Cocaine Epidemiological Research

The world is facing an epidemic of cocaine use by adolescents and young adults from all socioeconomic backgrounds.

Epidemiologic data suggest that cocaine use is a serious public health problem because it is highly addictive and is

associated with a variety of neurological complications.
Cocaine, a natural alkaloid, is extracted from leaves of an Andean shrub, Erythroxylon coca. Coca leaves were used by

the native populations to alleviate the rigors of high altitude and to diminish fatigue. Although cocaine was extracted in

pure form from coca in 1860, Europeans became aware of its potential medical complications only after Sigmund Freud's

Über Coca was published in 1884. It was described by Freud as a wonder drug that
could cure depressed mood and

alcohol dependence. It is used as an ophthalmic and spinal anesthetic.
An important factor in the most recent epidemic of cocaine use was the popularization in the late 1980s of the smoked

form, known as crack or rock. It was called crack supposedly because of the sound made by crystals of cocaine

popping when heated or rock because of its appearance.
Cocaine remains the primary nonalcoholic drug of abuse. It has been sold on the streets for many years as a

water-soluble hydrochloride (HCl) salt for nasal insufflation (snorting) or intravenous injection. It may be injected

subcutaneously or intramuscularly, but this route rarely is used because vasoconstriction slows absorption and the drug

thus is less likely to result in a "rush."
Cocaine can be smoked only when it is altered to form cocaine base . Smoking of the base results in an almost

instantaneous high due to rapid absorption through the large pulmonary surface area and swift penetration into the brain.

Smoking of cocaine base has increased in many cities throughout the world. Although the nasal route and smoking of the

base currently are in vogue, cocaine can be absorbed readily from any mucous membrane. Irrespective of route of

administration, it causes neurological complications.
Pathophysiology: The most important pharmacological actions of cocaine are blocking the initiation or conduction of the

action potential following local application to a nerve and stimulating the CNS.
The local anesthetic effect of cocaine is due to a direct membrane effect. Cocaine blocks the initiation and conduction of

electrical impulses within nerve cells by preventing the rapid increase in cell-membrane permeability to sodium ions during

depolarization. Its systemic effects on the nervous system probably are mediated by alterations in synaptic transmissions.

The most noticeable systemic activity of cocaine is stimulation of the CNS by altering the uptake and metabolism of

norepinephrine, dopamine, serotonin, and acetylcholine.
By blocking presynaptic reuptake of the neurotransmitters norepinephrine and dopamine, cocaine increases the quantity

of neurotransmitters at the postsynaptic receptor sites. The resultant activation of the sympathetic nervous system

produces an acute rise in arterial pressure, tachycardia, and a predisposition to ventricular arrhythmias and seizures.

Sympathetic activation also may result in mydriasis, hyperglycemia, and hyperthermia. The effects of cocaine on

dopaminergic neuronal systems may be involved in producing euphoria and addiction.
In the short term, cocaine appears to stimulate dopaminergic neurotransmission by blocking the reuptake of dopamine.

However, evidence suggests that, with long-term use, the nerve terminals may be depleted of dopamine. Dopamine

depletion has been theorized to contribute to the dysphoria that develops during withdrawal from cocaine and the

subsequent craving for more of the drug. In this way, alterations in dopamine neurotransmission may be responsible for

the development of compulsive use patterns. With higher doses and regular use, other neurotransmitter systems probably

are involved, directly or indirectly, in mediating CNS toxicity. With regular use, moreover, neuroadaptive mechanisms

result in development of tolerance, reverse tolerance, and dependence.
Frequency:

In the US: Cocaine use in the United States has reached epidemic proportions. In the second half of the last century,

cocaine consumption in North America rose rapidly; by the late 1980s, 30 million people were cocaine users and 6

million were cocaine addicts. In the United States, 5 million people take cocaine regularly, and every day approximately

5000 people try cocaine for the first time. Estimates in the 1990s suggested that 30-40 million Americans have some

experience with cocaine and that 1 of every 2 persons aged 25-30 years has used the drug. The incidence of neurological

complications is not known.
Internationally: The figures for the consumption of cocaine have risen progressively in all Central American countries,

Europe, and parts of Asia. Worldwide, hundreds of millions of people are believed to use cocaine.
Mortality/Morbidity:
Neuropsychiatric complications occur in approximately 40% of cocaine users. Headaches occur in approximately 3.5%

and convulsions in approximately 3.5% of cocaine users. A relative risk of 49.4% was found for cocaine use less than 6

hours before stroke onset and a relative risk of 6.5% for drug use of unknown interval before stroke onset when

compared with controls matched for sex, age, and year of discharge.
Ischemic and hemorrhagic strokes are equally likely

after alkaloid cocaine use, whereas cocaine HCl use is more likely (approximately 80% of the time) to cause hemorrhagic

stroke; approximately half the intracranial hemorrhages occurring after cocaine use are from ruptured cerebral saccular

aneurysms or vascular malformations. Acute effects of cocaine include decreased food intake, increased activity,

effusiveness, and diminished fatigue. Repetitive motor activity is observed with higher doses. Overdose can result in

convulsions, hyperthermia, coma, and death. A dose-dependent increase in heart rate and blood pressure can occur.

Regular cocaine use interferes with sleep and suppresses rapid eye movement (REM) sleep. Also, cocaine can lower

seizure threshold. Tolerance and dependence: Some, but not all, of the central effects (eg, euphoria, anorexia,

hyperthermia) reveal tolerance. Tolerance may lead to the escalation of dose required to produce the same CNS effect.

Despite evidence of a recent overall decline in cocaine use, cocaine-related health and criminal justice problems
are

increasing. A change in the pattern of cocaine use, from relatively innocuous intermittent recreational use of cocaine HCl

powder among the affluent to heavy smoking of crack cocaine among poor and criminal segments of the population in the

inner cities has been noted. Examination of cocaine abusers revealed deficiencies in interpersonal, financial, physical, and

vocational faculties. Crack cocaine users are at high risk for HIV, with high-frequency crack users increasingly engaging

in HIV-related sexual risk behaviors. Studies conducted in East Harlem, NY, reported 33% of crack users to be female;

91% of the population using cocaine were African American or Hispanic. Interview data collected from the National

Household Surveys on Drug Abuse (NHSDA) from 1979-1994 showed that an estimated 23% of US residents have

tried cocaine. Among those who eventually abused the drug, the vast majority made the transition from first trial to regular

use within 1 year. Males were more likely than females to try cocaine but were not more likely than females to progress

to actual abuse. The typical cocaine user is a young man with a higher-than-average income. Many users are

professionals in positions of authority that entail a high level of responsibility. The highest prevalence rates of cocaine use

in the United States are among young white men aged 18-25 years residing in the west and the northeast.
Young-adult cocaine users are likely to consume the drug occasionally and to use alcohol or marijuana more frequently

than cocaine. Use of marijuana and cocaine in combination is not unusual. In the United States, the use of cocaine is most

prevalent among younger people; however, the number of younger people using cocaine generally has declined, while the

number of older individuals using cocaine has increased. According to the NHSDA, the rate of cocaine use in 1998 was

highest among Americans aged 18-25 years. Nineteen percent of the respondents in this age group had used cocaine

within the prior year, and one third of these persons reported that they had used cocaine during the previous month.

Acute effects of cocaine:
Decreased food intake
Increased activity
Effusiveness
Diminished fatigue
Long-term cocaine use
Interferes with sleep
Can lower seizure threshold
Overdose of cocaine
Convulsions
Hyperthermia
Coma
Neuropsychiatric complications: Psychiatric disturbances include depression, suicidal ideation, paranoia, kleptomania,

violent antisocial behavior, catatonia, and auditory or visual hallucinations.
Headache is a relatively frequent symptom (3.5%) in cocaine users. Headaches occur in 11% of cocaine paste smokers.
Convulsions
Convulsions occur in about 3% of cocaine users. Convulsions caused by cocaine can be generalized or partial, simple or

complex. The majority of seizures are single, generalized, induced by intravenous or crack cocaine, and not associated

with any lasting neurological deficits. Most focal, multiple, or induced seizures caused by nasal insufflation of cocaine are

associated with an acute intracerebral complication or concurrent use of other drugs.
Generally, seizures caused by cocaine use are associated with cerebral lesions or with interictal EEG abnormalities.
All routes of administration are associated with seizures, and seizures can be induced in some persons by small quantities

of cocaine. Once intoxication has passed, these individuals do not require long-term anticonvulsant therapy.
Although most cocaine-induced seizures are benign and self-limiting, seizures may be due to other more severe

complications, such as infarction and intracranial hemorrhage.
Physical: A dose-dependent increase in heart rate and blood pressure can occur

Lab tests should be ordered on the basis of patient presentation. Indications for ordering labs are as follows:
Diagnosis of cocaine use
Urine drug screen: Qualitative drug screens usually test for the inactive cocaine metabolite, benzoylecgonine, which may

be present for as long as 36 hours after a single use. Metabolites can be demonstrated in the urine within 5 minutes after

intravenous administration. With long-term use, urine metabolites may be detected for as long as 3 weeks after

discontinuation of the drug. Urine drug screen in the neonate also can be used to detect possible in utero exposure to

cocaine. The persistence of benzoylecgonine, which can be detected in the neonate's urine for as long as 4 days, is due to

slow metabolism, probably related to immaturity or relative deficiency of plasma cholinesterases in the newborn.
Serum level of cocaine: This can be determined but has not been found to be useful clinically because of the rapid

metabolism and short half-life of the drug.
Diagnosis of neurological complications: Tests used for diagnosing neurological complications include antinuclear antibody

(ANA), creatine kinase (CK), CT scan, brain MRI, magnetic resonance angiography (MRA) of neck and intracranial

vessels, 4-vessel angiogram, echocardiogram (transthoracic, transesophageal), positron emission tomography (PET), and

single-photon emission computed tomography (SPECT).
CK: Urine should be evaluated routinely for the presence of myoglobin. Of patients with cocaine-induced

rhabdomyolysis, 75% have a positive urine dipstick result for the orthotolidine reaction for heme, 67% yield positive

findings for urine protein, and many manifest microscopic hematuria.
Imaging Studies:

CT scan of brain: Focal neurological deficits or alterations in mental status are indications for performing CT scan of the

brain. With long-term cocaine use, significant cerebral atrophy, enlarged lateral ventricles, and widened sylvian fissures

may be seen. CT scan also reveals intracerebral hemorrhage.
MRI of brain: MRI of newborns exposed to cocaine in utero may reveal evidence of cortical infarction, major congenital

malformations, and mainly midline CNS abnormalities.
MRA of brain and intracranial vessels: MRA is indicated in patients with ischemic stroke or subarachnoid hemorrhage.

MRA may show evidence of vasculitis or aneurysm; venous phase may show evidence of venous thrombosis.
Four-vessel angiogram: This study is indicated in patients with a history of cocaine abuse and presenting with intracerebral

hemorrhage, especially subarachnoid hemorrhage. Angiogram may show underlying vascular abnormalities. Berry

aneurysms of the circle of Willis are a common finding. Arteriovenous (AV) malformations or tumor may be seen as well.

Rarely, superior sagittal sinus thrombosis with hemorrhagic venous infarction, dural AV fistula, rupture of multiple mycotic

aneurysms, and large-vessel thrombosis have been described. Angiographic beading can be seen in patients with

vasculitis.
Neuroradiological study of newborns born to mothers who had used cocaine during pregnancy may reveal periventricular

leukomalacia or holoprosencephaly. Evidence of intracerebral, intraventricular or subarachnoid hemorrhage may be

observed. Sonography, CT scan, and MRI revealed cortical infarcts and midline congenital malformations in 15% of

infants exposed to cocaine in utero.
Other Tests:

ECG: Perform ECG if patient has chest pain.
EEG: Perform EEG in patients with seizures and a history of cocaine use. Habitual cocaine use can be associated with

diffuse slowing on EEG. Focal abnormalities in the form of spikes or slowing can be seen in patients with focal seizures or

intracerebral complications.
Transthoracic and transesophageal echocardiogram: Perform transthoracic and transesophageal echocardiogram in

patients with embolic stroke caused by cocaine use. These studies may show evidence of vegetations in patients with

infective endocarditis.
PET and SPECT: These studies are indicated in long-term cocaine users presenting with neuropsychiatric manifestations.

Cerebral blood flow is reduced in habitual cocaine abusers, and abnormalities are most marked in the prefrontal cortex.

Some investigators using PET have found reduced glucose metabolism over the entire cerebral cortex, thalamus, and

midbrain. SPECT with iodine-123 isopropyl iodoamphetamine (IMP) revealed irregularly reduced cerebral perfusion

even among asymptomatic social cocaine users who had normal findings on CT scans. In cocaine-dependent polydrug

users (many of whom also used opioids and/or ethanol), some authors have found abnormal cerebral perfusion that

primarily involved parietal, temporal, frontal, and basal ganglia.
Acute intoxication requires hospitalization for detoxification and management of acute neurovascular complications.
For long-term management, drug-dependence programs can be effective in decreasing drug use by behavioral

interventions. Cognitive behavioral therapy can be effective in decreasing craving for the drug.
No pharmacotherapies have been approved for cocaine addiction. Some drugs have been tested with promising results.

Disulfiram, amantadine, tiagabine, topiramate, and baclofen are some drugs that have been reported to be of possible

benefit in cocaine addiction. A recent double blind, placebo-controlled trial of modafinil for cocaine dependence showed

that modafinil improved clinical outcome when combined with psychosocial treatment for cocaine dependence.
Patients require follow-up for neurological complications.

Neuropsychiatric complications
Neuropsychiatric complications occur in about 40% of cocaine users. Psychiatric disturbances include depression,

suicidal ideation, paranoia, kleptomania, violent antisocial behavior, catatonia, and auditory or visual hallucinations.

Hallucinations occurring with cocaine intoxication can be simple or complex, affecting various sensory categories (eg,

visual, auditory, cutaneous, visceral, cenesthesic), and may be associated with delusions of persecution.
A moderate proportion of addicts develop panic attacks, which are different from primary panic attacks in that cocaine

users frequently have psychosensory symptoms, infrequent agoraphobia, hypersensitivity to caffeine, untoward responses

to antidepressants, partial improvement with alprazolam, and marked recovery with clonazepam or carbamazepine.
Cocaine panic attacks can be explained in terms of limbic-neuronal hyperexcitability.
Suspicious and paranoid attitudes can easily be aroused experimentally by cocaine use. The paranoid symptoms are more

severe and develop more rapidly with continuous use of cocaine.
Convulsions
Convulsions occur in about 3% of cocaine users. Convulsions caused by cocaine can be generalized or partial, simple or

complex. The majority of seizures are single, generalized, induced by intravenous or crack cocaine, and not associated

with any lasting neurological deficits. Most focal, multiple, or induced seizures caused by nasal insufflation of cocaine are

associated with an acute intracerebral complication or concurrent use of other drugs.
The mechanism of cocaine-induced seizures is thought to be related to the local anesthetic action of the drug. Like

lidocaine, cocaine lowers the seizure threshold and can block nerve cell conduction. Generally, seizures caused by

cocaine use are associated with cerebral lesions or with interictal EEG abnormalities.
Seizures are one of the few complications of cocaine use in which a direct relationship with dose has been shown.
All routes of administration are associated with seizures, and seizures can be induced in some persons by small quantities

of cocaine. Once intoxication has passed, these individuals do not require long-term anticonvulsant therapy.
Although most cocaine-induced seizures are benign and self-limiting, seizures may be due to other more severe

complications, such as infarction and intracranial hemorrhage.
Cerebrovascular disorders
Cerebrovascular disorders may be secondary to arterial or venous etiology. Arterial complications include either ischemic

or hemorrhagic strokes.
Hemorrhagic manifestations may be intraparenchymal or subarachnoid hemorrhage. Hemorrhage occurs about twice as

frequently as ischemia. When neurological signs are present, imaging studies show findings associated with neurological

abnormalities in nearly 80% of cases.
Ischemic manifestations of cocaine are postulated to be secondary to vasospasm or vasculitis or due to the procoagulant

effect of the drug, which enhances platelet aggregation by depletion of arachidonic acid and thromboxane.
With intravenous use of cocaine, ischemic stroke may be cardioembolic–a complication of endocarditis. Complications

include anterior spinal artery syndrome, lateral bulbar syndrome, and transient ischemic attacks.
Rarely, inhalation of cocaine also can lead to subarachnoid hemorrhage. An extensive infarct of the middle cerebral artery

can occur after smoking free-base cocaine or cocaine paste.
Hemorrhages can be subcortical, pontine, or subarachnoid and may be associated with malformations, tumors, or

aneurysms.
Cocaine-induced stroke in patients with underlying vascular malformations is thought to be due to the transient elevation

of blood pressure that occurs after cocaine ingestion.
Hemorrhage may occur within seconds of cocaine use or may lag cocaine use by as long as 12 hours. In many cases,

however, it occurs within a few minutes. This corresponds well with the known transient period of increased systolic

blood pressure seen in these patients.
Although most cocaine-induced strokes occur in patients younger than 50 years, age and hypertension are regarded as

risk factors for cocaine-induced stroke. Alkaloid cocaine probably is associated more commonly with ischemic and

hemorrhagic accidents than other forms of cocaine. Impurities of street cocaine, such as talc or sugar, may embolize to

the brain after intravenous injection.
Subarachnoid hemorrhages primarily occur in patients with underlying vascular malformations. Berry aneurysms of the

circle of Willis are a common finding; AV malformations or tumors may be seen as well.
Ruptures of multiple mycotic aneurysms and large-vessel thromboses have been described. Venous complications include

superior sagittal sinus thrombosis with hemorrhagic venous infarction, ie, dural AV fistula.
Movement disorders
One single cocaine inhalation in patients with Tourette syndrome can worsen the clinical picture considerably, possibly

reflecting the intrinsic receptor hypersensitivity to dopaminergic transmission in the CNS.
Opsoclonus and myoclonus also are seen after cocaine inhalation.
Cocaine addicts can develop marked dystonic reactions during the withdrawal phase. These attacks subside quickly with

administration of diphenhydramine HCl. The dystonia probably is precipitated by the functional dopamine deficiency in

these patients.
Muscular disorders
In regions of the world with warm climates, cocaine-intoxicated patients in emergency rooms may show rhabdomyolysis.

These patients have blood CK values exceeding 12,000 U/L. More than one third of these patients develop severe

kidney insufficiency with hypotension, hyperpyrexia, disseminated intravascular coagulation, hepatic dysfunction, and CK

values greater than 30,000 U/L. Dialysis is indicated in such patients.
The pathogenesis of rhabdomyolysis remains obscure and speculative.
Probably because of dopamine depletion, administration of neuroleptics in agitated long-term cocaine users can worsen

the clinical picture and cause development of malignant hyperthermia. These patients should be treated with a

dopaminergic agonist (eg, bromocriptine) and not with neuroleptics.
Secondary complications
Cocaine-induced arterial thrombosis may occur in patients with a recent history of cocaine abuse. This presents as acute

limb ischemia without an identifiable cardiovascular risk factor. Prompt angiography with operative or endovascular

intervention should be performed.
The effects of cocaine on other organ systems may lead to CNS complications.
Cocaine may lead to myocardial infarction, cardiac arrhythmias, and respiratory arrest; any of these complications could

lead to cerebral hypoperfusion or cerebral embolization of blood products.
Spinal cord involvement: Infarction of the spinal cord due to anterior spinal artery involvement leading to quadriplegia has

been reported as a complication following acute cocaine intoxication.
Pregnancy and newborns
Women using cocaine have higher numbers of spontaneous abortions, premature births, and placenta previa than

nonusers. Babies born to these mothers exhibit significant depression in behavior and response to stimuli. Newborn

babies may develop cerebral infarcts. Intrauterine fetal growth may be retarded; microcephaly, small-for-date birth

weights, convulsions, infarcts, cerebral hemorrhages, hypertonicity, motor restlessness, and absence of saccadic

movements on oculovestibular stimuli are more common than in newborns of mothers who do not use the drug.
Congenital malformations are postulated to result from fetal ischemia during the first trimester, and occlusive stroke is a

consequence of ischemia during the third trimester.
Respiratory anomalies in newborns are more noticeable during sleep. Severe respiratory difficulty syndromes and failures

of the awakening mechanism have been documented. Sonography, CT scan, and MRI revealed cortical infarcts and

midline congenital malformations in 15% of infants born to mothers who used cocaine.
Prenatal exposure to cocaine is related to aggressive behavior at age 5
years.

Pure cocaine was first used in the 1880s as a local anesthetic in eye, nose, and throat surgeries because of its ability to

provide anesthesia as well as to constrict blood vessels and limit bleeding. Many of its therapeutic applications are now

obsolete though due to the development of safer drugs.
Cocaine is the most potent stimulant of natural origin. This substance can be snorted, smoked, or injected. When snorted,

cocaine powder is inhaled through the nose where it is absorbed into the bloodstream through the nasal tissues. When

injected, the user uses a needle to release the drug directly into the bloodstream. Smoking involves inhaling cocaine vapor

or smoke into the lungs where absorption into the bloodstream is as rapid as by injection. Each of these methods of

administration pose great risks to the user.
Crack is cocaine that has been processed from cocaine hydrochloride to a free base for smoking. Crack cocaine is

processed with ammonia or sodium bicarbonate (baking soda) and water. It is then heated to remove the hydrochloride

producing a form of cocaine that can be smoked.