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videos in clinical medicine

summary points

Julie R. Ingelfinger, M.D., Editor

Intranasal Naloxone Administration

Rafael Ortega, M.D., Ala Nozari, M.D., Ph.D., William Baker, M.D.,
Sannoor Surani, M.D., and Melinda Edwards, M.D.

The following text summarizes information provided in the video.

Overview

I
ntranasal naloxone is used to treat patients with respiratory From the Departments of Anesthesiology
and central nervous system depression that is known or suspected to be caused (R.O., A.N., S.S., M.E.) and Emergency
Medicine (W.B.), Boston Medical Center,
by an opioid overdose. Opioid overdose should be suspected in patients with Boston. Address reprint requests to Dr.
impaired arousal and respiratory depression, which can lead to hypoxemia and Ortega, Department of Anesthesiology,
cyanosis if left untreated. Miosis is generally expected in patients with opioid Boston Medical Center, 750 Albany St.,
Boston, MA 02118, or at rafael.ortega@
overdose but may not be present if there has been concomitant use of other drugs bmc.org.
that also affect pupillary size. Opioid intoxication can also be complicated by hypo-
N Engl J Med 2021;384:e44.
thermia, seizure, and aspiration pneumonia, and patients with prolonged loss of DOI: 10.1056/NEJMvcm2020745
consciousness may have rhabdomyolysis. The clinical presentation may be influ- Copyright © 2021 Massachusetts Medical Society.
enced by the type and dose of the opioid used, the presence of active opioid metabo-
lites, and the patient’s opioid tolerance.
When an opioid overdose is suspected, it is important to rule out alternative
causes of loss of consciousness, such as hypoglycemia and stroke, and to obtain
a blood glucose level, if possible. Some patients with opioid overdose have simul-
taneously used additional substances, and in such cases a reversal of the effects
of the opioid may not achieve the desired clinical response.
The safety of medical personnel should be considered during the treatment of
a patient with suspected opioid overdose. There may be needles in the patient’s
clothing or other belongings. Personal protective equipment, including gloves,
should be worn if available and the situation allows.

Pharmacology and Uses of Naloxone

Naloxone is a synthetic derivative of thebaine, a morphinane alkaloid, and has a
chemical structure resembling that of oxymorphone. Oxymorphone and other opi-
oids exert their effects by binding to and activating opioid receptors in the central
nervous system, causing analgesia, respiratory depression, and other sequelae.
Although its precise mechanism of action is not fully understood, naloxone ap-
pears to act as a competitive antagonist at these opioid receptors and has the great-
est affinity for mu opioid receptors. In binding to the opioid receptors, naloxone
displaces opioid agonists and thereby reverses their effects. Because naloxone is a
low-molecular-weight, lipophilic, uncharged compound, it is readily absorbed. Its
reversal effect is usually rapid and complete but also short-lasting. Naloxone has a
half-life of approximately 2 hours, a shorter duration of action than most opioids.
Figure 1. Using the Nasal Cavity
Therefore, careful monitoring of respiration is warranted when naloxone is used as a Portal for Drug Delivery.
as an antagonist to longer-acting opioids. The nasal cavity can be used as a
Naloxone is available in two formulations for clinical use: an injectable formu- portal for the systemic delivery of
lation intended for intravenous, intramuscular, or subcutaneous administration and drugs, including naloxone.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

a concentrated formulation intended for intranasal administration. Intranasal ad-

ministration of the injectable formulation of naloxone has been reported, but this
approach has not been approved by the Food and Drug Administration, is less effective
than injection of this formulation, and requires time-consuming assembly of an
atomization device.1
The intravenous route of administration is favored if intravenous access is eas-
ily obtained. When naloxone is administered intravenously, the plasma level rises
immediately, and the onset of action is usually apparent within 2 minutes. When
naloxone is administered intranasally, it is still effective but acts more slowly; an
equipotent dose achieves more than 50% of the peak plasma level within 10 min-
utes and achieves the peak level within 15 to 30 minutes.2 The advantages of the
intranasal delivery of naloxone include ease of administration, rapid onset of action, Figure 2. Administering Intranasal
and the avoidance of a phenomenon known as the first-pass effect, in which the Naloxone.
concentration of a drug administered orally is reduced before it reaches the sys- Before intranasal naloxone is admin-
temic circulation. The nasal mucosa is highly vascularized and permeable, making istered, the back of the patient’s neck
should be supported and the head
it a suitable portal for the systemic delivery of drugs (Fig. 1). With intranasal ad-
should be allowed to tilt back.
ministration, drug diffusion depends on the concentration gradient at the absorp-
tion site. Changes in nasal blood flow and local vasoconstriction or vasodilatation
can alter the increase in the plasma level of the administered compound and, conse-
quently, the onset of the drug’s effect.

Procedure for Intranasal Administration of Naloxone

Naloxone nasal spray is available in cartons with two blister packs, each containing
a 4-mg dose in a 0.1-ml aqueous solution. To start the procedure, open one of the
packs by peeling back its tab. Do not prime or test the spray. Each blister pack
contains a single dose of naloxone and cannot be reused. Place the patient in the
supine position. With one hand, support the back of the patient’s neck, allowing
the head to tilt (Fig. 2). Hold the nasal spray in your other hand. Place your thumb
on the end of the plunger and your first and middle fingers on either side of the
nozzle. Then, administer the nasal spray by gently inserting the tip of the nozzle Figure 3. Pressing the Plunger.
into one of the patient’s nostrils until both fingers are pressed against the patient’s Naloxone nasal spray is delivered by
nostril (Fig. 3). Press the plunger firmly to make sure that the entire dose has been inserting the tip of the nozzle into
one of the patient’s nostrils and
delivered. pressing the plunger.
If the patient remains unresponsive or has a relapse of respiratory depression,
a new pack can be opened and the spray can be administered every 2 to 3 minutes
until the patient becomes responsive. However, if spontaneous breathing does not
occur or remains insufficient despite the use of intranasal naloxone, additional
supportive and resuscitative measures should be taken and the patient’s airway
secured (Fig. 4).

Common Problems and Complications

The administration of naloxone can precipitate symptoms of opioid withdrawal,
including diaphoresis, a runny nose, nervousness, and shivering or trembling.3 Ad-
verse cardiovascular effects, such as tachycardia and hypertension, as well as stom-
ach cramping, nausea, vomiting, or weakness, may also occur.

Postprocedural Care Figure 4. Managing Airway Obstruction.

After successful reversal of opioid toxicity, monitor the patient for complications Upper airway obstruction can be
managed by thrusting the patient’s
such as opioid withdrawal and, in rare instances, noncardiogenic pulmonary
jaw forward.
edema, and maintain surveillance. Provide cardiovascular and respiratory support
as needed. Once the patient is conscious, obtain a complete patient history and
conduct a physical examination to identify any coexisting conditions or injuries.

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The New England Journal of Medicine
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 The n e w e ng l a n d j o u r na l of m e dic i n e

Patients with complications such as pulmonary aspiration or anoxic brain injury

may require airway management and admission to an intensive care unit. A com-
plete evaluation for substance use disorder and a referral for treatment are critical,
since the short-term mortality for survivors of nonfatal opioid overdose is high,
particularly in the first 2 days after overdose.4

Summary
Timely intranasal administration of naloxone can prevent irreversible anoxic brain
injury or death by reversing life-threatening depression of the central nervous and
respiratory systems caused by an opioid overdose.
No potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References
1. Tippey KG, Yovanoff M, McGrath LS, Sneeringer P. Comparative human factors evaluation of two nasal
naloxone administration devices: NARCAN® Nasal Spray and naloxone prefilled syringe with nasal atomizer.
Pain Ther 2019;​8:​89-98.
2. Mundin G, McDonald R, Smith K, Harris S, Strang J. Pharmacokinetics of concentrated naloxone nasal
spray over first 30 minutes post-dosing: analysis of suitability for opioid overdose reversal. Addiction 2017;​
112:​1647-52.
3. Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal: current evidence and clinical implica-
tions. Ther Adv Drug Saf 2018;​9:​63-88.
4. Weiner SG, Baker O, Bernson D, Schuur JD. One-year mortality of patients after emergency department
treatment for nonfatal opioid overdose. Ann Emerg Med 2020;​75:​13-7.
Copyright © 2021 Massachusetts Medical Society.

n engl j med 384;12  nejm.org  March 25, 2021 e44(3)

The New England Journal of Medicine
Downloaded from nejm.org by JHON TICONA on August 1, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.