From the Department of Emergency Med-
`icine, Division of Medical Toxicology, Uni-
`versity of Massachusetts Medical Center,
`Worcester. Address reprint requests to Dr.
`Boyer at the Department of Emergency
`Medicine, Division of Medical Toxicology,
`University of Massachusetts Medical Cen-
`ter, 55 Lake Ave. N., Worcester, MA 01655,
`or at edward.boyer@childrens.harvard.edu.
`
`This article was updated on July 12, 2012,
`at NEJM.org.
`
`N Engl J Med 2012;367:146-55.
`DOI: 10.1056/NEJMra1202561
`Copyright © 2012 Massachusetts Medical Society.
`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`review article
`
`Drug Therapy
`Management of Opioid Analgesic Overdose
`Edward W. Boyer, M.D., Ph.D.
`
`Opioid analgesic overdose is a preventable and potentially
`
` lethal condition that results from prescribing practices, inadequate under-
`standing on the patient’s part of the risks of medication misuse, errors in
`drug administration, and pharmaceutical abuse.1,2 Three features are key to an un-
`derstanding of opioid analgesic toxicity. First, opioid analgesic overdose can have life-
`threatening toxic effects in multiple organ systems. Second, normal pharmacokinetic
`properties are often disrupted during an overdose and can prolong intoxication
`dramatically.3 Third, the duration of action varies among opioid formulations, and
`failure to recognize such variations can lead to inappropriate treatment decisions,
`sometimes with lethal results.2,4
`
`Epidemiology of Over dose
`
`The number of opioid analgesic overdoses is proportional to the number of opioid
`prescriptions and the dose prescribed.5 Between 1997 and 2007, prescriptions for
`opioid analgesics in the United States increased by 700%; the number of grams of
`methadone prescribed over the same period increased by more than 1200%.6 In 2010,
`the National Poison Data System, which receives case descriptions from offices, hos-
`pitals, and emergency departments, reported more than 107,000 exposures to opioid
`analgesics, which led to more than 27,500 admissions to health care facilities.7 There
`is considerable overlap between psychiatric disease and chronic pain syndromes;
`patients with depressive or anxiety disorders are at increased risk for overdose, as
`compared with patients without these conditions, because they are more likely to
`receive higher doses of opioids.8 Such patients are also more likely to receive sedative
`hypnotic agents (e.g., benzodiazepines) that have been strongly associated with death
`from opioid overdose.9 In addition, data indicate that the frequent prescription of
`opioid analgesics contributes to overdose-related mortality among children, who
`may find and ingest agents in the home that were intended for adults.10,11
`
`Pathophysiology of Opioid Analgesics
`
`Opioids increase activity at one or more G-protein–coupled transmembrane mole-
`cules, known as the mu, delta, and kappa opioid receptors, that develop operational
`diversity from splice variants, post-translational modification and scaffolding of gene
`products, and the formation of receptor heterodimers and homodimers.12 Opioid
`receptors are activated by endogenous peptides and exogenous ligands; morphine
`is the prototypical compound of the latter.13 The receptors are widely distributed
`throughout the human body; those in the anterior and ventrolateral thalamus, the
`amygdala, and the dorsal-root ganglia mediate nociception.14 With contributions
`from dopaminergic neurons, brain-stem opioid receptors modulate respiratory re-
`sponses to hypercarbia and hypoxemia, and receptors in the Edinger–Westphal
`nucleus of the oculomotor nerve control pupillary constriction.15 Opioid agonists
`bind to receptors in the gastrointestinal tract to decrease gut motility.
`
`146
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 1 of 10
`
`

`

`drug therapy
`
`The mu opioid receptor is responsible for the
`preponderance of clinical effects caused by opi-
`oids. Studies in knockout mice confirm that ago-
`nism of these receptors mediates both analgesia
`and opioid dependence.16 Furthermore, the devel-
`opment of tolerance, in which drug doses must be
`escalated to achieve a desired clinical effect, in-
`volves the progressive inability of mu opioid re-
`ceptors to propagate a signal after opioid binding.
`Receptor desensitization, a critical event in the
`development of tolerance, is a highly conserved
`process that involves the uncoupling of the recep-
`tors from G-protein, and their subsequent entry
`into an intracellular compartment during endocy-
`tosis. The receptors may then be returned to the
`membrane in a process that resensitizes the cell
`to opioid binding.17 This dynamic process of en-
`docytosis and recycling is postulated to limit the
`tolerance of mu opioid receptors for endogenous
`opioid ligands as they undergo phasic secretion
`and rapid clearance.17 In contrast, opioid analge-
`sics, which are administered repetitively in long-
`acting formulations, persist in the extracellular
`matrix and signal through mu opioid receptors
`for prolonged periods.17 Whereas endogenous
`native ligands foster dynamic receptor cycling,
`opioid analgesics facilitate tolerance by persis-
`tently binding and desensitizing the receptors as
`they blunt receptor recycling.17
`However, tolerance of the analgesic and respi-
`ratory depressive effects of opioids is not solely
`related to the desensitization of mu opioid re-
`ceptors. Conditioned tolerance develops when
`patients learn to associate the reinforcing effect
`of opioids with environmental signals that reli-
`ably predict drug administration.18 Opioid use in
`the presence of these signals has attenuated ef-
`fects; conversely, opioid use in the absence of
`these stimuli or in new environments results in
`heightened effects.18 Tolerance of respiratory de-
`pression appears to develop at a slower rate than
`analgesic tolerance; over time, this delayed toler-
`ance narrows the therapeutic window, paradoxi-
`cally placing patients with a long history of opioid
`use at increased risk for respiratory depres-
`sion.19-21
`
`Toxicok inetics of Opioid
`Analgesics
`
`The pharmacokinetics of particular opioid anal-
`gesic agents — their absorption, onset of action,
`clearance, and biologic half-life — are often irrel-
`
`evant in overdose. For example, bezoars formed
`after large ingestions of pills may produce erratic
`rates of drug absorption, and the delayed gastric
`emptying and diminished gastrointestinal motil-
`ity caused by opioids may prolong drug absorp-
`tion.22 Conversely, behaviors associated with drug
`misuse (e.g., insufflating or injecting ground opi-
`oid analgesic tablets, heating fentanyl patches, or
`applying one or more patches to skin) often in-
`crease the rate of absorption, albeit unpredictably.
`After absorption, most medications, including opi-
`oid analgesics, undergo first-order elimination
`pharmacokinetics, in which a constant fraction
`of the drug is converted by enzymatic processes
`per unit of time.3 In the case of an overdose, how-
`ever, high concentrations of the drug may over-
`whelm the ability of an enzyme to handle a sub-
`strate, a process known as saturation.3 Saturated
`biologic processes are characterized by a transition
`from first-order to zero-order elimination kinetics.3
`Two phenomena occur in zero-order elimination.
`First, small increases in the drug dose can lead to
`disproportionate increases in plasma concentra-
`tions and hence to intoxication.23 Second, a con-
`stant amount (as opposed to a constant propor-
`tion) of drug is eliminated per unit of time.23
`Collectively, these toxicokinetic effects converge
`to produce opioid toxicity that may be severe, de-
`layed in onset, and protracted as compared with
`the expected therapeutic actions (Fig. 1).24-31
`
`Clinical M anifes tations
`of Over dose
`
`Opioid analgesic overdose encompasses a range
`of clinical findings (Fig. 2). Although the classic
`toxidrome of apnea, stupor, and miosis suggests
`the diagnosis of opioid toxicity, all of these find-
`ings are not consistently present.32 The sine qua
`non of opioid intoxication is respiratory depres-
`sion. Administration of therapeutic doses of opi-
`oids in persons without tolerance to opioids causes
`a discernible decline in all phases of respiratory
`activity, with the extent of the decline dependent
`on the administered dose.33 At the bedside, how-
`ever, the most easily recognized abnormality in
`cases of opioid overdose is a decline in respiratory
`rate culminating in apnea. A respiratory rate of
`12 breaths per minute or less in a patient who is
`not in physiologic sleep strongly suggests acute
`opioid intoxication, particularly when accompa-
`nied by miosis or stupor.34 Miosis alone is insuf-
`ficient to infer the diagnosis of opioid intoxication.
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`147
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 2 of 10
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Methadone
`
`Morphine
`
`Buprenorphine
`
`Oxycodone
`(extended release)
`
`Fentanyl
`
`Naloxone (after administration
`of single dose)
`
`Therapeutic dose
`Overdose
`
`0
`
`4
`
`8
`
`12
`
`24
`
`48
`
`72
`
`96
`
`120
`
`Hours
`
`Figure 1. Onset and Duration of Action in Therapeutic Dosing and Overdose of Selected Opioid Analgesic Agents.
`Information about the toxic effects of opioid analgesic overdose often must be synthesized from case reports, the
`clinical observations of medical toxicologists, and forensic data.24-31 The difference between the clinical effects of
`therapeutic use and poisoning for these selected agents arises from the toxicokinetics of overdose, patterns of
`abuse, and the variation in drug effects in special populations.
`
`Polysubstance ingestions may produce normally
`reactive or mydriatic pupils, as can poisoning
`from meperidine, propoxyphene, or tramadol.35,36
`Conversely, overdose from antipsychotic drugs,
`anticonvulsant agents, ethanol, and other seda-
`tive hypnotic agents can cause miosis and coma,
`but the respiratory depression that defines opioid
`toxicity is usually absent.37,38
`Failure of oxygenation, defined as an oxygen
`saturation of less than 90% while the patient is
`breathing ambient air and with ventilation ade-
`quate to achieve normal arterial carbon dioxide
`tension (partial pressure of carbon dioxide), is of-
`ten caused by pulmonary edema that becomes
`apparent later in the clinical course.39,40 There are
`several potential causes of pulmonary edema.
`One likely cause is that attempted inspiration
`against a closed glottis leads to a decrease in in-
`trathoracic pressure, which causes fluid extrava-
`sation. Alternatively, acute lung injury may arise
`from a mechanism similar to that postulated for
`neurogenic pulmonary edema.41 In this scenar-
`io, sympathetic vasoactive responses to stress in
`a patient who has reawakened after reversal of
`intoxication culminate in leakage from pulmo-
`nary capillaries.
`Hypothermia may arise from a persistently
`unresponsive state in a cool environment or from
`misguided attempts by bystanders to reverse opi-
`oid intoxication by immersing a patient in cold
`water.42 In addition, persons who have been lying
`immobile in an opioid-induced stupor may be
`
`subject to rhabdomyolysis, myoglobinuric renal
`failure, and the compartment syndrome. Other
`laboratory abnormalities include elevated serum
`aminotransferase concentrations in association
`with liver injury caused by acetaminophen or
`hypoxemia. Seizures have been associated with
`overdose of tramadol, propoxyphene, and me-
`peridine.43,44
`
`Diagnosis of Over dose
`
`The presence of hypopnea or apnea, miosis, and
`stupor should lead the clinician to consider the
`diagnosis of opioid analgesic overdose, which may
`be inferred from the patient’s vital signs, history,
`and physical examination. In patients with severe
`respiratory depression, restoration of ventilation
`and oxygenation takes precedence over obtaining
`the history of the present illness or performing a
`physical examination or diagnostic testing.
`After the patient’s condition is stabilized, the
`clinician should inquire about the use of all opioid
`analgesics, acetaminophen (including products co-
`formulated with acetaminophen), and illicit sub-
`stances and determine whether the patient has had
`contact with anyone receiving pharmacologic treat-
`ment for chronic pain or opioid dependence.27,45
`In performing the physical examination, the clini-
`cian should evaluate the size and reactivity of the
`pupils and the degree of respiratory effort and
`look for auscultatory findings suggestive of pulmo-
`nary edema. The patient should be completely un-
`
`148
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 3 of 10
`
`

`

`drug therapy
`
`Figure 2. Clinical Findings in Opioid Analgesic Intoxication.
`The sine qua non of opioid intoxication is respiratory depression, but miosis and stupor are often observed in poi-
`soned patients. Hypoxemia or ingestion of drugs that are coformulated with acetaminophen can cause hepatic injury;
`acute renal failure can result from hypoxemia or precipitation of myoglobin due to rhabdomyolysis. Opioid analgesics
`decrease intestinal peristalsis by binding to opioid receptors in the gut. Patients with stupor who are motionless
`often have compressed fascia-bounded muscle groups, culminating in the compartment syndrome; they may also
`have hypothermia as a result of environmental exposure or misguided attempts at reversing intoxication. Since
`fentanyl can be a source of overdose, patients should be examined for the presence of fentanyl patches.
`
`dressed to allow for a thorough search for fen-
`tanyl patches. In addition, the clinician should
`palpate muscle groups; the firmness, swelling, and
`tenderness that characterize the compartment syn-
`
`drome (which results when comatose patients lie
`on a muscle compartment for a long time) war-
`rant direct measurement of compartment pres-
`sures. Finally, the acetaminophen concentration
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`149
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 4 of 10
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`should be measured in all patients because of
`the prevalence of diversion and misuse of acet-
`aminophen-containing opioids. Clinicians often
`overlook acetaminophen hepatotoxicity.46
`Qualitative analyses of urine for drugs of abuse
`(toxicology screens) rarely affect decisions about
`patient care and have little role in the immediate
`evaluation and management of opioid intoxica-
`tion, for several reasons.47 First, naloxone should
`never be withheld from a patient with apnea
`because the results of qualitative tests are un-
`available. Second, the management of opioid
`overdose, irrespective of the causative agent, var-
`ies little. Finally, standard toxic screens, which
`detect methadone, fentanyl, hydromorphone, and
`other compounds only infrequently, provide little
`useful clinical information.48 Newer qualitative
`screens that detect a broader range of opioid an-
`algesics may allow clinicians specializing in pain
`treatment, mental health, or other areas of medi-
`cine to identify patients who have strayed from
`prescribed treatment regimens; greater analytic
`precision, however, does not change the manage-
`ment of acute overdose. Quantitative measures of
`drug concentrations are useless in cases of over-
`dose because patients who have been prescribed
`elevated doses of opioid analgesics may have thera-
`peutic serum concentrations that greatly exceed
`laboratory reference ranges.
`
`M anagement of Over dose
`
`Patients with apnea need a pharmacologic or me-
`chanical stimulus in order to breathe. For pa-
`tients with stupor who have respiratory rates of
`12 breaths per minute or less, ventilation should
`be provided with a bag-valve mask; chin-lift and
`jaw-thrust maneuvers should be performed to
`ensure that anatomical positioning helps to di-
`minish hypercarbia. Although the relationship
`between the partial pressure of carbon dioxide and
`acute lung injury is unclear, providing adequate
`ventilation is a simple response that offers the
`certain benefits of restoring oxygenation and pre-
`venting the postulated sympathetic surge that
`triggers pulmonary edema after the reversal of
`apnea, with minimal risk.
`Naloxone, the antidote for opioid overdose, is
`a competitive mu opioid–receptor antagonist that
`reverses all signs of opioid intoxication. It is ac-
`tive when the parenteral, intranasal, or pulmonary
`route of administration is used but has negligi-
`ble bioavailability after oral administration be-
`
`cause of extensive first-pass metabolism.49 In
`patients with opioid dependence, plasma levels of
`naloxone are initially lower, the volume of distri-
`bution is higher, and the elimination half-life is
`longer than in patients without dependence.50
`The onset of action is less than 2 minutes when
`naloxone for adults is administered intravenously,
`and its apparent duration of action is 20 to 90
`minutes, a much shorter period than that of
`many opioids (Fig. 1).51,52
`Dosing of naloxone is empirical. The effective
`dose depends on the amount of opioid analgesic
`the patient has taken or received, the relative af-
`finity of naloxone for the mu opioid receptor and
`the opioid to be displaced, the patient’s weight,
`and the degree of penetrance of the opioid anal-
`gesic into the central nervous system.25,52 Because
`most of this information will be unknown, clini-
`cians must rely on the results of therapeutic
`trials to determine the effective dose of anti-
`dote.25 The initial dose of naloxone for adults is
`0.04 mg; if there is no response, the dose should
`be increased every 2 minutes according to the
`schedule shown in Figure 3, to a maximum of
`15 mg. If there is no abatement in respiratory de-
`pression after the administration of 15 mg of nal-
`oxone, it is unlikely that the cause of the depres-
`sion is opioid overdose.30,31 Reversal of opioid
`analgesic toxicity after the administration of sin-
`gle doses of naloxone is often transient; recurrent
`respiratory depression is an indication for a con-
`tinuous infusion (see the Supplementary Appendix,
`available with the full text of this article at NEJM
`.org) or for orotracheal intubation.53
`Naloxone can be administered without com-
`punction in any patient, including patients with
`opioid dependence. Concerns that naloxone will
`harm patients with opioid dependence are un-
`founded; all signs of opioid abstinence (e.g.,
`yawning, lacrimation, piloerection, diaphoresis,
`myalgias, vomiting, and diarrhea) are unpleas-
`ant but not life-threatening.25 In addition, pa-
`tients with opioid tolerance frequently have a
`response to low doses of naloxone that are suf-
`ficient to restore breathing without provoking
`withdrawal.54 Once the respiratory rate improves
`after the administration of naloxone, the patient
`should be observed for 4 to 6 hours before dis-
`charge is considered (Fig. 4).57,58
`An alternative to the administration of nalox-
`one is orotracheal intubation, a procedure that
`safely ensures oxygenation and ventilation while
`providing protection against aspiration.30 Gastro-
`
`150
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 5 of 10
`
`

`

`drug therapy
`
`intestinal decontamination with activated char-
`coal should be reserved for patients who present
`within 1 hour after ingestion; charcoal offers no
`benefit outside this time frame and complicates
`visualization of airway anatomy during orotra-
`cheal intubation.59 Patients who are intoxicated by
`long-acting or extended-release opioid formula-
`tions, have recurrent respiratory depression, or re-
`quire a naloxone infusion or orotracheal intubation
`should be admitted to an intensive care unit.26
`Once the patient’s condition is stable, the clini-
`cian should search the patient for fentanyl patches,
`even when fentanyl abuse is not suspected.45 Fen-
`tanyl patches have been associated with delayed
`toxicity after cursory physical examination.45 The
`axillae, perineum, scrotum, and oropharynx, in
`particular, should be examined; any patches should
`be removed, and skin decontaminated with soap
`and cool water.60 A patient who has ingested a
`fentanyl patch may benefit from whole-bowel ir-
`rigation with polyethylene glycol to accelerate
`elimination of the patch.30
`Persistent hypoxemia after the administration
`of naloxone may signify the presence of negative-
`pressure pulmonary edema. Mild cases resolve
`with supportive care, but patients with severe
`hypoxemia often benefit from orotracheal intu-
`bation and positive-pressure ventilation. Resolution
`of lung injury, if uncomplicated by aspiration of
`gastric contents, normally occurs within 24 hours.
`Because the probable cause of lung injury is not
`fluid overload, reducing the intravascular volume
`with diuretics is unlikely to be effective and may
`worsen myoglobinuric renal failure, if present.
`Naloxone has been mistakenly implicated as a
`cause of pulmonary edema. However, pulmo-
`nary edema is present in nearly all fatal cases of
`opioid overdose, including those that occurred
`before the development of naloxone.39,40,61 More-
`over, studies have shown that pulmonary edema
`does not develop in patients who receive large
`doses of naloxone by means of continuous infu-
`sion.62-64 Finally, auscultatory signs of pulmo-
`nary edema, which are often obscure in patients
`with apnea, become apparent only after naloxone
`restores ventilation.
`Rhabdomyolysis (defined as a creatine kinase
`concentration that is five times as high as the up-
`per end of the normal range) should be treated
`with fluid resuscitation to prevent myoglobin pre-
`cipitation in the renal tubules; the addition of bi-
`carbonate does not improve outcomes and should
`be avoided.65 Patients with the compartment syn-
`
`Support respiration with bag-valve mask
`before administering naloxone
`
`Support respiration with bag-valve mask
`before administering naloxone
`
`Initial adult dose: 0.04 mg
`
`Initial pediatric dose: 0.1 mg/kg of body
`weight
`
`If an increase in respiratory rate
`does not occur in 2–3 min
`
`Administer 0.5 mg of naloxone
`
`If no response in 2–3 min
`
`Administer 2 mg of naloxone
`
`If no response in 2–3 min
`
`Administer 4 mg of naloxone
`
`If no response in 2–3 min
`
`Administer 10 mg of naloxone
`
`If no response in 2–3 min
`
`Administer 15 mg of naloxone
`
`Figure 3. Naloxone Dosing.
`Empirical trials are needed to determine the effective dose of naloxone. Patients
`who do not have a response to an initial dose of naloxone should receive
`escalating doses until respiratory effort is restored. Naloxone, which is fre-
`quently dispensed as an injectable solution in doses of 0.4 mg per milliliter
`and 1 mg per milliliter for adults, is almost devoid of adverse effects. Pedi-
`atric patients are defined as children up to the age of about 5 years or with
`a body weight of up to 20 kg. Pediatric patients with opioid intoxication fre-
`quently require larger doses of naloxone to reverse the effects of overdose
`because of the relatively higher ingested dose per kilogram of body weight.
`
`drome should receive an emergency surgical con-
`sultation for possible fasciotomy. Patients with
`hypothermia may require immediate rewarm-
`ing. Elevated aminotransferase concentrations,
`the presence of acetaminophen in the blood, or
`both may indicate the need for treatment with
`N-acetylcysteine.66 Cerebrospinal fluid lavage and
`the administration of naloxone may be needed
`in rare instances in which profound toxicity oc-
`curs as a result of overfilled or incorrectly pro-
`grammed intrathecal pumps, which can contain
`hundreds of times the daily dose of an opioid
`analgesic.67 Finally, determining the cause of the
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`151
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 6 of 10
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`Opioid overdose: respiratory rate <12 breaths/min
`when patient is not asleep
`
`Yes
`
`No
`
`Methadone, fentanyl patch, or another
`long-acting opioid analgesic used?
`
`Oxygenate with bag-valve mask
`Administer naloxone; adjust dose to
`reverse respiratory depression while
`avoiding effects of opioid withdrawal
`
`Methadone, fentanyl patch, or another
`long-acting or extended-release opioid
`analgesic used?
`
`Yes
`
`No
`
`No
`
`Yes
`
`Admit to intensive care unit
`
`Observe for 4–6 hr after
`last naloxone dose
`
`Observe for minimum of 8 hr
`
`Patient awake and alert in the absence of oral or tactile stimuli?
`
`No
`
`Yes
`
`Initiate continuous naloxone infusion
`or perform orotracheal intubation for
`recurrent respiratory depression
`
`Admit to intensive care unit
`
`Continue with therapy until patient has
`normal respiratory effort and normal
`mental status
`Observe for 4–6 hr after naloxone
`infusion stopped
`
`Consider discharge when patient is
`awake and alert with normal vital signs
`
`Figure 4. Decision Tree for Managing Opioid Analgesic Overdose in Adults.
`Because of the long duration of action of many opioid analgesic formulations, the brief effectiveness of naloxone, and the potential
` lethality of an opioid analgesic overdose, there should be a low threshold for admitting intoxicated patients to a hospital unit that
` provides close monitoring, such as an intensive care unit.26,53,54 Published guidelines for the management of opioid intoxication
`were developed on the basis of data from patients with heroin overdose and should not be applied to patients with opioid analgesic
`overdose.55,56
`
`overdose will identify patients who require refer-
`ral to psychiatric or drug treatment.
`
`Consider ations in Special
`Popul ations
`
`Opioid overdose in children is often characterized
`by a delayed onset of toxicity, unexpectedly severe
`poisoning, and prolonged toxic effects.24-26 These
`
`seemingly paradoxical effects result from ontog-
`eny-related pharmacokinetics: children have rates
`of drug absorption, distribution into the central
`nervous system, and metabolism that differ from
`those in adults.68 Children 3 years of age or
`younger who have been exposed to any opioid
`analgesic other than immediate-release opioid
`formulations (e.g., methadone, fentanyl patches,
`and extended-release formulations) should be ad-
`
`152
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Nalox1023
`Nalox-1 Pharmaceuticals, LLC
`Page 7 of 10
`
`

`

`drug therapy
`
`mitted for a 24-hour observation period, even if in-
`gestion of these agents cannot be confirmed.28,29
`Similarly, all toddlers exposed to buprenorphine
`formulations, including buprenorphine–naloxone
`products, must be admitted for close observa-
`tion.27,69 The reported “ceiling effect” of buprenor-
`phine, in which escalating doses do not cause
`additional respiratory depression, has not been
`observed in children.70 Children who ingest opi-
`oid formulations often ingest a higher dose than
`adults per kilogram of body weight and therefore
`require larger doses of naloxone to reverse the
`effects of overdose (Fig. 3).
`Elderly patients also have increased suscepti-
`bility to opioid effects and should be watched
`closely. A coexisting condition (e.g., renal insuf-
`ficiency, chronic obstructive pulmonary disease,
`or sleep apnea) may exacerbate the inhibitory
`effects of opioids on respiration; age-related chang-
`es in physiology (e.g., decreased stroke volume,
`leading to diminished hepatic blood flow) and
`in body composition (leading to reduced binding
`of the drug to plasma proteins) may cause unex-
`pected, persistent intoxication.71,72 These phar-
`macokinetic effects have been implicated in the
`failure of naloxone to successfully reverse cases
`of intoxication caused by short-acting opioid
`analgesics.73
`
`Pitfalls of Over dose
`M anagement
`
`Lack of knowledge about several aspects of opi-
`oid analgesic toxicity may complicate patient
`care. First, even clinicians with experience treat-
`ing heroin overdose may believe that naloxone
`will prevent the recurrence of opioid analgesic
`toxicity.55 Naloxone, with its transient duration
`of action, does not truncate opioid toxicity; in
`many patients with intoxication from opioid an-
`algesics, naloxone treatment does not forestall
`recrudescent respiratory depression. Second, cli-
`nicians may incorrectly assume that the dose of
`naloxone that is required to restore respiration
`correlates with the severity of intoxication. Be-
`cause patients with opioid dependence frequently
`require low initial doses of antidote, physicians
`often provide only a brief period of patient obser-
`vation, decide not to readminister the antidote,
`or admit patients to units that cannot perform
`intensive monitoring. Third, clinicians may as-
`sociate peak plasma opioid concentrations with
`
`the greatest degree of respiratory depression.74
`Opioid-induced respiratory depression is unre-
`lated to the peak concentration, the timing of
`which cannot be reliably determined in cases of
`overdose.74 Fourth, early acetaminophen toxicity
`may go unrecognized at the time when interven-
`tion is most effective.47,66 Finally, clinicians may
`believe that pharmacologic responses in children
`and elderly patients are in keeping with the phar-
`macokinetic findings in healthy young adults
`and thus may inappropriately curtail the observa-
`tion period.75
`
`Pr evention of Over dose
`
`Several strategies may limit the harm of opioid
`analgesics, which are among the most effective
`drugs used to treat pain. Clinicians who pre-
`scribe these agents should understand the basics
`of safe opioid dosing, screen for mental illness in
`potential recipients of opioids, perform behav-
`ioral testing and urine screens to detect problem-
`atic opioid use, and use electronic prescription-
`drug monitoring programs (see the Supplementary
`Appendix) to help identify patients who may be
`receiving opioids inappropriately from multiple
`prescribers.8,76,77 The manufacturers of opioid
`analgesics should be assiduously honest in mar-
`keting their products, fund the independent de-
`velopment of objective prescribing information,
`and help prevent opioid exposure in children by
`distributing child-safety devices and educational
`materials for prescribers, patients, and families.2
`Finally, patients should understand that opioid
`analgesics are not effective in treating all painful
`conditions, can engender long-term use, and are
`highly lethal when used inappropriately.78
`
`Summ ary
`
`Opioid analgesic overdose is a life-threatening
`condition, and the antidote naloxone may have
`limited effectiveness in patients with poisoning
`from long-acting agents. The unpredictable clini-
`cal course of intoxication demands empirical
`management of this potentially lethal condition.
`
`Dr. Boyer reports reviewing medical malpractice documents
`for CRICO (Controlled Risk Insurance Company) Vermont, MCIC
`Vermont, and PMSLIC (Pennsylvania Medical Group Manage-
`ment Association). No other potential conflict of interest rele-
`vant to this article was reported.
`Disclosure forms provided by the author are available with the
`full text of this article at NEJM.org.
`
`n engl j med 367;2 nejm.org
`
`july 12, 2012
`
`153
`
`The New England Journal of Medicine
`Downloaded from nejm.org on August 13, 2018. For personal use only. No other uses without permission.
` Copyright © 2012 Massachusetts Medical Soci