Thomas M. Penders, MD, MS

is Resident Physician, Department of Psychiatry and Behavioral Sciences, Nassau University Medical Center, East Meadow, NY;

is Addiction Psychiatry Fellow, Dartmouth-Hitchcock Medical Center, Lebanon, NH; and 

is Clinical Associate Professor, Department of Psychiatry and Behavioral Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, and Medical Director, Consultation-Liaison Psychiatry, Cape Cod Healthcare, Hyannis, MA.

Opioid-related overdoses are now the leading cause of death in Americans aged younger than 50 years, with a resultant 2.5 months of life expectancy lost.

 While this includes deaths from pain pills and illicit heroin, the overwhelming initial source of addiction is prescribed opioids; 83% of heroin users started off abusing prescription opioids. More than 6 out of 10 deaths involve prescribed opioids.

 in the number of prescriptions written as well as dosages per prescription.

 yearly to supply every American with an average of 36 pills. In addition, in 2016, overprescribing of postsurgical opioids resulted in 3.3 billion unused pills flooding into communities, making these available for diversion and misuse.

Use of naloxone, an opioid receptor antagonist, has been shown to reverse opioid-induced respiratory suppression. Current evidence suggests that bystanders can and will use naloxone to reverse opioid overdoses when appropriately trained. This training is possible through community-based opioid overdose prevention programs. There is a movement to increase public awareness and training on the use of naloxone, with laws being passed that require students as young as elementary school age to receive training.

Despite this, there has been only a modest increase in naloxone prescribing between 2009 and 2015, from 2.8 million to 3.2 million.

 The relatively slow adoption of naloxone is in part due to stigmatization and absence of familiarity with the treatment among clinicians and opioid users. Most physicians do not receive formal training on the use of naloxone and its various methods of delivery. There is a need to increase prescribing and to improve clinicians’ training to effectively help ameliorate overdose response and deaths (

Because of the effects of the overdose epidemic, states passed legislation designed to enhance layman access to naloxone and give legal immunity to medical professionals who prescribe or dispense naloxone as well as to those who administer naloxone. Individuals such as emergency medical services personnel, police officers, and firefighters as well as those authorized to administer naloxone are required to undergo training and education in recognition of signs and symptoms of overdose, techniques for administration of naloxone, and referral to emergency medical services. Residents and fellows are the exception. They undergo training in clinical skills such as advanced cardiac life support, pediatric advanced life support, and basic life support; however, they do not receive naloxone and opioid reversal training. Training is relatively simple in part because of the absence of complicated administration requirements or serious adverse reactions (

Naloxone competitively antagonizes the delta (Î´), mu (Î¼), and kappa(Îº) receptors with a 10-fold higher affinity for Î¼ than Îº. Given its ability to displace receptor-bound opioid molecules, its main use is intended for reversal of opioid-induced respiratory 

 Evidence of efficacy is noted within 30 seconds of intravenous administration; however, the most common route is nasally with a spray. This allows for convenient administration to patients by their relatives at home. The recommendation is to create an “overdose plan” to share with friends, partners, and/or caregivers. Such a plan contains information on the signs of overdose and how to administer naloxone or otherwise provide emergency care.

A medical provider must have a high suspicion and low threshold for use of naloxone, since overdose patients are usually found unresponsive or sedated. This is particularly true in cases where getting a collaborative history from a relative or close companion is difficult.

Currently, there are 4 naloxone delivery systems (

The onset of action of naltrexone and the duration depend on the route of administration. When used intravenously, it has the quickest onset of action (1-2 min) compared with subcutaneously (5 min), intramuscular (6 min), and nebulized (5 min).

 recommend initial doses of 0.4 to 2 mg via intramuscular or intravenous routes, followed by repeated doses up to 10 mg.

 Dosing is empirically determined; however, many factors need to be considered including morphine equivalence in the system, naloxone administration route, concurrent medications in the system such as benzodiazepines, and overall opioid tolerance.

Typical administration begins with a low dose to avoid precipitating withdrawal. Considerably higher doses of naloxone are required for potent opioids such as fentanyl.

 This should be a consideration in an individual who does not respond to the initial dose. Because of the increased prevalence of fentanyl and other powerful synthetic opioids, the naloxone requirements are on the rise. Given the potency of fentanyl, even multiple doses are sometimes unsuccessful.

Naloxone’s safety profile is extremely high especially when used in low doses and titrated to effect. When administered to nonopioid-dependent and nonopioid-intoxicated healthy volunteers, it produces no clinical effects even at high doses. Even in tolerant patients, rapid opioid withdrawal-although unpleasant-is not always life-threatening.

The duration of action of some opioids exceeds that of naloxone and can result in recurrence of CNS and respiratory system depression. It is important to be prepared for additional administrations and to be able to facilitate ICU admission for monitoring after reversal. It is also pertinent to consider the limitation of naloxone when dealing with mixed agonists/antagonists and partial agonists because of the low efficacy of the drug.

When used in cases of opioid overdoses, the abrupt reversal can sometimes result in vomiting, sweating, increased blood pressure, tremulousness, and tachycardia. Naloxone can also cause acute withdrawal symptoms in opioid-dependent individuals. Agitation, yawning, diaphoresis, rhinorrhea, lacrimation, nausea, vomiting, and diarrhea are not life-threatening.

 At the same time, in rare cases, it is possible to encounter 

 such as pulmonary edema, acute respiratory distress syndrome, seizures, and cardiac arrhythmias.

 Because of the short half-life of naloxone, withdrawal symptoms have a tendency to dissipate in approximately 30 minutes to 1 hour. In the case of an overdose, the risk of the symptoms listed above are balanced against the risk of death. (It is important to note that most overdoses typically involve co-administrations of benzodiazepines and opioids; hence, it is important to consider and be able to manage both.)

There has been criticism from some emergency department physicians who view naloxone prescription as perpetuating drug abuse. Some argue that users are not afraid to indulge in drug use because they know that there is a potent antidote. As users indulge more and more in this practice, they develop tolerance to the effects of the opioid drugs. An increased tolerance results in a continuous and upsurge use of 

 and leads to emergency department presentations.

 Emergency department physicians frequently face serious ethical dilemmas of either medically helping patients recover or playing a part in propagating their drug use.

An increasing number of individuals refuse naloxone treatment because they fear that it will precipitate withdrawal symptoms. This can be prevented through appropriate dosing, and patients can be reassured on arrival to the hospital that if withdrawal symptoms are noted, supportive treatment will be initiated. Some patients who experience these unpleasant symptoms will ask for early discharge with the hope of going back to using opioids to control their symptoms. Thus, there is a need for close collaboration between all the stakeholders concerned with the care of these patients.

Instead of discharge, best outcomes are achieved when patients are referred to drug rehabilitation centers for further management and law enforcement authorities notified to ensure that the patient is compliant with rehabilitation.

 This is even more effective when medication-assisted therapy with buprenorphine-naloxone is initiated before hospital discharge.

Individuals who have DNR statuses and are found comatose should still receive naloxone resuscitation as part of correct medical ethics conduct. If upon reversal, when they awaken, they continue to maintain a DNR stance, subsequent dosing should still be administered if needed, provided it is part of the overdose sequela while collaborating with the institution’s medical ethics council.

There is reassurance that prescribing naloxone to manage opioid overdose is consistent with the drug’s FDA indication, which results in no increased liability as long as the prescriber adheres to general rules of professional conduct. State laws and regulations generally 

 from prescribing to a third party, such as a caregiver. Illinois, Massachusetts, New York, and Washington State are the exceptions to this general principle.

The authors report no conflicts of interest concerning the subject matter of this article.

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 Centers for Disease Control and Prevention. Wide-ranging online data for epidemiologic research (WONDER). 2016. https://www.healthdata.gov/dataset/wide-ranging-online-data-epidemiologic-research-wonder. Accessed November 16, 2017.

 New Research: Overprescribing of Postsurgical Opioids Poses a Serious Threat to Patients and Their Communities. 2017. https://finance.yahoo.com/news/research-overprescribing-postsurgical-opioids-poses-120000057.html?.tsrc=rss. Accessed November 16, 2017.

 Gupta R, Shah ND, Ross JS. The rising price of naloxone: risks to efforts to stem overdose deaths. 

 Walley AY, Sorensen-Alawad A, Dwyer K, et al. Nasal naloxone rescue kits in an emergency department overdose education program. 

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 FDA Advisory Committee on the Most Appropriate Dose or Doses of Naloxone to Reverse the Effects of Life-threatening Opioid Overdose in the Community Settings. 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM522688.pdf. Accessed November 16, 2017.

 Clark AK, Wilder CM, Winstanley EL. A systematic review of community opioid overdose prevention and naloxone distribution programs. 

 Greene S, Dargan PI, Jones AL. Acute poisoning: understanding 90% of cases in a nutshell. 

 Rudd-Barnard G, Pangarkar S, Moaleji N, Glassman P. Epidemiology of naloxone use for opioid overdose in a tertiary care medical center. 

 Lin RJ, Reid MC, Chused AE, Evans AT. Quality assessment of acute inpatient pain management in an academic health center. 

 Jones JD, Roux P, Stancliff S, et al. Brief overdose education can significantly increase accurate recognition of opioid overdose among heroin users. 

 The Network for Public Health Law. Using Law to Support Pharmacy Naloxone Distribution. https://www.networkforphl.org/_asset/qdkn97/Pharmacy-Naloxone-Distributions.pdf. Accessed November 16, 2017.

 Guidelines for Opioid Overdose Education and Naloxone Distribution. 2015. http://www.ct.gov/dph/lib/dph/aids_and_chronic/prevention/pdf/open_access_ct_guidelines.pdf. Accessed November 16, 2017.

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