78: Cocaine

Cocaine is contained in the leaves of Erythroxylum coca, a shrub that grows abundantly in Colombia, Peru, Bolivia, the West Indies, and Indonesia. As early as the 6th century, the inhabitants of Peru chewed or sucked on the leaves for social and religious reasons. In the 1100s, the Incas used cocaine-filled saliva as local anesthesia for ritual trephinations of the skull.⁶⁸

In 1859, Albert Niemann isolated cocaine as the active ingredient of the plant. By 1879, Vassili von Anrep demonstrated that cocaine could numb the tongue.¹⁰⁸ However, Europeans knew little about cocaine until 1884, when the Austrian ophthalmologist Karl Koller introduced cocaine as an effective local anesthetic for eye surgery and Koller’s colleague, Sigmund Freud, wrote extensively on the psychoactive properties of cocaine.⁵⁵ Following these revelations, Merck, Europe’s main cocaine producer, increased production from less than 0.75 pounds in 1883 to more than 150,000 pounds in 1886.¹⁰⁴

Simultaneously, reports of complications from the therapeutic use of cocaine began to appear. In 1886, a 25 year-old man had a “pulseless” syncope after cocaine was applied to his eye to remove a foreign body.²¹¹ By 1887, more than 30 cases of severe toxicity were reported,¹⁸¹ and by 1895 at least eight fatalities resulting from a variety of doses and routes of administration were summarized in one article.⁵⁷ Recreational cocaine use was legal in the United States until the passage of the Harrison Narcotic Act of 1914, when cocaine was restricted to medical use. Not until 1982, however, was the first cocaine-associated myocardial infarction reported in the United States.²⁸

Currently, cocaine is an approved pharmaceutical. It is used primarily for topical anesthesia of cutaneous lacerations or during otolaryngology procedures as a vasoconstrictor and topical anesthetic. Although multiple factors have fostered a decline in the medicinal use of cocaine,^18,63,130 the recreational use of cocaine remains a significant problem.

The United Nations office on Drugs and Crime estimates that there are 13 to 19 million cocaine users worldwide.³⁴ In the United States, it is estimated that there are 1.5 million cocaine users.⁴³

The alkaloid form of cocaine, benzoylmethylecgonine, is a weak base that is relatively insoluble in water. It is extracted from the leaf by mechanical degradation in the presence of a hydrocarbon. The resulting product is converted into a hydrochloride salt to yield a white powder, cocaine hydrochloride, which is very water soluble. Cocaine hydrochloride can be insufflated, applied topically to mucous membranes, dissolved in water and injected, or ingested; however, it degrades rapidly when pyrolyzed. Smokable cocaine (crack) is formed by dissolving cocaine hydrochloride in water and adding a strong base. A hydrocarbon solvent is added, the cocaine base is extracted into the organic phase, and then evaporated. The term “free-base” refers to the use of cocaine base in solution.

Cocaine is rapidly absorbed following all routes of exposure; however, when applied to mucous membranes or ingested, its vasoconstrictive properties slow the rate of absorption and delay the peak effect. Bioavailability for smoking cocaine exceeds 90%, and is approximately 80% following nasal ­application.¹⁰⁰ Data for ingested cocaine and application to other mucous membranes such as the urethra, vagina, or rectum are inadequately documented. Table 78–1 lists the typical onsets and durations of action for various routes of cocaine exposure.

Following absorption cocaine is approximately 90% bound to plasma proteins, primarily α₁-acid glycoprotein.¹⁶⁴ Based on human volunteer studies with small doses of cocaine, the volume of distribution is reported to be about 2.7 L/kg,¹⁰⁰ but it is unclear if the volume of distribution changes with overdose.

The metabolism of cocaine is complex and dependent on both genetic and acquired factors. Three major pathways of cocaine metabolism are well described (Fig. 78–1). Cocaine undergoes N-demethylation in the liver to form norcocaine, a minor metabolite that rarely accounts for more than 5% of drug.^96,205 However, norcocaine readily crosses the blood–brain barrier and produces clinical effects in animals that are quite similar to cocaine.^13,103,192 Nearly half of a dose of cocaine is both nonenzymatically²⁰⁴ and enzymatically hydrolyzed⁴¹ to form benzoylecgonine (BE). When BE is injected into animals, some reports suggest that it is virtually inactive,^105,200 while other studies demonstrate cerebral vasoconstriction³² and seizures.^112,146 When either injected directly into the cerebral ventricles^147,192 or applied to the surface of cerebral arteries,¹³³ BE is a potent vasoconstrictor. Although BE traverses the blood–brain barrier poorly,¹⁴⁸ the potential effects are of concern as some BE is probably formed from cocaine that has already entered the central nervous system (CNS). In vitro, BE has little or no effect on cardiac sodium or potassium channels.^32,49 Finally, plasma cholinesterase (PChE) and other esterases metabolize cocaine to ecgonine methyl ester (EME). In normal individuals, between 32% and 49% of cocaine is metabolized to EME.^4,96 Like BE, EME crosses the blood–brain barrier poorly.¹⁴⁷ Although many authors state that EME has little or no pharmacologic activity,^146,147,189 diverse animal models demonstrate contradictory results, concluding that EME is a vasodilator,^133,162,190 sedative, anticonvulsant,¹⁹² and protective metabolite against lethal doses of cocaine.⁸¹

The role of genetic or acquired alterations in PChE activity has been of interest for many years. Early in vitro studies showed that cocaine was poorly metabolized in serum from patients with succinylcholine sensitivity (low PChE activity). In subsequent studies and case series, patients with low PChE activity demonstrate increased sensitivity to cocaine,^80,159 findings that are corroborated in multiple animal models.^20,79,131

Multiple other metabolites of cocaine are well characterized.³⁰ Several have clinical or diagnostic importance. In 1990, a unique metabolite was identified in patients who smoke cocaine, now known either as anhydroecgonine methyl ester (AEME) or methylecgonide.⁹⁸ The presence of this compound and its metabolite, ecgonidine, can be used to help determine the route of administration in cocaine users.¹⁸⁸ Additionally, AEME has demonstrable agonism at the muscarinic (M₂) receptors, which may have important clinical implications.²³⁰

Ethanol has a unique pharmacologic interaction with cocaine. A transesterification reaction between the two drugs produces benzoylethylecgonine, which is also called “ethyl cocaine” or “cocaethylene” (CE).¹³ In human volunteers given cocaine and ethanol, CE accounted for approximately 17% of the metabolites, producing a decrease in the amount of BE and an increase in the amount of EME formed.^72,73 CE has a longer duration of action than cocaine and similar neurotoxic and cardiotoxic effects.

Neurotransmitter Effects

Cocaine blocks the reuptake of biogenic amines. Specifically, these effects are described on serotonin and the catecholamines dopamine, norepinephrine, and epinephrine. Several animal investigations have elucidated the particular roles of each neurotransmitter. Mice lacking the dopamine transporter are relatively insensitive to the locomotor effects of cocaine.⁵⁹ Tachycardia emanates from adrenally derived epinephrine, whereas hypertension results from neuronally derived norepinephrine.^209,210 Serotonin is an important modulator of dopamine and has a role in cocaine addiction, reward, and seizures.^70,122,141

Although much emphasis has been placed on the reuptake blockade of these biogenic amines, it is clear that this effect is insufficient to account for the clinical manifestations of cocaine toxicity. Other xenobiotics that block the reuptake of biogenic amines, such as cyclic antidepressants, produce quite distinct clinical manifestations²¹² (Chap. 71). Xenobiotics that block the effects of dopamine, epinephrine, and norepinephrine not only fail to protect against cocaine toxicity but actually exacerbate it.^{23,65,130,184} Although this may, in part, result from an unopposed α-adrenergic effect, hypertension and vasospasm fail to explain the increase in psychomotor agitation, seizures, and hyperthermia that result.^23,65 These effects most likely result from an interaction between cocaine and excitatory amino acids. Cocaine increases excitatory amino acid concentrations in the brain,¹⁹⁹ and excitatory amino acid antagonists prevent both seizures and death in experimental animals.^14,175 Finally, because experimental evidence in animals^22,65,193 and clinical experience in humans demonstrate that sedation treats both the central effects of cocaine and the peripheral effects of biogenic amines, a newer model was proposed (Fig. 78–2). This model emphasizes the necessity of diffuse CNS excitation as a prerequisite for cocaine toxicity, explains experimental and clinical observations, and provides insight into the treatment of acute toxicity.

Cardiovascular Effects

Cocaine use is associated with myocardial ischemia and myocardial infarction (MI). The increased risk of MI results from several different mechanisms. Hypertension and tachycardia increase myocardial oxygen demand, induces vasospasm, accelerated atherogenesis, and hypercoagulability.

Vasospasm.

Although increased myocardial oxygen demand may be sufficient to cause ischemia in some individuals, it is clear that cocaine also produces profound vasoconstriction. Evidence suggests that cocaine-induced vasoconstriction is mediated through both neuronal norepinephrine and BE.^117,132 BE has a direct effect on vessels that appears to be calcium mediated.¹³² Additionally nicotine, which is simultaneously used by many substance users, has additive, if not synergistic, effects with cocaine.¹⁵²

Atherogenesis.

Cocaine use accelerates atherosclerosis. Rabbits fed a normal diet supplemented with cholesterol do not develop atherosclerotic vascular disease. However, when that diet includes cocaine, rabbits develop classic atherosclerotic lesions.^110,119,120 Experiments with human endothelial cells demonstrate that cocaine directly increases the permeability to lipids by altering tight junctions.¹¹¹ This probably promotes the formation of subendothelial atherosclerotic plaques.

Dysrhythmias.

Like other local anesthetics (Chap. 67), cocaine blocks neuronal sodium channels, thereby preventing saltatory conduction. Because of homology between neuronal and cardiac sodium channels, cocaine also inhibits the rapid inward Na⁺ current responsible for phase 0depolarization of the cardiac action potential (Chaps. 16 and 71). Experimental evidence suggests that cocaine enters the sodium channel and binds on the inner membrane.^35,109,169 Like many sodium channel blockers, binding is both pH and use dependent (ie, binding increases as pH falls or heart rate increases; Chap. 71).^36,221 Furthermore, although norcocaine has a greater affinity for inactivated sodium channels, it has a much more rapid offset of action than cocaine.³⁵ Consequently, cocaine can be characterized as a Vaughan-Williams class 1C antidysrhythmic²²⁹ (Chap. 64). Cocaine-induced QRS prolongation is exacerbated by Vaughan-Williams class IA antidysrhythmics²²⁶ and ameliorated by hypertonic sodium bicarbonate, hypertonic sodium chloride, and lidocaine^9,63,163 Another effect of sodium channel blockade, the Brugada pattern, is also associated with cocaine use (Fig. 16–12).^129,157

In addition to its sodium channel-blocking properties, cocaine also blocks cardiac potassium channels (Chap. 16). This results in QT prolongation^167,208,221 and may produce torsade de pointes.¹⁹¹ Cocaethylene also has dysrhythmogenic effects.¹⁵⁸ In vivo experiments demonstrated inhibition of the myocardial HERG potassium channels, which may explain this phenomenon.⁴⁹ In animal studies, CE is associated with increased incidence of dysrhythmias, prolonged myocardial depression, and increased lethality.^105,225

Hematologic Effects

Enhanced coagulation and impaired thrombolysis compound the effects of accelerated atherogenesis and vasospasm. Cocaine activates human platelets and causes α-granule release, resulting in platelet aggregation.^75,116 Thus, even in the absence of endothelial injury, cocaine can initiate a thrombotic cascade while simultaneously enhancing the activity of plasminogen activator inhibitor type 1 (PAI-1), thereby impairing clot lysis.¹⁵¹

Pulmonary Effects

Bronchospasm.

The association between cocaine use and asthma¹⁷⁸ was not recognized until smoked cocaine became prevalent.⁴⁷ Furthermore, experiments in human volunteers demonstrate that only smoked cocaine (not intravenous cocaine) produces bronchospasm.²⁰⁷ Although it is possible that bronchospasm results from direct administration of cocaine to the airways, inhaled contaminants of cocaine, or thermal insult, and the unique pyrolytic metabolite of cocaine that acts as a muscarinic agonist (AEME) produces bronchospasm in experimental animals.²⁵

Many clinical manifestations of toxicity develop immediately following cocaine use. These are typically associated with the sympathetic overactivity, and their duration of effect is predictable based on the pharmacokinetics of cocaine use. Other manifestations, such as those associated with tissue ischemia, may present in a delayed fashion, with a clinical latency of hours to even days after last cocaine use. The reasons for this delay are not clear but may relate to the presence of an altered sensorium associated with acute cocaine use and its anesthetic effects (see Cessation of Use below).

Vital sign abnormalities that develop during cocaine toxicity are characteristic of the sympathomimetic toxic syndrome. Thus, varying degrees of hypertension, tachycardia, tachypnea, and hyperthermia occur. Although any of these vital sign abnormalities can be life threatening, experimental and clinical evidence suggests that hyperthermia is the most critical.^23,65,138 Initially, with typically used doses, and at any time with a massive dose, apnea, hypotension, and bradycardia can result, all from direct suppression (anesthesia) of brainstem centers.^117,130,144 These effects are fleeting and rarely noted when patients present to health care, as either the sympathetic overdrive rapidly ensues, or sudden death results. Additional sympathomimetic findings include mydriasis, diaphoresis, and neuropsychiatric manifestations.

Cocaine produces end-organ toxicity in virtually every organ system in the body. These events result from vasospasm, hemorrhage secondary to increased vascular shear force (dP/dT), or enhanced coagulation. Each organ system is discussed separately in the following sections.

Central Nervous System

Seizures, coma, headache, focal neurologic signs or symptoms, or behavioral abnormalities that persist longer than the predicted duration of effect of cocaine should alert the clinician to a potential catastrophic CNS event. Hemorrhage can occur at any anatomic site in the CNS. Subarachnoid, intraventricular, and intraparenchymal bleeding are all well described in association with cocaine use.^{2,39,125,136,171,194} Early discussions suggested an underlying predisposition due to the presence of arteriovenous malformations or congenital aneurysms,²²⁸ but subsequent larger studies failed to support this analysis, suggesting that effects can occur independently of preexisting disease.^2,156,218 Ruptured intracerebral aneurysms in cocaine users are almost exclusively in the carotid artery circulation.^2,156,218 Presumably, CNS bleeding is a manifestation of abnormal shear force. Spontaneous extraaxial bleeding is also associated with cocaine use.¹⁸³

Both vasospastic infarction and transient ischemic attack are reported in association with cocaine use.^39,40,125 In one epidemiologic study, women younger than age 45 years who had strokes were seven times more likely to report cocaine use than controls.¹⁶⁸ Patients can present with any of the classic physical findings associated with thrombotic or embolic stroke. Vasospasm can injure the spinal cord, resulting in paralysis from an anterior spinal artery syndrome.^39,150

Seizures are commonly provoked by cocaine use.^83,153 Cocaine use can serve as a trigger in patients with epilepsy, although an underlying focus is not necessary for seizures to occur.¹¹³

Headache is also well described in cocaine users. While the exact mechanism is unclear, hypertension or dysregulation of neurotransmitters may be contributory. In addition to typical tension headache, classic migraine and cluster headaches are also reported.^166,185

Eyes, Nose, and Throat

Sympathetic excess produces mydriasis through stimulation of the dilator fibers of the iris with characteristic retention of the ability to respond to light. Like other mydriatics, cocaine can produce acute narrow angle-closure glaucoma.⁷¹ Vasospasm of the retinal vessels causes both unilateral and bilateral loss of vision.^82,127 Additionally, although cocaine produces excellent corneal anesthesia, it is highly toxic to the corneal epithelium. Following application of cocaine to the eye, the superficial corneal layer is shed, resulting in pain and decreased acuity.¹⁷² The loss of eyebrow and eyelash hair from thermal injury associated with smoking crack cocaine is called madarosis.²⁰⁶

Chronic intranasal insufflation of cocaine can produce perforation of the nasal septum. This finding most likely results from repeated ischemic injury with resultant cartilage loss. This ischemia is usually asymptomatic, and necrotic tissue is sloughed. At least one reported case of wound botulism (Chap. 41) has been associated with intranasal insufflation. Presumably this resulted from accumulation of necrotic tissue in the nose, serving as a culture medium for Clostridium botulinum.¹¹⁵.

Angioedema and oropharyngeal burns, located as far distally as the esophagus, are associated with smoking crack cocaine.^{21,26,107,145} These effects are most likely the result of inhalation or ingestion of superheated fumes and hot liquid (from the smoking apparatus) rather than direct toxicity from cocaine.

Pulmonary

Pneumothorax, pneumomediastinum, and pneumopericardium are repor­ted following both smoked and intranasal cocaine use.^{134,173,187,212,215} These findings do not result directly from cocaine toxicity but rather are epiphenomena related to the mechanism of drug use. Following insufflation or inhalation, the user commonly performs a Valsalva maneuver in an attempt to retain the drug. Bearing down against a closed epiglottis increases intrathoracic pressure, and an alveolar bleb can rupture against the pleural, mediastinal, or pericardial surfaces.

Cocaine use exacerbates reversible airways disease, and it is common for patients to present with shortness of breath and wheezing.^{47,124,160,177} Like so many manifestations of cocaine toxicity, it is unclear whether this is a direct effect of cocaine or related to inhalation of some contaminant of the drug. However, as discussed above, the M₂ agonistic effects of the pyrolysis metabolite AEME might be contributory.

Crack lung is the term given to an acute pulmonary syndrome that occurs after inhalational use of crack cocaine. The syndrome is a poorly defined constellation of symptoms, including fever, hemoptysis, hypoxia, acute respiratory distress syndrome, and respiratory failure. It is associated with diffuse alveolar and interstitial infiltrates on chest radiography.¹⁷³ Histopathology shows diffuse alveolar damage and hemorrhage with inflammatory cell infiltration and hemosiderin-laden macrophages. Eosinophilia was noted in several cases.⁵³ The syndrome has been variously attributed to impurities mixed with the crack, carbonaceous material generated from pyrolysis, and direct cocaine toxicity.

Vasospasm and subsequent thrombosis of the pulmonary artery or its branches can produce pulmonary infarction.⁴² Patients present with shortness of breath and pleuritic chest pain characteristic of a pulmonary embolus. Clinical signs and symptoms of ventilation–perfusion (V/Q) mismatch (Chap. 29), as well as abnormalities on arterial blood gas analysis, are noted.

Cardiovascular

Chest pain or discomfort is a common emergency department complaint in cocaine users.¹⁷ Cocaine use is associated with cardiac ischemia and infarction in young people and may account for as much as 25% of myocardial infarctions in patients younger than 45 years of age.¹⁷⁰ Although myocardial infarction is of concern, only approximately 6% of patients with complaints referable to the heart will manifest biochemical evidence of myocardial injury.^88,222 Many others will have an ischemic cardiac event, but for the remainder, the differential diagnosis is broad.¹¹⁸ Entities to consider include the pulmonary and esophageal etiologies described previously, referred abdominal symptoms (see Abdominal), chest wall injury,^{37,62,94,126,128} aortic dissection, coronary artery dissection,^186,203 and dysrhythmias. No single sign or symptom or combination of signs and symptoms reliably identifies cardiovascular injury from among the discussed differential diagnosis.⁸⁸

Catecholamine-induced direct myocardial catecholamine toxicity contributes to both acute and chronic cardiac disease. Takotsubo cardiomyopathy is a reversible form of left ventricular apical ballooning associated with myocardial ischemia in the absence of atherosclerotic lesions. It is thought to result from catecholamine toxicity on the myocardium during high levels of stress and is also reported after cocaine use.⁵ Chronic cocaine use is associated with a dilated cardiomyopathy,^76,118 the etiology of which is presumed to be the result of repeated subclinical ischemic events. Patients may present with signs and symptoms of congestive heart failure or pulmonary edema. The pathologic finding of contraction band necrosis also suggests that there may be some direct catecholamine toxicity as this finding only commonly occurs with cocaine and amphetamine use, pheochromocytoma, and in patients receiving high-dose vasopressors.^51,219

Abdominal

Abdominal pain, or other gastrointestinal complaints, suggests a broad differential diagnosis. Cocaine users have a disproportionate incidence of perforated ulcers.^123,165,197 The etiology has not been elucidated but may be related to local ischemia of the gastrointestinal tract or increased acid production associated with sympathetic activity. Vasospasm produces ischemic colitis that can present with abdominal pain or bloody stools.^128,155 More severe vasospasm, with or without thrombosis, can lead to intestinal infarction^56,77,91,161 with attendant hypotension and metabolic acidosis. Signs and symptoms of bowel obstruction such as vomiting or distension might suggest body packing (gastrointestinal drug smuggling). Although less common, splenic¹⁵⁷ and renal infarctions^44,149,182 may also occur. Spontaneous hemoperitoneum is also reported, although occult trauma could not be definitively excluded.¹⁰

Animals frequently develop hepatotoxicity following cocaine administration. In human cocaine users, minor elevations of liver enzyme concentrations are common and rarely associated with symptoms.^19,114 When more severe liver injury occurs, it is usually associated with multisystem organ dysfunction from hyperthermia or another type of hepatic injury.⁶ Isolated hepatic injury from cocaine is distinctly uncommon and may result from differences in metabolic pathways, as animals are known to make a hepatotoxic metabolite of cocaine that has not been described in humans.²¹⁷

Musculoskeletal

Rhabdomyolysis is common in all conditions that produce an agitated delirium and or hyperthermia; cocaine is no exception.^31,93,179 Unlike most other toxicologic disorders, however, psychomotor agitation is not a prerequisite for cocaine-associated rhabdomyolysis.²³¹ Muscle injury may result from vasospasm or direct muscle toxicity; however, the mechanism remains unclear. Patients with cocaine toxicity present with a spectrum of illness that ranges from asymptomatic enzyme and electrolyte abnormalities characteristic of rhabdomyolysis, to localized or diffuse muscle pain, to frank compartment syndrome and acute kidney injury.⁴⁵

Limb ischemia associated with cocaine use is reported.⁶⁶ Vasospasm, accelerated atherogenesis, and increased thrombogenesis (see Pathophysiology) place users at increased risk.

Traumatic injury is also fairly common in the setting of cocaine use.¹⁴⁰ Clinicians should be aware of the possibilities of occult fractures or other injuries that may be masked by the anesthetic properties of cocaine or the patient’s altered level of consciousness.^130,139

Neuropsychiatric

The neuropsychiatric effects of cocaine are most likely dose dependent. Low-dose administration produces alertness, exhilaration, hypersexual behavior, and other “desired” effects. These effects rarely bring users to health care facilities. As the cocaine dose increases, agitation, aggressive behavior, confusion, disorientation, and hallucinations can develop.

Other possible manifestations include a variety of movement disorders that most likely result from depletion or dysregulation of dopamine. Patients may develop acute dystonias^22,50,216 or choreoathetoid movements that have been referred to as “crack-dancing.”^38,67

Obstetrical

The majority of obstetrical findings associated with cocaine use involve developmental problems in the fetus and neonate and are probably a result of a combination of chronic vascular insufficiency from cocaine-induced spasm of the uterine artery or distal vessels and other risk factors, such as poor maternal nutrition, cigarette smoking, and a lack of prenatal care (Chap. 31). These events are extensively reviewed elsewhere.^24,48,196 Acute cocaine use during pregnancy is associated with abruptio placentae, causing patients to present with abdominal pain and vaginal bleeding.^1,52 The remaining maternal and fetal complications comprise every possible complication described in nonpregnant patients.

Cocaine and benzoylecgonine, its principal metabolite, can be detected in blood, urine, saliva, hair, and meconium. Routine drug-of-abuse testing relies on urine testing using a variety of immunologic techniques (Chap. 6) Although cocaine is rapidly eliminated within just a few hours of use, BE is easily detected in the urine for 2 to 3 days following last use.⁴ When more sophisticated testing methodology is applied to chronic users, cocaine metabolites can be identified for several weeks following last use.²²⁴

Urine testing, even using rapid point-of-care assays, offers little to clinicians managing patients with presumed cocaine toxicity because it cannot distinguish recent from remote cocaine use. In addition, false-negative testing can result when there is a large quantity of urine in the bladder with very recent cocaine use or when the urine is intentionally diluted by increased fluid intake,²⁹ leading to a urine cocaine concentration below the cutoff value and interpretation of the test as negative. Under these circumstances, repeat testing is almost always positive. False-positive tests are extremely unlikely. However, external contamination is possible, particularly with hair testing.

While false-positive tests do occur, they are more common with hair testing than urine or blood because of the increased risk of external contamination.^29,176 Because of the very low rate of false-positive results, confirmation of a positive urine is unnecessary for medical indications (Chap. 6).

The greatest benefit for cocaine testing is in cases of unintentional poisoning or suspected child abuse and neglect. Here confirmation of a clinical suspicion is essential to support a legal argument. In addition, there may be some usefulness for urine testing of body packers, especially when the concealed xenobiotic is unknown.²¹⁴ While many body packers will have negative urine throughout their hospitalization, a positive urine test is suggestive of the concealed drug but obviously not confirmatory. More importantly, a conversion from a negative study on admission to a positive study not only confirms the substance ingested but also suggests packet leakage, which could be a harbinger of life-threatening toxicity (Special Considerations: SC5). Another indication for urine testing for cocaine occurs in young patients with chest pain syndromes where the history of drug use, specifically cocaine, is not forthcoming.⁸⁵ Routine diagnostic tests such as a bedside rapid reagent glucose, electrolytes, renal function tests, and markers of skeletal muscle and cardiac muscle injury are more likely to be useful than urine drug screening. An electrocardiogram (ECG) may show signs of ­ischemia or infarction, or dysrhythmias that require specific therapy. Unfortunately, in the setting of cocaine-associated chest pain, the ECG has neither the sensitivity nor the specificity necessary to permit exclusion or confirmation of cardiac injury.⁹⁰ Cardiac markers are therefore always required adjuncts when considering myocardial ischemia or infarction. Because cocaine use is associated with diffuse muscle injury, assays for troponin are preferred over myoglobin or myocardial band enzymes of creatine phosphokinase.⁸⁹ Additionally, computed tomography (CT) angiography of the coronary arteries has been reported to be a useful tool to exclude MI after cocaine use.²²⁰ This test exposes the patient to high levels of radiation, and relative risk versus benefit has not been studied. Chest radiography may be useful to exclude certain etiologies in patients with chest discomfort or to identify free air under the diaphragm when gastrointestinal perforation is suspected. Supplemental diagnostic studies, such as CT scans of the head, chest, or abdomen and functional cardiac imaging, should be guided by the clinical condition of the patient.^33,46,69

A cocaine withdrawal syndrome is not reported. Following binge use of cocaine, a “washed-out” syndrome occurs that is best described by dopamine depletion.^202,213 Patients complain of anhedonia and lethargy, and they have trouble initiating and sustaining movement. However, they are arousable with minimal stimulation and usually remain cognitively intact.

Symptoms typically associated with cocaine toxicity can prevent in a delayed fashion after cessation of cocaine use. The reasons for this delay are multifactorial and not entirely apparent but may be related to prolonged elimination of metabolites such as CE; changes in receptor regulation¹⁵⁴; or affects on platelets, coagulation, and thrombolysis that incite a slow cascade leading to thrombosis.

General Supportive Care

As in the case of all poisoned patients, the initial emphasis must be on stabilization and control of the patient’s airway, breathing, and circulation. If tracheal intubation is required, it is important to recognize that cocaine toxicity may be a relative contraindication to the use of succinylcholine.¹⁴² Specifically, in the setting of rhabdomyolysis, hyperkalemia may be exacerbated by succinylcholine administration, and life-threatening dysrhythmias may result (Chap. 69). Additionally, it is essential to recognize that PChE metabolizes both cocaine and succinylcholine.⁹⁹ Thus, their simultaneous use could either prolong cocaine toxicity or paralysis or both. Human data are insufficient to predict which interaction is more likely to occur. If hypotension is present, the initial approach should be infusion of intravenous 0.9% sodium chloride solution as many patients are volume depleted as a result of poor oral intake and excessive fluid losses from uncontrolled agitation, diaphoresis, and hyperthermia.

In the setting of cocaine toxicity it is important to recognize that both animal^23,65 and human¹³⁸ experience suggests that elevated temperature represents the most critical vital sign abnormality. Determination of the core temperature is an essential element of the initial evaluation, even when patients are severely agitated. When hyperthermia is present, rapid cooling with ice water immersion preferably, or the combined use of mist and fanning, is required to achieve a rapid return to normal core body temperature (Chap. 30). Sedation or paralysis and intubation may be necessary to facilitate the rapid cooling process. Pharmacotherapy, including antipyretics, drugs that prevent shivering (chlorpromazine or meperidine), and dantrolene,⁵⁴ are not indicated as they are ineffective and have the potential for adverse drug interactions such as serotonin toxicity (meperidine) (Chap. 38) or seizures (chlorpromazine).

Sedation remains the mainstay of therapy in patients with cocaine-associated agitation. It is important to remember that cocaine use is associated with hypoglycemia due to catecholamine discharge.^15,149 Clinical findings of hypoglycemia and increased catecholamines may be similar; consequently, a rapid bedside glucose should be obtained or hypertonic dextrose should be empirically administered if indicated, prior to or while simultaneously achieving sedation.

Both animal models^23,65 and extensive clinical experience in humans support the central role of benzodiazepines. Antipsychotics have also been used in the treatment of acute cocaine intoxication. A meta-analysis evaluating benzodiazepines and antipsychotics in animal modes of cocaine toxicity found that both reduced mortality. However, benzodiazepine treatment reduced mortality by 52% compared with only 29% for antipsychotics.⁷⁴ Although the choice among individual benzodiazepines is not well studied, an understanding of the pharmacology of these drugs allows for rational decision making. The goal is to use parenteral therapy with a drug that has a rapid onset and a rapid peak of action, making titration easy. Using this rationale, midazolam and diazepam are preferable to lorazepam, because significant delay to peak effect for lorazepam often results in oversedation when it is dosed rapidly or in prolonged agitation when the appropriate dosing interval is used. Drugs should be administered in initial doses that are consistent with routine practices and increased incrementally based on an appropriate understanding of their pharmacology. For example, if using diazepam, the starting dose might be 5–10 mg intravenously, which can be repeated every 3 to 5 minutes and increased if necessary. Large doses of benzodiazepines may be necessary (on the order of 1 mg/kg of diazepam). This may result from cocaine-induced alterations in benzodiazepine receptor function^60,61,102 (Antidotes in Depth: A23).

On the rare occasion when benzodiazepines fail to achieve an adequate level of sedation, either a rapidly acting barbiturate or propofol should be administered. Controlled animal studies clearly show that the use of phenothiazines or butyrophenones is contraindicated.^23,65,227 In animal models, these drugs enhance toxicity (seizures), lethality, or both. Additional concerns about these drugs include interference with heat dissipation, exacerbation of tachycardia, prolongation of the QT interval, induction of torsade de pointes, and precipitation of dystonic reactions.

Once sedation is accomplished, often no additional therapy is required. Specifically, hypertension and tachycardia usually respond to sedation and volume resuscitation. In the uncommon event that hypertension and or tachycardia persists, the use of a β-adrenergic antagonist or a mixed α- and β-adrenergic antagonists is contraindicated. Again, in both animal models and human reports, these drugs increase lethality and fail to treat the underlying central nervous system excitation.^{12,23,65,184,213} (See Specific Management below.) The resultant unopposed α-adrenergic effect may produce severe and life-threatening hypertension or vasospasm. A direct-acting vasodilator such as nitroglycerin, nicardipine, or an α-adrenergic antagonist (such as phentolamine) may be considered. Other nonspecific therapies for rhabdomyolysis such as intravenous fluid should also be considered.

Decontamination

The majority of patients who present to the hospital following cocaine use will not require gastrointestinal decontamination as the most popular methods of cocaine use are smoking and intravenous and intranasal administration. If the nares contain residual white powder presumed to be cocaine, gentle irrigation with 0.9% sodium chloride solution will help remove adherent material. Less commonly, patients may ingest cocaine unintentionally or in an attempt to conceal evidence during an arrest (body stuffing)^{78,101,135,201} or transport large quantities of drug across international borders (body packing).^58,63 These patients may require intensive decontamination and possibly surgical removal²³² (Special Considerations: SC5).

Specific Management

End-organ manifestations of vasospasm that do not resolve with sedation, cooling, and volume resuscitation should be treated with vasodilators (such as phentolamine). When possible, direct delivery via intraarterial administration to the affected vascular bed is preferable. Because this approach is not always feasible, systemic therapy is typically indicated. Phentolamine can be dosed intravenously in increments of 1 to 2.5 mg and repeated as necessary until symptoms resolve or systemic hypotension develops.

Acute Coronary Syndrome.

A significant amount of animal, in vitro, and in vivo human experimentation has been directed at defining the appropriate approach to a patient with presumed cardiac ischemia or infarction. In some instances, an approach that is similar to the treatment of coronary artery disease is indicated, although there are certain notable exceptions. An overall approach to care is available in the American Heart Association guidelines and a number of reviews.^3,84,117,143

High-flow oxygen therapy is clearly indicated as it may help overcome some of the supply–demand mismatch that occurs with coronary insufficiency. Aspirin is likely safe in patients with cocaine associated chest pain and is recommended for routine use.¹⁴³ In addition, administration of morphine is likely to be effective as it relieves cocaine-induced vasoconstriction.¹⁸¹ Morphine also offers the same theoretical benefits of preload reduction and reduction of catecholamine release in response to pain that is thought to be responsible for its usefulness in patients with coronary artery disease.

After these interventions, the treatment of patients with cocaine-associated chest pain begins to deviate from the standard accepted approach to patients with coronary artery disease. Nitroglycerin is clearly beneficial as it reduces cocaine-associated coronary constriction of both normal and diseased vessels and relieves chest pain and associated symptoms.⁸⁰ Interestingly, in several clinical trials of cocaine-associated chest pain, benzodiazepines are at least as effective or superior to nitroglycerin.^8,92 Although the reasons for this are unclear, possible etiologies include blunting of central catecholamines or direct effects on cardiac benzodiazepine receptors. Either or both drugs can be used in standard dosing (Antidotes in Depth: A23).

Over the past decade, the benefits of β-adrenergic antagonism have been demonstrated in patients with CAD. In contrast, β-adrenergic antagonism increases lethality in cocaine-toxic animals^23,65 and in humans, exacerbates cocaine-induced coronary vasoconstriction, and produces severe paradoxical hypertension.¹⁸⁴ Mixed alpha and beta adrenergic antagonists do not appear to offer any advantage in the treatment of patients with cocaine associated chest pain. For the treatment of coronary constriction, labetalol is no better than placebo.¹² This is likely due in part to the relative ratios receptor blockade. Intravenous labetalol has a relative β:α receptor blockage of 7:1.¹⁷⁴ Carvedilol has a ratio of 2.4:1.¹⁶

Thus, in the setting of cocaine use, β-adrenergic antagonism is absolutely contraindicated. The 2008 American Heart Association Guidelines for the treatment of cocaine-associated chest pain and MI state that use of β-adrenergic antagonists should be avoided in the acute setting.¹⁴³ If, after the measures mentioned previously have been initiated, hypertension or vasospasm is still present and treatment is indicated, phentolamine is preferred based on its demonstrable experimental and clinical results.^87,117 If tachycardia does not respond to accepted therapies above, then diltiazem can be administered and titrated to effect.¹¹ Prior to the administration of any negative inotrope, it is essential to confirm that the tachycardia is not compensatory for a low cardiac output resulting from global myocardial dysfunction. Noninvasive methods of assessment of cardiac function have been used successfully in patients with cocaine-associated acute coronary syndromes.⁷

There are no data on the use of either unfractionated or low-molecular-weight heparins, glycoprotein IIb/IIIa inhibitors, or clopidogrel. The recent American Heart Association guidelines recommend the administration of unfractionated heparin or low-molecular-weight heparin in patients with cocaine-associated MI.¹⁴³ The decision to use any of these medications should be based on a risk-to-benefit analysis. Consideration should be given to the possibility of underlying atherosclerotic heart disease. When acute thrombosis is likely, thrombolytic therapy should be considered. Mechanistically, cocaine inhibits endogenous thrombolysis through augmentation of the inhibitor of tissue plasminogen activator. Additionally, there is sufficient clinical evidence to support the safety of thrombolytic therapy in patients with cocaine-associated MI.^80,86 Even though the number of patients treated with thrombolytic therapy is insufficient to demonstrate efficacy in terms of mortality, evidence of revascularization is encouraging. If available, cardiac catheterization with revascularization is preferable to thrombolysis.^195,198 A high rate of stent thrombosis after MI is reported in cocaine users. Thrombolysis would not be expected to be useful in treating ischemia caused by vasospasm. Due to the high incidence of coexisting atherosclerotic disease and an increased hypercoagulable state in cocaine-associated MI, thrombolysis is an acceptable alternative when catheterization is unavailable. Standard contraindications such as persistent hypertension, aortic dissection, trauma, and altered mental status must be considered prior to thrombolysis.

Dysrhythmias.

Most patients present with sinus tachycardia that resolves following sedation, cooling, rehydration, and time to metabolize the drug. Other stable dysrhythmias should be treated similarly and will often spontaneously revert because of the short duration of effect of cocaine. However, cocaine use is associated with atrial, supraventricular, and ventricular dysrhythmias, including torsade de pointes.^97,118,191 Most notably, wide complex tachycardias result from sodium channel blockade.

When approaching patients with cocaine-associated dysrhythmias, there are several important points to consider. The first is that β-adrenergic antagonism is contraindicated. Furthermore, class 1A and 1C antidysrhythmics are also contraindicated because of their ability to exacerbate cocaine-induced sodium and potassium channel blockade.^118,226 Additionally, although popular in many advanced cardiac life support dysrhythmia algorithms, the effects of amiodarone are largely unknown in the setting of cocaine toxicity. Because of the lack of data demonstrating a benefit for amiodarone, and because of concerns about its β-adrenergic antagonist effects, the use of this drug cannot be recommended. Finally, although adenosine and synchronized cardioversion may transiently help convert narrow complex tachycardias, if a substantial amount of cocaine is unmetabolized, the patient will likely revert back to the original dysrhythmia as these therapeutic interventions have short durations of effect. Thus for rapid atrial fibrillation and narrow complex reentrant tachycardias, a calcium channel blocker such as diltiazem is preferred. For wide-complex dysrhythmias, a trial of hypertonic sodium bicarbonate has demonstrable usefulness analogous to treating patients with cyclic antidepressant overdose (Antidotes in Depth: A5).^{106,116,163,181,221,226,239,246} When the use of hypertonic sodium bicarbonate fails to treat the dysrhythmia, lidocaine can be used. Although lidocaine blocks sodium channels, its fast-on, fast-off properties allow it to antagonize the effects of cocaine. The benefits and safety of lidocaine were demonstrated in multiple animal models^{64,69,75,81,226,246} and in humans with cocaine-associated MI.^105,215

Ischemic Stroke.

The safety of thrombolysis in cocaine-associated ischemic stroke is uncertain. Cocaine use can increase the risk of both ischemic stroke and intracerebral hemorrhage. One study found no increase in intracerebral hemorrhage after administration of tissue plasminogen activator in patients who had recently used cocaine, although acute cocaine intoxication was not specifically investigated.¹³⁷

Adulterants are present in illicit drugs for varied reasons, including impure manufacturing processes, increasing drug bulk, and mimicking or enhancing effects. Historically, cocaine has included inert substances such starches, sympathomimetic agents and other local anesthetics.²⁷

In 2003, a new adulterant, levamisole, was identified. Levamisole is an antihelminthic immunomodulator. It was withdrawn from the US market in 2000 primarily because of agranulocytosis. By 2009, the US Drug Enforcement Agency estimated that 69% of cocaine contained levamisole.¹²¹ Two primary categories of levamisole toxicity are identified. The first is hematologic effects, including neutropenia and agranulocytosis. The second is dermatologic effects, including vasculitis and purpura. Reexposure to cocaine with levamisole may cause reoccurrence of these symptoms. A multifocal inflammatory leukoencephalopathy is also reported after use of contaminated cocaine.

Patients who present to health care facilities with classic sympathomimetic signs and symptoms that resolve spontaneously in the absence of signs of end-organ damage can be safely discharged after short periods of observation. Once hyperthermia, rhabdomyolysis, or other signs of end-organ damage are evident, hospital admission is usually required. Patients who use cocaine are at increased risk for sudden death likely related in part to dysrhythmias and myocardial ischemia. In one series, patients with cardiac arrest after smoking crack cocaine were younger, more likely to survive, and less likely to have neurologic sequelae than case controls.⁹⁵

For patients with chest pain, a specific management algorithm has been derived based on substantial clinical experience. Those patients with clearly diagnostic or evolving ECGs suggestive of ischemia or infarction, positive cardiac biomarkers, dysrhythmias other than sinus tachycardia, congestive heart failure, or persistent pain require admission. Patients who become pain free and whose ECGs are stable are candidates for discharge if a single cardiac marker obtained at least 8 hours after the onset of chest pain is normal.²²³ The American Heart Association guidelines recommend 9 to 12 hours of observation for low-and intermediate-risk patients with cocaine-associated chest pain.¹⁴³

For all patients, it is essential to provide a referral for detoxification. Repeated cocaine use is the greatest risk factor for future cardiovascular complications.^88,180,224 Additionally, cocaine use in patients treated for traumatic injury is a risk factor for subsequent death from unintentional injury.

• A sympathomimetic toxidrome is the typical clinical presentation.

• Life-threatening hyperthermia may occur.

• Treatment of agitation should focus on rapid sedation with a benzodiazepine and cooling if indicated.

• Myocardial infarction and dysrhythmias occur via diverse mechanisms.

• Both ischemic and hemorrhagic stroke may occur.

References