Early development
Naloxone was patented in 1961 by Mozes J. Lewenstein, Jack Fishman, and Sankyo. It received approval in the United States in 1971 and was included on the World Health Organization's List of Essential Medicines.13
Legality
International
Not a controlled substance worldwide
Prescription drug in most countries
By Country
GermanyPrescription only
SwitzerlandPrescription only
TurkeyPrescription only
United KingdomPrescription only
United StatesLegal (regulated)
AustraliaLegal (regulated)
CanadaLegal (regulated)References
Citations
Article Status
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