Toxicology & Substance Use · Topic 4 of 17

Opioid Overdose

Toxicology · respiratory depression

Opioid Overdose

Breathing first: ventilate, then titrate naloxone to adequate respirations — and watch for the opioid to outlast the antidote.

Key numbers

Naloxone IV, titrated to breathing0.04–0.4 mg IV

Naloxone wears off before many opioidsNaloxone t½ ≈ 1 h

01 · FirstVentilate first: airway and bag-mask

Maintaining the airway and adequate ventilation is the first priority: bag-mask ventilate the apneic or hypopneic patient while naloxone is prepared; death results mainly from hypoxia.

02 · GiveNaloxone IV, titrated to breathing

Titrate IV naloxone to adequate breathing, not full arousal: start 0.04 mg in opioid-dependent patients (0.4 mg otherwise), repeat or escalate every 2–3 minutes toward 2 mg; apneic patients can receive 2 mg at once.

03 · WatchNaloxone wears off before many opioids

Naloxone's half-life is about 1 hour, so respiratory depression can recur after long-acting opioids (methadone, extended-release oxycodone or morphine): observe at least 2–3 hours after the last dose and admit long-acting overdoses.

Presentation

What you'll see

Respiratory depression, miosis, sedation must knowOpioid overdose = decreased respiratory rate and tidal volume progressing to apnea, miotic pupils and sedation to coma; hypotension, bradycardia, hypothermia and urinary retention may accompany it.

Do right now

In this order

First moves

Ventilate first: airway and bag-mask

→

Naloxone IV, titrated to breathing0.04–0.4 mg IV

→

No naloxone response: intubate, reconsider diagnosis

→

Naloxone wears off before many opioidsNaloxone t½ ≈ 1 h

Why each step

Ventilate first: airway and bag-maskMaintaining the airway and adequate ventilation is the first priority: bag-mask ventilate the apneic or hypopneic patient while naloxone is prepared; death results mainly from hypoxia.

Naloxone IV, titrated to breathingTitrate IV naloxone to adequate breathing, not full arousal: start 0.04 mg in opioid-dependent patients (0.4 mg otherwise), repeat or escalate every 2–3 minutes toward 2 mg; apneic patients can receive 2 mg at once.

No naloxone response: intubate, reconsider diagnosisIf respiratory depression persists despite naloxone, intubate and ventilate, and look for other causes — sedative co-ingestion, xylazine, head injury, hypoglycemia or CNS infection.

Naloxone wears off before many opioidsNaloxone's half-life is about 1 hour, so respiratory depression can recur after long-acting opioids (methadone, extended-release oxycodone or morphine): observe at least 2–3 hours after the last dose and admit long-acting overdoses.

Management

Orders

Recurrent depression: naloxone infusion two-thirds per hourFor recurrent depression, repeat the effective bolus or start an infusion at about two-thirds of the initially effective dose per hour in the ICU, titrated to respiratory rate without precipitating withdrawal.

No IV: intranasal or IM naloxoneWithout IV access, naloxone works intramuscularly, subcutaneously or intranasally; the OTC nasal spray delivers 4 mg per device, repeated every 2–3 minutes until the person wakes.

Before discharge: start OUD treatment, give naloxoneOffer medication for opioid use disorder (buprenorphine or methadone) and a take-home naloxone kit; withdrawal management without starting maintenance treatment carries a high risk of fatal overdose.

Red flags & don'ts

Avoid harm

Naloxone precipitates withdrawal and agitation complicationIn dependent patients naloxone precipitates acute withdrawal — agitation, combativeness, vomiting — so titrate small doses when the situation allows; withdrawal is still preferable to severe respiratory depression.

Opioid overdose can cause pulmonary edema complicationNoncardiogenic pulmonary edema can develop within minutes to hours of an overdose; treat with oxygen and noninvasive ventilation or intubation as needed.

Opioid or sedative-hypnotic overdose?

Commonly confused

Pupils	Pinpoint (miosis)
Breathing	Low rate and depth, apnea
Typical drugs	Fentanyl, heroin, oxycodone, methadone
Antidote	Naloxone, titrated to breathing

Commonly confused

Tell apart

Fentanyl may need higher naloxone dosesPotent synthetic opioids such as fentanyl and its analogs may require higher or repeated naloxone doses, and the standard urine opioid immunoassay does not detect fentanyl or methadone.

Xylazine: naloxone won't reverse itXylazine, a common fentanyl adulterant, is not reversed by naloxone — still give naloxone for the opioid, support ventilation, and examine for xylazine-associated wounds that can become severe.

More detail

Reference

Show 6 reference facts

Nalmefene nasal spray (2.7 mg) is a longer-acting opioid antagonist (half-life about 11 hours) for out-of-hospital rescue; patients still need emergency care after a dose.

Serotonin syndrome can occur when fentanyl, meperidine, tramadol, methadone, codeine or oxycodone is combined with serotonergic drugs such as SSRIs or MAOIs.

Methadone prolongs the QTc and can cause torsades de pointes; check an ECG and monitor it when methadone is started or titrated.

Heroin has a short half-life, so recurrent respiratory depression after naloxone reversal of IV heroin is rare and patients may be discharged after several hours of observation.

Signs specific to opioid withdrawal include mydriasis, piloerection, yawning, lacrimation and rhinorrhea; withdrawal is distressing but not life-threatening.

Tolerance to respiratory depression and euphoria develops unevenly, while miosis and constipation persist; the dose that stops breathing depends on each patient's opioid tolerance.

Pearl

Naloxone's goal is breathing, not waking — titrate to respirations, and remember the opioid may outlast the antidote.

Sources · Merck Manual Professional — Opioid Toxicity and Withdrawal (2026) · Merck Manual Professional — General Principles of Poisoning (initial stabilization, naloxone) · Kim HK, Nelson LS. Reducing the harm of opioid overdose with the safe use of naloxone: a pharmacologic review. Expert Opin Drug Saf 2015 (low-dose naloxone 0.04 mg, titrated) · Narcan (naloxone HCl) 4 mg nasal spray OTC drug facts — DailyMed · CDC — What You Should Know About Xylazine · Chandran J, Krishna B. Initial Management of Poisoned Patient. Indian J Crit Care Med 2019 (toxidrome table) · Dutta S et al. A Narrative Review on Toxidromes in the Psychiatric Population. J Clin Med 2025 (sedative-hypnotic toxidrome, flumazenil) · Opvee (nalmefene) nasal spray prescribing information — DailyMed · Dowell D et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. MMWR Recomm Rep 2022;71(3) (offer naloxone, incl. history of overdose) · Starter sheet built from the verified AGACNP fact map (facts reviewed 2026-10-15).