Embed Size (px)
Citation preview
Official reprint from UpToDate
www.uptodate.com ©2015 UpToDate
Authors
Andrew Stolbach, MD
Robert S Hoffman, MD
Section Editor
Stephen J Traub, MD
Deputy Editor
Jonathan Grayzel, MD, FAAEM
Acute opioid intoxication in adults
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2014. | This topic last updated: Apr 03, 2014.
INTRODUCTION — Opiates extracted from the poppy plant (Papaver somniferum) have been used recreationally
and medicinally for millennia. Opiates belong to the larger class of drugs, the opioids, which include synthetic and
semi-synthetic drugs, as well. Opioid abuse is a worldwide problem and deaths from opioid overdose are numerous
and increasing [1-4].
This topic review will discuss the mechanisms, clinical manifestations, and management of acute opioid
intoxication. A summary table to facilitate emergent management is provided (table 1). Issues related to opioid
withdrawal, chronic opioid abuse, and general management of the poisoned patient are found elsewhere. (See
"Opioid withdrawal in the emergency setting" and "Treatment of opioid use disorder" and "Opioid use disorder:
Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "General
approach to drug poisoning in adults".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY — The opioid pharmaceuticals are analogous to the three
families of endogenous opioid peptides: enkephalins, endorphins, and dynorphin. The most recent classification
scheme identifies three major classes of opioid receptor, with several minor classes [5]. Within each receptor class
there are distinct subtypes. Each subtype produces a variety of distinct clinical effects, although there is some
overlap (table 2). For most clinicians, the nomenclature derived from the Greek alphabet is more familiar, although
the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature has recommended a
change from the original Greek system to make opioid receptor names more consistent with other neurotransmitter
systems [5].
The opioid receptors are distinct in their locations and clinical effects, but they are structurally similar (table 2).
Each consists of seven transmembrane segments, with amino acid and carboxy termini. Although the opioid
receptors are all coupled to G proteins, they use a variety of signal transduction mechanisms [5]. These include
reducing the capacity of adenylate cyclase to produce cAMP, closing calcium channels that reduce the signal to
release neurotransmitters, or opening potassium channels to hyperpolarize the cell [5].
The end result of these mechanisms is to modulate the release of neurotransmitters. Opioid receptors exist
throughout the central and peripheral nervous system and are linked to a variety of neurotransmitters, which
explains the diversity of their clinical effects. The analgesic effects of opioids result from inhibition of nociceptive
information at multiple points of its transmission from the peripheral nerve to the spinal cord to the brain. Euphoria
results from increased dopamine released in the mesolimbic system [6]. Anxiolysis results from effects on
noradrenergic neurons in the locus ceruleus [7].
KINETICS — The vast number of opioids precludes presenting pharmacokinetic data for each one, but a few
clinically important generalizations can be made. The majority of opioids have volumes of distribution of 1 to 10
L/kg, which makes removal of a significant quantity of drug by hemodialysis impossible. They have variable protein
binding (from 89 percent for methadone to 7.1 percent for hydrocodone) and are renally eliminated. Many opioids
are metabolized by the liver to active metabolites. Examples include hydrocodone (metabolized to hydromorphone
by Cytochrome [CY] P2D6) and morphine (metabolized to morphine-6-glucuronide). Cytochrome P polymorphisms
cause variations in clinical effect.
®
®
The most clinically important pharmacokinetic difference is a wide variation in serum half-life (table 3). The half-life
data in these tables, taken from healthy subjects receiving therapeutic doses, should serve only as a rough guide to
duration of clinical effect. Actual effects are influenced by dose, an individual's tolerance, and the presence of active
metabolites.
In overdose the serum half-life may vary significantly from therapeutic dosing. If many tablets are taken, dissolution
and absorption will be delayed, prolonging the apparent half-life. Duration of action may also be shortened in
overdose. As an example, when a sustained-release formulation of oxycodone is crushed before ingestion, the drug
is rapidly absorbed. While the user's intent may be to increase euphoria, the chance of significant morbidity is
increased as well.
Although active metabolites of some opioids (eg, morphine) may accumulate in patients with renal insufficiency,
such metabolites are not dialyzable and management is unchanged [8].
CLINICAL FEATURES OF OVERDOSE — Important clinical features related to opioid intoxication are discussed
here. A general approach to the overdose patient is found elsewhere. (See "General approach to drug poisoning in
adults".)
History — The clinician should attempt to identify the specific drug, dose, and formulation to which the patient was
exposed, the presence of nonopioid coexposures, and the individual's prior history of opioid use. One review found
the "typical" heroin death to involve experienced users in their 20s to 30s using coingestants [9]. While not
essential for management, historical features may help predict the expected duration of poisoning. History should
also determine the reason for poisoning, as the patient's intention will influence post-overdose management.
Generally, opioid exposures will fall into one of several categories: therapeutic use, recreational use, intended self-
harm, attempt to hide drugs from law enforcement out of fear for arrest ("body stuffing"), swallowing large quantities
of packaged drugs in order to transport them across borders ("body packing"), and unintentional pediatric
exposures.
Physical examination — Physical examination helps to confirm the diagnosis of opioid poisoning, determine the
extent of intoxication, identify other conditions requiring treatment, and prevent further exposure (table 4).
The classic signs of opioid intoxication include:
Normal pupil examination does not exclude opioid intoxication. Users of meperidine [10] and propoxyphene may
present with normal pupils, and the presence of coingestants (such as sympathomimetics or anticholinergics) may
make pupils appear normal or large. The best predictor of opioid poisoning is a respiratory rate <12, which predicted
response to naloxone in virtually all patients in one series [11]. The clinician should measure the respiratory rate
and pay close attention to chest wall excursion, as subtle changes may not be identified in triage vital signs.
While decreased respiratory rate is the most notable vital sign abnormality, heart rate ranges from normal to low,
although this is not usually consequential. Mild hypotension (from histamine release) may also be present [12].
Pulse oximetry should be performed in every patient, although the clinician should be wary that hypercapnia can be
present in the setting of normal oxygen saturation, particularly when the patient is placed on supplemental oxygen.
Obtain a core temperature from any patient more than mildly intoxicated. Hypothermia, which results from a
combination of environmental exposure and impaired thermogenesis, may be present. In a severely obtunded
patient, room temperature may produce significant hypothermia. Elevated temperature may suggest early aspiration
pneumonia or complications of injection drug use, such as endocarditis.
Depressed mental status●
Decreased respiratory rate●
Decreased tidal volume●
Decreased bowel sounds●
Miotic (constricted) pupils●
Mental status can range from euphoria to coma, or may be nearly normal. Seizures can occur in the setting of
propoxyphene, tramadol, or meperidine exposure, or as a result of hypoxia from any opioid.
During the secondary survey, look for signs of trauma, particularly to the head. Not only do opioids predispose the
patient to trauma, but obtundation from traumatic brain injury can be misidentified as drug intoxication. Pulmonary
findings, such as rales, can indicate the presence of aspiration or acute lung injury. If the patient is suspected of
attempting to hide drugs out of fear for arrest, rectal and vaginal examination should be performed with the patient's
permission. If the patient cannot give consent because of poisoning, consent is inferred based on medical
necessity. Examination of the skin may identify medication patches that must be removed, track marks suggesting
history of chronic injection drug use, or coexisting soft tissue infections (picture 1).
Toxicities of specific agents — In addition to the general features described above, some agents have specific
toxicities. A brief description of the notable, albeit infrequent, effects and characteristics of several opioids
commonly encountered in the overdose patient follows:
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of opioid intoxication includes toxic and nontoxic
conditions.
There are myriad drugs that can produce coma (table 5). Ethanol, clonidine, and sedative-hypnotics (eg,
benzodiazepines) may be the most clinically-relevant toxic agents in the differential diagnosis, because they are so
frequently seen. While clonidine may produce miosis and obtundation, bradycardia, and hypotension are more
prominent. Ethanol intoxication produces little to no miosis and no change in bowel sounds. The sedative-hypnotic
agents result in much less respiratory depression than the opioids, especially when taken orally. (See "Ethanol
intoxication in adults".)
The presence of coingestants often confounds the diagnosis of opioid intoxication. While it is frequently impossible
to determine the exact substances to which the patient was exposed, a careful history, physical examination, and
judicious use of laboratory studies can determine the correct course of management. The sine qua non of opioid
intoxication is clinical response to an antagonist, although giving large doses of antagonist to establish the
diagnosis of opioid poisoning is usually not helpful and potentially dangerous, and therefore not recommended. (See
'Management' below and "General approach to drug poisoning in adults".)
Any medical condition that can produce coma may be mistaken for (or occur in conjunction with) opioid poisoning.
The most important conditions to exclude are those in which delay of diagnosis will delay definitive care, such as
cerebrovascular accident, electrolyte abnormality, and sepsis (table 6). (See "Stupor and coma in adults".)
LABORATORY EVALUATION AND ANCILLARY STUDIES
Laboratory evaluation — A rapid serum glucose concentration should be obtained in all suspected cases of
opioid overdose. Hypoglycemia is prevalent, easily detectable, rapidly correctable, and potentially confused with
opioid poisoning. Most patients with mild or moderate unintentional or recreational poisoning can be managed
successfully without any further laboratory investigation.
Buprenorphine – Partial opioid agonist, may induce withdrawal in opioid-dependent patients●
Dextromethorphan – Serotonin syndrome, at high doses exhibits some µ effects of opioids (miosis,
respiratory and CNS depression), but is not a pure opioid agonist
●
Fentanyl – Very short acting●
Hydrocodone – Often combined with acetaminophen●
Meperidine – Seizure, serotonin syndrome (in combination with other agents) (see "Serotonin syndrome")●
Methadone – Very long-acting; QTc prolongation, Torsades de Pointes (see 'Electrocardiography' below)●
Oxycodone – Often combined with acetaminophen; possible QTc interval prolongation●
Propoxyphene – QRS prolongation, seizure●
Tramadol – Seizure●
After any overdose in which the opioid is formulated with acetaminophen, or any overdose that is the result of
intended self-harm, serum acetaminophen concentration should be obtained. In one series, 1 in 365 individuals with
suicidal ingestion and history negative for acetaminophen ingestion had a potentially hepatotoxic acetaminophen
concentration [13]. It is not essential to obtain a salicylate concentration in the absence of clinical suspicion or
signs of overdose (eg, tachypnea or increased anion gap). (See "Acetaminophen (paracetamol) poisoning in adults:
Treatment" and "Salicylate (aspirin) poisoning in adults".)
To exclude rhabdomyolysis in the patient presenting after prolonged immobilization, serum creatine phosphokinase
concentration should be obtained. Further testing, such as serum creatinine and electrolytes, may be needed
depending on clinical circumstances. (See "Clinical manifestations and diagnosis of rhabdomyolysis" and "Clinical
features and diagnosis of heme pigment-induced acute kidney injury (acute renal failure)", section on 'Clinical
manifestations'.)
Urine toxicologic screens should NOT be routinely obtained. Acute opioid poisoning is a clinical diagnosis; the
management of a patient with an opioid toxidrome is unchanged by the result of a urine opioid screen. A positive
test may indicate recent use but not current intoxication, or may even represent a false positive. Conversely, many
opioids, especially the synthetic drugs, will produce false-negative results in many commonly available urine
screens. Commonly available laboratory assays (eg, for phenytoin) can be performed if the history or examination
suggests coingestion.
Electrocardiography — An electrocardiogram (ECG) should be obtained when the patient is suspected of
intended self-harm or a coexposure likely to cause cardiovascular complications is possible (eg, cocaine or a cyclic
antidepressant). With a few exceptions, electrocardiography can be omitted in other types of opioid exposure.
Propoxyphene is unique among the opioids for its type IA antidysrhythmic properties. Prolongation of the QRS
interval can occur and is responsive to sodium bicarbonate administration [14]. (See 'Specific agents' below.)
Methadone can cause QTc interval prolongation and Torsades de Pointes. This phenomenon more commonly
occurs in patients taking high daily doses of the drug [15]. However, the observations that most people who take
very large doses of methadone tolerate it well and that some have developed QTc prolongation from lower doses
suggest individual susceptibility to the condition varies. There may also be an association with oxycodone toxicity
and QTc prolongation [16].
The benefit of performing an ECG on every individual with a history of methadone or oxycodone exposure is
unstudied and cannot be recommended. Rather, the test should generally be reserved for those patients presenting
after a large dose increase or with complaints suggesting a dysrhythmia, such as palpitations or syncope. (See
'Specific agents' below and "Acquired long QT syndrome".)
Imaging — Chest radiography is reserved for those patients with adventitious lung sounds or hypoxia that does not
correct when ventilation is addressed. Abnormal lung sounds may represent aspiration pneumonia or acute lung
injury. (See 'Acute lung injury' below.)
Imaging of drug packets is discussed below. (See 'Body packing and body stuffing' below.)
MANAGEMENT
Basic measures and antidotal therapy — General management of the overdose patient is discussed elsewhere.
(See "General approach to drug poisoning in adults".) Specific management strategies for opioid overdose are
discussed below. A summary table to facilitate emergent management is provided (table 1).
Once opioid poisoning is suspected, initial management should focus on support of the patient's airway and
breathing. Attention should be paid to the depth and rate of ventilation. While pulse-oximetry is useful in monitoring
oxygenation, it may not be useful in gauging ventilation when supplemental oxygen is being given. While not yet
widely used for this purpose, capnography may prove to be an excellent tool to monitor the ventilatory effort of
opioid-poisoned patients. Several studies in patients undergoing procedural sedation show that ventilatory difficulty
manifests as elevations in end-tidal CO2 earlier than declines in oxygenation by pulse oximetry. (See "Carbon
dioxide monitoring (capnography)".)
Administer naloxone, a short-acting opioid antagonist, by the intravenous route. The apneic patient and patients
with extremely low respiratory rates or shallow respirations should be ventilated by bag-valve mask attached to
supplemental oxygen prior to and during naloxone administration to reduce the chance of acute lung injury [17].
Apneic patients should receive higher initial doses of naloxone (0.2 to 1 mg). Patients in cardiorespiratory arrest
following possible opioid overdose should be given a minimum of 2 mg of naloxone [18,19]. (See 'Acute lung injury'
below and "Basic airway management in adults".)
When spontaneous ventilations are present, an initial dose of 0.05 mg is an appropriate starting point, and the dose
should be titrated upward every few minutes until the respiratory rate is 12 or greater [20]. The goal of naloxone
administration is NOT a normal level of consciousness, but adequate ventilation. In the absence of signs of opioid
withdrawal, there is no maximum safe dose of naloxone. However, if a clinical effect does not occur after 5 to 10
mg, the diagnosis should be reconsidered.
Naloxone may be given subcutaneously or intramuscularly if there is a delay in securing intravenous access. When
given by these routes, there is slower absorption and delayed elimination, making the drug much more difficult to
titrate. Naloxone can be absorbed in the respiratory tract, and thus, can be administered into an endotracheal tube
or nebulized. Conceptually, there is little role for nebulized or nasal naloxone because the dose administered is
determined by the patient's ventilation, thus the most severely poisoned patients will absorb the least amount of
antidote [21]. The respiratory route and other routes of administration are less predictable. In addition, intravenous
access is required in these patients as other medications (such as hypertonic dextrose) may be needed.
If the clinician "overshoots" the appropriate dose of naloxone in an opioid-dependent individual, withdrawal will
ensue. Symptoms of withdrawal should be managed expectantly only, NOT with opioids. To overcome naloxone
antagonism requires a large dose of opioids. More importantly, because naloxone has a short duration of action,
any opioid administered will result in even more sedation once naloxone's effects subside. (See "Opioid withdrawal
in the emergency setting".)
After ventilation is restored with naloxone, repeat doses may be required, depending on the quantity and duration of
action of the opioid. As an alternative to repeat dosing, a naloxone infusion can be prepared by determining the total
initial dose required to reinstate breathing, and delivering two thirds of that dose every hour [22]. If the patient
develops withdrawal signs or symptoms during the infusion, stop the infusion. If intoxication returns, restart the
infusion at half the initial rate. If the patient develops respiratory depression during the infusion, re-administer half
the initial bolus every few minutes until symptoms improve, then increase the infusion by half the initial rate.
GI decontamination — Activated charcoal and gastric emptying are almost never indicated in opioid poisoning.
Gastrointestinal decontamination is not without risk and opioid poisoning is readily treatable by other means. While
orogastric lavage could remove tablets still in the stomach, and activated charcoal binds opioids, each of these
therapies produces a risk of aspiration, especially in the obtunded, opioid-poisoned patient. Gastrointestinal
decontamination should be reserved for patients presenting with potentially life-threatening coingestants, not for
opioids alone, and should be performed only if the airway is secure. (See "Gastrointestinal decontamination of
poisoned adults".)
Extracorporeal removal — The large volume of distribution of the opioids precludes removal of a significant
quantity of drug by hemodialysis.
Body packing and body stuffing — Body packing is described as the act of swallowing packets or containers of
drug for the purposes of smuggling. Body packers are generally participants in international drug networks who are
transporting drugs across international borders. Heroin and cocaine are more frequently implicated than other drugs
[23]. The smugglers carry massive amounts of well-packaged drugs. While the majority of body packers do not
present to health care, those who do should be evaluated for signs of intoxication (from ruptured or leaking
packets), obstruction, or rarely, gastrointestinal perforation. A detailed discussion of body packing is found
elsewhere. (See "Internal concealment of drugs of abuse (body packing)".)
Plain radiography has a sensitivity of 85 to 90 percent for finding packets [24]. Computed tomography of the
abdomen will be more sensitive, as well as offer the ability to identify complications, such as obstruction or
perforation. A negative urine screen may be useful to exclude the presence of ruptured packets.
If the history reveals that the patient has smuggled packets of heroin, the goals of management are to support the
airway and assist in elimination of the packets. Intravenous naloxone should be given until ventilation is adequate.
The total dose required should be given hourly to preserve the effect. The dose requirement may increase if further
packet rupture or leakage occurs.
After confirming bowel sounds, polyethylene glycol electrolyte lavage solution (PEG-ELS) should be administered
orally at a rate of 2 L/h until all packets have been passed. Though placement of a nasogastric tube is not
necessary (and should be avoided in the patient with a depressed mental status), it may facilitate administration of
the solution.
Operative management will be required only if gastrointestinal obstruction or perforation occur.
"Body stuffing" refers to the swallowing of a smaller quantity of drug because of fear of arrest. Compared with body
packers, body stuffers are carrying a far smaller quantity of drug and the drug is more poorly packaged. In contrast
to the "body packer", it may not be necessary to routinely administer PEG-ELS to the opioid "body stuffer". While
the regimen could theoretically cause some packages to pass before drug is absorbed, the clinician may elect to
manage the patient by close observation and administration of naloxone if symptoms arise. Oral activated charcoal
alone may be sufficient.
The body stuffer should be observed for signs of intoxication. The ideal length of time is not known, but 6 to 12
hours is reasonable. If signs of opioid poisoning develop, the patient can be managed as described above. (See
'Management' above.)
Acute lung injury — Acute lung injury (ALI) is a potential adverse effect of morphine, heroin, methadone, and other
opioids [25-27]. The signs, which typically include rales, hypoxia, and occasionally frothy sputum, often occur as a
patient is recovering from opioid-induced respiratory depression. The pathophysiology is unclear, but in some cases
ALI occurs in the setting of iatrogenic reversal of opioid toxicity (such as with naloxone). In such cases, rapid
precipitation of withdrawal in the setting of elevated PCO2 may cause a surge in catecholamine concentrations,
thereby increasing afterload, which causes interstitial edema followed by alveolar filling [17]. Because of this, very
small doses of naloxone (0.05 mg to start) should be used on those patients with marked hypoventilation and they
should be ventilated with a bag-valve mask prior to administration of naloxone. (See 'Basic measures and antidotal
therapy' above and "Basic airway management in adults".)
Management of opioid and naloxone-related acute lung injury (ALI) is supportive and the prognosis is generally good
if it is identified and addressed promptly. The clinical manifestations and management of ALI are discussed
elsewhere. (See "Acute respiratory distress syndrome: Clinical features and diagnosis in adults" and "Mechanical
ventilation of adults in acute respiratory distress syndrome" and "Acute respiratory distress syndrome: Supportive
care and oxygenation in adults".)
Specific agents — Several opioids possess uncommon toxicities requiring specific management. Propoxyphene
is unique among the opioids for its type IA antidysrhythmic properties. Prolongation of the QRS interval can occur
and is responsive to sodium bicarbonate administration [14]. The clinical benefit of this intervention is unknown, but
if QRS prolongation is encountered it seems reasonable to administer a bolus of 1 to 2 mEq/kg of sodium
bicarbonate intravenously in the absence of contraindications. If the complex narrows, a bicarbonate infusion can be
performed. We mix 132 mEq of NaHCO3 in 1 liter of D5W, and infuse at 250 mL/hour.
Methadone can cause QTc interval prolongation and Torsades de Pointes. If the QTc is determined to be greater
than 500 msec, the patient should be observed on a cardiac monitor for a 24-hour period and hypocalcemia,
hypokalemia, and hypomagnesemia should be corrected when present. The clinician should consider either
stopping methadone therapy, or switching to buprenorphine, if the patient's psychosocial situation permits this.
(See 'Electrocardiography' above and "Acquired long QT syndrome".)
Opioid adulterants, including krokodil — Illicitly-purchased drugs frequently contain adulterants, some of which
may cause clinical problems distinct from the desired compound. From the perspective of the drug seller, the ideal
adulterant would be inexpensive, appear and taste similar to the desired drug, and not harm the user. Nonetheless,
opioids containing harmful adulterants are common.
One example is “krokodil” (from the Russian word for crocodile), a homemade formulation of the potent, short-acting
opioid desomorphine [28,29]. Derived from codeine, which is available without prescription in Russia, krokodil is
reported to contain solvents, such as gasoline and lighter fluid. Other potential contaminants include iodine,
hydrochloric acid, and red phosphorous. Subcutaneous injection has resulted in local tissue damage, including
ulcers, skin necrosis, and infection. The name of the drug is derived from the scaly skin lesions observed in some
users. Such lesions are likely the result of infection and/or direct tissue injury from adulterants, as desomorphine
itself would not be expected to cause tissue toxicity, and similar findings were commonly seen with subcutaneous
injection of impure heroin in the 1980’s in the United States. Although there has been an epidemic of cases of
tissue damage from krokodil injection in former Soviet republics, cases outside this region are uncommon [28].
Alkaloids, such as quinine and strychnine, are additional examples of harmful adulterants that have been implicated
in heroin-related deaths [30]. Heroin has also been tainted with the anticholinergic scopolamine and the beta-
adrenergic agonist clenbuterol, both of which have caused widespread toxicity [31,32].
Buprenorphine and naloxone — Buprenorphine is a partial agonist at the opioid receptor. When taken alone,
buprenorphine can cause respiratory depression, but likely to a limited degree. Although most fatalities associated
with buprenorphine have occurred in the setting of mixed overdose where the coingestant may produce or contribute
to respiratory depression (eg, alcohol or benzodiazepines), fatalities may occur from buprenorphine alone [33].
Buprenorphine binds to the opioid receptor with high affinity. In experimental models, high doses of naloxone were
needed to reverse respiratory depression. Interestingly, because of complex physiology, respiratory depression can
recur with very high doses of naloxone. This effect has been described as a “bell-shaped” dose-response curve and
may be a result of the high affinity of buprenorphine for the opioid receptor compared to naloxone [34].
Such research has led some to conclude that respiratory depression from buprenorphine may be difficult to reverse
with naloxone. In observational studies of buprenorphine toxicity, the response to naloxone is mixed. In a case
series of patients with buprenorphine or methadone overdose, none of the 19 patients administered 0.4 to 0.8 mg of
naloxone had an adequate response [35]. In contrast, standard naloxone doses were adequate for reversal of
buprenorphine effects in a small series of pediatric patients treated in an intensive care unit for buprenorphine
toxicity [36].
We suggest that clinicians start with standard naloxone doses (0.04 to 0.05 mg IV) when treating patients with
buprenorphine-associated respiratory depression, but be prepared to titrate to higher doses (single doses of up to 2
mg, for a total of 10 mg) than are typically required to treat respiratory depression from other opioids. After initial
reversal is achieved, a naloxone infusion may be preferable to serial boluses. Infusion dosing is described above.
(See 'Basic measures and antidotal therapy' above.)
Disposition — With the exception of overdoses involving the long-acting opioid methadone, most opioid poisonings
can be managed in the emergency department without need for hospital admission. Generally, the patient may be
discharged or transferred for psychiatric evaluation once respiration and mental status are normal and naloxone has
not been administered for two to three hours. Although the half-life of naloxone is just over one hour, the duration of
the drug's effect is shorter. Therefore, a two to three hour period of observation is generally sufficient.
Management of opioid intoxication in children is discussed elsewhere. (See "Opioid intoxication in children and
adolescents".)
ADDITIONAL RESOURCES — Regional poison control centers in the United States are available at all times for
consultation on patients who are critically ill, require admission, or have clinical pictures that are unclear (1-800-
222-1222). In addition, some hospitals have clinical and/or medical toxicologists available for bedside consultation
and/or inpatient care. Whenever available, these are invaluable resources to help in the diagnosis and management
of ingestions or overdoses. The World Health Organization provides a listing of international poison centers at its
website: www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html
SUMMARY AND RECOMMENDATIONS
Pharmacology and presentation
Management — A summary table to facilitate emergent management is provided (table 1).
There is a wide variation in the serum half-life of opioids (table 3). Actual drug effects are influenced by dose,
an individual's tolerance, and the presence of active metabolites. In overdose the serum half-life may vary
significantly from therapeutic dosing. (See 'Pharmacology and cellular toxicology' above and 'Kinetics' above.)
●
The classic signs of opioid intoxication include: depressed mental status, decreased respiratory rate,
decreased tidal volume, decreased bowel sounds, and miotic pupils. The best predictor of opioid poisoning is
a respiratory rate <12. Normal pupil examination does NOT exclude opioid intoxication. Users of meperidine
and propoxyphene may present with normal pupils; the presence of coingestants (such as sympathomimetics
or anticholinergics) may make pupils appear normal or large. (See 'Physical examination' above.)
●
Although suppression of respiratory drive is most prominent, opioid intoxication can also be complicated by
hypothermia, coma, seizure, head trauma, aspiration pneumonia, and rhabdomyolysis. Coingestants are
frequently present. (See 'Clinical features of overdose' above.)
●
Any medical condition that can produce coma may be mistaken for (or occur in conjunction with) opioid
poisoning. The most important conditions to exclude are those in which delay of diagnosis will delay definitive
care, such as intracranial hemorrhage, electrolyte abnormality, and sepsis. (See 'Differential diagnosis'
above.)
●
A rapid serum glucose concentration should be obtained in all suspected cases of opioid overdose. Most
patients with mild or moderate unintentional poisoning can be managed successfully without any further
laboratory investigation. (See 'Laboratory evaluation' above.)
●
An electrocardiogram (ECG) should be obtained when the patient is suspected of intended self-harm or a
coexposure likely to cause cardiovascular complications is possible. Propoxyphene can cause QRS
prolongation; methadone can cause QTc prolongation. (See 'Electrocardiography' above.)
●
Initial management should focus on support of the patient's airway and breathing. (See 'Basic measures and
antidotal therapy' above.)
●
In cases of suspected opioid overdose, we recommend the short-acting opioid antagonist naloxone be given
(Grade 1B). While the intravenous (IV) route is preferred, naloxone may be given subcutaneously or
intramuscularly if IV access is unavailable.
●
When spontaneous ventilations are present, an initial naloxone dose of 0.05 mg is an appropriate starting
point, and the dose should be titrated upward every few minutes until the respiratory rate is 12 or greater. Bag
mask ventilation should be performed prior to and during administration of naloxone in apneic patients and
patients with very low respiratory rates or shallow respirations. Apneic patients should receive higher initial
doses of naloxone (0.2 to 1 mg). Patients in cardiac arrest should receive a dose no less than 2 mg. (See
'Basic measures and antidotal therapy' above.)
●
The goal of naloxone administration is NOT a normal level of consciousness, but adequate ventilation. In the
absence of signs of opioid withdrawal, there is no maximum safe dose of naloxone. If a clinical effect does not
occur after 5 to 10 mg, the diagnosis should be reconsidered. (See 'Basic measures and antidotal therapy'
●
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2004 Annual report of the American Association of Poison
Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2005; 23:589.
2. Substance Abuse and Mental Health Services Administration. Results from the 2004 National Survey on Drug
Use and Health: National Findings Office of Applied Studies, NSDUH Series H-28, DHHS Publication No.
SMA 05-4062, Rockville, MD 2005.
3. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. Drug Abuse Warning
Network, 2004: National Estimates of Drug-Related Emergency Department Visits. DAWN Series D-28,
DHHS Publication No. (SMA) 06-4143, Rockville, MD 2006.
4. QuickStats: Number of Deaths From Poisoning,* Drug Poisoning,† and Drug Poisoning Involving Opioid
Analgesics§ — United States, 1999–2010 www.cdc.gov/mmwr/preview/mmwrhtml/mm6212a7.htm?
s_cid=mm6212a7_e (Accessed on April 08, 2013).
5. Waldhoer M, Bartlett SE, Whistler JL. Opioid receptors. Annu Rev Biochem 2004; 73:953.
6. Bonci A, Bernardi G, Grillner P, Mercuri NB. The dopamine-containing neuron: maestro or simple musician in
the orchestra of addiction? Trends Pharmacol Sci 2003; 24:172.
7. Aghajanian GK, Wang YY. Common alpha 2- and opiate effector mechanisms in the locus coeruleus:
intracellular studies in brain slices. Neuropharmacology 1987; 26:793.
8. Davies G, Kingswood C, Street M. Pharmacokinetics of opioids in renal dysfunction. Clin Pharmacokinet
1996; 31:410.
9. Darke S, Zador D. Fatal heroin 'overdose': a review. Addiction 1996; 91:1765.
10. Ghoneim MM, Dhanaraj J, Choi WW. Comparison of four opioid analgesics as supplements to nitrous oxide
anesthesia. Anesth Analg 1984; 63:405.
11. Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a
reappraisal. Ann Emerg Med 1991; 20:246.
12. Fahmy NR, Sunder N, Soter NA. Role of histamine in the hemodynamic and plasma catecholamine
responses to morphine. Clin Pharmacol Ther 1983; 33:615.
13. Ashbourne JF, Olson KR, Khayam-Bashi H. Value of rapid screening for acetaminophen in all patients with
intentional drug overdose. Ann Emerg Med 1989; 18:1035.
14. Stork CM, Redd JT, Fine K, Hoffman RS. Propoxyphene-induced wide QRS complex dysrhythmia responsive
to sodium bicarbonate--a case report. J Toxicol Clin Toxicol 1995; 33:179.
15. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of methadone on QT prolongation in
a series of patients with torsade de pointes. Pharmacotherapy 2003; 23:802.
16. Berling I, Whyte IM, Isbister GK. Oxycodone overdose causes naloxone responsive coma and QT
above.)
If the clinician "overshoots" the appropriate dose of naloxone in an opioid-dependent individual, withdrawal will
ensue. Symptoms of withdrawal should be managed expectantly only, NOT with opioids. (See "Opioid
withdrawal in the emergency setting".)
●
Activated charcoal and gastric emptying are almost never indicated in opioid poisoning. The large volume of
distribution of the opioids precludes removal of a significant quantity of drug by hemodialysis. (See 'GI
decontamination' above and 'Extracorporeal removal' above.)
●
In most cases, the patient may be discharged or transferred for psychiatric evaluation once respiration and
mental status are normal and naloxone has not been administered for two to three hours. (See 'Disposition'
above.)
●
prolongation. QJM 2013; 106:35.
17. Mills CA, Flacke JW, Flacke WE, et al. Narcotic reversal in hypercapnic dogs: comparison of naloxone and
nalbuphine. Can J Anaesth 1990; 37:238.
18. Berlot G, Gullo A, Romano E, Rinaldi A. Naloxone in cardiorespiratory arrest. Anaesthesia 1985; 40:819.
19. Bertini G, Russo L, Cricelli F, et al. Role of a prehospital medical system in reducing heroin-related deaths.
Crit Care Med 1992; 20:493.
20. Osterwalder JJ. Naloxone--for intoxications with intravenous heroin and heroin mixtures--harmless or
hazardous? A prospective clinical study. J Toxicol Clin Toxicol 1996; 34:409.
21. Dowling J, Isbister GK, Kirkpatrick CM, et al. Population pharmacokinetics of intravenous, intramuscular, and
intranasal naloxone in human volunteers. Ther Drug Monit 2008; 30:490.
22. Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion intravenous
naloxone. Ann Emerg Med 1986; 15:566.
23. Gill JR, Graham SM. Ten years of "body packers" in New York City: 50 deaths. J Forensic Sci 2002; 47:843.
24. Traub SJ, Hoffman RS, Nelson LS. Body packing--the internal concealment of illicit drugs. N Engl J Med
2003; 349:2519.
25. Duberstein JL, Kaufman DM. A clinical study of an epidemic of heroin intoxication and heroin-induced
pulmonary edema. Am J Med 1971; 51:704.
26. Osler W. Oedema of the left lung—morphia poisoning. Montreal General Hospital Reports Clinical and
Pathological, vol 1, Dawson Bros Publishers, Montreal 1880. p.291.
27. Frand UI, Shim CS, Williams MH Jr. Methadone-induced pulmonary edema. Ann Intern Med 1972; 76:975.
28. Gahr M, Freudenmann RW, Hiemke C, et al. "Krokodil":revival of an old drug with new problems. Subst Use
Misuse 2012; 47:861.
29. Grund JP, Latypov A, Harris M. Breaking worse: the emergence of krokodil and excessive injuries among
people who inject drugs in Eurasia. Int J Drug Policy 2013; 24:265.
30. Helpern M, Rho YM. Deaths from narcotism in New York City. Incidence, circumstances, and postmortem
findings. N Y State J Med 1966; 66:2391.
31. Hoffman RS, Kirrane BM, Marcus SM, Clenbuterol Study Investigators. A descriptive study of an outbreak of
clenbuterol-containing heroin. Ann Emerg Med 2008; 52:548.
32. Hamilton RJ, Perrone J, Hoffman R, et al. A descriptive study of an epidemic of poisoning caused by heroin
adulterated with scopolamine. J Toxicol Clin Toxicol 2000; 38:597.
33. Kintz P. A new series of 13 buprenorphine-related deaths. Clin Biochem 2002; 35:513.
34. van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression.
Anesthesiology 2006; 105:51.
35. Mégarbane B, Buisine A, Jacobs F, et al. Prospective comparative assessment of buprenorphine overdose
with heroin and methadone: clinical characteristics and response to antidotal treatment. J Subst Abuse Treat
2010; 38:403.
36. Pedapati EV, Bateman ST. Toddlers requiring pediatric intensive care unit admission following at-home
exposure to buprenorphine/naloxone. Pediatr Crit Care Med 2011; 12:e102.
Topic 300 Version 14.0
GRAPHICS
Opioid intoxication (adult): Rapid overview
To obtain emergent consultation with a medical toxicologist, call the United States Poison
Control Network at 1-800-222-1222, or access the World Health Organization's list of
international poison centers
(www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html).
Clinical and laboratory features
Altered mental status ranging from mild euphoria or lethargy to coma
Miotic pupils
Decreased bowel sounds
Low to normal heart rate and blood pressure
Hypoventilation
Diagnostic evaluation
Obtain rapid bedside serum glucose concentration, to exclude hypoglycemia as cause of
coma.
Obtain creatine kinase (if history indicates prolonged immobilization).
Obtain chest radiograph (if physical examination suggests acute lung injury or aspiration).
Obtain serum acetaminophen concentration (if opioid was taken with intent of self-harm or in
opioid/acetaminophen combination product).
Obtain electrocardiogram (if methadone or propoxyphene is suspected).
Treatment
Ensure adequate ventilation. If respiratory rate is ≥12 breaths/minute and O2 saturation >90
percent on room air, observe the patient in a monitored setting and reassess frequently.
End-tidal CO2 monitoring using capnography is an excellent means to monitor ventilation.
If the O2 saturation is <90 percent on room air but the patient is breathing spontaneously,
administer supplemental oxygen followed by intravenous naloxone, 0.05 mg. In absence of IV
access, naloxone can be given intramuscularly. Repeat until ventilation is adequate. The goal
of treatment is adequate ventilation, NOT normal mental status. If the response is
inadequate after 5 to 10 mg, reconsider the diagnosis.
If the patient is apneic, ventilate using a bag-valve mask attached to supplemental oxygen
and administer naloxone in doses of 0.2 to 1 mg IV or IM. If no response occurs after a total
of 5 to 10 mg of naloxone, reconsider the diagnosis and perform tracheal intubation.
If hypoventilation recurs following the initial naloxone bolus, give additional bolus doses to
restore adequate ventilation. When ventilation is adequate, a naloxone infusion can be
instituted in lieu of frequent rebolusing. Begin the infusion rate at 2/3 of the total dose of
naloxone needed to restore breathing, delivered every hour.
If the patient develops respiratory depression despite a naloxone infusion, administer a
naloxone bolus (using half the original bolus dose) and repeat if necessary until adequate
ventilation returns, then increase the infusion rate.
If the patient develops signs of opioid withdrawal, stop the infusion. If respiratory depression
returns, start the infusion at half the original rate.
The patient is medically stable for transfer or discharge when their mental status and
ventilation remain normal for more than one hour after cessation of naloxone.
Psychiatry consultation may be required to assess suicidality.
Graphic 55540 Version 9.0
Opioid effects by receptor
Traditional* IUPHAR* Clinical Effects
µ1 MOP Supraspinal analgesia
Peripheral analgesia
Sedation
Euphoria
Prolactin release
µ2 Spinal analgesia
Respiratory depression
Physical dependence
Gastrointestinal dysmotility
Pruritus
Bradycardia
Growth hormone release
κ1 KOP Spinal analgesia
Miosis
Diuresis
κ2 Psychotomimesis
Dysphoria
κ3 Supraspinal analgesia
δ DOP Spinal and supraspinal analgesia
Modulations of µ-receptor function
Nociceptin/orphanin NOP Anxiolysis
Analgesia
* International Union of Pharmacology Committee on Receptor Nomenclature has recommended
new naming schema to replace traditional Greek nomenclature.
Graphic 64386 Version 1.0
Frequently encountered opioids
Source
Serum
half-life
(hours)*
Approximate
equivalence
to 10 mg
morphine
injection
(mg)
Important clinical features
IMPORTANT: The doses included here are NOT recommended for the initiation of therapy;
they provide equivalents for the purpose of comparing different opioids.
Natural
Morphine 1.9 +/– 0.5 10 SC/IM/IV
30 PO
Codeine 2.9 +/– 0.7 75 SC/IM/IV
130 to 200 PO
Metabolized by CYP2D6 to active
drug (morphine). Metabolism and
effects are subject to pronounced
individual variability. Single oral
doses over 65 mg tend to
produce disproportionately
greater adverse effects than
analgesia.
Semi-synthetic
Hydromorphone 2.4 +/– 0.6 1.5 SC/IM/IV
7.5 PO
Hepatically metabolized to
metabolites that can accumulate
in organ failure and prolong
effects. Some metabolites have
been linked to neurotoxicity.
Oxycodone 2.6 (2.1-
3.1)
20 to 30 PO Metabolized by CYP3A4 and 2D6.
Prolonged effects and elevated
serum concentrations with renal
or hepatic insufficiency. May
cause QTc prolongation.
Hydrocodone 4.24 +/–
0.99
30 PO
Diacetylmorphine
(diamorphine, heroin)
5 SC Highly lipophilic causing more
rapid CNS effects than morphine.
Largely metabolized to morphine.
Due to abuse potential is not
available for clinical use in many
countries.
Synthetic
Meperidine 3.2 +/– 0.8 75 to 100 SC/IM
300 PO
Excitatory neurotoxicity may
occur when normeperidine, a
renally-eliminated metabolite,
accumulates.
Methadone 27 +/– 12 10 SC/IM/IV
Highly variable.
See clinical
features.
Used in opioid substitution
therapy. Can cause QTc
prolongation. May be far more
potent than indicated in this
table. Metabolized by CYP3A4.
Due to its highly variable and
prolonged half-life (up to 150
hours), methadone has the
highest risk among opioids of
accumulation and toxicity during
initial titration and after changes
in dose.
Propoxyphene
(dextropropoxyphene)
65 to 130 PO Usual initial dose for mild
analgesia shown; NOT equivalent
to parenteral morphine 10 mg.
Has IA anti-dysrhythmic
properties, leading to widened
QRS, negative inotropy, and
conduction abnormalities. Can
cause seizures. Onset of toxic
effects is 15 to 60 minutes in
overdose.
Tramadol 5.5 (4.5-
7.5)
50 to 100 PO Usual initial dose for mild
analgesia shown; NOT equivalent
to parenteral morphine 10 mg.
Effects NOT completely reversed
by naloxone. Noted to cause
seizures. Metabolized by CYP2D6
and 3A4. Subject to interactions
including serotonin excess.
Fentanyl 3.7 +/– 0.4 0.05 to 0.1
SC/IM/IV
Short acting when administered
IV/IM as a single dose. Highly
lipophilic. Parent drug
accumulates with repeated or
prolonged administration.
Agonist/antagonist
Pentazocine 2 to 3 30 to 60 SC/IM
75 to 150 PO
Partial agonist
Buprenorphine 2.33 +/–
0.24
0.3 to 0.4 IM/IV
0.4 sublingual
Used in opioid substitution
therapy. Significantly longer
duration of effect than 10 mg
parenteral morphine. Metabolized
by and subject to interactions
involving CYP3A4.
•
•
Gastrointestinally insoluble - not analgesic
Diphenoxylate 2.5 to 5 PO
(anti-diarrheal
dose)
Poor solubility limits potential for
parenteral injection and abuse.
Usually formulated with atropine
(US trade name Lomotil®, 0.025
mg atropine and 2.5 mg
diphenoxylate) to further
decrease abuse potential.
Loperamide 2 to 4 PO (anti-
diarrheal
dose)
Very low abuse potential due to
lack of effect on CNS receptors.
* Half-life and equal analgesic dosing approximations apply only to immediate release or SQ/IM
preparations, single dose, in opioid naive patients. The actual duration of effect may be longer or
shorter than suggested by the serum half-life depending upon the dose, the patient's tolerance,
the presence of active metabolites, organ function, and redistribution of the drug.
• Not a dose equivalent. Usual initial dose shown.
Graphic 70480 Version 6.0
•
•
Physical examination findings of opioid poisoning
Vital Signs
Heart rate decreased or unchanged
Blood pressure decreased or unchanged
Respiratory rate decreased
Temperature decreased or unchanged
Gastrointestinal
Decreased bowel sounds
Neurological
Sedation or coma
Seizure (Meperidine, Propoxyphene, Tramadol, or as a result of hypoxia)
Ophthalmologic
Miosis
Graphic 77213 Version 2.0
"Skin popping" in substance abuse
Repeated subcutaneous or intramuscular injection by drug abusers can lead to chronic
skin lesions, including abscesses and scarring, as seen in the photograph above.
Reproduced with permission from: www.visualdx.com. Copyright Logical Images, Inc.
Graphic 86745 Version 3.0
Select toxic agents causing coma
Toxic agent Features which may distinguish from opioids
Antihistamines Anticholinergic toxidrome
Antipsychotics Pupils, bowel sounds normal
Barbiturates Mild to severe hypotension, serum concentration
β-adrenergic
antagonists
Cardiovascular findings (hypotension, bradycardia) more prominent
than mental status findings
Calcium channel
blockers
Cardiovascular findings (hypotension, bradycardia, or tachycardia)
more prominent than mental status findings
Carbamazepine Serum concentration
Carbon monoxide Carboxyhemoglobin level
Clonidine Bradycardia, hypotension
Cyclic
antidepressants
QRS prolongation, hypotension, tachycardia
Ethanol Pupils, bowel sounds normal, serum concentration
Ethylene glycol Pupils, bowel sounds normal
Hypoglycemic
agents
Serum glucose concentration
Isoniazid History of seizures, normal pupils, bowel sounds
Isopropanol Pupils, bowel sounds normal
Lithium Tremor, hyperreflexia, serum concentration
Methanol Pupils, bowel sounds normal
Organic-
phosphorous
compounds
Cholinergic toxidrome
Phencyclidine Nystagmus (horizontal, vertical, or rotary)
Sedative-hypnotic
agents
Pupil size normal to decreased, bowel sounds normal, less respiratory
depression
Graphic 59515 Version 1.0
Causes of coma
I. Symmetrical, nonstructural
Toxins
Lead
Thallium
Mushrooms
Cyanide
Methanol
Ethylene glycol
Carbon monoxide
Drugs
Sedatives
Barbiturates*
Other hypnotics
Tranquilizers
Bromides
Alcohol
Opiates
Paraldehyde
Salicylate
Psychotropics
Anticholinergics
Amphetamines
Lithium
Phencylidine
Monoamine oxidase inhibitors
Metabolic
Hypoxia
Hypercapnia
Hypernatremia*
Hypoglycemia*
Hypergylcemic nonketotic coma
Diabetic ketoacidosis
Lactic acidosis
Hypercalcemia
II. Symmetrical, structural
Supratentorial
Bilateral internal carotid occlusion
Bilateral anterior cerebral artery occlusion
Sagittal sinus thrombosis
Subarachnoid hemorrhage
Thalamic hemorrhage*
Trauma-contusion, concussion*
Hydrocephalus
Infratentorial
Basilar occlusion*
Midline brainstem tumor
Pontine hemorrhage*
Central pontine myelinolysis
III. Asymmetrical, structural
Supratentorial
Thrombotic thrombocytopenic purpura•
Disseminated intravascular coagulation
Nonbacterial thrombotic endocarditis
(marantic endocarditis)
Subacute bacterial endocarditis
Fat emboli
Unilateral hemispheric mass (tumor,
abscess, bleed) with herniation
Subdural hemorrhage bilateral
Intracerebral bleed
Pituitary apoplexy•
Massive or bilateral supratentorial
infarction
Multifocal leukoencephalopathy
Creutzfeldt-Jakob disease
Adrenal leukodystrophy
Cerebral vasculitis
Cerebral abscess
Hypocalcemia
Hypermagnesemia
Hyperthermia
Hypothermia
Reye's encephalopathy
Aminoacidemia
Wernicke's encephalopathy
Porphyria
Hepatic encephalopathy*
Uremia
Dialysis encephalopathy
Addisonian crisis
Hypothyroidism
Infections
Bacterial meningitis
Viral encephalitis
Postinfectious encephalomyelitis
Syphilis
Sepsis
Typhoid fever
Malaria
Waterhouse-Friderichsen syndrome
Psychiatric
Catatonia
Other
Postictal seizure*
Diffuse ischemia (myocardial infarction,
heart failure, arrhythmia)
Hypotension
Fat embolism*
Hypertensive encephalopathy
Hypothyroidism
Nonconvulsive status epilepticus
Heat stroke
Subdural empyema
Thrombophlebitis•
Multiple sclerosis
Leukoencephalopathy associated with
chemotherapy
Acute disseminated encephalomyelitis
Infratentorial
Brainstem infarction
Brainstem hemorrhage
Brainstem thrombencephalitis
* Relatively common asymmetrical presentation.
• Relatively symmetrical presentation.
Reproduced with permission from: Berger, Joseph R. Clinical Approach to Stupor and Coma. In:
Neurology in Clinical Practice: Principles of diagnosis and Management, 4th ed, Bradley, WG, Daroff, RB,
Fenichel, GM, Jankovic, J (Eds), Butterworth Heinmann, Philadelphia, PA 2004. p.46. Copyright © 2004
Elsevier.
Graphic 65571 Version 2.0
Disclosures: Andrew Stolbach, MD Nothing to disclose. Robert S Hoffman, MD Nothing to disclose. Stephen J Traub, MD Nothing
to disclose. Jonathan Grayzel, MD, FAAEM Employee of UpToDate, Inc.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting through
a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
Disclosures
