Opioid intoxication in children and adolescents
Prem Shukla, MD, MS, FACEP
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.3 is current through August 2007; this topic was last changed on September 7, 2006. The next version of UpToDate (16.1) will be released in March 2008.
INTRODUCTION — Opioids have analgesic and central nervous system (CNS) depressant effects, as well as the potential to cause euphoria. Morphine is the prototypic opioid. Heroin is a derivative of morphine and is the most commonly abused opiate.
Opiate medications are effective in the treatment of acute and chronic pain, as sedatives, and as anesthetic agents. They have the potential to be abused for these effects and the associated feeling of euphoria. The epidemiology, pharmacology, clinical manifestations, and management of opioid toxicity and withdrawal in children and adolescents are reviewed here. Other drugs of abuse, as well as opiate withdrawal in the neonate, are discussed separately. (See appropriate topic reviews). Opioid abuse, intoxication, withdrawal, and treatment in adults is also discussed elsewhere. (See "Heroin and other opioids: Overview and patient evaluation", and see "Heroin and other opioids: Management of chronic use" and see "Opioid intoxication in adults").
DEFINITIONS — The term opioid refers to natural and synthetic substances with morphine-like activity. The term opiate refers to a subclass of opioids consisting of alkaloid compounds extracted from opium, including morphine, codeine, and semisynthetic derivatives of the poppy plant. The term endorphin refers to another subclass of opioids consisting of endogenous peptides that produce pain relief, including enkephalins, dynorphins, and beta-endorphins.
Prescription opioids include morphine, codeine, meperidine, oxycodone, and hydromorphone. Morphine and codeine are derived from opium. Oxycodone and hydromorphone are semisynthetic opioids. Meperidine and methadone are fully synthetic (show table 1).
"Designer" opioids are synthetic derivatives of opioids created in makeshift laboratories and include 3-methylfentanyl (meperidine and fentanyl) and other agents such as MPTP (1, methyl, 4 phenyl 1,2,3,6 tetrahydropyridine). The agents in this class of opioids change frequently because of variation in laboratories and the attempt to evade law enforcement. (See "Designer drugs in children and adolescents", section on Opioid analogs).
Opiate dependence or addiction is defined as continued use of opiates despite significant opiate-induced problems; these problems may be cognitive, behavioral, or physiologic [1]. Repeated drug use results in opiate tolerance (requiring escalating doses to achieve the same effect), withdrawal symptoms, and compulsive drug taking.
EPIDEMIOLOGY — Opioid abuse is a major international public health problem [2,3] as indicated by the following statistics:
-
Opioids were a primary or coingestant in approximately 12 percent of 1153 reported toxic exposure deaths in the United States in 2002 [4].
-
The prevalence of nonmedical use of prescription opioids among 12 to 17-year-olds in the United States increased from 2 percent in 1992 to 11 percent in 2002 [5].
-
The lifetime prevalence of heroin use among twelfth graders in the United States increased from 1.2 in 1994 to a peak of 2.4 in 2000 and has subsequently declined to 1.5 in 2004 [6].
-
Heroin abuse-related emergency department visits in the United States increased by 35 percent between 1995 and 2002 [7].
-
Heroin-related deaths in Victoria, Australia increased fivefold between 1990 and 1998 [8].
-
Most deaths caused by heroin intoxication occur among drug-dependent users who are in their late 20s to early 30s and have used heroin for 5 to 10 years; only 17 percent of deaths occur among novice users [9].
-
The healthcare expenditure for opioid dependence in the United States is estimated to be 1.2 billion dollars per year [1].
PHARMACOLOGY — The activity of opioids resembles that of the body's endogenous opioid peptides (enkephalins, endorphins, and dynorphins) [10]. 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.
Three
types of receptors have been identified: mu (µ), kappa (k), and
delta (
);
most opioids interact with more than one type [10].
The primary sites of opioid action are the limbic system, thalamus,
and hypothalamus.
General considerations
Classes — Opioids are classified into three groups based upon their actions [10]:
-
Morphine-like opioid agonists, including heroin, codeine, meperidine, hydrocodone, diphenoxylate, loperamide, sublimaze, and methadone.
-
Opioid antagonists competitively block receptor activation by occupying opioid receptor sites. Examples include naloxone, nalmefene, and naltrexone.
-
Mixed agonist-antagonists/partial agonists have different effects depending upon the predominance of agonistic or antagonistic activity in the opioid receptor and prior exposure to opiates.
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.
Route 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 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") [11]. In addition, cases of "body packing" (swallowing large amounts of well-packaged opioids for the purpose of smuggling) have been described in children and adolescents [12,13]. (See "Internal concealment of drugs of abuse (body packing)").
Pharmacokinetics — The pharmacokinetics of opioids in children between age 1 and 15 years are similar to those in adults [14]. Intravenous use of opioids gives an immediate euphoric effect, subcutaneous administration produces euphoria in 15 minutes, and snorting in approximately 30 minutes. When taken orally, opioids such as methadone produce a peak effect in four to six hours.
Clinical effects of most opioids persist for three to six hours; fentanyl for one hour; and methadone for 24 to 48 hours [10]. 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 [15].
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 [14]. 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. 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) [14]. Renal dysfunction can lead to toxicity caused by accumulation of active metabolites.
Drug interactions — Opioids interact with various drugs [14,16]:
-
Phenothiazines potentiate their action, possibly by interfering with their metabolism.
-
Cyclic antidepressants increase the bioavailability and plasma level of opioids.
-
Kaolin reduces opioid absorption from the gastrointestinal tract.
-
Cimetidine may enhance effects through prolonging the duration of action.
-
Antibiotics may increase (erythromycin) or decrease (rifampin) opioid effect.
Morphine — Compared to 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 [14].
Morphine's main metabolite, morphine-6-glucuronide, is more potent than morphine and is responsible for most of the clinical effects [14]. It can be detected in large quantities soon after oral or intravenous administration.
Heroin — Heroin (diacetylmorphine) is the prototypic opioid. Street names include "dope," "horse," "smack," and "tar." Heroin is produced as a pure white crystal but may be adulterated with lactose, procaine, mannitol, dextrose, talc, or other substances [17]; 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. In one study, the action of both inhaled and intravenous heroin peaked within one to five minutes and decreased to the limit of detection within 30 minutes [18].
CLINICAL MANIFESTATIONS — The diagnosis of opioid overdose is based upon the history and physical examination. Laboratory tests have a limited role because not all opioids are detected on drug screens (see "Drug testing" below). The classic findings of opioid toxicity are miosis, respiratory depression, and CNS depression. Other findings, including hyporeflexia, hypothermia, hypotension, or decreased bowel sounds, may be present (show table 2).
Ophthalmologic — Miosis (pupillary constriction) usually occurs within five minutes of intravenous administration and lasts for at least six hours [18]. 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 Lomotil poisoning, and after the use of naloxone [10,19,20]. Mydriasis or normal pupils also may be seen if heroin was coingested with a stimulant, such as cocaine (ie, "speedball") or if hypoxic brain injury occurred because of prolonged respiratory depression [11].
Respiratory — Respiratory evaluation should include assessment of ventilation, respiratory rate, cyanosis, hypercarbia, and hypoxia by pulse oximetry or arterial blood gas.
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 [3].
The pathophysiology of this form of pulmonary edema is not known. Proposed mechanisms include direct toxicity of the drug, hypoxia, and acidosis secondary to hyperventilation and/or cerebral edema. Resolution of pulmonary edema is rapid once assisted ventilation is instituted and hyperventilation and hypoxia are reversed.
The incidence of noncardiogenic pulmonary edema in patients hospitalized with heroin overdose is 48 to 80 percent [21,22]. 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 [3] and less than 6 to 12 hours for those associated with methadone.
Bronchospasm can occur a few days to 18 months after regular heroin use by inhalation or injection. The dyspnea and wheezing are relieved with standard therapy.
Cardiovascular — Opiates cause bradycardia and hypotension via the increased parasympathetic activity, decreased sympathetic activity, and release of histamine brought about by their effects on the vasomotor center [23]. The drug-induced bradycardia and increased automaticity can cause arrhythmia, including potentially lethal ventricular tachyarrhythmia [24].
Neurologic — Mental status can vary from mild sedation to coma and affect from euphoria to dysphoria. Patients presenting to the emergency department typically are stuporous or in a state of coma. 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 or pentazocine [25].
Gastrointestinal — Opioids cause various gastrointestinal effects. 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 [15].
Musculoskeletal — All opioid agonists can produce skeletal muscle rigidity, even at low doses [26]. Acute rhabdomyolysis and renal failure may occur with the use of heroin, methadone, and propoxyphene. A Parkinsonian-like syndrome has been associated with some opioid-based designer drugs.
Reproductive — In girls, opioids cause amenorrhea, anovulatory cycles, and impaired fertility caused by abnormal prolactin secretion secondary to the opioid action on the dopaminergic system. In addition, opioids cause decreased libido in both males and females [27].
DRUG TESTING — Mass spectrometry, gas chromatography, and radioimmunoassay are used to test urine for opioids. However, the results of these tests are difficult to interpret 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).
-
False-negative results — Some synthetic opioids (eg, 3-methyl-fentanyl) do not metabolize to opioids.
-
Opioids are detectable in the urine for only two to four days after use.
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 (show table 3), including bacterial endocarditis, blood-borne infection, septic pulmonary emboli, nephropathy, abscesses, and cellulitis [26].
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 [28].
The social and behavioral consequences of opioid use are influenced by the lifestyle of the addict. 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 is a significant risk for violence-related injury (See "Peer violence and violence prevention", section on adolescent screening).
MANAGEMENT OF ACUTE TOXICITY — Most of the direct morbidity and mortality related to opiate use occur after acute ingestion and are caused by anaphylaxis, pulmonary edema, acute respiratory acidosis, and aspiration pneumonitis. Immediate management involves airway management and administration of an opioid antagonist (show table 4).
General considerations — Patients whose respiratory status is compromised should be supported with bag mask ventilation and 100 percent oxygen while the opioid antagonist is administered [29]. They may require supplemental oxygen, endotracheal intubation, and positive end expiratory pressure if pulmonary edema is suspected.
Glucose should be administered intravenously if indicated by immediate bed-side glucose testing (<70 mg/dL). The recommended dose is 0.5 to 1.0 g/kg of D25W (or D10W for a child).
Gastrointestinal decontamination should be performed in patients who are known to have ingested opioids with delayed absorption (eg, diphenoxylate-atropine [Lomotil], and sustained-release morphine products). (See "Decontamination of poisoned children"). Activated charcoal (1 g/kg PO or NG with a maximum of 50 to 60 mg) should be administered. Concomitant use of naloxone may facilitate gastrointestinal decontamination by improving motility.
Whole-bowel irrigation using polyethylene glycol solution (eg, GoLYTELY®) is recommended in the management of retained packets in body packers. Polyethylene glycol solution can be administered at a rate of 50 to 250 mL/kg per hour orally or through a nasogastric tube. Passing of a clear rectal effluent is considered the end point of therapy. (See "Decontamination of poisoned children", section on Whole bowel irrigation).
Seizures and cardiac dysrhythmias occur rarely and should be managed with standard therapies. (See "Clinical features and complications of status epilepticus in children").
Opioid antagonists
Naloxone — Naloxone is a synthetic derivative of oxymorphone that competitively binds opioid receptors and is the antagonist of choice for opioid toxicity [30]. It has a greater affinity for the 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 CNS, and has an onset of action of one minute when given intravenously [30]. Clinical effects of naloxone typically last 45 to 70 minutes.
Naloxone use should be restricted to patients with altered mental status and diminished respirations, miotic pupils, or circumstantial evidence of opiate abuse [31,32]. In one retrospective review, only 8 percent of 730 patients with acute mental status changes who received naloxone for diagnostic or therapeutic purposes responded to naloxone; 92 percent of the responders had diminished respirations (<12 per minute), pinpoint pupils, or a clinical presentation consistent with opioid use [32].
The dose of naloxone varies depending upon the age of the patient and the clinical scenario. For life-threatening toxicity:
-
Children younger than five years of age receive naloxone (0.1 mg/kg IV with a maximum of 2 mg per dose)
-
Children older than five years of age receive naloxone (2.0 mg IV)
The dose should be repeated every three minutes until improvement in respiratory depression is noted. The maximum cumulative dose of naloxone is 10 mg for older children and adults with acute opioid toxicity in whom respiratory depression has failed to improve since isolated opioid toxicity is unlikely if there is no response after a cumulative dose of 10 mg. Although naloxone is quite safe even at high dosages, the maximum dose of naloxone for younger children or neonates with acute opioid toxicity has not been established [31].
For non-life-threatening toxicity:
-
Children younger than five years of age receive naloxone (0.01 mg/kg IV)
-
Children older than five years of age receive naloxone (0.4 mg IV)
Repeat doses (every three to five minutes) are titrated to patient response. The goal is to awaken the patient without precipitating withdrawal symptoms.
Naloxone has a shorter duration of action (one to two hours) than do most opioids except fentanyl and may need to be administered repeatedly or continuously. Naloxone (0.01 mg/kg IV) may be administered repeatedly, every two to three minutes, to reverse respiratory depression.
Continuous infusions have been used safely in children [33]. Naloxone should be mixed in a solution of 5 percent dextrose and half isotonic (normal) saline (0.5 NS) and infused at a rate that does not exceed the hourly maintenance rate for weight. (See "Maintenance fluid therapy in children"). One method for administering a constant infusion is as follows [31]:
-
Determine the amount of naloxone that was required to restore respiratory function during bolus infusions. 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 opiate 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 [31].
-
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 should 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.
Larger than customary doses of naloxone may be required to reverse the effects of drugs with prolonged action or delayed absorption (eg, codeine, diphenoxylate, methadone, propoxyphene, pentazocine, nalbuphine, buprenorphine, and butorphanol) [30]. Up to 24 mg of naloxone has been administered without any significant signs of toxicity [34].
Naloxone is optimally administered intravenously. However, it can also be administered intramuscularly, subcutaneously, endotracheally, or intralingually (ie, injected into the sublingual vein) [30].
In a prospective, observational study, the administrations of naloxone (0.8 mg SQ) and naloxone (0.4 mg IV) were compared in 196 prehospital patients [35]. Outcomes for the two groups were equal; the slower subcutaneous absorption was offset by the delay required for establishment of intravenous access. In another study of urban prehospital patients, intramuscular administration was safe and effective. Intramuscular and subcutaneous administration decrease the risk of needlestick injury to healthcare workers [36].
As a general rule, naloxone is a safe drug. Complications are reported in 1 percent of heroin users [36]. Reported complications include pulmonary edema, hypertension, hypotension, dysrhythmia, and sudden death [30,37,38]. However, many of these adverse effects probably are caused by the effects of other drugs or sudden opiate withdrawal rather than direct activity of naloxone.
Naloxone should be used with caution in patients with cardiovascular disease and in those receiving medications that cause hypotension, pulmonary edema, or arrhythmia.
The major complication of concern is the precipitation of withdrawal because the duration of action of naloxone is one to two hours whereas the duration of action of most opiates is three to six hours. Patients who have an initial response to naloxone must be carefully monitored every 15 minutes for level of consciousness, respirations, pulse, blood pressure, and vomiting.
Withdrawal caused by naloxone administration is not life-threatening; however, 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 [39]. Symptoms typically subside 20 to 30 minutes after the administration of naloxone because the antagonist effect diminishes.
Nalmefene — Nalmefene has a longer duration of action than that of naloxone. Its use in the acute care setting is controversial. Compared to 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 opioid-dependent patients or recurrent symptoms in patients who have taken synthetic opioids with duration of action equal to or longer than that of nalmefene [10].
Nalmefene may be considered for use in children who have had a single opiate exposure or in those who are being admitted to the hospital and do not experience withdrawal after a trial dose of naloxone [40]. Nalmefene may be used safely in potentially opioid-dependent patients after a trial dose of naloxone has been tolerated safely [40].
Doses of 0.5 to 2.0 mg have been reported to be safe and effective in adults [40]. Doses of 0.25 to 1.0 micrograms/kg (to a maximum of 40 micrograms) have been safely used to reverse sedation in pediatric patients [41]. Nalmefene dosage for opioid overdose has not been studied in children. The duration of action is 4 to 10 hours if the dose is 0.5 to 1.0 mg, and greater than 8 hours if the dose is 2.0 mg [40].
Adverse effects of nalmefene are uncommon and include nausea and vomiting, tachycardia, myoclonus, dizziness, and drowsiness [40].
Naltrexone — Naltrexone is an oral opioid antagonist with a longer duration of action than that of naloxone. It is used primarily for long-term opioid detoxification. 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 [42].
Disposition — The plans for long-term management of the drug problem and referrals to local substance abuse treatment resources should be made before discharge. (See "Treatment programs" below).
Observation or admission is indicated for patients who have recurrence of respiratory depression, noncardiogenic pulmonary edema, or ingestion of long-acting or delayed absorption opioids. The duration of observation for patients who do not meet these criteria or for those who are opioid-dependent is controversial.
Noncardiogenic pulmonary edema in heroin users usually develops within two hours of presentation to the emergency department; less than 1 percent of patients have delayed onset of pulmonary edema [3]. Thus, observation for more than two hours may not be required. Additional support for brief observation periods is provided by the following studies:
-
In a retrospective review of 124 patients with intravenous heroin overdose (98 of whom received naloxone at some point in their treatment), noncardiogenic pulmonary edema or hypoxic encephalopathy was evident upon or within 20 minutes of arrival [43]. No patients had recurrence of respiratory depression. However, this study was limited by the short period of observation (40 percent were observed for less than two hours) and poor follow-up [44].
|
||||||||||||
|
printer-friendly
format
e-mail
this to a colleague
