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Cocaine Abuse
- From the University of South Florida, Tampa, Florida. Requests for Reprints: Elizabeth A. Warner, MD, Box 19, University of South Florida, Department of Internal Medicine, 12901 Bruce B. Downs Boulevard, Tampa, FL 33612. Acknowledgments: The author thanks Susan W. Smith and Paul Wallach, MD, for reviewing the manuscript.
Abstract
Purpose: To discuss the forms of cocaine that are available and their methods of administration and to review the medical complications of cocaine abuse.
Data Sources: Pertinent articles were identified through a MEDLINE search of the English-language literature from 1986 to 1992 and through a manual search of bibliographies of all identified articles.
Study Selection: All articles describing complications of cocaine use were either case reports, review articles, or small series. No controlled studies on the subject were available.
Data Synthesis: A qualitative description of reported complications without the use of quantitative methods.
Results: Multiple complications of cocaine use have been described and are often related to the method of administration of cocaine. Since the introduction of freebase and crack cocaine, new complications have been noted, and nearly all organ systems have been affected. Indirect complications, related to violent behavior and infectious diseases, are also important consequences of cocaine use.
Conclusions: Adverse reactions to cocaine use should be considered in the differential diagnosis of various disorders, particularly ischemic events in young adults. The actual frequency of each complication is unknown.
In the last decade, cocaine use has increased dramatically, causing significant social, economic, and medical complications. As early as 1983, the medical community began to recognize the drastic escalation of hospitalizations due to cocaine abuse, starting in the Bahamas, at the approximate time that crack cocaine became available there [1]. Since then, the 1990 National Household Drug Survey found that 11% of Americans older than 12 years have used cocaine, and 7% of adults between 18 and 34 years old had used cocaine in the last year [2, 3] (Table 1). In a 1987 survey of primary-care practices, 35% of physicians saw at least one patient with cocaine-related problems in the month before the survey compared with 20% in 1982 [4]. Because of the increased frequency of cocaine use in our society, clinicians should learn to recognize the patterns of use and the potential risks associated with cocaine abuse.
This review examined English-language articles cited in MEDLINE from 1986 to 1992 as identified by the term cocaine and focused on toxicity, adverse effects, and poisoning. The bibliographies of all pertinent articles were also reviewed. This review presents an overview of the history of cocaine, the various forms of cocaine that are used today, the currently available tests for the diagnosis of cocaine use, and the medical complications associated with cocaine. The social and legal issues relating to cocaine use are not discussed here but have been reviewed elsewhere [5-7].
History
Cocaine is an alkaloid derived from the coca plant, which is native to South America. Archeologic specimens dating from 3000 B.C. give the first definitive proof of human use of the coca leaf. At that time, coca was recognized for its ability to boost energy, relieve fatigue, and lessen hunger [8].
Chewing the coca leaf was the predominant mode of ingestion of cocaine until 1860, when the drug was isolated by Albert Niemann. The leaves have also been steeped into teas and incorporated into beverages, such as Coca Cola (which no longer contains cocaine.) In the United States, cocaine was once an ingredient in many patented medicines. In the late 1880s and 1890s, cocaine use became popular and many reports of addiction began to emerge, leading to the recognition of its potentially dangerous effects. The Harrison Narcotic Act of 1914, which was subsequently modified in 1922, prohibited the importation of cocaine and coca leaves, except for pharmaceutical purposes. The Controlled Substances Act of 1970 prohibits the manufacture, distribution, and possession of cocaine, except for limited medical purposes. The use of cocaine in the United States tapered in the 1920s, when amphetamines replaced cocaine as the most prevalent stimulant [8]. In the 1970s and 1980s, the development of freebase and crack cocaine revolutionized the use of the drug by providing a form that could be smoked.
Forms of Cocaine
Cocaine can be absorbed through any mucous membrane, smoked, or injected intravenously. Data from the National Household Drug Survey show that 90% of cocaine users have snorted cocaine, making intranasal insufflation the most common route of use. About one third of users have smoked the drug, and fewer than 10% of users have injected it [2].
Cocaine is found in all parts of the coca plant, comprising approximately 1% of the weight of the leaves. Chewing the leaves remains a frequent mode of administration in South America. Because of the limited gastrointestinal absorption of cocaine and because of the relatively low content of cocaine in coca leaves, the chewing of coca leaves does not produce the serious medical toxicity associated with purified forms of cocaine. The cocaine concentration in the leaves decreases with storage and is negligible within 6 months. To ensure more durable transportation, most cocaine is processed in South America into coca paste and then into cocaine hydrochloride (powder) before exportation.
Cocaine hydrochloride is a water-soluble powder and can be absorbed through the nasal mucosa or injected intravenously. It is often cut with adulterants, which may provide bulk (mannitol, lactose), or which imitate either its stimulant effects (caffeine) or its local anesthetic effect (procaine, lidocaine). Because of its high melting point, cocaine hydrochloride decomposes when burned; this form of cocaine is therefore not suitable for smoking.
Cocaine can be effectively smoked when it has been transformed into its alkaloid form, either freebase or crack. The medical literature is often ambiguous when differentiating between freebase and crack cocaine. Freebase and crack are the same chemical form of cocaine but are made using different techniques. Freebase is made by dissolving cocaine hydrochloride in water, adding a base such as ammonia, and then a solvent such as ether. The cocaine base dissolves in the ether layer and can then be extracted by evaporation. By preparing freebase this way, many of the water-soluble adulterants may be removed. Because some of the highly volatile ether may remain after extraction, smokers of freebase cocaine are at risk for burns. With the increased availability of crack, freebase use has declined.
Crack cocaine is made by a simpler process. Cocaine hydrochloride is dissolved with water, mixed with baking soda, and heated. The cocaine base precipitates into a soft mass that becomes hard when dry [9]. The name crack is derived from the sound of cocaine crystals popping during preparation. Crack is typically sold premade, ready to smoke, without the danger of flammability. Crack and freebase melt at a much lower temperature (80 C) compared with cocaine hydrochloride (180 C). Experiments with human volunteers have shown that smoking cocaine can achieve blood levels comparable to those reached through intravenous injection [10]. Both crack and freebase cocaine can be smoked in pipes or mixed with marijuana or tobacco and smoked in a cigarette.
Coca paste, a crude extract of coca leaves mixed with water, kerosene, and sulfuric acid, is commonly smoked in South America. Sometimes called bazooka, it is not widely used in the United States.
Physiologic Effects
Cocaine acts by blocking reuptake of neurotransmitters (norepinephrine, dopamine, and serotonin) at the synaptic junctions, resulting in increased neurotransmitter concentrations. Because norepinephrine is the primary neurotransmitter of the sympathetic nervous system, sympathetic stimulation results and leads to vasoconstriction, tachycardia, mydriasis, and hyperthermia [11]. Central nervous system stimulation may appear as increased alertness, energy, talkativeness, repetitive behavior, diminished appetite, and altered sexual behavior [12]. Psychological stimulation by cocaine produces an intense euphoria that is often compared to orgasm. The mechanism responsible for this effect is uncertain and may be related to cocaine's ability to block dopamine and serotonin reuptake in the central nervous system.
The other major pharmacologic effect of cocaine is its local anesthetic action, which results from its ability to block the sodium channel in neuronal cells.
Pharmacokinetic Effects
The method of cocaine use affects its pharmacokinetics (Table 2 and Figure 1). Smoking cocaine provides the fastest route of entry into the cerebral circulation (approximately 6 to 8 seconds). When injected intravenously, the drug reaches the brain in approximately twice the time as when it is smoked, reflecting the longer transit time through the pulmonary and later the systemic circulation. Nasal insufflation (snorting) produces euphoria in 3 to 5 minutes, with peak cocaine levels achieved in 30 to 60 minutes [14]. The amount of cocaine that can be absorbed by the nasal mucosa is self-limited due the drug's concurrent vasoconstrictive properties. Estimates of the bioavailability of snorted cocaine range from 20% to 60% [14]. Much higher peak levels of cocaine can be achieved by smoking rather than snorting because smoking directs the drug into the vast pulmonary vascular bed, providing a larger surface area for absorption. The potency of a dose of cocaine that is smoked is equivalent to approximately 60% of the same dose given intravenously (that is, smoking 50 mg produces blood levels similar to those produced by an intravenous injection of 32 mg) [15].
The biological half-life of cocaine in the blood is approximately 1 hour, with less than 5% of cocaine appearing unchanged in the urine. Most urinary excretion of cocaine and its metabolites occurs within the first 24 hours after administration, regardless of route. Two major metabolites, benzoylecgonine and ecgonine methyl ester, which have biological half-lives of approximately 6 and 4 hours, respectively [14], account for more than 80% of cocaine's known metabolites. Rapid enzymatic hydrolysis by plasma esterase (including pseudocholinesterase) and liver esterase yields ecgonine methyl ester [16]. Spontaneous nonenzymatic hydrolysis in the blood yields benzoylecgonine, which can be found in the urine at concentrations nearly 50 to 100 times greater than that of cocaine, making it the major metabolite used for drug testing [17]. Both benzoylecgonine and ecgonine methyl ester are thought to be inactive metabolites. Less than 10% of cocaine is N-demethylated by the liver into norcocaine, a potentially toxic metabolite. It has been postulated that persons with a pseudocholinesterase deficiency may be more sensitive to the toxicity of cocaine. One study showed an association with more serious toxicity in people who had lower plasma cholinesterase levels [18].
Drug Testing
Testing for cocaine includes screening and confirmatory studies. The screening tests are designed to be relatively simple, rapid, and inexpensive and to have a high sensitivity rate. Confirmation tests may be more expensive and labor-intensive but are valuable because of their greater specificity [19]. Immunoassays are widely used for screening, with gas chromatography combined with mass spectroscopy being the main confirmatory procedure used in testing [20]. The combination of a screening immunoassay with a confirmatory gas chromatography and mass spectroscopy test is thought to be fully defensible in legal settings [21].
Because of the short half-life of cocaine, measurements of blood levels will only detect recent ingestion. Unlike ethanol, blood levels of cocaine do not predict toxicity [22]. In addition, cocaine undergoes continued hydrolysis in a test tube after the sample is drawn. Sodium fluoride can be added to the venipuncture tube to inhibit continued hydrolysis [16].
The duration of detection of urinary cocaine metabolites depends on two factors: the amount of cocaine absorbed or injected and the sensitivity of the drug assay used. Most assays for detecting cocaine abuse are designed to measure urinary benzoylecgonine levels. Thin-layer chromatography is an inexpensive method for detecting cocaine metabolites in urine specimens, but it is limited by its relatively poor sensitivity, requiring more than 1000 ng/mL of benzoylecgonine for detection. The enzyme-linked immunoassay technique is the most widely used mass screening test, with a threshold of 300 ng/mL for detection. Gas chromatography with mass spectroscopy is the gold standard for testing because it is the most sensitive and specific test for detection and because it can detect benzoylecgonine at concentrations of 1 to 10 ng/mL [17]. When used for drug abuse screening, it is recommended that positive test results be confirmed by gas chromatography with mass spectroscopy [22].
The sensitivity of cocaine detection depends on the cutoff level chosen to indicate a positive result. When lowering the cutoff for a positive immunoassay result from the conventional 300 ng/mL to 80 ng/mL and the gas chromatography plus mass spectroscopy limit from 100 ng/mL to 30 ng/mL, twice as many persons were found to have positive immunoassay results, all of which were confirmed by gas chromatography with mass spectroscopy [23]. Drano (S. C. Johnson, Racine, Wisconsin), bleach, and table salt, when added to urine specimens, have been found to cause false-negative results on immunoassays [24]. With the exception of prilocaine, compounds structurally or pharmacologically similar to cocaine and benzoylecgonine (including atropine and several local anesthetics) have not been found to cross-react with immunoassays for benzoylecgonine [25]. One study found a specificity of 100% using an enzyme-linked immunoassay for benzoylecgonine, testing 162 different drugs for cross-reactivity [26]. High proficiency can be achieved in commercial laboratories; one survey of 47 laboratories documented a 99.2% accuracy rate for testing cocaine metabolites in 376 specimens, with a sensitivity of 96% and a specificity of 100% [27].
The approximate time window for detection of cocaine metabolites is 1 to 2 days for the enzyme-linked immunoassay technique and 5 to 6 days for gas chromatography with mass spectroscopy [17]. The data on the yield of drug analysis are limited because most studies are done on persons after single, relatively low doses. With high-dose, long-term cocaine use, benzoylecgonine may be detected 10 to 22 days after cocaine use [28].
A new method of testing for cocaine use involves hair sampling [29]. Both cocaine and benzoylecgonine are deposited in the hair shaft. Using this method, one can estimate the duration and intensity of a person's cocaine use for the previous several months. Assuming an average hair growth of 0.5 inches in 30 days, samples can be taken for radioimmunoassay to determine whether cocaine or benzoylecgonine is present along the hair shaft at isolated times or in a steady pattern. The presence of benzoylecgonine in the hair shaft has been found to distinguish cocaine use from external contamination of hair with cocaine smoke [30]. Hair sampling does not give a precise measurement of the amount of cocaine used but provides a temporal pattern of its use.
Medical Complications Associated with Cocaine Use
A wide range of medical complications are associated with cocaine use, including direct toxicity and indirect effects (Table 3). Because most of the knowledge about cocaine's toxicity is derived from individual case reports and small series of observed patients, the actual frequency of each complication is difficult to determine. No large surveys have documented the natural history of cocaine use or the frequency of complications. The method of administration affects the type of complications that develop. Changing patterns of use in the last decade may cause different types of complications [31]. An increase in the number of patients smoking cocaine (as opposed to injecting the drug) has shifted the emphasis away from predominantly infectious complications [31, 32]. The most common complaints of cocaine users who come to emergency rooms are psychiatric (altered mental status, suicide attempts), cardiac (chest pains, palpitations, or syncope), or neurologic (seizures) [32]. It is difficult to prove the precise toxicity of cocaine, as currently used, because of the lack of standard doses, unreliable histories, and concomitant multidrug use by cocaine abusers. In addition, other adulterants mixed with cocaine may cause toxicity.
Systemic Complications
Sudden Death
Cocaine use has been associated with sudden death, but the lethal doses and blood levels of persons dying suddenly have varied widely [33]. Several mechanisms may be responsible for sudden death, including arrhythmias, status epilepticus, centrally mediated respiratory arrest, and intracerebral hemorrhage. Sudden death may be preceded by an agitated delirium, hyperpyrexia, or generalized seizures [34]. Autopsy studies of victims of suspected cocaine-related sudden death must rely on the history and toxicology studies because no pathognomonic features of cocaine abuse exist [35].
Psychiatric
Cocaine addiction is a neurophysiologic process with prominent psychologic manifestations. Intoxication may produce psychological effects such as euphoria, poor judgment, psychomotor agitation, and physiologic effects such as tachycardia, hypertension, dilated pupils, nausea, and vomiting. High doses may also be associated with a transient psychosis, delirium, paranoid ideation, and bizarre behavior [36]. Tachyphylaxis to the euphoria produced by cocaine develops, requiring higher doses to achieve the same effect and leading to binges in which the user may readminister the drug repeatedly [7]. Binge use is thought to be a marker for compulsive use and cocaine addiction. Chronic users may exhibit symptoms suggestive of depression or an attention-deficit disorder [37].
Abstinence from cocaine has been divided into three phases, as described by Gawin and Kleber [12]. The crash is the immediate rebound effect after cessation of cocaine use, usually lasting a few hours. Dysphoria, cocaine craving, anxiety, depression, and profound exhaustion (leading to hypersomnolence) may follow. The hypersomnolence may last a few days and is often interrupted by periods of hyperphagia. The second phase is the withdrawal period, which is less dramatic than the crash. Psychological symptoms include anxiety, depression, anhedonia, with the major complication being suicide. Many users develop a conditioned craving in which the memories of cocaine smoking are so pleasurable that they tempt the user to resume drug use. Unlike withdrawal from other substances, no gross physiologic changes are associated with cessation of cocaine use [38]. The third phase, lasting months and possibly years, is called extinction, in which bursts of craving may tempt persons to resume use.
Most persons who have used cocaine have not become addicted; it is not known why some persons become compulsive users [38].
Pulmonary
Most pulmonary complications resulting from cocaine use have been associated with smoking cocaine [39]. Users have found that having another person forcefully blow smoke into one's mouth augments the intensity of the drug's effect, probably by increasing the distribution of the cocaine in the pulmonary circulation. Mouth-to-mouth positive pressure by another person after smoking has been associated with barotrauma, including pneumothorax, pneumomediastinum, and pneumopericardium [40, 41].
Sporadic reports have described pulmonary edema associated with cocaine use [42, 43]. Many of these patients have resolution of the pulmonary edema without specific therapy [43]. The mechanism underlying the pulmonary edema is unclear, although transient left ventricular dysfunction or altered permeability in the pulmonary capillaries have been offered as possible causes. Chest radiographs of these persons have shown cardiac silhouettes of normal size [44]. No reports have given hemodynamic data for these patients with pulmonary edema. One patient underwent bronchoalveolar lavage and was found to have a protein level elevated to approximately four times the normal value, suggesting the possibility of altered capillary permeability [43].
An association has been described between asthma and smoking cocaine. Severe exacerbations of asthma in patients with long-term disease have been described [45, 46]. Inhaled or smoked cocaine may induce a nonspecific bronchial irritation. One study reported that one third of cocaine smokers noted wheezing during cocaine use [47].
Other findings associated with cocaine smoking include pulmonary hemorrhage [48, 49], the presence of alveolar macrophages laden with hemosiderin, bronchiolitis obliterans [50], and crack lung [51, 52]. Crack lung refers to the syndrome associated with chest pain, hemoptysis, and diffuse alveolar infiltrates. Whether this syndrome represents hypersensitivity to the cocaine itself or to an adulterant is unknown.
The long-term pulmonary effects of cocaine smoking have not been established. Pulmonary function tests have shown reductions in diffusing capacity of carbon monoxide in cocaine smokers [53], but definite abnormalities in spirometry have not been shown [42, 53]. Studies evaluating pulmonary dysfunction in cocaine users have been confounded by the inclusion of cigarette and marijuana smokers [54].
Cardiovascular
Cocaine use has been linked to heart disease. Many of the cardiac toxicities described with cocaine use can be related to the drug's physiologic effects. Cocaine can cause increased myocardial oxygen demand because of its association with tachycardia and hypertension, while also reducing coronary artery caliber and increasing coronary vascular resistance [55].
The first case report of myocardial infarction after cocaine use was published in 1982 [56]. Since then, more than 100 cases have been described. The average age for patients with myocardial infarction related to cocaine use is 31 years [57, 58], well below the usual age associated with coronary artery disease. Myocardial infarctions have been reported after smoking cocaine as well as after intravenous and intranasal use.
Angiographic studies in patients with cocaine-related myocardial infarctions show both diseased and normal coronary arteries [57, 59-63], with approximately one third of the patients having normal coronary arteries [55]. The mechanism for myocardial infarction in patients with normal coronary arteries is unknown. Theories include coronary vasospasm, enhanced platelet aggregation, and an increased myocardial oxygen demand due to the heightened sympathetic response after cocaine use. Unlike patients with Prinzmetal angina, those with cocaine-related myocardial infarction and normal coronary arteries have not developed vasospasm after intracoronary ergonovine injections [57, 61, 63]. Cold pressor testing failed to produce angina or electrocardiographic changes in patients with non-Q-wave myocardial infarctions [57]. Several angiographic studies have documented the narrowing of coronary arteries after intranasal administration of cocaine [64, 65].
An autopsy study of cocaine users found significant stenotic lesions in the coronary arteries, greater than that which would be expected in this fairly young population [66, 67]. Coronary angiograms from cocaine users with cardiac symptoms have shown atherosclerotic disease in about 60% of patients, despite their relatively young age [68]. Whether cocaine use actually triggers the atherosclerosis or simply acts as a marker to identify users with severe coronary artery disease is unknown. Animals fed a high-cholesterol diet along with repeated doses of cocaine have been shown to develop accelerated atherosclerosis [55].
The time course for myocardial ischemia associated with cocaine use varies. Some reports have described chest pain within minutes after cocaine use [62]; others have shown that the median time to the development of ischemic symptoms after cocaine use is 18 hours [59]. Nademanaee and colleagues [69] reported a high incidence of silent ischemia, as documented by ambulatory electrocardiographic monitors, in cocaine users during withdrawal. These electrocardiographic changes were most prominent during the first week after cessation of cocaine use. Only 1 of 20 patients with silent ischemia had an abnormal stress test result, suggesting the absence of fixed coronary disease.
In the last 10 years, the evaluation of chest pain related to cocaine use has become a significant management problem, particularly in emergency departments. Varying reports have described the incidence of myocardial infarctions associated with cocaine use. Considering the widespread use of cocaine, myocardial infarction is not a frequent event. Chest pain associated with cocaine use may not be the result of cardiac ischemia. Of 101 consecutive patients in Minnesota who were hospitalized with chest pain and a history of recent cocaine use, none proved to have a myocardial infarction. Forty percent of the patients had abnormal results of electrocardiograms, 32% of which were thought to be early repolarizations. None of these patients had elevations in the MB fraction of creatine kinase [70]. These authors warn against the use of thrombolytic agents in patients with chest pain associated with cocaine use, unless unequivocal evidence indicates myocardial injury. In a contrasting study from the Bronx, 31% of patients hospitalized with chest pains and a history of recent cocaine use were diagnosed with acute myocardial infarction [59]. The reason for the disparity in the frequency of myocardial infarction in these two studies is unclear.
Cocaine has been associated with various cardiac arrhythmias: accelerated ventricular rhythm [71], asystole [72], and ventricular fibrillation [73]. Cocaine use appears to be associated with cardiomyopathy [74, 75], myocarditis [76], and contraction band necrosis [77]. Because cocaine blocks reuptake of norepinephrine, cocaine users may have increased circulating norepinephrine. Elevated norepinephrine levels may cause myocardial damage similar to that seen with pheochromocytoma. Contraction band necrosis, a nonspecific finding related to hypercontraction and also seen with pheochromocytoma, has been reported in some autopsy studies of cocaine users. Some reports have described aortic rupture occurring after cocaine use [78].
Neurologic
Multiple acute and long-term neurologic complications have been reported with cocaine use [79], the most common being headaches. A telephone hotline for cocaine users showed that approximately two thirds of callers had intermittent headaches associated with cocaine use. Vascular headaches are most commonly reported; they may occur during cocaine use or during withdrawal [80, 81].
Seizures, both partial and generalized, have been reported with cocaine use. Cocaine is believed to lower the seizure threshold. Isolated seizures may be seen with cocaine use, or seizures may occur as a preterminal event. Most seizures occurring in cocaine users are associated with either smoking crack or with intravenous injection of cocaine. Nasal insufflation of cocaine is more likely to precipitate seizures in those patients with a previous history of a seizure disorder [82].
Strokes can be a devastating complication of cocaine use, particularly in young persons who have no other risk factors for cerebrovascular disease [83]. The use of cocaine hydrochloride is associated with hemorrhagic strokes [84]; many of these patients have underlying aneurysms or arteriovenous malformations. Cerebral infarctions are more common with crack than with cocaine hydrochloride [85, 86], possibly due to the higher serum concentrations obtained by smoking cocaine. High levels of cocaine may precipitate cerebral vasospasm. Most infarctions occur in the cerebral hemispheres, although brain stem and spinal cord infarctions have been reported [87]. Cocaine users who have dilated cardiomyopathies are at risk for embolic strokes.
Long-term, habitual cocaine users may develop cerebral atrophy, primarily in the frontal and temporal areas. Computed tomographic scans have shown a higher rate of cerebral atrophy in chronic compared with new cocaine users [88]. Neuropsychological testing in heavy cocaine users has shown mild impairment [89]. A few case reports have described cerebral vasculitis [90] in cocaine users; three such cases were confirmed histologically [91, 92].
Renal
Acute renal failure as a consequence of rhabdomyolysis is the most common renal complication of cocaine use. The patients often have no or relatively mild neuromuscular symptoms [93]. In one study, 24% of emergency department patients with complaints related to cocaine use were found to have rhabdomyolysis, as defined by elevations of creatine kinase levels to more than five times normal values [94]. In the largest series of cocaine-associated rhabdomyolysis, approximately one third of patients who had rhabdomyolysis developed acute renal failure, and one half of the patients with renal failure died [95]. The average creatine kinase level in that series of patients with rhabdomyolysis was 200 katal/L (12 000 U/L), and the value in those who developed renal failure was 467 katal/L (28 000 U/L). A low serum calcium level was predictive of more severe rhabdomyolysis. When associated with renal failure, rhabdomyolysis was sometimes accompanied by disseminated intravascular coagulation and elevated liver enzyme levels [95]. The mechanism of the rhabdomyolysis is unclear. It can be associated with hyperthermia and seizures [96]; however, many patients have neither been febrile nor had a seizure.
Gastrointestinal
Several intestinal disorders have been associated with cocaine use. Intestinal ischemia has been reported after oral, intravenous, and intranasal cocaine use [97-99]. Gastroduodenal perforations have been noted in young patients after using crack [100, 101]. A few cases of colitis have been reported in cocaine users. Colonoscopies have shown findings suggestive of pseudomembranous colitis or ischemic colitis [102, 103].
Persons wishing to smuggle or conceal cocaine may ingest packets of cocaine. If the wrapping of a packet deteriorates or is damaged, acute toxicity can result from exposure to large quantities of cocaine. The management of these body packers has been controversial; surgery and removal of the packets was initially thought to be the best treatment. More recently, conservative management has been recommended, reserving surgery only for those patients who developed obstruction or perforation [104].
Since 1967, it has been recognized that some cocaine and heroin users have abnormal liver enzyme levels; however, cocaine itself has not been determined to be a hepatotoxin. A mouse model of hepatic cocaine toxicity has been developed but whether this model applies to humans remains unclear. A small amount of cocaine is metabolized in the cytochrome p450 microsomal system to norcocaine, which is then transformed to N-hydroxynorcocaine. A byproduct of this chemical reaction may be nicotinamide-adenine dinucleotide phosphate depletion and depressed glutathione stores, which may also contribute to hepatotoxicity [105]. Of six cocaine users with abnormal liver enzyme levels and histologic findings, all also had elevated creatine kinase levels, myoglobinuria, or acute renal failure [106-108].
Endocrine
The adrenergic effects of cocaine use can mimic hyperthyroidism. Studies have shown a blunted thyroid-stimulating hormone response to thyroid-releasing hormone stimulation in chronic cocaine users [109]; however, routine thyroid function test results are normal in cocaine users [110]. Abnormalities of testosterone, cortisol, and luteinizing hormone have not been found in chronic cocaine users [111]. Dopamine, one of the neurotransmitters affected by cocaine use, inhibits prolactin secretion. Dopamine levels are increased during initial use of cocaine, resulting in decreased prolactin levels. During long-term use or withdrawal, dopamine levels become depleted, with resultant hyperprolactinemia [112].
Obstetric
The use of cocaine during pregnancy has been linked to an increased risk for placental abruption, lower infant weights, prematurity, and microcephaly [113] and possibly to congenital urologic abnormalities and neurobehavioral dysfunction [114]. Testing of infant hair by radioimmunoassay is more sensitive than testing of infant urine to determine fetal cocaine exposure [115].
Sexual Function
Long believed to have aphrodisiac properties, cocaine actually produces variable effects on sexual function. Reports of both enhanced and inhibited sexual function have been described with cocaine use [116]. Some cocaine users experience greater sexual arousal and prolonged stamina during intercourse while using cocaine [117]. Compulsive sexuality, defined by excessive preoccupation, loss of control, and continuation of sexual practices despite adverse effects, has been associated with cocaine use [118]. Sometimes referred to as sexual addiction, compulsive sexuality may be related to the higher incidence of sexually transmitted diseases in cocaine users. As a form of barter, sexual activities may be performed in exchange for cocaine [119].
Erectile difficulties have also been associated with cocaine use. Perhaps the most commonly described effect on male sexual function is delayed or inhibited ejaculation. Small doses of cocaine may have a stimulant effect, whereas larger doses and long-term use cause sexual dysfunction. A few cases of priapism have been reported after cocaine use [120-122]. The route of administration may have some effect on sexual function; intravenous users commonly have the most negative sexual experiences [123].
Head and Neck
Oral complications of cocaine use include erosions of the dental enamel [124] and gingival ulceration at the site of application of oral cocaine [125]. Ocular complications reported with cocaine use include keratitis [126] and corneal epithelial defects [127]. Otolaryngologic complications include chronic rhinitis, a rhinitis similar to rhinitis medicamentosa, perforated nasal septum, aspiration of the nasal septum [128], midline granuloma [129], altered olfaction [130], optic neuropathy, and osteolytic sinusitis [131].
Indirect Complications
Infectious
In addition to the direct toxicity associated with cocaine, some infectious diseases are increased in cocaine users, due in part to the setting in which cocaine is used. Because of increased sexual activity, cocaine users may be at an increased risk for sexually transmitted diseases, such as the acquired immunodeficiency syndrome, gonorrhea, and syphilis [132]. The practice of exchanging drugs for sex with a prostitute or having sex in a crack house is associated with an increased risk for syphilis [133]. Serologic testing in Philadelphia found that 27% of clients at a crack house had positive rapid plasma reagin test results [134]. Pregnant women who tested positive for cocaine at the time of delivery were more likely to have positive rapid plasma reagin test results (18.7% compared with 2.4%) and to test positive for antibodies to human immunodeficiency virus (HIV) (7.6% compared with 1.4%) [135]. Intravenous use of cocaine has been associated with HIV transmission [136].
Because crack is often smoked in crowded, poorly ventilated rooms, the potential for transmission of respiratory infections exists. One report described a tuberculosis epidemic associated with a crack house in California [137].
Homicides
Cocaine use has been associated with violent behavior. The most common forms of death associated with cocaine use are homicide, suicide, or accidental causes. In 1989, 40% of homicide victims in Fulton County, Georgia tested positive for cocaine metabolites in their blood [138]. Firearm-related homicides are more common in persons testing positive for cocaine metabolites at autopsy [138, 139]. In 1985, 21% of suicide victims younger than 60 years in New York City tested positive for cocaine at autopsy [140].
Treatment
Much controversy exists regarding the optimal treatment for cocaine abuse, with no long-term controlled studies on outcome of cocaine abuse treatment. Most investigations have been open studies, which do not distinguish the effect of patient compliance on treatment results. Much current treatment for cocaine abuse is modeled after alcohol and heroin addiction treatment programs [141]. Previously, 28-day inpatient programs had been considered standard without controlled studies to document efficacy. Because of the expense associated with these programs, much treatment has been shifted to outpatient settings. The goals of treatment for cocaine abuse are to initiate abstinence and to prevent relapse [12]. Intensive, structured supportive therapy can be provided in an outpatient setting [142], given that cocaine is not associated with gross physiologic symptoms requiring inpatient care [38]. Hospitalization can be reserved for those patients who are too dysfunctional to participate in an outpatient setting. Intensive personal and group therapy is usually needed to prevent relapse, particularly during the early withdrawal period when craving is powerful and is stimulated by conditioned cues [143].
Frequent urine testing is important to confirm abstinence. Under investigation is the role of pharmacotherapy to relieve the symptoms of cocaine withdrawal and to prevent relapse. A controlled study of desipramine has shown less cocaine use and craving in the early withdrawal period [144], but long-term relapse prevention has not been documented. Other drugs, such as bromocriptine and amantadine, have been studied and have produced variable results. Practical measures to remove access to cocaine may help to prevent early relapse. Long-term relapse prevention involves training to ignore conditioned cues and to avoid situations in which cocaine is used. An individual's personal resources correlate with rates of abstinence [141]. Unlike the treatment for alcohol or opiate dependence, no equivalent of disulfiram or naltrexone exists to deter relapse. Cocaine Anonymous, a 12-step support group modeled after Alcoholics Anonymous, has been established for cocaine users.
Conclusions
The scope and number of complications relating to cocaine abuse have increased since the development of a smokable form of the drug. Further research may focus on the frequency of these complications and on the long-term consequences of cocaine use. Optimal treatment regimens, including the use of pharmacologic adjuncts to facilitate abstinence and prevent relapse, deserve further study.
- Copyright 2004 by the American College of Physicians
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