Scope, Epidemiology, and Definitions

Addiction is a personal state of inner tyranny. Addicts hold traditional concerns of family, work, health, and the law as secondary to one primal urge—getting the drug or drink. Many are familiar with the destructive effects of drugs or alcohol for the addict on the street, but most are unaware of the cumulative consequences of addiction on society.

From several viewpoints the problem is vast. Regarding alcohol, the Centers for Disease Control and Prevention reports that approximately 79,000 deaths are attributable to excessive alcohol use annually in the United States, which makes it the third leading lifestyle-related cause of death for the nation. In addition, excessive alcohol use accounts for 2.3 million years of potential life lost annually—an average of about 30 years of potential life lost for each death.¹ Concerning drugs, the Substance Abuse and Mental Services Administration of the U.S. Department of Health and Human Services reported that in 2009, 21.8 million Americans used an illegal drug during the month before the survey, which represents 8.7% of the population aged 12 years or older. Illegal drugs include marijuana or hashish, cocaine (including crack cocaine), heroin, hallucinogens, inhalants, and nonmedical use of prescription-type psychotherapeutics.²

Many of those abusing or dependent on alcohol or drugs, or both, disproportionately consume public health care resources, particularly emergency services. Between 1992 and 2000, alcohol-related visits to U.S. emergency departments (EDs) averaged 76 million per year, which accounted for 7.9% of the total ED visits.³ The Drug Abuse and Warning Network reported that in 2007, 1.9 million ED visits were associated with drug misuse or abuse. Although the overall number of ED visits attributable to drug misuse and abuse was stable from 2004 to 2007, ED visits involving nonmedical use of pharmaceuticals with no other drug involvement rose significantly (73%), as did the nonmedical use of pharmaceuticals with alcohol (36%).⁴

The societal burdens of substance abuse extend well beyond EDs. The U.S. Office of National Drug Control Policy reported that incarcerated offenders were often under the influence of drugs when they committed their offenses and that offenders often commit crimes to support their drug habit. In addition, trafficking in illicit drugs tends to be associated with the commission of particularly violent crimes.⁵

The cumulative economic cost of substance abuse is astounding. In 1998, alcohol abuse in the United States cost approximately $185 billion, with 47% of this cost simply being due to lost productivity at work.⁶ The same year, drug abuse in the United States cost $143 billion.⁷ When adjusted for 2010 dollars, abuse of both drugs and alcohol costs the nation $440 billion—the equivalent of 80% of all revenue raised to fund public education for grades prekindergarten through 12.⁸ Substance abuse is as much a public crisis for our nation as it is a personal crisis for the addict.

To address the problem of substance-related disorders, we must understand the clinical condition. To understand, we must speak the same language by sharing a common terminology. In general, these disorders are classified not by the quantity of the cause but rather by the effect.

With substance abuse, adverse consequences occur but the pattern has not yet deteriorated into a state of dependence. More specifically, the American Psychiatric Association defines substance abuse as “a maladaptive pattern of substance use” revealed by the recurrent and significant consequences arising from repeated use of the substance: failure to fulfill major role obligations, recurrent use in situations in which it is physically hazardous, multiple substance-related legal problems, and recurrent social and interpersonal problems⁹ (Box 199.1). Although the consequences of use are significant, some degree of control is present.

In contrast, substance dependence is defined as severe impairment or absence of control. Use is compulsive and occurs under the ever-present threats of tolerance and withdrawal. As stated earlier, the American Psychiatric Association more specifically defines substance dependence as a cluster of cognitive, behavioral, and physiologic symptoms indicating continued use of the substance despite significant substance-related problems⁹ (Box 199.2).

Tolerance is reflected by the “need for increasing amounts of the substance to achieve intoxication or desired effect … or diminished effect with continued use of the same amount of the substance.”⁹

Withdrawal is a physiologic response manifested by the characteristic “withdrawal” syndrome for the particular substance or use of the same or a closely related substance to relieve or avoid such symptoms.⁹

Addiction is a term of more general public reference that includes drug and alcohol dependence but also includes other inherent self-destructive behavioral patterns, such as eating disorders, compulsive gambling, and excessive sexual behavior.

This chapter focuses on drug- and alcohol-related disorders. Although multiple agents of abuse exist, most substances commonly encountered in the ED can be classified as either central nervous system depressants (alcohol, sedatives, hypnotics, and anxiolytics) or stimulants (cocaine, amphetamines, and sympathomimetics).

Pathophysiology and Anatomy

Insight into the pathophysiology of substance-related disorders has progressed substantially in recent years. Neuropharmacologic animal studies and human imaging modalities, in particular, positron emission tomography and functional magnetic resonance imaging brain scans, have identified the neurochemical processes and anatomic structures most affected in states of substance abuse and dependence.

Addiction changes brain physiology, thus prompting designation of this condition as a brain disorder.¹⁰ Addictive substances alter multiple neurotransmitter pathways within the brain, including N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid (GABA) receptors, as well as the endogenous opioid, serotonin, and dopamine systems.¹¹ Changes particularly occur within the mesolimbic system of the brain. Projecting from the ventral tegmental area to the nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala, the mesolimbic system is regarded as the “reward center” of the brain¹² (Fig. 199.1). These neurocircuits presumably evolved to reward survival-enhancing behavior, including productive familial and social interactions, reproduction, and other such behavior. Some suggest that mesolimbic dopamine is a direct mediator of reward, whereas others emphasize that dopamine signals an interest in reward or the expectation that reward is forthcoming. Either way, evidence suggests that the common reinforcing and incentive effects of addictive substances are substantially mediated by increasing extracellular dopamine within the mesolimbic system. On an elementary level, this drug-induced efflux of dopamine is pleasurable.¹⁰

See Figure 199.1, Mesolimbic Dopaminergic System, online at www.expertconsult.com

Fig. 199.1 Mesolimbic dopaminergic system.

As addicts and clinicians mutually recognize, artificially inducing the mesolimbic system with drugs and alcohol for these pleasant effects is accompanied by grave shortcomings. Neurochemical pleasure circuits, overwhelmed by excessive stimulation, adapt by desensitizing.¹³ Evaluation by multiple disciplines, including anatomic, behavioral, biochemical, and electrophysiologic studies, commonly shows that dopamine neurons function insufficiently in addicts. A hypodopaminergic state develops.¹⁰ The dopamine deficiency associated with acute withdrawal is manifested clinically as acute dysphoria, depression, irritability, and anxiety. Neurochemically, baseline levels of the “reward” neurotransmitters are depressed.¹² The traditional social and behavioral stimulants of the mesolimbic system that function effectively in the nonaddictive state, such as family and positive affirmation from work or friends, become inadequate to generate a significant perception of pleasure. Drugs and alcohol are the sole stimuli sufficient to activate the impaired mesolimbic neurocircuits and generate pleasure.¹³ Yet even though the baseline mesolimbic system remains hypodopaminergic in addicts, the system remains hyperresponsive to abused drugs and alcohol, thereby conferring long-lasting vulnerability even after extensive periods of abstinence.¹⁰ The most promising avenues of treatment for addicts are pharmacologic agents aimed at restoring these dopaminergic neurocircuits.¹⁰

Not all individuals are equally susceptible. Those with risk-taking and novelty-seeking traits favor the use of addictive drugs. Psychiatric conditions, in particular, schizophrenia, bipolar disorder, and attention-deficit/hyperactivity disorder, are associated with increased risk for substance abuse and dependency. A dual diagnosis of substance abuse and mental disorder has especially unfavorable implications for both management and outcome.¹⁴

Genetic factors clearly increase the risk for addiction. First-degree relatives of alcoholics (e.g., parents, siblings, children) have a threefold to fourfold greater prevalence of alcohol abuse than the general population does.¹⁵ Men whose parents were alcoholics have an increased likelihood for alcoholism even when adopted at birth and raised by nonalcoholic parents.¹⁴ Genetic factors, as revealed by studies in identical twins, account for approximately half of the risk for alcohol abuse.¹⁵

Some of this genetic predilection for addiction is expressed through enzymatic variants. For instance, highly active forms of aldehyde dehydrogenase increase alcohol metabolism and decrease the negative side effects of alcohol intake, thereby enhancing consumption and addiction (Fig. 199.2). In contrast, less active variants of aldehyde dehydrogenase (i.e., the ALDH2*2 allele initially detected in eastern Asian populations) allow accumulation of acetaldehyde, the toxic intermediary by-product of alcohol metabolism. Sensitivity to alcohol increases with a subsequent reduction in the rates of alcoholism.¹⁶ Genetic influence is also expressed through neurotransmitter variants. Neuropeptide Y, a 36–amino acid peptide neurotransmitter, regulates appetite, anxiety, and reward. A functional Lue7Pro polymorphism in the neuropeptide Y gene increases the risk for alcohol dependence by 7.3%, primarily in European Americans.¹⁷ Although the initial use of a drug or alcohol is a willful act, for those predisposed to abuse or dependency, some if not most of what follows is progressively beyond their control.

Fig. 199.2 Metabolism of alcohol.

NAD⁺, Oxidized form of nicotinamide adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.

Presenting Signs and Symptoms

The signs and symptoms of substance abuse and dependency result from acute states of intoxication and withdrawal. Although some manifestations are specific to the substance, common patterns exist.

Acute intoxication with central nervous system depressants—alcohol, sedatives, hypnotics, and anxiolytics—is characterized by dysfunctional behavioral and neurologic changes. Individuals suffer mood swings and impaired social or occupational functioning. Poor judgment prevails, often reflected by inappropriate sexual or aggressive behavior. Neurologic dysfunction occurs along a clinical spectrum determined by the degree of intoxication and ranges from slurred speech, incoordination, and unsteady gait to impairment of memory and attention, stupor, and coma (Box 199.3). In contrast, acute withdrawal from central nervous system depressants is manifested as physiologic and behavioral agitation. Psychomotor distress can be significant, with transient visual, tactile, or auditory hallucinations. Patients experience autonomic hyperactivity, evident as tachycardia and diaphoresis. Nausea and vomiting may be prevalent, as well as hand tremors. Generalized seizures can occur. Mentally, emotionally, and physically miserable, such patients cannot function.⁹

Though also central nervous system depressants, opiates confer somewhat unique states of intoxication and withdrawal. Because of the rapid but variable degrees of tolerance that develops to opiates, incremental doses are required to achieve euphoria. However, the unreliable concentration of opiates in street drugs complicates attempts by addicts to self-administer a specific dose. Overdosage frequently results in extreme drowsiness and potentially coma and death from respiratory depression (Box 199.4). In contrast, opiate withdrawal is an extremely unpleasant, conscious experience. Patients experience severe dysphoria, diaphoresis, vomiting, and diarrhea.⁹

The signs and symptoms of acute intoxication with central nervous system stimulants—cocaine, amphetamines, and sympathomimetics—are determined by the pattern, route, and amount of drug used, as well as the specific agent. Intermittent “binge” use is often accompanied by euphoria and heightened psychomotor and autonomic activity (e.g., tachycardia, hypertension, seizures, cardiac arrhythmias, chest pain). Chronic daily users have a contrasting scenario. Psychomotor depression and affective blunting may be present, often in the setting of hypotension, bradycardia, and respiratory insufficiency (Box 199.5). Withdrawal from central nervous system stimulants occurs after a period of heavy and prolonged use. The withdrawal symptoms of dysphoria, suicidal ideation, extreme fatigue, and hypersomnia are the antithesis of those of acute intoxication.⁹

Emergency physicians often encounter a particularly challenging if not frustrating clinical scenario arising from addiction—drug-seeking activity. Those seeking drugs may engage in “doctor shopping” by visiting multiple outpatient clinics, EDs, and pain management clinics to obtain prescriptions for controlled substances. At times, “scam” situations are presented, such as chronic toothaches, lost or stolen prescriptions, or multiple drug allergies. While recognizing the need to evaluate each situation separately, the physician must be particularly vigilant when patients insist on specific controlled substances, self-assert a high tolerance to medications, or issue veiled threats. Additional clues to drug-seeking behavior are listed in Box 199.6. When in doubt, the signs and symptoms can often be validated through contact with the patient’s personal physician, review of recently issued prescription drugs with the patient’s pharmacist, or perusal of previous medical records.¹⁸

See Box 199.6, Drug-Seeking Behavior, online at www.expertconsult.com

Differential Diagnosis

The differential diagnosis of substance abuse–related disorders is limited (Box 199.7). Hypochondriasis and somatization disorders are generally difficult to distinguish from true addiction in a single ED encounter. Pseudoaddiction describes behavior similar to that of addiction but arising from mismanaged pain. Pseudoaddiction patients are highly focused on obtaining medications, though usually through appropriate routes. They may be “clock watchers” and be focused on the scheduled delivery of approved analgesics. When suspecting a disruption in their expected regimen, a pseudoaddict may become deceptive or overly dramatic in attempts to ensure treatment. As noted, distinguishing between addicts and pseudoaddicts is challenging in an isolated encounter. In a broader perspective, however, pseudoaddicts generally function well once their pain is treated effectively, usually with long-acting opioids.¹⁹

See Box 199.7, Differential Diagnosis of Substance-Related Disorders, online at www.expertconsult.com

Diagnostic Testing

In contrast to the increasing reliance on technology in diagnosing other medical disorders, the clinical interview remains the best tool for the diagnosis of substance-related disorders. Patients should be questioned about the quantity and frequency of use in an empathetic, nonjudgmental manner. Problems and symptoms current and past should be addressed, including any other family members with substance-related disorders. A number of screening tools are available: CAGE, the Michigan Alcoholism Screening Test (MAST), the Alcohol Use Disorders Identification Test (AUDIT), and the Drug Abuse Screening Test (DAST). These interview tools consist of anywhere from 4 to 28 “yes or no” or multiple choice questions and require from 30 seconds to 7 minutes to complete.²⁰

When substance use is suspected, toxicologic analysis is recommended to establish or confirm a diagnosis. Qualitative analysis is generally sufficient to substantiate drug use, although quantitative levels are indicated for ethanol.

Treatment and Disposition

The treatment goals of substance abuse, in particular, substance dependency, are twofold: detoxification and prevention of relapse (Table 199.1). These objectives are approached through two strategies: pharmacotherapy and behavioral therapy.

Table 199.1 Treatment

Prevention of Relapse

Prevention of relapse is the second, yet most critical component of treatment because it primarily determines overall morbidity and mortality. Pharmacologic and behavioral therapies, though considered separately, appear to be most effective if combined.

In the past 25 years, a new class of psychoactive medications has emerged that show substantial promise in the treatment of addiction disorders. These “anticraving” medications reduce desire for the drug or alcohol in detoxified patients and deter relapse into compulsive substance abuse.²¹

Three medications have been approved by the FDA for the prevention of alcohol relapse: naltrexone, acamprosate, and disulfiram. As noted earlier in the section “Pathophysiology and Anatomy,” alcohol increases extracellular dopamine in the nucleus accumbens.²¹ In mice pretreated with naltrexone, an opioid µ-receptor antagonist, the alcohol-induced increase in dopamine is blocked. These mice do not self-administer alcohol.²⁶ Similarly, in a study of 99 alcoholic men, naltrexone-treated subjects reported reduced alcohol craving and drinking and decreased alcohol-related euphoria. Relapse rates in naltrexone-treated men were also significantly lower.

Naltrexone can be administered in two formats: an oral daily dosage of 50 mg and depot intramuscular injections of 380 mg every 4 weeks. A metaanalysis of 18 trials of naltrexone for alcohol dependence demonstrated a decrease in the risk for relapse with naltrexone when compared with placebo (relative risk, 0.64; 95% confidence interval, 0.51 to 0.82), as well as a reduction in craving and return to drinking and an increase in time to the first drink. The effect size for reducing relapse was modest (number needed to treat, 7).²⁷

Not unexpectedly, daily dosing regimens with naltrexone limit compliance. Depot injections of naltrexone every 4 weeks both enhance compliance and establish more stable therapeutic levels. Three extended-release injectable formulations of naltrexone are available: Vivitrol, Naltrel, and Depotrex.²⁷

Acamprosate was approved by the FDA in 2004 for the maintenance of abstinence in detoxified alcohol-dependent patients. The neurochemical effect of acamprosate is attributed to modification of glutamate neurotransmission.²⁷ Administered orally three times daily, acamprosate is less convenient than either oral or depot naltrexone. In addition, the impact of acamprosate on abstinence is unclear. Several largely positive clinical trials in Europe were contradicted by three negative clinical trials in the United States and Australia. Thus the clinical benefits of acamprosate are equivocal.²⁷

Disulfiram blocks aldehyde dehydrogenase, an enzyme fundamental to alcohol metabolism. When someone consumes alcohol while taking disulfiram, acetaldehyde, an intermediate and relatively toxic by-product, accumulates 5- to 10-fold relative to normal circumstances. A most disagreeable clinical consequence, the “disulfiram reaction,” develops. Diaphoresis, headache, dyspnea, hypotension, flushing, palpitations, nausea, and vomiting can all occur. Individuals taking disulfiram have poor compliance because of the unpleasantness of this effect.²¹ Disulfiram is administered at 500 mg/day for 1 to 2 weeks, followed by an average maintenance dose of 250 mg/day. Reviews of efficacy show mixed results.²⁷

Topiramate, though approved by the FDA as an anticonvulsant, has shown promise in preventing alcohol relapse. A multisite U.S. trial showed that topiramate reduced the percentage of heavy drinking days when compared with placebo (43.8% versus 51.8%) in 371 men and women with alcohol dependence over a period of 14 weeks. Topiramate was also more effective than placebo in improving the secondary outcomes of percent days abstinent and number of drinks per day.²⁸

Additional agents under investigation for the prevention of relapse include baclofen, nalmefene, selective serotonin reuptake inhibitors, and ondansetron, among others.²⁹

Three medications have been approved by the FDA for the prevention of relapse from opiates: methadone, buprenorphine, and naltrexone. Methadone and buprenorphine act as complete (methadone) or partial (buprenorphine) µ-receptor agonists. Conceptually, methadone and buprenorphine provide long-term replacement therapy for the brain disorder of addiction, comparable with the use of prednisone in patients with adrenal insufficiency or levothyroxine in those with hypothyroidism. Naltrexone, a µ-receptor antagonist, blocks the euphoric effects of opioids. Compliance is relatively poor with naltrexone.²¹

Unfortunately, no medications have been approved by the FDA for the prevention of relapse from cocaine addiction. However, five agents that are FDA-approved for other indications have been found in randomized, controlled trials to be effective for cocaine addiction. Topiramate, modafinil, and vigabatrin affect glutamate and GABA neurotransmission. The mechanism of two others, disulfiram and propranolol, is unknown.²¹

Clinical trials have yet to demonstrate any clear therapeutic options for prevention of relapse from methamphetamine.³⁰

Disposition

ED patients with substance-related disorders should be referred to behavioral change programs. Success is determined by the pharmacologic anticraving therapy available to prevent relapse and the patient’s intrinsic motivation for change.

Multiple behavioral therapies are available to diminish the likelihood of relapse. Contingency management is based on the operant conditioning principle that behavior resulting in positive consequences is more likely to recur. Patients meeting specific drug-free goals receive incentives or rewards. Cognitive behavioral and skills training emphasizes a functional analysis of drug use by taking into account the antecedents and consequences of drug use. Addicts then learn to identify situations at high risk for drug use and relapse. Through rehearsal and role-playing, addicts develop strategies to either avoid such situations or cope effectively. Motivational enhancement therapy (MET) seeks to develop the individual’s inner drive for change. Couples and family treatment takes into account the familial and social systems in which substance use commonly occurs. Alcoholics Anonymous (AA) provides a facilitative form of behavioral therapy that consists of a 12-step program based on self-assessment and fellowship activities.³¹

As noted earlier, pharmacologic and behavioral therapies appear to be most effective when used together. To assess this assumption, from 2001 through 2004 the National Institute on Alcohol Abuse and Alcoholism (NIAAA) compared the efficacy of acamprosate, naltrexone, and placebo in combination with behavioral treatments among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 U.S. academic sites in the nationwide clinical study COMBINE (Combining Medications and Behavioral Intervention). Patients receiving medical management with naltrexone, combined behavioral intervention (CBI), or both fared better on drinking outcomes. Acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than did naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.^32,33

Treatment Efficacy