The reversal, not the blockade
17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one · C19H21NO4 · MW 327.37 g/mol · CAS 465-65-6 · Narcan, Evzio, Kloxxado · ChEMBL CHEMBL80
Naloxone (Narcan). A competitive µ-opioid antagonist built for right now: reverse an overdose, restore breathing, buy time. It is not naltrexone (#070). Naltrexone is the long-acting oral/depot blocker for people who are already opioid-free. Naloxone is the rescue ligand — poor oral bioavailability, t½ measured in minutes to an hour, and a clock that can run out before fentanyl does.
Naloxone binds MOR (and, less potently, KOR/DOR) and produces no Gi signal. It outcompetes morphine, heroin metabolites, oxycodone, and fentanyl for the orthosteric site. Breathing resumes if the problem was µ-tone in the pre-Bötzinger complex. If the person has a physical dependence, that same displacement is precipitated withdrawal — miserable, not lethal by itself, and not a reason to withhold the drug from someone who is not breathing.
The pharmacokinetic catch versus modern illicit supply: naloxone's occupancy can fade while fentanyl is still there. Redose. Stay. Call emergency services. Intranasal 4 mg (Narcan) and higher-dose 8 mg (Kloxxado) exist because potency and lipophilicity of illicit opioids moved. Naltrexone cannot substitute in this scene — wrong kinetics, wrong setting, and it is not an antidote kit.
Allyl-substituted morphinan antagonist. Occupies the pocket, zero intrinsic efficacy. Ki ~1 nM at MOR.
IV: under a minute. IM/IN: a few minutes. Do not wait for perfection — any route that is in your hand is the right one.
30–80 min terminal half-life. Fentanyl and especially longer analogs can outlast it → apparent 'naloxone failure' is often redistribution. Redose.
Expected in dependent people. Not a reason to skip dosing an apneic patient. Manage supportively; do not chase with more opioid in the field.
Naltrexone is oral/depot maintenance after a washout. Naloxone is rescue. Mixing the names in a crisis is how people die with the wrong bottle.
Naloxone will not reverse benzos, alcohol, xylazine, or gabapentinoids. Still give it if opioids might be in the mix — they often are.
High hepatic first-pass is why naloxone is not an oral maintenance drug (that job is naltrexone). IN bioavailability is a fraction of IV but enough; IM is reliable. Onset minutes, duration often shorter than the agonist you just reversed.
Apparent naloxone failure is usually: (1) not an opioid, or not only an opioid (xylazine, benzos); (2) too little dose versus a high-potency fentanyl analog; (3) you left before renarcotization. Give it anyway when breathing is slow. Rescue breaths matter. See naltrexone #070 for the maintenance cousin — and do not start that cousin until the person is opioid-free.
PDB 4DKL is inactive-state MOR with the covalent antagonist β-FNA — no naloxone co-crystal is claimed here. The allyl-morphinan antagonists stabilize a transducer-incompetent pocket: ligand occupancy high, Gi Shannon collapse low. That is antagonism as an entropy story — you pay binding ΔG and refuse to spend it on receptor activation.
You cannot naloxone-overdose someone in any way that competes with not giving it to an apneic opioid overdose.
| Target | Affinity | Rel. | Action |
|---|---|---|---|
|
µ / MOR
mu-opioid receptor
|
Ki ≈ 1 nM
competitive antagonist
|
Antagonist | |
|
κ / KOR
kappa-opioid receptor
|
Ki low-nM
antagonist
|
Antagonist | |
|
δ / DOR
delta-opioid receptor
|
weaker
antagonist
|
Antagonist | |
|
Duration
vs illicit fentanyl
|
t½ 30–80 min
often outlasted
|
Redose |