OVERVIEW

During the last decade, the number of patients treated for substance abuse–related problems in the United States has grown steadily. Between 1997 and 2002, the number of emergency department (ED) visits for drug-related events increased by more than 24%.¹ In 2004, 1.3 million ED visits involved drug misuse or abuse.² The National Survey on Drug Use and Health (NSDUH) findings in 2004 showed that 19.1 million Americans, or 7.9% of the population age 12 and older, used an illicit drug in the past month.³ Clinical presentations are also becoming more complex. More than 55% of the drug-related problems seen in EDs in the first half of 2002 involved the use of multiple drugs. In 37% of these cases, drug dependence was identified as the primary problem; 20% of the cases involved individuals seeking drug-induced psychic effects and 20% involved suicide attempts. Among individuals who abuse drugs, 53% have a second co-occurring psychiatric disorder. Successful treatment of this expanding group of patients requires that clinicians improve their skills in the management of patients with substance use disorders and co-occurring psychiatric disorders. Although physicians may feel comfortable treating the symptoms of substance abuse, they are often reluctant to deal with the core disease process, and little effort is made to refer patients for substance abuse treatment. The chronic, relapsing nature of substance abuse is inappropriately thought to imply that substance abuse treatment is not helpful. This leads clinicians to ignore multiple opportunities to intervene in the disease process. Most clinicians fail to appreciate that the relapse rate in other common chronic medical disorders (such as diabetes, hypertension, and asthma) exceeds that for the substance abuse disorders, and, hence, they do not handle substance abuse patients with comparable therapeutic diligence.⁴ Problems related to substance abuse should always be addressed with the same degree of compassion and persistence that is directed to other common relapsing medical disorders.

THE NEUROBIOLOGY OF ADDICTION

Disruption of the endogenous reward systems in the brain is a common feature of all of the major drugs of abuse; most of these drugs act by disrupting dopamine circuits in the brain. Acute changes increase synaptic dopamine and disrupt circuits that mediate motivation and drive, conditioned learning, and inhibitory controls (Figure 27-1). This enhancement of synaptic dopamine is particularly rewarding for individuals with abnormally low density of the D₂dopamine receptor (D₂DR). Normal individuals (with normal levels of the D₂DR) find this experience too intense and aversive and thus may be shielded from the risk of addiction. Low D₂DR availability is associated with an increased risk for abuse of cocaine, heroin, methamphetamine, alcohol, and methylphenidate. Chronic drug use produces long-lasting and significant decreases in dopamine brain function, manifested by decreases in both the D₂DR and dopamine cell activity. These decreases are also associated with dysfunction in the prefrontal cortex, including the orbitofrontal cortex (which is involved in salience attribution) and the cingulated gyrus (which is involved in inhibitory control and mood regulation).⁵ Low baseline levels of beta-plasma endorphins are associated with a higher endorphin response to alcohol and an increased risk for alcohol dependence; it is less clear whether this abnormality also increases the risk for opiate dependence. Table 27-1 lists the major drugs of abuse and the associated disruption of CNS neurotransmitter systems.

Figure 27-1 Converging acute actions of drugs of abuse on the ventral tegmental area and nucleus accumbens. DA, dopamine; GABA, γ-aminobutyric acid; LDT, laterodorsal tegmentum; NAc, nucleus accumbens; PCP, phencyclidine; PPT, pedunculopontine tegmentum; VTA, ventral tegmental area.

(Redrawn from Nestler EJ: Is there a common molecular pathway for addiction? Nat Neurosci 8[11]:1445-1449, 2005.)

Table 27-1 Neurobiology of Drug Reinforcement

Drug Type	Mechanism of Reinforcement
Cocaine Amphetamines Nicotine	Mesolimbic dopamine system
Opioids	Mesolimbic dopamine system
Alcohol	GABA and glutamate Dopamine and serotonin Opioid peptide systems
Cannabinoids	Dopamine in the nucleus accumbens

GABA, γ-aminobutyric acid.

COCAINE

Abuse

After alcohol, cocaine is the leading drug of abuse in terms of frequency of ED contacts, general hospital admissions, family violence, and other social problems.⁶ The Drug Abuse Warning Network (DAWN) estimates that out of 940,953 illicit drug-related ED visits in 2004, cocaine was involved in nearly 40% of them.² Even mature individuals with normal psychological profiles are vulnerable to compulsive cocaine use. Acute users experience intense euphoria often associated with increased sexual desire and with improved sexual function. These acute rewards are often followed by a moderate-to-severe post–cocaine use depression that provides a strong compulsion for further cocaine use. These responses are primarily mediated by disruptions of synaptic dopamine. The initial cocaine response is stimulated by elevated dopamine generated by blockade of the dopamine reuptake transporter (DAT) and the inhibition of the reuptake of synaptic dopamine. Chronic cocaine use leads to down-regulation of dopamine receptors and ultimately depletion of synaptic dopamine, which is thought to be the cause of post–cocaine use depression (Figures 27-1 and 27-3). Like other stimulants, cocaine also disrupts the synthesis and reuptake of serotonin. Other receptors affected include norepinephrine, N-methyl-d-aspartate (NMDA), γ-aminobutyric acid (GABA), and opioid receptors. Plasma cholinesterases rapidly convert cocaine into benzoylecognine (BE), an inactive metabolite that can be detected in the urine for 3 days. When alcohol is taken in conjunction with cocaine, liver esterases produce cocaethylene, an active metabolite that is longer lasting (2- to 4-hour half-life) and more cardiotoxic than is cocaine. The combination of cocaine and marijuana also produces more intense euphoria, higher plasma levels, and more cardiotoxicity than does cocaine alone.

Figure 27-3 Schematic of the effects of cocaine and heroin in the synapse.

(Redrawn and adapted from Leshner A and the US National Institute on Drug Abuse: New understandings of drug addiction, Hospital Practice Special Report, April 1997, McGraw-Hill.)

The signs and the symptoms of acute cocaine intoxication are similar to those of amphetamine abuse. Typical complaints associated with intoxication include anorexia, insomnia, anxiety, hyperactivity, and rapid speech and thought processes (“speeding”). Signs of adrenergic hyperactivity (such as hyperreflexia, tachycardia, diaphoresis, and dilated pupils responsive to light) may also be seen. More severe symptoms (such as hyperpyrexia, hypertension, and cocaine-induced vasospastic events [e.g., stroke or myocardial infarction]) are relatively rare among users, but are fairly common in those seen in hospital EDs. Patients may also manifest stereotyped movements of the mouth, face, or extremities. Snorting may produce rhinitis or sinusitis and, rarely, perforations of the nasal septum. Free-basing (inhalation of cocaine alkaloid vapors) may produce bronchitis. Grand mal seizures are another infrequent complication. Patients also describe “snowlights” (i.e., flashes of light usually seen at the periphery of the visual field). Crack is a highly addictive free-base form of cocaine that is sold in crystals and can be smoked.

The most serious psychiatric problem associated with chronic cocaine use is a cocaine-induced psychosis (manifest by visual and auditory hallucinations and paranoid delusions often associated with violent behavior). Tactile hallucinations (called “coke bugs”) involve the perception that something is crawling under the skin. A cocaine psychosis may be indistinguishable from an amphetamine psychosis, but it is usually shorter in duration. High doses of stimulants can also cause a state of excitation and mental confusion known as “stimulant delirium.”

Management

Cocaine abuse became common among affluent young people in the early to mid-1980s, but with the availability of packaged smokable cocaine, or crack, in low-cost doses, all classes and racial groups have become potential users. Occasional cocaine use does not require specific treatment except in the case of a life-threatening overdose. Most lethal doses are metabolized within 1 hour. In the interim, intubation and assisted breathing with oxygen may be necessary. Stroke has been reported, and death can be caused by ventricular fibrillation or myocardial infarction. The cardiac status should therefore be monitored closely. High doses of benzodia-zepines are recommended for management of stimulant-induced delirium and agitation. Neuroleptics should be avoided because of the risk of potentially fatal hyperther-mia. Intravenous (IV) diazepam should be used to control convulsions.

Chronic cocaine use produces tolerance, severe psychological dependency, and physiological dependence (marked by irritability, anhedonia, low mood, insomnia or hypersomnia, and anxiety).⁷ Dependent users typically follow a cyclical pattern of 2 or 3 days of heavy binge use, followed by a withdrawal “crash.” Use is resumed again in 3 to 4 days, depending on the availability of cash and the drug. A gradual reduction in use of the drug is almost never possible. Detoxification is accomplished by the abrupt cessation of all cocaine use, usually through restricted access (e.g., a loss of funds or contacts, or incarceration). Withdrawal symptoms begin to resolve within 7 days; the value of medication treatment for withdrawal symptoms has yet to be confirmed. Drugs that enhance central nervous system (CNS) catecholamine function may reduce craving, although they are of limited clinical benefit and they have not been proven effective in double-blind placebo-controlled trials. There is some indication that amantadine (an indirect dopamine agonist) and propranolol may help individuals with severe withdrawal symptoms. The major complication of withdrawal is a severe depression with suicidal ideation. If this occurs, the patient requires psychiatric hospitalization. The need for inpatient care may be brief, since suicidal ideation usually clears promptly with the cessation of cocaine use. A less severe anhedonic state may persist for 2 to 3 months and is thought to reflect a more persistent state of dopamine depletion.

For the cocaine addict, the compulsion to use is overwhelming. For this reason, a hospitalized, cocaine-dependent patient should be monitored closely and should have a drug screen performed after behavioral change, particularly after departures from the floor or receiving visitors. Urine should be examined for cocaine metabolites and, preferably, for all drugs of abuse.

Once compulsive cocaine use has begun, it is almost impossible for the user to return to a pattern of occasional, controlled use. Such individuals are also likely to develop problems with alcohol and other drugs. For that reason, the goal of treatment should be abstinence from cocaine and all other drugs. All cocaine abusers should be referred for individual or group counseling, and participation in 12-step self-help programs should be strongly recommended. Manual-guided cognitive-behavioral therapy (CBT) has been efficacious in the treatment of cocaine dependence.⁸ Twelve-step facilitation and CBT appear to be helpful, particularly in individuals with more severe dependence and in those with co-morbid disorders.⁹ Family members or significant others should be referred separately to Al-Anon because they will gain insights that may help them eliminate systemic support for the patient’s drug use. There is no Food and Drug Administration (FDA)–approved pharmacotherapy for cocaine dependence. Trials with desipramine, fluoxetine, bupropion, amantadine, and carbamazepine have had inconsistent results. Positive responses have been reported in trials with topiramate, baclofen, and modafinil, but these drugs require further investigation. Several trials with disulfiram have shown benefit, with reduced craving and use, and a reported increase in the aversive effects of cocaine should the patient relapse. These reactions are thought to be mediated by the inhibitory effect of disulfiram on dopamine beta-hydroxylase. This action will elevate depleted plasma dopamine levels in chronic users and will produce abnormally high dopamine levels if cocaine is ingested; this results in a dysphoric experience for most users.

AMPHETAMINES

Abuse

Stricter federal controls on the production and distribution of amphetamines have greatly reduced the number of amphetamine abusers. Nonetheless, stimulants (including amphetamine and methamphetamine) were involved in 10% of all illicit drug–related ED visits in 2004.² Illicitly produced methamphetamine has fueled a major abuse epidemic on the West Coast and in much of the Midwest.

The primary action of these drugs is to increase synaptic dopamine by causing the release of dopamine stores into the synapse; methamphetamine also blocks the DAT. This produces a dopamine “high” that is both more intense and longer lasting than is cocaine, lasting anywhere from 8 to 24 hours. Methamphetamine, invented for military use by the Japanese in World War I, is currently a schedule II drug, approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) and obesity. The 2003 NHSDUH estimates that more than 5% of individuals age 12 and over have experimented with the drug. Long-term use can cause cognitive impairment (including dulled awareness, decreased intellectual capacity, memory impairment, and motor retardation). Positron emission tomography (PET) studies show loss of DAT in the caudate and the putamen. Magnetic resonance imaging (MRI) studies show decreased perfusion in the putaman and the frontal cortex and loss of volume in both the amygdala and the hippocampus. Methamphetamine can be taken orally (“speed”), taken anally, smoked (“crystal”), snorted, or injected.

Routine medical evaluation may uncover the most common type of amphetamine abuse seen in clinical settings. Typically, this involves a patient who began using amphetamines to control obesity and later became a chronic amphetamine abuser. The patient quickly develops tolerance and may use 100 mg or more each day in an unsuccessful effort to control weight. This type of amphetamine abuse can be treated by abruptly discontinuing usage of the drug or by gradually tapering the dose, whichever is more acceptable to the patient. In either case, the patient should be given a more appropriate program for weight control.

A more serious problem involves the patient who develops a severe psychological dependence on amphetamines or methamphetamine and who may have the same symptoms seen in younger street-drug abusers. Amphetamine and methamphetamine (speed) accounted for a total of 16,215 ED visits in the first half of 2002.¹ The signs and symptoms of acute amphetamine intoxication are similar to those of cocaine abuse. Long-term effects also include depression, brain dysfunction, and weight loss. The other classic syndrome seen in either acute or chronic amphetamine intoxication is a paranoid psychosis without delirium. Although typically seen in young people who use IV methamphetamine hydrochloride, it can also occur in chronic users of dextroamphetamine or other amphetamines. A paranoid psychosis may also occur with or without other manifestations of amphetamine intoxication. The absence of disorientation distinguishes this condition from most other toxic psychoses. This syndrome is clinically indistinguishable from an acute schizophrenic episode of the paranoid type, and the correct diagnosis is often made in retrospect, based on a history of amphetamine use and with a urine test that is positive for amphetamines. Use of haloperidol or low-dose atypical antipsychotics is often effective in the acute management of this type of substance-induced psychosis.

Other distinctive features of chronic stimulant abuse include dental problems (e.g., caries, missing teeth, and bleeding and infected gums), muscle cramps (related to dehydration and low levels of magnesium and potassium), constipation (due to dehydration), nasal perforations, and excoriated skin lesions (speed bumps) (see Figure 27-2). The urine may have a stale smell due to ammonia constituents used in the illicit manufacture of methamphetamine.

Figure 27-2 Face of a patient with chronic methamphetamine abuse. Before use (A) and after 3 months of use (B).

Treatment

Amphetamines can be withdrawn abruptly. If the intoxication is mild, the patient’s agitation should be handled by reassurance alone. The patient should be “talked down,” much as one would handle an adverse D-lysergic acid diethylamide (LSD) reaction. If sedation is necessary, benzodiazepines are the drugs of choice. Phenothiazines should be avoided because they may heighten dysphoria and increase the patient’s agitation. Hypertension will usually respond to sedation with benzodiazepines. When severe hypertension arises, phentolamine is recommended for vasodilation. Beta- or mixed alpha- and beta-adrenergic blockers (such as propranolol or labetalol) are to be avoided because they may exacerbate stimulant-induced cardiovascular toxicity.

Most signs of intoxication clear in 2 to 4 days. The major problem is appropriate psychiatric management of post–amphetamine use depression. In mild cases, this depression is manifest by feelings of lethargy, as well as by the subsequent temptation to use amphetamines again for energy. In more serious cases, the patient may become suicidal and require inpatient psychiatric treatment. The efficacy of antidepressants in such cases has not been adequately documented.Even with support and psychotherapy, most patients experience symptoms of depression for 3 to 6 months following the cessation of chronic amphetamine abuse. CBT has been helpful, but it may need to be adapted to allow for the cognitive impairment associated with long-term methamphetamine use.

CLUB DRUGS

During the 1990s there was a steady increase in the abuse of “club drugs,” primarily 3,4-methylenedioxy-methamphetamine (MDMA, or “Ecstasy”), γ-hydroxybutyrate (GHB), and ketamine. This trend was reversed between 1998 and 2001 when the Monitoring the Future Survey reported a steep decline in the use of Ecstasy. The drop has been attributed to a general recognition of the dangers associated with the use of this drug. The NSDUH reported that the number of current users of Ecstasy for individuals age 12 and older remained the same in 2003 and 2004.³ MDMA has both amphetamine-like and hallucinogenic effects. Its primary mechanism of action is via indirect serotonin agonism, but it also affects dopamine and other neurotransmitter systems. These drugs increase synaptic dopamine and alter serotonergic neurotransmission. MDMA was initially used experimentally to facilitate psychotherapy, but its use was banned after it was found to be neurotoxic in animals. The intense feelings of empathy experienced by users may be a result of the flooding of the serotonin system. In toxic amounts, it produces distorted perceptions, confusion, hypertension, hyperactivity, and potentially fatal hyperthermia. With chronic use, serotonin stores are depleted and subsequent doses produce a less robust high and more unpleasant side effects (such as teeth gnashing and restlessness). Frequent users learn to anticipate these effects and tend to limit their long-term consumption of the drug.

GHB (sodium oxybate) is structurally similar to GABA and acts as a CNS depressant. It has been approved by the FDA as a schedule III controlled substance for the treatment of narcolepsy. GHB has a relatively low therapeutic index; as little as twice the dose that produces euphoria can cause CNS depression. In overdose it can produce a potentially fatal coma; it has also been identified as a “date rape” drug. Ketamine (“Special K,” “Super K,” or “K”) is a noncompetitive NMDA antagonist and is classified as a dissociative anesthetic. It is currently used as a veterinary anesthetic and it can produce delirium, amnesia, and respiratory depression when abused. Ketamine, like phencyclidine (PCP), binds to the NMDA receptor site and blocks the action of excitatory neurotransmission; it affects perceptions, memory, and cognition.

The treatment for overdoses of all of these drugs is primarily symptomatic.

NARCOTICS

While abuse of all major drug classes increased during the 1990s, the most dramatic increase was seen among new abusers of prescription pain relievers. In 2004, of all illicit drug–related ED visits, the DAWN survey estimates that 17% involved heroin.² However, the 2004 NSDUH estimated that 31.8 million Americans used pain relievers nonmedically during their lifetime, up from 29.6 million in 2002⁹; 4.4 million persons age 12 and older used opiates nonmedically in 2004.³ Lifetime nonmedical use of OxyContin increased from 1.9 to 3.1 million persons between 2002 and 2004.¹⁰ In 2004, among those age 12 and older, 2.4 million initiated nonmedical use of prescription pain relievers.¹⁰ This pattern of use has reached epidemic proportions on the East Coast, and OxyContin has replaced heroin as the entry point for opiate addiction. According to the 2005 Monitoring the Future Survey, the annual prevalence of OxyContin use among twelfth-graders was 5.5%, representing a 40% increase since 2002.¹¹ Among nonmedical use of prescription drugs, opioid analgesics (including oxycodone and combination forms) were the most frequent drugs reported in the DAWN survey, present in 32% of the ED visits.² Nearly one-third (31%) of acquired immunodeficiency syndrome (AIDS) cases in the United States are related to a history of injection drug use.¹² As a result, the treatment of opiate dependence is becoming commonplace on medical and surgical floors of general hospitals. Proper management of such patients necessitates knowledge of FDA regulations and community treatment resources, and competence in the management of detoxification and opiate substitution therapy.

All opiates act by binding to the mu opioid receptor. Binding to receptors in the ventral tegmental area stimulates the release of dopamine (Figure 27-3), which activates brain reward centers in the nucleus accumbens (Figure 27-4). Opiates produce a wide range of effects (including analgesia, euphoria, sedation, decreased secretions, nausea, vomiting, constipation, miosis, urinary hesitation, and hypotension [Table 27-2]). The classic signs of opiate withdrawal are easily recognized and usually begin 8 to 12 hours after the last dose (of a short-lasting agent) (Table 27-3). The patient generally admits the need for drugs and shows sweating, yawning, lacrimation, tremor, rhinorrhea, marked irritability, dilated pupils, piloerection (“gooseflesh”), and an increased respiratory rate. More severe signs of withdrawal occur 24 to 36 hours after the last dose and include tachycardia, hypertension, insomnia, nausea, vomiting, and abdominal cramps. Untreated, the syndrome subsides in 3 to 7 days. Withdrawal symptoms are similar in patients addicted to methadone, but they may not appear until 24 to 36 hours after the last dose (because of methadone’s longer half-life) and abate over 2 to 4 weeks. Patients addicted to oxycodone may present a particularly severe and prolonged withdrawal syndrome and may require high doses of opiates for adequate control.

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