Continuing Education Activity

Over the past 2 decades, the increase in opioid overdose incidents nationwide has resulted in a significant surge in morbidity and mortality rates. Naloxone is a crucial intervention in this crisis and has been used for over 50 years as an opioid antidote. Naloxone operates as a competitive antagonist to the μ-opioid receptor. Beyond its conventional hospital deployment, naloxone is used extensively by emergency medical personnel and law enforcement agencies, and its accessibility as an over-the-counter product allows family members and caregivers to administer this antidote when needed. This activity provides healthcare professionals with important information about naloxone, including its indications, mechanism of action, administration modalities, notable adverse effects, contraindications, monitoring protocols, precautions, and pharmacokinetic profiles. The focus of this discussion is to deliver the requisite knowledge and discuss resources for proficient patient management during naloxone administration. By fostering a deeper understanding, this educational endeavor allows learners to determine effective dosage regimens, mitigate adverse reactions, and enhance overall patient outcomes in situations requiring naloxone intervention.

Objectives:

• Identify the FDA-approved indications and off-label uses for naloxone.

• Evaluate the mechanism of action of naloxone.

• Assess the adverse effects of naloxone.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from naloxone therapy.

Indications

The rate of opioid overdose has increased significantly across the United States over the past 20 years. While many factors have contributed to this escalation, the rate of overdose appears to be highest in rural communities compared to urban areas. West Virginia has the highest per-capita overdose rate in the country, and over 50% of this state's population resides in rural areas. Opioid use disorder is associated with severely elevated morbidity and mortality rates.

Naloxone has been used as an antidote to opioids for over 50 years, and the drug has been readily available as a parenteral formula. Naloxone acts as a pure μ-opioid receptor competitive antagonist and is instrumental in preventing accidental overdose of opioids. Due to its effectiveness in preventing death due to opioid overdose, the federal government has recommended that naloxone should be available over-the-counter at most pharmacies. Naloxone can be obtained without a prescription in 43 states and can be administered by emergency medical personnel and law enforcement officials. With the availability of naloxone over the counter, it is now easier for family members and caregivers of patients with opioid use disorder to administer naloxone and potentially save lives.[1] 

FDA-Approved Indications

Naloxone is indicated for the treatment of opioid toxicity, specifically to reverse respiratory depression from opioid use. This drug is useful in accidental or intentional overdose and acute or chronic toxicity. Common substance overdoses treated with naloxone include heroin, fentanyl, carfentanil, hydrocodone, oxycodone, and methadone. The Centers for Disease Control and Prevention (CDC) issued an alert in October 2015 reporting an increase in fentanyl-related accidental overdose deaths due to illicitly manufactured fentanyl. In August 2016, the CDC updated its previous alert after a sharp rise in the availability of counterfeit opioid pills sold on the street containing varying amounts of fentanyl and other similar compounds.[2] A case report in the CDC's Morbidity and Mortality Weekly Report (MMWR) from February 2017 highlighted multiple cases of opioid overdoses in a short period in patients who believed they were using cocaine. This white powder was later determined to be fentanyl with trace amounts of cocaine, highlighting the need for healthcare providers to consider opioid co-ingestion, either known or unknown, in patients who appear to have taken other illicit drugs.[3] According to the American Heart Association (AHA), most opioid overdoses progress to out-of-hospital arrest (OA-OHCA) due to loss of airway patency and respiratory insufficiency. Therefore, alongside naloxone administration, it is crucial to address respiratory failure to stabilize the individual.[4]

Off-Label Uses

The naloxone challenge test involves administering this opioid-receptor antagonist to evaluate and quantify the level of physiological opioid dependence. The naloxone challenge is used to assess the absence of physical opioid dependence. Naloxone can be administered via intravenous, subcutaneous, or IM routes to patients who reported an adequate period of opioid abstinence and had a negative opioid urine test. A negative naloxone challenge does not guarantee that the patient will not experience precipitated opioid withdrawal upon naltrexone administration. This diagnostic tool is necessary when managing opioid use disorder (OUD).[5] The American Society of Clinical Oncology (ASCO) guidelines suggest using low-dose naloxone infusion in combination with other treatments to manage pruritus in patients with cancer.[6] Studies have shown that naloxone can be beneficial in treating chronic kidney disease-associated pruritus (CKD-aP); further research is needed to validate these findings.[7][8][9]

Mechanism of Action

Naloxone is a pure, competitive opioid antagonist with the highest affinity for the μ-opioid receptor, allowing for the reversal of opioid effects. Evidence indicates that naloxone antagonizes opioid effects by competitively binding to μ, κ, and σ-opioid receptors in the central nervous system (CNS), displaying the highest affinity for the μ receptor. At lower dosages, naloxone causes minimal blockade of δ and κ-opioid receptors while maintaining a significant blockade of μ-opioid receptors.[10] 

Pharmacokinetics

Absorption: The onset of action varies depending on the route of administration but can be as soon as 1 minute when delivered intravenously (IV) or intraosseously (IO). The bioavailability of nasal naloxone is about 50%. In most overdose cases, the reversal is observable within minutes. If no signs of reversal are apparent after the administration of 10 mg of naloxone, the clinician should consider the presence of coingestants like alcohol, benzodiazepines, cocaine, and methamphetamine.[11][12] Fentanyl overdoses often require higher doses of naloxone.[13]

Distribution: Naloxone is distributed extensively throughout the body and does cross the placenta. This drug binds weakly to plasma proteins, primarily albumin.

Metabolism: The metabolism of naloxone occurs via glucuronide conjugation in the liver.[14]

Excretion: Approximately 25% to 40% of naloxone is eliminated as metabolites in urine within 6 hours post-administration, with up to 70% excreted within 72 hours. Following intranasal administration, the plasma half-life of naloxone hydrochloride ranges from 1.85 to 2.08 hours in healthy adults, exceeding that of intramuscular injection (1.24 hours).

Administration

Available Dosage Forms and Strengths

Naloxone is usually administered intravenously. However, if IV access can't be achieved, it can also be administered via an intraosseous (IO), subcutaneous (SQ), intramuscular (IM), or intranasal (NAS) route. When administered intravenously, naloxone completely reverses the effects of opioids within a few minutes. Naloxone is available as an injectable solution in concentrations of 0.4 mg/mL and 1 mg/mL and a high-dose (5 mg/0.5 mL) prefilled syringe. An intranasal formulation of naloxone is available as a solution in concentrations of 3 mg/0.1 mL actuation, 4 mg/0.1 mL actuation, and 8 mg/0.1 mL actuation.

Adult Dosage

The dose is titrated to increase the patient's respiratory drive and allow for adequate spontaneous respiration and oxygenation, but not full reversal. This can result in withdrawal and include combative or aggressive behavior. A small initial IV dose (usually 0.04 mg to 0.1 mg) is recommended in patients who are opioid-dependent with symptoms of opioid overdose to avoid opioid withdrawal symptoms. Larger initial doses (such as 0.4 mg) are recommended in patients without a known history of opioid dependency. In patients who present with apnea or near-apnea with cyanosis, especially in the prehospital setting, providers should not hesitate to administer larger initial doses, such as 1 mg to 2 mg IV or 2mg intranasal, IM, or SQ. Clinicians can administer subsequent doses of 0.1 mg to 0.4 mg IV or 0.4 mg to 1 mg NAS, IM, or SQ in any opioid overdose patient until reaching the desired effect.[15][16]

Continuous Intravenous infusion (Off-Label)

Some patients may present after overdosing on long-acting opioids like methadone. In such cases, an intravenous drip of naloxone may be useful. Generally, clinicians can use two-thirds of the initial effective dose of naloxone (0.1 to 6 mg/h) as a bolus every 60 minutes or administer half the initial bolus dose 15 minutes after starting a continuous IV infusion; this maintains a consistently elevated dose of naloxone.

Endotracheal Administration(Off-Label)

Although emergency medical personnel and workers often administer naloxone via an endotracheal tube, there is little evidence to support the effectiveness of this mode of administration. In urgent medical scenarios with a patient in critical condition, endotracheal administration of naloxone may be necessary when alternative interventions are unavailable. Naloxone doses commonly administered in such circumstances range from 0.8 to 5 mg.

Intranasal Spray

Recently, the FDA approved the intranasal spray (NAS), which is available as an autoinjector. This device delivers 4 mg of naloxone and is usable by caregivers or family members. The initial spray provides 4 mg of naloxone. Since the NAS is recommended in non-healthcare professions, there are a few recommendations when using this agent to reverse opioid overdose:

• Immediately following the administration of the first NAS, caregivers should seek emergency medical assistance and not assume that the patient is fine, even if full mental recovery occurs.
• The overdosing individual requires close monitoring of their vital signs; repeat dosing may be necessary. If the patient relapses and the respiration rate decreases before emergency medical personnel arrive, it is appropriate to administer a second dose.
• If repeat dosing is necessary, it should be administered in alternating nostrils every 2 to 3 minutes.
• If the patient fails to respond to additional dosing, caregivers must be prepared to perform other resuscitative maneuvers, including CPR.
• The advantage of the NAS formula is that it eliminates the risk of accidental needle sticks or surgical contamination. Additionally, the NAS formula doesn't require needles or sharps disposal.

The key reason for the development of the NAS formula is to permit medically untrained individuals to safely administer naloxone with a good probability of reversing opioid-induced respiratory depression, especially if the patient has labored and shallow breathing. Unlike the parenteral route of administration, there is no need to worry about the accessibility of the peripheral veins, needlestick injuries, or disposal of sharps. However, even though NAS naloxone campaigns are widely promoted in most states, the price of this formula is still a major issue and might be a deterrent to widespread acceptance. Until a low-cost alternative is available, some consumers may not buy this product because of its expense, and the opioid epidemic will continue unabated.

Out-of-Hospital use

The administration of naloxone can reverse respiratory depression and prevent out-of-hospital cardiac arrest (OA-OHCA). The presence of miosis in a prehospital patient with altered mental status is highly indicative of responsiveness to naloxone.[4] According to the AHA, laypersons and others who cannot reliably confirm the presence of a pulse should initiate cardiopulmonary resuscitation in any individual who is unconscious and not breathing normally, with the additional recommendation to administer naloxone if opioid overdose is suspected.[4]

Dosage Modifications (Partial Opioid Agonists or Mixed Agonists/Antagonists): If the patient has overdosed on longer-acting opioids or partial agonists (eg, buprenorphine, pentazocine), the recovery may be incomplete, and higher doses of naloxone or repeated administration may be required. Repeat dosing of naloxone can be performed every 2 to 5 minutes. In some cases, the patient may benefit from an IV naloxone drip.

Dosing Considerations in the Emergency Department: Naloxone is not a substitute for emergency medical care, and clinicians must follow the trauma and ACLS protocol when resuscitating these patients. Providers should be aware that redosing of naloxone may be required after the first dose. Synthetic opioids (eg, fentanyl or carfentanil) are commonly implicated in overdoses, so providers should prepare to deliver larger total doses (at least 10 mg) of naloxone. This was highlighted in a paper from Jackson Memorial Hospital in Miami, Florida, which described a 119% increase in opioid overdoses over 3 months in 2016 compared to the same 3 months the previous year. There was a disproportionate increase in the amount of naloxone administered to patients during this period, with the number of naloxone vials used increasing by 476%. The authors credit this increase in naloxone use to a more potent synthetic opioid, such as fentanyl, being present in the heroin circulating through the area in 2016 compared to more traditional heroin in 2015.[17]

A continuous naloxone infusion may be necessary for patients in the emergency department who require multiple doses of naloxone and are being considered for admission. The typical dose for this infusion is two-thirds of the patient's wake-up dose per hour.

If the patient fails to respond to repeated doses of naloxone, providers must consider other causes of unconsciousness. After the acute treatment of the overdose, the patient should be enrolled in substance use disorder and encouraged to join rehabilitation.[18][19] According to the CDC 2022 guidelines:

• Clinicians are advised to exercise caution before escalating opioid dosages to 50 morphine milligram equivalents (MME) per day or higher. Evidence suggests that doses exceeding this threshold typically fail to significantly enhance pain relief for most patients while simultaneously increasing the risk of overdose. At this juncture, healthcare providers conduct a careful reassessment of the balance between the benefits and risks of continued opioid therapy.
• When a patient's total opioid dosage from all sources reaches or exceeds 50 MME/day, clinicians should implement additional precautions. These may include scheduling more frequent follow-up appointments and providing naloxone and overdose prevention education not only to the patient but also to their household members.[20]

Specific Patient Populations

Hepatic impairment: Patients suffering from opioid overdose often present with underlying chronic liver diseases such as alcoholic liver disease, hepatitis B, or hepatitis C. However, the use of naloxone does not seem to exacerbate these conditions.[14]

Renal impairment: Naloxone has been associated with the improvement of chronic kidney disease-associated pruritus (CKD-aP). A cautious and low-dosage approach is advised.[7]

Pregnancy considerations: As per the guidelines of the American Society of Addiction Medicine (ASAM), in the case of an overdose, naloxone administration is recommended during pregnancy. Additionally, it can be used along with buprenorphine/naloxone formulations for managing opioid use disorder since the naloxone component has minimal absorption when taken as prescribed. However, using naloxone to assess opioid dependence in pregnant women is not recommended as it may lead to potential risks like inducing withdrawal, which can cause preterm labor or fetal distress.[21]

Breastfeeding considerations: Naloxone is excreted into breast milk in minimal quantities, and due to its extremely low oral bioavailability, it is not detectable in the plasma of breastfed infants. Furthermore, naloxone has no impact on the levels of oxytocin or prolactin.[22]

Pediatric patients: Mortality resulting from unintentional overdose among adolescents peaked in 2020. The predominant cause of death (81%) was attributed to fentanyl and other synthetic opioids. Various life-saving interventions for adolescents, such as Medications for Opioid Use Disorder (MOUD) and harm-reduction strategies like naloxone, have been researched and proven effective.[23] 

Older patients: Older adults may exhibit decreased renal, hepatic, or cardiac function alongside polypharmacy, theoretically leading to increased systemic exposure to naloxone. According to the National Poison Data System Reporting, there is an increased prevalence of severe medical outcomes due to opioid exposure in older adults.[24]

Adverse Effects

The most common adverse effects associated with naloxone occur after acute withdrawal from opioids. These include anxiety, aggression, nausea, vomiting, diarrhea, abdominal pain, and rhinorrhea. In rare cases, the use of naloxone can precipitate noncardiogenic pulmonary edema. The incidence of naloxone-induced noncardiogenic pulmonary edema is estimated to be between 0.2% and 3.6% of patients who have received naloxone and are transported to the emergency department. Symptoms include persistent hypoxia despite the resolution of respiratory depression secondary to acute overdose. Patients may also have a cough productive of the classic "pink, frothy sputum," which indicates pulmonary edema. Chest radiography will be consistent with the findings of pulmonary edema. The onset of noncardiogenic pulmonary edema occurs within 4 hours in most patients. However, there have been case reports of delayed onset up to 8 hours after naloxone administration.[16][25] Naloxone is listed in the Key Potentially Inappropriate Drugs in Pediatrics: The KIDs List due to the increased risk of seizure. Therefore, it should be administered with extreme caution in neonates for postpartum resuscitation.[26]

Contraindications

There are no absolute contraindications to using naloxone in an emergency. The only relative contraindication is known hypersensitivity to naloxone.

Warnings and Precautions

CDC guidelines state that severe adverse reactions, such as pulmonary edema, cardiovascular instability, and seizures, have been documented but occur infrequently at dosages in line with those recommended for opioid overdose management.[20]

According to ASAM, the onset of maximal precipitated withdrawal typically occurs in the following scenarios:

• Within 1 minute following IV naloxone
• Several minutes after IM naloxone
• Up to several hours after the administration of extended-release injectable naltrexone [21]

Monitoring

Patients who overdose on opioids are at an increased risk of respiratory depression and hypotension. These patients should be resuscitated like any other patient and monitored. Additionally, naloxone administration can also trigger an acute withdrawal syndrome, which can present with the following symptoms:

• Nausea
• Diaphoresis
• Vomiting
• Tachycardia
• Cardiac Arrest

In chronic opioid users, naloxone requires slow administration to individuals who are dependent on opioids. All patients who have responded to naloxone should be continuously monitored for 6 to 12 hours since some opioids (methadone, fentanyl, buprenorphine) have a much longer half-life than naloxone. The half-life of naloxone in adults varies from 30 to 80 minutes. The patient's vital signs, including pulse oximetry, should be monitored until obtaining a full recovery. Even after reversing respiratory depression, the patient must be monitored for 6 to 12 hours because the patient may have ingested the longer-acting opioids, which will continue to exert their effects after excretion of the naloxone. Any patient who requires IV naloxone doses of more than 5 mg should be admitted.

For those whose respiratory depression is completely reversed with 0.4 to 2 mg of naloxone, observation in the emergency room for 2 to 4 hours is advised. If the patient is stable, discharge is recommended. In general, patients considered for discharge after reversal of the opioid overdose with naloxone should have:[27]

• A Glasgow coma scale of 15
• No need for additional naloxone doses
• An oxygen saturation of at least 92% on room air
• A respiration rate of no less than 10 breaths/min
• A pulse rate of no less than 50 bpm or no more than 120 bpm
• A blood pressure between 110/90 and 140/90 mm Hg
• Tolerance for clear liquids, ambulation, and have no withdrawal symptoms
• Someone to drive home and monitor the patient for the next 12 to 24 hours

Current Guidelines

Because of the current opioid epidemic, recent legislation has been passed in the United States that allows physicians to prescribe naloxone to patients with opioid use disorder to reverse the overdose. More than a dozen states have passed good samaritan laws that permit healthcare workers to prescribe naloxone to the family members or caregivers of patients with opioid use disorder. There are now nationwide campaigns to make naloxone easily available to the public, firefighters, police, and other professionals.[28][29] 

Naloxone storage

Naloxone is stored at room temperature and contained in a protective outer case. This type of packaging makes the product impact-resistant and easy to transport in the ambulance. The Substance Abuse and Mental Health Services Administration (SAMHSA) recommends that patients be prescribed an automatic injection device or nasal spray containing naloxone to ensure its accessibility at all times. Professionals should remember the necessity of replacing the medication upon expiration and if it has been exposed to temperatures below 3.8 °C (39 °F) or above 40 °C (104 °F). 

Discussion

Proper training by healthcare professionals can address any concerns about administering naloxone. Patients should be educated that once the pharmacological effects of naloxone have worn off, there is a possibility of respiratory depression.

Prescription Drug Monitoring Program (PDMP)

A Prescription Drug Monitoring Program (PDMP) is an electronic system that monitors prescriptions for controlled substances. PDMPs play a crucial role in identifying patients who may be at risk of overdose. PDMP data can be valuable when a patient's medication history is unavailable or during transitions to new healthcare providers. Utilizing the PDMP is a critical step in enhancing opioid prescribing practices. Healthcare providers should routinely review PDMP data to assess the opioid prescriptions and other controlled medications previously received by patients from different providers. PDMP helps in determining whether patients are receiving opioids or combinations (eg, opioids combined with benzodiazepines) that increase the risk of overdose.

As per CDC recommendations, implementation of PDMP should occur:

• When initiating the use of opioids to alleviate acute, subacute, or chronic pain
• Every 3 months or more frequently when continuing opioid therapy 

Toxicity

Signs and Symptoms of Overdose

The abrupt reversal of narcotic-induced depression through naloxone administration harbors the potential for adverse cardiovascular sequelae, including tachycardia, hypertension, and potentially cardiac arrest, especially in hypoxic states characteristic of narcotic overdose. Concurrent ingestion of substances like cocaine may exacerbate these risks. There have been reports of pulmonary edema occurring after the administration of naloxone. The precise mechanistic underpinnings remain unclear, although a centrally mediated surge in catecholamine levels, precipitating a substantial shift of blood volume into the pulmonary vascular bed and subsequent elevation of hydrostatic pressures, is postulated.[30] In one study, 36 patients with acute ischemic cerebral infarction received high doses of naloxone to assess potential efficacy and toxicity. All patients received a loading dose of 160 mg/m² followed by a 24-hour infusion of 80 mg/m²/h. While no statistically significant changes in group mean arterial pressure, respiratory rate, or heart rate were observed in response to the loading dose or infusion, clinically substantial changes occurred in 4 patients. Adverse reactions possibly related to naloxone were noted in 23 patients, with nausea being the most common, followed by bradycardia, myoclonus, and hypertension. Naloxone was discontinued in 7 patients due to possible adverse reactions, all resolved with cessation of naloxone and appropriate pharmacological intervention. No deaths were attributed to naloxone treatment.[31]

Management of Overdose

Patients who experience an overdose of naloxone should receive symptomatic treatment under close supervision. Physicians are advised to consult a poison control center for the latest information.

Enhancing Healthcare Team Outcomes

The past 2 decades have seen the development of many community education-based campaigns to educate the public about opioids. These community preventive programs are estimated to have averted over 10,000 opioid overdoses. A more recent pilot study reveals that an individual who has received overdose education versus those receiving overdose education and naloxone rescue kits does not differ in overdose rate, opioid use, or response to witnessed overdoses, indicating the usefulness of training regarding opioid overdose.

Unfortunately, the majority of opioid campaigns and education awareness programs are in urban areas. Similar campaigns must be started in rural areas, where the majority of opioid overdoses occur, to make any significant impact.

Even though making naloxone available as an over-the-counter drug is a useful and practical idea, concerns about administration remain. With the right resources and support, individuals who may want to self-administer naloxone can overcome any barriers to understanding the instructions. Empowering those in need and helping them take charge of their health and well-being is possible. The second issue pertains to the rapid onset of moderate-to-severe withdrawal symptoms. In many cases, the intensity of the withdrawal symptoms can be serious and warrant immediate medical attention.

Today, pharmacists and nurses have been educating the public at large about the consequences of opioid overdose and its management. Nurses have already been offering education in schools, colleges, and the workplace on the signs and symptoms of opioid overdose and when there is an indication for naloxone. More importantly, pharmacists are now educating the public who obtain narcotic prescriptions on the benefits of having naloxone in the home.[32][33] Patients should be educated that other modalities of pain management are safer and just as effective as opioids.

Outcomes

Naloxone has been used in the United States for over 50 years and has treated more than 10,000 opioid-related overdoses during this period. Unfortunately, despite its well-proven benefits and safety,  naloxone use is not accepted in all states. There is also a risk of developing withdrawal reactions following naloxone administration. Despite these concerns, naloxone is quickly gaining acceptance in mainstream American society, and the passage of the good samaritan laws has made it readily available as an over-the-counter drug.

Naloxone can reverse an opioid overdose. Consultation with addiction medicine specialists and psychiatrists is recommended for patients with opioid use disorder regarding the appropriate use of naloxone to improve patient outcomes.[34][35]