Take Home Points
- Opioids bind to the mu opioid receptor to produce analgesia; however, stimulation of opioid receptors can lead to decreased respiratory drive and possible respiratory arrest.
- Naloxone can reverse respiratory depression in opioid overdose through competitive antagonism, and can be given intravenously (IV), intramuscularly (IM), subcutaneously (SC), or intranasally (IN).
- Initial dosing of naloxone depends on the initial patient presentation, the type of opioid taken, and if the patient is a naive or chronic opioid user.
- Naloxone can have a shorter half-life than the culprit opioid, requiring repeated boluses or a continuous infusion
Opioids
The first recorded use of opium from the opium poppy plant dates back to more than 5,000 years ago.1 Natural opioids, like morphine derived from the opium plant, and synthetic opioids all act on opioid receptors in the brain to produce analgesia.1 There are three subtypes of opioid receptors: mu, delta, and kappa.2 Agonism of the mu opioid receptor leads to analgesia and dependence (mu-1), as well as euphoria, dependence, respiratory depression, miosis, and decreased gastrointestinal motility (mu-2).2,3 Mu opioid receptor binding inhibits ascending pain pathways thus producing analgesia.3
While opioids have a therapeutic place in the management of acute, chronic, and palliative pain, they are highly addictive and are sought out and misused for their euphoric effects.
The Opioid Epidemic
On average, 217 people die from an opioid overdose in the United States (US) each day.4 The opioid epidemic remains a significant health crisis. Starting in the late 1990s, the US saw a rise in prescription opioid overdose deaths due to increased opioid prescribing.4 The rise of the first extended release formulation of morphine, known as MS Contin, in 1987 marked the beginning of liberal opioid prescribing, and foreshadowed the misuse and addiction to follow.5 In 2010, a rapid increase in opioid overdose deaths were attributable to heroin, although heroin overdose deaths are now declining.4 Beginning in 2013 and constituting the third wave of the epidemic, there have been more overdose deaths involving synthetic opioids like fentanyl and carfentanil.4 These synthetic opioids have increased potency, making them more lethal, with fentanyl being 100 times stronger than morphine and 50 times stronger than heroin.6
Opioid Overdose
Opioid overdose occurs when there is unopposed, excessive stimulation of opioid receptors that control respiratory function in the central nervous system, leading to a decrease in respiratory drive.2 This is a medical emergency as respiratory depression can lead to death. Signs and symptoms of an overdose include the following: slowed or absent breathing, small or pinpoint pupils, loss of alertness and responsiveness, purple or blue lips or fingernails, and slowed heart rate.2
Naloxone
Fortunately, a reversal agent for opioid toxicity exists. Naloxone is a competitive opioid antagonist that displaces and binds to opioid receptor sites, effectively “kicking off” the opioid that was bound.7 The goal of giving this antidote is to reverse respiratory depression and avoid the need for more invasive therapies like intubation and mechanical ventilation.
This life-saving drug was first approved by the FDA in 1971 as an injection for intravenous, intramuscular, or subcutaneous administration.8 In 2015, the FDA approved the first naloxone nasal spray which has greatly impacted opioid overdose prevention strategies and expanded public access and availability of this reversal agent.9
Naloxone is available in vials for intravenous, intramuscular, or subcutaneous injection, in pre-filled syringes and cartridges, and as a liquid spray for intranasal administration.7 Intravenous administration of naloxone is preferred, but intranasal and intramuscular routes can be considered when the intravenous route is unavailable.
The onset of action of naloxone is almost immediate with effects seen within 1-2 minutes; onset is quicker when given intravenously compared to subcutaneously or intramuscularly.7 When given intranasally, the onset of action is the most prolonged at up to 3-7 minutes, due to nasal mucosal absorption.10 The half-life of naloxone is around 30 to 45 minutes, with a duration of action around 90 to 180 minutes, and a longer duration seen with a higher dose.7 It is important to consider the need to give additional naloxone later in the course of an overdose if caused by longer acting or extended-release formulated opioids, or recurrence of opioid toxicity and respiratory depression can occur.
Intranasal doses of naloxone are higher than doses given via other routes due to lower intranasal absorption of the drug.10 Administering medications intranasally can lead to some of the medication running out of the nostril or down the throat before it can be absorbed and work effectively.10 As previously mentioned, an advantage of intranasal naloxone is easier access and administration by the general public, at a dose to likely reverse an overdose without the need for repeated doses titrated to clinical reversal while waiting for first responders to arrive to the scene to evaluate the patient for the need for additional observation and treatment.
Naloxone Side Effects
Overall, naloxone is very safe. The main adverse effect of its administration to patients exposed to opioids is the precipitation of opioid withdrawal, marked by irritability, agitation, pain, diaphoresis, and an autonomic surge. Precipitation of withdrawal occurs in chronic opioid users and the dose of naloxone given can affect the withdrawal severity. Administration of naloxone to someone who does not use opioids chronically and was not exposed to opioids will have minimal effect. To reiterate, the goal of naloxone administration is to compete for enough opioid receptor sites to clinically reverse respiratory depression and maintain an adequate airway, rather than fully reverse all opioid binding.
Rarely, administration of naloxone is associated with non-cardiogenic pulmonary edema, possibly secondary to an increase in sympathetic activity and subsequent catecholamine release.11 However, the possible benefits of naloxone outweigh the risks when contemplating whether to give it to a person with respiratory depression in the setting of a possible opioid overdose.
Intermittent Dosing7
Route |
Dose |
Dosing/Administration Considerations |
|---|---|---|
| Intranasal | 3 or 4 mg* in each spray |
Give a single dose in one nostril Can repeat with a new nasal spray every 2-3 minutes, alternating nostrils Can have poorer absorption via this route |
|
Intravenous Intramuscular Subcutaneous |
0.04 to 2 mg |
Initial dose should be patient-specific If no response with previous dose, consider administering double the dose with each administration every 2-3 minutes If no response is observed after cumulative dose of 10 mg, consider other causes of respiratory depression |
| Endotracheal | 0.5-8 mg | Consider only when no other routes are available |
*An 8 mg intranasal product is available; however, this dose has a greater risk of precipitating opioid withdrawal without any greater benefit than the 3 and 4 mg doses12
Naloxone Dosing Strategies
Ultimately, dosing naloxone should be based on patient-specific response as mentioned above. When selecting an empirical dose of naloxone, there are several factors to consider, which are discussed below.
Initial presentation/symptoms
In patients in a health care facility and not at immediate risk of apnea, initial low doses of naloxone can be given, like 0.04-0.4 mg. Increasing doses (typically by doubling) can be given subsequently every 2 to 3 minutes, ultimately titrated until a clinical response is achieved. Higher doses are warranted initially when a patient presents apneic or in cardiorespiratory arrest. It is important to note, though, evidence is lacking for improved patient outcomes during cardiac arrest from naloxone administration.11 Naloxone can be given if there is concern for opioid-induced cardiac arrest, along with standard of care, but it should not delay cardiopulmonary resuscitation.13
Type of opioid
An opioid’s binding affinity at the mu-opioid receptor and the amount taken determine the dose of naloxone required for its reversal.14 Higher doses of naloxone are required for reversal of partial opioid agonists like buprenorphine, and prompt initiation of a continuous infusion of naloxone is recommended.15 Due to the high binding affinity of buprenorphine to the mu opioid receptor and its slower receptor dissociation, the onset of action of naloxone is typically delayed in these cases.15,16 Animal data indicate standard doses of naloxone are sufficient to reverse fentanyl analogs, contrary to initial anecdotal reports suggesting higher-than-normal reversal doses.14
Chronic versus naive opioid user
Patients who are on opioids chronically are at risk for precipitation of withdrawal following naloxone administration. In these patients, lower effective doses initially are more beneficial to achieve adequate respiratory status without eliciting withdrawal. When treating an acute opioid intoxication in an opioid naïve patient, there is no risk of precipitating withdrawal so higher initial naloxone doses can be given to fully antagonize any opioid effect without any concern.
Continuous Infusion
As mentioned previously, naloxone can have a shorter duration of action compared to the opioid it is competing against for the receptor. To prevent a recurrence of opioid toxicity and respiratory depression when large quantities of short-acting or smaller quantities of long-acting or extended-release opioids are involved, a continuous naloxone infusion may be needed. Patients requiring two or more separate boluses more than a few minutes apart may benefit from a continuous infusion. The infusion should be started at two-thirds of the initial effective and cumulative bolus doses of naloxone per hour.7 Titration of the infusion rate is based on patient mentation and respiratory drive.
The Utah Poison Control Center is available 24 hours a day, 7 days a week at 1-800-222-1222 to answer questions about naloxone administration and opioid overdose.
References
- Shenoy SS, Lui F. Biochemistry, Endogenous Opioids. PubMed. Published 2020. https://www.ncbi.nlm.nih.gov/books/NBK532899/
- Schiller EY, Mechanic OJ. Opioid overdose. National Library of Medicine. Published 2023. https://www.ncbi.nlm.nih.gov/books/NBK470415/
- Dhaliwal A, Gupta M. Physiology, Opioid Receptor. PubMed. Published July 24, 2023. https://www.ncbi.nlm.nih.gov/books/NBK546642/
- CDC. Understanding the opioid overdose epidemic. Overdose Prevention. Published June 9, 2025. https://www.cdc.gov/overdose-prevention/about/understanding-the-opioid-overdose-epidemic.html
- Center for Drug Evaluation and Research. Timeline of Selected FDA Activities and Significant Events Addressing Substance Use and Overdose Prevention. FDA. Published online July 11, 2024. https://www.fda.gov/drugs/food-and-drug-administration-overdose-prevention-framework/timeline-selected-fda-activities-and-significant-events-addressing-substance-use-and-overdose
- CDC. Fentanyl Facts. Stop Overdose. Published April 2, 2024. https://www.cdc.gov/stop-overdose/caring/fentanyl-facts.html
- Naloxone. Up To Date Lexi-Drug. Naloxone. Accessed August 20, 2025. Naloxone (Lexi-Drugs) - UpToDate® Lexidrug™
- Naloxone. Package insert. Kaleo, Inc; 2022.
- Narcan nasal spray. Package insert. Adapt Pharma; 2015.
- Utrilla MG, Chesney E, Neale J, et al. Naloxone dosing in the era of synthetic opioids: Applying the Goldilocks principle. Addiction. Published online April 8, 2025. doi: https://doi.org/10.1111/add.70060
- Elkattawy S, Alyacoub R, Ejikeme C, Noori MAM, Remolina C. Naloxone induced pulmonary edema. Journal of Community Hospital Internal Medicine Perspectives. 2021;11(1):139-142. doi: https://doi.org/10.1080/20009666.2020.1854417
- Payne ER, Stancliff S, Rowe K, Christie JA, Dailey MW. Comparison of Administration of 8-Milligram and 4-Milligram Intranasal Naloxone by Law Enforcement During Response to Suspected Opioid Overdose — New York, March 2022–August 2023. MMWR Morb Mortal Wkly Rep 2024;73:110–113. DOI: http://dx.doi.org/10.15585/mmwr.mm7305a4
- Lavonas EJ, Akpunonu P, Arens AM, et al. 2023 American Heart Association focused update on the management of patients with cardiac arrest or life-threatening toxicity due to poisoning: An update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2023;148(16). doi: https://doi.org/10.1161/cir.0000000000001161
- Moss MJ, Warrick BJ, Nelson LS, et al. ACMT and AACT position statement: preventing occupational fentanyl and fentanyl analog exposure to emergency responders. Clin Toxicol (Phila). 2018;56(4):297-300. https://doi.org/10.1080/15563650.2017.1373782
- Yassen A, Olofsen E, van Dorp E, et al. Mechanism-Based Pharmacokinetic-Pharmacodynamic Modelling of the Reversal of Buprenorphine-Induced Respiratory Depression by Naloxone. Clinical Pharmacokinetics. 2007;46(11):965-980. doi: https://doi.org/10.2165/00003088-200746110-00004
- van Dorp E, Yassen A, Sarton E, et al. Naloxone Reversal of Buprenorphine-induced Respiratory Depression. Anesthesiology. 2006;105(1):51-57. doi: https://doi.org/10.1097/00000542-200607000-00012