What is Naloxone – and More Importantly, How Does It Work? 

The ongoing opioid epidemic continues to be a public health concern in Canada and many other parts of the world, fuelled by both prescription and illegally obtained opioids (Belzak and Halverson 2018). Naloxone, generally known by its brand name Narcan, is the most commonly used medication that is administered during opioid overdose emergencies (Theriot et al. 2025). It acts as an opioid antagonist that works against drugs such as morphine, oxycodone, heroin, and fentanyl (Sirohi et al. 2009). It is important to note that naloxone is not effective against non-opioid stimulants such as cocaine, methamphetamine, and benzodiazepines (PubChem 2025). Naloxone has a high affinity for μ-opioid receptors in the ventral tegmental area of the brain, making them the primary target for pain-relieving drugs (Theriot et al. 2025). By binding to these receptors, naloxone helps to temporarily reverse the effects that opioids have on the body such as arrested respiration, respiratory and central nervous system (CNS) depression, apnea, unconsciousness, and miosis (Saari et al. 2024). The efficacy of naloxone is dependent on several factors, which include the dose of the opioid that is ingested, the pharmacological mechanism of the opioid, as well as the medical history of the victim (Jordan et al. 2025). 

The chemical formula of naloxone is C19H21NO4, with a molecular weight of approx. 327.38 g/mol (PubChem 2025). It is a congener of oxymorphone, differing by only an allyl group that reverses the effect of the opioid ingested. Narcan is chemically formulated as naloxone HCl, the hydrochloride salt form of naloxone that enhances stability, solubility, and bioavailability (Wermeling 2013). Due to its lipophilic nature, naloxone is able to cross the blood-brain barrier within 2 minutes of being administered, to bind to the μ-opioid receptor’s orthosteric site, where it displaces the opioid molecule (Moss and Carlo 2019). This displacement prevents G-protein activation, thereby increasing the activity of adenylyl cyclase and restoring cyclic Adenosine Monophosphate (cAMP) production in the neurons.

Restored cAMP levels lead to the reopening of voltage-gated calcium channels and normal neuronal activity (figure 1). In the brainstem, this restores respiration, reversing opioid-induced respiratory depression. After its action in the CNS, naloxone is metabolized in the liver and is excreted through the kidneys (Moss and Carlo 2019). 

Figure 1. Cell signaling cascade of the binding of an opioid agonist. This figure illustrates how opioid receptor activation inhibits adenylate cyclase, reducing cAMP, suppressing calcium entry, and upregulating potassium efflux from the neuron. This leads to a decline in neuronal excitability and neurotransmitter release, which controls the pain-relieving effects of opioids. Naloxone blocks the opioid from the receptor, preventing G-protein activation, which leads to the restoration of respiratory function (Pathan and Williams 2012). 

 The Food and Drug Administration (FDA) approved of the parenteral (injectable) use of naloxone in 1971, which made its way into clinics, hospitals, and prehospital medicine settings (Saari et al. 2024). However, intranasal naloxone was approved for use by the FDA in 2015 (Jenco 2023). This was primarily done to allow general members of the public such as social workers, family members, residents of high-risk communities to able to administer naloxone efficiently, in response to the rising rates of opioid-related deaths and overdoses (Urmanche and Harocopos 2023). In Canada, there is an Increased availability of naloxone to enforce extra precautions that can be taken regarding the opioid epidemic (Tsuyuki et al. 2020). Enacted policies now allow first responders including firefighters to carry naloxone, and it is freely available at local pharmacies. In some provinces, pharmacies are also required to provide a naloxone kit when patients are prescribed opioids (Government of Ontario 2023). 

Naloxone has proven to serve as a critical, fast acting opioid antagonist that can effectively reverse life-threatening symptoms of overdose by restoring normal respiratory and neurological function. Its widespread availability has made it an essential public health tool in controlling and mitigating the devastating impact of the opioid epidemic. 

References

Belzak, Lisa, and Jessica Haverson. 2018. “Evidence Synthesis – The Opioid Crisis in Canada: A National Perspective.” Health Promotion and Chronic Disease Prevention in Canada: Research, Policy and Practice 38 (6): 224–33. https://doi.org/10.24095/hpcdp.38.6.02  

Government of Ontario. 2023. “Ontario Take-Home Naloxone Programs | Ontario.Ca.” November 2. https://www.ontario.ca/page/ontario-take-home-naloxone-programs

Jenco, Melissa. 2023. AAP Expert: FDA Approval of OTC Naloxone Nasal Spray Is a ‘Win.’ March 30. https://publications.aap.org/aapnews/news/23940/AAP-expert-FDA-approval-of-OTC-naloxone-nasal. 

Jordan, Matthew R., Preeti Patel, and Daphne Morrisonponce. 2025. “Naloxone.” In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK441910/. 

Moss, Ronald B., and Dennis J. Carlo. 2019. “Higher Doses of Naloxone Are Needed in the Synthetic Opioid Era.” Substance Abuse Treatment, Prevention, and Policy 14 (1): 6. https://doi.org/10.1186/s13011-019-0195-4. 

Pathan, Hasan, and John Williams. 2012. “Basic Opioid Pharmacology: An Update.” British Journal of Pain 6 (1): 11–16. https://doi.org/10.1177/2049463712438493. 

PubChem. 2025. “Naloxone.” Accessed October 12, 2025. https://pubchem.ncbi.nlm.nih.gov/compound/5284596. 

Saari, Teijo I., John Strang, and Ola Dale. 2024. “Clinical Pharmacokinetics and Pharmacodynamics of Naloxone.” Clinical Pharmacokinetics 63 (4): 397–422. https://doi.org/10.1007/s40262-024-01355-6. 

Sirohi, Sunil, Shveta V. Dighe, Priyanka A. Madia, and Byron C. Yoburn. 2009. “The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity.” The Journal of Pharmacology and Experimental Therapeutics 330 (2): 513–19. https://doi.org/10.1124/jpet.109.152678. 

Theriot, Jonathan, Sarah Sabir, and Mohammadreza Azadfard. 2025. “Opioid Antagonists.” In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK537079/. 

Tsuyuki, Ross T., Vinita Arora, Mark Barnes, et al. 2020. “Canadian National Consensus Guidelines for Naloxone Prescribing by Pharmacists.” Canadian Pharmacists Journal / Revue Des Pharmaciens Du Canada 153 (6): 347–51. https://doi.org/10.1177/1715163520949973. 

Urmanche, Adelya A., and Alex Harocopos. 2023. “Experiences Administering Naloxone Among People in Different Social Roles: People Who Use Opioids and Family Members and Friends.” Journal of Drug Issues 53 (3): 475–89. https://doi.org/10.1177/00220426221133024. 

Wermeling, Daniel P. 2013. “A Response to the Opioid Overdose Epidemic: Naloxone Nasal Spray.” Drug Delivery and Translational Research 3 (1): 63–74. https://doi.org/10.1007/s13346-012-0092-0.