Opioid intoxication in children and adolescents

INTRODUCTION — The epidemiology, pharmacology, clinical manifestations, and management of opioid toxicity in children and adolescents are reviewed here.

Opioid withdrawal in the pediatric patient and opioid use disorder, intoxication, withdrawal, and treatment in adults are discussed separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes" and "Opioid withdrawal in adolescents" and "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment" and "Opioid use disorder: Pharmacologic management" and "Acute opioid intoxication in adults".)

DEFINITIONS — Several terms are used to describe opioid substances:

●Opioid refers to natural and synthetic substances with morphine-like activity.

●Opiate describes a subclass of opioids consisting of alkaloid compounds extracted from opium, including morphine, heroin, codeine, and semisynthetic derivatives of the poppy plant.

●Endorphins are endogenous peptides that produce pain relief and comprise another subclass of opioids which includes enkephalins, dynorphins, and beta-endorphins.

●Prescription opioids include morphine, codeine, buprenorphine, hydromorphone, meperidine, methadone, oxycodone, and oxymorphone. Morphine and codeine are derived from opium. Buprenorphine, hydromorphone, oxycodone, and oxymorphone are semisynthetic opioids. Meperidine and methadone are fully synthetic (table 1).

●"Designer" opioids are synthetic derivatives of opioids created in makeshift laboratories and include 3-methylfentanyl (implicated in the Moscow theater hostage crisis of 2002), α-fentanyl ("China White"), desomorphine ("krokodil"), MPTP (1, methyl, 4 phenyl 1,2,3,6 tetrahydropyridine), isotonitazene, brorphine, 2-methyl-AP-237, U-47700, and others [1-7]. The agents in this class of opioids change frequently because of variation in laboratories and the attempt to evade law enforcement. (See "Acute opioid intoxication in adults", section on 'Pharmacology and cellular toxicology' and "Acute opioid intoxication in adults", section on 'Opioid adulterants, including krokodil'.)

These derivatives have a much higher potency than does heroin (up to 1000 times more potent) and have been responsible for deaths caused by inadvertent overdose [1,2]. Other health hazards relating to their use involve impurities from improper synthesis.

Fentanyl is an opiate with 100 times the potency of morphine. Its analogs can be injected, smoked, or snorted. Street names for fentanyl analogs include "Mexican brown" and "Persian white.” One of the first recognized designer opioids, alpha-methyl-fentanyl, was popularly known as "China White" and appeared in California in 1980 [3]. It is estimated to be a thousand times more potent than heroin. Hundreds of fatal overdoses of "China White" and other fentanyl derivatives occurred as a result of this increased potency [1]. Three-methyl-fentanyl, another fentanyl analog with 16 times the potency of fentanyl, and acetyl fentanyl also have been found in street samples [2]. Carfentanil, a fentanyl derivative typically used as a veterinary anesthetic, has also been found in heroin samples in the United States and Canada [8].

MPPP (1-methyl-4-phenyl-4-propionoxypiperidine), a meperidine analog, also known as "new heroin" or "designer heroin," appeared on the streets in the early 1980s. In 1982, one batch of "new heroin" was contaminated through an error in synthesis with a by-product of MPTP (methylphenyltetrahydropyridine) and caused chronic Parkinsonism in many users [4-6]. This incident underscores the dangers of using drugs that are produced in laboratories with no controls for purity or potency.

The definitions for opioid dependence or abuse are discussed separately. (See "Opioid withdrawal in adolescents" and "Opioid withdrawal in the emergency setting" and "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)

EPIDEMIOLOGY — Opioid abuse is a major international public health problem with up to 22 million people using opium or heroin worldwide [9]. Recreational use of opioids is high in the adolescent and young adult population:

●The Centers for Disease Control (CDC) report that deaths from unintentional drug overdoses have been rising steeply in the United States since the early 1990s and are a leading cause of death due to injury [10,11]. Based on CDC data, the pediatric mortality rate from prescription and illicit opioids increased by nearly threefold between 1999 and 2016 [12]. In 2021, fentanyl was implicated in 94 percent of deaths, compared with only 5 percent in 1999; between 2013 and 2021, the mortality rate from fentanyl increased 37-fold [13]. Death is thought to be secondary to respiratory depression, although prolongation of the QT interval in patients on methadone may also be contributory. While mortality is highest in people ages 45 to 54 years of age, adolescents and young adults are seen in emergency departments more frequently from abuse of opioids and other drugs.

●From 1997 to 2012, hospitalizations for prescription opioid poisoning among United States children 1 to 19 years of age increased to an annual incidence of 3.7 admissions per 100,000 children [14]. Marked increases in admissions caused by heroin and methadone poisoning were also seen during this time frame among adolescents 15 to 19 years of age.

●Nonmedical use of prescription opioids was reported by 9 percent of a nationally representative sample of high school seniors in the United States during 2007 to 2009 [15]. Intranasal use of prescription opioids was described by 37 percent of nonmedical prescription opioid users. In 2010, 68 percent of all opioid overdoses involved prescription medications with 5000 children younger than 17 years of age requiring emergency department treatment [16]. From 2000 to 2015, the rate of prescription opioid poisoning among teenagers, based upon almost 190,000 poison control center calls, varied from 20 to 40 exposures per 100,000 children with exposures due to suspected suicide increasing over 50 percent during the study period [17].

●Annual health care costs in the United States due to prescription opioid abuse are estimated to be greater than 25 billion dollars [18].

In children under age six years, opioid intoxication typically occurs as an exploratory ingestion of prescription opioids that were available within their environment. Some of these medications, such as methadone and buprenorphine pills or fentanyl patches, may cause life-threatening respiratory depression or death despite ingestion of only one or two pills or exposure to one patch [17,19-29].

●In the United States, buprenorphine was the oral prescription opioid accounting for the most emergency hospitalizations for poisoning in children younger than six years of age from 2007 to 2011 [30]. Buprenorphine ingestion by children younger than six years of age is associated with high rates of hospital admissions (up to 45 percent) and serious medical outcomes (over 20 percent of exposures) [31]. If available, unit dose packaging of buprenorphine may decrease hospitalization [32].

●Among children younger than six years of age, methadone prescribed to caregivers and accessible to the child in their home was the most common opioid involved in deaths based on 2010 to 2018 data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS) System Poison Center Program [33].

●From 2005 to 2018, opioids increasingly contributed to fatal poisonings in children ≤5 years of age [34]. Opioids contributed to 24 percent of deaths in 2005 compared with 52 percent in 2018 and were the most common substance contributing to death during the study period.

●Children can also be exposed to opioids maliciously by their caretakers or inadvertently in households where illegal drugs are accessible, often with fatal results [35-37]. (See "Physical child abuse: Diagnostic evaluation and management", section on 'Toxicology'.)

PHARMACOLOGY — The activity of opioids resembles that of the body's endogenous opioid peptides (enkephalins, endorphins, and dynorphins) [38]. Opioid peptides produce their effects through interaction with receptors throughout the nervous system and the gastrointestinal tract. In contrast, local anesthetics alter pain sensory thresholds.

Mechanism of action and pharmacokinetics — Three types of receptors have been identified: mu (µ), kappa (k), and delta (δ); most opioids interact with more than one type [38]. An opioid-receptor-like 1 (ORL-1) receptor or "orphan" receptor has also been described [38]. The primary sites of opioid action are the limbic system, thalamus, and hypothalamus.

In 1996, there was a proposal by the International Union of Basic and Clinical Pharmacology (IUPHAR) to rename the opioid receptors OP3, OP2, OP1, and OP4 respectively although this nomenclature has not been widely adopted [39]. The IUPHAR has subsequently recommended adopting the terms MOP, KOP, DOP, and NOP [40]. However, the original Greek letter nomenclature still predominates.

Opioids are classified into three groups based upon their actions [38]:

●Morphine-like opioid agonists, which include heroin, codeine, meperidine, hydrocodone, diphenoxylate-atropine, loperamide, fentanyl, and methadone.

●Opioid antagonists, which competitively block receptor activation by occupying opioid receptor sites. Examples include naloxone, nalmefene, and naltrexone.

●Mixed agonist-antagonists/partial agonists, which have different effects depending upon the predominance of agonistic or antagonistic activity in the opioid receptor and prior exposure to opioids.

The use of a mixed agent in an opioid-naive subject results in analgesia and possibly dependence if the agent is used for a long period of time. On the other hand, the use of a mixed agent in an opioid dependent subject may result in withdrawal. Examples of drugs in this class include pentazocine, nalbuphine, and buprenorphine.

●Pharmacokinetics – The pharmacokinetics of opioids in children between age 1 and 15 years are similar to those in adults [41]. Intravenous use of opioids gives an immediate euphoric effect, subcutaneous administration produces euphoria in 15 minutes, and snorting leads to effect in approximately 30 minutes. When taken orally, opioids such as methadone typically produce a peak effect in four to six hours.

Clinical effects of pharmacological doses of most opioids persist for three to six hours; fentanyl for one hour; and methadone for 24 to 48 hours [38]. The absorption of orally administered diphenoxylate-atropine (Lomotil) usually is delayed because of the atropine (anticholinergic) component. Meperidine has erratic absorption when it is used intramuscularly [42]. The toxicokinetics of opioid drugs after overdose have not been fully defined leading to uncertainty as to the length of time necessary for observation of the asymptomatic patient.

●Metabolism – Most opioids are metabolized by the liver. Patients with liver disease have impaired metabolism and are at increased risk for toxicity caused by accumulation of active metabolites [41]. The active metabolites of opioids bind to specific mu, delta, and kappa receptors in the central nervous system (CNS) to elicit their clinical effects. The µ2 receptor mediates many of the life-threatening effects, including respiratory depression. CYP 2D6 is the enzyme responsible for converting codeine to morphine, for example, and individuals with duplicate genes are considered to be ultrarapid metabolizers with an increased risk for toxicity [43]. Opioid metabolites are excreted primarily by the kidneys and can be detected on urine drug screen up to four days after the last use (occasionally longer in chronic users) [41]. Renal dysfunction can lead to toxicity caused by accumulation of active metabolites.

●Drug interactions – Opioids interact with various drugs [41,44]:

•Proserotonergic opioids such as fentanyl and meperidine in combination with monoamine oxidase inhibitors, serotonin-specific reuptake inhibitors, and cyclic antidepressants can produce serotonin syndrome [45].

•Phenothiazines potentiate the action of opioids, possibly by interfering with their metabolism.

•Cyclic antidepressants increase the bioavailability and plasma level of opioids.

•Several drugs impact metabolism of opioids through inhibition or induction of cytochrome oxidase enzyme systems. For example, cimetidine may enhance effects through prolonging the duration of action. Certain antibiotics may increase (erythromycin) or decrease (rifampin) opioid effects.

Morphine — Compared with intravenous administration, sublingual, buccal, and sustained-release preparations of morphine have delayed absorption, attenuating and delaying the peak plasma concentrations. Sustained-release morphine attains one-half the peak plasma level of a comparable dose of immediate-release morphine; levels peak three to four hours after use and depending upon preparation provide pain relief in opioid naïve patients from 4 to 10 hours [41].

Morphine's main metabolite, morphine-6-glucuronide, is more potent than morphine and is responsible for most of the clinical effects [41]. It can be detected in large quantities soon after oral or intravenous administration and levels directly correlate with medication effect as described above. (See 'Mechanism of action and pharmacokinetics' above.)

Heroin — Heroin (diacetylmorphine) is the prototypic recreationally abused opioid, and it is sold under various creative street names Heroin is produced as a pure white crystal or impure tar-like substance, depending upon the supplier. It is typically adulterated with lactose, procaine, calcium-channel blockers, mannitol, dextrose, talc, or other substances [46]; final concentration varies between 1 to 20 mg per dose from dealer to dealer and day to day. For this reason, overdoses are more likely to occur with heroin than with prescription opiates.

Heroin typically is injected. It has a quick onset and brief duration of action. It is rapidly cleared by the liver and excreted in the urine as morphine. The pharmacokinetics of inhaling heroin fumes ("chasing the dragon") or smoking cigarettes dipped in heroin ("ack ack") are similar to that of heroin that is injected intravenously. Chronic fume inhalation can result in spongiform leukoencephalopathy and may represent chronic aluminum toxicity [47]. In one study, the blood concentrations of heroin, either inhaled or intravenous peaked within one to five minutes and decreased to the limit of detection within 30 minutes [48].

Routes of use — Opioids can be administered intravenously ("mainlining"), subcutaneously ("skin popping"), intranasally ("snorting"), orally, or by inhaling (smoking, "free-basing," "chasing the dragon"). Most American adolescents initiate heroin or prescription opioid use by snorting because snorting requires minimal equipment, is not associated with the health risks of injection, and the onset of action is rapid enough to produce euphoria (the "rush") [15,49]. Cases of "body packing" (swallowing large amounts of well-packaged opioids for the purpose of smuggling) have also been described in children and adolescents [50,51]. (See "Internal concealment of drugs of abuse (body packing)".)

CLINICAL MANIFESTATIONS — The diagnosis of opioid overdose is based upon the history and physical examination.

History — The clinician should attempt to identify the specific drug, dose, and formulation to which the patient was exposed, the presence of nonopioid co-exposures, and the individual's prior history of opioid use. In young children, the history is typically a small, exploratory ingestion and a list of drugs available within the child’s environment should be detailed. The caregiver should also be asked about administration of medicines containing diphenoxylate-atropine (eg, Lomotil) or dextromethorphan (present in many over-the-counter cough medicines), both of which can cause serious opioid toxicity in young children [52,53]. When infants or young children are ultimately identified with serious opioid overdose and there is no clear initial history of opioid use, health care providers should give consideration to the possibility of a malicious intentional overdose by a caregiver.

In adolescents, opioid exposures will fall into one of several categories: recreational use, intended self-harm, or attempt to hide drugs from law enforcement out of fear for arrest ("body stuffing"), or rarely, swallowing large quantities of packaged drugs in order to transport them across borders ("body packing"). In this patient population, additional history should identify the likelihood of trauma (particularly head trauma) and sexual assault. Often, emergency medical services reports regarding where and how the patient was found and whether they were partially or fully undressed can assist in identifying physical or sexual assault.

Physical examination — The classic findings of opioid toxicity are (table 2 and table 3):

●Miosis

●Central nervous system (CNS) depression

●Respiratory depression

●Other findings, including hyporeflexia, hypothermia, dermal "track marks", flushing, pruritus, bradycardia, hypotension, or decreased bowel sounds

Opioids can also cause multiple physical findings in various organ systems:

●Pupillary response – Miosis (pupillary constriction) usually occurs within five minutes of intravenous administration and lasts for at least six hours [48]. Although miosis is the usual finding, mydriasis or normal pupils may be seen with overdose of meperidine, morphine (rarely), propoxyphene, dextromethorphan, or pentazocine, in the early stages of diphenoxylate-atropine (Lomotil poisoning), and after the use of naloxone [38,54,55]. Mydriasis or normal pupils also may be seen if heroin was coingested with a stimulant or anticholinergic drug, such as cocaine (ie, "speedball") or scopolamine, or if hypoxic brain injury occurred because of prolonged respiratory depression [49].

●Respiratory depression and noncardiogenic pulmonary edema – Most opioid-related deaths are caused by respiratory depression, which is caused by central and peripheral effects. Respiratory depression may be subtle. The isolated respiratory rate is not a reliable measure of ventilation because a small decrease in tidal volume occurs before the respiratory rate declines.

Noncardiogenic pulmonary edema may complicate opioid overdose. The characteristic findings include pink, frothy bronchial secretions, cyanosis, and rales in a stuporous or comatose patient with respiratory depression and miotic pupils. The distribution of pulmonary edema on chest radiograph usually is nonuniform [56]. The pathophysiology of this form of pulmonary edema is not known. Proposed mechanisms include forceful inspiration (negative pressure) against a closed glottis, direct toxicity of the drug, hypoxia, and acidosis secondary to hypoventilation and/or cerebral edema. Resolution of pulmonary edema is rapid once assisted ventilation is instituted and both hypoventilation and hypoxia are reversed.

The incidence of noncardiogenic pulmonary edema in patients hospitalized with heroin overdose is 48 to 80 percent [57]. Methadone, morphine, and propoxyphene also can cause noncardiogenic pulmonary edema. The interval between exposure and symptom onset usually is less than two hours for heroin-related cases [56] and less than 6 to 12 hours for those associated with methadone. Some case reports have suggested that naloxone itself precipitates noncardiogenic pulmonary edema in patients with opioid overdose. However, alveolar filling was noted on autopsy in 50 to 90 percent of heroin overdose patients that did not receive naloxone [58].

●Cardiovascular – Opioids cause bradycardia and hypotension via increased parasympathetic activity, decreased sympathetic activity, and release of histamine brought about by their effects on the vasomotor center [59]. The drug-induced bradycardia and increased automaticity can cause arrhythmia, including potentially lethal ventricular tachyarrhythmia [60]. Methadone, in particular, can block the inwardly rectifying potassium current with subsequent prolongation of the QT interval [61]. According to case reports, heroin contaminated with clenbuterol, a beta2 agonist, has resulted in tachycardia [62].

●Neurologic – Patients presenting to the emergency department typically are stuporous or comatose. Patients with profound CNS depression are at risk for aspiration of gastric contents because of impaired gag reflex and centrally mediated nausea and vomiting.

Generalized seizures can occur after intravenous fentanyl and sufentanil administration, the prolonged use of meperidine, and large ingestions of propoxyphene, tramadol, or pentazocine [63].

A Parkinsonian-like syndrome has been associated with some opioid-based designer drugs, such as MPTP (1, methyl, 4 phenyl 1,2,3,6 tetrahydropyridine) [64].

●Gastrointestinal – Constipation results from decreased motility and increased sphincter tone in the rectum. The classic recommendation that morphine should not be used in the treatment of biliary colic was based upon the long-standing teaching that morphine causes spasm of the sphincter of Oddi. However, no significant differences in intrabiliary pressures were found in clinical studies comparing morphine and meperidine [42].

●Muscle rigidity and rhabdomyolysis – All opioid agonists can produce skeletal muscle rigidity, even at low doses [65]. Acute rhabdomyolysis and renal failure may occur with the use of heroin, methadone, and propoxyphene.

●Skin – Track marks can be seen frequently in those opioid users who routinely use the intravenous route for injection. Those injecting drug subcutaneously ("skin poppers") may be at risk for wound botulism. (See "Botulism", section on 'Types of botulism and their sources'.)

●Reproductive – In girls, opioids may cause amenorrhea, anovulatory cycles, and impaired fertility caused by abnormal prolactin secretion secondary to the opioid action on the dopaminergic system. In addition, opioids may cause decreased libido in both males and females [66].

●Endocrine – Hypoketotic hypoglycemia with hyperinsulinism has been described in one toddler after unintentional exposure to methadone [67].

DIFFERENTIAL DIAGNOSIS — In adolescents, the differential diagnosis for opioid intoxication is similar to adults. (See "Acute opioid intoxication in adults", section on 'Differential diagnosis'.)

In children under six years of age, common toxicologic causes of coma include benzodiazepines and other sedative-hypnotic agents, alpha-2 receptor agonists (eg, clonidine, xylazine), oral hypoglycemic agents, ethanol, psychotropic medications, and exposure to carbon monoxide (table 4):

●While clonidine may produce miosis and obtundation, bradycardia, and hypotension are more prominent than in patients with opioid intoxication. Xylazine, an alpha-2 receptor agonist (similar to clonidine) used as a veterinary sedative, can be found in illicit heroin and fentanyl. It can also cause miosis, obtundation, bradycardia, and hypotension that is not reversed by naloxone, and with repeat parenteral use, can lead to severe, necrotic skin ulcerations. (See "Clonidine, xylazine, and related imidazoline poisoning", section on 'Xylazine'.)

●Ethanol intoxication produces little to no miosis and no change in bowel sounds. Nystagmus and hypoglycemia may be prominent features in young children. (See "Ethanol intoxication in children: Clinical features, evaluation, and management", section on 'Clinical features'.)

●The sedative-hypnotic agents and gabapentinoids result in much less respiratory depression than the opioids, especially when taken orally. Pupils are typically not pinpoint, and ataxia may be a prominent feature in children. (See "Benzodiazepine poisoning", section on 'Clinical features of overdose' and "Gabapentinoid poisoning and withdrawal", section on 'Clinical features of overdose'.)

●Organophosphate-containing substances may cause miosis and coma in children but are also accompanied by prominent parasympathetic and preganglionic sympathetic symptoms (eg, vomiting, diarrhea, sweating, bronchorrhea, salivation, bradycardia or tachycardia, hypo- or hypertension), fasciculations and paralysis. (See "Organophosphate and carbamate poisoning", section on 'Acute toxicity'.)

●Baclofen, a gamma-aminobutyric acid (GABA) B receptor agonist, can cause coma, respiratory depression, bradycardia, and hypotension after ingestion in children and adolescents [68,69]. Myoclonus and seizures can occur. (See "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal", section on 'Clinical features of overdose'.)

Any medical condition that causes coma may mimic opioid poisoning in children. Key conditions to exclude are those in which delayed diagnosis also delays specific care, such as hypoxemia, hypoglycemia, sepsis, central nervous system (CNS) infection, and abusive head trauma. (See "Evaluation of stupor and coma in children", section on 'Etiologies'.)

Intussusception may present with coma and miosis, and CNS depression associated with intussusception may respond to naloxone therapy, presumably due to elaboration of endogenous endorphins.

ANCILLARY STUDIES — Children and adolescents with altered mental status and suspected opioid intoxication warrant the following studies (table 3):

●Blood glucose

●Pulse oximetry and, if respiratory status does not improve after naloxone administration, blood gas measurement

●Serum acetaminophen concentration if suicidal intent or if ingestion of combination agents (eg, acetaminophen with hydrocodone or oxycodone)

●Serum ethanol level (adolescents with recreational or suicidal overdose)

●Electrocardiogram, especially in patients with methadone overdose to evaluate for prolonged QTc

●Chest radiograph, in patients with persistent respiratory findings suggestive of pulmonary aspiration or noncardiogenic pulmonary edema

●Rapid urine pregnancy test in postmenarcheal girls

●Urinalysis, serum electrolytes, blood urea nitrogen, creatinine, and creatine kinase in patients at risk for rhabdomyolysis (eg, prolonged immobilization, muscular rigidity)

Further laboratory evaluation of opioid overdose varies depending upon the circumstances of exposure. A witnessed exploratory ingestion in a toddler or a known recreational overdose with full recovery after antidotal therapy may merit little laboratory investigation whereas an unwitnessed suicidal overdose may lead to more extensive testing, especially if the patient displays persistent symptoms despite antidotal therapy or has evidence of serious coingestants. Other ancillary studies may be indicated in selected patients in whom trauma, infection, or other etiologies besides poisoning are suspected. (See "Evaluation of stupor and coma in children" and "Approach to the child with occult toxic exposure".)

Testing for opioids — Rapid enzyme-mediated immunoassay technique (EMIT), mass spectrophotometry, gas chromatography, and radioimmunoassay are available to test urine for opioids. However, the results of these tests require interpretation based upon the clinical scenario for a number of reasons:

●False-positive results – The metabolites of some medications and foods are the same as the metabolites of opioids of abuse (eg, acetaminophen with codeine, codeine cough syrup, and poppy seeds). In addition, fluoroquinolones have been described as a cause for false positive opiate screens [70,71]. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)

●False-negative results – Some synthetic opioids (eg, methadone, fentanyl) do not contain the phenanthrene nucleus that is needed for detection on typical commercially obtained hospital toxicology screens for opioids. Furthermore, tampering methods or dilute samples may interfere with actual toxicology screening results [72,73].

●Urine detection – Opioids are detectable in the urine for only two to four days after use. (See "Opioid use disorder: Epidemiology, clinical features, health consequences, screening, and assessment".)

In an adolescent with a known recreational exposure to opioids who responds to antidotal therapy, the diagnosis is confirmed. Urine toxicologic testing does not add anything further to acute clinical management and is not recommended. However, healthcare providers involved in adolescent substance use disorder treatment programs may utilize toxicology screening results to further enhance outpatient therapy [74].

In children under six years of age in whom the cause of coma is unknown or in whom malicious administration of opioids is suspected, the most accurate form of testing (eg, gas chromatography mass spectrophotometry, or GCMS), may be indicated to definitively document the exposure for legal reasons.

MANAGEMENT OF ACUTE TOXICITY — A rapid overview provides a summary for the evaluation and treatment of opioid overdose (table 3). Most of the direct morbidity and mortality related to opiate use occur after acute ingestion and are caused by hypoxemia, aspiration pneumonitis, pulmonary edema, acute respiratory acidosis, and anaphylaxis. Immediate management involves airway management and administration of an opioid antagonist (table 3).

Supportive care — Patients whose respiratory status is compromised should be supported with bag mask ventilation and 100 percent oxygen while the opioid antagonist, naloxone, is administered [75]. They may require supplemental oxygen, endotracheal intubation, and positive end expiratory pressure if there is inadequate response to naloxone or if pulmonary edema is present. If endotracheal intubation has been performed, and mechanical ventilation is being administered, then naloxone administration may be counterproductive.

Glucose should be administered intravenously if indicated by immediate bed-side glucose testing (<60 mg/dL). (See "Approach to hypoglycemia in infants and children", section on 'Glucose therapy'.)

Seizures and cardiac dysrhythmias occur rarely and should be managed with standard therapies. (See "Clinical features and complications of status epilepticus in children".)

Body packers and stuffers — Treatment, including recommendations for activated charcoal administration and initiation of whole bowel irrigation in body packers or body stuffers, is discussed in detail separately. (See "Acute opioid intoxication in adults", section on 'Body packing and body stuffing' and "Internal concealment of drugs of abuse (body packing)".)

Gastrointestinal decontamination — We recommend administration of activated charcoal (AC, 1 g/kg PO or NG with a maximum of 50 g) to alert young children and adolescents who have ingested opioids and who present within one hour of oral overdose. In patients with altered mental status, activated charcoal administration should be delayed until reversal of symptoms with naloxone has restored consciousness or the airway has been secured. Alternatively, AC may be withheld in such patients if toxicity is well-controlled with naloxone and the presence of unabsorbed opioid medication is unlikely. Patients who have orally ingested large amounts of opioids (body stuffers or packers), sustained release opioids, or opioid patch medications should receive gastrointestinal decontamination with AC and whole bowel irrigation as described separately. (See "Acute opioid intoxication in adults", section on 'Body packing and body stuffing'.)

This recommendation for activated charcoal administration following oral opioid overdose derives from indirect evidence of benefit in volunteers, animal studies, and evidence of benefit following ingestions of other medications. Opioids, like most other xenobiotics, bind well to activated charcoal. Sorbitol is an osmotically active carbohydrate often used to sweeten activated charcoal and to speed its intestinal transit: evidence for benefit from sorbitol is scant and it should not be used for more than a single dose of activated charcoal. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Cathartics' and "Gastrointestinal decontamination of the poisoned patient", section on 'Evidence of efficacy and adverse effects'.)

The greatest benefit occurs if AC is given within one hour. The efficacy of AC as a function of time from ingestion is discussed in detail separately. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Activated charcoal'.)

AC administration is not indicated following intravenous or inhalational opioid overdose.

Naloxone — Naloxone is a synthetic derivative of oxymorphone that competitively binds opioid receptors and is the antagonist of choice for reversal of acute opioid toxicity [76]. It has a greater affinity for the mu receptors than do opioid agonists; for example, the effects of 25 mg of heroin are blocked by 1 mg of naloxone. Naloxone is highly lipophilic, moves rapidly into the central nervous system, and has an onset of action of one minute when given intravenously [76]. Clinical effects of naloxone typically last 45 to 70 minutes.

Dosing and administration — We recommend that children and adolescents with clinical findings of coma, depressed respirations and miosis or circumstantial evidence of opioid abuse receive naloxone rather than supportive care alone. Although the greatest amount of evidence supporting naloxone use for opioid intoxication is derived from adult studies, observational studies and case reports in children have also shown that naloxone effectively reverses severe opioid poisoning with minimal adverse effects [24,77]. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and 'Adverse effects' below.)

●Dose – The dose of naloxone for serious opioid intoxication varies depending upon the size of the patient and the clinical scenario (table 3):

•Children <20 kg should receive naloxone 0.1 mg/kg IV (maximum 2 mg per dose). The use of naloxone in neonates in the delivery room is discussed separately. (See "Neonatal resuscitation in the delivery room", section on 'Naloxone'.)

•Children ≥20 kg should receive naloxone 2 mg IV.

•Adolescents suspected of opioid dependence who are breathing spontaneously should receive an initial dose of 0.04 mg IV, and the dose should be titrated upward every few minutes until the respiratory rate is 12 or greater to avoid iatrogenic opioid withdrawal [75,78]. A common approach is to dilute 1 mL of a naloxone 0.4 mg/mL formulation with 9 mL of normal saline or sterile water for injection (creating a total volume of 10 mL with a 0.04 mg/mL concentration) and administering 1 to 2 mL aliquots. Apneic adolescents should receive higher initial doses of naloxone (0.2 to 1 mg), while those in cardiorespiratory arrest following possible opioid overdose should be given a minimum of 2 mg of naloxone [79,80].

Naloxone should be repeated every few minutes until improvement in respiratory depression is noted. Cumulative doses of naloxone great than 10 mg in the first half hour are unlikely to yield additional benefit. Larger than customary doses of naloxone may be required to reverse the effects of drugs with higher receptor affinity than morphine (eg, codeine, diphenoxylate-atropine, methadone, fentanyl, fentanyl analogs, propoxyphene, pentazocine, nalbuphine, buprenorphine, and butorphanol) [76]. If respiratory depression of unknown etiology has failed to improve with a cumulative dose of 10 mg of naloxone, then isolated opioid toxicity is unlikely.

●Route of administration – Naloxone is preferably administered intravenously. However, it can also be administered intranasally, intramuscularly, subcutaneously, endotracheally, or intralingually (ie, injected into the sublingual vein) as well as via an intraosseous needle [76,81].

●Treatment of recurrent toxicity – Naloxone has a shorter duration of action (one-half to one hour) than do most opioids and may need to be administered as repeated boluses or continuous infusion until full opioid metabolism has occurred. As an example, children with methadone overdose may require naloxone therapy for several days [24].

Continuous infusions of naloxone have been used safely in children [82,83]. Naloxone should be mixed in a solution of 5 percent dextrose OR normal saline and infused at a rate that does not exceed the hourly maintenance rate for weight. (See "Maintenance intravenous fluid therapy in children".)

One method for administering a constant infusion is as follows [84]:

•Determine the amount of naloxone that was required to restore respiratory function during bolus dosing. Two-thirds of this dose is then administered as an hourly infusion. Care must be taken to avoid induction of withdrawal symptoms in patients who are opioid dependent.

•A transient drop in naloxone levels may occur 20 to 30 minutes after the continuous infusion is initiated. To prevent this from occurring, one-half of the loading dose (the dose required to reverse respiratory depression) should be administered 15 minutes after the continuous infusion is started [84].

•The rate of infusion should be titrated to maintain respiration and avoid withdrawal symptoms. Respiratory and mental status must be closely monitored.

•The infusion rate may be decreased by 50 percent every hour for the next 6 to 12 hours (the duration of action of most opiates). The naloxone infusion should be continued until complete or near complete reversal of the respiratory depression occurs.

Adverse effects — Precipitation of opioid withdrawal by naloxone administration is the most common adverse effect. Although withdrawal is not life-threatening except in the neonatal period, the agitation, nausea, vomiting, and anxiety are distressing to the patient. Patients in acute withdrawal may become violent, potentially causing harm to themselves or healthcare providers [85]. Symptoms typically subside 20 to 30 minutes after the administration of naloxone because the antagonist effect diminishes. Incremental low dosing of naloxone in patients with suspected opioid use disorder is the main way to avoid withdrawal.

Rare complications possibly attributable to naloxone therapy of opioid intoxication and reported in adults include pulmonary edema, hypertension, hypotension, dysrhythmia, and sudden death [76,86,87]. No sudden death attributable to naloxone has been reported in children outside of the neonatal period.

Other opioid antagonists — Naloxone is the preferred drug for acute treatment of opioid intoxication. Other longer acting opioid antagonists have been occasionally used as acute therapy in adults, instead of naloxone infusion in patients with prolonged intoxication, and for long-term opioid detoxification:

●Nalmefene – Nalmefene has a longer duration of action than that of naloxone. Its use in the acute care setting is controversial. Compared with naloxone, it causes fewer fluctuations in the patient's level of consciousness and decreased risk for recurrent opioid toxicity in patients who leave against medical advice soon after initial resuscitation. On the other hand, nalmefene may precipitate prolonged withdrawal in patients with opioid use disorder or recurrent symptoms in patients who have taken synthetic opioids with duration of action equal to or longer than that of nalmefene [38].

Nalmefene may be considered for use in children who have had a single opioid exposure or in those who are being admitted to the hospital and do not experience withdrawal after a trial dose of naloxone [88]. Nalmefene may also be used safely in potentially opioid-dependent adolescents after a trial dose of naloxone has been tolerated safely. Intravenous doses of 0.5 to 2 mg have been reported to be safe and effective in adults. The duration of action is 4 to 10 hours if the dose is 0.5 to 1 mg, and greater than 8 hours if the dose is 2 mg. Adverse effects of nalmefene are uncommon and include nausea and vomiting, tachycardia, myoclonus, dizziness, and drowsiness.

Although the optimal nalmefene dose for pediatric opioid overdose has not been studied, intravenous doses of 0.25 to 1 mcg/kg (to a maximum of 40 mcg) have been safely used to reverse sedation in 15 pediatric patients [89]. An intranasal formulation of nalmefene (2.7 mg dose) is also approved in the United States for acute opioid intoxication in adolescents and adults.

●Naltrexone – Naltrexone is an oral opioid antagonist with a longer duration of action than that of naloxone. It is used primarily to promote long-term opioid abstinence. Naltrexone is not indicated in the treatment of acute opioid toxicity because it is administered orally and because it can induce a prolonged withdrawal state [90].

Child protection — In cases where child abuse is suspected, involvement of an experienced child protection team is crucial and in many parts of the world (including the United States, United Kingdom, and Australia) reporting to a governmental agency is mandatory. The safety of other children in the home must be ensured by local Child Protective Services. (See "Child abuse: Social and medicolegal issues", section on 'Reporting suspected abuse' and "Physical child abuse: Diagnostic evaluation and management".)

Disposition — The following patients warrant hospital admission:

●Infants and young children who require naloxone administration to reverse opioid effects or in whom intentional poisoning by the caretaker is suspected.

●Patients in whom delayed or prolonged opioid intoxication is likely (eg, ingestion of diphenoxylate-atropine [Lomotil], methadone, or buprenorphine).

●Patients who are suicidal or whose social setting does not provide a safe environment for the child.

●Adolescents who have recurrence of respiratory depression or noncardiogenic pulmonary edema. As in adults, recurrent symptoms of intoxication or respiratory distress should be evident within two hours of initial treatment and observation beyond that time is not necessary. (See "Acute opioid intoxication in adults", section on 'Disposition'.)

For adolescent patients in whom opioid use disorder is identified, the plans for long-term management of the drug problem and referrals to local substance abuse treatment resources should be made before discharge. (See "Substance use disorder in adolescents: Treatment overview".)

COMPLICATIONS — Many of the complications of opioid use are related to the method of administration. Snorting is associated with chronic rhinitis and septal ulcers with disintegration. Smoking can cause burns and exacerbate preexisting asthma and respiratory illnesses. Intravenous administration is associated with many complications (table 5), including bacterial endocarditis, blood-borne infection, septic pulmonary emboli, nephropathy, abscesses, and cellulitis [65]. (See "Acute opioid intoxication in adults", section on 'Opioid adulterants, including krokodil'.)

Opioid use impairs judgment and can put the user at risk for unintentional injury. One-tenth of the adolescent trauma victims in one emergency department had urine toxicology screens that were positive for opioids [91].

The social and behavioral consequences of opioid use disorder are influenced by the lifestyle of drug dependence. Adolescents who use opioids typically are involved in other high-risk behaviors (eg, polysubstance abuse, high-risk sexual practices, delinquency, and school failure). These adolescents often run away from home or become homeless. They may resort to prostitution, robbery, or burglary to obtain drugs or money for drugs. In addition, adolescent substance use disorder is a significant risk for violence-related injury. (See "Peer violence and violence prevention", section on 'Adolescent screening'.)

The life-threatening effects of opioids are related to respiratory failure and failure of physiological oxygen delivery. Ischemic injury to the brain, heart, and other body organs are dire complications of opioid poisoning.

PREVENTION — Although evidence is limited regarding specific strategies that health care providers can follow to prevent opioid intoxication in children and adolescents, observational studies identify the following activities for emphasis:

Safe storage — Health care providers should advise that all prescription opioid medications be kept in a secured location at home (eg, locked cabinet).

This recommendation is based upon national trends that implicate prescription opioids as a frequent source of opioid intoxication and deaths in children and adolescents and a driver of opioid dependence and opioid use disorder. (See 'Epidemiology' above and "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Epidemiology'.)

Despite these trends, preliminary evidence suggests that safe storage is uncommon. For example, in a nationally representative survey of 1032 adults with prescription opioid use in the past 12 months, only 9 percent reported safe storage of their medications [92]. Furthermore, of the 681 adults in this survey who had children younger than 18 years of age in the household, safe storage was reported in only 29 to 33 percent of households with young children and 12 percent of households with children older than six years of age [93]. Safe storage was more likely among adults with younger children who worried about their child’s access to the drugs and who were certain that they could store medications in a locked location at all times.

These surveys support public health campaigns and anticipatory guidance by health care providers that emphasize how safe storage may reduce opioid overdose and limit opioid misuse (ie, opioid abuse, or diversion) in children and adolescents. Further research should focus on developing and implementing effective means of secure storage in households.

Safe prescribing — Health care providers should follow guidance for safe prescribing developed by the Centers for Disease Control and Prevention [94]:

●When treating pain in children and adolescents, health care providers should discuss therapeutic options with the caregiver and patient, including treatments other than prescription opioids. In one study in which children without major chronic diseases were prescribed opioids as an outpatient, one of every 2611 study opioid prescriptions was followed by an opioid-related adverse event (71.2 percent were related to therapeutic use) [95].

●Health care providers should use prescription drug monitoring programs, where available, to identify patients or caregivers who might be misusing (ie, abusing or diverting) prescription opioid medications.

●When indicated, providers should prescribe the lowest effective dose and minimum quantity of prescription opioid medications. When not contraindicated, acetaminophen and ibuprofen should also be used to decrease the amount of opioid medication required.

●Concurrent prescription of sedatives with opioids should be avoided.

Long term trends based upon surveys of high school seniors in the United States over 40 years show that the use of prescription opioids is strongly correlated with misuse in adolescents and that misuse typically follows medical use by the patient [96]. In adults, greater daily opioid doses and greater numbers of prescriptions per month are associated with a higher risk of overdose death. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Limiting exposure'.)

Thus, safe prescribing habits may have a significant impact on reducing opioid intoxication although further study is needed to document their impact.

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opioid use disorder and withdrawal" and "Society guideline links: Poisoning prevention" and "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use".)

SUMMARY AND RECOMMENDATIONS

●Rapid overview – A rapid overview provides clinical features, recommended ancillary studies, and suggested management of opioid intoxication in children and adolescents (table 3).

●Epidemiology – Opioid intoxication in adolescents primarily results from recreational use or intentional exposure with suicidal intent. In young children, opioid poisoning typically occurs following exploratory ingestion, although the possibility of malicious exposure by a caretaker should be evaluated. (See 'Epidemiology' above.)

●Clinical manifestations and diagnosis – The diagnosis of opioid intoxication is usually made based upon clinical findings. 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 respiratory depression. Normal pupil examination or mydriasis does not exclude opioid intoxication. (See 'Physical examination' above.)

●Differential diagnosis – Any medical condition that causes coma may mimic opioid poisoning in children. Key conditions to exclude are those in which delayed diagnosis also delays specific care, such as hypoxemia, hypoglycemia, sepsis, central nervous system infection, and abusive head trauma. (See 'Differential diagnosis' above.)

●Management – Management of opioid intoxication includes:

•Support airway, breathing, and circulation – Support of the child’s airway and breathing using bag-mask ventilation with 100 percent inspired oxygen until an opioid antagonist is administered. (See 'Supportive care' above.)

•Naloxone – We recommend that children and adolescents with suspected opioid overdose receive naloxone rather than supportive care alone (Grade 1A). The first dose of naloxone varies depending upon the size of the patient and the clinical scenario (see 'Dosing and administration' above):

-Children <20 kg: 0.1 mg/kg IV (maximum 2 mg per dose).

-Children ≥20 kg: 2 mg IV.

-Adolescents with suspected opioid dependence and spontaneous ventilation should receive lower doses of naloxone (similar to adult treatment strategy) to avoid precipitation of opioid withdrawal (table 6). A naloxone dose of 0.04 mg is an appropriate starting point, and the dose should be titrated upward every few minutes until the respiratory rate is 12 or greater. May dilute 1 mL of a naloxone 0.4 mg/mL formulation with 9 mL of normal saline or sterile water for injection (creating a total volume of 10 mL with a 0.04 mg/mL concentration) and administer 1 to 2 mL aliquots. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy'.)

The use of naloxone in neonates is discussed separately. (See "Neonatal resuscitation in the delivery room", section on 'Naloxone'.)

•Gastrointestinal decontamination – We recommend administration of activated charcoal (1 g/kg PO or NG with a maximum of 50 g) to alert young children and adolescents who have ingested opioids and who present within one hour of overdose (Grade 1B). Activated charcoal administration is not indicated following intravenous or inhalational opioid overdose. (See 'Gastrointestinal decontamination' above.)

Beyond one hour of overdose, patients who have orally ingested large amounts of opioids (body stuffers or packers), sustained release opioids, or opioid patch medications may warrant whole bowel irrigation as described separately. (See "Acute opioid intoxication in adults", section on 'Body packing and body stuffing' and "Internal concealment of drugs of abuse (body packing)".)

●Disposition – The following patients warrant hospitalization after opioid intoxication (see 'Disposition' above):

•Infants and young children who require naloxone administration to reverse opioid effects or in whom intentional poisoning by the caretaker is suspected.

•Patients in whom delayed or prolonged opioid intoxication is likely (eg, ingestion of diphenoxylate-atropine [Lomotil], methadone, or buprenorphine).

•Patients who are suicidal or whose social setting does not provide a safe environment for the child.

•Adolescents who have recurrence of respiratory depression or noncardiogenic pulmonary edema. As in adults, recurrent symptoms of intoxication or respiratory distress should be evident within two hours of initial treatment and observation beyond that time is not necessary. (See "Acute opioid intoxication in adults", section on 'Disposition'.)

●Child protection – In cases of suspected child abuse, perform further evaluation (table 7), preferably in consultation with a multidisciplinary children protection team (if available) and report suspicion to the appropriate governmental agency. (See "Physical child abuse: Diagnostic evaluation and management".)

●Referral for opioid use disorder – For adolescent patients in whom opioid use disorder is identified, the plans for long-term management of the drug problem and referrals to local substance abuse treatment resources should be made before discharge. (See "Substance use disorder in adolescents: Treatment overview".)