Fentanyl Misuse and Toxicity Materials

HIDDEN THREATS: UNDERSTANDING FENTANYL MISUSE AND TOXICITY

Faculty:

Sandra Rogers, MD

Sandra Rogers, MD, 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.

Jennifer Salvon, RPh

Jennifer Salvon, RPh, is a clinical pharmacist at Mercy Medical Center and a freelance medical writer at Salvon Scientific in Massachusetts. Her career includes practice in hospital, retail, managed care, academic, and clinical research settings. As a lifelong learner, Jen enjoys researching and writing to educate herself and others.

Pamela Sardo, PharmD, BS

Pamela Sardo, PharmD, BS, is a freelance medical writer and currently licensed pharmacist in 2 states. 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:

Fentanyl is a potent synthetic opioid used for anesthesia and analgesia. Illegally made fentanyl has become a dominant driver of opioid-related overdose deaths due to its high potency and widespread presence in street drugs. Use of illegal fentanyl has caused significant morbidity and mortality, placing a sizable burden on healthcare systems. Management of fentanyl overdose involves clinical assessment of the patient's airway, breathing, and circulation. Naloxone administration is instrumental in treating opioid overdoses, including fentanyl. Public education initiatives regarding opioid overdoses and the distribution of intranasal naloxone to civilians, law enforcement, firefighters, and emergency service personnel aim to facilitate recognition of opioid overdoses and enable rapid intervention.

Accreditation Statement

RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is 

Pharmacist  0669-0000-25-053-H08-P

Pharmacy Technician  0669-0000-25-054-H08-T

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

Type of Activity: Knowledge

Media: Internet/Home study Fee Information: $8.99

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

Release Date: May 3, 2025 Expiration Date: May 3, 2028

Target Audience: This educational activity is for pharmacists and pharmacy technicians.

Secondary Audiences: This educational activity is also for other healthcare professionals, such as nurses, physicians, or others who may be part of a healthcare team and may be interested in this educational topic. A healthcare team approach to patient care may be discussed in this activity, as applicable. No state board or professional organization has evaluated this activity to determine whether it meets the continuing education requirements of nurses, physicians, or other professions not listed under the “Target Audience” described above. Always verify with individual employers or supervisors whether they will accept this educational activity upon completion.

How to Earn Credit: From May 3, 2025, through May 3, 2028, 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.)

Credit for this course will be uploaded to CPE Monitor®.

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

Describe the pharmacologic profile of fentanyl

Explain the benefits and risks of fentanyl and its role in the opioid crisis

Describe treatment options in situations of fentanyl toxicity

Discuss the role of healthcare professionals in the management and prevention of fentanyl toxicity

Disclosures

The following individuals were involved in developing this activity: Sandra Rogers, MD, Jennifer Salvon RPh, and Pamela Sardo, PharmD, BS. None of these individuals has a conflict of interest or financial relationship regarding the development of this activity. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity.

© RxCe.com LLC 2025: 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

Hidden Threats: Understanding Fentanyl Misuse and Toxicity Introduction

The use of fentanyl and fentanyl analogs has increased significantly in the past ten years due to the influx of illegal forms of fentanyl. The consumption of these drugs is a primary contributor to the current opioid crisis in the United States. Illegally manufactured fentanyl is widely available on the street, and it is a relatively common adulterant in heroin. Unfortunately, some of the beneficial pharmacologic properties of fentanyl, such as the rapid onset of action and its high potency relative to other opioids, also make it very dangerous when it is misused. Physicians, nurses, pharmacists, and other healthcare professionals are tasked with identifying potential fentanyl misuse and may need to manage acute opioid toxicity in the clinical setting.

Fentanyl Medical Uses

Fentanyl is a synthetic opioid.1-4 It was introduced in 1960 to replace morphine and other opioids for use in cardiac surgery due to its higher potency, fewer adverse cardiovascular effects, and less histamine release.4 Fentanyl has a faster onset than morphine and a much shorter duration of analgesic action.5 Fentanyl is a highly lipophilic drug that allows it to cross the blood-brain barrier and readily produce analgesia and sedation.2,6 These characteristics contribute to fentanyl’s greater potency when compared to other opioids.5 For example, it is estimated to be 50-100 times stronger than morphine.2 Carfentanil, a fentanyl analog, is estimated to be 10,000 times stronger than morphine.5 Fentanyl is classified as a Schedule II drug under the Controlled Substances Act.7

Fentanyl is used to treat post-operative pain and medical conditions that are accompanied by severe pain.1 Transdermal fentanyl is used to treat chronic pain, generally in an outpatient setting.4

The following formulations of fentanyl are available:5,6

Sublingual tablets

Sublingual sprays

Mucosal lozenges

Nasal sprays

Transdermal patches (available with a drug reservoir or as a matrix system described below)

Injectable formulations

The transdermal patch allows for discreet, convenient, noninvasive, and generally safe opioid analgesia.8 The fentanyl transdermal delivery system (TDDS) is available as a transdermal therapeutic system with a drug reservoir or matrix system. Both systems have comparable efficacy and safety.6

Reservoir System

The fentanyl flux to skin (the rate at which the drug moves across the skin membrane) is controlled by a “rate control membrane.”6 The drug reservoir system has four functional layers and a protective peel strip. The four layers include the backing, fentanyl reservoir, adhesive, rate-controlling release membrane, and adhesive with a protective peel strip.9

Matrix System

The fentanyl transdermal matrix patch is newer and contains two functional layers and a protective peel strip.6 With the matrix system, fentanyl is dissolved in a polyacrylate adhesive.6 The amount of fentanyl absorbed by the skin is based on the surface size of the patch: the bigger the patch, the higher the dose of fentanyl.6

Fentanyl and the Opioid Crisis

The opioid crisis began with increased prescribing of opioids in the 1990s.10 Prescription opioids, such as natural and semi-synthetic opioids and

methadone, were implicated in overdose deaths, which increased at the end of the 1990s.10

Overdose deaths have declined in recent years.10 However, progress has been uneven across geographical regions and population groups, with certain groups faring better or worse, depending on the period studied.11-14

Fentanyl’s euphoria-inducing effects have encouraged it’s misuse.1 Fentanyl is currently the primary driver of the opioid crisis.1 It is involved in many deaths from its misuse as a prescription and illicit drug.15 In fact, approximately 70% of U.S., overdose deaths in 2023 were estimated to involve illegally manufactured fentanyl products.16 Deaths can result from fentanyl ingestion because it is extremely potent. Fentanyl’s rapid and potentially lethal potency is driven by two factors: its high lipophilicity and the fact that a small amount of the drug - “the equivalent of several grains of salt”

— can lead to death.17,18 This danger is more pronounced with fentanyl analogs like acetylfentanyl, carfentanil, and furanylfentanyl. This is troubling because certain parts of the country report a reemergence of fentanyl analogs.16 Because of this reemergence, fentanyl analogs are increasingly responsible for deaths from synthetic opioids.2,16

Fentanyl as an Adulterant

Illicit fentanyl is commonly used in powder form to adulterate heroin. It is also found with cocaine and amphetamines.2 It can also be made into pills that purposely resemble prescription opioids (e.g., benzodiazepines and prescription oxycodone/acetaminophen tablets).2,19 These adulterated drugs are extremely dangerous, and many people are unaware they are ingesting fentanyl.2

The Pattern of Fentanyl Misuse

Fentanyl may be inadvertently injected if it has been used to adulterate heroin, but there are other ways to misuse fentanyl that are specific to the drug that clinicians should know about.20 Perhaps the most important of these

is the misuse of fentanyl patches. Patients may apply multiple patches, and if an opioid overdose is suspected, a complete examination of the patient’s skin should be done.20 Reported ways of misuse also include heating and inhaling the vapors of transdermal patches, rectal insertion of a transdermal patch, and drinking water in which the transdermal patch was steeped like a tea bag.21-24

The reservoir in TDDS patches accounts for much of the potential for misuse because the fentanyl fluid can be extracted. Every transdermal device contains a significant quantity of fentanyl, which means they still contain potent amounts of the drug even after the 72-hour use period has expired. Misuse of the fentanyl-containing gel extracted from the reservoir device in IV formulations also contributes to many fatalities due to fentanyl overdose.25-31 The fentanyl transdermal system does not have a fluid fentanyl reservoir; however, some opioid misusers cut the matrix into desired sizes and place the fragment in their mouth for transmucosal absorption.32

Transdermal Fentanyl Absorption

Variations in skin thickness and degree of keratinization can alter Fentanyl’s systemic bioavailability and account for individual variability in transdermal fentanyl absorption.33-35 If applied to broken skin, blood fentanyl concentrations can rise 5-fold.32 An increase in skin temperature enhances the absorption of transdermal fentanyl, and a 3° Celsius body temperature increase can raise the peak fentanyl blood concentrations by 25%.32 Case reports suggest sources raising ambient temperatures may lead to a fentanyl overdose. Sources that may raise the skin's temperature include fever, hot tubs, heating blankets, sunbathing, and engaging in heavy exercise.32-36

The potential for toxicity is also raised when an overlay to hold a non- sticking transdermal device is applied to the patch, and may be associated with altered fentanyl absorption.32 Patches should be applied to clean, non- damaged skin over the lateral, dorsal thorax, and deltoid muscles.32

Since fentanyl can be absorbed through the skin, anyone involved in the use, administration, and disposal of fentanyl patches must use caution when handling the patches, as unintentional exposure must be avoided.32-37 Medical

team members should be aware of proper administration and disposal techniques.

Preventing Fentanyl Overdose

Physicians, nurses, pharmacists, and other medical team members should make sure patients are aware of the specific risks described above and the proper application of fentanyl patches.38 They should also counsel patients and caregivers about the appropriate storage and disposal of fentanyl patches.38

Used fentanyl patches require proper disposal after use. The Food and Drug Administration (FDA) recommends folding the patch with its sticky sides together and flushing it down the toilet immediately.38,39

Detecting Fentanyl Overdose

The signs, symptoms, and medical care of patients who have overdosed on fentanyl are often similar to other opioid drug overdoses and include respiratory depression, miosis (constricted pupils), and stupor.17-19 Patients may present with an unexplained respiratory depression.17 In each of these cases, fentanyl overdose should be in the differential diagnosis for the patient.17 This is especially the case with pediatric patients.40,41

Although the signs of a fentanyl overdose are similar to other opioid drugs, fentanyl overdose does have distinctive symptoms that clinicians should look for.17 For example, respiratory depression may be more profound with fentanyl toxicity than with other opioids.17 Chest wall rigidity, also known as wooden chest syndrome, can be present.17,42 This may lead to a rapid onset of overdose death.17 Chest wall rigidity may occur at very low fentanyl doses.42 This requires a clinician to make an early diagnosis and provide treatment to save the patient’s life.17,42

A complete physical examination assessing the patient’s airway, breathing, and circulation should be performed.41,43 This examination should include checking for fentanyl patches and signs and symptoms of

compartment syndrome that are often due to prolonged compression in an unconscious patient.43

Screening for Fentanyl: Urine Samples

The standard for drug toxicology or screening involves a urinalysis, providing prompt results.44 However, these screens only detect the presence of five drugs and/or their metabolites: amphetamine, cocaine, marijuana, opioids (morphine and its metabolites and structurally similar drugs), and phencyclidine (PCP).19 Urine and serum tests remain the most commonly used tests for other misused substances by medical professionals.44 Fentanyl lacks the structural similarity to produce a positive test result on the opioid/opiate component of a standard immunoassay-based “urine drug screen;” therefore, liquid chromatography-mass spectrometry is the standard for measuring serum fentanyl concentrations.44,45 Rapid result drug screens that can detect fentanyl are available, but they are not in common use, and laboratory confirmation of fentanyl in blood or other biologic specimens cannot be done within a timeframe that is useful for anyone caring for a patient who has overdosed on fentanyl.17,44,45

Screening for Fentanyl: Fentanyl Test Strips

Rapid fentanyl test strips may be an important, inexpensive harm reduction tool for fentanyl toxicity.17,46 Fentanyl test strips can detect fentanyl and some of its analogs in other drugs.46 People taking drugs can test their drug supply for fentanyl to determine if it is adulterated with fentanyl. The person puts a small amount of their drug in water, and within 2-5 minutes, the tester shows whether the drug contains fentanyl.46,47 Research has shown that people who use drugs are receptive to using the test strips and discarding the drug if adulterated.46 It is nearly impossible to tell if drugs have been mixed with fentanyl unless tested with fentanyl test strips.47 Testing for fentanyl and discarding contaminated drugs can be the difference between life and death.47 Patients should be cautioned that even if a rapid fentanyl test is negative, they should exercise caution because test strips may not detect more potent fentanyl-related drugs, such as carfentanil.47

Pediatric Exposure to Fentanyl

Outside of therapeutic use in a monitored setting, pediatric exposure to fentanyl is very dangerous.41,48 Fentanyl toxicity involves severe neurological and cardiovascular symptoms.49-51 Fentanyl suppresses respiration rapidly, leading to drowsiness or unconsciousness, respiratory failure, trouble breathing, stiff muscles, cyanosis, or death.41 Even minimal exposure, such as chewing a patch or ingesting a pill, can be lethal due to fentanyl’s high potency.41

Pediatric exposure to fentanyl has surged in recent years, posing severe risks to young children. A study of FDA data (2004–2013) found a 48% case- fatality rate among children exposed to fentanyl, with 76% of cases involving children aged 2–4 and a striking male predominance.41 The U.S. Poison Centers reported 539 cases of illicit fentanyl exposure in children under 6 in 2023—a 5,390% increase since 2016.52

Children are often exposed to accidental opioid ingestion and malicious or careless exposure to illegal drugs, frequently with fatal outcomes.39-41 Any child who has or may have been exposed to fentanyl requires immediate assessment of the child’s airway, breathing, and circulation.41

Stringent safety measures are needed to protect children from accidental exposure to illicit and prescription fentanyl.38,39 It is important to store all medication out of reach of children securely.38,39 Patches must be disposed of properly as discussed above.38,39 Caregivers using fentanyl should avoid skin-to-skin contact with children while wearing patches. Education on home safety and naloxone accessibility is critical.38,39

An Emerging Threat: Fentanyl Adulterated with Xylazine

A troubling trend with fentanyl misuse and overdoses is the increasing appearance of xylazine as an adulterant in illicit fentanyl and other drugs.53-56 Xylazine is a non-opioid veterinary tranquilizer used to sedate large animals.

Xylazine is not approved for human use.53 Xylazine is added to illicit drugs to cheaply increase the quantity, leading to higher profits.53

A study reporting on data from all four U.S. Census Regions found that in 98.4% of overdose deaths, illicit fentanyl and xylazine were present.53,54 Philadelphia, Pennsylvania, has the highest reported incidence of xylazine- adulterated illegal drugs.54 Maryland and Connecticut also see higher misuse of this combination than other states.53,54

Vasoconstriction from xylazine reduces blood flow and skin perfusion.54 This impairs wound healing, increasing the risk of soft tissue infections, including abscesses, cellulitis, and skin ulceration.53,54 Patients misusing xylazine may develop these abscesses and painful ulcers away from the injection sites.55 Xylazine also causes hypotension, bradycardia, and respiratory depression, which lowers skin tissue oxygenation.54

Important Takeaway

The presence of xylazine in a patient experiencing an overdose may render naloxone’s life-saving reversal treatment ineffective.

Xylazine use contributes to naloxone-resistant overdoses.53,54 This means that the presence of xylazine in the patient experiencing an overdose may render naloxone’s treatment as a reversal agent ineffective at saving the patient’s life.53,54 Additionally, there is no reversal agent for xylazine poisoning.53

During a clinician’s emergency assessment of a possible opioid overdose patient, the presence of abscesses or ulcers may indicate that the patient has also ingested xylazine. This could impact the treatment approach discussed below since a patient presenting with fentanyl toxicity may require a higher dose of naloxone because the drug was contaminated with xylazine.56-57

The rise in fentanyl adulterated with xylazine prompted the U.S. Drug Enforcement Agency and the Centers for Disease Control and Prevention to issue warnings and recite the dangers of this lethal combination.55,56 Clinicians need to be aware of the rising trend of xylazine-adulterated fentanyl and consider testing for the drug’s presence.53

Treatment of Opioid and Fentanyl Overdoses

Treatment should begin by assessing the patient’s airway, breathing, and circulation.39,41,43 Fundamental to treating an overdose patient is knowing the drug type and amount that the patient took before overdosing. This can be difficult because people typically do not know they have taken fentanyl. In most cases, the patient will need to be screened for fentanyl, as well as other drugs.41,43 Nurses and physicians, being tasked with managing acute opioid toxicity, must often administer naloxone and provide intensive resuscitative efforts.

Hypotension can be treated with intravenous (IV) fluids and supportive care. Hypothermia caused by prolonged immobility and/or exposure to the cold should be treated with standard care.58 Respiratory depression and hypoventilation should be treated with supplemental oxygen (and endotracheal intubation if indicated).58 If there is any suspicion that the patient may have taken an overdose of methadone, an electrocardiogram should be done to look for QTc prolongation.59

Naloxone and Opioid Overdoses

Naloxone is primarily used to reverse respiratory depression caused by an opioid overdose.60 The goal of naloxone use in an opioid overdose is to restore adequate ventilation, not to bring the patient to a fully conscious state.60 Death from an opioid overdose is regarded as a result of the cardiopulmonary effects of opioids, not necessarily from the central nervous system (CNS) depression.43

Naloxone should always be given if there is any suspicion of an opioid overdose.61 Naloxone is an opioid antagonist that blocks opioids from binding to mu-opioid receptors and can displace opioids from mu-opioid receptors. Healthcare professionals should discuss the availability of naloxone with all patients who are prescribed opioids. Clinicians are encouraged to consider prescribing naloxone to patients who are at increased risk of opioid overdose.45 Ideally, clinicians should inform family members how to use naloxone in an emergency. 61,62

Discussions with patients and family regarding naloxone should also include contraindications and warnings. Naloxone is contraindicated in patients with hypersensitivity to naloxone hydrochloride or any of the other ingredients in the drug.60 The only significant adverse effect of naloxone is the precipitation of withdrawal in patients who are opioid users.60 Other adverse effects may be reviewed in the package insert.60 Acute lung injury and ventricular fibrillation have been reported after the administration of naloxone, but these reports are rare, and the association between the drug and these complications is tenuous and has been questioned.63

Naloxone and Fentanyl Overdoses

Fentanyl metabolites are almost nonexistent in tissue from patients who died of a fentanyl overdose, suggesting rapid cardiopulmonary collapse.64 This has raised two questions or concerns: 1) whether naloxone should be used in fentanyl overdoses, and 2) if it should be, are the standard doses of naloxone sufficient for the reversal of fentanyl intoxication.65 Due to limited clinical reports against it’s use, naloxone remains the standard of care for fentanyl overdoses.66 Earlier expert reviews advise against using higher than standard doses of naloxone for reversal of fentanyl toxicity.66-68 More recent studies report positive outcomes using a slightly higher dose of naloxone.69,70 A higher dose could also be important if the patient has co-ingested xylazine.53

Finally, as mentioned above, fentanyl overdose may be characterized by chest wall rigidity.17,42 Naloxone may not be effective in treating fentanyl- induced muscle rigidity or wooden chest.65

Dispensing and Administering Naloxone

Most states have passed laws that allow pharmacists to dispense naloxone under a standing order, which takes the place of a prescription written by a provider. Some states allow pharmacists to prescribe and sell naloxone to patients. It is important to keep current on naloxone dispensing laws and regulations by pharmacists in your current state of practice.70

Naloxone can be given by several different routes of administration for opioid overdose.60,71-73 The choice will depend on the setting and the routes of administration that are available.60,71-73 Naloxone is available as brand or generic products.

Combining different forms of naloxone for opioid overdose reversal is not a standard practice and is not FDA-approved. However, the idea of sequential or layered administration benefits has been discussed. This involves leveraging different routes, such as combining nasal and injection naloxone. Since the half-life of nasal and injection naloxone is similar, combining them may be preferable to the risk of undertreating, but this is not fully supported by clinical evidence and is not part of the standard of care.65,74

Injectable Naloxone

Intravenous naloxone is the preferred route of administration in a clinical setting, but the administration should not be delayed if the patient

does not have IV access. If IV access is not possible (such as with an opioid overdose in the community), intramuscular and intranasal routes are preferred.71-73

The initial IV dose for an adult is 0.4 – 2 mg, which can be repeated every two to three minutes as needed for several doses.72,-73 If it is known or suspected that a patient is opioid-dependent, a lower initial dose may be used (0.1 – 0.2 mg) to avoid precipitating withdrawal. Lower doses may also be used to reverse respiratory depression caused by the therapeutic use of an opioid.72,73

Naloxone may be delivered through a single-dose, prefilled syringe.71 The syringe is intended to be administered by people 12 years of age or older because younger children or those with limited hand strength may find it difficult to use. The single-use syringe delivers 5 mg of naloxone hydrochloride (equivalent to 4.5 mg naloxone).71

Naloxone in a prefilled syringe is administered intramuscularly or subcutaneously into the anterolateral aspect of the thigh with the needle facing downwards. Inject through clothing if necessary. Embed the needle completely before transferring the thumb to the syringe plunger.71 Slide the safety guard over the needle immediately after injection. Use only one hand with your fingers behind the needle to avoid a needlestick injury.71

If the desired response is not obtained after 2 or 3 minutes, a second prefilled syringe may be used to administer an additional dose. If there is still no response and additional prefilled syringes are available, additional doses may be administered every 2 to 3 minutes until emergency medical assistance arrives.71

Intranasal Naloxone

The intranasal dose of naloxone is generally one spray (4 mg) in one nostril and is available over the counter (OTC). The dose can be repeated every 2 to 3 minutes, alternating nostrils, only until the patient responds.63 A

solution given intranasally using an atomization device may also be used. When using this method, the dose is 2 mg (1 mg per nostril) and repeated every three to five minutes.73,75

A longer-acting opioid antagonist, nalmefene, has benefits in clinical practice. Nalmefene has a plasma half-life of approximately 11 hours.76 Nalmefene is available by prescription only and is indicated for the emergency treatment of known or suspected overdose induced by natural or synthetic opioids in adults and pediatric patients aged 12 years and older, as manifested by respiratory and/or central nervous system depression. It is intended for immediate administration as emergency therapy in settings where opioids may be present. Each unit-dose nasal spray device delivers a single spray containing 2.7 mg and cannot be reused.76

In 2021, a higher dose of a naloxone hydrochloride nasal spray was approved for the treatment of an opioid overdose.60 This new product, marketed under the trade name KLOXXADOTM is available by prescription only. It delivers 8 mg of naloxone intranasally.60 The manufacturer provides dosing and delivery instructions for adult and pediatric patients.60 One 8 mg dose of naloxone is sprayed into one nostril. If the desired response is not reached after 2 or 3 minutes, another dose may be administered in the other nostril, alternating nostrils every 2 to 3 minutes until emergency medical help arrives.60 The drug comes with two warnings of potentially serious adverse reactions: recurrent respiratory and CNS depression and severe opioid withdrawal.60 This means the patient can improve with dosing, then relapse into unconsciousness or respiratory depression and need another dose.60

For infants and children weighing ≤ 20 kg, the dose is 0.1 mg/kg, up to a maximum of 2 mg. For the reversal of respiratory depression caused by the therapeutic use of an opioid, the pediatric dose is 0.001 to 0.005 mg/kg, repeated every two to three minutes as needed.60

The table below contains information about some of the nasal spray and injection formulas of naloxone, along with the recommended dosing. More

information about these drugs can be found in the package inserts, including dosing for infants and children weighing ≤ 20 kg.

Select Nasal Spray and Injection Agents60,71,73-76

Buprenorphine

Buprenorphine sublingual tablets may be indicated for the treatment of opioid dependence. They are preferred for induction and should be used as part of a complete treatment plan to include counseling and psychosocial support.77,78 Buprenorphine sublingual tablets are administered as a single daily dose and do not contain naloxone. Common adverse effects include headache, nausea, vomiting, hyperhidrosis, constipation, signs and symptoms of withdrawal, insomnia, and pain.78

Monitoring Fentanyl Overdose Patients

Naloxone

After administering a dose of naloxone to a person who has overdosed on fentanyl, the clinician should observe the patient for several hours after the last dose.79 The clinician should monitor the patient for signs of reversal, such as an increased level of consciousness, increased respiratory rate, or improved ventilation. The patient should also be monitored for signs of opioid withdrawal, which may not be life-threatening but can be very uncomfortable.60

If a total of 10 mg is used and there is no significant clinical response, it is unlikely that the patient is experiencing an opioid overdose.72 If a continuous infusion is needed, two-thirds of the effective dose should be administered every hour. For example, if 6 mg is the effective dose, the continuous infusion rate would be 4 mg/hour.72,73

At such time as the patient is awake, alert, and oriented, and has normal vital signs, discharge may be considered, provided the patient is going to a safe environment and arrangements have been made for follow-up care.80

Buprenorphine

Patients should be monitored for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.78 For patients with severe liver impairment, clinicians should consider reducing buprenorphine’s starting and incremental titration doses by half compared to the doses for patients with normal liver function.78 Depending on the case, buprenorphine sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms. Patients with a substance use disorder should be monitored for continued drug misuse.78

Education on Opioid Overdose and Response

In response to the opioid crisis, a majority of U.S., states have implemented programs that provide opioid overdose education and distribution of intranasal naloxone to laypersons, law enforcement officers, firefighters, and emergency services personnel.45,54 These programs, which are intended to promote recognition of opioid overdose and quick reversal of effects, have been proven to be effective, reducing opioid toxicity and mortality rates from the overdose. Naloxone is recognized as a well- established medication that can reverse an opioid overdose in an emergency and prevent death. Distribution of naloxone, patient counseling, and training of varied segments of the public will benefit opioid users who are not in treatment and those using opioids for non-acute pain management.61,62,81 For patients using illicit fentanyl, attempts should be made to engage social work to see if the patient would benefit from an inpatient treatment facility.46,62 The FDA and other government agencies continue to support efforts to increase the availability of all forms of naloxone and other treatments to help reduce opioid overdose deaths.82

Resources for Patients and Families

Poison Control 1-800-222-1222

Emergency Dial 911

Interprofessional Collaborative Approach

Interprofessional care is often preferred during emergencies because it fosters a coordinated, efficient response and can lead to better patient outcomes.83 Healthcare professionals report that an interprofessional approach positively impacted changes in provider workflow and individual attitudes. They found that clinical pharmacists often took the lead in procuring naloxone kits and developing teaching protocols.83 Social workers provided counseling and case management services to address potential substance misuse issues. Physicians were instrumental in providing oversight, strengthening motivational interviewing, and improving counseling skills. These skills are critical in addressing the current opioid overdose crisis.62

Case Study: Fentanyl Transdermal for Chronic Pain

A 70-year-old woman was diagnosed with fentanyl patch toxicity.84 The case study authors reported that the patient had been on a transdermal fentanyl patch for chronic back pain for approximately 10 years.84 Gradually, the patient accumulated 100 mcg fentanyl patches from prescription refills and then applied 14 patches combined with oral mirtazapine, tramadol, and morphine sulfate oral solution with the intention of suicide. The patient did not die; instead, she awakened to the telephone ringing after 24 hours of deep sleep. She expressed disbelief that her effort to die had failed.84

Psychiatry was consulted, and the pain management team, who had managed the patient’s prior pain treatment, took charge of her case.84 The patient had a history of chronic non-malignant back pain from severe lumbar scoliosis and osteoarthritis, for which she had received numerous treatments, including spinal decompression surgery and joint injections. She had also been diagnosed with breast cancer and underwent chemotherapy and surgery. Chemotherapy was stopped due to side effects before the planned course of administration.84

Psychiatrically, she was diagnosed with generalized anxiety disorder but not treated with the standard treatment of serotonin reuptake inhibitors.84 Two months before her suicide attempt, the patient was started on mirtazapine 15 mg daily. Static risk factors for suicidality included comorbid chronic pain and a diagnosis of cancer.84

The authors reported that opioid analgesics were prescribed; transdermal buprenorphine was increased from 5 to 20 mcg and then changed to fentanyl patches.84 The fentanyl dosing was rapidly increased from 25 to 100 mcg for 7 weeks. The patient developed side effects of drowsiness and nausea, and the patient was switched to modified-release oxycodone 10 mg twice a day. She missed scheduled appointments with an orthopedic surgeon and physiotherapist, and eventually was restarted on fentanyl 100 mcg patches.84

The patient was also prescribed morphine sulfate solution and had two more prescriptions over several months following breast cancer treatment and surgery.84 Chronic back pain continued, and an extra fentanyl 50 mcg was prescribed in addition to the fentanyl 100 mcg patch.84

It was discovered that the patient’s opioid prescription was running out every 3 days.84 Morphine sulfate was limited to 20 ml per day by pain clinic clinicians, with consideration given to the fentanyl 100 mcg patch prescribed. When the patient intentionally overdosed with 14-100 mcg transdermal fentanyl patches, laboratory testing was performed in the emergency department, with normal findings in the urea and electrolytes, liver function tests, and clotting results.84

The patient was discharged after being evaluated as low risk and referred to outpatient services for follow-up by a multidisciplinary health team of pain specialists and psychology services.84 Low-dose fentanyl patches were continued along with duloxetine for mood instability, with improved outcomes in the patient’s mood symptoms and quality of life.84

Discussion

The case authors reported that the patient had no evidence of insensitivity to opioids; however, she had an extensive pain history, which possibly explained her survival.84 No prior cases were found of people who survived deliberate self-poisoning with such a high dose of transdermal fentanyl. However, a literature search highlighted three other case reports of suicide by fentanyl patches in adults: “in a woman aged 42 years with eleven 100 mcg patches, an assisted suicide of a woman aged 46 years with 34 mixed dose patches, and suicide of a woman aged 78 years with ten 100 mcg patches. These cases are a testament to the lethality of the fentanyl dose presented here and how remarkable it was that the patient was able to survive.”84

This case depicts interprofessional opportunities for communication between team members and a discussion of solutions. Prescription monitoring is important for any controlled substance. The primary care physician and pharmacies have access to prescription drug monitoring programs in all states, and some states require physicians and pharmacists to check them before prescribing and dispensing them.

Summary

Fentanyl is a synthetic opioid that has long been used as an analgesic, most often to treat breakthrough cancer pain and chronic pain, and as an adjunct to anesthesia. It is available in multiple forms and is a potent opioid with potentially severe adverse effects. Even therapeutic use can cause serious central nervous system and respiratory system depression. Fentanyl should be used cautiously, especially in patients with known cardiovascular or respiratory diseases and in patients taking other CNS depressants (for example, benzodiazepines). Before prescribing or administering fentanyl, clinicians should carefully review a patient’s medical history and drug profile.

The high potency and rapid onset of the effects of fentanyl make it an attractive drug to people who misuse opioids. Fentanyl is a major contributor to the opioid epidemic. The use of fentanyl and fentanyl analogs has increased dramatically in the U.S., and fentanyl has become one of the major causes of fatal drug overdose. Efforts to control the supply of opioids and fentanyl have, in part, helped to make the drug even more sought after because illegally manufactured fentanyl is much cheaper to produce than heroin. Education, treatment, and the availability of naloxone to the lay public, law enforcement officers, and emergency personnel have been proven to be effective at reducing deaths from opioid overdoses. Despite these efforts, the use of fentanyl has been steadily increasing and may potentially worsen.

Interdisciplinary healthcare teams that include medical and psychiatric professionals can develop a comprehensive treatment plan for patients who misuse fentanyl. Case studies have shown that even in patients with a severe opioid use disorder, patients can recover and progress to an improved quality of life through proper treatment, careful monitoring, and follow-up.

Course Test

                         is a fentanyl analog that has been estimated to be 10,000 times stronger than morphine.

Acetylfentanyl

Furanylfentanyl

Carfentanil

Oxycodone

Fentanyl crosses the blood-brain barrier and produces

hypertension.

psychosis.

analgesia.

anesthesia.

Illicitly manufactured fentanyl is the source of most of the fentanyl that is commonly used as an adulterant in

heroin.

opioids.

ecstasy.

benzodiazepines.

The dosing and administration instructions for the 8 mg intranasal naloxone product KLOXXADOTM provide for

two 4 mg doses delivered simultaneously to each nostril.

a maximum dose of 4 mg for pediatric patients.

one 8 mg dose only, and then wait for medical emergency personnel to arrive.

one 8 mg dose in one nostril, then every 2 or 3 minutes thereafter as needed in alternating nostrils.

A patient may misuse fentanyl patches by

using a matrix system patch instead of a reservoir system.

removing the protective peel strip.

steeping the patch in water like a tea bag.

folding the patch with its sticky sides together and flushing it down the toilet.

The typical signs and symptoms of a fentanyl overdose include

respiratory depression.

dilated pupils.

hyperventilation.

psychosis.

The preferred route for the administration of naloxone to treat an opioid overdose in a clinical setting is

intramuscularly (IM).

intravenously (IV).

intranasally.

by a nebulizer.

Naloxone is primarily used to reverse                         caused by an opioid overdose.

hypertensive effects

hallucinogenic effects

severe mood changes

respiratory depression

Fentanyl is a synthetic opioid that is used to treat

severe mood disorders.

bradycardia.

post-operative pain.

pulmonary depression.

Interprofessional collaborative care may include a social worker whose primary role is

to dispense opioids and naloxone kits.

to provide counseling and case management services to address potential substance misuse issues.

to diagnose a fentanyl overdose.

to diagnose substance misuse and develop a treatment plan.

References

Bird HE, Huhn AS, Dunn KE. Fentanyl Absorption, Distribution, Metabolism, and Excretion: Narrative Review and Clinical Significance Related to Illicitly Manufactured Fentanyl. J Addict Med. 2023;17(5):503-508. doi:10.1097/ADM.0000000000001185

Centers for Disease Control and Prevention. Stop Overdose. Fentanyl Facts. CDC. April 2, 2024. Accessed April 8, 2025. https://www.cdc.gov/stop-overdose/caring/fentanyl- facts.html?CDC_AAref_Val=https://www.cdc.gov/stopoverdose/fentanyl

/index.html

Ahn JS, Lin J, Ogawa S, et al. Transdermal buprenorphine and fentanyl patches in cancer pain: a network systematic review. J Pain Res. 2017;10:1963-1972. Published 2017 Aug 18. doi:10.2147/JPR.S140320

Fleischman RJ, Frazer DG, Daya M, Jui J, Newgard CD. Effectiveness and safety of fentanyl compared with morphine for out-of-hospital analgesia. Prehosp Emerg Care. 2010;14(2):167-175. doi:10.3109/10903120903572301

Comer SD, Cahill CM. Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019;106:49-57. doi:10.1016/j.neubiorev.2018.12.005

Cukic M, Annaheim S, Bahrami F, Defraeye T, De Nys K, Jörger M. Is personal physiology-based rapid prediction digital twin for minimal effective fentanyl dose better than standard practice: a pilot study protocol. BMJ Open. 2024;14(9):e085296. Published 2024 Sep 24. doi:10.1136/bmjopen-2024-085296

Weedn VW, Elizabeth Zaney M, McCord B, Lurie I, Baker A. Fentanyl- related substance scheduling as an effective drug control strategy. J Forensic Sci. 2021;66(4):1186-1200. doi:10.1111/1556-4029.14712

Ahn JS, Lin J, Ogawa S, et al. Transdermal buprenorphine and fentanyl patches in cancer pain: a network systematic review. J Pain Res. 2017;10:1963-1972. Published 2017 Aug 18. doi:10.2147/JPR.S140320

Freynhagen R, von Giesen HJ, Busche P, Sabatowski R, Konrad C, Grond S. Switching from reservoir to matrix systems for the transdermal delivery of fentanyl: a prospective, multicenter pilot study in outpatients with chronic pain. J Pain Symptom Manage. 2005;30(3):289-297. doi:10.1016/j.jpainsymman.2005.03.015

Centers for Disease Control and Prevention. Overdose Prevention. Understanding the Opioid Overdose Epidemic. CDC. November 1, 2024. Accessed March 20, 2025. https://www.cdc.gov/overdose- prevention/about/understanding-the-opioid-overdose- epidemic.html#:~:text=Opioid%20overdose%20deaths%20remain%20 high&text=Nearly%20108%2C000%20people%20died%20from,involve d%20opioids%20(about%2076%25)

King B, Holmes LM, Rishworth A, Patel R. Geographic variations in opioid overdose patterns in Pennsylvania during the COVID-19 pandemic. Health Place. 2023;79:102938. doi:10.1016/j.healthplace.2022.102938

Han B, Einstein EB, Jones CM, Cotto J, Compton WM, Volkow ND. Racial and Ethnic Disparities in Drug Overdose Deaths in the US During the COVID-19 Pandemic. JAMA Netw Open. 2022;5(9):e2232314. Published 2022 Sep 1. doi:10.1001/jamanetworkopen.2022.32314

Rudolph KE, Kinnard EN, Aguirre AR, et al. The Relative Economy and Drug Overdose Deaths. Epidemiology. 2020;31(4):551-558. doi:10.1097/EDE.0000000000001199

Walters SM, Baker R, Frank D, et al. Strategies used to reduce harms associated with fentanyl exposure among rural people who use drugs: multi-site qualitative findings from the rural opioid initiative. Harm Reduct J. 2024;21(1):154. Published 2024 Aug 24. doi:10.1186/s12954-024-01062-2

Ciccarone D. The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis. Curr Opin Psychiatry. 2021;34(4):344-

350. doi:10.1097/YCO.0000000000000717

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;73(48):1099-1105. Published 2024 Dec 5.

doi:10.15585/mmwr.mm7348a2

Goldman JE, Waye KM, Periera KA, Krieger MS, Yedinak JL, Marshall BDL. Perspectives on rapid fentanyl test strips as a harm reduction practice among young adults who use drugs: a qualitative study. Harm Reduct J. 2019;16(1):3. Published 2019 Jan 8. doi:10.1186/s12954-

018-0276-0

Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2022;233:108019. doi:10.1016/j.pharmthera.2021.108019

Arya S, Nagappala S, Krawczyk N, Gi Y, Meacham MC, Bunting AM. Fentanyl in Pressed Oxycodone Pills: A Qualitative Analysis of Online Community Experiences with an Emerging Drug Trend. Subst Use Misuse. 2022;57(13):1940-1945. doi:10.1080/10826084.2022.2120365

Ciccarone D. Fentanyl in the US heroin supply: A rapidly changing risk environment. Int J Drug Policy. 2017;46:107-111. doi:10.1016/j.drugpo.2017.06.010

BradycardiaGrissinger M. Fentanyl Patch Fatalities: We ALL Have a Role in Prevention!. P T. 2016; 41(7):405-406.

Marquardt KA, Tharratt RS. Inhalational abuse of fentanyl patch. Clin Toxicol. 1994;32:75–78.

Barrueto F, Howland MA, Hoffman RS, et al. The fentanyl tea bag. Vet Human Toxicol. 2004;46:30–31.

Coon TP, Miller M, Kaylor D, et al. Rectal insertion of fentanyl patches: a new route of toxicity (letter). Ann Emerg Med. 2005;46:473.

Kuhlman JJ, McCaulley R, Valouch TJ, et al. Fentanyl use, misuse, and abuse: a summary of 23 postmortem cases. J Anal Toxicol. 2003;27:499–504.

Jost U, Wolter E, Bohrer H. Repeated improper intravenous injection of fentanyl from a transdermal system. Dtsch Med Wochenschr. 2004;129:313–314.

Reeves MD, Ginifer C. Fatal intravenous misuse of transdermal fentanyl.

Med J Aust. 2002;18:552–553.

Purucker M, Swann W. Potential for duragesic patch abuse (letter). Ann Emerg Med. 2000;35:314.

Tharp AM, Winecker RE, Winston DC. Fatal intravenous fentanyl abuse: four cases involving extraction from transdermal patches. Am J Forensic Med Pathol. 2004;25:178–181.

Lilleng PK, Mehlum LI, Bachs L, et al. Deaths after intravenous misuse of transdermal fentanyl. J Forensic Sci. 2004;49:1–3.95.

Schauer CK, Shand JA, Reynolds TM. The Fentanyl Patch Boil-Up - A Novel Method of Opioid Abuse. Basic Clin Pharmacol Toxicol. 2015;117(5):358-359. doi:10.1111/bcpt.12412

Nelson L, Schwaner R. Transdermal fentanyl: pharmacology and toxicology. J Med Toxicol. 2009;5(4):230-241. doi:10.1007/BF03178274

Bird D, Ravindra NM. Transdermal drug delivery and patches - an overview. Med Devices Sens. 2020; 3(6):e10069. doi.org/10.1002/mds3.10069

Gupta SK, Southam M, Gale R, et al. System functionality and physiochemical model of fentanyl transdermal system. J Pain Symptom Manage. 1992;7:S17–S26.

Frolich M, Giannotti A, Modell JH. Opioid overdose in a patient using a fentanyl patch during treatment with a warming blanket. Anesth Analg. 2001;93:647–648.

Kuip EJ, Zandvliet ML, Koolen SL, Mathijssen RH, van der Rijt CC. A review of factors explaining variability in fentanyl pharmacokinetics; focus on implications for cancer patients. Br J Clin Pharmacol. 2017;83(2):294-313. doi:10.1111/bcp.13129

Reinfeld HB. Fentanyl Patch Overdose-Case Report. J Cardiol Cardiovasc Res. 2022;3(3):1-5.

U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA requiring color changes to Duragesic (fentanyl) pain patches to aid safety―emphasizing that accidental exposure to used patches can cause death. FDA. February 21, 2018. Accessed on April 21, 2025.

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug- safety-communication-fda-requiring-color-changes-duragesic-fentanyl- pain-patches-aid-safety

U.S. Food and Drug Administration. Accidental Exposures to Fentanyl Patches Continue to Be Deadly to Children. FDA. 05/18/2023. Accessed April 6, 2025. https://www.fda.gov/consumers/consumer- updates/accidental-exposures-fentanyl-patches-continue-be-deadly- children

Ivanov I, Weber E, Javorsky E. Fentanyl in an Infant: Taking Our Breath Away. Cureus. 2023;15(5):e39216. Published 2023 May 19. doi:10.7759/cureus.39216

Sandelich S, Hooley G, Hsu G, et al. Acute opioid overdose in pediatric patients. J Am Coll Emerg Physicians Open. 2024;5(2):e13134. Published 2024 Mar 7. doi:10.1002/emp2.13134

Zoorob R, Uptegrove L, Park BL. Case Report of Very-Low-Dose Fentanyl Causing Fentanyl-Induced Chest Wall Rigidity. Cureus. 2023;15(8):e43788. Published 2023 Aug 20. doi:10.7759/cureus.43788

Boyer EW. Management of opioid analgesic overdose. N Engl J Med.

2012;367(2):146-155. doi:10.1056/NEJMra1202561

Rainey PM. Laboratory Principles. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, Howland MA, Lewin N, Nelson LS, eds. Goldfrank’s Toxicologic Emergencies. 8th ed. McGraw-Hill: New York; 2006:88–108.

Thomasy SM, Mama KR, Stanley SD. Comparison of liquid chromatography-mass spectrometry and radioimmunoassay for measurement of fentanyl and determination of pharmacokinetics in equine plasma. J Anal Toxicol. 2008;39:754–759.

Reed MK, Salcedo VJ, Hsiao T, et al. Pilot testing fentanyl test strip distribution in an emergency department setting: Experiences, lessons learned, and suggestions from staff. Acad Emerg Med. 2023;30(6):626- 635. doi:10.1111/acem.14624

Centers for Disease Control and Prevention. What You Can Do to Test for Fentanyl. Stop Overdose. CDC. Published May 22, 2024. Accessed April 6, 2025. https://www.cdc.gov/stop-overdose/safety/index.html

Stoecker WV, Madsen DE, Cole JG, Woolsey Z. Boys at Risk: Fatal Accidental Fentanyl Ingestions in Children: Analysis of Cases Reported to the FDA 2004-2013. Mo Med. 2016;113(6):476-479.

Hilado MA, Getz A, Rosenthal R, Im DD. Fatal Transdermal Fentanyl Patch Overdose in a Child. Cureus. 2020;12(1):e6755. Published 2020 Jan 23. doi:10.7759/cureus.6755

Foy L, Seeyave DM, Bradin SA. Toxic leukoencephalopathy due to transdermal fentanyl overdose. Pediatr Emerg Care. 2011;27(9):854- 856. doi:10.1097/PEC.0b013e31822c281f

Lovegrove MC, Mathew J, Hampp C, Governale L, Wysowski DK, Budnitz DS. Emergency hospitalizations for unsupervised prescription

medication ingestions by young children. Pediatrics. 2014;134(4):e1009-e1016. doi:10.1542/peds.2014-0840

Temple C, Hendrickson RG. Increasing Exposure of Young Children to Illicit Fentanyl in the United States. N Engl J Med. 2024;390(10):956- 957. doi:10.1056/NEJMc2313270

Edinoff AN, Sall S, Upshaw WC, et al. Xylazine: A Drug Adulterant of Clinical Concern. Curr Pain Headache Rep. 2024;28(5):417-426. doi:10.1007/s11916-024-01211-z

Friedman J, Montero F, Bourgois P, et al. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend. 2022;233:109380. doi:10.1016/j.drugalcdep.2022.109380

Malayala SV, Papudesi BN, Bobb R, Wimbush A. Xylazine-Induced Skin Ulcers in a Person Who Injects Drugs in Philadelphia, Pennsylvania, USA. Cureus. 2022;14(8):e28160. Published 2022 Aug 19. doi:10.7759/cureus.28160

Kariisa M, O'Donnell J, Kumar S, Mattson CL, Goldberger BA. Illicitly Manufactured Fentanyl-Involved Overdose Deaths with Detected Xylazine - United States, January 2019-June 2022. MMWR Morb Mortal Wkly Rep. 2023;72(26):721-727. Published 2023 Jun 30. doi:10.15585/mmwr.mm7226a4

National Institute on Drug Abuse. Xylazine. National Institute on Drug Abuse. NIDA. Published April 21, 2022. Accessed April 6, 2025. https://nida.nih.gov/research-topics/xylazine

Chou R, Korthuis PT, McCarty D, et al. Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review. Ann Intern Med. 2017;167(12):867-875. doi:10.7326/M17- 2224

Hoffman JP, Serdiuk AA, Escher AR Jr, Bordoni B, Evans R. Diphenhydramine-Induced Torsade De Pointes With Pharmacological Cardioversion in a Patient With Methadone-Induced QT Prolongation. Cureus. 2022;14(2):e22534. Published 2022 Feb 23. doi:10.7759/cureus.22534

Hikma. Highlights of Prescribing Information. 04/2021. Accessed on March 20, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212045s0 00lbl.pdf

Centers for Disease Control and Prevention. National Fentanyl Prevention and Awareness Day Toolkit. CDC. August 21, 2024. Accessed April 24, 2025. https://www.cdc.gov/overdose- prevention/php/toolkits/fentanyl-prevention-awareness- day.html#:~:text=Naloxone%20is%20a%20life%2Dsaving,most%20st ates%20without%20a%20prescription

Han JK, Hill LG, Koenig ME, Das N. Naloxone Counseling for Harm Reduction and Patient Engagement. Fam Med. 2017;49(9):730-733.

Narcan. Prescribing Information. Adapt Pharmaceuticals. November 2015. Accessed April 28, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208411lbl

.pdf

Torralva R, Eshleman AJ, Swanson TL, et al. Fentanyl but not Morphine Interacts with Nonopioid Recombinant Human Neurotransmitter Receptors and Transporters. J Pharmacol Exp Ther. 2020;374(3):376-

391. doi:10.1124/jpet.120.265561

Britch SC, Walsh SL. Treatment of opioid overdose: current approaches and recent advances. Psychopharmacology (Berl). 2022;239(7):2063- 2081. doi:10.1007/s00213-022-06125-5

Traynor K. Experts weigh minimum naloxone dose as opioid crisis evolves. Am J Health Syst Pharm. 2016; 73(23):1892-1894.

Klebacher R, et al. Incidence of naloxone redosing in the age of the new opioid epidemic. Prehosp Emerg Care. 2017; 21(6):682-687.

Kerensky T, Walley AY. Opioid overdose prevention and naloxone rescue kits: what we know and what we don't know. Addict Sci Clin Pract. 2017; 12(1):4.

Rock P, Slavova S, Westgate PM, Nakamura A, Walsh SL. Examination of naloxone dosing patterns for opioid overdose by emergency medical services in Kentucky during increased fentanyl use from 2018 to 2021. Drug Alcohol Depend. 2024;255:111062. doi:10.1016/j.drugalcdep.2023.111062

U.S. Food and Drug Administration. FDA Approves Higher Dosage of Naloxone Nasal Spray to Treat Opioid Overdose [news release]. FDA. April 30, 2021. Accessed on April 24, 2025. https://www.fda.gov/news- events/press-announcements/fda-approves-higher-dosage-naloxone- nasal-spray-treat-opioid-overdose

ZIMHI Prescribing Information. Adamis Pharmaceuticals Corporation. October 2021. Accessed April 30, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212854s0 00lbl.pdf

Zang X, Skinner A, Krieger MS, et al. Evaluation of Strategies to Enhance Community-Based Naloxone Distribution Supported by an Opioid Settlement. JAMA Netw Open. 2024;7(5):e2413861. Published 2024 May 1. doi:10.1001/jamanetworkopen.2024.13861

Wermeling DP. Review of naloxone safety for opioid overdose: practical considerations for new technology and expanded public access. Ther Adv Drug Saf. 2015;6(1):20-31. doi:10.1177/2042098614564776

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

Dietze P, Jauncey M, Salmon A, et al. Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial [published correction appears in JAMA Netw Open. 2020 Apr 1;3(4):e206593. doi: 10.1001/jamanetworkopen.2020.6593.]. JAMA Netw Open. 2019;2(11):e1914977. Published 2019 Nov 1. doi:10.1001/jamanetworkopen.2019.14977

Opvee. Prescribing Information. Opiant Pharmaceuticals. May 2023. Accessed April 28, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217470Or ig1s000.pdf

National Institute of Health. Buprenorphine use in the emergency department safe for people who use fentanyl. NIH. April 11, 2023. Accessed April 28, 2025. https://www.nih.gov/news-events/nih- research-matters/buprenorphine-use-emergency-department-safe- people-who-use-fentanyl

Buprenorphine sublingual HCL. Prescribing Information. Roxane Laboratories, Inc. February 2015. Accessed April 28, 2025. https://docs.boehringer- ingelheim.com/Prescribing%20Information/PIs/Roxane/Buprenorphine

%20HCl%20Sublingual%20Tabs/10004964_01%20Buprenorphine%20 HCl%20Sublingual%20Tabs.pdf

National Institute on Drug Abuse. Naloxone DrugFacts. NIDA. Published January 11, 2022. Accessed April 26, 2025. https://nida.nih.gov/publications/drugfacts/naloxone

Christenson J, Etherington J, Grafstein E, et al. Early discharge of patients with presumed opioid overdose: development of a clinical prediction rule. Acad Emerg Med. 2000;7(10):1110-1118. doi:10.1111/j.1553-2712.2000.tb01260.x

Zambole K. A Dose of Truth: A Qualitative Assessment of Reactions to Messages about Fentanyl for People Who Use Drugs. Subst Use Misuse. 2023;58(4):520-527. doi: 10.1080/10826084.2023.2177112

U.S. Food and Drug Administration. Statement on continued efforts to increase availability of all forms of naloxone to help reduce opioid overdose deaths [news release]. FDA. 2019. Accessed on April 20, 2025. https://www.fda.gov/news-events/press- announcements/statement-continued-efforts-increase-availability-all- forms-naloxone-help-reduce-opioid- overdose?utm_campaign=092019_Statement_FDA%E2%80%99s%20e fforts%20to%20increase%20availability%20of%20all%20forms%20of

%20naloxone&utm_medium=email&utm_source=Eloqua

Rosen MA, DiazGranados D, Dietz AS, et.al. Teamwork in healthcare: Key discoveries enabling safer, high-quality care. Am Psychol. 2018;73(4):433-450. doi: 10.1037/amp0000298

Trist AJ, Sahota H, Williams L. Not so patchy story of attempted suicide…leading to 24 hours of deep sleep and survival!. BMJ Case Rep. 2017;2017:bcr2016217231. Published 2017 Jan 17. doi:10.1136/bcr-

2016-217231

DISCLAIMER

The information provided in this course is general in nature and it is solely designed 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, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are 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 are constantly changing, and any person taking this course understands that such person must make an independent review of medication information prior to 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 2025: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.