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InternalMed_Harrison. Primary care physicians may encounter situations in which family, domestic, or societal violence is discovered or suspected. Such an awareness can carry legal and moral obligations; many state laws mandate reporting of child, spousal, and elder abuse. Physicians are frequently the first point of contact for both victim and abuser. Approximately 2 million older Americans and 1.5 million U.S. children are thought to experience some form of physical maltreatment each year. Spousal abuse is thought to be even more prevalent. An interview study of 24,000 women in 10 countries found a lifetime prevalence of physical or sexual violence that ranged from 15 to 71%; these individuals are more likely to suffer from depression, anxiety, and substance abuse and to have attempted suicide. In addition, abused individuals frequently express low self-esteem, vague somatic symptomatology, social isolation, and a passive feeling of loss of control. Although it is essential to treat these elements in the


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InternalMed_Harrison. individuals frequently express low self-esteem, vague somatic symptomatology, social isolation, and a passive feeling of loss of control. Although it is essential to treat these elements in the victim, the first obligation is to ensure that the perpetrator has taken responsibility for preventing any further violence. Substance abuse and/or dependence and serious mental illness in the abuser may contribute to the risk of harm and require direct intervention. Depending on the situation, law enforcement agencies, community resources such as support groups and shelters, and individual and family counseling can be appropriate components of a treatment plan. A safety plan should be formulated with the victim, in addition to providing information about abuse, its likelihood of recurrence, and its tendency to increase in severity and frequency. Antianxiety and antidepressant medications may sometimes be useful in treating the acute symptoms, but only if independent evidence for an appropriate


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InternalMed_Harrison. tendency to increase in severity and frequency. Antianxiety and antidepressant medications may sometimes be useful in treating the acute symptoms, but only if independent evidence for an appropriate psychiatric diagnosis exists.


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InternalMed_Harrison. There is a high prevalence of mental disorders and substance abuse among homeless and impoverished individuals. Depending on the definition used, estimates of the total number of homeless individuals in the United States range from 800,000 to 2 million, one-third of whom qualify as having a serious mental disorder. Poor hygiene and nutrition, substance abuse, psychiatric illness, physical trauma, and exposure to the elements combine to make the provision of medical care challenging. Only a minority of these individuals receives formal mental health care; the main points of contact are outpatient medical clinics and emergency departments. Primary care settings represent a critical site in which housing needs, treatment of substance dependence, and evaluation and treatment of psychiatric illness can most efficiently take place. Successful intervention is dependent on breaking down traditional administrative barriers to health care and recognizing the physical constraints and emotional


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InternalMed_Harrison. can most efficiently take place. Successful intervention is dependent on breaking down traditional administrative barriers to health care and recognizing the physical constraints and emotional costs imposed by homelessness. Simplifying health care instructions and follow-up, allowing frequent visits, and dispensing medications in limited amounts that require ongoing contact are possible techniques for establishing a successful therapeutic relationship.


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InternalMed_Harrison. Marc A. Schuckit Alcohol (beverage ethanol) distributes throughout the body, affecting almost all systems and altering nearly every neurochemical process in the brain. This drug is likely to exacerbate most medical problems, affect medications metabolized in the liver, and temporarily mimic many medical (e.g., diabetes) and psychiatric (e.g., depression) conditions. The lifetime risk for repetitive alcohol problems is almost 20% for men and 10% for women, regardless of a person’s education or income. Although low doses of alcohol might have healthful benefits, greater than three standard drinks per day enhances the risk for cancer and vascular disease, and alcohol use disorders decrease the life span by about 10 years. Unfortunately, most clinicians have had only limited training regarding alcohol-related disorders. This chapter presents a brief overview of clinically useful information about alcohol use and problems.


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InternalMed_Harrison. Ethanol blood levels are expressed as milligrams or grams of ethanol per deciliter (e.g., 100 mg/dL = 0.10 g/dL), with values of ~0.02 g/dL resulting from the ingestion of one typical drink. In round figures, a 2723 standard drink is 10–12 g, as seen in 340 mL (12 oz) of beer, 115 mL (4 oz) of nonfortified wine, and 43 mL (1.5 oz) (a shot) of 80-proof beverage (e.g., whisky); 0.5 L (1 pint) of 80-proof beverage contains ~160 g of ethanol (about 16 standard drinks), and 750 mL of wine contains ~60 g of ethanol. These beverages also have additional components (congeners) that affect the drink’s taste and might contribute to adverse effects on the body. Congeners include methanol, butanol, acetaldehyde, histamine, tannins, iron, and lead. Alcohol acutely decreases neuronal activity and has similar behavioral effects and cross-tolerance with other depressants, including benzodiazepines and barbiturates.


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InternalMed_Harrison. Alcohol is absorbed from mucous membranes of the mouth and esophagus (in small amounts), from the stomach and large bowel (in modest amounts), and from the proximal portion of the small intestine (the major site). The rate of absorption is increased by rapid gastric emptying (as seen with carbonation); by the absence of proteins, fats, or carbohydrates (which interfere with absorption); and by dilution to a modest percentage of ethanol (maximum at ~20% by volume).


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InternalMed_Harrison. Between 2% (at low blood alcohol concentrations) and 10% (at high blood alcohol concentrations) of ethanol is excreted directly through the lungs, urine, or sweat, but most is metabolized to acetaldehyde, primarily in the liver. The most important pathway occurs in the cell cytosol where alcohol dehydrogenase (ADH) produces acetaldehyde, which is then rapidly destroyed by aldehyde dehydrogenase (ALDH) in the cytosol and mitochondria (Fig. 467-1). A second pathway occurs in the microsomes of the smooth endoplasmic reticulum (the microsomal ethanol-oxidizing system, or MEOS) that is responsible for ≥10% of ethanol oxidation at high blood alcohol concentrations.


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InternalMed_Harrison. Although a drink contains ~300 kJ, or 70–100 kcal, these are devoid of minerals, proteins, and vitamins. In addition, alcohol interferes with absorption of vitamins in the small intestine and decreases their storage in the liver with modest effects on folate (folacin or folic acid), pyridoxine (B6), thiamine (B1), nicotinic acid (niacin, B3), and vitamin A.


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InternalMed_Harrison. Heavy drinking in a fasting, healthy individual can produce transient hypoglycemia within 6–36 h, secondary to the acute actions of ethanol on gluconeogenesis. This can result in temporary abnormal glucose tolerance tests (with a resulting erroneous diagnosis of diabetes mellitus) until the alcoholic has abstained for 2–4 weeks. Alcohol ketoacidosis, probably reflecting a decrease in fatty acid oxidation coupled with poor diet or recurrent vomiting, can be misdiagnosed as diabetic ketosis. With the former, patients show an increase in serum ketones along with a mild increase in glucose but a large anion gap, a mild to moderate increase in serum lactate, and a β-hydroxybutyrate/ lactate ratio of between 2:1 and 9:1 (with normal being 1:1).


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InternalMed_Harrison. In the brain, alcohol affects almost all neurotransmitter systems, with acute effects that are often the opposite of those seen following desistance after a period of heavy drinking. The most prominent actions relate to boosting γ-aminobutyric acid (GABA) activity, FIGURE 467-1 The metabolism of alcohol. CoA, coenzyme A; MEOS, microsomal ethanoloxidizing system.


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InternalMed_Harrison. 2724 especially at GABAA receptors. Enhancement of this complex chloride channel system contributes to anticonvulsant, sleep-inducing, antianxiety, and muscle relaxation effects of all GABA-boosting drugs. Acutely administered alcohol produces a release of GABA, and continued use increases density of GABAA receptors, whereas alcohol withdrawal states are characterized by decreases in GABA-related activity. Equally important is the ability of acute alcohol to inhibit postsynaptic N-methyl-d-aspartate (NMDA) excitatory glutamate receptors, whereas chronic drinking and desistance are associated with an upregulation of these excitatory receptor subunits. The relationships between greater GABA and diminished NMDA receptor activity during acute intoxication and diminished GABA with enhanced NMDA actions during alcohol withdrawal explain much of intoxication and withdrawal phenomena. As with all pleasurable activities, alcohol acutely increases dopamine levels in the ventral tegmentum and


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InternalMed_Harrison. actions during alcohol withdrawal explain much of intoxication and withdrawal phenomena. As with all pleasurable activities, alcohol acutely increases dopamine levels in the ventral tegmentum and related brain regions, and this effect plays an important role in continued alcohol use, craving, and relapse. The changes in dopamine pathways are also linked to increases in “stress hormones,” including cortisol and adrenocorticotropic hormone (ACTH) during intoxication and withdrawal. Such alterations are likely to contribute to both feelings of reward during intoxication and depression during falling blood alcohol concentrations. Also closely linked to alterations in dopamine (especially in the nucleus accumbens) are alcohol-induced changes in opioid receptors, with acute alcohol causing release of beta endorphins. Additional neurochemical changes include increases in synaptic levels of serotonin during acute intoxication and subsequent upregulation of serotonin receptors. Acute increases


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InternalMed_Harrison. of beta endorphins. Additional neurochemical changes include increases in synaptic levels of serotonin during acute intoxication and subsequent upregulation of serotonin receptors. Acute increases in nicotinic acetylcholine systems contribute to the impact of alcohol in the ventral tegmental region, which occurs in concert with enhanced dopamine activity. In the same regions, alcohol impacts on cannabinol receptors, with resulting release of dopamine, GABA, and glutamate as well as subsequent effects on brain reward circuits.


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InternalMed_Harrison. BEHAVIORAL EFFECTS, TOLERANCE, AND WITHDRAWAL The acute effects of a drug depend on the dose, the rate of increase in plasma, the concomitant presence of other drugs, and past experience with the agent. “Legal intoxication” with alcohol in most states requires a blood alcohol concentration of 0.08 g/dL, but levels of 0.04 are cited in some other countries. However, behavioral, psychomotor, and cognitive changes are seen at 0.02–0.04 g/dL (i.e., after one to two drinks) (Table 467-1). Deep but disturbed sleep can be seen at twice the legal intoxication level, and death can occur with levels between 0.30 and 0.40 g/dL. Beverage alcohol is probably responsible for more overdose deaths than any other drug.


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InternalMed_Harrison. Repeated use of alcohol contributes to acquired tolerance, a phenomenon involving at least three compensatory mechanisms. (1) After 1–2 weeks of daily drinking, metabolic or pharmacokinetic tolerance can be seen, with up to 30% increases in the rate of hepatic ethanol metabolism. This alteration disappears almost as rapidly as it develops. (2) Cellular or pharmacodynamic tolerance develops through neurochemical changes that maintain relatively normal physiologic functioning despite the presence of alcohol. Subsequent decreases in blood levels contribute to symptoms of withdrawal. (3) Individuals learn to adapt their behavior so that they can function better than expected under influence of the drug (learned or behavioral tolerance). Blood Level, g/dL Usual Effect 0.02 Decreased inhibitions, a slight feeling of intoxication 0.08 0.20 Obvious slurred speech, motor incoordination, irritability, and poor judgment 0.30 Light coma and depressed vital signs 0.40 Death


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InternalMed_Harrison. The cellular changes caused by chronic ethanol exposure may not resolve for several weeks or longer following cessation of drinking. Rapid decreases in blood alcohol levels before that time can produce a withdrawal syndrome, which is most intense during the first 5 days, but some symptoms (e.g., disturbed sleep and anxiety) can take up to 4–6 months to resolve.


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InternalMed_Harrison. Relatively low doses of alcohol (one or two drinks per day) have potential beneficial effects of increasing high-density lipoprotein cholesterol and decreasing aggregation of platelets, with a resulting decrease in risk for occlusive coronary disease and embolic strokes. Red wine has additional potential health-promoting qualities at relatively low doses due to flavinols and related substances. Modest drinking might also decrease the risk for vascular dementia and, possibly, Alzheimer’s disease. However, any potential healthful effects disappear with the regular consumption of three or more drinks per day, and knowledge about the deleterious effects of alcohol can both help the physician to identify patients with an alcohol use disorder and to supply them with information that might help motivate a change in behavior.


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InternalMed_Harrison. Approximately 35% of drinkers (and a much higher proportion of alcoholics) experience a blackout, an episode of temporary anterograde amnesia, in which the person forgets all or part of what occurred during a drinking evening. Another common problem, one seen after as few as one or two drinks shortly before bedtime, is disturbed sleep. Although alcohol might initially help a person fall asleep, it disrupts sleep throughout the rest of the night. The stages of sleep are altered, and time spent in rapid eye movement (REM) and deep sleep is reduced. Alcohol relaxes muscles in the pharynx, which can cause snoring and exacerbate sleep apnea; symptoms of the latter occur in 75% of alcoholic men older than age 60 years. Patients may also experience prominent and sometimes disturbing dreams later in the night. All of these sleep problems are more pronounced in alcoholics, and their persistence may contribute to relapse.


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InternalMed_Harrison. Another common consequence of alcohol use is impaired judgment and coordination, increasing the risk of injury. In the United States, ~40% of drinkers have at some time driven while intoxicated. Heavy drinking can also be associated with headache, thirst, nausea, vomiting, and fatigue the following day, a hangover syndrome that is responsible for much missed time and temporary cognitive deficits at work and school.


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InternalMed_Harrison. Chronic high doses cause peripheral neuropathy in ~10% of alcoholics: similar to diabetes, patients experience bilateral limb numbness, tingling, and paresthesias, all of which are more pronounced distally. Approximately 1% of alcoholics develop cerebellar degeneration or atrophy, producing a syndrome of progressive unsteady stance and gait often accompanied by mild nystagmus; neuroimaging studies reveal atrophy of the cerebellar vermis. Fortunately, very few alcoholics (perhaps as few as 1 in 500 for the full syndrome) develop Wernicke’s (ophthalmoparesis, ataxia, and encephalopathy) and Korsakoff’s (retrograde and anterograde amnesia) syndromes, although a higher proportion have one or more neuropathologic findings related to these conditions. These result from low levels of thiamine, especially in predisposed individuals with transketolase deficiencies. Alcoholics can manifest cognitive problems and temporary memory impairment lasting for weeks to months after drinking heavily for


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InternalMed_Harrison. in predisposed individuals with transketolase deficiencies. Alcoholics can manifest cognitive problems and temporary memory impairment lasting for weeks to months after drinking heavily for days or weeks. Brain atrophy, evident as ventricular enlargement and widened cortical sulci on magnetic resonance imaging (MRI) and computed tomography (CT) scans, occurs in ~50% of chronic alcoholics; these changes are usually reversible if abstinence is maintained. There is no single alcoholic dementia syndrome; rather, this label describes patients who have irreversible cognitive changes (possibly from diverse causes) in the context of chronic alcoholism.


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InternalMed_Harrison. Psychiatric Comorbidity As many as two-thirds of individuals with alcohol use disorders meet the criteria for another psychiatric syndrome in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association (Chap. 466). Half of these relate to a preexisting antisocial personality manifesting as impulsivity and disinhibition that contribute to both alcohol and drug use disorders. The lifetime risk is 3% in males, and ≥80% of such individuals demonstrate alcoholand/or drug-related conditions. Another common comorbidity occurs with problems regarding illicit substances. The remainder of alcoholics with psychiatric syndromes have preexisting conditions such as schizophrenia or manic-depressive disease and anxiety syndromes such as panic disorder. The comorbidities of alcoholism with independent psychiatric disorders might represent an overlap in genetic vulnerabilities, impaired judgment in the use of alcohol from the


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InternalMed_Harrison. such as panic disorder. The comorbidities of alcoholism with independent psychiatric disorders might represent an overlap in genetic vulnerabilities, impaired judgment in the use of alcohol from the independent psychiatric condition, or an attempt to use alcohol to alleviate symptoms of the disorder or side effects of medications.


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InternalMed_Harrison. Many psychiatric syndromes can be seen temporarily during heavy drinking and subsequent withdrawal. These alcohol-induced conditions include an intense sadness lasting for days to weeks in the midst of heavy drinking seen in 40% of alcoholics, which tends to disappear over several weeks of abstinence (alcohol-induced mood disorder); temporary severe anxiety in 10–30% of alcoholics, often beginning during alcohol withdrawal, which can persist for a month or more after cessation of drinking (alcohol-induced anxiety disorder); and auditory hallucinations and/or paranoid delusions in a person who is alert and oriented, seen in 3–5% of alcoholics (alcohol-induced psychotic disorder).


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InternalMed_Harrison. Treatment of all forms of alcohol-induced psychopathology includes helping patients achieve abstinence and offering supportive care, as well as reassurance and “talk therapy” such as cognitive-behavioral approaches. However, with the exception of short-term antipsychotics or similar drugs for substance-induced psychoses, substance-induced psychiatric conditions only rarely require medications. Recovery is likely within several days to 4 weeks of abstinence. Conversely, because alcohol-induced conditions are temporary and do not indicate a need for long-term pharmacotherapy, a history of alcohol intake is an important part of the workup for any patient with one of these psychiatric symptoms.


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InternalMed_Harrison. THE GASTROINTESTINAL SYSTEM Esophagus and Stomach Alcohol can cause inflammation of the esophagus and stomach causing epigastric distress and gastrointestinal bleeding, making alcohol one of the most common causes of hemorrhagic gastritis. Violent vomiting can produce severe bleeding through a Mallory-Weiss lesion, a longitudinal tear in the mucosa at the gastroesophageal junction.


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InternalMed_Harrison. Pancreas and Liver The incidence of acute pancreatitis (~25 per 1000 per year) is almost threefold higher in alcoholics than in the general population, accounting for an estimated 10% or more of the total cases. Alcohol impairs gluconeogenesis in the liver, resulting in a fall in the amount of glucose produced from glycogen, increased lactate production, and decreased oxidation of fatty acids. This contributes to an increase in fat accumulation in liver cells. In healthy individuals these changes are reversible, but with repeated exposure to ethanol, especially daily heavy drinking, more severe changes in the liver occur, including alcohol-induced hepatitis, perivenular sclerosis, and cirrhosis, with the latter observed in an estimated 15% of alcoholics (Chap. 363). Perhaps through an enhanced vulnerability to infections, alcoholics have an elevated rate of hepatitis C, and drinking in the context of that disease is associated with more severe liver deterioration.


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InternalMed_Harrison. As few as 1.5 drinks per day increases a woman’s risk of breast cancer 1.4-fold. For both genders, four drinks per day increases the risk for oral and esophageal cancers approximately threefold and rectal cancers by a factor of 1.5; seven to eight or more drinks per day produces an approximately fivefold increased risk for many cancers. These consequences may result directly from cancer-promoting effects of alcohol and acetaldehyde or indirectly by interfering with immune homeostasis.


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InternalMed_Harrison. Ethanol causes an increase in red blood cell size (mean corpuscular volume [MCV]), which reflects its effects on stem cells. If heavy drinking is accompanied by folic acid deficiency, there can also be 2725 hypersegmented neutrophils, reticulocytopenia, and a hyperplastic bone marrow; if malnutrition is present, sideroblastic changes can be observed. Chronic heavy drinking can decrease production of white blood cells, decrease granulocyte mobility and adherence, and impair delayed-hypersensitivity responses to novel antigens (with a possible false-negative tuberculin skin test). Associated immune deficiencies can contribute to vulnerability toward infections, including hepatitis and HIV, and interfere with their treatment. Finally, many alcoholics have mild thrombocytopenia, which usually resolves within a week of abstinence unless there is hepatic cirrhosis or congestive splenomegaly.


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InternalMed_Harrison. Acutely, ethanol decreases myocardial contractility and causes peripheral vasodilation, with a resulting mild decrease in blood pressure and a compensatory increase in cardiac output. Exercise-induced increases in cardiac oxygen consumption are higher after alcohol intake. These acute effects have little clinical significance for the average healthy drinker but can be problematic when persisting cardiac disease is present.


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InternalMed_Harrison. The consumption of three or more drinks per day results in a dose-dependent increase in blood pressure, which returns to normal within weeks of abstinence. Thus, heavy drinking is an important factor in mild to moderate hypertension. Chronic heavy drinkers also have a sixfold increased risk for coronary artery disease, related, in part, to increased low-density lipoprotein cholesterol, and carry an increased risk for cardiomyopathy through direct effects of alcohol on heart muscle. Symptoms of the latter include unexplained arrhythmias in the presence of left ventricular impairment, heart failure, hypocontractility of heart muscle, and dilation of all four heart chambers with associated mural thrombi and mitral valve regurgitation. Atrial or ventricular arrhythmias, especially paroxysmal tachycardia, can also occur temporarily after heavy drinking in individuals showing no other evidence of heart disease—a syndrome known as the “holiday heart.”


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InternalMed_Harrison. GENITOURINARY SYSTEM CHANGES, SEXUAL FUNCTIONING, AND FETAL DEVELOPMENT Drinking in adolescence can affect normal sexual development and reproductive onset. At any age, modest ethanol doses (e.g., blood alcohol concentrations of 0.06 g/dL) can increase sexual drive but also decrease erectile capacity in men. Even in the absence of liver impairment, a significant minority of chronic alcoholic men show irreversible testicular atrophy with shrinkage of the seminiferous tubules, decreases in ejaculate volume, and a lower sperm count (Chap. 411).


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InternalMed_Harrison. The repeated ingestion of high doses of ethanol by women can result in amenorrhea, a decrease in ovarian size, absence of corpora lutea with associated infertility, and an increased risk of spontaneous abortion. Heavy drinking during pregnancy results in the rapid placental transfer of both ethanol and acetaldehyde, which may contribute to a range of consequences known as fetal alcohol spectrum disorder (FASD). One severe result is the fetal alcohol syndrome (FAS), seen in ~5% of children born to heavy-drinking mothers, which can include any of the following: facial changes with epicanthal eye folds; poorly formed ear concha; small teeth with faulty enamel; cardiac atrial or ventricular septal defects; an aberrant palmar crease and limitation in joint movement; and microcephaly with mental retardation. Less pervasive FASD conditions include combinations of low birth weight, a lower intelligence quotient (IQ), hyperactive behavior, and some modest cognitive deficits. The amount of


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InternalMed_Harrison. retardation. Less pervasive FASD conditions include combinations of low birth weight, a lower intelligence quotient (IQ), hyperactive behavior, and some modest cognitive deficits. The amount of ethanol required and the time of vulnerability during pregnancy have not been defined, making it advisable for pregnant women to abstain completely.


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InternalMed_Harrison. Between one-half and two-thirds of alcoholics have skeletal muscle weakness caused by acute alcoholic myopathy, a condition that improves but which might not fully remit with abstinence. Effects of repeated heavy drinking on the skeletal system include changes in calcium metabolism, lower bone density, and decreased growth in the epiphyses, leading to an increased risk for fractures and osteonecrosis of the femoral head. Hormonal changes include an increase in cortisol 2726 levels, which can remain elevated during heavy drinking; inhibition of vasopressin secretion at rising blood alcohol concentrations and enhanced secretion at falling blood alcohol concentrations (with the final result that most alcoholics are likely to be slightly overhydrated); a modest and reversible decrease in serum thyroxine (T4); and a more marked decrease in serum triiodothyronine (T3). Hormone irregularities should be reevaluated because they may disappear after a month of abstinence.


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InternalMed_Harrison. Because many drinkers occasionally imbibe to excess, temporary alcohol-related problems are common in nonalcoholics, especially in the late teens to the late twenties. However, repeated problems in multiple life areas can indicate an alcohol use disorder as defined in DSM-5. An alcohol use disorder is defined as repeated alcohol-related difficulties in at least 2 of 11 life areas that cluster together in the same 12-month period (Table 467-2). Ten of the 11 items were taken directly from the 7 dependence and 4 abuse criteria in DSM-IV, after deleting legal problems and adding craving. Severity of an alcohol use disorder is based on the number of items endorsed: mild is two or three items; moderate is four or five; and severe is six or more of the criterion items. The new diagnostic approach is similar enough to DSM-IV that the following descriptions of associated phenomena are still accurate.


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InternalMed_Harrison. The lifetime risk for an alcohol use disorder in most Western countries is about 10–15% for men and 5–8% for women. Rates are similar in the United States, Canada, Germany, Australia, and the United Kingdom, tend to be lower in most Mediterranean countries, such as Italy, Greece, and Israel, and may be higher in Ireland, France, and Scandinavia. An even higher lifetime prevalence has been reported for most native cultures, including American Indians, Eskimos, Maori groups, and aboriginal tribes of Australia. These differences reflect both cultural and genetic influences, as described below. In Western countries, the typical alcoholic is more often a blueor white-collar worker or homemaker. The lifetime risk for alcoholism among physicians is similar to that of the general population.


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InternalMed_Harrison. Approximately 60% of the risk for alcohol use disorders is attributed to genes, as indicated by the fourfold higher risk in children of alcoholics (even if adopted early in life and raised by nonalcoholics) and a higher risk in identical twins compared to fraternal twins of alcoholics. The genetic variations operate primarily through intermediate DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS, fifth eDitioN, CLassifiCatioN of aLCohoL use DisorDer (auD) Two or more of the following items occurring in the same 12-month period must be endorsed for the diagnosis of an alcohol use disordera: Drinking resulting in recurrent failure to fulfill role obligations


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InternalMed_Harrison. Tolerance Withdrawal, or substance use for relief/avoidance of withdrawal Drinking in larger amounts or for longer than intended Persistent desire/unsuccessful attempts to stop or reduce drinking Great deal of time spent obtaining, using, or recovering from alcohol Important activities given up/reduced because of drinking Continued drinking despite knowledge of physical or psychological problems caused by alcohol Alcohol craving aMild AUD: 2–3 criteria required; Moderate AUD: 4–5 items endorsed; severe AUD: 6 or more items endorsed.


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InternalMed_Harrison. characteristics that subsequently combine with environmental influences to alter the risk for heavy drinking and alcohol problems. These include genes relating to a high risk for all substance use disorders that operate through impulsivity, schizophrenia, and bipolar disorder. Another characteristic, an intense flushing response when drinking, decreases the risk for only alcohol use disorders through gene variations for several alcohol-metabolizing enzymes, especially aldehyde dehydrogenase (a mutation only seen in Asians), and to a lesser extent, variations in ADH.


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InternalMed_Harrison. An additional genetically influenced characteristic, a low sensitivity to alcohol, affects the risk for heavy drinking and may operate, in part, through variations in genes relating to calcium and potassium channels, GABA, nicotinic, and serotonin systems. A low response per drink is observed early in the drinking career and before alcohol use disorders develop. All follow-up studies have demonstrated that this need for higher doses of alcohol to achieve effects predicts future heavy drinking, alcohol problems, and alcohol use disorders. The impact of a low response to alcohol on adverse drinking outcomes is partially mediated by a range of environmental influences, including the selection of heavier-drinking friends, more positive expectations of the effects of high doses of alcohol, and suboptimal ways of coping with stress.


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InternalMed_Harrison. Although the age of the first drink (~15 years) is similar in most alcoholics and nonalcoholics, a slightly earlier onset of regular drinking and drunkenness, especially in the context of conduct problems, is associated with a higher risk for later alcohol use disorders. By the mid-twenties, most nonalcoholic men and women moderate their drinking (perhaps learning from problems), whereas alcoholics are likely to escalate their patterns of drinking despite difficulties. The first major life problem from alcohol often appears in the late teens to early twenties, and a pattern of multiple alcohol difficulties by the midtwenties. Once established, the course of alcoholism is likely to include exacerbations and remissions, with little difficulty in temporarily stopping or controlling alcohol use when problems develop, but without help, desistance usually gives way to escalations in alcohol intake and subsequent problems. Following treatment, between half and two-thirds of alcoholics


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InternalMed_Harrison. use when problems develop, but without help, desistance usually gives way to escalations in alcohol intake and subsequent problems. Following treatment, between half and two-thirds of alcoholics maintain abstinence for years, and often permanently. Even without formal treatment or self-help groups, there is at least a 20% chance of spontaneous remission with long-term abstinence. However, should the alcoholic continue to drink heavily, the life span is shortened by ~10 years on average, with the leading causes of death being heart disease, cancer, accidents, and suicide.


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InternalMed_Harrison. The approach to treating alcohol-related conditions is relatively straightforward: (1) recognize that at least 20% of all patients have an alcohol use disorder; (2) learn how to identify and treat acute alcohol-related conditions; (3) know how to help patients begin to address their alcohol problems; and (4) know enough about treating alcoholism to appropriately refer patients for additional help.


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InternalMed_Harrison. Even in affluent locales, ~20% of patients have an alcohol use disorder. These men and women can be identified by asking questions about alcohol problems and noting laboratory test results that can reflect regular consumption of six to eight or more drinks per day. The two blood tests with ≥60% sensitivity and specificity for heavy alcohol consumption are γ-glutamyl transferase (GGT) (>35 U) and carbohydrate-deficient transferrin (CDT) (>20 U/L or >2.6%); the combination of the two is likely to be more accurate than either alone. The values for these serologic markers are likely to return toward normal within several weeks of abstinence. Other useful blood tests include high-normal MCVs (≥91 μm3) and serum uric acid (>416 mol/L, or 7 mg/dL).


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InternalMed_Harrison. The diagnosis of an alcohol use disorder ultimately rests on the documentation of a pattern of repeated difficulties associated with alcohol (Table 467-2). Thus, in screening, it is important to probe for marital or job problems, legal difficulties, histories of accidents, medical problems, evidence of tolerance, and so on, and then attempt to tie in use 5-Point Scale Item (Least to Most) 1. How often do you have a drink containing alcohol? 2. How many drinks containing alcohol do you have on a typical day? 3. How often do you have six or more drinks on one occasion? 4. How often during the last year have you found that you were not able to stop drinking once you had started? 5. How often during the last year have you failed to do what was normally expected from you because of drinking? 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? 7.


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InternalMed_Harrison. 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? 7. How often during the last year have you had a feeling of guilt or remorse after drinking? 8. How often during the last year have you been unable to remember what happened the night before because you had been drinking? 9. Have you or someone else been injured as a result of your drinking? 10. Has a relative, friend, doctor or other health worker been concerned about your drinking or suggested that you should cut down? Never (0) to 4+ per week (4) 1 or 2 (0) to 10+ (4) Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) No (0) to yes, during the last year (4)


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InternalMed_Harrison. Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) Never (0) to daily or almost daily (4) No (0) to yes, during the last year (4) No (0) to yes, during the last year (4) aThe AUDIT is scored by simply summing the values associated with the endorsed response. A score ≥8 may indicate harmful alcohol use. of alcohol or another substance. Some standardized questionnaires can be helpful, including the 10-item Alcohol Use Disorders Identification Test (AUDIT) (Table 467-3), but these are only screening tools, and a face-to-face interview is still required for a meaningful diagnosis.


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InternalMed_Harrison. The first priority in treating severe intoxication is to assess vital signs and manage respiratory depression, cardiac arrhythmias, or blood pressure instability, if present. The possibility of intoxication with other drugs should be considered by obtaining toxicology screens for other central nervous system (CNS) depressants such as benzodiazepines and for opioids. Aggressive behavior should be handled by offering reassurance but also by considering a possible show of force with an intervention team. If the aggressive behavior continues, relatively low doses of a short-acting benzodiazepine such as lorazepam (e.g., 1–2 mg PO or IV) may be used and can be repeated as needed, but care must be taken not to destabilize vital signs or worsen confusion. An alternative approach is to use an anti-psychotic medication (e.g., 0.5–5 mg of haloperidol PO or IM every 4–8 h as needed, or olanzapine 2.5–10 mg IM repeated at 2 and 6 h, if needed).


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InternalMed_Harrison. There are two main elements to intervention in a person with alcoholism: motivational interviewing and brief interventions. During motivational interviewing, the clinician helps the patient to think through the assets (e.g., comfort in social situations) and liabilities (e.g., healthand interpersonal-related problems) of the current pattern of drinking. The patient’s responses are key, and the clinician should listen empathetically, helping to weigh options and encouraging the patient to take responsibility for needed changes. Patients should be reminded that only they can decide to avoid the consequences that will occur without changes in drinking. The 2727 process of brief intervention has been summarized by the acronym FRAMES: Feedback to the patient; Responsibility to be taken by the patient; Advice, rather than orders, on what needs to be done; Menus of options that might be considered; Empathy for understanding the patient’s thoughts and feelings; and Self-efficacy, i.e.,


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InternalMed_Harrison. the patient; Advice, rather than orders, on what needs to be done; Menus of options that might be considered; Empathy for understanding the patient’s thoughts and feelings; and Self-efficacy, i.e., offering support for the capacity of the patient to make changes.


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InternalMed_Harrison. Once the patient begins to consider change, the emphasis shifts to brief interventions designed to help them understand more about potential actions. Discussions focus on consequences of high alcohol consumption, suggested approaches to stopping drinking, and help in recognizing and avoiding situations likely to lead to heavy drinking. Both motivational interviewing and brief interventions can be carried out in 15-min sessions, but because patients do not always change behavior immediately, multiple meetings are often required to explain the problem, discuss optimal treatments, and explain the benefits of abstinence.


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InternalMed_Harrison. If the patient agrees to stop drinking, sudden decreases in alcohol intake can produce withdrawal symptoms, many of which are the opposite of those produced by intoxication. Features include tremor of the hands (shakes); agitation and anxiety; autonomic nervous system overactivity including an increase in pulse, respiratory rate, sweating, and body temperature; and insomnia. These symptoms usually begin within 5–10 h of decreasing ethanol intake, peak on day 2 or 3, and improve by day 4 or 5, although mild levels of these problems may persist for 4–6 months as a protracted abstinence syndrome.


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InternalMed_Harrison. About 2% of alcoholics experience a withdrawal seizure, with the risk increasing in the context of concomitant medical problems, misuse of additional drugs, and higher alcohol quantities. The same risk factors also contribute to a similar rate of delirium tremens (DTs), where the withdrawal includes delirium (mental confusion, agitation, and fluctuating levels of consciousness) associated with a tremor and autonomic overactivity (e.g., marked increases in pulse, blood pressure, and respirations). The risks for seizures and DTs can be diminished by identifying and treating any underlying medical conditions early in the course of withdrawal.


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InternalMed_Harrison. Thus, the first step is a thorough physical examination in all alcoholics considering abstinence, including a search for evidence of liver failure, gastrointestinal bleeding, cardiac arrhythmia, infection, and glucose or electrolyte imbalances. It is also important to offer adequate nutrition and oral multiple B vitamins, including 50–100 mg of thiamine daily for a week or more. Because most alcoholics who enter withdrawal are either normally hydrated or mildly overhydrated, IV fluids should be avoided unless there is a relevant medical problem or significant recent bleeding, vomiting, or diarrhea.


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InternalMed_Harrison. The next step is to recognize that because withdrawal symptoms reflect the rapid removal of a CNS depressant, alcohol, the symptoms can be controlled by administering any depressant in doses that decrease symptoms (e.g., a rapid pulse and tremor) and then tapering the dose over 3–5 days. Although most depressants are effective, benzodiazepines (Chap. 466) have the highest margin of safety and lowest cost and are, therefore, the preferred class of drugs. Short-half-life benzodiazepines can be considered for patients with serious liver impairment or evidence of significant brain damage, but they must be given every 4 h to avoid abrupt blood-level fluctuations that may increase the risk for seizures. Therefore, most clinicians use drugs with longer half-lives (e.g., chlordiazepoxide), adjusting the dose if signs of withdrawal escalate, and withholding the drug if the patient is sleeping or has orthostatic hypotension. The average patient requires 25–50 mg of chlordiazepoxide or 10 mg of


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InternalMed_Harrison. the dose if signs of withdrawal escalate, and withholding the drug if the patient is sleeping or has orthostatic hypotension. The average patient requires 25–50 mg of chlordiazepoxide or 10 mg of diazepam given PO every 4–6 h on the first day, with doses then decreased to zero over the next 5 days. Although alcohol withdrawal can be treated in a hospital, patients in good physical condition who demonstrate mild signs of withdrawal despite low blood alcohol concentrations and who have no prior history of DTs or withdrawal seizures can be considered for outpatient detoxification. For the next 2728 4 or 5 days, these patients should return daily for evaluation of vital signs and can be hospitalized if signs and symptoms of withdrawal escalate.


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InternalMed_Harrison. Treatment of patient with DTs can be challenging, and the condition is likely to run a course of 3–5 days regardless of the therapy used. The focus of care is to identify and correct medical problems and to control behavior and prevent injuries. Many clinicians recommend the use of high doses of a benzodiazepine (as much as 800 mg/d of chlordiazepoxide has been reported), a treatment that will decrease agitation and raise the seizure threshold but probably does little to improve the confusion. Other clinicians recommend the use of antipsychotic medications, such as haloperidol or olanzapine as discussed above, although these drugs have not been directly evaluated for DTs. Antipsychotics are less likely to exacerbate confusion but may increase the risk of seizures; they have no place in the treatment of mild withdrawal symptoms.


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InternalMed_Harrison. Generalized withdrawal seizures rarely require more than giving an adequate dose of benzodiazepines. There is little evidence that anticonvulsants such as phenytoin or gabapentin are more effective in drug-withdrawal seizures, and the risk of seizures has usually passed by the time effective drug levels are reached. The rare patient with status epilepticus must be treated aggressively (Chap. 445).


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InternalMed_Harrison. REHABILITATION OF ALCOHOLICS An Overview After completing alcoholic rehabilitation, ≥60% of alcoholics, especially middle-class patients, maintain abstinence for at least a year, and many achieve lifetime sobriety. The core of treatment uses cognitive-behavioral approaches to help patients recognize the need to change, while working with them to alter their behaviors to enhance compliance. A key step is to optimize motivation toward abstinence through education about alcoholism and instructions to family members to stop protecting the patient from problems caused by alcohol. After years of heavy drinking, many patients also need counseling, some require vocational or avocational help to structure their days, and all should try self-help groups such as Alcoholics Anonymous (AA) to help them develop a sober peer group and learn how to deal with life’s stresses while sober. A third component, relapse prevention, helps the patient identify situations in which a return to drinking is


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InternalMed_Harrison. them develop a sober peer group and learn how to deal with life’s stresses while sober. A third component, relapse prevention, helps the patient identify situations in which a return to drinking is likely, formulate ways of managing these risks, and develop coping strategies that increase the chances of a return to abstinence if a slip occurs.


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InternalMed_Harrison. Although many can be treated as outpatients, more intense interventions are more effective, and some alcoholics do not respond to AA or outpatient groups. Whatever the setting, subsequent contact with outpatient treatment staff should be maintained for at least 6 months and preferably a year after abstinence. Counseling focuses on areas of improved functioning in the absence of alcohol (i.e., why it is a good idea to continue abstinence) and helping the patient to manage free time without alcohol, develop a nondrinking peer group, and handle stresses.


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InternalMed_Harrison. The physician serves an important role in identifying the alcoholic, diagnosing and treating associated medical and psychiatric syndromes, overseeing detoxification, referring the patient to rehabilitation programs, providing counseling, and, if appropriate, selecting which (if any) medication might be needed. For insomnia, patients should be reassured that troubled sleep is normal after alcohol withdrawal and will improve over subsequent weeks. They should be taught the elements of “sleep hygiene” including maintaining consistent schedules for bedtime and awakening. Sleep medications have the danger of being misused and of rebound insomnia when stopped. Sedating antidepressants (e.g., trazodone) should not be used because they interfere with cognitive functioning the next morning and disturb the normal sleep architecture, but occasional use of over-the-counter sleeping medications (sedating antihistamines) can be considered. Anxiety can be addressed by increasing the patient’s


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InternalMed_Harrison. disturb the normal sleep architecture, but occasional use of over-the-counter sleeping medications (sedating antihistamines) can be considered. Anxiety can be addressed by increasing the patient’s insight into the temporary nature of the symptoms and helping the patient to develop strategies to achieve relaxation by using forms of cognitive therapy.


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InternalMed_Harrison. Medications for Rehabilitation Several medications have modest benefits when used for the first 6 months of recovery. The opioid antagonist, naltrexone, 50–150 mg/d orally, may shorten subsequent relapses, whether used in the oral form or as a once-per-month 380-mg injection, especially in individuals with the G allele of the AII8G polymorphism of the μ opioid receptor. By blocking opioid receptors, naltrexone decreases activity in the dopamine-rich ventral tegmental reward system and decreases the feeling of pleasure if alcohol is imbibed. A second medication, acamprosate (Campral) at ~2 g/d divided into three oral doses, has similar modest effects; acamprosate inhibits NMDA receptors, decreasing mild symptoms of protracted withdrawal. Several trials of combined naltrexone and acamprosate have reported that the combination may be superior to either drug alone, although not all studies agree.


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InternalMed_Harrison. It is more difficult to establish the asset-to-liability ratio of a third drug, disulfiram, an ALDH inhibitor, used at doses of 250 mg/d. This drug produces vomiting and autonomic nervous system instability in the presence of alcohol as a result of rapidly rising blood levels of acetaldehyde. This reaction can be dangerous, especially for patients with heart disease, stroke, diabetes mellitus, or hypertension. The drug itself carries potential risks of depression, psychotic symptoms, peripheral neuropathy, and liver damage. Disulfiram is best given under supervision by someone (such as a spouse), especially during high-risk drinking situations (such as the Christmas holiday). Other drugs under investigation include another opioid antagonist nalmefene, the nicotinic receptor agonist varenicline, the serotonin antagonist ondansetron, the α-adrenergic agonist prazosin, the GABAB receptor agonist baclofen, the anticonvulsant topiramate, and cannabinol receptor antagonists. At present,


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InternalMed_Harrison. the serotonin antagonist ondansetron, the α-adrenergic agonist prazosin, the GABAB receptor agonist baclofen, the anticonvulsant topiramate, and cannabinol receptor antagonists. At present, there are insufficient data to determine the asset-to-liability ratio for these medications in treating alcoholism and, therefore, no data to offer solid support for their use in routine clinical settings.


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InternalMed_Harrison. As described above, rates of alcohol use disorders differ across sex, age, ethnicity, and country. There are also differences across countries regarding the definition of a standard drink (e.g., 10–12 g of ethanol in the United States and 8 g in the United Kingdom) and the definition of being legally drunk. The preferred alcoholic beverage also varies across groups, even within countries. That said, regardless of sex, ethnicity, or country, the actual drug in the drink is still ethanol, and the risks for problems, course of alcohol use disorders, and approaches to treatment are similar across the world. Thomas R. Kosten, Colin N. Haile this is a digital-only chapter. it is available on the DvD that accompanies this book, as well as on access medicine/harrison’s online, and the eBook and “app” editions of hpim 19e.


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InternalMed_Harrison. Opiate analgesics have been abused since at least 300 b.c. Nepenthe (Greek “free from sorrow”) helped the hero of the Odyssey, but widespread opium smoking in China and the Near East has caused harm for centuries. Since the first chemical isolation of opium and codeine 200 years ago, a wide range of synthetic opioids have been developed, and opioid receptors were cloned in the 1990s. Two of the most important adverse effects of all these agents are the development of opioid use disorder and overdose. The 0.1% annual prevalence of heroin dependence in the United States is only about one-third the rate of prescription opiate use and is substantially lower than the 2% rate of morphine users in Southeast and Southwest Asia.


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InternalMed_Harrison. Opioid-related Disorders Thomas R. Kosten, Colin N. Haile Opiate analgesics have been abused since at least 300 b.c. Nepenthe (Greek “free from sorrow”) helped the hero of the Odyssey, but widespread opium smoking in China and the Near East has caused harm for centuries. Since the first chemical isola-468e tion of opium and codeine 200 years ago, a wide range of synthetic opioids have been developed, and opioid receptors were cloned in the 1990s. Two of the most important adverse effects of all these agents are the development of opioid use disorder and overdose. The 0.1% annual prevalence of heroin dependence in the United States is only about one-third the rate of prescription opiate use and is substantially lower than the 2% rate of morphine users in Southeast and Southwest Asia. Prescription opiates are primarily used for pain management, but due to ease of availability, adolescents procure and use these drugs with dire consequences. In 2011, for example, 11 million individuals in


InternalMed_Harrison

InternalMed_Harrison. opiates are primarily used for pain management, but due to ease of availability, adolescents procure and use these drugs with dire consequences. In 2011, for example, 11 million individuals in the United States used nonmedically prescribed pain killers that were linked to over 420,000 emergency department visits and nearly 17,000 overdose deaths. Although these rates are low relative to other abused substances, their disease burden is substantial, with high rates of morbidity and mortality; disease transmission; increased health care, crime, and law enforcement costs; and less tangible costs of family distress and lost productivity.


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InternalMed_Harrison. The terms “dependence” and “addiction” are no longer used to describe substance use disorders. Opioid-related disorders encompass opioid use disorder, opioid intoxication, and opioid withdrawal. The diagnosis of opioid use disorder as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) requires the repeated use of the opiate while producing problems in two or more areas in a 12-month period. The areas include tolerance, withdrawal, use of greater amounts of opiates than intended, craving, and use despite adverse consequences. This new definition of opiate use disorder, reducing the criteria for diagnosis from three problem areas to two, is not expected to change the rates of these disorders because most individuals using these substances meet more than three criteria.


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InternalMed_Harrison. A striking recent aspect of illicit opiate use has been its marked increase as the gateway to illicit drugs in the United States. Since 2007, prescription opiates have surpassed marijuana as the most common illicit drug that adolescents initially use, although overall rates of opiate dependence are far lower than marijuana. The most commonly used opiates are diverted prescriptions for oxycodone and hydrocodone, followed by heroin and morphine, and—among health professionals—meperidine and fentanyl. Heroin is derived from morphine and acts as a prodrug that more readily penetrates the brain and is converted rapidly to morphine in the body. Two opiate maintenance treatment agents—methadone and buprenorphine—are also misused, but at substantially lower rates, and the partial opiate agonists such as butorphanol, tramadol, and pentazocine are misused even less frequently. Because the chemistry and general pharmacology of these agents are covered in major pharmacology texts, this chapter


InternalMed_Harrison

InternalMed_Harrison. such as butorphanol, tramadol, and pentazocine are misused even less frequently. Because the chemistry and general pharmacology of these agents are covered in major pharmacology texts, this chapter focuses on the neurobiology and pharmacology relevant to dependence and its treatments. Although the neurobiology of abuse involves all four of the known opiate receptors—mu, kappa, delta, and nociceptin/orphanin—this discussion focuses on the mu receptor, at which most of the clinically used opiates are active.


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InternalMed_Harrison. The neurobiology of opiates and their effects not only include opiate receptors, but also the downstream intracellular messenger systems and ion channels that the receptors regulate. The different functional activities of opiate receptors are summarized in Table 468e-1. Abuse liability of opiates is primarily associated with the mu receptor. All opiate receptors are G protein–linked and coupled to the cyclic adenosine monophosphate (cAMP) second messenger system and to G protein– coupled, inwardly rectifying potassium channels (GIRKs). Opiates activate GIRKs, increasing permeability to potassium ions to cause Mu (μ) (e.g., morphine, Analgesia, reinforcement euphoria, cough and buprenorphine) appetite suppression, decreased respirations, decreased GI motility, sedation, hormone changes, dopamine and acetylcholine release Kappa (κ) (e.g., butorphanol) Dysphoria, decreased GI motility, decreased appetite, decreased respiration, psychotic symptoms, sedation, diuresis, analgesia


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InternalMed_Harrison. Kappa (κ) (e.g., butorphanol) Dysphoria, decreased GI motility, decreased appetite, decreased respiration, psychotic symptoms, sedation, diuresis, analgesia Delta (δ) (e.g., etorphine) Analgesia, euphoria, physical dependence, Hormone changes, appetite suppression, Nociceptin/orphanin (e.g., Analgesia, appetite, anxiety, tolerance to opi buprenorphine) oids, hypotension, decreased GI motility, 5-HT Abbreviations: GI, gastrointestinal; 5-HT, serotonin; NE, norepinephrine. hyperpolarization, which inhibits the production of action potentials. Thus, opiates inhibit the activity of diverse and widely distributed neuronal types. The major effects of opiates, such as analgesia, sedation, and drug reinforcement are produced through this inhibition of neurons that belong to specific brain pathways.


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InternalMed_Harrison. Many opiate actions are related to the specific neuroanatomic locations of mu receptors. Reinforcing and euphoric effects of opiates occur in the mesolimbic dopaminergic pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), where opiates increase synaptic levels of dopamine. This increase is due to inhibition of GABAergic neurons that inhibit both the activity of neurons within the VTA and the NAc. The positive subjective effects of opioid drugs also include mu receptor desensitization and internalization, potentially related to stimulation of beta-arrestin signalizing pathways. However, the “high” only occurs when the rate of change in dopamine is fast. Large, rapidly administered doses of opiates block γ-aminobutyric acid (GABA) inhibition and produce a burst of VTA dopamine neuron activity that is associated with “high” in all abused drugs. Therefore, routes of administration that slowly increase opiate blood and brain levels, such as oral and transdermal


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InternalMed_Harrison. VTA dopamine neuron activity that is associated with “high” in all abused drugs. Therefore, routes of administration that slowly increase opiate blood and brain levels, such as oral and transdermal routes, are effective for analgesia and sedation but do not produce an opiate “high” that follows smoking and intravenous routes. Other acute effects such as analgesia and respiratory depression involve opiate receptors located in other brain areas such as the locus coeruleus (LC).


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InternalMed_Harrison. Opiate tolerance and withdrawal are chronic effects related to the cAMP-protein kinase A (PKA)-cAMP response-element binding protein (CREB) intracellular cascade (Fig. 468e-1). These effects are also reflective of genetic risk factors for developing opiate use disorder, with estimates of up to 50% of the risk for dependence due to polygenic inheritance. Specific functional polymorphisms in the mu opiate receptor gene appear to be associated with this risk for opiate abuse, including one producing a threefold increase in this receptor’s affinity for opiates and the endogenous ligand beta endorphin. Epigenetic methylation changes also occur on the DNA of the mu receptor gene of opiate addicts, inhibiting gene transcription. This molecular cascade links acute intoxication and sedation to opiate tolerance and withdrawal mediated by the LC. Noradrenergic neurons in the LC mediate activation of the cortical hemispheres. When large opiate doses saturate and activate all of its mu receptors,


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InternalMed_Harrison. tolerance and withdrawal mediated by the LC. Noradrenergic neurons in the LC mediate activation of the cortical hemispheres. When large opiate doses saturate and activate all of its mu receptors, action potentials cease. When this direct inhibitory effect is sustained over weeks and months of opiate use, a secondary set of adaptive changes occur that lead to tolerance and withdrawal symptoms (Fig. 468e-1). Withdrawal symptoms reflect, in part, overactivity of norepinephrine (NE) neurons in the LC. This molecular model of NE neuronal activation during withdrawal has had important treatment implications, such as the use of the alpha-2 agonist clonidine to treat opioid withdrawal. Other contributors to withdrawal include deficits within the dopamine reward system.


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InternalMed_Harrison. Tolerance and withdrawal commonly occur with chronic daily use, developing as quickly as 6–8 weeks depending on dose concentration B-endorphineenkephalinsK+Na+Na+K+˜˜Gi/oGi/oACcAMPcAMPNucleusNucleusPKAPKABDNFBDNFTHTHCREBCREBNCH3HHHOOHOABAC Modified gene expression, neuroplasticity, genetic effects


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InternalMed_Harrison. FIGURE 468e-1 Normal mu-receptor activation by endogenous opioids inhibits the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response-element binding protein (CREB) cascade in noradrenergic neurons within the locus coeruleus (A) through inhibitory Gi/o protein influence on adenylyl cyclase (AC). Similarly, acute exposure to opiates (e.g., morphine) inhibits this system, whereas chronic exposure to opiates (B) leads to upregulation of the cAMP pathway in an attempt to oppose opiate-induced inhibitory influence. Upregulation of this system is involved in opiate tolerance, and when the opiate is removed, unopposed noradrenergic neurotransmission is involved in opiate withdrawal. Upregulated PKA phosphorylates CREB, initiating the expression of various genes such as tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF). BDNF is implicated in long-term neuroplastic changes in response to chronic opiates.


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InternalMed_Harrison. and dosing frequency. Tolerance appears to be primarily a pharmacodynamic rather than pharmacokinetic effect, with relatively limited induction of cytochrome P450 or other liver enzymes. The metabolism of opiates occurs in the liver primarily through the cytochrome P450 systems of 2D6 and 3A4. They then are conjugated to glucuronic acid and excreted in small amounts in feces. The plasma half-lives generally range from 2.5 to 3 h for morphine and more than 22 h for methadone. The shortest half-lives of several minutes are for fentanyl-related opiates and the longest are for buprenorphine and its active metabolites, which can block opiate withdrawal for up to 3 days after a single dose. Tolerance to opioids leads to the need for increasing amounts of drugs to sustain the desired euphoric effects—as well as to avoid the discomfort of withdrawal. This combination has the expected consequence of strongly reinforcing dependence once it has started. Methadone taken chronically at maintenance


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InternalMed_Harrison. well as to avoid the discomfort of withdrawal. This combination has the expected consequence of strongly reinforcing dependence once it has started. Methadone taken chronically at maintenance doses is stored in the liver, which may reduce the occurrence of withdrawal between daily doses. The role of endogenous opioid peptides in tolerance and withdrawal is uncertain.


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InternalMed_Harrison. The clinical features of abuse are tied to route of administration and the rapidity of an opiate bolus in reaching the brain. Intravenous and smoked administration rapidly produces a bolus of high drug concentration in the brain. This bolus produces a “rush,” followed by euphoria, a feeling of tranquility, and sleepiness (“the nod”). Heroin produces effects that last 3–5 h, and several doses a day are required to forestall manifestations of withdrawal in chronic users. Symptoms of opioid withdrawal begin 8–10 h after the last dose; lacrimation, rhinorrhea, yawning, and sweating appear first. Restless sleep followed by weakness, chills, gooseflesh (“cold turkey”), nausea and vomiting, muscle aches, and involuntary movements (“kicking the habit”), hyperpnea, hyperthermia, and hypertension occur in later stages of the withdrawal syndrome. The acute course of withdrawal may last 7–10 days. A secondary phase of protracted abstinence lasts for 26–30 weeks and is characterized by


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InternalMed_Harrison. occur in later stages of the withdrawal syndrome. The acute course of withdrawal may last 7–10 days. A secondary phase of protracted abstinence lasts for 26–30 weeks and is characterized by hypotension, bradycardia, hypothermia, mydriasis, and decreased responsiveness of the respiratory center to carbon dioxide.


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InternalMed_Harrison. Besides the brain effects of opioids on sedation and euphoria and the combined brain and peripheral nervous system effects on analgesia, a wide range of other organs can be affected. The cough reflex is inhibited through the brain, leading to the use of some opiates as an antitussive, and nausea and vomiting are due to effects on the medulla. The release of several pituitary hormones is inhibited, including corticotropin-releasing factor (CRF) and luteinizing hormone, which reduces levels of cortisol and sex hormones and can lead to impaired stress responses and reduced libido. An increase in prolactin also contributes to the reduced sex drive in males. Two other hormones affected are thyrotropin, which is reduced, and growth hormone, which is increased. Respiratory depression results from opiate-induced insensitivity of brainstem neurons to increases in carbon dioxide, and in patients with pulmonary disease, this can result in clinically significant complications. In overdoses,


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InternalMed_Harrison. from opiate-induced insensitivity of brainstem neurons to increases in carbon dioxide, and in patients with pulmonary disease, this can result in clinically significant complications. In overdoses, aspiration pneumonia is common due to loss of the gag reflex. Opiates reduce gut motility, which is helpful for treating diarrhea, but can lead to nausea, constipation, and anorexia with weight loss. Deaths occurred in early methadone maintenance programs due to severe constipation and toxic megacolon. Opiates such as methadone may prolong QT intervals and lead to sudden death in some patients. Orthostatic hypotension may occur due to histamine release and peripheral blood vessel dilation, which is an opiate effect usefully applied to managing acute myocardial infarction. During opiate maintenance, interactions with other medications are of concern; these include inducers of the cytochrome P450 system (usually CYP3A4) such as rifampin and carbamazepine.


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InternalMed_Harrison. Heroin users in particular tend to use opiates intravenously and are likely to be polydrug users, also using alcohol, sedatives, cannabinoids, and stimulants. None of these other drugs are substitutes for opioids, but they have desired additive effects. Therefore, one needs to be sure that the person undergoing a withdrawal reaction is not also withdrawing from alcohol or sedatives, which might be more dangerous and more difficult to manage.


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InternalMed_Harrison. Intravenous opiate use carries with it the risk of serious complications. The common sharing of hypodermic syringes can lead to infections with hepatitis B and HIV/AIDS, among others. Bacterial infections can lead to septic complications such as meningitis, osteomyelitis, and abscesses in various organs. Off-target effects of opiates synthesized in illicit drug labs can lead to serious toxicity. For example, attempts to illicitly manufacture meperidine in the 1980s resulted in the production of a highly specific neurotoxin, MPTP, which produced parkinsonism in users (Chap. 449).


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InternalMed_Harrison. Lethal overdose is a relatively common complication of opiate use disorder. Rapid recognition and treatment with naloxone, a highly specific reversal agent that is relatively free of complications, is essential. The diagnosis is based on recognition of characteristic signs and symptoms, including shallow and slow respirations, pupillary miosis (mydriasis does not occur until significant brain anoxia supervenes), bradycardia, hypothermia, and stupor or coma. Blood or urine toxicology studies can confirm a suspected diagnosis, but immediate management must be based on clinical criteria. If naloxone is not administered, progression to respiratory and cardiovascular collapse leading to death occurs. At autopsy, cerebral edema and sometimes frothy pulmonary edema are generally found. Opiates generally do not produce seizures except for unusual cases of polydrug use with the opiate meperidine, with high doses of tramadol, or in the newborn.


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InternalMed_Harrison. Beyond the acute treatment of opiate overdose with naloxone, clinicians have two general treatment options: opioid maintenance or detoxification. Opioid agonist and partial agonist medications are commonly used for both maintenance and detoxification purposes. Alpha-2-adrenergic agonists are primarily used for detoxification. Antagonists are used to accelerate detoxification and then continued after detoxification to prevent relapse. Only the residential medication-free programs have had success that comes close to matching that of the medication-based programs. Success of the various treatment approaches is assessed as retention in treatment and reduced opioid and other drug use; secondary outcomes, such as reduced HIV risk behaviors, crime, psychiatric symptoms, and medical comorbidity, also indicate successful treatment.


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InternalMed_Harrison. Stopping opiates is much easier than preventing relapse. Longterm relapse prevention for opioid-dependent persons requires combined pharmacologic and psychosocial approaches. Chronic users tend to prefer pharmacologic approaches; those with shorter histories of drug abuse are more amenable to detoxification and psychosocial interventions.


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InternalMed_Harrison. Managing overdose requires naloxone and support of vital functions, including intubation if needed (Table 468e-2). If the overdose is due to buprenorphine, then naloxone might be required at total doses of 10 mg or greater, but primary buprenorphine overdose is nearly impossible because this agent is a partial opiate agonist, meaning that as the dose of buprenorphine is increased it has greater opiate antagonist than agonist activity. Thus, a 0.2-mg buprenorphine dose leads to analgesia and sedation, while a hundred times greater 20-mg dose produces profound opiate antagonism, precipitating opiate withdrawal in a person who was opiate dependent on morphine or methadone. It is important to recognize that the goal is to reverse the respiratory depression and not to administer so much naloxone that it precipitates opiate withdrawal. Because naloxone only lasts a few hours and most opiates last considerably longer, an IV naloxone drip with close monitoring is frequently employed to


InternalMed_Harrison

InternalMed_Harrison. naloxone that it precipitates opiate withdrawal. Because naloxone only lasts a few hours and most opiates last considerably longer, an IV naloxone drip with close monitoring is frequently employed to provide a continuous level of antagonism for 24–72 h depending on the opiate used in the overdose (e.g., morphine vs methadone). Whenever naloxone has only a limited effect, other sedative drugs that produce significant overdoses must be considered. The most common are benzodiazepines, which have produced overdoses and deaths in combination with buprenorphine. A specific antagonist for benzodiazepines—flumazenil at 0.2 mg/min—can be given to a maximum of 3 g/h, but it may precipitate seizures and increase intracranial pressure. Like naloxone, administration for a prolonged period is usually required because most benzodiazepines remain active for considerably longer than flumazenil. Support of vital functions may include oxygen and positive-pressure breathing, IV fluids, pressor agents for


InternalMed_Harrison

InternalMed_Harrison. because most benzodiazepines remain active for considerably longer than flumazenil. Support of vital functions may include oxygen and positive-pressure breathing, IV fluids, pressor agents for hypotension, and cardiac monitoring to detect QT prolongation, which might require specific treatment. Activated


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InternalMed_Harrison. Establish airway. Intubation and mechanical ventilation may be necessary. Naloxone 0.4–2.0 mg (IV, IM, or endotracheal tube). Onset of action with IV is approximately 1–2 min. Repeat doses of naloxone if needed to restore adequate respiration or a continuous infusion of naloxone can be used. One-half to two-thirds of the initial naloxone dose that reversed the respiratory depression is administered on an hourly basis (note: naloxone dosing is not necessary if the patient has been intubated). charcoal and gastric lavage may be helpful for oral ingestions, but 468e-3 intubation will be needed if the patient is stuporous.


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InternalMed_Harrison. charcoal and gastric lavage may be helpful for oral ingestions, but 468e-3 intubation will be needed if the patient is stuporous. The principles of detoxification are the same for all drugs: to substitute a longer-acting, orally active, pharmacologically equivalent medication for the substance being used, stabilize the patient on that medication, and then gradually withdraw the substituted medication. Methadone or buprenorphine are the two medications used to treat opioid use disorder. Clonidine, a centrally acting sympatholytic agent, has also been used for detoxification in the United States. By reducing central sympathetic outflow, clonidine mitigates many of the signs of sympathetic overactivity but typically requires augmentation with other agents. Clonidine has no narcotic action and is not addictive. Lofexidine, a clonidine analogue with less hypotensive effect, is not yet approved in the United States.


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InternalMed_Harrison. Methadone for Detoxification Dose-tapering regimens for detoxification using methadone range from 2–3 weeks to as long as 180 days, but this approach is controversial given the relative effectiveness of methadone maintenance and the low success rates of detoxification. Unfortunately, the vast majority of patients tend to relapse to heroin or other opiates during or after the detoxification period, indicative of the chronic and relapsing nature of opioid use disorder. Buprenorphine for Detoxification Buprenorphine does not appear to lead to better outcomes than methadone but is superior to clonidine in reducing symptoms of withdrawal, retaining patients in a withdrawal protocol, and in completing treatment.


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InternalMed_Harrison. Alpha-2-Adrenergic Agonists for Detoxification Several alpha-2-adrenergic agonists have relieved opioid withdrawal by suppressing brain noradrenergic hyperactivity. Clonidine relieves some signs and symptoms of opiate withdrawal such as lacrimation, rhinorrhea, muscle pain, joint pain, restlessness, and gastrointestinal symptoms. Related agents are lofexidine, guanfacine, and guanabenz acetate. Lofexidine can be dosed up to ~2 mg/d and appears to be associated with fewer adverse effects. Clonidine or lofexidine is typically administered orally, in three or four doses per day, with dizziness, sedation, lethargy, and dry mouth as the primary adverse side effects. Outpatient-managed withdrawal will require close follow-up often with naltrexone maintenance to prevent relapse.


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InternalMed_Harrison. Rapid and Ultrarapid Opiate Detoxification The opioid antagonist naltrexone typically combined with an alpha-2-adrenergic agonist has been purported to shorten the duration of withdrawal without significantly increasing patient discomfort. Completion rates using naltrexone and clonidine range from 75 to 81% compared to 40 to 65% for methadone or clonidine alone. Ultrarapid opiate detoxification is an extension of this approach using anesthetics but is highly controversial due to the medical risks and mortality associated with it.


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InternalMed_Harrison. Opioid Agonist Medications for Maintenance Methadone maintenance substitutes a once-daily oral opioid dose for threeto four-times daily heroin. Methadone saturates the opioid receptors and, by inducing a high level of opiate tolerance, blocks the euphoria from additional opiates. Buprenorphine, a partial opioid agonist, also can be given once daily at sublingual doses of 4–32 mg daily, and in contrast to methadone, it can be given in an office-based primary care setting.


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InternalMed_Harrison. METHADONE MAINTENANCE Methadone’s slow onset of action when taken orally, long elimination half-life (24–36 h), and production of cross-tolerance at doses from 80 to 150 mg are the basis for its efficacy in treatment retention and reductions in IV drug use, criminal activity, and HIV risk behaviors and mortality. Methadone can prolong the QT interval at rates as high as 16% above the rates in non-methadonemaintained, drug-injecting patients, but it has been used safely in the treatment of opioid dependence for 40 years.


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InternalMed_Harrison. BUPRENORPHINE MAINTENANCE While France and Australia have had sublingual buprenorphine maintenance since 1996, it was first approved by the U.S. Food and Drug Administration (FDA) in 2002 as a Schedule III drug for managing opioid use disorder. Unlike the full agonist methadone, buprenorphine is a partial agonist of mu-opioid receptors with a slow onset and long duration of action. Its partial agonism reduces the risk of unintentional overdose but limits its efficacy to patients who need the equivalent of only 60–70 mg of methadone, and many patients in methadone maintenance require higher doses up to 150 mg daily. Buprenorphine is combined with naloxone at a 4:1 ratio in order to reduce its abuse liability. Because of pediatric exposures and diversion of buprenorphine to illicit use, a new formulation, using mucosal films rather than sublingual pills that were crushed and snorted, is now marketed. A subcutaneous buprenorphine implant that lasts up to 6 months has also been tested and


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InternalMed_Harrison. formulation, using mucosal films rather than sublingual pills that were crushed and snorted, is now marketed. A subcutaneous buprenorphine implant that lasts up to 6 months has also been tested and is pending FDA approval as a formulation improvement to prevent pediatric exposures and illicit diversion and enhance compliance.


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InternalMed_Harrison. In the United States, the ability of primary care physicians to prescribe buprenorphine for opioid use disorder represents an important opportunity to improve access and quality of treatment as well as reduce social harm. Europe, Asia, and Australia have found reduced opioid-related deaths and drug-injection-related medical morbidity with buprenorphine available in primary care. Retention in office-based buprenorphine treatment has been high as 70% at 6-month follow-ups.


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InternalMed_Harrison. Opioid Antagonist Medications The rationale for using narcotic antagonist therapy is that blocking the action of self-administered opioids should eventually extinguish the habit, but this therapy is poorly accepted by patients. Naltrexone, a long-acting orally active pure opioid antagonist, can be given three times a week at doses of 100–150 mg. Because it is an antagonist, the patient must first be detoxified from opioid dependence before starting naltrexone. It is safe even when taken chronically for years, is associated with few side effects (headache, nausea, abdominal pain), and can be given to patients infected with hepatitis B or C without producing hepatotoxicity. However, most providers refrain from prescribing naltrexone if liver function tests are three times above normal levels. Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use, but medication adherence is low. Depot injection formulations lasting up to 4 weeks markedly improve


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InternalMed_Harrison. Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use, but medication adherence is low. Depot injection formulations lasting up to 4 weeks markedly improve adherence, retention, and drug use. Subcutaneous naltrexone implants in Russia, China, and Australia have doubled treatment retention and reduced relapse to half that of oral naltrexone. In the United States, a depot naltrexone formulation is available for monthly use and maintains blood levels equivalent to 25 mg of daily oral use.


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InternalMed_Harrison. Medication-Free Treatment Most opiate addicts enter medication-free treatments in inpatient, residential, or outpatient settings, but 1to 5-year outcomes are very poor compared to pharmacotherapy except for residential settings lasting 6 to 18 months. The residential programs require full immersion in a regimented system with progressively increasing levels of independence and responsibility within a controlled community of fellow drug abusers. These medication-free programs, as well as the pharmacotherapy programs, also include counseling and behavioral treatments designed to teach interpersonal and cognitive skills for coping with stress and for avoiding situations leading to easy access to drugs or to craving. Relapse is prevented by having the individual very gradually reintroduced to greater responsibilities and to the working environment outside of the protected therapeutic community.


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InternalMed_Harrison. Preventing opiate abuse represents a critically important challenge for physicians. Opiate prescriptions are the most common source of drugs accessed by adolescents who begin a pattern of illicit drug use. The major sources of these drugs are family members, not drug dealers or the Internet. Pain management involves providing sufficient opiates to relieve the pain over as short a period of time as the pain warrants (Chap. 18). The patient then needs to dispose of any remaining opiates, not save them in the medicine cabinet, because this behavior leads to diversion by adolescents. Finally, physicians should never prescribe opiates for themselves.


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InternalMed_Harrison. Cocaine and Other Commonly Abused Drugs Nancy K. Mello1, Jack H. Mendelson1 The abuse of cocaine and other psychostimulants reflects a complex interaction between the pharmacology of the drug, the personality and 469e expectations of the user, and the environmental context in which the drug is used. Polydrug abuse involving the concurrent use of several drugs with different pharmacologic effects is increasingly common. Sometimes one drug is used to enhance the effects of another, as with the combined use of cocaine and nicotine, benzodiazepines and methadone, or cocaine and heroin in methadone-maintained patients. Some forms of polydrug abuse, such as the combined use of IV heroin and cocaine, are especially dangerous and account for many hospital emergency room visits.


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InternalMed_Harrison. number of adverse health consequences and may exacerbate preexisting disorders such as hypertension and cardiac disease. The combined use of two or more drugs may accentuate medical complications associated with abuse of one drug. Chronic drug abuse is often associated with immune system dysfunction and increased vulnerability to infections, including risk for HIV infection. In addition, concurrent use of cocaine and opiates (the “speedball”) is frequently associated with needle sharing by IV drug users. IV drug abusers continue to be the largest single group of persons with HIV infection in several major metropolitan areas in the United States as well as in many parts of Europe and Asia.


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InternalMed_Harrison. Stimulants and hallucinogens have been used to induce euphoria and alter consciousness for centuries. Cocaine and marijuana are two of the most commonly abused drugs today. Synthetic variations of marijuana and a variety of hallucinogens have become popular recently, and new drugs are continually being developed. This chapter describes the subjective and adverse medical effects of cocaine, marijuana, and lysergic acid diethylamide (LSD), as well as methamphetamine, 3,4-methylenedioxyN-methamphetamine (MDMA), synthetic cathinones (bath salts), phencyclidine (PCP), Salvia divinorum, and other drugs of abuse (flunitrazepam, γ-hydroxybutyric acid [GHB], ketamine). Some options for medical management of severe adverse effects are also described.


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InternalMed_Harrison. Cocaine is a stimulant and a local anesthetic with potent vasoconstrictor properties. The leaves of the coca plant (Erythroxylum coca) contain ~0.5–1% cocaine. The drug produces physiologic and behavioral effects after oral, intranasal, IV, or inhalation/smoking routes of administration. The reinforcing effects of cocaine are related to activation of dopaminergic neurons in the mesolimbic system (Chap. 465e). Cocaine increases synaptic concentrations of the monoamine neurotransmitters dopamine, norepinephrine, and serotonin by binding to transporter proteins in presynaptic neurons and blocking reuptake.


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InternalMed_Harrison. Cocaine is widely available and is abused in virtually all social and economic strata of society. In 2012, an estimated 1.6 million persons in the United States used cocaine, and 1.1 million abused or were dependent on cocaine. Emergency room admissions involving cocaine totaled 505,224 in 2011. Cocaine abuse is prevalent in the general population and in heroin-dependent persons, including those in methadone maintenance programs. IV cocaine is often used concurrently with IV heroin in a combination called a “speedball.” This combination purportedly attenuates the postcocaine “crash” and substitutes a cocaine “high” for the heroin “high” blocked by methadone.


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InternalMed_Harrison. There has been an increase in both IV administration and inhalation of pyrolyzed cocaine via smoking. Following intranasal administration, changes in mood and sensation are perceived within 3–5 min, and peak effects occur at 10–20 min. These effects rarely last more than 1 h. Inhalation of pyrolyzed materials includes inhaling crack/cocaine or smoking coca paste, a product made by extracting cocaine preparations with flammable solvents, and cocaine free-base smoking. Freebase cocaine, including the free-base prepared with sodium bicarbonate (crack), has become increasingly popular because of its relative high potency and rapid onset of action (8–10 seconds following smoking).


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InternalMed_Harrison. Cocaine produces a brief, dose-related stimulation and euphoria and an increase in cardiac rate and blood pressure. Body temperature usually increases following cocaine administration, and high doses of cocaine may induce lethal pyrexia or hypertension. Because cocaine inhibits reuptake of catecholamines at adrenergic nerve endings, it potentiates sympathetic nervous system activity. Cocaine has a short plasma half-life of approximately 45–60 min. Cocaine is metabolized by plasma esterases, and cocaine metabolites are excreted in urine. The brief duration of the euphorigenic effects of cocaine reported by chronic abusers is probably due to both acute and chronic tolerance. Cocaine may be used as often as two to three times per hour. Alcohol is often used to modulate both the cocaine high and the dysphoria associated with the abrupt disappearance of cocaine’s effects. A metabolite of cocaine, cocaethylene, has been detected in blood and urine of persons who concurrently abuse alcohol


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InternalMed_Harrison. and the dysphoria associated with the abrupt disappearance of cocaine’s effects. A metabolite of cocaine, cocaethylene, has been detected in blood and urine of persons who concurrently abuse alcohol and cocaine. Cocaethylene induces changes in cardiovascular function similar to those of cocaine alone, and the pathophysiologic consequences of the concurrent abuse of alcohol plus cocaine may be additive.


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InternalMed_Harrison. Cocaine may cause serious medical consequences by any route of administration. The prevalent assumption that cocaine inhalation or IV administration is relatively safe is contradicted by reports of death from respiratory depression, cardiac arrhythmias, and convulsions associated with cocaine use. In addition to generalized seizures, neurologic complications may include headache, ischemic or hemorrhagic stroke, or subarachnoid hemorrhage. Disorders of cerebral blood flow and perfusion in cocaine-dependent persons have been detected with magnetic resonance spectroscopy (MRS). Inhalation of crack cocaine may lead to severe pulmonary disease due to the direct effects of cocaine and to residual contaminants in the smoked material. Hepatic necrosis may occur following chronic crack/cocaine use. Protracted cocaine abuse may also cause paranoid ideation and visual and auditory hallucinations, a state that resembles alcoholic hallucinosis.


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InternalMed_Harrison. Although men and women who abuse cocaine may report that the drug enhances libidinal drive, chronic cocaine use causes significant loss of libido and adversely affects sexual function. Impotence and gynecomastia have been observed in male cocaine abusers, and these abnormalities often persist for long periods following cessation of drug use. Cocaine abuse may produce major derangements in menstrual cycle function including galactorrhea, amenorrhea, and infertility in women and in a rhesus monkey model of cocaine self-administration. Chronic cocaine abuse may cause persistent hyperprolactinemia as a consequence of disordered dopaminergic inhibition of prolactin secretion by the anterior pituitary. Cocaine abuse by pregnant women, particularly crack smoking, has been associated with both an increased risk of congenital malformations in the fetus and perinatal cardiovascular and cerebrovascular disease in the mother. However, cocaine abuse per se is probably not the sole cause of these


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InternalMed_Harrison. increased risk of congenital malformations in the fetus and perinatal cardiovascular and cerebrovascular disease in the mother. However, cocaine abuse per se is probably not the sole cause of these perinatal disorders, because maternal cocaine abuse is often associated with poor nutrition and prenatal health care as well as polydrug abuse that may contribute to the risk for perinatal disease.


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InternalMed_Harrison. Psychological dependence on cocaine, indicated by inability to abstain from frequent compulsive use, has been reported. Although the occurrence of withdrawal syndromes involving psychomotor agitation and autonomic hyperactivity remains controversial, severe depression (“crashing”) following cocaine intoxication may accompany drug withdrawal.


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InternalMed_Harrison. Treatment of cocaine overdose is a medical emergency that is best managed in an intensive care unit. Cocaine toxicity produces a hyperadrenergic state characterized by hypertension, tachycardia, tonic-clonic seizures, dyspnea, and ventricular arrhythmias. IV diazepam in doses up to 0.5 mg/kg administered over an 8-h period has been shown to be effective for control of seizures. Ventricular arrhythmias have been managed successfully by administration of 0.5–1.0 mg of propranolol IV. Because many instances of cocaine-related mortality have been associated with concurrent use of other illicit drugs (particularly heroin), the physician must be prepared to institute effective emergency treatment for multiple drug toxicities.


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InternalMed_Harrison. Treatment of chronic cocaine abuse requires the combined efforts of primary care physicians, psychiatrists, and psychosocial care providers. Early abstinence from cocaine use is often complicated by symptoms of depression and guilt, insomnia, and anorexia, which may be as severe as those observed in major affective disorders. Individual and group psychotherapy, family therapy, and peer group assistance programs are often useful for inducing prolonged remission from drug use. Although psychotherapy may be helpful, no specific form of psychotherapy or behavioral modification is uniquely beneficial.


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InternalMed_Harrison. A number of medications used for the treatment of various medical and psychiatric disorders have been administered to reduce the duration and severity of cocaine abuse and dependence. The search for a medication that is both safe and highly effective for cocaine detoxification or maintenance of abstinence is continuing. Clinical trials of buspirone (BuSpar), a nonbenzodiazepine anxiolytic with dopamine D3 and D4 receptor antagonist properties, are ongoing. Buspirone reduced use of cocaine, nicotine, and cocaine plus nicotine in combination in a nonhuman primate model of stimulant addiction.


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InternalMed_Harrison. Another approach to reducing cocaine abuse is the development of vaccines to actively immunize against cocaine or to functionally antagonize cocaine by preventing it from reaching the brain. Cocaine is converted into inactive metabolites by the plasma enzyme, butyrylcholinesterase (BChE). When this enzyme is modified to increase its catalytic efficiency and accelerate cocaine metabolism, it can both prevent and reverse cocaine-induced toxicity in animals. Importantly, it remains effective even when high doses of cocaine are administered. Ongoing development of this approach includes cocaine hydrolase gene therapy. Vaccines for both cocaine and nicotine have been designed and shown to be safe and somewhat effective in clinical trials. Individual variability in antibody titers and difficulties in determining the optimally effective antibody titer that will neutralize responses to increasing doses of cocaine and have a relatively long duration of action are among the challenges that


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InternalMed_Harrison. in determining the optimally effective antibody titer that will neutralize responses to increasing doses of cocaine and have a relatively long duration of action are among the challenges that remain to be resolved.


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InternalMed_Harrison. Cannabis sativa contains >400 compounds in addition to the psychoactive substance, delta-9-tetrahydrocannabinol (THC). Marijuana cigarettes are prepared from the leaves and flowering tops of the plant, and a typical marijuana cigarette contains 0.5–1 g of plant material. The usual THC concentration varies between 10 and 40 mg, but concentrations <100 mg per cigarette have been detected. Hashish is prepared from concentrated resin of C. sativa and contains a THC concentration of between 8 and 12% by weight. “Hash oil,” a lipid-soluble plant extract, may contain THC between 25 and 60% and may be added to marijuana or hashish to enhance its THC concentration. Smoking is the most common mode of marijuana or hashish use. During pyrolysis, <150 compounds in addition to THC are released in the smoke. Although most of these compounds do not have psychoactive properties, they may have physiologic effects.


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InternalMed_Harrison. THC is quickly absorbed from the lungs into blood and then rapidly sequestered in tissues. THC is metabolized primarily in the liver, where it is converted to 11-hydroxy-THC, a psychoactive compound, and >20 other metabolites. Many THC metabolites are excreted through the feces at a relatively slow rate of clearance compared with most other psychoactive drugs. Specific cannabinoid receptors (CB1 and CB2) have been identified in the central and peripheral nervous system. High densities of cannabinoid receptors have been found in the cerebral cortex, basal ganglia, and hippocampus. T and B lymphocytes also contain cannabinoid receptors, and these appear to mediate the anti-inflammatory and immunoregulatory properties of cannabinoids. A naturally occurring THC-like ligand has been identified and is widely distributed in the nervous system.