Rates of overdose deaths due to use of opioids have risen steadily since 1999. Although illicit substances, such as heroin and illegally manufactured synthetic opiates, are increasingly recognized as major contributors to increases in opioid overdose mortality since 2013, prescription opioids still account for the largest proportion (nearly 50%) of opioid overdose deaths.^1,2,3 In addition, prior use of prescription opioids, and particularly misuse, is strongly correlated with initiation of heroin use, and opioid prescribing rates have mirrored the increasing rates of opioid-related deaths, highlighting the important role of prescription opioids in fueling this epidemic.^4,5 Nonfatal overdoses also account for innumerable preventable health care expenses, morbidity, and emotional suffering.

In recognition of opioid overdose deaths as a major public health concern, the US Department of Health and Human Services has identified 3 priority areas to address the opioid crisis: prescriber education and training, expanding access to medication-assisted treatment for opioid use disorder, and increasing community access to naloxone.⁶

Naloxone has long been utilized by emergency medical personnel in suspected opioid overdoses, primarily intravenously. However, the majority of opioid-related fatalities occur in nonmedical facilities, typically in the patient’s home.⁷ In 1996, community-based opioid overdose prevention programs began providing naloxone to community members as a strategy to reduce overdose deaths.⁸ Distribution of naloxone continued to increase over the following 15 years, and many states have now adopted laws and regulations aimed at increasing access to naloxone as a community-provided overdose reversal agent. Two new formulations of naloxone were approved by the US Food and Drug Administration (FDA) in 2014 and 2015, which are designed for ease of use by laypersons. Growing evidence supporting naloxone use in this capacity has led to widespread adoption of community-based programs and recommendations for prescribing naloxone in the Centers for Disease Control and Prevention (CDC) Guidelines for Prescribing Opioids for Chronic Pain.

Naloxone is a pure opioid antagonist. Through competitive antagonism at the mu, kappa, and sigma receptor sites in the central nervous system (CNS), with primary affinity for mu receptors, naloxone reverses the effects of opioids, including respiratory depression, sedation,
and hypotension.⁹ It has also demonstrated reversal of psychotomimetic and dysphoric effects produced by some agonist-antagonist opioids, such as pentazocine.⁹ Naloxone has essentially no pharmacologic activity when administered in usual dosages in the absence of opioids.⁹

In studies of healthy volunteers who were exposed to a 4-mg dose of the preformulated nasal spray, the most commonly reported adverse effects were increased blood pressure, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, and nasal inflammation.¹⁰ The most common adverse effects reported by healthy subjects who were exposed to naloxone via autoinjector (at 0.4-, 0.8-, or 2-mg doses) were dizziness and injection site erythema.¹¹ Agitation, disorientation, confusion, and anger have also been reported with use of the autoinjector in postmarketing studies.¹¹

In opioid-dependent patients, administration of naloxone may precipitate acute opioid withdrawal, characterized by body aches, nausea, vomiting, diarrhea, abdominal cramping, tachycardia, piloerection, sweating, yawning, rhinorrhea, shivering, tremor, irritability, restlessness, and increased blood pressure. Abrupt postoperative reversal of opioid-induced CNS depression with naloxone has been reported to cause the following: hypotension, hypertension, tachycardia, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Serious events such as coma, encephalopathy, or death have been reported as a result of these adverse effects, primarily in patients with a history of cardiovascular disease or who were receiving medications with similar adverse cardiovascular effects.^9,10,11

There are limited data available on overdose with naloxone. A small study in healthy volunteers did not demonstrate toxicity at doses of 0.2 to 0.4 mg/kg (24 mg/70 kg).^9,12 In another study of 36 patients with acute stroke who received naloxone at much higher doses (4-mg/kg loading dose followed by a continuous infusion of 2 mg/kg/h for 24 h), 23 patients reported adverse events and 7 discontinued naloxone use owing to adverse effects, including seizures, severe hypertension, hypotension, and bradycardia.^9,12 Adverse effects have also been reported in healthy subjects exposed to these higher doses (2 mg/kg), including anxiety, irritability, tension, sadness, difficulty concentrating, decreased appetite, dizziness, nausea, abdominal pain, and sweating.⁹ Behavioral symptoms have been reported to persist for up to 2 to 3 days. Treatment of naloxone overdose primarily includes supportive care and close monitoring.

Although the FDA has recently approved 2 easy-to-use formulations of naloxone that are intended to be administered in emergency situations by individuals who may not be medically trained, there are currently no over-the-counter products available. Federally, naloxone is approved to be dispensed only as a prescribed medication. However, efforts by harm reduction organizations, in addition to the American Medical Association and National Association of Boards of Pharmacy, have led many states to adopt laws and regulations that increase access to naloxone in the community. Nearly all states have adopted laws that allow for naloxone to be prescribed to people other than that person for whom use is intended (referred to as third-party prescribing) or to be dispensed by a retail pharmacy under a standing order, removing the need for a patient to see the prescriber before receiving the medication.¹³

Most states have also passed overdose “Good Samaritan” laws, which provide some protection for lay individuals who report an overdose from arrest and prosecution for drug-related charges. These laws also provide immunity for laypersons who administer naloxone and medical professionals who dispense or prescribe the medication.¹³ Refer to individual state laws and regulations for details.