Pharmacology and Pathophysiology

Alcohol (ethyl alcohol or ethanol) is rapidly absorbed in the stomach and is transported to the liver and metabolized by 2 pathways. The primary metabolic pathway contributes to the excess synthesis of triglycerides, a phenomenon that is responsible for producing a fatty liver, even in those who are well nourished. Engorgement of hepatocytes with fat causes necrosis, triggering an inflammatory process (alcoholic hepatitis), which is later followed by fibrosis, the hallmark of cirrhosis. Early hepatic involvement may result in elevation in γ-glutamyl transpeptidase and serum glutamic-pyruvic transaminase. The second metabolic pathway, which is utilized at high serum alcohol levels, involves the microsomal enzyme system of the liver, in which the cofactor is reduced nicotinamide-adenine dinucleotide phosphate. The net effect of activation of this pathway is to decrease metabolism of drugs that share this system and to allow for their accumulation, enhanced effect, and possible toxicity.

Clinical Manifestations

Alcohol acts primarily as a central nervous system depressant. It produces euphoria, grogginess, talkativeness, impaired short-term memory, and an increased pain threshold. Alcohol’s ability to produce vasodilation and hypothermia is also centrally mediated. At very high serum levels, respiratory depression occurs. Its inhibitory effect on pituitary antidiuretic hormone release is responsible for its diuretic effect. The gastrointestinal complications of alcohol use can occur from a single large ingestion. The most common is acute erosive gastritis, which is manifested by epigastric pain, anorexia, vomiting, and heme-positive stools. Less commonly, vomiting and midabdominal pain may be caused by acute alcoholic pancreatitis; diagnosis is confirmed by the finding of elevated serum amylase and lipase levels.

Diagnosis

Primary care settings provide opportunity to screen teens for alcohol use or problem behaviors. Brief alcohol screening instruments (CRAFFT [see Table 108-7] or AUDIT [Alcohol Use Disorders Identification Test, Table 108-12]) perform well in a clinical setting as techniques to identify Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)–defined adolescents with alcohol use disorders (Table 108-13). A score of ≥8 on the AUDIT questionnaire identifies people who drink excessively and who would benefit from reducing or ceasing drinking (see Table 108-12). Teenagers in the early phases of alcohol use exhibit few physical findings. Recent use of alcohol may be reflected in elevated gamma-glutamyl transferase (GGT) and amino transferase (AST).

Table 108-12 ALCOHOL USE DISORDERS IDENTIFICATION TEST (AUDIT)

* Score ≥8 = problem drinking.

From Schuckit MA: Alcohol-use disorders, Lancet 373:492–500, 2009, Table 1.

In acute care settings, the alcohol overdose syndrome should be suspected in any teenager who appears disoriented, lethargic, or comatose. Although the distinctive aroma of alcohol may assist in diagnosis, confirmation by analysis of blood is recommended. At levels >200 mg/dL, the adolescent is at risk of death, and levels >500 mg/dL (median lethal dose) are usually associated with a fatal outcome. When the level of obtundation appears excessive for the reported blood alcohol level, head trauma, hypoglycemia, or ingestion of other drugs should be considered as possible confounding factors.

Treatment

The usual mechanism of death from the alcohol overdose syndrome is respiratory depression, and artificial ventilatory support must be provided until the liver can eliminate sufficient amounts of alcohol from the body. In a patient without alcoholism, it generally takes 20 hr to reduce the blood level of alcohol from 400 mg/dL to zero. Dialysis should be considered when the blood level is >400 mg/dL. As a follow-up to acute treatment, referral for treatment of the alcohol use disorder is indicated. Group counseling, individualized counseling, and multifamily educational intervention have been found to be quite effective interventions for teens.

Cigarettes

Nearly 5 million persons die annually from smoking across the globe; the number of deaths is roughly equal between developing nations and industrialized nations. Compared to all other substances and firearms, tobacco kills more individuals in the USA each yr than all these other causes combined. The average smoker in the USA starts at age 12 yr, and most are regular smokers by age 14 yr. More than 90% of adolescent smokers become adult smokers. Factors associated with youth tobacco use include exposure to smokers (friends, parents), availability of tobacco, low socioeconomic status, poor school performance, low self-esteem, lack of perceived risk of use, and lack of skills to resist influences to tobacco use.

Current smoking rates among high school students have trended downward over the last decade for lifetime cigarette use (from 20.0% to 12.4%) and current frequent cigarette use (from 16.8% to 8.1%). Overall, more whites report current tobacco use (29.9%) than Hispanics (20.1%) or blacks (16.0%). Clove cigarettes (kreteks) and flavored cigarettes (bidis) are popular with younger students. Both types of flavored cigarettes contain tobacco with other additives and deliver more nicotine and other harmful substances because they are unfiltered. Cigar or mini-cigar (cigarillo) use is reported most frequently by older male students (26.2%). Tobacco use is linked to other high risk behaviors. Teens who smoke are more likely than nonsmokers to use alcohol and engage in unprotected sex, are 8 times more likely to use marijuana, and are 22 times more likely to use cocaine.

Tobacco is used by teens in all regions of the world, although the form of tobacco used differs. In the Americas and Europe, cigarette smoking prevalence is higher than other tobacco use, although cigars and smokeless tobacco are also used; in the Eastern Mediterranean, shisha (flavored tobacco smoked in hookah pipes) is prevalent; in Southeast Asia, smokeless tobacco products are used; in the Western Pacific, betel nut is chewed with tobacco; and pipe, snuff, and rolled tobacco leaves are used in Africa.

Pharmacology

Nicotine, the primary active ingredient in cigarettes, is addictive. Nicotine is absorbed by multiple sites in the body, including the lungs, skin, gastrointestinal tract, and buccal and nasal mucosa. The action of nicotine is mediated through nicotinic acetylcholine receptors located on noncholinergic presynaptic and postsynaptic sites in the brain and causes increased levels of dopamine. Nicotine also stimulates the adrenal glands to release epinephrine, causing an immediate elevation in blood pressure, respiration and heart rate. The average nicotine content of 1 cigarette is 10 mg and the average nicotine intake per cigarette ranges from 1.0 to 3 mg. Nicotine, as delivered in cigarette smoke, has a half-life of about 2 hr. Cotinine is the major metabolite of nicotine via C-oxidation. It has a biologic half-life of 19-24 hr and can be detected in urine, serum, and saliva.

Clinical Manifestations

Adverse health effects from regular smoking include an increased prevalence of chronic cough, sputum production, and wheezing. Smoking during pregnancy is associated with an average decrease in fetal weight of 200 g; this decrease, added to the already smaller size of infants born to teenagers, increases perinatal morbidity and mortality. Tobacco smoke induces hepatic smooth endoplasmic reticulum enzymes and, as a result, may also influence metabolism of drugs such as phenacetin, theophylline, and imipramine. Withdrawal symptoms can occur when adolescents try to quit. Irritability, decreased concentration, increased appetite, and strong cravings for tobacco are common withdrawal symptoms. Nicotine dependence is defined in Table 108-14.

Treatment

The approach to smoking cessation in adolescents includes the 5 A’s (Ask, Advise, Assess, Assist, and Arrange) and use of nicotine replacement therapy in addicted teens who are motivated to quit and are not using smokeless tobacco (SLT). Consensus panels recommend the 5 A’s although evidence of efficacy in adolescents is limited. Nicotine patch studies to date in adolescents suggest a positive effect on reducing withdrawal symptoms and that pharmacotherapy should be combined with behavioral therapy to reach higher cessation and lower relapse rates. Nicotine is also available as a gum, inhaler, nasal spray, lozenge, or microtab. Medications such as bupropion are not approved for use under 18 yr old; some pilot studies in adolescents report cessation efficacy with 150 mg or 300 mg of bupropion daily. Varenicline has successfully been used in adults but may be associated with a risk of suicide. Additional options may be available through formal smoking cessation programs offered by community agencies.

Smokeless Tobacco

Surveys in the late 1980s and 1990s indicating the increased use of SLT prompted the National Cancer Institute to lead the U.S. federal government’s effort to prevent SLT use, especially in adolescents. Surveys indicate that from the early to mid 1990s to 2008, lifetime prevalence of SLT use continues to decline in 8th, 10th, and 12th graders. It remains more popular with boys than girls (13.4% versus 2.3%). While it is less lethal, SLT carries risks of addiction and oral problems such as receding gums/gingivitis and precancerous leukoplakia.

Clinical Manifestations

In addition to the “desired” effects of elation and euphoria, marijuana may cause impairment of short-term memory, poor performance of tasks requiring divided attention (e.g., those involved in driving), loss of critical judgment, decreased coordination, and distortion of time perception (Table 108-15). Visual hallucinations and perceived body distortions occur rarely, but there may be “flashbacks” or recall of frightening hallucinations experienced under marijuana’s influence that usually occur during stress or with fever.

Smoking marijuana for a minimum of 4 days/wk for 6 mo appears to result in dose-related suppression of plasma testosterone levels and spermatogenesis, prompting concern about the potential deleterious effect of smoking marijuana before completion of pubertal growth and development. There is an antiemetic effect of oral THC or smoked marijuana, often followed by appetite stimulation, which is the basis of the drug’s use in patients receiving cancer chemotherapy. Although the possibility of teratogenicity has been raised because of findings in animals, there is no evidence of such effects in humans. An amotivational syndrome has been described in long-term marijuana users who lose interest in age-appropriate behavior, yet proof of the causative relationship remains equivocal. Chronic use is associated with increased anxiety and depression, learning problems, poor job performance, and respiratory problems such as pharyngitis, sinusitis, bronchitis, and asthma (see Table 108-15).

The increased THC content of marijuana of 5- to 15-fold in the 1990s, as compared to the 1970s, is related to the observation of a withdrawal syndrome, occurring 24 to 48 hr after discontinuing the drug. Heavy users experience malaise, irritability, agitation, insomnia, drug craving, shakiness, diaphoresis, night sweats, and gastrointestinal disturbance. The symptoms peak by the 4th day, and they resolve in 10-14 days. Certain drugs may interact with marijuana to potentiate sedation (alcohol, diazepam), potentiate stimulation (cocaine, amphetamines), or be antagonistic (propranolol, phenytoin).

Behavioral interventions, including cognitive-behavioral therapy and motivational incentives, have shown to be effective in treating marijuana dependency.

Clinical Manifestations

The major effects of inhalants are psychoactive (Table 108-17). The intoxication lasts only a few minutes, so a typical user will huff repeatedly over an extended period of time (hours) in order to maintain the high. The immediate effects of inhalants are similar to alcohol: euphoria, slurred speech, decreased coordination, and dizziness. Toluene, the main ingredient in model airplane glue and some rubber cements, causes relaxation and pleasant hallucinations for up to 2 hr. Euphoria is followed by violent excitement or coma may result from prolonged or rapid inhalation. Volatile nitrites, such as amyl nitrite, butyl nitrite, and related compounds marketed as room deodorizers, are used as euphoriants, enhancers of musical appreciation, and sexual enhancements among older adolescents and young adults. They may result in headaches, syncope, and lightheadedness; profound hypotension and cutaneous flushing followed by vasoconstriction and tachycardia; transiently inverted T waves and depressed ST segments on electrocardiography; methemoglobinemia; increased bronchial irritation; and increased intraocular pressure.

Table 108-17 STAGES IN SYMPTOM DEVELOPMENT

CNS, central nervous system; EEG, electroencephalogram.

From Harris D: Volatile substance abuse, Arch Dis Child Educ Pract Ed 91:ep93-ep100, 2006, Table 1.

Complications

Model airplane glue is responsible for a wide range of complications, related to chemical toxicity, to the method of administration (in plastic bags, with resultant suffocation), and to the often dangerous setting in which the inhalation occurs (inner-city roof tops). Common neuromuscular changes reported in chronic inhalant abusers include difficulty coordinating movement, gait disorders, muscle tremors, and spasticity, particularly in the legs (Table 108-18). Moreover, chronic use may cause pulmonary hypertension, restrictive lung defects or reduced diffusion capacity, peripheral neuropathy, hematuria, tubular acidosis, and possibly cerebral and cerebellar atrophy. Chronic inhalant abuse has long been linked to widespread brain damage and cognitive abnormalities that can range from mild impairment (poor memory, decreased learning ability) to severe dementia. Death in the acute phase may result from cerebral or pulmonary edema or myocardial involvement (see Table 108-18).

Table 108-18 DOCUMENTED CLINICAL PRESENTATIONS OF VOLATILE SUBSTANCE ABUSE (VSA)

From Harris D: Volatile substance abuse, Arch Dis Child Edu Pract Ed 91:ep93-ep100, 2006, Table 2.

Diagnosis

Diagnosis of inhalants is difficult because of the ubiquitous nature of the products and decreased parental awareness of their dangers. In the primary care setting, providers need to enquire of parents if they have witnessed any unusual behaviors in their teen; noticed high-risk products in their bedrooms; seen paint on the teen’s hands, nose, or mouth; or found paint coated or chemical coated rags. Complete blood counts, coagulation studies, and hepatic and renal function studies may identify the complications. In extreme intoxication, a user may manifest symptoms of restlessness, general muscle weakness, dysarthria, nystagmus, disruptive behavior, and occasionally hallucinations. Toluene is excreted rapidly in the urine as hippuric acid, with the residual detectable in the serum by gas chromatography.

Treatment

Treatment is generally supportive and directed toward control of arrhythmia and stabilization of respirations and circulation. Withdrawal symptoms do not usually occur.

Lysergic Acid Diethylamide

LSD (acid, big “d,” blotters) is a very potent hallucinogen that is made from lysergic acid found in ergot, a fungus that grows on rye and other grains. Its high potency allows effective doses to be applied to absorbent paper, or it can be taken as a liquid or a tablet. The onset of action can be between 30 and 60 min, and it peaks between 2 and 4 hr. By 10-12 hr, an individual returns to the predrug state. Four percent of U.S. 12th graders report trying LSD at least once.

Clinical Manifestations

The effects of LSD can be divided into 3 categories: somatic (physical effects), perceptual (altered changes in vision and hearing), and psychic effects (changes in sensorium). The common somatic symptoms are dizziness, dilated pupils, nausea, flushing, elevated temperature, and tachycardia. The sensation of synesthesia, or “seeing” smells and “hearing” colors, as well as major distortions of time and self have been reported with high doses of LSD. Delusional ideation, body distortion, and suspiciousness to the point of toxic psychosis are the more serious of the psychic symptoms. LSD is not considered to be an addictive drug since it does not typically produce drug-seeking behavior.

Treatment

An individual is considered to have a “bad trip” when the sensory experiences causes the user to become terrified or panicked. These episodes should be treated by removing the individual from the aggravating situation and placing him in a quiet room with a calming friend. In situations of extreme agitation or seizures, use of benzodiazepines may be warranted. “Flashbacks” or LSD-induced states after the drug has worn off and tolerance to the effects of the drug are additional complications of its use.

Methylenedioxymethamphetamine

MDMA (“X,” Ecstasy), a phenylisopropylamine hallucinogen, is a synthetic compound similar to hallucinogenic mescaline and the stimulant methamphetamine. Like other hallucinogens, this drug is proposed to interact with serotoninergic neurons in the central nervous system (CNS). It is the preferred drug at “raves,” all-night dance parties, and is also known as one of the “club drugs” along with γ-hydroxybutyrate (GHB) and ketamine (see Table 108-5). Between 2005 and 2008, past-year use of MDMA increased among both 10th and 12th graders. Six percent of 12th graders report having tried MDMA at least once. Similar increases were seen among European youth; the European School Survey Project on Alcohol and Other Drugs reported that in 2007, 3% of European students report having tried ecstasy during their lifetime, with 5 countries reporting ever-use rates of 6-7%.

Clinical Manifestations

Euphoria, a heightened sensual awareness, and increased psychic and emotional energy are acute effects. Compared to other hallucinogens, MDMA is less likely to produce emotional lability, depersonalization, and disturbances of thought. Nausea, jaw clenching, teeth grinding, and blurred vision are somatic symptoms, whereas anxiety, panic attacks, and psychosis are the adverse psychiatric outcomes. A few deaths have been reported after ingestion of the drug. In high doses, MDMA can interfere with the body’s ability to regulate temperature. The resultant hyperthermia in association with vigorous dancing at a “rave” has resulted in severe liver, kidney, and cardiovascular system failure and death. There are no specific treatment regimens recommended for acute toxicity. Chronic MDMA use can lead to changes in brain function, affecting cognitive tasks and memory. These symptoms may occur because of MDMA’s effects on neurons that use serotonin as a neurotransmitter. The serotonin system plays an important role in regulating mood, aggression, sexual activity, sleep, and sensitivity to pain. A high rate of dependence has been found among MDMA users. MDMA exposure may be associated with long-term neurotoxicity and damage to serotonin-containing neurons. In nonhuman primates, exposure to MDMA for only 4 days caused damage to serotonin nerve terminals that was evident 6-7 yr later. There are no specific pharmacologic treatments for MDMA addiction. Drug abuse recovery groups are recommended.

Phencyclidine

Phencyclidine (PCP) (sternyl, angel dust, “hog,” “peace pill,” “sheets”) is an arylcyclohexalamine whose popularity is related, in part, to its ease of synthesis in home laboratories. One of the by-products of home synthesis causes cramps, diarrhea, and hematemesis. It is a “dissociative drug” that produces feelings of detachment from the surrounding environment and self. The drug is thought to potentiate adrenergic effects by inhibiting neuronal reuptake of catecholamines. PCP is available as a tablet, liquid, or powder, which may be used alone or sprinkled on cigarettes (“joints”). The powders and tablets generally contain 2-6 mg of PCP, whereas joints average 1 mg for every 150 mg of tobacco leaves, or approximately 30-50 mg per joint.

Clinical Manifestations

The clinical manifestations are dose related and produce alterations of perception, behavior, and autonomic functions. Euphoria, nystagmus, ataxia, and emotional lability occur within 2-3 min after smoking 1-5 mg and last for 4-6 hr. At these low doses the user is likely to experience shallow breathing, flushing, generalized numbness of extremities, and loss of motor coordination. Hallucinations may involve bizarre distortions of body image that often precipitate panic reactions. With doses of 5-15 mg, a toxic psychosis may occur, with disorientation, hypersalivation, and abusive language lasting for >1 hr. Hypotension, generalized seizures, and cardiac arrhythmias commonly occur with plasma concentrations from 40-200 mg/dL. Death has been reported during psychotic delirium, from hypertension, hypotension, hypothermia, seizures, and trauma. The coma of PCP may be distinguished from that of the opiates by the absence of respiratory depression; the presence of muscle rigidity, hyperreflexia, and nystagmus; and lack of response to naloxone. PCP psychosis may be difficult to distinguish from schizophrenia. In the absence of a history of use, analysis of urine must be depended on for diagnosis.

Treatment

Management of the PCP-intoxicated patient includes placement in a darkened, quiet room on a floor pad, safe from injury. Acute alcohol intoxication may be present also. For recent oral ingestion, gastric absorption is poor and induction of emesis or gastric lavage is useful. Diazepam, in a dose of 5-10 mg orally or 2-5 mg intravenously, may be helpful if the patient is agitated and not comatose. Rapid excretion of the drug is promoted by acidification of the urine. Supportive therapy of the comatose patient is indicated with particular attention to hydration, which may be compromised by PCP-induced diuresis. Inpatient and/or behavioral treatments can be helpful for chronic PCP users.

Clinical Manifestations

Cocaine is a strong central nervous system stimulant that increases dopamine levels by preventing reuptake. Cocaine produces euphoria, increased motor activity, decreased fatigability, and mental alertness. Its sympathomimetic properties are responsible for pupillary dilatation, tachycardia, hypertension, and hyperthermia. Snorting cocaine chronically results in loss of sense of smell, nosebleeds, and chronic rhinorrhea. Injecting cocaine increases risk for HIV infection. Chronic abusers experience anxiety, irritability, and sometimes paranoid psychosis. Lethal effects are possible, especially when cocaine is used in combination with other drugs, such as heroin, in an injectable form known as a “speedball.” Cocaine, when taken with alcohol, is metabolized by the liver to produce cocaethylene, a substance that enhances the euphoria and is associated with a greater risk of sudden death than cocaine alone. Pregnant adolescents who use cocaine place their fetus at risk of premature delivery, complications of low birthweight, and possibly developmental disorders.

Treatment

There are no FDA-approved medications for treatment of cocaine addiction. Cognitive-behavioral therapy has been shown to be effective when provided in combination with additional services and social support.

Clinical Manifestations

Methamphetamine rapidly increases the release and blocks the reuptake of dopamine, a powerful “feel good” neurotransmitter (Table 108-19). The effects of amphetamines can be dose related. In small amounts amphetamine effects resemble other stimulants: increased physical activity, rapid and/or irregular heart rate, increased blood pressure and decreased appetite. High doses produce slowing of cardiac conduction in the face of ventricular irritability. Hypertensive and hyperpyrexic episodes can occur as seizures (see Table 108-6). Binge effects result in the development of psychotic ideation with the potential for sudden violence. Cerebrovascular damage, psychosis, severe receding of the gums with tooth decay, and infection with HIV and hepatitis B and C can result from long-term use. There is a withdrawal syndrome associated with amphetamine use, with early, intermediate, and late phases. The early phase is characterized as a “crash” phase with depression, agitation, fatigue, and desire for more of the drug. Loss of physical and mental energy, limited interest in the environment, and anhedonia mark the intermediate phase. In the final phase, drug craving returns, often triggered by particular situations or objects.

Table 108-19 SIGNS AND SYMPTOMS OF INTOXICATION AND WITHDRAWAL

Treatment

Acute agitation and delusional behaviors can be treated with haloperidol or droperidol. Phenothiazines are contraindicated and may cause a rapid drop in blood pressure or seizure activity. Other supportive treatment consists of a cooling blanket for hyperthermia and treatment of the hypertension and arrhythmias, which may respond to sedation with lorazepam or diazepam. For the chronic user, comprehensive cognitive-behavioral interventions have been shown to effective treatment options.

Clinical Manifestations

The clinical manifestations are determined by the purity of the heroin or its adulterants, combined with the route of administration. The immediate effects include euphoria, diminution in pain, flushing of the skin, and pinpoint pupils (Table 108-19). An effect on the hypothalamus is suggested by the lowering of body temperature. The most common dermatologic lesions are the “tracks,” the hypertrophic linear scars that follow the course of large veins. Smaller, discrete peripheral scars, resembling healed insect bites, may be easily overlooked. The adolescent who injects heroin subcutaneously may have fat necrosis, lipodystrophy, and atrophy over portions of the extremities. Attempts to conceal these stigmata may include amateur tattoos in unusual sites. Skin abscesses secondary to unsterile techniques of drug administration are commonly found. There is a loss of libido; the mechanism is unknown. The chronic heroin user may resort to prostitution to support the habit, thus increasing the risk of sexually transmitted diseases (including HIV), pregnancy, and other infectious diseases. Constipation results from decreased smooth muscle propulsive contractions and increased anal sphincter tone. The absence of sterile technique in injection may lead to cerebral microabscesses or endocarditis, usually caused by Staphylococcus aureus. Abnormal serologic reactions are also common, including false-positive Venereal Disease Research Laboratory and latex fixation tests.

Withdrawal

After a period of ≥8 hr without heroin, the addicted individual undergoes, during a 24-36 hr period, a series of physiologic disturbances referred to collectively as “withdrawal” or the abstinence syndrome (see Table 108-19). The earliest sign is yawning, followed by lacrimation, mydriasis, restlessness, insomnia, “goose flesh,” cramping of the voluntary musculature, bone pain, hyperactive bowel sounds and diarrhea, tachycardia, and systolic hypertension. While the administration of methadone has been the most common method of detoxification, the addition of buprenorphine, an opiate agonist-antagonist, is available for detoxification and maintenance treatment of heroin and other opiates. This medication has the advantage in that it offers less risk of addiction and overdose, and withdrawal effects and can be dispensed in the privacy of a physician’s office. Combined with behavioral interventions, it has a greater success rate of detoxification. A combination drug, buprenorphine/naloxone has been formulated to minimize abuse during detoxification.

Overdose Syndrome

The overdose syndrome is an acute reaction after the administration of an opiate. It is the leading cause of death among drug users. The clinical signs include stupor or coma, seizures, miotic pupils (unless severe anoxia has occurred), respiratory depression, cyanosis, and pulmonary edema. The differential diagnosis includes CNS trauma, diabetic coma, hepatic (and other) encephalopathy, Reye syndrome, as well as overdose of alcohol, barbiturates, PCP, or methadone. Diagnosis of opiate toxicity is facilitated by intravenous administration of the opiate antagonist naloxone, 0.01 mg/kg (2 mg is a common initial dose for an adolescent), which causes dilation of pupils constricted by the opiate. Diagnosis is confirmed by the finding of morphine in the serum.

Treatment

Treatment of acute heroin overdose consists of maintaining adequate oxygenation and continued administration of naloxone, a pure opioid antagonist. It may be given intravenously, intramuscularly, subcutaneously, or through the endotracheal tube. Naloxone has an ultrarapid onset of action (1 min) and a duration of action of 20-60 min. If there is no response then other etiologies for the respiratory depression must be explored. Naloxone may have to be continued for 24 hr if methadone, rather than shorter acting heroin, has been taken. Admission to the intensive care unit is indicated for patients who require continuous naloxone infusions (rebound coma, respiratory depression), and for those with life-threatening arrhythmias, shock, and seizures.