Is Naloxone Safe? Evidence-Based Use in Opioid Overdose

If you've spent much time in an emergency department or on a rig, you've seen how fast a patient given naloxone can go from zero breaths to fully awake, and sometimes straight into acute withdrawal. The answer to whether that risk makes widespread naloxone distribution dangerous is clear: naloxone is safe, serious adverse effects are rare, and the evidence strongly supports its expanded use as a core component of overdose management in both BLS and ACLS protocols.

In this article, we review the literature to give emergency providers the guidance and confidence to make evidence-based decisions.

Table of Contents

• The Rising Burden of Opioid Overdose in the United States 
• Why Naloxone Use Has Expanded Beyond Traditional Medical Settings 
• Why Naloxone Sparks Debate Among Emergency Providers 
• Standard Approach to Treating Opioid Overdose 
• Titrating Naloxone and the Goal of Treatment 
• Should Naloxone Restore Consciousness 
• Acute Withdrawal Syndrome After Naloxone 
• Serious Adverse Events and Naloxone What the Evidence Shows 
• Evidence From Prehospital Naloxone Studies 
• Transport Refusal After Naloxone Administration 
• Outcomes for Patients Who Refuse Transport 
• Ethical and Clinical Considerations in Naloxone Use 
• The Bottom Line: Naloxone is Safe and Effective 

The Rising Burden of Opioid Overdose in the United States

From 2004 to 2022, overdose deaths related to opioid use increased by almost 500% , a staggering increase driven largely by fentanyl deaths. Even though there was a sharp decline from 2022 to 2024, the total number of opioid-related deaths remained at or above 2019 levels with approximately 54,000 deaths in 2024.

For EMS personnel, nonfatal opioid overdose encounters increased from 98 to 179 per 10,000 EMS encounters, a 4% quarterly increase from 2018 to 2022. Meanwhile a similar rate of increase (5.4% quarterly) in opioid encounters occurred for emergency department encounters from 2020 to 2024.

Thus, an urgent push for public availability of naloxone has concurrently been bolstered by public health agencies across the nation in this timeframe.

Why Naloxone Use Has Expanded Beyond Traditional Medical Settings

Community officials have taken the initiative to reduce the number of overdose deaths by making naloxone available through non-traditional means, moving from a strategy of reaction by professionals to a proactive, “point-of-need” strategy by bystanders. This is achieved by making naloxone available over-the-counter in all 50 states.

Modern public health strategies aimed at preventing opioid deaths also include low-barrier access points such as 24/7 public naloxone “smart boxes” which house naloxone kits and having EMS and law enforcement leave naloxone kits behind at the scene of a non-fatal overdose.

Despite this public health push, there is still some hesitation by members of the medical community, particularly pre-hospital providers, regarding the safety and dosing of naloxone in widespread distribution.

Why Naloxone Sparks Debate Among Emergency Providers

With the potential for unpleasant side effects, emergency providers can passionately debate regarding the proper approach to naloxone dosing. Providers may have cultural and clinical resistance to mass availability of naloxone since they may believe that easy naloxone access will act as a safety net that enables increased opioid abuse. This is, in fact, a myth as research has shown that public distribution of naloxone kits is not associated with increased opioid use or overdose.

Standard Approach to Treating Opioid Overdose

Opioids are most dangerous in overdose because they cause respiratory depression, killing the respiratory drive of the patient and starving the patient of oxygen while accumulating carbon dioxide. For patients with respiratory depression, BMV ventilation is an initial priority (think ABC’s!) to treat hypoxia and hypercapnia, after which naloxone is the next priority.

As an aside, it’s important to note that naloxone is a reversal agent and not definitive care for the patient – it will effectively resolve the immediate opioid effects, but it will have no effect on the patient’s addiction or cravings for future opioid use.

Titrating Naloxone and the Goal of Treatment

After BVM ventilations are initiated, a common strategy for treating an opioid-related overdose is to then titrate naloxone until the patient’s respiratory effort becomes adequate, yet not to the point of the patient becoming lucid. This is a difficult line to tread since the half-life of naloxone is much shorter than most opioids in the patient’s system with differing peaks and troughs. I once had a patient on a continuous naloxone IV drip that we had to keep turning off and back on because the patient would swing from hypoventilation to sitting up retching with a heart rate in the 130’s at the lowest dose. As providers, we don’t want to cause horrible symptoms of withdrawal, but even more so we don’t want to risk the patient’s respiratory rate dipping to dangerous levels.

Should Naloxone Restore Consciousness

Historically, providers prefer partial reversal via the “lowest-dose-possible” technique because it’s a win-win: the patient doesn’t experience horrible withdrawal symptoms, and the provider doesn’t risk a combative patient. Nonetheless, full reversal often occurs because naloxone reaches peak effect and wears off at a rate unknown to the provider. Additionally, over-the-counter formulations of naloxone are made with a high enough dose to ensure full opioid reversal, often resulting in unpleasant symptoms when they are administered by bystanders. As will be discussed below, for the professional who is titrating the medication, it is always better to err on the side of fully reversing respiratory depression even as we want patients to not have to experience unpleasant side effects. For safety, providers should always pre-oxygenate the patient with a BVM before naloxone administration and position the patient on their side in the lateral recumbent position in case of vomiting upon regaining consciousness.

Acute Withdrawal Syndrome After Naloxone

Many emergency providers are apprehensive about giving naloxone due to undesirable side effects. Patients regaining consciousness after naloxone administration may experience multiple symptoms that are collectively referred to as Acute Withdrawal Syndrome (AWS).

Patients with AWS may exhibit nausea, vomiting, tachycardia, diarrhea, hypertension, nervousness, and restlessness. The degree of withdrawal symptoms is relatively proportional to the amount of naloxone given, so smaller amounts will normally result in less serious withdrawal symptoms.

While withdrawal symptoms brought about by naloxone are uncomfortable for the patient, they are rarely life-threatening.

Serious Adverse Events and Naloxone What the Evidence Shows

Rare but serious complications like cardiac arrest, seizures, acute pulmonary edema, and violent behavior are sometimes offered as reasons for not giving a high enough naloxone dose for the patient to regain consciousness. However, it is likely that these complications have been overstated, as the evidence has not been reproducible. For patients who experience these events, causation is complicated by multiple factors including polysubstance use and underlying medical conditions. This has been borne out in reports which are discussed below.

Evidence From Prehospital Naloxone Studies

Several important studies have laid the groundwork for the safety of naloxone, including:

• Osterwalder (1996) : Found that out of 453 patients treated with naloxone, only 6 experienced severe adverse effects. Three suffered convulsions, one asystole, one pulmonary edema, and one violent behavior.
• Burris (2000) : Reported research suggesting that complications are exceedingly rare and that past reports of complications may have been erroneous or occurred in patients with pre-existing heart disease.
• Yealy et al. (1990) : Retrospective study of 800 prehospital records of patients who received initial IV naloxone 0.4-0.8 mg. Found that no patients experienced ventricular tachycardia, fibrillation or asystole. One generalized tonic-clonic seizure occurred in a patient with a history of them. The authors thus concluded that lower doses of naloxone are not necessary.

These studies emphasize that naloxone is safe even in prehospital settings with the rarity of severe cardiac events, and more recent studies have only served to reinforce that fact. Additionally, these studies show that standard naloxone dosing is safe and effective, and that there is no need to begin with a smaller dose to prevent complications.

Transport Refusal After Naloxone Administration

Typically, patients are transported to the hospital after regaining consciousness following the administration of naloxone for recovery. However, some patients refuse, against the advice of treating paramedics.

Given the shorter half-life of naloxone compared to opioids, you might expect there to be a high mortality for patients refusing transport. What does the data say about post-reversal safety in situations of refusal of transport?

Outcomes for Patients Who Refuse Transport

Several studies in the past have shown the safety of patients refusing transport after naloxone administration in the field:

• Wampler et al. (2011) : Review of 552 patients treated with naloxone who refused transport. None were found in the Medical Examiner’s office database two days after refusing transport. Of note, while 9 patients subsequently passed away in a 30-day window, the shortest interval from refusal to death was four days after treatment.
• Vilke et al. (1999) : Found that, of 117 ME cases of opiate overdose deaths in a single year, there was no case in which a patient was treated by paramedics with naloxone within 12 hours of being found dead of an opiate overdose.

Thus, short term mortality data shows that it is appropriate for a patient to refuse transport once they are awoken from opioid overdose via naloxone. Refusal does not automatically predict poor outcomes since once a patient is awake and mobile, they rarely return to a state of total respiratory arrest unless additional substances are consumed.

Ethical and Clinical Considerations in Naloxone Use

In settings of substance use, there is a tension that providers feel in preserving the patient’s autonomy and safety. When adequate naloxone is given, the opioid’s effect has essentially been reversed and the patient can be assessed as oriented with their faculties intact. At this point, their refusal of transport is allowed so long as the patient is informed of the risks involved. EMS systems need to have a developed protocol outlining when the patient is allowed to make an informed refusal – typically, in the setting of confirmed orientation, normal vital signs, and an understanding of the risks of refusal – so that providers don’t feel the moral distress of thinking that they are operating in a “gray area”.

The Bottom Line: Naloxone is Safe and Effective

In conclusion, naloxone overwhelmingly saves lives and possesses a safety profile that can compete with any other drug as adverse effects are rare. Thus, fear of complications from administering more-than-needed naloxone should not delay treatment. Evidence-based protocols should be available to EMS and emergency personnel regarding both naloxone administration and patient transport decisions.

Emergency providers can gain confidence with BLS Training and ACLS Training to properly recognize overdose, manage patient airways, and provide correct medication intervention. Consider taking the next step in your clinical development by enrolling for the first time or for recertification today!

References

Boyer E. Management of Opioid Analgesic Overdose. New England Journal of Medicine. 2012;367(2):146-155.

Burris S, Norland J, Edlin B. Legal aspects of providing naloxone to heroin users in the United States. International Journal of Drug Policy. 2001;12(3):237-248.

Casillas SM, Pickens CM, Stokes EK, Walters J, Vivolo-Kantor A. Patient-level and county-level trends in nonfatal opioid-involved overdose emergency medical services encounters — 491 counties, United States, January 2018–March 2022. MMWR Morb Mortal Wkly Rep. 2022;71(34):1073-1080. doi:10.15585/mmwr.mm7134a1

Kim D, Irwin K, Khoshnood K. Expanded Access to Naloxone: Options for Critical Response to the Epidemic of Opioid Overdose Mortality. Am J Public Health. 2009;99(3):402-407.

Osterwalder JJ. Naloxone—for intoxications with intravenous heroin and heroin mixtures—harmless or hazardous? A prospective clinical study. J Toxicol Clin Toxicol. 1996;34(4):409-416. doi:10.3109/15563659609013811

Pickens CM, Park J, Casillas SM, et al. Trends in suspected fentanyl-involved nonfatal overdose emergency department visits, by age group, sex, and race and ethnicity — United States, October 2020–March 2024. MMWR Morb Mortal Wkly Rep. 2025;74(16):282-287. doi:10.15585/mmwr.mm7416a2

Saunders H, Panchal N, Rudowitz R. Opioid overdose deaths: national trends and variation by demographics and states. KFF. Published February 24, 2026. Accessed March 4, 2026. https://www.kff.org/mental-health/opioid-overdose-deaths-national-trends-and-variation-by-demographics-and-states/

Tse WC, Djordjevic F, Low SD, et al. The effect of take-home naloxone distribution on overdose knowledge and behavior: a systematic review. Int J Drug Policy. 2022;101:103538. doi:10.1016/j.drugpo.2021.103538

Vilke G, Buchanan J, Dunford J, Chan T. Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehosp Emerg Care. 1999;3(3):183-186. doi:10.1080/10903129908958937

Wampler D, Molina D, McManus J, Laws P, Manifold C. No Deaths Associated with Patient Refusal of Transport After Naloxone-Reversed Opioid Overdose. Prehospital Emergency Care. 2011;15(3):320-324.

Wermeling D. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Therapeutic Advances in Drug Safety. 2015;6(1):20-31.

Yealy DM, Paris PM, Kaplan RM, Heller MB, Marini SE. The safety of prehospital naloxone administration by paramedics. Ann Emerg Med. 1990;19(8):902-905. doi:10.1016/s0196-0644(05)81566-5