American Journal of Therapeutics 0, 1–8 (2017)

Acute Opiate Overdose: An Update on Management

Strategies in Emergency Department and Critical Care Unit

Rukma Parthvi, MBBS,1 Abhinav Agrawal, MD,2 Sameer Khanijo, MD,2

Adey Tsegaye, MD, FCCP,2 and Arunabh Talwar, MD, FCCP2*

Background: Opioids are natural, semisynthetic, or synthetic substances that act on opioid receptors
in the central nervous system. Clinically, they are prescribed for pain management. Opioid overdose
(OOD) occurs when the central nervous system and respiratory drive are suppressed because of
excessive consumption of the drug. Symptoms of OOD include drowsiness, slow breathing, pinpoint
pupils, cyanosis, loss of consciousness, and death. Due to their addictive potential and easy acces-
sibility opioid addiction is a growing problem worldwide. Emergency medical services and the
emergency department often perform initial management of OOD. Thereafter, some patients require
intensive care management because of respiratory failure, metabolic encephalopathy, acute kidney
injury, and other organ failure.

Areas of Uncertainty: We sought to review the literature and present the most up-to-date treatment
strategies of patients with acute OOD requiring critical care management.

Data Sources: A PubMed search was conducted to review all articles between 1950 and 2017 and the
relevant articles were cited.

Results & Conclusions: Worldwide, approximately 69,000 people die of OOD each year, and
approximately 15 million people have opioid addiction. In the United States, death from OOD
has increased almost 5-fold from 2001 to 2013. OOD leading to intensive care unit admission has
increased by 50% from 2009 to 2015. At the same time, the mortality associated with these
admissions has doubled. The management strategies include airway management, use of rever-
sal agents, assessing and treating coingestions and associated complications, treatment of opioid
withdrawal with alpha-agonists, and psychosocial support to help with opiate addiction and
withdrawal. This warrants awareness among clinicians regarding the adverse effects associated
with opioid use, management strategies, and calls for a multidisciplinary approach to treating
these patients.

Keywords: opioid overdose, critical care, naloxone, adults

1
Department of Internal Medicine, Forest Hills Hospital, New York, NY; and 2Division of Pulmonary, Critical Care and Sleep Medicine,
Department of Medicine, Hofstra Northwell School of Medicine, North Shore University Hospital & Long Island Jewish Medical Center,
New Hyde Park, NY.
The authors have no conflicts of interest to declare.
*Address for correspondence: Division of Pulmonary, Critical Care and Sleep Medicine, Northwell Health, 410 Lakeville Road, Suite 107,
New Hyde Park, NY 11040. E-mail: arunabhtalwar1@gmail.com

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 2 Parthvi et al
INTRODUCTION
Opioids are natural, semisynthetic, or synthetic sub-
stances, which act on opioid receptors of the brain.
The opium poppy has been used medicinally and rec-
reationally for millennia. Morphine was isolated from
a plant in the 19th century, and synthetic opioids were
first prepared in the 20th century. Examples of natural
opioids are morphine and codeine. Semisynthetic
opioids are derived from the naturally occurring
opium alkaloids and include heroin, hydrocodone, hy-
dromorphone, oxycodone, buprenorphine, and oxy-
morphone. Synthetic opioids are made from
chemicals not found in opium (eg, methadone, meper-
idine, and fentanyl).
Opioids can be categorized by their interaction with
the opioid receptors of the brain into agonists, antag-
onists, partial agonists, and mixed agonists (Figure 1).
Opioid agonists have clinical applications in the form
of analgesics. Opioid antagonists or reverse agonists
are competitive inhibitors of the opioid receptors and
are used clinically to treat opioid overdose (OOD).
Partial agonists can be used for long-term manage-
ment of opioid addiction.
The primary indication of opioid use is pain man-
agement (Figure 2). Although newer strategies with
nonopioid drugs are encouraged, opioids remain the
mainstay of pain management. These drugs have
a high addiction potential and are associated with
the development of tolerance. The use of opioids for
pain management, as well as the growth in the recre-
ational use of opioids has shown a marked increase in
FIGURE 1. Types of opioids based on interaction with
opioid receptors.
American Journal of Therapeutics (2017) 0(0)
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recent years.1–3 Worldwide, approximately 69,000 peo-
ple die of OOD each year, and approximately 15 mil-
lion people have opioid addiction.3 In the United
States, death from OOD has increased almost 5-fold
from 2001 to 2013.4 OOD leading to intensive care unit
(ICU) admission has increased by 50% from 2009 to
2015. At the same time, the mortality associated with
these admissions has doubled.5 Thus, it is essential to
discuss and review the management strategies of OOD
in critically ill patients.
PHARMACOLOGY OF OPIOIDS
Opioids bind to mu (m), kappa (k), and sigma (s) re-
ceptors in the brain.6 Mu receptors are further classi-
fied to Mu1 and Mu2 receptors. While Mu1 receptors
are associated with analgesia, Mu2 receptors are asso-
ciated with respiratory depression, bradycardia, and
physical dependence. Once opioids bind to a receptor,
a secondary messenger called G protein is activated.
This protein hyperpolarizes the membranes and inhib-
its neuronal activity in the medulla, spinal cord, spinal
trigeminal nucleus, and periaqueductal gray area with
resultant effects. The duration of action differs among
the different opioids and is listed in Table 1.
Oral opioids have variable pharmacokinetics. When
taken in low doses, they are metabolized through first-
order kinetics where dose elimination is exponential;
hence, risk of toxicity is low. At high doses, however,
zero-order kinetics occurs, which means that there is
fixed-dose elimination per unit of time. This delayed
elimination precipitates severe and late-onset opioid
toxicity. Other factors, which can lead to toxicity,
include improper use of the medications. Injecting
grounded opioid tablets or heating analgesic patches
before application can increase the rate of absorption.
A large ingestion of opioids may form bezoars, which
can cause an unpredictable rate of absorption and
elimination because of delayed gastric emptying
and decreased gastrointestinal motility.7 Patients with
chronic use of opioid analgesics develop tolerance to
analgesia and respiratory depression over time.
Because the rate of tolerance to respiratory depression
is less than the tolerance to analgesic effect, these pa-
tients have a much higher risk of respiratory failure.8
Most common coingestions with opioids are alcohol
and benzodiazepines.9 Central nervous system depres-
sants such as opioids combined with benzodiazepines
or alcohol can cause profound sedation and respira-
tory arrest, increasing the risk of death.3 In fact, alcohol
is involved in 1 of 5 of opioid-related deaths.10 Screen-
ing for coingestion is an important step in treating
OOD. Pfister et al showed that 91% of people with
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ER & ICU Management of Opiate Overdose
FIGURE 2. Pharmacological agents used in pain management.
coingestions required invasive mechanical ventilation
and an extended ICU stay.9 Some opioids are available
as a combination tablet with acetaminophen. When
patients take increasing doses of these preparations,
the risk of acetaminophen toxicity and liver failure in-
creases.11 The concomitant use of oxycodone with all
cytochrome P450 3A4 inhibitors such as macrolides
and protease inhibitors can lead to toxic plasma levels
of oxycodone.12
CLINICAL PRESENTATION AND
DIAGNOSIS OF OPIOID OVERDOSE
An OOD can be easily identified by a combination of 3
symptoms called the OOD triad, namely unconscious-
ness, respiratory depression, and pinpoint pupils.13
Common OOD symptoms are respiratory and mental
depression, miosis, mydriasis (if hypoxic), nausea or
uncontrolled vomiting, and atypical snoring. Less
common symptoms include acute lung injury, QT pro-
longation, seizure, bowel obstruction, and noncardio-
genic pulmonary edema.14
Decreased respiratory drive is one of the most dan-
gerous side effects of OOD and is the reason that
opioids are responsible for a high proportion of drug
overdose deaths around the world.3 Respiratory
depression indicated by a respiratory rate of less than
12 breaths per minute or apnea also rules out other
common toxicities that present with miosis and coma,
such as antipsychotics drugs, anticonvulsant agents,
alcohol, or other sedative hypnotic medications.15
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3
Negative pressure pulmonary edema can occur
because of fluid extravasation secondary to decreased
intrathoracic pressure from breathing against a closed
glottis. Also, acute lung injury may arise from sympa-
thetic vasoactive response after reversal of intoxication
resulting in leakage from pulmonary vessels causing
noncardiogenic pulmonary edema.16 Diagnostic inter-
ventions include a thorough physical examination,
complete blood count, serum chemistries, chest x-ray,
computed tomography or magnetic resonance imag-
ing of the brain if traumatic head injury is suspected
or in case of seizures, and an electrocardiogram to
screen for arrhythmias and myocardial ischemia.
INITIAL MANAGEMENT
Primary treatment focuses on the stabilization of the
cardiopulmonary status.17,18 Airway management and
the continuous assessment of oxygenation and venti-
lation, along with administration of naloxone, is the
standard of care for emergency medical services per-
sonnel treating OOD.19,20 Long-acting opioid patches
must be searched for and removed promptly.21,22 If
opioid ingestion occurred within 1 hour of presenta-
tion, activated charcoal may be used for gastrointesti-
nal decontamination.23 In case of heroin intoxication,24
patients can be discharged 1–2 hours after naloxone
administration if they can ambulate without assis-
tance, oxygen saturation is more than 92% on room
air, respiratory rate is more than 10 breaths
per minute, heart rate is more than 50 beats
per minute, normal temperature, and Glasgow coma
American Journal of Therapeutics (2017) 0(0)
 4 Parthvi et al

Table 1. Half-life of opioid agents.46,47 rhabdomyolysis and acute renal failure are also at an
elevated risk of arrhythmias either because of hyperkale-
Opioid Half-life mia or direct effect of opioids such as oxycodone and
Buprenorphine Intravenous: 2.2–3 h methadone.28 Drugs such as meperidine, tramadol, and
Sublingual tablet: ;37 h
tapentadol can cause breakthrough seizures that may
require intubation for airway protection.29,30 Acute
Transdermal patch: ;26 h
liver failure resulting in hepatic encephalopathy can
Butorphanol 2–9 h
occur from coingestion with acetaminophen. Rarely,
Codeine 3h anaphylactic and hypersensitivity reactions may
Fentanyl Intravenous: 2–4 h occur with acetaminophen and oxycodone. These
Transdermal patch: 20–27 h include generalized exanthematous pustulosis,
Transmucosal products: 3–14 h Stevens–Johnson syndrome, and toxic epidermal
Nasal spray: 15–25 h Necrolysis, which might warrant management in
Hydrocodone 3.3–4.4 h a closely monitored setting.31
Hydromorphone Immediate release: 2–3 h
Extended release: ;11 h
CRITICAL CARE MANAGEMENT OF
Levorphanol 11–16 h
Meperidine Adults: 2.5–4 h
OPIOID OVERDOSE
Liver disease: 7–11 h
Once the cardiopulmonary status of the patient has
Methadone Adults: 8–59 h. May be prolonged with
been stabilized, the primary focus of treatment is on
alkaline pH
the reversal of the opioid. Naloxone is a competitive
Morphine Immediate release forms: 2–4 h
antagonist of the mu opioid receptor and is used to
Oxycodone Oral: Immediate release: 7–9 h reverse the effects of opioids. It reverses and blocks
Extended release: 9–11 h the action of opioids. Naloxone is useful in reducing
Tapentadol Immediate release: 4 h respiratory and mental depression. It is available to
Long-acting formulations: 5–6 h be used through intravenous (IV), intramuscular
Tramadol Tramadol: 6–8 h (IM), subcutaneous (SC), intranasal, endotracheal,
nebulized/inhalational, and buccal or sublingual
routes.32 Endotracheal, parenteral, IM, and SC admin-
scale of 15. In case of non–heroin opioid intoxication, istration has an onset of action of 2–5 minutes; neb-
discharge can be considered 4–6 hours after naloxone ulized administration has an onset of action of
administration if the patient remains asymptomatic. In approximately 5 minutes, and intranasal preparation
methadone overdose, observation for 12–24 hours is has an onset of action of 8–13 minutes. The half-life of
recommended, given the longer half-life (Figure 3). naloxone is approximately 30–90 minutes. Some pa-
Emergency physicians must confirm that opioid detox- tients may require repeated doses of naloxone
ification is complete before discharging the patient.25 because of its relatively short half-life compared with
that of opioids. Naloxone administration may be
repeated without harm if required.33 Dosing of nal-
ETIOLOGY OF ADMISSION TO THE oxone should be performed carefully with repeated
INTENSIVE CARE UNIT dose escalation to avoid provoking severe opioid
withdrawal.34
Patients with OOD can develop respiratory depression Patients with very low respiratory rates or apnea
requiring intubation and thus, may warrant further man- should receive 0.4–2 mg IV/IM/SC as an initial dose,
agement in the ICU.9 Other pulmonary complications of and must be ventilated by bag-valve mask and pro-
OOD causing respiratory failure are noncardiogenic vided with oxygen supplementation. Patients who
pulmonary edema and aspiration pneumonitis.26 Present develop cardiorespiratory arrest should get at least
with hypothermia and profound hypotension requiring 2 mg of naloxone. Dose (0.005–0.01 mg/kg) may be
vasopressor support opioid poisoning can lead to ele- repeated every 2–3 minutes as needed, based on
vated serum aspartate aminotransferase and creatinine response. Once the patient has spontaneous ven-
kinase levels, myoglobinuria, hypocalcaemia, and hypo- tilations, an infusion of naloxone at a rate of 0.0025–
phosphatemia because of drug-induced myopathy caus- 0.16 mg/kg should be started. The rate of infusion
ing rhabdomyolysis. Patients may end up in acute renal can be titrated up to reach the goal of more than 12
failure and require hemodialysis.27 Patients with breaths per minute, for a maximum of 5–10 mg.35
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ER & ICU Management of Opiate Overdose
FIGURE 3. Discharge disposition from the emergency department.
Alternate diagnosis should be considered if there is
no response after 10 mg naloxone. If signs of with-
drawal are seen, the infusion should be stopped. If
the patient starts to get more lethargic and respiratory
rate decreases, the infusion should be restarted. The
goal of the treatment is to achieve a stable mental
status and ensure adequate ventilation. Capnography
can be used to monitor ventilator effort in OOD pa-
tients on mechanical ventilation. The large volume of
distribution does not allow extracorporeal removal of
opiates.36
Sodium bicarbonate at an initial bolus dose of 1–2
mEq/kg intravenously should be given for OOD-
associated wide complex arrhythmias. Patients who
develop pulmonary edema or acute respiratory dis-
tress syndrome should be managed with adequate
oxygenation, prone positioning, and low tidal volume
ventilation while using high positive end expiratory
pressure for alveolar recruitment.37 Acid–base disor-
ders are common in patients with OOD because of
central respiratory depression that causes CO2 reten-
tion leading to respiratory acidosis. These patients
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5
may require noninvasive or invasive ventilation to
treat the hypercapnia. OOD can also cause vomiting
and diarrhea that can manifest with metabolic alkalo-
sis and metabolic acidosis, respectively.38,39 Patients
presenting with rhabdomyolysis need aggressive fluid
resuscitation. Urgent fasciotomy may be required for
those who develop compartment syndrome from acute
myopathy. Patients may rarely develop OOD from
intrathecal analgesic infusion and may require cerebro-
spinal lavage and naloxone.40
Chronic opioid use suppresses catecholamine release
in the body. When patients are admitted to the ICU for
management of OOD, it results in an abrupt discontin-
uation of opioids, causing a rebound increase in norad-
renergic signal leading to signs and symptoms of opioid
withdrawal.41 Clonidine was the first alpha-agonist used
to manage opioid withdrawal and is widely studied in
heroin detoxification regimens.42 Although there are no
standardized regimens, the drug is initiated at doses of
0.1–0.2 mg orally 2–4 times daily in adults and titrated to
0.3 mg orally 3–4 times daily to control withdrawal
symptoms. Once the withdrawal symptoms have
American Journal of Therapeutics (2017) 0(0)
 6 Parthvi et al

FIGURE 4. Management strategies in emergency department and critical care unit.

subsided, the medications are tapered over 1–2 weeks.42
Transdermal clonidine can be used in patients with lack
of enteral access or concern for variable absorption, but
its use is limited because of delayed onset of action (12–
24 hours). Dexmedetomidine is an IV, highly selective
alpha 2-agonist that is commonly used as a sedative in
the ICU. It has been reported to facilitate opioid
detoxification and help acute withdrawal symptoms
in patients with chronic opioid use. In a case report,
dexmedetomidine was given as a continuous infu-
sion at 0.7 mg/kg per hour after a loading dose of
50 mg over 30 minutes.43 Honey et al reviewed mul-
tiple case reports and case series describing the use
of dexmedetomidine for iatrogenic opiate with-
drawal syndrome.44 They concluded that its short
half-life and route of administration make it more
suitable for use in the ICU setting.
The management strategy for OOD patients in the
emergency department and the critical care setting has
been summarized in Figure 4.
American Journal of Therapeutics (2017) 0(0)
LONG-TERM STRATEGIES
After ICU stay, patients should be monitored on
a medical floor before discharge to home or drug
detoxification centers.9 Management of overdose is
the initial step in addressing opioid addiction. Patients
are at high risk of recurrent OOD events.45 Long-term
management involves treatment for addiction with
medications such as naltrexone, methadone, and sub-
oxone, as well as psychosocial treatments such as indi-
vidual, group, and family therapy, and support
groups such as Narcotics Anonymous.
CONCLUSION
Opioids have an important role in pain management.
Unfortunately, the current crisis in opioid addiction
has increased the frequency of OOD, leading to
increased morbidity and mortality. The management
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ER & ICU Management of Opiate Overdose
of OOD starts with interventions by the emergency
medical services and continues in the emergency
department and the ICU. These management strate-
gies include airway management, use of reversal
agents, assessing and treating coingestions and associ-
ated complications, treatment of opioid withdrawal
with alpha-agonists, and psychosocial support to help
with opiate addiction and withdrawal. This warrants
awareness among clinicians regarding the adverse ef-
fects associated with opioid use, management strate-
gies, and calls for a multidisciplinary approach to
treating these patients.
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