Opioid Crisis: Use of Opioid Antagonists Materials

OPIOID CRISIS: THE USE OF OPIOID ANTAGONISTS IN PREVENTING OPIOID OVERDOSE-RELATED DEATHS

The following continuing medical education team members were involved in the initial planning, development, and review of this activity:

Faculty:

L. Austin Fredrickson, MD, FACP 

L. Austin Fredrickson is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care.

Sandra Rogers, MD

Sandra Rogers is a primary care physician in Texas. She is board-certified through the American Board of Family Medicine and the American Board of Internal Medicine. She completed her dual residency at Eastern Virginia Medical School in Norfolk, Virginia. She has been practicing in Allen, Texas, for over 20 years.

Becca Resnik, RN

Becca Resnik received her nursing degree from Chattanooga State Community College. She has an MA in Translation Studies from the University of Birmingham, United Kingdom, and a BS in Nuclear Engineering Technology from Excelsior University, Albany, New York. Becca Resnik also has a Medical Writing Certificate from the University of Connecticut School of Pharmacy. Becca Resnik maintains an active Registered Nurse license.

Steven Malen, PharmD, MBA

Steven Malen graduated with a dual degree in Doctor of Pharmacy (PharmD) and Master of Business Administration (MBA) from the University of Rhode Island. Steven Malen has worked as a clinical pharmacist in the retail, specialty, and compounding sectors.

Pamela Sardo, PharmD, BS

Pamela Sardo is a freelance medical writer and licensed pharmacist. She is the founder and principal at Sardo Solutions in Texas. Pam received her BS from the University of Connecticut and her PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, and managed health care responsibilities across a broad range of therapeutic classes and disease states.

Topic Overview 

Approximately 75% of overdose deaths in the United States involve opioids. If these numbers are to be reduced, efforts must be made to rescue victims of opioid overdoses. Naloxone has been used for decades in patients experiencing an opioid overdose. Naloxone reverses life-threatening respiratory depression, hypotension, sedation, and analgesia caused by the ingestion of an excess opioid dose. Nalmefene is an additional long-acting FDA-approved opioid antagonist. Naltrexone is another opioid antagonist that attenuates or completely blocks, reversibly, the effects of opioids. Healthcare teams are an important part of the efforts to combat the current opioid crisis. Clinicians should familiarize themselves with the characteristics of each treatment, when to use each medication, and administration techniques for the nasal spray and auto-injector. This will enable them to educate patients and caregivers on the proper use of opioid antagonists and optimize outcomes.

Accreditation Statements

In support of improving patient care, RxCe.com LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credits for learning and change.

Joint Universal Activity Number: The Joint Accreditation Universal Activity Numbers assigned to this activity are as follows:

Pharmacists: JA4008424-0000-26-015-H01-P

Pharmacy Technicians: JA4008424-0000-26-015-H01-T

Credits: 3 contact hour(s) (0.3 CEU(s)) of continuing education credit.

Credit Types:

IPCE Credits - 3 Credits

AAPA Category 1 Credit™️ - 3 Credits

AMA PRA Category 1 Credit™️ - 3 Credits

Pharmacy - 3 Credits

Type of Activity: Knowledge

Media: Computer-Based Training (i.e., online courses)

Estimated time to complete activity: 3 contact hour(s) (0.3 CEU(s)), including Course Test and course evaluation.

Release Date: February 7, 2026 Expiration Date: February 7, 2029

Target Audience: This educational activity is for Physicians, Physician Assistants, Pharmacists, and Pharmacy Technicians

How to Earn Credit: From February 7, 2026, through February 7, 2029, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Study the section entitled “Educational Activity;” and

Complete the Course Test and Evaluation form. The Course Test will be graded automatically. Following successful completion of the Course Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

CME Credit: Credit for this course will be uploaded to CPE Monitor^® for pharmacists. Physicians may receive AMA PRA Category 1 Credit™️and use these credits toward Maintenance of Certification (MOC) requirements. Physician Assistants may earn AAPA Category 1 CME credit, reportable through PA Portfolio. All learners shall verify their individual licensing board’s specific requirements and eligibility criteria.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Identify risk factors for opioid overdose

Compare the indications for naloxone, nalmefene, and naltrexone in opioid use disorder

Apply strategies for preventing opioid overdose

Explain interprofessional team opportunities for educating patients regarding opioid overdose

Disclosures

The following individuals were involved in developing this activity: Sandra Rogers, MD; Becca Resnik, RN; Steven Malen, PharmD, MBA; and Pamela Sardo, PharmD, BS. None of the faculty members has a conflict of interest or financial relationship related to the subject matter of this activity, except that Becca Resnik discloses that she is an independent contractor (Translator/Engineer, 08/12/2024 to present) for Johnson & Johnson, Zuchwil, Switzerland, and DePuy Synthes. Any relevant financial relationships have been mitigated.

© RxCe.com LLC 2026: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity

Opioid Crisis: The Use of Opioid Antagonists in Preventing Opioid Overdose-Related Deaths

Introduction

Opioid-related overdose deaths make up three-fourths of all overdose deaths in the United States. The availability and use of opioid antagonist medications are vital to reducing the number of deaths from opioid overdoses. Opioid antagonist medications associated with preventing opioid overdose include naloxone, naltrexone, and nalmefene. Naloxone, an opioid receptor antagonist, is the most effective medication to reverse the effects of an opioid overdose. Naloxone is available in several formulations to facilitate efficient, timely administration. Nalmefene is now available as an intranasal spray; however, its safety is currently under review. Naltrexone is an opioid use disorder treatment, but it is most effective when used in patients participating in a comprehensive occupational rehabilitation program, a behavioral contract, or another compliance-enhancing protocol. Other opioid antagonists, such as methylnaltrexone and naldemedine, indicated for opioid-induced constipation, are beyond the scope of this activity.

Clinicians play a crucial role in prescribing, dispensing, and administering opioid antagonist medications to at-risk patients and educating them on their proper use. This course will discuss the opioid crisis, the use of opioid antagonist medications to reduce opioid overdoses, the barriers to co-prescribing opioid antagonist medications to patients, and changes that can be made to overcome these barriers.

Overview of the Opioid Crisis

The opioid 'endemic' or 'crisis' has been brewing and evolving for decades.^1,2 Its impact is global.²

In the United States, recent data show that a staggering number of Americans are experiencing serious consequences from this crisis. The brief history below describes a crisis that saw opioid overdose deaths top 75,000 in 2021, up from 56,064 in 2020.³ Increased deaths in 2021 were due in part to synthetic opioids, including fentanyl, illegally manufactured fentanyl, and the fentanyl analog, carfentanil.^3,4 The increases in deaths are not limited to a specific population group, and the rate of drug overdose deaths increased for all sexes, ages, and races.⁵ Xylazine, also known as “tranq,” was in approximately 23% of fentanyl powder and 7% of fentanyl pills seized in 2022, with up to 80% in some regional samples. Xylazine causes skin ulcers, bradycardia, sedation, difficulty breathing, and lowered blood pressure, which are worsened when combined with opioids.⁶ Medetomidine, a veterinary sedative 100x stronger than xylazine, appeared in Midwest and Northeast supplies in 2025, leading to a 134% increase in Philadelphia ED visits in Q1 2025.⁷

There is a glimmer of hope in the news regarding drug overdose death statistics: they are expected to show a decline in 2025. Nevertheless, opioid-related deaths are expected to continue making up approximately 75% of all drug-overdose deaths.⁸

Main Reasons for Opioid Misuse

Overdose deaths are driven in large part by substance use disorders.⁴ In the 2024 National Survey on Drug Use and Health (NSDUH), approximately 7.6 million people aged 12 or older in the United States misused prescription pain relievers, of which 4.8 million had an opioid use disorder.⁹ The opioid use disorder included heroin and prescription opioid pain relievers.⁹ Opioids include prescription medications that are used to treat pain, such as morphine, codeine, methadone, oxycodone, hydrocodone, oxymorphone, fentanyl, hydromorphone, tramadol, buprenorphine, and Demerol^®, as well as illegal drugs such as heroin and illicit potent opioids such as illegally made fentanyl.⁹ The 2024 NSDUH found that hydrocodone products were the most commonly misused subtype of prescription pain relievers, followed by oxycodone products.⁹

The 2024 NSDUH surveyed respondents who misused prescription pain relievers to learn the reason they misused their last medication. The top responses included relieving physical pain, feeling good or getting high, being “hooked,” and relaxing and relieving tension.⁹ Less common reasons for misuse were to help with feelings and emotions, to help with sleep, to experiment, and to increase or decrease the effects of other drugs.⁹

A Brief Overview of Appropriate Opiate Use Indications

Opioids have analgesic and sedative effects and are most commonly used for the management of acute pain (e.g., post-operative pain), cancer pain, and chronic non-cancer pain, usually in the context of palliative care.¹⁰ Opioids such as methadone and buprenorphine may also be used for the maintenance treatment of opioid use disorder.¹¹

Opioid Use Dependence and Addiction

Physical dependence does not necessarily mean addiction.^12-14 The American Psychiatric Association’s DSM-5 committee removed the diagnosis of “addiction” in DSM-5 and replaced it with “opioid use disorder, moderate to severe.” The DSM-5 has also removed “opioid abuse” and replaced it with “opioid use disorder, mild.”^13,14 The term “opioid dependence” is used by the World Health Organization and the ICD-10.^2,13

Risk Factors for Opioid Overdose

Any patient on an opioid is at risk of overdose.¹² Not all opioid overdoses are fatal, with non-fatal overdoses being several times more common than fatal overdoses.¹⁵ There are identified risk factors for an opioid overdose.^15,16 Risk factors for an opioid-related overdose fall into six general categories: “patient demographics, mental health comorbidities, substance use disorders, physical health comorbidities, characteristics of opioids prescribed, and non-opioid medications prescribed.”¹⁵ Other factors to consider include a patient’s insurance type, reduced drug tolerance, and the method of drug administration.¹⁶ The breadth of these factors points to the importance of considering a patient’s entire clinical picture. Registered Nurses (RN), for example, should collect such data during a comprehensive assessment.

Patient Demographics

The published data on patient demographics are not in agreement. Weiner, et al. (2022) reported that patients who were at the highest risk of an overdose were ≥75 years of age or 18-24 years of age.¹⁶ Hedegaard, et al. (2020) reported the opposite, as national data showed that in 2019, individuals 65 years or older had the lowest rates of drug overdose deaths compared with other age groups.⁵

Race and ethnicity are also relevant. Black patients were at a significantly higher risk of an opioid overdose.¹⁶ Asian or Pacific Islander patients had a significantly lower risk of opioid overdose compared with White patients. Hispanic patients also had a lower risk for an opioid overdose; however, there are studies showing that opioid prescriptions are less likely to be prescribed to Asian or Pacific Islander, and Hispanic groups.¹⁶

Mental Health Diagnoses

Mental health diagnoses, especially mood and thought disorders, are associated with an increased risk of overdose.¹⁵ A psychiatric diagnosis of depression is also associated with a greater risk.¹⁶

Substance Use Disorders

A previous substance use disorder is a risk factor for an opioid overdose.^15,16 This includes substance use disorders such as opioid use disorders, non-opioid drug use disorders, alcohol use disorders, and tobacco use disorders.¹⁵

Medical Comorbidities

Medical comorbidities increase the risk of an opioid overdose, especially in patients with three or more comorbidities.^15,16 These comorbidities include chronic pain, lung disease, cardiovascular disease, diabetes, and cancer.^14,15

Opioid Prescription Characteristics

Patients prescribed higher doses, on longer treatment durations, and who are prescribed long-acting or extended-release opioid formulations are at greater risk of an opioid overdose.¹⁵

Patients may also be at greater risk of an overdose if they receive overlapping prescriptions, receive opioids from multiple prescribers or pharmacies, or live with a person taking prescription opioids.¹⁵ Concurrent use of benzodiazepines, or other non-opioid controlled substances, is also a confirmed risk factor for opioid-related overdose. Nurses and pharmacy technicians should perform a medication reconciliation when appropriate, such as when a patient transfers care facilities. This practice can help prevent unnecessary and potentially dangerous concurrent prescriptions.

Insurance

A patient’s insurance type may also be associated with an opioid overdose risk.¹⁶ In a cohort study of 236,921 opioid-naive patients, those eligible for Medicaid and Medicare Advantage had the highest risk. Patients on Medicaid had a 4-times greater risk of an opioid overdose compared with patients on private insurance.¹⁶

Reduced Tolerance and Other Factors

When tolerance declines after a period of abstinence, the risk of an opioid overdose increases.¹⁷ Common situations where reduced tolerance may be seen are after release from incarceration, discharge from a facility, or cessation of drug dependence treatment.¹⁷ The risk of overdose is significantly higher when doses are prescribed equal to or greater than 100 mg morphine equivalents per day.¹⁸ Overdose risk factors also include those taking higher prescribed dosages, male gender, mental health disorders, lower socioeconomic status, and household members of people in possession of strong opioids.¹⁹ Extended-release opioids carry a higher risk of overdose compared to immediate-release opioids.⁹ Individuals taking opioids by injection, combining alcohol and/or other substances such as benzodiazepines, and who are using opioids without medical supervision, are also at an increased risk of opioid overdose.^9,20

Mechanisms and Symptoms of Opioid Overdose

During an opioid overdose, respiration is depressed through a number of mechanisms and neuronal sites of action.²⁰ Opioids act at mu, delta, and kappa receptors throughout the body. Activation of mu-opioid receptors in specific sites in the central nervous system that control the respiratory rhythm-generating area in the pons induces respiratory depression.²¹ Opioids depress both rate and depth of breathing, with the most pronounced effect in individuals with chronic cardio-pulmonary and renal disease, as these individuals may already have diminished respiratory response.

Opioid overdose requires immediate emergency attention, and everyone, including the public, should know the signs of opioid overdose. These signs include combinations of the following symptoms: pinpoint pupils, body going limp, face extremely pale, feeling clammy to the touch, lips or fingernails having a purple or blue color, vomiting or making gurgling noises, the person cannot be awakened, unable to speak, breathing slows or stops, or heartbeat slows or stops. In the case of opioid overdose, 911 should be called immediately, and if naloxone is available, it should be administered to reverse the opioid overdose. If the person has stopped breathing, CPR should also be performed.^22,23 Most opioid overdoses occur in private homes and are sometimes witnessed by friends, a partner, family members, or coworkers. Ensuring individuals are educated and equipped with the tools and knowledge to recognize and prevent overdose death is a critical life-saving measure.

Link to SAMHSA Overdose Prevention and Response Toolkit23 https://library.samhsa.gov/sites/default/files/overdose-prevention-response-kit-pep23-03-00-001.pdf

Prevention of Opioid Overdose

To decrease the risk of opioid overdose, medication should always be taken as prescribed by the practitioner. Overdose may happen if a patient takes higher doses than prescribed or takes the medication more frequently than instructed. An overdose can occur if a patient takes the amount prescribed by the provider, but the dose has been miscalculated. Mixing pain medication with alcohol, sleep medication, or illicit substances is also a common cause of opioid overdose. Healthcare professionals should take extra caution when prescribing and dispensing opioid medications to ensure the correct drug, dose, and instructions are dispensed to the patient. Electronic health records, prescription records, and prescription drug monitoring databases should be checked to be sure there are not multiple opioid prescriptions for an individual that may increase the risk of overdose.²⁴

Many opioid overdoses are preventable. Caution should be taken when storing these medications, as it is easy for children or pets to unintentionally ingest medication, which may lead to overdose. Accidental overdoses have been reported due to improper medication storage. When medications are no longer needed, disposing of medications safely can help prevent overdose situations. The U.S. Food and Drug Administration (FDA) website lists permanent collection locations and periodic medication take-back events to help patients dispose of unused medication.²⁵

Medications for Opioid Use Disorder (MOUD)

Medications for Opioid Use Disorder (MOUD) is a treatment approach used to treat opioid use disorder.²⁶ The trend is for MOUD to replace Medication-Assisted Treatment (MAT).^27,28 This change is supported by research showing that these medications provide effective, tangible benefits to people with an opioid use disorder. Treatments should be individualized and centered on the core component of MOUD.²⁷

According to the Substance Abuse and Mental Health Services Administration, MOUD has been proven to be clinically effective and significantly reduces the need for inpatient detoxification services.²⁹ The prescribed medication operates to normalize brain chemistry, block the euphoric effects of alcohol and opioids, relieve physiological cravings, and normalize body functions without the negative and euphoric effects of the abused substance. FDA-approved medications for opioid use disorder used in MOUD include buprenorphine, methadone, and naltrexone.²⁹ When a person is using naltrexone for MOUD, they may have a reduced tolerance to opioids, making the same or even lower doses of opioids that they had used in the past fatal if they relapse.³⁰ Therapy should be individualized for each patient, with the lowest dose and frequency used to treat the condition.^11,30

Responsible Prescribing of Opioids

The lowest effective dose, frequency, and duration should always be prescribed, and the evidence of individual medication risks and benefits should be carefully reassessed.²⁴ When treating acute pain, three or fewer days of medication are often sufficient, and more than 7 days of therapy are rarely needed. When starting therapy for chronic pain or during dose escalation, clinicians should evaluate benefits and harms with patients within 1 to 4 weeks of dose changes and continue to assess the patient every 3 months, unless more frequent assessments are warranted.²⁴ A thorough review of a patient’s history should also be completed to ensure safe treatment with opioids. Naloxone prescription availability, overdose prevention education, and basic risk reduction messaging are important. Naloxone remains the medication of choice in these situations. Risk reduction strategies may include reviewing information about other medications a patient is taking and educating the patient that mixing medications can be fatal. Prescribers may also suggest that patients create an “overdose plan” that includes signs of overdose, how to administer naloxone, and to call 911 and share that information with friends, partners, and/or caregivers.³¹

When prescribers are dispensing opioids, several factors, including tolerance to opioids, degree of analgesia desired, environment, risk factors for severe opioid use disorder, misuse, and the physical and medical status of the patient, should be assessed.¹¹

Treating Opioid Overdose with Opioid Antagonists

Opioid Antagonist Highlights Opioid antagonist medications associated with preventing opioid overdose include naloxone, naltrexone, and nalmefene.32 Naloxone, an opioid receptor antagonist, is the most effective medication to reverse the effects of an opioid overdose. Naloxone is available in several formulations to facilitate efficient, timely administration.33-35 Nalmefene was introduced as a treatment for patients with confirmed opioid overdoses requiring repeated doses of naloxone.36 Its usefulness was due to its prolonged antagonism of opioid effects.36 Nalmefene is now available as an intranasal spray;37 however, safety data continues to be gathered and assessed.38 Current consensus states that nalmefene should not replace naloxone as the primary opioid overdose antidote at this time.39 Naltrexone is an opioid use disorder treatment, but it is most effective when used in patients participating in a comprehensive occupational rehabilitation program, a behavioral contract, or another compliance-enhancing protocol. Naltrexone may have a role as an antidote to the highly potent, synthetic opioid carfentanil.32

Naloxone for Suspected Opioid Overdose

All patients prescribed opioids should have the option to have naloxone readily available, as they all have a risk for opioid overdose. Both pharmacists and providers can open the topic of discussion with patients on the risks of opioid therapy as well as the benefits of readily available naloxone.^9,40

Increasing access to naloxone, so it is readily available when needed, is vital to combating the opioid crisis. A 2025 meta-analysis found community-based naloxone distribution programs effective in preventing opioid overdose deaths.⁴⁰

Naloxone Mechanism of Action

The timely administration of naloxone can help prevent opioid overdose-related deaths.^33,34,40 Naloxone displaces opioids from receptor sites in the brain and reverses respiratory depression, hypotension, sedation, and analgesia.^33,34 Naloxone is thought to antagonize mu-, kappa, and delta receptors, inhibiting both the toxic and clinical effects of opiates.^33,34 The antagonistic effect of naloxone is competitive and short-lived, sometimes necessitating repeat doses when long-acting opiates are involved. Naloxone is only effective when treating opioid overdose and is not effective in treating overdoses of benzodiazepines, barbiturates, clonidine, GHB, ketamine, or stimulants when used alone.²³ If a patient has not recently received opioid drugs, administration of naloxone shows little or no pharmacological effects and will not worsen respiratory depression if administered for a non-opiate overdose.⁴¹ Naloxone itself produces no physical or psychological dependence.^33,34

Naloxone is not a replacement for emergency care, and 911 should always be called when naloxone is administered.²³ Multiple doses of naloxone may need to be administered during an opioid overdose. Monitoring is necessary to ensure that the respiratory depressant effects of the opiate do not outlast the beneficial effects of naloxone. Naloxone products are effective in reversing opioid overdose, which includes fentanyl-involved overdose, although this may require a higher dose of naloxone.^23,41

Naloxone Formulations

The FDA-approved routes of administration of naloxone for treating opioid overdose include intravenous, intranasal, intramuscular, and subcutaneous.^23,42 In emergencies, naloxone may be administered off-label via intraosseous or endotracheal routes.⁴² Intranasal naloxone and naloxone auto-injectors that deliver a therapeutic dose of naloxone in an overdose situation are specifically helpful for overdose in the community setting, i.e., outside of a medical setting.⁴² The administration information for the formulations available for community use will be discussed below.

Naloxone Administration Information

If an opioid overdose is suspected, the following protocols should be followed:^41,43

Call 911

Give naloxone

Remain with the patient for several hours, or longer as clinically indicated

Offer MOUD, Medications for Opioid Use Disorder, the same day

When administered correctly, the response to naloxone is returning to spontaneous breathing and mild opioid withdrawal symptoms. The response generally occurs within 2 to 3 minutes of naloxone administration, but may take up to 15 to 20 minutes to reach maximal effects on breathing.²³ More than one dose may be required, especially in those who have taken longer-acting opioids or opioid partial agonists. Patients should be monitored for several hours as clinically needed.⁴⁵ Most opioids have longer-lasting effects than naloxone, potentially necessitating multiple doses of naloxone as well as emergency medical care.^23,46 It is important to remember that naloxone is not effective for overdoses caused by benzodiazepines, barbiturates, cocaine, amphetamines, and other stimulants.²³ Naloxone can be used on patients even if it has been used before, as tolerance cannot be developed to the effects of naloxone.^47,48 Outside of opioid overdose, naloxone has been used in oral administration to treat opioid-induced constipation and pruritus.

Video: Administering Various Dosage Forms44 https://www.ama-assn.org/public-health/behavioral-health/how-administer-naloxone

Naloxone nasal spray is a convenient administration form for caregivers and family members.^33,34 Naloxone nasal spray should be administered as quickly as possible in a patient with a suspected opioid overdose. To administer the nasal spray, hold the device with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle. The patient should be placed in the supine position, and the nozzle should be inserted into one of the patient’s nostrils, with support for the back and neck to allow the head to tilt back. Press the device plunger firmly to administer the dose. No priming or testing is necessary; doing so may be detrimental, as it could waste a dose. After administering the first dose, the patient should be turned onto their side, and immediate medical assistance should be called. Each device only holds a single dose, and a new nasal spray device can be re-administered every 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression while waiting for emergency medical services (EMS). If more than one dose is administered, the doses should be given in alternate nostrils. The over-the-counter naloxone formulation (Narcan^Ⓡ) is 4 mg, and the prescription naloxone formulation (Kloxxado^Ⓡ) is 8 mg, and both are available in 0.1 mL single-use nasal spray bottles.^33-35 Although the prescription naloxone formulation has a higher dose, there is limited evidence suggesting any superiority, and more concern about severe withdrawal symptoms. The 4 mg over-the-counter formulation is more readily available.³⁵

Rezenopy^Ⓡ (naloxone 10 mg nasal spray) represents the highest-dose intranasal formulation of naloxone approved by the FDA in April 2024 for the emergency reversal of known or suspected opioid overdose.⁴⁹ The escalated dosing in the 8 mg prescription formulation and 10 mg naloxone formulation addresses the challenges posed by potent synthetic opioids, which may require higher naloxone amounts for effective reversal compared to traditional opioids, potentially minimizing the need for repeated doses in severe cases.⁵⁰ However, clinicians must remain vigilant for dose-dependent risks such as precipitated withdrawal symptoms, and post-reversal monitoring is essential to ensure patient stability and facilitate linkage to ongoing addiction treatment.

Intramuscular injection with auto-injectors is another administration option for caregivers and families.⁵¹ These products should be inspected periodically to ensure they do not need to be replaced—the solution should be clear and replaced if discolored. To administer auto-injector products, the needle cap must be removed, and medication should be administered intramuscularly into the anterolateral aspect of the thigh. This may be done through clothing if necessary. The needle should be completely embedded before pushing the plunger. Once embedded in the patient, the caregiver should press the plunger firmly down until it clicks, then hold it in place for 2 seconds. Immediately after injection, the safety guard should be slid over the needle using one hand, as the needle will be exposed until the safety guard is deployed. It is normal to see some of the medication remaining in the syringe. As long as the plunger has been pushed all the way down during delivery, the correct dose has been injected. Each device contains a single dose of naloxone, and doses may be repeated every 2 to 3 minutes as needed to achieve the desired response until emergency medical assistance arrives.

The typical shelf life of naloxone products is 12 to 18 months. Risk factors for decreased potency include excessive heat, cold, or sunlight. Like most medications, naloxone should be stored at room temperature in a cool, dry place, away from direct sunlight. The medication’s potency may decrease if it has not been stored properly. When deciding where to store naloxone, remember it should be readily accessible in an emergency. Store it properly while ensuring quick access when needed. Expired naloxone should be replaced.^33,51

Naloxone in Pregnancy

The available data on naloxone use in pregnant women is limited.⁵¹ Naloxone prescribing information states that the risk of major birth defects, miscarriages, or other maternal or fetal adverse outcomes is unknown.⁵¹ There is insufficient data to inform a patient of a drug-associated risk.⁵¹

Treatment with naloxone for opioid overdose should not be withheld because of potential concerns regarding the effects of naloxone on the fetus.⁵² Opioid overdose is a medical emergency and can be fatal for the pregnant woman and fetus if left untreated.⁵²

Studies in breastfeeding mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels.⁵¹ Naloxone is excreted into breast milk in very small amounts and was not detectable in the plasma of breastfed infants.^51,53 The developmental and health benefits of breastfeeding, along with the mother’s clinical need for naloxone and any potential adverse effects on the breastfed infant from naloxone, should be considered.⁵¹ All of these points are critical for clinicians not only to understand in the context of providing care, but also to communicate during patient teaching.

Adverse Effects Associated with Naloxone Rescue Therapy

Naloxone has minimal adverse effects beyond the induction of opioid withdrawal symptoms and has essentially no pharmacological activity if opioids are not present in the system. The most commonly reported adverse reactions associated with intranasal naloxone include increased blood pressure, musculoskeletal pain, abdominal pain, constipation, dizziness, and headache. Individuals may also experience nasal symptoms, including dryness, swelling, congestion, and inflammation. Agitation was reported during post-marketing use of the naloxone auto-injector, along with mild injection-site reactions.⁹

Signs and symptoms of opioid withdrawal that can be triggered by naloxone rescue therapy can feel unpleasant and may include agitation or confusion, body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering, trembling, abdominal cramps, weakness, tearing, insomnia, opioid craving, dilated pupils and increased blood pressure.^51,54

Nalmefene: A Novel Opioid Antagonist for Overdose Reversal and Alcohol Management

Nalmefene is an opioid receptor antagonist. Nalmefene is marketed in a nasal spray formulation under the trade name OPVEE^®.³⁷ It is primarily used to treat opioid overdose and reduce alcohol consumption in adults with alcohol dependence. For overdose reversal, it counters life-threatening effects such as respiratory depression and low blood pressure, offering a longer duration of action than naloxone. It is available as a nasal spray or injectable forms (intramuscular, subcutaneous, or intravenous).³⁷

Nalmefene may be advantageous against long-acting or potent synthetic opioids like fentanyl (e.g., carfentanil);³² however, a more prolonged observation may be needed for nalmefene because of its longer-acting mechanism.^36,38 Prolonged observation is needed because nalmefene can trigger more severe withdrawal symptoms, leading to caution from some experts.

Common side effects include nausea, vomiting, dizziness, headache, insomnia, fatigue, tachycardia, hypertension, restlessness, and confusion.³⁷ In opioid-dependent individuals, it may precipitate intense withdrawal symptoms like body aches, diarrhea, fever, and abdominal cramps. Unlike opioids, nalmefene has no agonist activity and no abuse potential, and is not a controlled substance. Compared with naloxone, its extended half-life and stronger receptor affinity enhance efficacy against fentanyl but may intensify withdrawal.³⁷

The joint position statement from the American College of Medical Toxicology (ACMT) and the American Academy of Clinical Toxicology (AACT) asserts that nalmefene should not replace naloxone as the primary opioid antidote amid the ongoing opioid crisis.⁵⁵ While the FDA approved intranasal nalmefene for emergency overdose reversal, citing its longer half-life (7.11 hours vs naloxone's 2.08 hours intranasally) and higher opioid receptor affinity, the statement highlights limited clinical data and a lack of real-world evidence for its intranasal form or efficacy against fentanyl. Concerns include potential for prolonged precipitated withdrawal symptoms, extended observation periods up to several hours to monitor for re-sedation, increased emergency department resource strain, and higher cost ($98 for a 2-pack vs. $65-75 for naloxone).⁵⁵ The statement recommends that naloxone continue to be the first-line agent and that further studies be conducted on nalmefene’s safety and effectiveness in overdose settings.⁵⁵

Naltrexone and Overdose Reversal

Naltrexone is more commonly used as an opioid use disorder treatment, not as an emergency treatment for a suspected overdose. However, naltrexone is being studied as a potential antidote to the highly potent, synthetic opioid carfentanil.³² Naltrexone exhibited an approximate 65-times higher potency to inhibit carfentanil but not fentanyl compared to naloxone.³² Clinicians should monitor the progress of this research.

Co-Prescribing Recommendation

The CDC recommends co-prescribing naloxone to every patient on at least 50 MME/day or with benzodiazepine co-use, or those with a history of overdose, substance use disorder, or sleep-disordered breathing.⁵⁶ Evidence indicates that patients co-prescribed naloxone had significantly fewer emergency department visits.^57,58 Patients co-prescribed naloxone also had lower-risk opioid use behaviors.⁵⁸

Despite these positive results, naloxone co-prescribing has remained low nationally, with less than 2% of high-dose opioid prescriptions being co-prescribed naloxone.⁵⁷ Most physicians (65.42%) reported never intending to co-prescribe naloxone to patients.⁵⁸ Only 18.64% of physicians reported always intending to co-prescribe naloxone.⁴⁹ In the pharmacy setting, nearly half of pharmacists reported never intending to discuss co-dispensing naloxone. Only 21.51% reported they would always discuss co-dispensing.⁵⁸ This means that there are barriers to co-prescribing and room for improvement.^57,58

Barriers to Preventing Prescription Opioid Overdoses

Barriers to naloxone dispensing include limited education and training, workflow constraints, and insufficient management support. It is also helpful to be educated on medication disposal sites.^59,60 Clinicians should educate patients on the efficacy of naloxone compared with other ineffective methods, such as cold water.⁶⁰ They can request a provider referral for help with substance use disorder. Caregivers and other responsible adults in the patient’s household should be present if possible during patient teaching.

As described above, current guidelines recommend co-prescribing opioid antagonists for patients taking opioids, but barriers to co-prescribing remain.^58,61 They include a lack of knowledge of overdose risk factors, the fear that the patient will be “stigmatized” if the prescriber co-prescribes an opioid antagonist, and the cost of co-prescribing.^58,61 The stigma associated with opioid use disorder (OUD) remains a substantial barrier, discouraging individuals from seeking or continuing treatment.

Overcoming Barriers

As the 50 states implement policies to increase access to naloxone and remove barriers to its use, it is essential that all healthcare team members are equipped to address training gaps and ensure the safe, proper administration of naloxone by patients and families.^62,63 Clinicians and patients should be educated about the benefits of co-prescribing naloxone.⁶² Health systems can pursue proactive approaches such as implementing co-prescribing prompts into electronic health records.^57,62,64

Increasing access to naloxone can also overcome barriers to its use. As of 2025, all 50 states sell naloxone without a prescription.⁶⁵ Patients and families should also be counseled by members of the healthcare team on the safe storage and disposal of opioids, especially in the case of children in the home.²⁹

What can Physicians and Physician Assistants do to Reduce Prescription Opioid Overdoses?

Prescribers should be prepared to have open conversations about the risks of opioids and accidental overdose, especially when they are mixed with other medications such as benzodiazepines.^58,66 More frequent, routine discussions and prescriptions help reduce stigma and can make providers more comfortable and patients more informed. Many states and the Centers for Disease Control offer educational resources to help providers learn how to have meaningful conversations with patients and families.

Prescribers should always use their state’s prescription monitoring program, if available, to monitor the timing of fills and possible interactions with medications from other clinics. Providers are encouraged to use a short supply of medication if possible and to monitor for use with drug and alcohol screening if appropriate. Patients should be screened for signs of Opioid Use Disorder frequently. When a prescriber identifies a patient who is at high risk of opioid overdose, the prescriber should co-prescribe naloxone and instruct the nurse to teach overdose recognition. Further instruction on when to call 911 is also critical.

Increasing patient education and safety is often successful when patients receive information on opioid safety, recognizing overdoses, and how to administer opioid antagonists. Patient handouts are available for sending home to reinforce education on naloxone recommendations and use. Using an interprofessional care model, improving training, and normalizing naloxone access can ensure opioid antagonists are considered a standard of care.

What can Nurses do to Reduce Prescription Opioid Overdoses?

The pillar of nursing practice is assessment, which is no exception when it comes to the nurse’s role in helping prevent opioid overdose. RNs and APRNs (Advanced Practice Registered Nurses) should assess patients for their pain status and pain management history alongside risk factors and signs of substance use disorder. As a means of expeditious assessment, nurses can use screening tools such as the ORT-OUD, published by the National Institute on Drug Abuse.⁴¹ A comprehensive assessment to look for cues such as traumatic lesions or periodontitis can feed into the overall clinical picture that could cause the nurse to suspect substance abuse. Building rapport starting from the first contact can help the patient feel confident in being forthcoming and providing honest responses to assessment questions.^41,67,68

Registered nurses suspecting substance use disorder can initiate the process of obtaining a provider referral for mental health counseling. Nurse Practitioners (NP) with specialized training and credentials can diagnose and treat conditions such as substance use disorder. Accordingly, even beyond the scope of practice of RNs, NPs can follow the principles of this activity’s guidance for physicians, physician assistants, and pharmacy teams to prevent opioid overdose.^67,69

If a patient is about to begin opioid therapy or if there are risk factors but no signs of substance use disorder, the nurse can take a more proactive approach. Education, another pillar of nursing practice, is one of the most effective tools for doing so. When deemed necessary, nurses should teach patients about substance use disorder itself in addition to nonopioid and nonpharmacological pain management measures. After a thorough assessment for the presence of contraindications, the nurse can teach the patient how to safely and effectively use non-steroidal anti-inflammatory drugs (NSAIDs) as an initial or adjunctive pain management option. Nonpharmacological methods of pain management that the nurse can recommend include meditation, physical therapy, and massage therapy.^67,70

What can Pharmacy Teams do to Reduce Prescription Opioid Overdoses?

Utilizing prescription drug monitoring programs is a valuable way to aid in decreasing opioid overdose and assessing if a patient is using multiple pharmacies or providers.⁷¹ Counseling on opioid prescriptions, as well as providing Medication Guides (MedGuides) to patients, may be helpful, especially in cases where patients may be unaware of the risks of opioids or upon initiation of a new medication or increased dosages of either opioids or other concomitant high-risk medications.⁷² Monitoring medication therapy regimens for high-risk combinations, such as benzodiazepines or muscle relaxants, and identifying other medical conditions, such as lung disease, is very important for pharmacists, especially when patients may be using multiple prescribers. If a patient is on a treatment agreement, or “pain contract,” it is important to follow and maintain all its guidelines.⁷³ The agreement may include a provision that the patient agrees to have only one prescriber and one pharmacy.⁷³ As mentioned above, patients and families should be counseled on the safe storage and disposal of opioids.^29,74 Pharmacists may also keep an open dialogue with providers and alert them to potential prescription misuse and interactions that may increase overdose risk.^29,62,71

Naloxone may be provided to the patient or a third party (family member, friend, etc.) with or without a prescription from a prescriber, under protocols, legislation, or standing orders. State access rules and valuable resources on naloxone are available at www.safeproject.us and in individual state laws.^56,65 Three legal frameworks provide access to naloxone: Good Samaritan laws, liability protection/third-party administration laws, and collaborative practice agreements.^75,76 The Good Samaritan law protects individuals who call for help at the scene of an overdose from being arrested for drug possession.^75,76 The liability protection/third-party administration protects the bystander and prescriber who administer the naloxone and allows for bystanders to obtain a prescription for naloxone to use on others.^75,76 Collaborative practice agreements can be done with individual physicians or on a statewide basis, allowing pharmacists to prescribe naloxone to at-risk individuals.⁷⁵

Patient Case

Mr. A, a 27-year-old man with a history of opioid use disorder, was found unconscious at home by a family member. The family member reported seeing pinpoint pupils, observed shallow breathing, and limp extremities before loss of consciousness.

Pause and Ponder What is the next action?

The family member has naloxone at home but was afraid to use it. The family member called 911. Emergency medical services arrived in 4 minutes, and the EMS staff administered 2 mg of naloxone intranasally en route to the emergency department. The patient regained consciousness within minutes but was drowsy for several hours.

Pause and Ponder What should be the next action taken at the hospital?

In-hospital evaluation revealed vital signs had stabilized; oxygen saturation improved from 88% to 98% on supplemental oxygen. There were no signs of trauma or head injury. Urine drug screen was positive for opioids. After initial reversal, the patient was observed for recurrent respiratory depression as the naloxone effect waned. No adverse events were noted.

Pause and Ponder What should be the next action before discharge?

The patient should be monitored for withdrawal symptoms, agitation, or agitation-related complications. The physician may discuss implementing a “pain contract.” The patient should be evaluated for any underlying factors contributing to the infection or psychiatric needs. Overdose prevention education should be provided, including take-home naloxone training for family and caregivers. Emergency medicine clinicians may choose to initiate MOUD during this visit or ensure a timely referral for MOUD treatment.. The interaction and shared decision-making should be entered into the patient’s medical record.

Naloxone Executive Clinical Summary

Opioid-related overdose deaths make up three-fourths of all overdose deaths in the United States. These numbers are being driven by an increase in deaths from synthetic opioid overdoses, especially from fentanyl. The availability and use of opioid antagonist medications are vital to reducing the number of deaths from opioid overdoses. Opioid antagonist medications associated with preventing opioid overdose include naloxone, naltrexone, and nalmefene.

Any patient on an opioid is at risk of overdose. However, there are risk factors related to a patient’s demographics, mental health, substance use disorder history, physical health comorbidities, opioid and non-opioid prescriptions, type of insurance, and drug tolerance, as well as the manner of drug administration.

During an opioid overdose, respiration is depressed through several mechanisms and neuronal sites of action. Naloxone can reverse these mechanisms when administered properly and promptly.

Physicians, pharmacy teams, nurses, and other clinicians play a crucial role in the current opioid crisis. They should familiarize themselves with administration techniques for the nasal spray and auto-injector to help educate patients and caregivers on the proper use of naloxone.

Highest risk patients:

Prior diagnosis of OUD or overdose

Higher quantities of opioids (>50MME/day)

Overlapping prescriptions of CNS-affecting medications

Multiple prescribers

Live with a person taking opioids

Chronic lung diseases or sleep disorders (sleep apnea)

Co-occurring substance use disorders

Mental health co-occurring disorders

Long-acting or injectable opioid use

Physical Exam Findings during overdose:

Respiratory depression (slow, shallow, irregular, or no breathing)

Cyanosis

Pallor/clamminess

Pinpoint pupils

Decreased mentation or unresponsiveness

Immediate treatment:

Call 911

Give Naloxone

Support ABCs

Repeat naloxone if needed (q2-3 minutes if needed)

Extended Treatment:

Monitor for at least 2 hours until clinically stable

Monitor with withdrawal, agitation, aspiration

Prescribe or distribute naloxone

Prescribe or refer for MOUD

Key Naloxone Points:

Co-prescribing rates remain low: offer to any patient suspected, but especially high-risk patients (see list above)

Safe to use even if opiates are not present: use if suspected (don’t wait for toxicology confirmation)

Do not withhold during pregnancy

Minimal transfer during lactation

Multiple routes: intranasal, IM auto-injector, IV/IM/SQ

Distribute and educate patients: save lives

Course Test

Which of the following options does not represent risk factors for an opioid-related overdose?

Three dental visits in 6 months, on food aid assistance

Patient demographics, mental health comorbidities

Substance use disorders, physical health comorbidities

Reduced drug tolerance, and the method of drug administration

Which patient is at the highest risk for an opioid overdose and should be prioritized for naloxone education and co-prescribing?

A patient taking short-acting opioids for 2 days after minor surgery diagnosed with asthma

A patient using acetaminophen for chronic headaches without comorbidities

A patient prescribed over 100 mg of morphine per day, diagnosed with depression

A patient prescribed alprazolam and NSAIDs, diagnosed with depression

Which prescribing practice best aligns with overdose prevention recommendations for acute pain?

Start with the lowest effective dose and limit the prescription to 3 days supply

Prescribe 30 day supply of a long-acting fentanyl after bunion surgery

Extended-release opioids are recommended for treatment-naive patients undergoing wisdom tooth removal

Avoid scaring the patient by not discussing naloxone co-prescribing

Which strategy best reflects an approach to preventing opioid overdose?

Delegate all overdose prevention discussions to community organizations

Avoid prescribing opioids and refer all patients experiencing pain to a pain clinic

Review prescription drug monitoring database and electronic records for diphenoxylate use

In patients at high risk for an opioid overdose, counsel them on safe storage and disposal of opioids, and co-prescribe naloxone

Which strategy demonstrates interprofessional collaboration in educating a patient presenting with high risk for opioid overdose?

The nurse takes vital signs, documents gout as the reason for the visit, and tells the receptionist the patient has a new insurance card

The prescriber identifies the patient at high risk, orders naloxone, and instructs the nurse to teach overdose recognition and when to call 911

The social worker visits a hospice patient, and the patient’s spouse mentions that the pain medication bottle is empty

The prescriber identifies the patient at high risk and documents that finding in the medical record

Which statement best differentiates naltrexone from naloxone and nalmefene?

Naltrexone has replaced naloxone as the preferred antidote for diazepam overdose

Naltrexone is primarily used with a comprehensive occupational rehabilitation program or a behavioral contract

Use of naltrexone will not precipitate opioid withdrawal symptoms

Four doses of naltrexone are required to facilitate rescue from opioid overdose

When counseling a patient or family member about keeping naloxone at home in case of opioid overdose, which point is most important to emphasize?

Naloxone replaces the need to call 911

Naloxone works for any overdose

Naloxone should be reserved only for pulseless patients

Naloxone may need to be given more than once if breathing slows

Naloxone nasal spray can be re-administered every ______ if the patient does not respond or relapses into respiratory depression.

2 to 3 minutes

5 to 7 minutes

15 minutes

90 minutes

A patient overdoses on “tranq-dope.” You administer two doses of naloxone with a partial response. Next step?

Stop naloxone; xylazine is present

Give more naloxone and wound care referral

Switch to nalmefene only

Intubate immediately

Which instruction is correct when a healthcare professional teaches a patient or family member how to administer naloxone 4 mg OTC nasal spray during a suspected opioid overdose?

Prime the device by spraying 3 times into their nose, then spray into both nostrils 3 times.

Place the patient in the sitting position, insert the nozzle, and only partially press the plunger

Lay the patient on their back, insert the nozzle fully into one nostril, and press the plunger firmly for a single full dose.

Shake the device 20 times before use, prime it 4 times in the air, and split the dose between the nostrils.

References

Blum K, Baron D, Hauser M, et al. Americas' opioid/psychostimulant epidemic would benefit from general population early identification of genetic addiction risk especially in children of alcoholics (COAs). J Syst Integr Neurosci. 2019;5(2):1-3.

World Health Organization. Opioid overdose. WHO. 2021. https://www.who.int/news-room/fact-sheets/detail/opioid-overdose

Centers for Disease Control and Prevention. Drug Overdose Deaths in the U.S. Top 100,000 Annually. CDC. 2021. Accessed January 23, 2026. https://www.cdc.gov/nchs/pressroom/nchs_press_releases/2021/20211117.htm

Tanz LJ, Stewart A, Gladden RM, Ko JY, Owens L, O'Donnell J. Detection of Illegally Manufactured Fentanyls and Carfentanil in Drug Overdose Deaths - United States, 2021-2024. MMWR Morb Mortal Wkly Rep. 2024 Dec 5;73(48):1099-1105. doi: 10.15585/mmwr.mm7348a2

Hedegaard H, Miniño AM, Warner M. Drug Overdose Deaths in the United States, 1999-2019. NCHS Data Brief. 2020;(394):1-8.

What You Should Know About Xylazine. CDC. May 16, 2024. https://www.cdc.gov/overdose-prevention/about/what-you-should-know-about-xylazine.html

Medetomidine Webinar – Questions and Answers. Health Care Providers. CDC. Sept. 29, 2025. https://www.cdc.gov/overdose-prevention/hcp/trainings/medetomidine-qa.html

Centers for Disease Control and Prevention. Overdose Prevention. About Overdose Prevention. CDC. Jan. 16, 2026. Accessed January 25, 2026. https://www.cdc.gov/overdose-prevention/about/index.html

Substance Abuse and Mental Health Services Administration. (2025). Key substance use and mental health indicators in the United States: Results from the 2024 National Survey on Drug Use and Health (HHS Publication No. PEP25-07-007, NSDUH Series H-60). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Accessed January 25, 2026. https://www.samhsa.gov/data/sites/default/files/reports/rpt56287/2024-nsduh-annual-national-report.pdf?utm_source=SAMHSA&utm_campaign=51e955caaf-EMAIL_CAMPAIGN_2025_06_10_02_22_COPY_07&utm_medium=email&utm_term=0_-3d1afcc326-168829677

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on Pain Management and Regulatory Strategies to Address Prescription Opioid Abuse; Phillips JK, Ford MA, Bonnie RJ, editors. Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use. Washington (DC): National Academies Press (US); 2017 Jul 13. 2, Pain Management and the Intersection of Pain and Opioid Use Disorder. Accessed January 25, 2026. https://www.ncbi.nlm.nih.gov/books/NBK458655/

Cioe K, Biondi BE, Easly R, Simard A, Zheng X, Springer SA. A systematic review of patients' and providers' perspectives of medications for treatment of opioid use disorder. J Subst Abuse Treat. 2020;119:108146. doi:10.1016/j.jsat.2020.108146

Kim EJ, Hwang EJ, Yoo YM, Kim KH. Prevention, diagnosis, and treatment of opioid use disorder under the supervision of opioid stewardship programs: it's time to act now. Korean J Pain. 2022;35(4):361-382. doi:10.3344/kjp.2022.35.4.361

Szalavitz M, Rigg KK, Wakeman SE. Drug dependence is not addiction-and it matters. Ann Med. 2021;53(1):1989-1992. doi:10.1080/07853890.2021.1995623

American Psychiatric Association, author. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Association Publishing; Washington, D.C.: 2013. pp. 1–947.

Tseregounis IE, Henry SG. Assessing opioid overdose risk: a review of clinical prediction models utilizing patient-level data. Transl Res. 2021;234:74-87. doi:10.1016/j.trsl.2021.03.012

Weiner SG, El Ibrahimi S, Hendricks MA, et al. Factors Associated With Opioid Overdose After an Initial Opioid Prescription. JAMA Netw Open. 2022;5(1):e2145691. Published 2022 Jan 4. doi:10.1001/jamanetworkopen.2021.45691

Møller LF, Matic S, van den Bergh BJ, Moloney K, Hayton P, Gatherer A. Acute drug-related mortality of people recently released from prisons. Public Health. 2010;124(11):637-639. doi:10.1016/j.puhe.2010.08.012

Ilgen MA, Bohnert ASB, Ganoczy D, Bair MJ, McCarthy JF, Blow FC. Opioid dose and risk of suicide. Pain. 2016;157(5):1079-1084. doi:10.1097/j.pain.0000000000000484

Webster LR. Risk Factors for Opioid-Use Disorder and Overdose. Anesth Analg. 2017 Nov;125(5):1741-1748. doi: 10.1213/ANE.0000000000002496

Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747-758. doi:10.1093/bja/aen094

Boom M, Niesters M, Sarton E, Aarts L, Smith TW, Dahan A. Non-analgesic effects of opioids: opioid-induced respiratory depression. Curr Pharm Des. 2012;18(37):5994-6004. doi:10.2174/138161212803582469

Substance Abuse and Mental Health Services Administration. Opioid Overdose. SAMSHA. Last Updated: 12/22/2025. Accessed January 14, 2026. https://www.samhsa.gov/medications-substance-use-disorders/medications-counseling-related-conditions/opioid-overdose

Substance Abuse and Mental Health Services Administration: SAMHSA Overdose Prevention and Response Toolkit. Publication No. PEP23-03-00-001, Substance Abuse and Mental Health Services Administration, 2025. https://library.samhsa.gov/sites/default/files/overdose-prevention-response-kit-pep23-03-00-001.pdf

Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. MMWR Recomm Rep. 2022;71(3):1-95. Published 2022 Nov 4. doi:10.15585/mmwr.rr7103a1

US Food and Drug Administration. Drug Disposal: Drug Take Back Locations. FDA. 2022. Accessed January 14, 2026. https://www.fda.gov/drugs/disposal-unused-medicines-what-you-should-know/drug-disposal-drug-take-back-locations

Hoang BL, Sledge D. The association between medication for opioid use disorder and employment outcomes in the U.S.: The relevance of race and ethnicity. Drug Alcohol Depend Rep. 2022;4:100081. Published 2022 Jul 27. doi:10.1016/j.dadr.2022.100081

National Association of Counties. Opioid Solutions Center. Medication-Assisted Treatment (“MAT”) For Opioid Use Disorder. NACo. Undated. Accessed January 15, 2026. https://www.naco.org/sites/default/files/documents/OSC_Strategy_MOUD_References.pdf

Ashford RD, Brown AM, Curtis B. Substance use, recovery, and linguistics: The impact of word choice on explicit and implicit bias. Drug Alcohol Depend. 2018;189:131-138. doi:10.1016/j.drugalcdep.2018.05.005

Substance Abuse and Mental Health Services Administration. Substance Use Disorder Treatment Options. SAMHSA. Last Updated: 08/25/2025. Accessed January 14, 2026. https://www.samhsa.gov/medications-substance-use-disorders

Volkow ND, Blanco C. The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry. 2021;26(1):218-233. doi:10.1038/s41380-020-0661-4

Centers for Disease Control and Prevention. Fact Sheet: Family and Caregivers. When and how to use naloxone for an opioid overdose. CDC. Undated. Accessed January 14, 2026. https://www.cdc.gov/overdose-prevention/media/pdfs/2024/04/Naloxone-Fact-Sheet_FamilyandCaregivers_HowandWhen_4_11_2024.pdf

Endt F, Guo T, Steinritz D, Amend N, Gudermann T, Breit A. Carfentanil stabilizes µ opioid receptor conformations that are ultra-efficient in inhibiting cAMP, resistant to naloxone or nalmefene but sensitive to naltrexone. Arch Toxicol. 2025;99(7):2903-2915. doi:10.1007/s00204-025-04048-6

NARCAN- naloxone hydrochloride nasal spray. Prescribing Information. Emergent Devices Inc. Updated August 8, 2023. Accessed December 3, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0ebc83d-2892-40de-bc0a-775ce90b30db

KLOXXADO- naloxone hcl spray. Prescribing Information. Hikma Specialty USA Inc. Updated August 25, 2025. Accessed January 14, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ebf0f833-c1c0-487c-8f29-01fa8c61b6cb

Qayyum SN, Ansari RS, Ullah I, Siblini D. The FDA approves the second OTC naloxone - a step toward opioid crisis mitigation. Int J Surg. 2023;109(12):4349-4350. Published 2023 Dec 1. doi:10.1097/JS9.0000000000000677

Wang DS, Sternbach G, Varon J. Nalmefene: a long-acting opioid antagonist. Clinical applications in emergency medicine. J Emerg Med. 1998;16(3):471-475. doi:10.1016/s0736-4679(98)00019-5

OPVEE- nalmefene hydrochloride spray. Prescribing Information. Indivior Inc. Updated July 8, 2025. Accessed November 29, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=999a4269-9e54-4801-b2ac-2a7276f0b94f

Infante AF, Elmes AT, Gimbar RP, Messmer SE, Neeb C, Jarrett JB. Stronger, longer, better opioid antagonists? Nalmefene is NOT a naloxone replacement. Int J Drug Policy. 2024;124:104323. doi:10.1016/j.drugpo.2024.104323

ACMT & AACT Joint Position Statement on Nalmefene Should Not Replace Naloxone as the Primary Opioid Antidote at This Time. https://www.acmt.net/news/acmt-aact-joint-position-statement-on-nalmefene-should-not-replace-naloxone-as-the-primary-opioid-antidote-at-this-time/#:~:text=The%20longer%20duration%20of%20action%20of%20nalmefene%20does%20not%20eliminate,patients%20with%20synthetic%20opioid%20overdose

Fischer LS, Asher A, Stein R, et al. Effectiveness of naloxone distribution in community settings to reduce opioid overdose deaths among people who use drugs: a systematic review and meta-analysis. BMC Public Health. 2025;25(1):1135. Published 2025 Mar 25. doi:10.1186/s12889-025-22210-8

National Institute on Drug Abuse. Opioids. Naloxone Drug Facts. NIDA. January 11, 2022. Accessed January 14, 2026. https://nida.nih.gov/publications/drugfacts/naloxone

Dezfulian C, Orkin AM, Maron BA, et al. Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association. Circulation. 2021;143(16):e836-e870. doi:10.1161/CIR.0000000000000958

Centers for Disease Control and Prevention. How and When to Use Naloxone for an Opioid Overdose. CDC. Undated. Accessed January 23, 2026. https://www.cdc.gov/overdose-prevention/media/pdfs/2024/04/Naloxone-Fact-Sheet_FamilyandCaregivers_HowandWhen_4_11_2024.pdf

American Medical Association. How to administer Naloxone. AMA. Accessed January 14, 2026. https://www.ama-assn.org/public-health/behavioral-health/how-administer-naloxone

Gowing L, Ali R, White JM. Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev. 2017;5(5):CD002021. Published 2017 May 29. doi:10.1002/14651858.CD002021.pub4

College of Psychiatric and Neurologic Pharmacists. Naloxone Access. A Practical Guideline for Pharmacists. CPNP. February 30, 2015. Accessed January 14, 2026. https://prescribetoprevent.org/wp2015/wp-content/uploads/naloxone-access.pdf

Petty J, McNally S, Ryan J. Saving lives: Australian naloxone access model. Melbourne: Penington Insitute; 2018.

Upfal J. Australian Drug Guide. 8th edition ed. Victoria: Griffin Press; 2016.

REZENOPY- naloxone hydrochloride spray. Prescribing Information. Summit Biosciences Inc. Updated April 30, 2024. Accessed December 3, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3c3e1795-eea4-4b88-bcca-88658194a0b3

Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018;9(1):63-88. doi:10.1177/2042098617744161

EVZIO- R NALOXONE HCL injection, solution. HF Acquisition Co LLC, DBA HealthFirst. Updated February 23, 2020. Accessed January 14, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9be31bdf-e220-2978-e053-2a95a90a03c6

Saia KA, Schiff D, Wachman EM, et al. Caring for Pregnant Women with Opioid Use Disorder in the USA: Expanding and Improving Treatment. Curr Obstet Gynecol Rep. 2016;5(3):257-263. doi:10.1007/s13669-016-0168-9

Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006-. Naloxone. [Updated 2024 Feb 15]. Accessed January 14, 2026. https://www.ncbi.nlm.nih.gov/books/NBK501681/

Greenwald MK. Opioid craving and seeking behavior in physically dependent volunteers: effects of acute withdrawal and drug reinforcement opportunity. Exp Clin Psychopharmacol. 2005;13(1):3-14. doi:10.1037/1064-1297.13.1.3

Stolbach AI, Mazer-Amirshahi ME, Nelson LS, Cole JB. American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time. Clin Toxicol (Phila). 2023;61(11):952-955. doi:10.1080/15563650.2023.2283391

Centers for Disease Control and Prevention. Fact Sheet: Clinicians. When to Offer Naloxone to Patients. Undated. Accessed January 14, 2026. https://www.cdc.gov/overdose-prevention/media/pdfs/2024/07/Fact-Sheet-When-to-Offer-Naloxone-to-Patients.pdf

Cramer E, Kuperman E, Meyer N, Blum J. Improving Naloxone Co-prescribing Through Clinical Decision Support. Cureus. 2024;16(7):e63919. Published 2024 Jul 5. doi:10.7759/cureus.63919

Salwan A, Mathis SM, Brooks B, et al. A theoretical explanation of naloxone provision among primary care physicians and community pharmacists in Tennessee. Res Social Adm Pharm. 2024;20(10):978-985. doi:10.1016/j.sapharm.2024.07.001

Muzyk A, Smothers ZPW, Collins K, MacEachern M, Wu LT. Pharmacists' attitudes toward dispensing naloxone and medications for opioid use disorder: A scoping review of the literature. Subst Abus. 2019;40(4):476-483. doi:10.1080/08897077.2019.1616349

Bessen S, Metcalf SA, Saunders EC, et al. Barriers to naloxone use and acceptance among opioid users, first responders, and emergency department providers in New Hampshire, USA. Int J Drug Policy. 2019;74:144-151. doi:10.1016/j.drugpo.2019.09.008

Kyei EF, Ansong R, Kyei GK. Integrating Nursing Practice and Policy in Opioid Overdose Prevention: Analysis of the Opioid-Overdose Reduction Continuum of Care Approach Practice Guide. J Adv Nurs. 2025;81(3):1276-1285. doi:10.1111/jan.16451

Jones CM, Compton W, Vythilingam M, Giroir B. Naloxone Co-prescribing to Patients Receiving Prescription Opioids in the Medicare Part D Program, United States, 2016-2017. JAMA. 2019;322(5):462-464. doi:10.1001/jama.2019.7988

Hargraves D, White CC, Mauger MR, et al. Evaluation of an interprofessional naloxone didactic and skills session with medical residents and physician assistant learners. Pharm Pract (Granada). 2019;17(3):1591. doi:10.18549/PharmPract.2019.3.1591

Lebin JA, Mitchell K, Trinkley KE, et al. Clinical Decision Support to Increase Naloxone Co-prescribing from the Inpatient Setting. J Gen Intern Med. Published online July 28, 2025. doi:10.1007/s11606-025-09772-4

Safe Project. State Naloxone Access Rules and Resources. Undated. Accessed January 14, 2026. https://www.safeproject.us/naloxone/awareness-project/state-rules/

Ovalles Lacruz A, Valle MS, Santoyo K, Clarke RD, Bhoite P, Alarcon LN. Empowering Future Physicians: Enhancing Naloxone Competency Through Early Harm Reduction Training in Medical Education. MedEdPORTAL. 2025;21:11499. Published 2025 Feb 14. doi:10.15766/mep_2374-8265.11499

Griffiths D. Preventing opioid abuse: the role of the nurse. Washington State Nurses Association. Published August 17, 2017. Accessed December 16, 2025. https://www.wsna.org/news/2017/preventing-opioid-abuse-the-role-of-the-nurse

The College of St. Scholastica. What role can nurses play in combating opioid use disorder? css.edu. Published February 5, 2018. Accessed December 16, 2025. https://www.css.edu/about/blog/what-role-can-nurses-play-in-combating-opioid-use-disorder/

American Psychiatric Nurses Association. About PMH-APRNs. apna.org. Accessed December 16, 2025. https://www.apna.org/about-psychiatric-nursing/about-pmh-aprns/

National Library of Medicine. Non-drug pain management. MedlinePlus. Accessed December 16, 2025. https://medlineplus.gov/nondrugpainmanagement.html

St Marie BJ, Witry MJ, Reist JC. Barriers to Increasing Prescription Drug Monitoring Program Use: A Multidisciplinary Perspective. Comput Inform Nurs. 2023;41(8):556-562. Published 2023 Aug 1. doi:10.1097/CIN.0000000000000997

US Food and Drug Administration. FDA Drug Safety Communication. FDA. 07-31-2025. Accessed January 14, 2026. https://www.fda.gov/media/187944/download?attachment#:~:text=Be%20aware%20that%20overdose%20risk,opioid%20pain%20medicine%20doses%2C%20and&text=The%20Medication%20Guide%20explains%20the,to%20know%20about%20the%20medicine

Pacheco S, Nguyen LMT, Halphen JM, et al. Adherence to Opioid Patient Prescriber Agreements at a Safety Net Hospital. Cancers (Basel). 2023;15(11):2943. Published 2023 May 27. doi:10.3390/cancers15112943

Reddy A, de la Cruz M. Safe Opioid Use, Storage, and Disposal Strategies in Cancer Pain Management. Oncologist. 2019;24(11):1410-1415. doi:10.1634/theoncologist.2019-0242

Gabay M. Increasing Access to Naloxone and Legal Issues. Hosp Pharm. 2016;51(8):633-634. doi:10.1310/hpj5108-633

Bohler RM, Freeman PR, Villani J, et al. The policy landscape for naloxone distribution in four states highly impacted by fatal opioid overdoses. Drug Alcohol Depend Rep. 2023;6:100126. doi:10.1016/j.dadr.2022.100126

DISCLAIMER

The information provided in this course is general in nature, and it is designed solely to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals must consult their employer, healthcare facility, hospital, or other organization for guidelines, protocols, and procedures to follow. The information provided in this course does not replace those guidelines, protocols, and procedures, but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses is constantly changing. Any person taking this course understands that such a person must make an independent review of medication information before any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

Nothing contained in this course represents the opinions, views, judgments, or conclusions of RxCe.com LLC. RxCe.com LLC is not liable or responsible to any person for any inaccuracy, error, or omission with respect to this course or course material.

© RxCe.com LLC 2026: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

RxCe.com

© RxCe.com LLC 2025: All rights reserved.