The role of naloxone in out-of-hospital cardiac arrest management: a call for integration into Advanced Cardiac Life Support protocols

Article information

J EMS Med. 2025;.jemsm.2025.00164

Publication date (electronic) : 2025 April 16

doi : https://doi.org/10.35616/jemsm.2025.00164

Frank Harmon Colvett

University of Missouri, Columbia, MO, USA

Correspondence to: Frank Harmon Colvett University of Missouri, 416 S 6th St, Columbia, MO 65201, USA E-mail frank.colvett27@gmail.com

Received 2025 March 3; Revised 2025 March 8; Accepted 2025 March 23.

Abstract

INTRODUCTION

The opioid crisis has placed a significant burden on healthcare systems worldwide, especially in emergency medicine and prehospital care in America [1]. A newfound widespread misuse of opioids, whether from prescription painkillers or the unknown lacing of synthetic opioids such as fentanyl into other illicit narcotics, has led to an increasing number of opioid-related out-of-hospital cardiac arrests (OHCA) [2]. The rapid onset of respiratory depression induced by opioids can quickly progress to hypoxia and cardiac arrest if not promptly addressed, resulting in death if not permanent anoxic brain injury or other systemic hypoxic conditions. This growing public health emergency necessitates a reassessment of current resuscitation strategies by the potential incorporation of naloxone into Advanced Cardiac Life Support (ACLS) protocols.

ACLS guidelines primarily focus on the administration of epinephrine, airway management, and cardiac monitoring resulting in defibrillation when indicated; however, most do not currently include specific recommendations for naloxone use in opioid-induced cardiac arrest [3]. Given that respiratory depression is the fundamental mechanism of injury, targeted interventions, such as naloxone administration and prioritized airway management, may improve patient survival rates by reversing opioid-induced hypoxia before irreversible damage occurs.

Disparities in naloxone access and utilization further complicate its effectiveness. Naloxone distribution programs have expanded significantly through reduction initiatives and over-the-counter availability, but its role in cardiac arrest remains unclear in layperson responses [4]. Additionally, the efficacy of bystander-administered naloxone in severe opioid overdoses involving fentanyl analogs falls short due to the high potency and prolonged effects of these drugs [5]. This paper examines the pharmacology, clinical evidence, and potential for naloxone integration into ACLS protocols, with an emphasis on optimizing emergency response for opioid-induced OHCA.

PHARMACOLOGY AND MECHANISM OF ACTION

Naloxone is a competitive opioid receptor antagonist with high affinity for the μ-opioid receptor, as well as moderate binding to κ- and δ-opioid receptors [6]. By displacing opioid molecules from these receptors, naloxone effectively reverses respiratory depression and restores normal ventilatory function. Naloxone can be administered through various routes, including intravenous, intramuscular, subcutaneous, and intranasal delivery. Intranasal naloxone has gained popularity due to its ease of administration and effectiveness in reversing opioid toxicity outside of medical environments [7].

A significant challenge in naloxone pharmacology is its relatively short half-life of 30–45 minutes. Synthetic opioid analogs like fentanyl and carfentanil have much longer durations of action, increasing the risk of naloxone’s effects wearing off while opioids remain active in the body [8]. This continued risk emphasizes the need for repeated naloxone dosing, continuous monitoring, and infusion therapy for patients exposed to long-acting opioids.

Many recent studies have been done on the relationship of repeated naloxone administration and cardiovascular complications. Some studies suggest that naloxone induces unplanned catecholamine release, which can lead to transient hypertension and tachycardia [9,10]. While these effects could be beneficial in counteracting opioid-induced hypotension, they may also pose risks to patients with preexisting cardiovascular disease. Most of the downsides mentioned in these studies are short-term and caused by withdrawal which is a far easier condition to treat than death in the event of an unsuccessful resuscitation attempt. Further research is needed to determine the precise hemodynamic consequences of naloxone use during cardiac arrest resuscitation.

CLINICAL EVIDENCE SUPPORTING NALOXONE IN OHCA

Recent clinical evidence shows naloxone administration improves return of spontaneous circulation (ROSC) in opioid-related OHCA. Retrospective cohort studies have shown that patients who receive naloxone earlier in the resuscitation process have higher rates of ROSC and better neurological outcomes [2]. A study conducted in Northern California examining over 8,000 OHCA cases found that naloxone administration was associated with a statistically significant increase in ROSC rates and a modest improvement in survival to hospital discharge [7]. When compared to the lack of adverse reactions to naloxone, there is a clear sign clinical advantage for a more liberal application of naloxone in OHCA algorithms.

Other research has explored timing of naloxone administration and its impact on clinical outcomes. Some studies indicate that naloxone is most effective when administered before cardiac arrest occurs, during the pre-arrest period when respiratory depression is still reversible. The issue with this approach for emergency medical services (EMS) services is the inability to meet that time table. In contrast, its benefits appear to diminish once a patient is in full cardiac arrest, suggesting that naloxone may function best as a preventative rather than resuscitative measure in opioid overdose cases [5]. Again, with no sign of newfound contraindications of naloxone in cardiac arrest, there is not enough reason for EMS not to use naloxone during an OHCA.

To provide additional insights into its benefits, potential limitations, and optimal use cases, there is a need for expanding clinical studies and randomized controlled trials on naloxone’s role in OHCA. There are clear ethical limitations to a study that involves EMS treatments; however, studies that were done using various comparative studies with pigs or other species to demonstrate the importance of compressions in cardiopulmonary resuscitation (CPR) would also be useful in this situation given similar opioid pathways. Additionally, further examination of its integration with other resuscitation strategies, such as mechanical ventilation and alternative opioid antagonists, may enhance its effectiveness in prehospital and in-hospital settings.

Naloxone is the frontline tool in the fight against opioid-related condition. The ease of intranasal administration allows for everyone from lay providers to advanced EMS providers; however, further research with different species is needed to refine its application within ACLS protocols as has been done in the past. While retrospective data suggest benefits in improving ROSC, controlled trials will be essential to determine optimal dosing strategies, ideal timing of administration, and its interaction with other standard resuscitation interventions.

The current opioid epidemic demonstrates the importance of proactive treatment of these conditions combined with updated protocols. Expanding naloxone access, refining EMS protocols, and enhancing community awareness remain critical steps in reducing opioid-related fatalities. The future of naloxone in cardiac arrest management will depend on a multidisciplinary approach, incorporating pharmacological innovation, clinical best practices, and public policy reforms to ensure effective and equitable emergency response strategies.

DISCUSSION

Naloxone plays a clear, critical role in reversing opioid-induced respiratory depression and has clearly substantial benefits when integrated into OHCA resuscitation protocols. The reviewed literature demonstrates that naloxone administration is associated with improved rates of ROSC and discharge without deficits. Although its effectiveness in full cardiac arrest is debated, early administration of naloxone mixed with consideration of airway management leads to the most promising outcomes [7].

One of the key considerations in integrating naloxone into ACLS protocols is the need to recognize opioid-induced OHCA early. Several studies indicate that EMS providers often struggle to distinguish opioid toxicity from other causes of cardiac arrest in real time, leading to variability in naloxone administration [2]. The importance in education on naloxone’s large reward to risk ratio would lead to more liberal usage of naloxone. Furthermore, the current ACLS algorithms do not specify whether naloxone should be administered in conjunction with epinephrine or before other interventions. The concerns about optimal sequencing for maximizing patient outcomes can only be solved through thorough scientific testing.

Despite evidence supporting naloxone’s role in reversing opioid-induced hypoxia, there are several limitations to its widespread adoption in cardiac arrest protocols. One primary limitation is the short half-life of naloxone, which is insufficient to counteract the prolonged effects of high-potency opioids like fentanyl and carfentanil. This necessitates repeated dosing or continuous infusion strategies, which may not always be feasible in prehospital settings [5]. Naloxone can restore spontaneous breathing, but it does not directly address the cardiovascular collapse that often accompanies opioid-induced cardiac arrest. Further research is required to determine whether a combined mixture of naloxone and adrenaline would cause higher rates of ROSC.

Another concern is the potential for adverse hemodynamic effects associated with naloxone administration. Some studies report that naloxone-induced catecholamine release can lead to hypertension, tachycardia, or arrhythmias [3]. The old adages of comparing battles versus wars and short-term versus long-term goals are a constant struggle in EMS. Providers in emergency medicine are often taught that a patient living with an arrhythmia is better than a patient dead from an opioid overdose, but there is a fine line that needs to be found through rigorous research and prospective studies.

Additionally, disparities in naloxone accessibility and bystander utilization raise further concerns. Public health initiatives have expanded naloxone availability through over-the-counter distribution, but its administration during OHCA remains inconsistent. Bystanders often hesitate to use naloxone, either due to a lack of training or fear of causing harm. This issue is consistent across many different skills like CPR and abdominal thrusts. EMS systems must incorporate community-based education efforts that focus on naloxone’s safety profile and its role in preventing cardiac arrest progression [4,11]. More research is also needed to assess whether naloxone co-administration with other prehospital interventions, such as bag-valve-mask ventilation or automated external defibrillation use, improves survival outcomes in suspected opioid-related OHCA cases.

In summary, while naloxone has demonstrated clear benefits in opioid overdose management, its role in cardiac arrest resuscitation remains an area of ongoing investigation. The evidence suggests that naloxone is most effective when administered early, before full cardiac arrest occurs. However, gaps in EMS training, limited guidelines on optimal sequencing, and the pharmacokinetic limitations of naloxone must be addressed before it can be formally integrated into ACLS protocols. Future research should focus on defining best practices for naloxone use in OHCA, evaluating the potential of alternative opioid antagonists, and refining prehospital strategies to enhance early recognition and treatment of opioid toxicity. Addressing these factors will be critical in optimizing naloxone’s impact on survival rates and neurological outcomes in opioid-related OHCA cases.

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