National Institute on Drug Abuse

RESEARCH

MONOGRAPH SERIES

Acute Cocaine

Intoxication:

Current Methods

of Treatment

U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health

123
Acute Cocaine Intoxication:

Current Methods of

Treatment

Editor:

Heinz Sorer, Ph.D.

NIDA Research Monograph 123

1992

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Institutes of Health

National Institute on Drug Abuse

5600 Fishers Lane

Rockville, MD 20857
ACKNOWLEDGMENT

This Monograph is based on the papers and discussions from a technical

review on “Acute Cocaine Intoxication: Current Methods of Treatment” held

on July 9-10, 1991, in Bethesda, MD. The technical review was sponsored

by the National Institute on Drug Abuse (NIDA).

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained permission from the

copyright holders to reproduce certain previously published materials as noted

in the text. Further reproduction of this copyrighted material is permitted

only as part of a reprinting of the entire publication or chapter. For any other

use, the copyright holder’s permission is required. All other material in this

volume except quoted passages from copyrighted sources is in the public

domain and may be used or reproduced without permission from the Institute

or the authors. Citation of the source is appreciated.

Opinions expressed in this volume are those of the authors and do not

necessarily reflect the opinions or official policy of the National Institute on

Drug Abuse or any other part of the U.S. Department of Health and Human

Services.

The U.S. Government does not endorse or favor any specific commercial

product or company. Trade, proprietary, or company names appearing in this

publication are used only because they are considered essential in the context

of the studies reported herein.

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index, Biosciences

Information Service, Chemical Abstracts, Current Contents, Psychological

Abstracts, and Psvchopharmacology Abstracts .

NIH Publication No. 93-3498

Printed 1993

ii
Contents

Page

The Medications Development Program: A New Initiative of

the National Institute on Drug Abuse 1

Heinz Sorer

Cocaine-Related Medical Crises: Evidence From the Drug

Abuse Warning Network 20

James D. Colliver, Andrea N. Kopstein, and Arthur L. Hughes

Preclinical Assessment of Cocaine Toxicity: Mechanisms and

Pharmacotherapy 44

Jeffrey M. Witkin and Jonathan L. Katz

The Cardiovascular Effects of Cocaine—Update 1992 70

Lewis R. Goldfrank and Robert S. Hoffman

Cocaine-Related Emergency Department Presentations 110

Kathleen S. Schrank

Cerebrovascular Complications From Cocaine: Possible

Long-Term Sequelae 129

Bruce L. Miller, Frances Chiang, Lora McGill, Todd Sadow,

Mark A. Goldberg, and lsmael Mena

Cocaine Levels and Elimination in Inpatients and Outpatients:

Implications for Emergency Treatment of Cocaine

Complications 147

Michael C. Rowbotham

iii
Potential Adverse Interactions of Drugs With Cocaine 156

Paul R. Pentel and Timothy N. Thompson

The Pathology of Cocaine: Perspectives From the Autopsy

Table 172

Charles V. Wetli

Summary Comments 183

Marian W. Fischman, Reese T. Jones, and James W. Cornish

List of NIDA Research Monographs 185

iv
The Medications Development

Program: A New Initiative of the

National Institute on Drug Abuse

Heinz Sorer

INTRODUCTION

The National Institute on Drug Abuse (NIDA) plays a leading role in the Federal

research effort to increase knowledge about the causes and treatment of drug

abuse and addiction and to identify means of preventing and controlling drug

abuse and ultimately to eliminate the demand for illicit drugs in this country.

Congress passed the Anti-Drug Abuse Act of 1988 as a legislative response

to the drug abuse epidemic. Cocaine and crack use were important

considerations in the development and passage of this legislation, which

authorized up to $2.7 billion for all Federal activities in the War on Drugs.

NIDA received almost $300 million for use in data collection, treatment

evaluation, demonstration projects, and for the first time, the development

of new and improved medications to fight drug abuse. Of this $2.7 billion,

$10 million was allocated for medications development. In subsequent years,

the budget for medications development has increased as programs were

initiated and studies funded.

The 1988 act also entailed the setting up of a new division within NIDA, the

Medications Development Division (MDD), which was outlined in 1989 although

it did not become official until 1990. Its goals include:

Conducting necessary studies to identify, develop, and obtain Food and

Drug Administration (FDA) marketing approval for new medications for the

treatment of drug addiction and other brain and behavioral disorders

Developing and administering a national program of basic and clinical

pharmaceutical research designed to develop innovative biological and

pharmacological treatment approaches for addictive disorders

1
Establishing a close working relationship with pharmaceutical and chemical

companies in the United States and abroad and with medications

development programs in other agencies in the United States and abroad

Figure 1 shows the current organization of NIDA. MDD is one of six research

divisions within the Institute.

Figure 2 shows the organization of MDD. Its setup is much like that of a

minipharmaceutical company, with the same branches or departments that are

found at a large pharmaceutical manufacturer. The Division consists of the

following branches: Chemistry/Pharmaceutics, Pharmacology/Toxicology,

Clinical Trials, Regulatory Affairs, and Biometrics. Since 1989 MDD has grown

to 33 employees and a budget of $30 million. The Division is expected to reach

its projected size of 35 to 40 staff members within one year, with a growing

budget to meet its expanding needs and capabilities.

By hiring staff and contracting for scientific services, NIDA has the capacity to

develop medications from the point of discovery to preclinical studies to clinical

testing. By means of the Government contracting process, MDD is developing

the intrinsic capacity to perform all necessary chemistry, pharmacokinetic,

pharmacology, and toxicology studies necessary to support clinical trials to treat

substance abuse.

The Division has established a close working relationship with FDA and the

Pharmaceutical Manufacturers Association.

When used appropriately, medications work in the treatment of addiction.

There is a need to increase treatment capacity and effectiveness, and

medications are tools in this effort. NIDA is providing leadership by committing

itself on a long-term financial, programmatic, and scientific basis to the

development of such medications.

These medications will not be magic bullets; rather, they will be part of a

comprehensive treatment program addressing the psychological, social, and

behavioral aspects of addiction. It is hoped that the medications will be able to

normalize an individual whose brain has been biochemically deranged by drugs.

The aim is to bring as many patients as possible to a drug-free state; the

pharmacologic agents will act as bridges to such a state.

MDD is not focused solely on drug abuse treatment. It also coordinates

medications development with NIDA’s sister research institutes, the National

Institute on Alcohol Abuse and Alcoholism and the National Institute of Mental

Health. In this case, MDD will assist in developing studies of medications to

2
FIGURE 1. Current organization of NIDA
FIGURE 2. Current organization of MDD
treat alcoholism and less studied forms of mental illness, such as refractory

depression, a form of depression unresponsive to any marketed medications.

In fiscal year (FY) 1991, the budget for the Medications Development Program

was about $40 million, or about 9.5 percent of NIDA’s budget.

MDD has been using a multipronged approach to medications development

to help speed up the process. By hiring staff and contracting for scientific

services, NIDA has the capacity to develop medications from the point of

preclinical studies to clinical testing. By means of the Government contracting

process, MDD has developed the intrinsic chemistry, pharmacokinetic,

pharmacology, and toxicology studies necessary to support clinical trials for

medications to treat substance abuse.

The Division has brought together the Federal Government, pharmaceutical

companies, and academia in new and innovative cooperative ventures.

Specifically, the Division has expanded NIDA’s pharmacologic research

capabilities, forged drug development agreements with pharmaceutical firms,

and established a network of clinical research sites at universities and

Department of Veterans Affairs (DVA) medical centers nationwide.

The following are brief descriptions of some of the ongoing MDD programs.

This survey provides an overview and is not all inclusive.

COCAINE TREATMENT DISCOVERY PROGRAM

The goal of the program is to identify new pharmacologic entities that may be

of use in the treatment of cocaine abuse, which has proven to be refractory to

most standard methods of treatment.

Critical reviews of the current scientific literature are being carried out to

identify potential treatment medications. Efforts also are being directed

toward understanding the types of physiological mechanisms that mediate

the effects of cocaine to identify additional drug classes that might serve as

useful medications. These functions are being accomplished through the

efforts of a compound identification team, which draws on the expertise of

individuals with chemistry and pharmacology backgrounds.

Once specific compounds have been targeted, a compound acquisition team

contacts the appropriate commercial or academic concerns to secure the

compound for testing. Agreements are also established with industry to

provide incentives for the development of compounds identified as potential

treatments of cocaine abuse. These incentives are in place primarily to ensure

5
that proprietary rights to the compound are retained by the pharmaceutical

company and that the rights to the development and marketing of promising

compounds will rest with the company. Another significant incentive is that

preclinical testing (and, potentially, clinical testing) is carried out with minimal

expense to the company.

A decision tree has been established to determine the sequence of preclinical

tests to be conducted. This testing scheme has been designed to distinguish

those compounds that show promise as potential therapeutic agents from

those that do not. Two types of therapeutic approaches have been identified

according to how they decrease the effects of cocaine, and the decision tree

has been organized to identify compounds that possess the pharmacological

profile necessary for either treatment strategy. In one approach, medications

that antagonize the effects of cocaine are identified. In the other, compounds

are identified for their ability to substitute for cocaine, in much the same manner

as methadone is used to substitute for heroin. Pharmacokinetic characteristics

of the medications are of critical importance for the success of either type of

treatment program. For example, the duration of action of the medication

must be of sufficient length to make the treatment practical. Substitution

medications have some unique pharmacokinetic requirements. Such a

medication should have a slow onset of action so that it does not produce a

rapid “high” associated with its administration. A rapid onset may confer

abuse liability to the medication itself. An additional feature of a substitution

medication is that it should have less activity than cocaine, to further limit its

abuse liability.

Testing is conducted at several different facilities, including universities

under contractual arrangements and Government laboratories under

interagency agreements. These sites test compounds by means of several

testing procedures using protocols outlined by the Cocaine Treatment

Discovery Program. The sequence for conducting the various tests is

determined by the decision tree. The initial testing, which involves in vitro

receptor binding assays as well as associated functional assays, is conducted

as a means of pharmacologically profiling new compounds. Since specific

neurochemical mechanisms of action have been targeted as potential leads

for medication development, the results obtained from these in vitro assays

are used to prioritize compounds for subsequent in vivo behavioral testing.

Three primary behavioral tests have been shown to be reliable in measuring

cocaine effects and are thought to be valid measures of the abuse potential

of cocaine. The initial assay is stimulation of locomotor activity. Those

compounds that stimulate activity in a manner similar to cocaine are not

subjected to further testing. Compounds that do not stimulate behavior,

6
or show weak stimulant effects, are examined further. Subsequent testing is

directed toward assessing whether these potential medications are effective

in blocking or attenuating the effects of cocaine, including the ability of the

compounds to attenuate cocaine-induced stimulation of locomotor compounds.

Other assays involve more complex behavioral effects of cocaine. Another

test, cocaine discrimination, examines interoceptive cues, which are thought

to be analogous to the use of cocaine in humans, and determines whether

medications alter or attenuate those effects. Cocaine self-administration

examines the rewarding effects of cocaine and determines how frequently

subjects take cocaine when being treated with the medication. Although

most of these experiments are conducted in rodents, additional cocaine

discrimination and self-administration studies will be conducted in primates

to provide information for investigational new drug application (IND)

submissions.

Once a compound has been examined in all tests as determined by the

decision tree, the results are evaluated and recommendations are made

regarding its status as a clinical trials candidate. In addition, both positive and

negative results are further considered by the Cocaine Treatment Discovery

Program. The information is of considerable use in providing insights into new

directions and approaches as well as in determining which directions are not

likely to be profitable.

At present, attention is directed toward examining compounds with particular

mechanisms of action that have been identified by examining the scientific

literature. According to this literature, there are three basic physiological

systems on which drugs might act to attenuate the effects of cocaine: the

neurotransmitters dopamine and serotonin as well as receptors for ligands.

The Cocaine Treatment Discovery Program has prioritized drugs that act

according to these mechanisms for immediate and close examination.

There are also indications, based on more preliminary data, that compounds

acting via different mechanisms may be of some consequence in modifying the

effects of cocaine; these compounds also are being tested. Some drugs with

mechanisms of action of unknown utility in treating cocaine abuse are also

being evaluated, since the results from such tests can be of value in serving

as pharmacological standards. In addition, these drugs may have unexpected

activity in altering the effects of cocaine.

DEVELOPMENT OF NEW AND NOVEL DOSAGE FORMS TO IMPROVE

COMPLIANCE, MINIMIZE DIVERSION, AND IMPROVE EFFICACY

Recent advances in pharmaceutical technology make it possible to develop

controlled-release delivery systems that provide optimum drug effects by

7
controlling the rate at which a drug enters the body. Of particular interest

among the controlled-release systems are the injectable/implantable depot

formulations to reduce dosing frequency, thus improving treatment compliance

and reducing the necessity for frequent clinic visits. In addition, the diversion

problems associated with take-home doses are eliminated.

NIDA has supported research in this area by means of grants and contracts.

An injectable naltrexone depot preparation has been developed and will

soon be tested in humans for safety and efficacy. In addition, efforts on the

development of 1 -week sustained-release dosage forms for narcotic agonists

(methadone) and l-month systems for antagonists (naltrexone and nalmefene)

and a mixed agonist/antagonist (buprenorphine) are ongoing and currently

funded.

PRECLINICAL TOXICOLOGY PROGRAM

Inherent in the development of any new medication is a series of studies

designed to determine medication safety for ethical reasons. These studies

must be conducted in animals before the medication is given to humans.

Generally, toxicity studies are tests that directly identify and quantify the

adverse effects, at high doses, that a drug is capable of producing. The

results of these studies in animals are of great assistance to the clinician in

monitoring the subjects for potential adverse effects of the drug in clinical trials.

The studies are classified by the number of doses administered to the animal:

For example, acute is a single dose, subchronic (also called subacute) is

usually 2 to 14 weeks of continuous dosing, and chronic studies are usually

for 1 year. In addition, evaluation of the carcinogenic potential, conducted in

rodents, requires 18 to 24 months of dosing. The cost and amount of time to

conduct these studies are directly proportional to the duration of dosing and

the number of animals required. An acute study can be conducted for $20,000,

whereas a carcinogenicity study in a rodent costs more than $2 million.

To ensure that resources are used wisely and that the toxicology studies

are conducted well in advance of the clinical investigations, MDD has

established a formal peer review committee that develops a long-range plan

for new studies, including the development of interagency agreements and

contracts. Furthermore, the peer review committee finalizes all new protocols,

assists the project officer in monitoring the studies, and reviews all final reports.

The time to conduct a complete series of tests—starting with the acute study

and finishing with the carcinogenicity evaluation—typically covers at least 5

years. The studies are conducted to set meaningful dose levels for longer term

studies.

8
To ensure the safety of the drugs to women of childbearing potential,

reproductive and teratology testing in rats and rabbits must be conducted

to assess any adverse effects.

Although the technology of toxicology testing in the development of new

medications is not anticipated to change substantially, consideration must be

given to the interactions between abused drugs and new medications. This is

particularly important in medications to be tested for the treatment of cocaine

addiction, since the mechanisms of cocaine’s effects on human organs are

more complex than the effects of opiates. MDD has developed a paradigm to

address the issue of adverse drug interactions. These studies will likely be

included in INDs to support safety of medications to treat cocaine addiction.

The cost of providing additional toxicology testing services (including interaction

studies) must be borne in the development of new medications.

Toxicology studies (in animals) must be conducted prior to conducting clinical

trials. The duration and the type of toxicology study are dependent on the type

of trial (i.e., number of days dosed).

PHARMACOKINETICS AND PHARMACODYNAMICS

Pharmacokinetics is a quantitative description of the processes-absorption,

distribution, metabolism, and excretion (ADME)-that a drug undergoes in the

body. Pharmacodynamics is a quantitative description of the time course of

drug effects. Since the effects of a drug are in general related to the quantity

of a drug that reaches the site of action and how long it remains there, the

integration of pharmacokinetics and pharmacodynamics is of significant

importance in enhancing the understanding of basic mechanisms governing

drug action and provides a means to establish the correlation of drug responses

with the concentration in biological fluids.

Thus, pharmacokinetic/pharmacodynamic information is essential in every

phase of medication development such as the selection of the drug, route and

dose of administration for pharmacology/toxicity assessments, design and

evaluation of dosage forms, and establishment of dosage regimens for clinical

use. In addition, the pharmacokinetic/pharmacodynamic information is required

by FDA for the approval of INDs and new drug applications (NDAs).

NIDA has supported pharmacokinetic/pharmacodynamic studies in both

animals and humans for potential treatment drugs through contracts and

interagency agreements with DVA. The pharmacokinetic/pharmacodynamic

information covering the dose range proposed for pharmacological/toxicological

and clinical studies is generated for candidate treatment drugs following single

9
and multiple doses. When appropriate, interaction studies of the drugs with

alcohol, cocaine, and other drugs will be conducted to determine if there is

any pharmacokinetic or pharmacodynamic interaction. The work involved in

these studies includes the development of analytical methods; identification

of metabolites; quantification of drugs/metabolites in biological samples;

determination of pharmacokinetic parameters such as bioavailability, volume of

distribution, protein binding, clearance, and half-life monitoring pharmacological

responses; and establishment of correlation of pharmacological responses

with drug plasma Ievel/pharmacokinetic parameters. Pharmacokinetic/

pharmacodynamic studies are in progress for l-alpha-acetyl methadol (LAAM),

naloxone, and buprenorphine. Studies with ibogaine are planned.

The utility of pharmacodynamic/pharmacokinetic studies in relation to clinical

studies is illustrated by the following examples.

The results of a study on buprenorphine indicate that it is quickly absorbed

following the sublingual route of administration. These data provide the basis

for the establishment of a sound clinical protocol regarding the time required

for holding buprenorphine under the tongue for a pivotal clinical trial (N. Chiang,

personal communication, February 1992).

Pharmacokinetic and pharmacodynamic data indicate that buprenorphine

(a mixed opioid agonist) is much more bioavailable than naloxone (an opioid

antagonist) following the sublingual route of administration (N. Chiang, personal

communication, February 1992). One can take advantage of this differential in

bioavailability between buprenorphine and naloxone in such a manner that

buprenorphine effects are predominant (only slightly attenuated by naloxone)

following the prescribed sublingual route of administration, whereas naloxone

effects are predominant following the illicit parenteral route of administration.

Consequently, when given by the prescribed route, buprenorphine will be

effective for addiction treatment, whereas taken by the illicit intravenous route,

it may be ineffective or may precipitate withdrawal in opiate-dependent patients.

Therefore, this product will have very low abuse potential and can be dispensed

as a “take-home” drug. Clinical pharmacokinetic and pharmacodynamic studies

are in progress to determine the optimal doses of buprenorphine and naloxone

for the development of such a combination sublingual product.

REGULATORY AFFAIRS

A major role in the development of new medications has been assumed by

FDA since the Kefauver-Harris amendments to the Food, Drug, and Cosmetic

Act were passed by Congress in 1962. All sponsors are required to submit an

IND before embarking on research in humans with a nonmarketed drug or a

10
marketed drug for a new indication or a new medication; throughout the entire

development of a new medication, numerous INDs and eventually an NDA will

be filed. The sponsor and FDA interact frequently (e.g., in the pre-IND and

pre-NDA meetings) to ensure a thorough mutual understanding and productive

collaboration.

The MDD Regulatory Affairs Branch prepares and files INDs involving

chemistry, formulation, pharmacology, toxicology, and clinical data and

serves as liaison with the relevant FDA reviewing division, including

arranging all necessary pre-IND and end of Phase I and II trial meetings

for non-Government sponsors working with NIDA in obtaining approval for an

indication of drug abuse or addiction. The Branch also performs liaison with

other essential U.S. Public Health Service agencies to secure the regulatory

approvals necessary to undertake Government-sponsored or cosponsored

trials.

The Regulatory Affairs Branch is responsible for implementating the Federal

Technology Transfer Act for NIDA. In this role, the Branch examines invention

reports submitted by intramural scientists and makes recommendations

regarding domestic and foreign patent filings, material transfer agreements,

and licensing provisions to the National Institutes of Health Office of Technology

Transfer. The Branch also provides technical assistance and primary review

of intramural Cooperative Research and Development Agreements (CRADAs)

and is the progenitor of extramural CRADAs involving attempts to

commercialize new medications and dosage form technologies.

In line with its responsibilities involving technology transfer, interagency liaison,

and regulatory filings, the Branch serves as the contact point for all entities

(governmental and nongovernmental) that wish to explore the possibility of

pursuing development of medications to treat addiction. The Branch not only

provides guidance in the area of interacting with MDD on projects of mutual

interest but also serves as a broker in suggesting alternative resources that

may be available to meet the needs of investigators and sponsors when MDD

cannot provide these services or cannot provide them in a timely manner. MDD

considers these activities, which may potentially expedite development of new

addiction treatment medications, to be worthwhile regardless of the level of

MDD involvement.

BIOMETRICS BRANCH

The Biometrics Branch is engaged in the design and formulation of research

protocols and the collection, computer entry, management, and analysis of

data of preclinical and clinical studies. The objectives of these studies include

11
the identification of potential medications and, by means of appropriate clinical

trails, the preclinical and clinical development of new medications useful in the

treatment of drug dependency and addiction.

CLINICAL TRIAL PROGRAM

The purpose of the clinical trial is to determine—by means of the collection of

clear and well-documented evidence—whether the investigational medication is

effective and safe when used according to the manner intended. Clinical

evaluation of a compound is initiated when there are adequate, sufficient, and

appropriate preclinical data to support the investigation in humans. An IND

must be filed with FDA prior to initiation of the trials. Conventionally, clinical

trials are conducted according to the following approach:

Phase I trials establish the human dose range and the ADME profile as well

as any adverse reaction to the new medication in normal, healthy volunteers.

Such studies are open (i.e., not blinded) and are often carried out in clinical

research centers by a clinical pharmacologist.

Phase II trials test the medication in a small population of patients with the

target disease to determine efficacy and to develop additional safety data.

Studies are carried out under controlled double-blind conditions.

In Phase III trials the medication is evaluated in a wider range of patients to

substantiate further the efficacy of the medication. These trials are usually

conducted in clinical settings similar to those anticipated for the ultimate use

of the medication. The investigators are usually specialists in the treatment of

the targeted disease.

The implementation of clinical trials for the development of drug abuse

treatment medications is a highly complex task. It requires an integrated

effort of multidisciplinary expertise with resources. These activities may be

described as the development of (1) sensitive clinical efficacy trial methodology,

(2) clinical trial infrastructure and resources, and (3) clinical data management.

Clinical trials for the development of new medications are highly focused

activities with safety and efficacy as the common primary outcomes. The

design of the trial is of great importance in achieving these goals. By optimizing

the sensitivity of the trial, highly predictive clinical efficacy data will be

generated.

Currently, the treatment of cocaine abuse and dependence is an area of

controversy. Basically, there is a lack of consensus in the field about (1) the

12
perception of the biological nature of the disorder as well as a treatment

rationale, (2) a well-accepted and widely utilized effective treatment paradigm,

and (3) possible useful medications as adjunctive therapy.

MDD is seeking medications that will treat overdose, reduce use, initiate

abstinence, and/or prolong abstinence or prevent relapse of cocaine abuse.

In recent years, a variety of pharmacological approaches have been introduced

to reduce cocaine craving and use. Most of these have been tested in openlabel, noncontrolled trials with little value for assessing the aforementioned

efficacy outcome of the medications. Several clinical pharmacology trial

paradigms have been used by researchers to explore a medication’s effect

on human drug discrimination, drug self-administration, or drug-seeking

behavior. However, the clinical implications of such study results in predicting

the aforementioned efficacy outcome of the investigational medications are not

clear.

MDD has created a diverse portfolio of clinical capabilities. NIDA’s Addiction

Research Center (ARC) in Baltimore, MD, maintains a 24-bed inpatient unit

and an outpatient clinic. This facility has pioneered the testing of medications

for the treatment of narcotic and stimulant abuse. Medication development

studies have included opiate agonists and antagonists, antidepressants,

dopaminergic agents, calcium channel blockers, and antiepileptic medications.

ARC has the capacity to conduct Phase I and early Phase II trials with new

medications selected by MDD for possible development. A Phase I pilot study

of depot naltrexone is being conducted at ARC for MDD.

By means of grants, MDD and the Division of Clinical Research support several

well-recognized Treatment Research Units (TRUs) around the United States,

which are well respected in the field of pharmacotherapy of substance abuse

disorders. Several marketed compounds with central nervous system activity

were studied for efficacy of cocaine abuse treatment in various TRUs in 1991.

Under an interagency agreement between NIDA and the Washington, DC,

DVA Medical Center, the Institute supports a 24-bed inpatient/outpatient facility

for the conduct of clinical trials of medications to treat substance abuse

disorders. Operated by the Psychiatry Service, the unit became operational in

April 1991. Both Phase I and early Phase II trials may be performed at this

facility. Interagency agreements between NIDA and two other DVA medical

centers have also been developed with the goal of developing the capacity for

multicenter trials. Existing agreements involve the DVA medical centers in

Philadelphia and West Los Angeles.

13
In addition to developing these DVA sites, MDD also developed an interagency

agreement with the DVA’s Cooperative Studies Program (CSP) to conduct

clinical trials. Under this agreement, CSP will select participating DVA medical

centers to provide inpatient and outpatient facilities and services necessary for

the implementation of clinical trials. Currently, MDD has two multicenter clinical

trials planned on buprenorphine, as well as a multicenter study on LAAM. Both

projects will utilize a combination of the DVA, the DVA CSP, and some of the

TRU sites.

Clinical Data Management

Clinical trials are focused, organized research studies conducted in humans

to determine the risk or benefit ratio of a new therapeutic agent. These

studies must be conducted under FDA regulations. The end products of

clinical trials are data and observations, which are analyzed according to

preselected statistical tests. To ensure the integrity of the study database

and the consistency between and among different study sites, the need for

proper and effective study monitoring and data management cannot be

overemphasized.

The scope of clinical data management activities includes:

Carefully designed clinical protocol and case report forms

Efficient management of clinical data

Quality assurance of the consistency and documentation of all modification

and transformation of data

The objectives of clinical data management are to maximize the accuracy,

speed, and cost-effectiveness of data transfer from the case report forms to the

study master file that is appropriate for the statistical analysis that will be used

to support the efficacy of the drug under study. During the process, the data

must be verified by quality control audit prior to the submission of each report.

For various management and analytical purposes, the study master file and its

subsets must be organized in a manner readily available to retrieval and

manipulation for an extended period.

To ensure smooth clinical data flow and accurate recordkeeping, clinical data

management involves not just statistical design and analysis of the clinical trial

but also development of software for data collection, storage and retrieval,

encoding, and entry; database validation; and generation of listings, reports,

and summaries. This activity usually involves such personnel as physicians,

clinical data processors, computer specialists, and statisticians.

14
At the present time, MDD is utilizing the Perry Point, MD, Data Coordinating

Center, DVA, via the DVA CSP agreement, to manage the buprenorphine and

LAAM multicenter trials.

Clinical Study Monitoring

The function of clinical study monitoring is to ensure smooth and productive

interactions among the study sponsor, MDD, study investigators (e.g., ARC,

TRUs, DVA, medical centers, or other sites), and the regulatory body (FDA).

Each party has a scientific as well as a societal role in the process of

medications development and use. Since each tends to see its roles differently,

conflicting views are inevitable. Therefore, the clinical monitors must ensure

that the study is conducted according to the protocol in compliance with Good

Clinical Practices and FDA regulations and that each clinical study conforms

to accepted medical standards for the protection of subjects. The investigators

and their associates must be thoroughly instructed in their responsibilities,

including reporting procedures and study drug accountability. All relevant data

must be accurately recorded when the study has been completed. Any side

effects are promptly evaluated and communicated as appropriate to other

investigators and regulatory agencies. Thus, clinical study monitoring is an

important, continual effort during the life of a clinical trial. The effort is much

more extensive if the trial is a large multicenter trial.

COMPOUNDS CURRENTLY IN CLINICAL DEVELOPMENT

Opiate Treatment Compounds

LAAM. Although methadone maintenance had been shown repeatedly to

be the most effective treatment of opiate addiction in the late 1960s, several

investigators realized that significant problems existed with regard to the

pharmacology of methadone. At the doses used, methadone did not suppress

the narcotic craving for a full 24 hours in many addicts. Very large doses of

methadone were necessary to provide sustained relief of abstinence symptoms

for sedation, which caused the patient to “nod” for the first several hours after

consumption.

Furthermore, the patient was required to attend a methadone dispensing

clinic daily to consume his or her medication under staff supervision. This

inconvenient and burdensome time and travel demand was often draining

physically and emotionally. When the patient was assuming responsibility

and trying to engage in work, this requirement was considered by some to be

antitherapeutic. A compromise solution was reached. After demonstrating

satisfactory adherence to the program regulations for at least 3 months and

15
showing substantial progress in rehabilitation by participating in educational,

vocational, and homemaking activities, those patients whose employment,

education, or homemaking responsibilities would be hindered by daily

attendance may be permitted to reduce to three times weekly the times

when they must ingest the drug under observation (Federal Register 1972).

Take-home doses could be dispensed for the other 4 days after this regulation

was implemented.

The practice of permitting take-home supplies of methadone for unsupervised

self-administration contributed to new problems. Accidental ingestion of

methadone by nontolerant persons, especially children, led to an alarming

increase in toxic reactions and overdose fatalities. Also, a market developed

for the illicit sale and redistribution of methadone to heroin addict peers

suffering from withdrawal or to nonaddict drug users seeking a new euphoriant.

The treatment agent was becoming a new source of addiction. Finally, the

patient might skip or delay a dose of methadone to “shoot up” with heroin

after the blockade had diminished. Thus, the take-home privileges inadvertently

negated much of the usefulness of random urine monitoring for illicit heroin use.

Furthermore, an adversary system or “game” was created in which the patient

might attempt to deceive the treatment staff to gain or retain take-home

privileges. These issues demonstrated the need for opioid maintenance

pharmacotherapy.

In 1969, LAAM was tested in a clinical narcotic treatment program. LAAM

was selected because of its long duration of action. It also offered the patient

a smoother, sustained effect, appeared to have fewer sedative properties, and

produced a lower degree of euphoria. Patients could be maintained on a threetimes-weekly dosage schedule that eliminated the daily necessity of engaging

in drug-seeking and drug-taking behavior. This approach represents an

important therapeutic advance because the destructive, habitual pattern of

behavior associated with the heroin addict lifestyle is broken. The patient is

less psychologically and physically dependent when not involved with daily

drug taking; this can strengthen the addicts identification with the drug-free

population and break association with the drug culture.

LAAM offers a practical answer to the problems related to take-home

methadone. Illicit redistribution can be reduced because three-times-weekly

LAAM reduces the amount of take-home medication a clinic must provide

patients for out-of-clinic administration. If necessary, a no-take-home policy

can be established by a clinic or program where redistribution and accidental

overdose is especially prevalent.

16
Furthermore, several pharmacological properties make LAAM less prone to

abuse than methadone. LAAM is one-tenth as active as its metabolites.

Because metabolism requires time, several hours pass between taking

LAAM and the onset of psychoactivity. Therefore, LAAM is less likely to be

a reinforcer of drug-taking behavior because substances with a rapid,

immediate onset of euphoric effects are much more desired by drug users.

LAAM has another unique characteristic that makes it less desired: Its onset of

action is more rapid when administered orally than intravenously, the preferred

route of heroin addicts, which makes it different from opiates abused by the

intravenous route, namely, heroin.

LAAM may offer treatment programs advantages over methadone by improving

the logistics of drug distribution. A three-times-weekly dosage allows for more

controlled drug delivery to increasingly large numbers of patients. By reducing

the required number of clinical visits, efficiency of treatment may be increased

because fewer staff members are needed to dispense drugs and provide

pharmacy services. Thus, conversion either reduces the cost of treatment

or increases the number of available treatment slots.

MDD has reviewed preclinical and clinical data generated in the 1970s and

early 1980s and is working with a contractor to bring them into a suitable format

for assessment of an NDA. An observational labeling assessment study with

LAAM is planned in 15 to 30 methadone treatment clinics. Preclinical toxicity

studies are being reviewed to determine what deficiencies, if any, still exist, and

steps are being taken to address these. Current plans focus on a December

1992 “NDA Day for LAAM” with FDA.

Buprenorphine. Buprenorphine is a member of a relatively new class of

chemical compounds, a so-called partial p-agonist. It combines some of

the best attributes of medications such as methadone and naltrexone in a

single compound. The Medications Development Program is examining

buprenorphine as a maintenance and detoxification agent for opiate

dependence, and initial findings appear promising. Results of a study

performed at ARC show that an 8-mg dose of buprenorphine was as effective

as 60 mg (recommended therapeutic dose) of methadone in retaining clients in

treatment and in preventing illicit opiate use. On standard addiction rating tests,

the patients on buprenorphine scored as having less need for, less liking of, and

were less “hooked” on buprenorphine than patients on methadone. Other trials

are being initiated by MDD at NIDA-funded TRUs and at DVA medical centers.

MDD has prepared a comprehensive development plan for additional clinical

trials and related research necessary to obtain FDA approval of buprenorphine

for treatment of heroin addiction. Buprenorphine should be superior to

methadone in other ways. It produces significantly less physical dependence;

17
it is much easier to withdraw someone from the medication; and it should have

less abuse liability and overdose potential. NIDA has begun a 12-site, 500- to

700-subject clinical trial of buprenorphine in FY 1992. If this trial produces

confirmatory results, NIDA will also pursue the development of buprenorphine

combined with a suitable antagonist. Such a combination product would

precipitate withdrawal in addicts who have not been carefully acclimated to

buprenorphine, thus greatly reducing its desirability for diversion for illicit use

and potentially making this form of treatment available through a wider range

of providers than is possible under the current law regarding treatment with

narcotic agonist medications such as methadone. If a full development program

with an antagonist combination were to be pursued, it would require 2 to 3 years

of intensive effort and a commitment of several million dollars. As mentioned

previously, the buprenorphine/naloxone combination would be targeted for takehome use.

Depot Naltrexone. Naltrexone is an opiate antagonist currently marketed in

an oral dosage form that blocks the effects of opiates such as heroin. However,

patient compliance is low. Therefore, NIDA has developed a preliminary

version of a time-release depot dosage form to increase patient compliance.

A single injection of naltrexone utilizing this dosage form has blocked the effects

of opiate challenges for up to 7 weeks in rhesus monkeys. It is hoped that this

formulation may provide opiate blockade for periods of at least 30 days in

humans. NIDA has recently initiated a Phase I clinical trial in normal volunteers

at ARC to determine tolerance levels to various amounts of this new dosage

form. Additional funding will be needed to bring this dosage form to the stage

necessary to attract a commercial sponsor.

Ibogaine. NIDA has received information from individuals and groups of former

addicts concerning ibogaine. These individuals and groups have presented

anecdotal evidence of successful treatment of addiction to opiates and other

drugs in Europe using ibogaine, although these trials have not been run in

accordance with standards recognized by FDA or MDD. MDD has met with

these individuals and groups to discuss the types and quality of data that must

be generated to substantiate any of the claims made for this compound. NIDA

has agreed to pursue research on the pharmacology and toxicology of this

compound. The results of these studies will indicate whether clinical trials with

ibogaine are warranted.

SUMMARY

The NIDA Medications Development Program involves the discovery and

development of pharmacotherapies for drug dependence. The program

is proceeding along two fronts: development of pharmacotherapies for

18
(1) cocaine abuse and (2) opiate abuse. Discovery and development of

pharmacotherapies for cocaine abuse is a relatively new initiative being

vigorously and systematically pursued. Discovery and development of

pharmacotherapies for opiate abuse has been ongoing for more than 40 years;

knowledge in this area is greater than that for cocaine abuse. Nevertheless,

this effort will continue as the demand for new and nonaddicting analgesic

agents and pharmacotherapies for opiate abuse continues. It is expected

that MDD will grow as efforts to reduce cocaine and opiate continue.

REFERENCE

Federal Register. 37(242):26790, December 15, 1972.

AUTHOR

Heinz Sorer, Ph.D.

Pharmacologist

Medications Development Division

National Institute on Drug Abuse

Parklawn Building, Room 11A-55

5600 Fishers Lane

Rockville, MD 20857

19
Cocaine-Related Medical Crises:

Evidence From the Drug Abuse

Warning Network

James D. Colliver, Andrea N. Kopstein, and Arthur L. Hughes

INTRODUCTION

This chapter presents information on cocaine-related emergency room (ER)

episodes that occurred in the United States during 1989 and 1990. It is based

on data from the Drug Abuse Warning Network (DAWN) sponsored by the

National Institute on Drug Abuse (NIDA). Supplementary data on cocainerelated deaths seen by medical examiners (MEs) participating in DAWN also

are discussed. The rather restricted period of the trend analysis is necessary

because the ER data presented are weighted estimates from the new DAWN

sample of hospitals; comparable estimates for years prior to 1989 are not

available.

Trends in cocaine-related ER episodes in DAWN over longer periods have

been studied using raw data from hospitals that reported consistently (figure 1).

In the decade from 1976 through 1985, cocaine-related ER episodes increased

more than ninefold (National Institute on Drug Abuse 1987). From 1985 to

1988, these episodes underwent a further increase of more than fourfold

(Adams et al. 1990). In the second half of 1986, cocaine overtook both

heroin/morphine and alcohol-in-combination to become the most frequently

reported drug in the DAWN ER data (National Institute on Drug Abuse 1989).

More recently, unpublished trend analyses—based first on raw data from

consistently reporting hospitals and later on weighted estimates from the new

statistical sample—showed that cocaine mentions in ER episodes leveled off

from the second quarter to the third quarter of 1989 and then dropped 25

percent in the fourth quarter of that year. Subsequent data through the end of

1990 show additional, less dramatic decreases in cocaine mentions in ER drug

abuse episodes.

The first objective of this chapter is to examine this decrease in cocaine

mentions in the DAWN ER data to ascertain whether it can be credibly

20
FIGURE 1. Annual ER mentions of cocaine based on raw data from different

consistent panels, DAWN, 1976-90

interpreted as an actual decline in acute morbidity associated with cocaine use

or whether some other explanation would be consistent with the facts.

A second objective of the chapter is to examine cocaine-related episodes that

are reported as overdoses and compare these cases with other episodes in

which cocaine is mentioned. Overdose episodes-particularly those in which

cocaine is the only drug reported-would appear to most closely approximate

cases of acute cocaine intoxication, which is the topic of this monograph. In

addition to overdoses, DAWN collects data on drug-related episodes where the

reason for the ER visit is an unexpected reaction to the drug, chronic effects of

use, withdrawal, an accident or injury related to drug use, or to obtain medical

clearance or prior treatment in preparation for entry into a drug detoxification

program. However, DAWN data are collected through a record review system,

and information on factors such as the reason for the ER visit is frequently

unavailable or inconclusive. Therefore, it is important to look at both the overall

data on cocaine-related episodes and those episodes that involve an overdose.

In addition to ER data, this chapter provides information on cocaine-related

deaths reported by MEs affiliated with DAWN. Excluding data from the New

York and Newark metropolitan areas, which were incomplete, DAWN ME

cases involving cocaine increased from 53 in 1975 to 2,332 in 1989, a 44-fold

increase (National Institute on Drug Abuse 1987, 1990).

21
BACKGROUND AND METHOD

General Information on DAWN

DAWN is a large, ongoing data collection system designed to identify

emerging drug problems, monitor drug abuse patterns and trends, and

identify substances associated with acute morbidity and mortality. Morbidity

data are obtained from hospital ERs, and mortality data are collected from

MEs’ offices. Hospitals in 21 large metropolitan areas and a national panel

of facilities from outside those areas participate in DAWN on a voluntary basis.

ME facilities affiliated with DAWN are located in 27 metropolitan areas. The

data are collected by a reporter, generally a member of the facility staff, using

a record review procedure. Reportable cases are defined as those in which

a substance is used nonmedically to achieve psychic effects, because of

dependence, or in a suicide attempt or gesture. Nonmedical use includes

(1) use of a prescription drug in a manner inconsistent with accepted medical

practice, (2) use of an over-the-counter (OTC) drug contrary to approved

labeling, or (3) any use of another substance (such as an illicit drug) for psychic

effect, dependence, or suicide. As the DAWN data reflect only those instances

of drug abuse that have resulted in a medical emergency or death, patterns in

the DAWN data do not necessarily reflect profiles in the prevalence of drug use

in the general population. However, they are regarded as valid indicators of

acute health consequences of drug use.

New DAWN Statistical Sample and Estimates

DAWN was begun in 1972 by the Drug Enforcement Administration. A

representative statistical sample of hospitals was selected at the outset, but

over the ensuing years, attrition and recruitment of additional sample units

that had not been selected randomly caused the DAWN ER reporting base

to become nonrepresentative. During those years, data from DAWN did not

reflect total drug abuse ER episodes in the Nation or the respective DAWN

metropolitan areas. The trends and profiles of drug abuse cases were not

necessarily representative of such cases occurring at hospitals that did not

report to DAWN.

NIDA assumed responsibility for DAWN in 1980. One of its objectives was

to implement a new sample that could be used to produce representative

estimates for the Nation as a whole and for the separate DAWN metropolitan

areas. The project started in 1982 with the development of a sampling plan.

This plan required the recruitment of 300 new hospitals but was delayed until

1985 because of budgetary constraints. Recruitment of new sample hospitals

is now complete enough for the data to be used, and the weighting and

22
estimation procedures have been developed and refined. The annual ER

data report for 1990 (National Institute on Drug Abuse 1991 a) was the first

such document to be based on the weighted estimates, which represent NIDA’s

best estimate of the total number of drug abuse-related ER cases in the

coterminous United States (i.e., the 48 contiguous continental States and the

District of Columbia) and the 21 oversampled DAWN metropolitan areas.

The new sample provides weighted estimates for ER episodes starting

with the first quarter of 1989. Estimates produced for earlier periods are not

directly comparable with the weighted estimates because they were not based

on a representative sample of hospitals and because they were based on raw,

unweighted data. In both the old hospital reporting base and the new sample,

there are more facilities from the oversampled DAWN metropolitan areas than

from outside those areas (i.e., the national panel). In the new sample, for

example, about 18 percent of hospitals are in the national panel. However,

the territory covered by the national panel includes about 84 percent of all

eligible hospitals in the Nation. Thus, without the weights, the raw data

overemphasize cases occurring in the DAWN metropolitan areas. The new

estimates are calculated using weights that compensate for the different

sampling rates, nonresponse, and other factors. The data released by NIDA

in past years do not include these adjustments and also were not based on a

representative sample.

Important changes in the profile of DAWN cases occur when the weights are

used to create the estimates. In the unweighted data for 1989, for example,

cocaine was reported in 40.1 percent of ER episodes (National Institute on

Drug Abuse 1990). With the new estimates, the proportion of cocaine-related

episodes for 1989 was 25.8 percent based on weighted data from sample

hospitals. This change reflects the effects of properly weighting the data from

hospitals outside the 21 oversampled metropolitan areas. Transition to the

weighted data from the new sample changed the distributions for many

variables, including sex, age, race/ethnicity, and motive for drug use.

Although estimation procedures for the new sample have been developed,

variance estimation is expensive and somewhat difficult because of the complex

nature of the sample and the use of direct variance estimation methods. In

the tables in this chapter, estimates with a relative standard error (RSE) of 50

percent or higher are suppressed; refer to the Annual Emergency Room Data

1990 report (National Institute on Drug Abuse 1991a) for further information

about RSEs and the implications of the 50-percent criterion. Statistical tests

of selected differences have been performed as part of the analysis.

23
Method

Information on the general methods used in analyzing DAWN data can be

found in the Annual Emergency Room Data 1990 (National Institute on Drug

Abuse 1991 a) and Annual Medical Examiner Data 1990 reports (National

Institute on Drug Abuse 1991b). For this study, episodes involving cocaine

have been extracted from the overall files. Data on mentions of other drugs

in combination with cocaine are included in the analysis, and it should be

recognized that some of the patterns seen in the data for cocaine may be

more related to these other drugs than to cocaine.

A variety of drug coding schemes are used in DAWN, but the data that are

published usually show aggregate drug groups and therapeutic classes. The

DAWN drug vocabulary contains 46 separate substance, street, or metabolite

names for cocaine, but only 15 of these names were reported to DAWN during

1989-90. In 81.4 percent of cocaine-related emergencies, the substance

reported was simply cocaine. For the majority of the remaining cases, the

street name “crack” was reported to DAWN (18.0 percent). Other street names

reported for cocaine-related emergencies included “coke” (0.4 percent) and

“rock” cocaine (0.07 percent). Benzoylecgonine, a metabolite of cocaine, was

reported in 0.07 percent of cases.

In accordance with the focus on acute cocaine intoxication, special analyses

on cases reported as overdoses are included. However, in the numerous

episodes in which other drugs are mentioned in combination with cocaine,

attribution of causality is uncertain. In analyzing the contribution of cocaine

as a causal agent, it would be possible to select overdose cases involving

cocaine and no other drug. In 1990, 3,405 weighted cases (4 percent of all

cocaine cases) met this criterion. However, this procedure was not followed

because reducing the number of cases in this way increases the sampling

variability of the estimates to an unacceptably high level.

The ER and ME data presented in this chapter are based on records received

by the end of May 1991 and correspond to the data used for the 1990 annual

reports (National Institute on Drug Abuse 1991a, 1991b). The ME data exclude

cases in which the manner of death was reported as homicide and cases in

which acquired immunodeficiency syndrome was noted on the form.

FINDINGS

Recent Trends in Cocaine-Related ER Episodes

Figure 2 shows quarterly provisional estimates of cocaine-related ER episodes

in the total coterminous United States for 1989 and 1990. These episodes rose

24
FIGURE 2. Estimates of quarterly ER cocaine mentions (95-percent

confidence interval) in total coterminous United States, DAWN,

first quarter 1989 through fourth quarter 1990

from 27,803 in the first quarter of 1989 to 29,939 in the third quarter of that

year then dropped sharply to 22,646 in the fourth quarter. This decrease was

followed by two additional quarterly declines, and cocaine cases reached a

2-year low of 19,381 in the fourth quarter of 1990.

The sharp decrease from the third to the fourth quarter of 1990 could not be

accounted for by data from just a few hospitals because it was widespread

across the 21 metropolitan areas. Table 1 examines the estimates for calendar

years 1989 and 1990 by metropolitan area and includes a test of the differences

between the two years. In 1990 New York led the other metropolitan areas with

12,633 cocaine episodes, followed by Philadelphia with 8,920. Trailing behind

were Chicago with 4,904 cocaine-related episodes, Washington, DC, with

4,788, and Los Angeles-Long Beach with 4,129. The largest decreases in

cocaine-related cases were in Seattle (down 54 percent) and Minneapolis-St.

Paul (down 46 percent). Decreases of 35 percent or more also were observed

in the Detroit, Los Angeles-Long Beach, and Washington, DC, areas. In stark

contrast to the national trend, cocaine cases in Baltimore increased 64 percent,

from 1,839 in 1989 to 3,023 in 1990. Data by quarter (not shown) revealed a

steady increase in cocaine cases in Baltimore from the fourth quarter of 1989

through the fourth quarter of 1990.

25
TABLE 1. Estimate of the number of ER episodes involving cocaine in 1989

and 1990 and percent change from 1989 to 1990, by metropolitan

area

NOTE: These estimates are based on a representative sample of non-Federal

short-stay hospitals with 24-hour ERs.

Significance level of difference from 1989 to 1990: *p<.05; **p<.01; ***p<.001.

SOURCE: NIDA, DAWN (May 1991 files)

The distribution of cocaine patients by race/ethnicity changed from 1989 to

1990. As shown in figure 3 and table 2, black patients outnumbered white

patients in cocaine-related cases throughout the period. Considering the

estimates by quarter (figure 3), the sharp decrease in cocaine cases from the

26
third to the fourth quarter of 1989 occurred for both black and white patients.

However, subsequent decreases across quarters in 1990 occurred for white

patients, whereas cases involving black patients remained about the same.

Analysis of the distributions across the two calendar years (table 2) shows

that the proportion of white patients decreased from 35 percent in 1989 to 30

percent in 1990 (p<.001), whereas the proportion of black patients increased

from 46 to 54 percent (p<.001). The proportion of Hispanic patients held steady

at 8 to 9 percent.

From 1989 to 1990 the age distribution of patients in cocaine-related ER

episodes shifted slightly upward (table 2). The proportion of patients 18 to 25

years old decreased from 29 to 24 percent (p<.001); the proportion ages 35 to

44 years increased from 20 to 24 percent (p<.001); and the proportion 45 years

of age and older increased from 3.7 to 4.8 percent (p<.01).

There was no significant change in the sex distribution of cocaine patients from

1989 to 1990. In each year 65 percent of these patients were male and 34

percent were female.

FIGURE 3. Estimates of quarterly ER cocaine mentions involving white,

black, and Hispanic patients, DAWN, first quarter 1989 through

fourth quarter 1990

27
TABLE 2. Estimate of the number and percentage of cocaine-related ER

episodes by selected demographic and episode characteristics,

1989 and 1990

NOTE: These estimates are based on a representative sample of non-Federal

short-stay hospitals with 24-hour ERs in the coterminous United States.

a

Total includes unknown sex, race/ethnicity, and age categories that are not shown

separately. Percentages for these variables will not sum to 100.

Significance level of difference from 1989 to 1990: *p<.01; **p<.001

SOURCE: NIDA, DAWN (May 1991 files)

Data on cocaine-related episodes by drug use motive reveal that the proportion

of cases in which drugs were taken to achieve psychic effects (e.g., recreational

use) decreased from 22 percent in 1989 to 18 percent in 1990 (p<.01, data not

shown). The proportion of dependence cases increased slightly from 60 to 63

percent (not significant). Increases in the proportion of dependence cases

28
among cocaine episodes have been noted in previous studies (e.g., Colliver

and Kopstein 1991; National Institute on Drug Abuse 1987).

Overdoses accounted for 14 percent of cocaine-related episodes in both

1989 and 1990. Among other categories of reason for ER contact, the only

statistically significant difference between the two years was observed for the

proportion of unexpected reaction cases, which decreased from 26 percent in

1989 to 23 percent in 1990 (p<.05). Patients seeking detoxification accounted

for 27 to 28 percent of cocaine-related episodes, and those experiencing

chronic effects accounted for 18 to 19 percent.

Cocaine was smoked in approximately 28 percent of the cases in 1990, injected

in 22 percent, and sniffed or snorted in 12 percent. These proportions were not

significantly different from those observed in 1989.

Drug concomitance is one of the key moderating variables in this analysis.

In single-drug episodes, the role of cocaine as a causal factor is clearer than

when other drugs are mentioned in combination. In 1989 other drugs were

reported in combination with cocaine in 54 percent of the episodes in which it

was mentioned, and this proportion increased to 58 percent in 1990 (p<.001,

table 2). Complementing this increase, the proportion of cases in which

cocaine was mentioned alone decreased from 46 to 42 percent (p<.001).

The specific drugs mentioned in combination with cocaine may be important

in making decisions regarding clinical strategies in treating emergency cases

(discussed in the next section). For the most part, the proportions of cases

involving specific combination drugs did not differ greatly from 1989 to 1990.

One exception is that mentions of alcohol-in-combination increased from 38

percent of cocaine-related episodes in 1989 to 43 percent in 1990 (p<.001,

data not shown).

All Cocaine-Related Cases vs. Cocaine-Related Overdoses

As indicated above, overdose was the reported reason for ER contact in

approximately one cocaine-related episode in seven (14 percent) in 1990.

Many of these cases involved other drugs in addition to cocaine, and in some

instances, the overdose may be related primarily to these other drugs rather

than to cocaine.

Figure 4 shows the volume and trends of overdose cases in relation to the

overall cocaine-related cases for the quarters of 1989 and 1990. Cocaine

overdoses increased from 3,617 in the first quarter of 1989 to 4,389 in the third

quarter of 1989 then decreased sharply in the fourth quarter of 1989 to 3,011.

29
In the next quarter, they reached a 2-year low of 2,607. Subsequently, cocainerelated overdose cases increased to 2,964 in the second quarter of 1990 and

then decreased to 2,620 in the fourth quarter of 1990.

In tables 3 through 6, data for overdose cases are compared with data for all

cocaine-related episodes based on demographic, episode, and drug use

characteristics. Percent distributions of these variables in all cocaine-related

episodes are compared with the corresponding percentages among cocainerelated overdose episodes. The data shown are weighted estimates for 1990.

Across the 21 DAWN metropolitan areas (table 3), ER overdose episodes

involving cocaine were most numerous in Philadelphia (1,400). New York,

Los Angeles-Long Beach, and Chicago trailed far behind Philadelphia with

641, 574, and 502 cases, respectively. Hospitals in the national panel

accounted for 42 percent of cocaine mentions in overdose episodes but for

only 23 percent of all cocaine mentions. Considered in relationship to all

cocaine-related episodes, Minneapolis-St. Paul had the highest proportion

FIGURE 4. Estimates of quarterly ER cocaine mentions involving overdose

and other reasons for visit, DAWN, first quarter 1989 through

fourth quarter 1990

30
TABLE 3. Estimate of all ER episodes involving cocaine and overdose

episodes involving cocaine by metropolitan area, 1990

Metropolitan Area All Episodes Overdose Episodes Percent

Episodes involving Cocaine Involving Cocaine Overdose

Total coterminous U.S. 80,355 11,022 13.7

Atlanta 2,743 183 6.7

Baltimore 3,023 220 7.3

Boston 1,961 371 18.9

Buffalo 282 43 15.2

Chicago 4,904 502 10.2

Dallas 1,028 239 23.2

Denver 569 131 23.0

Detroit 3,888 341 8.8

Los Angeles-Long Beach 4,129 574 13.9

Miami-Hialeah 748 138 18.4

Minneapolis-St. Paul 299 113 37.8

New Orleans 3,397 200 5.9

New York 12,633 641 5.1

Newark 3,752 161 4.3

Philadelphia 8,920 1,400 15.7

Phoenix 614 155 25.2

St. Louis 700 65 9.3

San Diego 725 82 11.3

San Francisco 2,297 390 17.0

Seattle 777 99 12.7

Washington, DC 4,788 318 6.6

National panel 18,177 4,659 25.6

NOTE: These estimates are based on a representative sample of non-Federal

short-stay hospitals with 24-hour ERs.

SOURCE: NIDA, DAWN (May 1991 files)

of overdose cases (38 percent), whereas Newark had the lowest (4.3 percent).

In addition to Minneapolis-St. Paul, areas with at least 20 percent overdose

cases were Dallas, Denver, and Phoenix. The Atlanta, Baltimore, Chicago,

Detroit, New Orleans, New York, Newark, St. Louis, and Washington, DC,

areas had 10 percent or less overdose episodes among cocaine-related cases.

Based on the data for 1990, male patients accounted for 65 percent of all

cocaine cases and 61 percent of cocaine-related episodes involving an

overdose (table 4). The race/ethnicity distribution of patients in cocaine

overdose cases was different from that in all cocaine cases. Patients were

31
TABLE 4. Estimate of all ER episodes involving cocaine and overdose

episodes involving cocaine by selected demographic

characteristics, 1990

Selected Demographic

Characteristics

and Facility Location

Total cocaine episodesa

Sexa

Male

Female

Race/ethnicitya

White

Black

Hispanic

Other

Agea

6-17 years

18-25 years

26-34 years

35-44 years

45 years and older

Facility locationb

Central city

Outside central city

All Episodes

Involving Cocaine

Number Percent

80,355 100.0

52,213 65.0

27,150 33.8

24,100 30.0

43,010 53.5

6,627 8.2

344 0.4

1,877 2.3

19,614 24.4

35,639 44.4

19,186 23.9

3,868 4.8

45,361 73.0

16,816 27.0

Overdose Episodes

Involving Cocaine

Number Percent

11,022

6,732 61.1

4,199 38.1

4,733 42.9**

4,378 39.7**

870 7.9

92 0.8

540

3,012

4,632

2,444

359

4,283 67.3

2,080 32.7

100.0

4.9

42.0

22.2

3.3 

NOTE: These estimates are based on a representative sample of non-Federal

short-stay hospitals with 24-hour ERs in the coterminous United States.

a

Total includes unknown age, sex, and race/ethnicity categories that are not shown

separately. Percentages will not sum to 100.

bExcludes data from the national panel.

Significance level of difference between percentages in all episodes and overdose

episodes: *p<.05; **p<.01.

SOURCE: NIDA, DAWN (May 1991 files)

32
white in 43 percent of cocaine-related overdose cases, compared with 30

percent of all cocaine-related cases (p<.01). Black patients accounted for 40

percent of cocaine-related episodes in which the reason for contact was an

overdose, compared with 54 percent of all cocaine-related episodes (p<.01).

The proportion of Hispanics was 8.2 percent for all episodes and 8 percent

for overdose episodes.

Patients in cocaine-related overdoses seen in hospital ERs in 1990 were, on

average, somewhat younger than those involved in all cocaine episodes in that

year (table 4). Patients 6 to 25 years old accounted for 32 percent of cocainerelated overdose cases, compared with 27 percent of all cocaine-related ER

episodes. At the opposite end of the age spectrum, the proportion of patients

45 years of age and older was 3.3 percent among cocaine-related overdose

cases, compared with 4.8 percent of all cocaine-related cases (p<.05).

Among all cocaine-related cases in the 21 DAWN metropolitan areas, 73

percent were reported by central city hospitals and 27 percent by hospitals in

the suburbs (table 4). Among overdose cases, the comparable proportions

were 67 percent for central city hospitals and 33 percent for suburban hospitals,

A reversal in the distribution of cocaine cases by drug use motive is seen

when all episodes are compared with overdose episodes (table 5). In 1990,

dependence was the drug use motive in 63 percent of all cocaine-related

episodes but in only 29 percent of cocaine-related episodes that involved a

drug overdose (p<.001). Conversely, suicide was reported as the drug use

motive in 7 percent of all cocaine cases compared with 37 percent of cocainerelated overdose cases (p<.001). Although drug use motive is reported once

for an episode regardless of the number of drugs mentioned, the actual motive

may differ for the separate drugs. Thus, when multiple drugs are involved, it is

possible to misinterpret the data on motive when looking at any particular drug.

Although statistically nonsignificant, the proportion of cases with unknown drug

use motive, which occurred frequently enough to affect the interpretation of the

data, was 4 percentage points higher in the overdose cases than in all cocainerelated episodes (16 vs. 12 percent).

The distribution of cocaine patients by disposition (episode outcome) was

different for overdose episodes compared with all episodes (table 5). Patients

were admitted as inpatients in 47 percent of overdose cases compared with 37

percent of all cases (p<.01). Patients who had overdosed died in the ER in 1.7

percent of cases compared with 0.4 percent among all cocaine-related cases.

Smoking was less likely to be the route of administration of cocaine in overdose

cases than in all cases in which cocaine was mentioned (p<.001, table 5). In

33
TABLE 5. Estimate of all ER episodes involving cocaine and overdose

episodes involving cocaine by selected episode and drug use

characteristics, 1990

Selected Demographic

Characteristics

and Facility Location

All Episodes Overdose Episodes

Involving Cocaine Involving Cocaine

Number Percent Number Percent

Total cocaine episodesa

11,022 100.0

Drug use motive

Psychic effects

Dependence

Suicide

Unknown/other

2,031 18.4

3,176 28.8**

4,035 36.6**

1,780 16.1

Dispositiona

Treated and released

or referred

Admitted to hospital

Left against advice

Died

5,281 47.9*

5,120 46.5*

396 3.6

192 1.7

Route of administration

Injected

Smoked

Sniffed/snorted

Unknown

Other/multiple

Drug concomitance

Mentioned alone

Mentioned in combination

80,355 100.0

14,687 18.3

50,831 63.3

5,203 6.5

9,634 12.0

47,795 59.5

29,336 36.5

2,206 2.7

299 0.4

17,301 21.5

22,696 28.2

9,661 12.0

25,722 32.0

4,975 6.2

33,787 42.0

46,568 58.0

2,921 26.5

1,906 17.3**

1,478 13.4

3,796 34.4

922 8.4

3,405 30.9*

7,617 69.1*

NOTE: These estimates are based on a representative sample of non-Federal

short-stay hospitals with 24-hour ERs in the coterminous United States.

a

Total includes unknown categories of reason for ER visit, disposition, and route of

administration that are not shown separately. Percentages will not sum to 100.

Significance level of difference between percentages in all episodes and overdose

episodes: *p<.01; **p<.001.

SOURCE: NIDA, DAWN (May 1991 files)

34
1990 cocaine-related ER episodes involving a drug overdose, the drug was

injected in 27 percent of cases, smoked in 17 percent, and sniffed or snorted in

13 percent. Among all cocaine-related episodes, the drug was injected in 22

percent of cases, smoked in 28 percent, and sniffed or snorted in 12 percent.

It should be noted, however, that route of administration was unknown in

approximately one-third of cocaine mentions. Although the proportion of

unknowns did not differ significantly between all cocaine episodes and cocaine

episodes involving an overdose, the magnitude of the unknowns makes the

interpretation of the data on route of administration uncertain.

Overdose cases were more likely than other episodes to involve additional

drugs in combination with cocaine (table 5). In 69 percent of cocaine-related

overdose episodes, the drug was reported in combination with other

substances; the comparable figure among all cocaine-related episodes was

58 percent (p<.01). This information raises the question of how often one of

the other drugs or the combination of drugs, rather than cocaine alone, was

responsible for the overdose.

As shown in table 6, alcohol was the drug most frequently mentioned in

combination with cocaine, both in all cocaine-related episodes (43 percent)

and in cocaine-related overdose episodes (46 percent). Heroin/morphine

ranked second and was reported in 12 percent of all cocaine episodes and in

11 percent of overdoses involving cocaine. Marijuana/hashish was reported

in 7.4 percent of all cocaine cases and in 6.7 percent of cocaine-related

overdoses. Phencyclidine (PCP) was mentioned in 1.6 percent of all cocaine

cases and in 1.1 percent of overdose cases involving cocaine. Diazepam was

more likely to be reported in cocaine-related overdose cases than in all cocainerelated episodes (3.2 vs. 1.2 percent, respectively, p<.05). Ibuprofen was

reported in 2.6 percent of cocaine-related overdoses, compared with 0.4

percent of all cocaine-related cases (p<.01). Unspecified benzodiazepines

were more frequently reported when overdose was the reason for the ER visit

than overall (1.6 vs. 0.7 percent, respectively, p<.05). The same was true of

alprazolam (1.5 percent in cocaine-related overdoses vs. 0.4 percent in all

cocaine-related cases, p<.05) and acetaminophen (1.4 vs. 0.3 percent, p<.001).

Cocaine-Related ME Cases

As indicated previously, DAWN ME cases involving cocaine increased 44-fold

between 1975 and 1989. Quarterly trends for 1986 to 1990 are shown in figure

5. Although the file was held open for 5 months to include all records received

by the end of May 1991, the data for the last one or two quarters may still be

somewhat incomplete. In addition, it should be noted that the trends are shown

with and without data for the New York metropolitan area because ME data for

35
TABLE 6. Drugs mentioned in combination with cocaine in all ER episodes

and overdose episodes, 1990a

Combination Drug

Percent Among All

Episodes Involving

Cocaineb

Percent Among Overdose

Episodes Involving

Cocaineb

Alcohol-in-combination 42.5 46.0

Heroin/morphine 12.4 10.9

Marijuana/hashish 7.4 6.7

PCP/PCP combinations 1.6 1.1

Diazepam 1.2 3.2*

Methamphetamine/speed 1.1 1.2

LSD 0.8 1.8

Amphetamine 0.7 1.7

Unspecified benzodiazepine 0.7 1.6*

Alprazolam 0.4 1.5*

Ibuprofen 0.4 2.6**

Codeine 0.3 ___c

Acetaminophen 0.3 1.4***

Diphenhydramine 0.3 1.4

Lorazepam 0.3 1.0

Clonazepam 0.3 1.5

Acetaminophen with codeine 0.2 1.3

Phenobarbital 0.2 1.4

Propoxyphene 0.2 1.0

OTC sleep aids 0.2 ___c

Aspirin 0.2 1.0***

Fluoxetine 0.2 ___c

Desipramine 0.2 1.0

NOTE: These estimates are based on a representative sample of non-Federal

short-stay hospitals with 24-hour ERs in the coterminous United States.

a

lncludes drugs mentioned in at least 1.0 percent of all episodes involving cocaine

or 1.0 percent of overdose episodes involving cocaine.

bBecause up to three drugs can be reported in combination with cocaine, these

percentages could sum to more than 100.

c

Figure does not meet standard of precision (RSE 50 percent).

Significance level of difference between percentages in all episodes and overdose

episodes: *p<.05; **p<.01; ***p<.001

SOURCE: NIDA, DAWN (May 1991 files)

36
FIGURE 5. Quarterly number of cocaine mentions reported by DAWN MEs,

first quarter 1986 through fourth quarter 1990

New York City were not available for the first 2 years shown in the graph. What

is most notable, however, is that the trends show a sharp drop in cocainerelated cases between the third and fourth quarters of 1989, the same time the

drop in ER cases occurred.

Table 7 shows the number of cocaine-related ME cases in 1989 and 1990 and

the percent change according to metropolitan area. Overall, cocaine-related

deaths decreased 32 percent from 3,663 in 1989 to 2,483 in 1990. Most of the

27 metropolitan areas experienced decreases in deaths involving cocaine. Two

exceptions were Atlanta, where these cases increased from 67 in 1989 to 73 in

1990, and San Francisco, where they increased from 138 to 143.

The key variable distinguishing ME cases according to the causal role of the

reported drug(s) is concomitance/cause of death. Directly caused, druginduced deaths are distinguished from indirectly caused, drug-related deaths;

in these latter cases, the drug interacts with a physiological condition, physical

event, or medical disorder to cause the death. Drug-induced deaths are further

categorized as single- and multiple-drug cases. Of the 2,483 DAWN ME cases

in 1990 in which cocaine was mentioned, 64 percent were direct, drug-induced

cases. Seven percent (172 deaths) involved only cocaine. In table 8, the data

for these single-drug, cocaine-induced cases are compared with the data for all

cases in which cocaine was reported.

37
TABLE 7. Number of cocaine-related deaths reported by MEs participating in

DAWN, 1989 and 1990

Metropolitan Area 1989 1990 Percent Change

Total DAWN system 3,663

Atlanta 67

Baltimore 47

Boston 113

Buffalo 7

Chicago 219

Cleveland 20

Dallas 74

Denver 14

Detroit 124

Indianapolis 2

Kansas City 15

Los Angeles/Long Beach 630

Miami 73

Minneapolis/St. Paul 1 1

New Orleans 43

New York 1,141

Newark 148

Norfolk 5

Oklahoma City 16

Philadelphia 324

Phoenix 35

St. Louis 45

San Antonio 18

San Diego 81

San Francisco 138

Seattle 38

Washington, DC 215

2,483

73

29

51

5

126

13

39

13

74

1

8

422

29

2

35

848

81

5

10

215

24

38

17

53

143

29

100

-32.2

+9.0

-38.3

-54.9

___

-42.5

-35.0

-47.3

-7.1

-40.3

___

-46.7

-33.0

-60.3

-81.8

-18.6

-25.7

-45.3

__

-37.5

-33.6

-31.4

-15.6

-5.6

-34.6

+3.6

-23.7

-53.5

*Denominator for percent change is less than 10.

SOURCE: NIDA, DAWN (May 1991 files)

Data on race/ethnicity show that 34 percent of all decedents in cocaine-related

cases were white, 44 percent were black, and 20 percent were Hispanic (table

8). However, in the data for single-drug, cocaine-induced deaths, 57 percent

were black and 8 percent were Hispanic. The proportion of white decedents,

32 percent, was similar to that in all cocaine-related ME cases.

Data on cocaine-related deaths according to sex show a slightly higher

proportion of female decedents among single-drug, cocaine-induced cases

than among all cocaine-related cases (27 vs. 23 percent, respectively).

38
TABLE 8. Number of cocaine-related deaths and number of direct, singledrug, cocaine-induced deaths reported by DAWN MEs by

decedent demographic characteristics and cause of death, 1990

Demographic and

Case Characteristics

Total cocaine-related

cases

Race/ethnicity*

White

Black

Hispanic

Sex’

Male

Female

Age*

6-17 years

18-25 years

26-34 years

35-44 years

45 years and older

Concomitance/cause of death’

Direct-single drug

Direct-multiple drug

Drug(s) and physiological

condition

Drug(s) and physical event

Drug(s) and medical disorder

All Cases Single-Drug,

Involving Cocaine Cocaine-Induced Deaths

Number Percent Number Percent

2,483 100.0 172 100.0

837 33.7 55 32.0

1,098 44.2 98 57.0

502 20.2 13 7.6

1,904 76.7 125 72.7

570 23.0 46 26.7

14 0.6 2 1.2

306 12.3 17 9.9

955 38.5 61 35.5

848 34.2 67 39.0

344 13.9 22 12.8

172 6.9 172 100.0

1,410 56.6 NA NA

115 4.6 NA NA

560 22.6 NA NA

212 8.5 NA NA

*Total includes other and/or unknown concomitance/cause of death, sex, age race

ethnicity categories that are not shown separately. Percentages will not sum to

100.

NA=not applicable

SOURCE: NIDA, DAWN (May 1991 files)

The age distribution of single-drug, cocaine-induced deaths shows a somewhat

higher proportion in the 35 to 44-year age group than among all deaths in

which cocaine was mentioned (39 vs. 34 percent). However, the two

distributions were similar.

39
Table 9 presents information on drugs mentioned in combination with cocaine

in all ME cases in 1990. Alcohol ranked first and was reported in 41 percent

of cases involving cocaine. Heroin/morphine (including unspecified opiates)

ranked second with 29 percent. These drugs were followed by codeine and

methadone with 8.1 and 6.9 percent, respectively. Diazepam was reported in

4.1 percent of cocaine-related cases.

SUMMARY AND DISCUSSION

The most important findings of this study relate to the recent decrease in

cocaine-related ER episodes and ME cases. First, decreases starting in the

fourth quarter of 1989 for most of the 21 DAWN metropolitan areas as well as

in the total data suggest, as previously indicated, that the changes are not

isolated and could not have been associated with changes affecting just a few

hospitals. If only a few hospitals or metropolitan areas had been involved, the

drop in cocaine cases might be argued to have resulted from factors such as

administrative changes initiated to deal with ER overcrowding. Because the

decrease was widespread, however, such an explanation seems less likely.

The second finding related to recent trends is the simultaneous decrease in

ER and ME cases related to cocaine. Both types of cases showed decreases

beginning in the fourth quarter of 1989 and continuing into 1990. This, too,

suggests that the change is real.

A third point related to these trends is that, for the most part, decreases

occurred for all demographic groups and all categories of episode and drug

use variables. However, some differences in trends were observed. Notably,

the secondary decreases in cocaine-related ER episodes that occurred in the

first two quarters of 1990 affected white patients to a far greater extent than

black patients. The increase in the Baltimore area, which is quite significant,

occurred after the initial wave of decreases.

Another point related to recent trends is the increasing involvement of other

drugs mentioned in combination with cocaine. Assuming that the decrease

in the overall numbers of cocaine-related medical emergencies is real, this

pattern, together with the slight aging trend, might be consistent with the

hypothesis of reduced current use of cocaine by casual users but continued

use by individuals more dependent on it. These latter users might be more

likely than casual users to have a secondary drug problem. Recent increase

in the proportion of dependence cases among cocaine-related episodes, though

not statistically significant in the present analysis, are also consistent with this

hypothesis.

40
TABLE 9. Drugs most frequently mentioned in combination with cocaine in

ME cases reported to DAWN, 1990

Combination Drug Number of Mentions

Alcohol 1,005

Heroin/morphine* 726

Codeine 200

Methadone 172

Diazepam 103

Lidocaine 81

Amitriptyline 69

Nortriptyline 58

Marijuana/hashish 47

Diphenhydramine 45

PCP/PCP combinations 37

Propoxyphene 34

Methamphetamine/speed 33

Acetaminophen 32

Quinine 23

Unspecified benzodiazepine 23

Phenobarbital 22

Doxepin 20

Chlordiazepoxide 16

Amphetamine 13

Chlorpheniramine 13

Caffeine 12

Hydantoin 12

Aspirin 11

Doxylamine succinate 11

Desipramine 10

Thioridazine 10

*Includes opiates not specified as to type.

Percent of Cases

40.5

29.2

8.1

6.9

4.1

3.3

2.8

2.3

1.9

1.8

1.5

1.4

1.3

1.3

0.9

0.9

0.9

0.8

0.6

0.5

0.5

0.5

0.5

0.4

0.4

0.4

0.4

SOURCE: NIDA, DAWN (May 1991 files)

The slight plurality of white patients in overdose episodes, with black patients

predominating in cocaine-related episodes overall, has several possible

explanations. For example, smoking is less likely to be the route of

administration in overdose episodes than in other episodes (table 5), and

other studies (e.g., Colliver and Kopstein 1991) have shown that ER patients

who smoke cocaine are more likely to be black. However, if there is an

association here, the direction of causality, if any, is uncertain.

The high proportion of suicide cases among overdose episodes involving

cocaine also is curious. It may be that the overdose in these cases was

41
associated with another drug rather than cocaine. That overdose cases are

more likely to involve other drugs is consistent with the pattern of suicides,

in which individuals take whatever is available. Together with the possible

involvement of individuals receiving medication under a physician’s direction

and persons self-medicating for emotional difficulties, this availability factor

may partially account for the high proportion of drugs such as diazepam,

unspecified benzodiazepines, and alprazolam in overdose cases. The

differential involvement of drugs such as ibuprofen and acetaminophen in

overdose cases are particularly suggestive of the “take-anything” suicide

syndrome. An alternative explanation, of course, is that cocaine may disinhibit

latent suicidal tendencies.

It is uncertain how many overdoses result from cocaine and how many from

another drug mentioned in combination with it. The blame clearly rests with

cocaine in the 31 percent of overdoses in which it was the only drug reported

(3,405 weighted emergency cases in 1990 or 4 percent of all cocaine cases in

that year). Unfortunately, data in DAWN do not provide adequate information

to answer this question for the remaining 69 percent of overdoses, and

researchers are left to make what they can of the drug combination data.

In practice, the ER staff must distinguish between symptoms of cocaine

overdose and opiate or other drug overdoses and select a treatment strategy

commensurate with the diagnosis. In selecting medications in these situations,

physicians must consider possible interaction with any other drugs the patient

might have taken in addition to cocaine. Acutely intoxicated patients may be

unable to respond to questions about the drugs they have taken. In these

cases, information on other drugs frequently reported in combination with

cocaine, provided by studies such as this one, may be useful in suggesting

the types of interactions that must be anticipated. Possible interactions with

other drugs patients may have taken also must be considered in any effort to

develop new medications to combat cocaine intoxication.

REFERENCES

Adams, E.H.; Blanken, A.J.; Ferguson, L.D.; and Kopstein, A.N. “Overview

of Selected Drugs.” Unpublished report disseminated by the Division of

Epidemiology and Prevention Research, National Institute on Drug Abuse,

1990.

Colliver, J.D., and Kopstein, A.N. Trends in cocaine abuse reflected in

emergency room episodes reported to DAWN. Public Health Rep 106(1):

59-68, 1991.

National Institute on Drug Abuse. Trends in Drug-Abuse Related Hospital

Emergency Room Episodes and Medical Examiner Cases for Selected

42
Drugs. DAWN 1976-1985. Statistical Series H, No. 3. DHHS Pub. No.

(ADM)87-1524. Washington, DC: Supt. of Docs., U.S. Govt. Print Off.,

1987.

National Institute on Drug Abuse. Semiannual Report, Trend Data Through

January-June 1988, Data From the Drug Abuse Warning Network (DAWN).

Statistical Series G, No. 22. DHHS Pub. No. (ADM)80-1607. Washington,

DC: Supt. of Docs., U.S. Govt. Print Off., 1989.

National Institute on Drug Abuse. Annual Data 1989, Data From the Drug

Abuse Warning Network (DAWN). Statistical Series I, No. 9. DHHS Pub.

No. (ADM)90-1717. Washington, DC: Supt. of Docs., U.S. Govt. Print Off.,

1990.

National Institute on Drug Abuse. Annual Emergency Room Data 1990, Data

from the Drug Abuse Warning Network (DAWN). Statistical Series I, No. 10-

A. DHHS Pub. No. (ADM)91-1839. Washington, DC: Supt. of Docs., U.S.

Govt. Print Off., 1991a.

National Institute on Drug Abuse. Annual Medical Examiner Data 1990, Data

From the Drug Abuse Warning Network (DAWN). Statistical Series I, No. 10-

B. DHHS Pub. No. (ADM)91-1840. Washington, DC: Supt. of Docs., U.S.

Govt. Print Off., 1991 b.

AUTHORS

James D. Colliver, Ph.D.

Senior Research Analyst

CSR, Incorporated

Suite 600

1400 I Street, NW

Washington, DC 20005

Andrea N. Kopstein, M.P.H.

Statistician

Arthur L. Hughes, M.A.

Mathematical Statistician

Division of Epidemiology and Prevention Research

National Institute on Drug Abuse

Rockwall II, Suite 620

5600 Fishers Lane

Rockville, MD 20857

43
Preclinical Assessment of Cocaine

Toxicity: Mechanisms and

Pharmacotherapy

Jeffrey M. Witkin and Jonathan L. Katz

INTRODUCTION

Data on emergency room admissions and cocaine-related deaths document

the toxic consequences of cocaine abuse. In 1990 approximately 20,000

individuals required emergency treatment for cocaine toxicity (Colliver et al.,

this volume). Of these, most were treated by relatively standard emergency

medical procedures and released without hospital admission (Schrank, this

volume). Nonetheless, some cocaine toxicities result in cardiovascular

abnormalities, central nervous system (CNS) damage, neurological impairment,

and death (see Miller et al.; Rowbotham; and Wetli, this volume).

Pharmacotherapy currently used to treat cocaine toxicity generally involves

standard emergency medications directed at the specific symptomotologies

listed below (e.g., arrhythmias, high blood pressure, convulsions). Although

many of the symptoms of cocaine toxicity can be managed with existing

medications, new compounds to treat cocaine overdose could improve on

efficacy, provide more rapid control of acute cocaine toxicity, or treat symptoms

or sequelae (e.g., kindling, neurotoxicity) for which there are currently no

treatments.

Acute behavioral toxicity

—Psychosis

—Agitation

—Delirium

Long-term toxicity

—Neurotoxicity

—Kindling (seizures, psychosis)

—Stroke damage

44
Convulsions

—Anticonvulsant resistant

Lethality

—Cardiovascular

—Respiratory

—Thermoregulatory

The acute behavioral toxicities associated with cocaine abuse are not well

controlled by haloperidol or chlorpromazine and appear to be best controlled

by heavy sedation induced with benzodiazepines or barbiturates (Schrank,

this volume). Thus, improvements in the pharmacological specificity of control

over these toxic symptoms may have some utility in increasing the degree of

treatment specificity. Until such sedation can be achieved, the physical restraint

sometimes needed by patients suffering from cocaine toxicity, typically requiring

several people, suggests that a more rapid means of drug delivery could be

designed (suggested by Dr. Charles Wetli) that would avoid injury to the patient

and to those in attendance.

Several potential outcomes of a toxic episode currently have no specific

pharmacological treatment. For example, there can be a progression of

neural damage from ischemia and stroke related to cocaine use. Excitatory

amino acid antagonists could be useful for minimizing neurological impairment

(Meldrum and Garthwaite 1990). Ketamine is clinically available and could

provide such protection, although better experimental agents likely will be

forthcoming. Compounds also might be developed that block the development

of the kindled seizures and psychosis that can result from repeated highdose cocaine exposure (see below). Convulsions resistant to standard

anticonvulsant therapy can be life threatening and require severe treatment

measures. Therefore, novel anticonvulsant agents that are effective against

these resistant convulsions would appear to have some utility. Finally,

compounds that improve the chances of survival after life-threatening cocaine

toxicities, regardless of the mechanisms of lethality or protection, also would

be welcome improvements.

Preclinical studies of cocaine overdose can provide valuable assistance for

drug development in three major areas. First, these studies can advance

understanding of the clinical phenomena associated with cocaine toxicity by

investigating the basic mechanisms involved with cocaine toxicity. This

includes the development of preclinical models to evaluate specific aspects

of the clinical state. Second, these studies can evaluate treatments using

appropriate preclinical models; existing compounds, new molecular entities,

and adjunct therapies can be investigated. Third, they can evaluate the safety

45
of proposed cocaine abuse and cocaine toxicity treatments. This work includes

an assessment of the effects of the drugs in combination with cocaine and, as

dictated by known mechanisms, other drugs of abuse.

ACUTE COCAINE TOXICITY: MODELS

Various classes of models can be used for preclinical investigation, although

discussion of these are beyond the scope of this chapter (for an overview,

see Witkin, in press; Witkin and Katz 1990). For the present purposes, it is

important to distinguish predictive models from functional models. Predictive

models are those that generate data that are predictive of clinical efficacy

or safety but need not be functionally equivalent to the clinical state (i.e.,

preclinical signs and clinical symptoms controlled by the same mechanism).

Predictive models are not required to resemble the clinical situation. If novel

anticonvulsants block convulsions in mice after acute doses of cocaine and

these compounds are clinically effective, the model is predictive regardless

of whether the preclinical and clinical phenomena are mediated by similar

mechanisms. In this example, there is often a delay in convulsions after

cocaine administration in humans that does not occur in the preclinical model,

suggesting some differing mechanisms that do not detract from the predictive

validity of the model. Functional models are those in which the mechanisms

underlying the preclinical and the clinical phenomena are the same. Thus,

functional models are typically predictive models, whereas the converse is not

necessarily true. The primary difficulty in obtaining adequate functional models

is the lack of understanding of the mechanisms underlying the clinical

symptoms of cocaine toxicity.

In many of the animal models of cocaine toxicity, the choice of an appropriate

species or procedure is not straightforward. For example, significant variation

in the acute sensitivity to cocaine convulsions can be observed even across

mouse strains (Marley et al. 1991). Other experimental procedures, albeit

important in their own right, do not appear to adequately model specific clinical

features of cocaine toxicity. For example, Tella and colleagues (1991) have

shown that prazosin can increase the dose of intravenously infused cocaine

required to produce convulsions and lethality in rats; however, observation

of cardiovascular function and body temperature with cocaine either alone

or in conjunction with prazosin did not suggest any direct involvement of these

systems in the pathological effects of cocaine. Other species or procedures will

be necessary to model the specific cardiovascular changes (e.g., arrhythmias,

ventricular tachycardia, ventricular fibrillation, vesicular spasms) that have been

associated with the toxic effects of cocaine in human drug abusers

(Nadeemanee 1991).

46
ACUTE COCAINE TOXICITY: MECHANISTIC STUDIES

High-bolus doses of cocaine produce dose-dependent increases in convulsions

and lethality in rodent models of acute toxicity. Under these conditions,

convulsions and lethality are described by different functions, with convulsions

being produced at significantly lower doses than those producing death (Witkin

and Katz 1991). These data, in addition to drug-interaction information

described below, provide the first indication that convulsions, often associated

with cocaine lethality, are not inextricably linked mechanistically to lethality

(Witkin et al. 1989a).

Stereospecificity

Using optically pure samples of the unnatural (+)-enantiomer of cocaine,

Katz and colleagues (1990) showed that only the natural isomer of cocaine

possesses behavioral activity. Doses of (+)-cocaine were devoid of behavioral

effects across a range in excess of 200 times those of active doses of

(-)-cocaine. This dose range of the (+)-isomer was sufficient to ensure

that differences in affinities of the isomers for the dopamine or serotonin

transporters were not responsible for the lack of activity observed (see Katz et

al. 1990 for discussion). In contrast, convulsions and lethality were produced

with only a tenfold difference in potency of the two enantiomers (figure 1).

These results suggest that the acute toxic effects of bolus (-)-cocaine may be

due to mechanisms different from those that mediate its behavioral activity. The

toxicity of cocaine may be due to actions of cocaine other than or in addition to

its ability to block catecholamine and indoleamine uptake processes.

Dopamine Receptor Subtypes

The role of specific dopamine receptor subtype blockers in the toxicity of

cocaine has been evaluated. Haloperidot, a preferential antagonist at

dopamine D2 receptors, is ineffective in altering the lethal effects of cocaine in

rodents (figure 2, left panel) (Derlet et al. 1989; Witkin et al. 1989a; Witkin and

Katz 1991). Other D2

 antagonists also have been reported to be inactive

against the lethal effects of cocaine (see references in Witkin et al. 1989a).

Likewise, haloperidol does not prevent the development of cocaine-kindled

seizures (Karler et al. 1989). However, haloperidol effectively prevents the

lethal effects of amphetamines (figure 2, right panel) (Derlet et al. 1989; Witkin

et al. 1990). The contrasting effects of haloperidol against cocaine- or

amphetamine-induced lethality points to the difficulty in extrapolating from

one class of psychomotor toxicant to another.

47
FIGURE 1. Convulsive and lethal effects of the stereoisomers of cocaine.

Both isomers produced dose-dependent increases in convulsions

and lethality, with (-)-cocaine tenfold more potent than

(+)-cocaine.

SOURCE: Katz et al. 1990. Copyright 1990 by Clinical Neuroscience

Publishers (London).

48
FIGURE 2. Left panel: Haloperidol does not prevent the lethal effects of cocaine in rats. Middle panel: Lethal

effects of methamphetamins (MA) and N,N-dimethylamphetamine (NNDMA) in rats. Right panel:

Protection against the lethal effects of MA and NNDMA by 1.0 mg/kg haloperidol in rats.

SOURCE: Left: Witkin et al. 1989a. Reprinted with permission from Life Sciences, vol. 44, Witkin, J.M.; Goldberg,

S.R.; and Katz, J.L. Lethal effects of cocaine are reduced by the dopamine-1 receptor antagonist SCH

23390 but not by haloperidol. Copyright 1989 by Pergamon Press plc (Elmsford, NY). Middle and right:

Witkin, J.M.; Ricaurte; G.A.; and Katz, J.L. Behavioral effects of N-methylamphetamine and N,Ndimethylamphetamine in rats and squirrel monkeys. J Pharmacol Exp Ther 253:466-474, 1990. Copyright

1990 by American Society for Pharmacology and Experimental Therapeutics (Baltimore, MD).
FIGURE 3. Protection against the lethal effects of cocaine by the D1

dopamine antagonist SCH 23390 in rats

SOURCE: Witkin et al. 1989a. Reprinted with permission from Life Sciences,

vol. 44, Witkin, J.M.; Goldberg, S.R.; and Katz J.L. Lethal effects of

cocaine are reduced by the dopamine-1 receptor antagonist SCH

23390 but not by haloperidol. Copyright 1989 by Pergamon Press

plc (Elmsford, NY).

In contrast to haloperidol, lethal effects of cocaine have been reported to be

blocked by the D1 antagonist SCH 23390 (figure 3) (Derlet et al. 1990; Witkin et

al. 1989a; Witkin and Katz 1991). Interestingly, neither SCH 23390 nor related

D1 antagonists alter the convulsive effects of cocaine, and yet they increase the

LD50 for cocaine in rats and mice. Specific D1 antagonists also have been

suggested as potential candidates for use in the treatment of cocaine abuse

based on their efficacy in preclinical studies of the discriminative and reinforcing

effects of cocaine and their potentially low side-effect profile (Kleven et al.

50
1990; Witkin, in press). For example, SCH 23390, but not haloperidol, partially

prevented the discriminative stimulus effects of cocaine in a rodent model

predictive of the subjective effects of cocaine in humans (Witkin et al. 1991a).

The involvement of D1 receptors in the lethal effects of cocaine is further

documented by results of experiments with other compounds (Witkin and

Katz 1991). Similar protection against cocaine lethality is conferred by the

D1 antagonists SCH 39166 and SKF 83566. The effects of SCH 23390 are

stereospecific; the inactive enantiomer SCH 23388 does not protect even

when given in doses 30 times those of SCH 23390 required to prevent

lethality. The pharmacological specificity of D1

 antagonists for cocaine was

demonstrated by the lack of effect of 23390 against lethal effects of the local

anesthetic lidocaine, a compound relatively devoid of dopaminergic activity.

Thus, although lidocaine and cocaine may share local anesthetic mechanisms,

only the dopaminerigically triggered toxic events are prevented with D1

antagonists.

Dopamine antagonists appear to play a limited role in modifying the

cardiovascular effects of cocaine. Schindler and colleagues (1991) showed

that haloperidol attenuated cocaine-induced tachycardia in squirrel monkeys

but did not block the increases in blood pressure produced by intravenous

cocaine. SCH 23390 was ineffective in altering either effect of cocaine on

cardiovascular function despite its ability to attenuate the pressor effects of

the D, agonist SKF 38393. However, evaluation of these drugs in other

cardiovascular models (e.g., vascular spasms, arrhythmias) will be useful in

defining the role of cardiovascular events in the D1 receptor-sensitive lethality.

Noradrenergic Mechanisms

Neurotransmitter depletion studies have suggested a modulatory role for

norepinephrine but not dopamine in seizure susceptibility to some convulsants

but not to cocaine (Mason and Corcoran 1979). Nonetheless, several

antagonists, including prazosin, propranolol, and labetalol, protected against

the lethal effect of cocaine in rats, but additional protection was not afforded

by combined treatment with prazosin and propranolol (Derlet and Albertson

1990a). However, combined treatment with propranolol and phentolamine

(but not separate treatment) was found to protect against the lethal effects

of cocaine in mice without affecting convulsions (figure 4). The combined

- and ß-noradrenergic antagonist labetalol has found clinical use in the

medical management of cardiovascular toxicity induced by cocaine (Gay and

Loper 1968). The -2 antagonists idazoxan and RX811059A did not alter the

convulsive or lethal effects of cocaine in mice (Jackson et al. 1990). In squirrel

monkeys, cocaine-induced pressor activity (tachycardia in rats) (Jones and

51
FIGURE 4. Protection by combined and ß-adrenergic blockade against the lethal but not the convulsive effects of

cocaine. Data represent effects observed in groups of at least eight male Swiss Webster mice each.
Tackett 1990) was antagonized by -blockade with phentolamine, and the

tachycardiac response to cocaine was antagonized with propranolol (Tella et

al. 1990). However, in rat models of acute toxicity in which cocaine is infused

intravenously until death, protection against the cardiovascular consequences

of cocaine with noradrenergic blockers is not inextricably linked to protection

against lethality (Tella et al. 1991).

Cholinergic Mechanisms

Sharkey and coworkers (1988) demonstrated that cocaine binds to muscarinic

receptors and has weak antimuscarinic actions in vitro. Based on these

results, the authors suggested that cocaine at high doses may interfere with

the dampening of sympathetic cardiac influences, thereby rendering the

cardiovascular system vulnerable to potentially lethal consequences. Increases

in the cardiotoxic effects of cocaine have been reported in dogs treated with

atropine (Wilkerson 1989). Similar enhancement was reported with the

quaternary antimuscarinic, scopolamine methylbromide, suggesting a peripheral

influence of anticholinergics in the cardiotoxicity of cocaine. In other studies,

it has been shown that physostigmine could significantly protect rats against

the acute lethal effects of cocaine (Witkin et al. 1989b). This effect was

additionally surprising since physostigmine would be anticipated to block the

plasma hydrolysis of cocaine (Stewart et al. 1977). However, the mechanism

of protection did not appear to be via the indirect muscarinic agonist actions of

physostigmine, since direct-acting muscarinic agonists were ineffective and the

protection was not sensitive to atropine.

Calcium Channels

Results of studies with calcium channel antagonists on cocaine toxicity have

been mixed. Trouve and Nahas (1986) report significant protection against

the cardiotoxic effects of cocaine and increases in survival time with

nitrendipine pretreatment in rats. Rats pretreated with diltiazem, nifedipine,

or verapamil exhibited shortened onset to convulsions and, at some doses,

increased lethality induced by cocaine (Derlet and Albertson 1989). In both

squirrel monkeys and rats, calcium channel antagonists only blocked the

pressor effects of cocaine and did not afford protection against cocaineinduced lethality in rats (C.W. Schindler, personal communication, July

1991; Tella et al. 1991).

Peripheral Mechanisms

To evaluate the contribution of peripheral actions of cocaine to its toxicity, the

stable charged methiodide analog of cocaine (Shriver and Long 1971; Tessel

53
et al. 1978) was used to mimic the peripheral actions of cocaine. The lack of

CNS actions of cocaine methiodide was verified by bioassay. In mice, cocaine

methiodide was devoid of locomotor stimulatory actions (Witkin and Katz 1991)

and did not fully reproduce the discriminative stimulus effects of cocaine in

rats (Witkin et al. 1991a). In contrast, lethal effects of cocaine and cocaine

methiodide showed a relative potency close to one with parallel dose-response

curves suggesting comparable mechanisms of action. Doses of the D1

antagonists about two orders of magnitude lower than those effective against

cocaine lethality were effective in preventing death from cocaine methiodide;

haloperidol did not alter the lethal effects of cocaine methiodide despite

complete protection against convulsions at neuroleptic doses of haloperidol

(Witkin and Katz 1991). These data suggest that peripheral mechanisms

significantly contribute to cocaine lethality. The mechanism by which D1

antagonists protect against the peripheral manifestations of cocaine toxicity

(cocaine methiodide) or the combined peripheral/central actions of cocaine are

not known. Wilkerson (1988) and Tella and colleagues (1990) have provided

evidence to suggest that the cardiovascular effects of cocaine are controlled by

both central and peripheral actions and that some of these peripheral effects

of cocaine may be centrally driven. The discovery of a peripherally acting,

selective D1 antagonist would be a useful research tool in this regard.

Metabolites

Cocaine metabolites, although generally thought to be behaviorally inactive,

may have toxic actions that act alone or in concert with the parent compound.

Benzoylecgonine has been reported to be a potent vasoconstrictor in isolated

cat cerebral arteries and to display greater efficacy than cocaine (Madden

and Powers 1990). The recently identified metabolite of cocaine, cocaine

ethyl-ester (cocaethylene), is formed in liver in the presence of alcohol.

Cocaethylene has been associated with emergency room admissions related

to cocaine and with cocaine-related deaths (Hearn et al. 1991a). The

pharmacology of cocaethylene appears to be very similar to that of cocaine

(Hearn et al. 1991a; Jatlow et al. 1991). However, compared with cocaine,

cocaethylene is slightly less potent in stimulating locomotor activity in mice and

in producing discriminative stimulus effects comparable to cocaine in squirrel

monkeys (Katz and Witkin, in press). The toxicity of cocaethylene, on the

other hand, is at least as potent as that of cocaine. The compounds are

equipotent in producing clonic convulsions in mice (Katz and Witkin, in press),

whereas cocaethylene is more potent in producing lethality (Katz and Witkin,

in press; Hearn et al. 1991b). Thus, given the high incidence of alcohol use

in association with cocaine toxicity (Colliver et al., this volume), the contribution

of cocaethylene to the toxicity of cocaine cannot be ignored.

54
SAFETY EVALUATION OF PROPOSED COCAINE ABUSE TREATMENT

AGENTS

Preclinical evaluation of the potential toxicity of treatment compounds must

provide safety assurance before Phase I clinical evaluations can begin. In

the case of drugs of abuse, new potential therapeutic entities also must be

scrutinized closely for drug interactions, primarily with the target drug of

abuse. However, given the prevalence of polydrug abuse, certain drug

interactions guided by known mechanisms of action cannot be neglected.

An additional concern of drug abuse treatment agents stems from the potential

sensitization to the toxic effects of cocaine induced by repeated treatment

with the therapeutic agent. For example, repeated treatment with a dopamine

receptor blocking agent may increase the likelihood of a toxic cocaine episode

due to adaptive CNS mechanisms.

Drug Interactions

Safety evaluation and drug-interaction studies can be approached from a

number of angles (see Pentel and Thompson, this volume). One approach is

to give the test compound in conjunction with relatively low, yet psychoactive

doses of cocaine (e.g., doses that increase locomotor activity but are far from

the lethal range). Indications of toxicity from the combined treatment can be

gleaned by close observation of the animals. However, if the dose of cocaine

is too low, enhanced toxicity may not be observed. For example, if the ED50

for behavioral activity of cocaine is used (e.g., for locomotor stimulation, the

ED50 is about 10 mg/kg in mice), an additional amount of test substance with

an effect equivalent to about 45 mg/kg of cocaine (based on data of Witkin and

Katz 1991) would be needed to observe the first dramatic overt signs of toxicity

due to the drug interaction (convulsions).

Figure 5 illustrates some potential interactions of cocaine with hypothetical

treatments using ED50 values and slopes of dose-effect curves that correspond

to actual data. The ED50 for behavioral effects is shown as X, whereas that

for convulsions is 6X. Thus, large alterations in the convulsive threshold

for cocaine would be required to observe convulsions if the ED50 dose of

cocaine for behavioral activity were given in conjunction with the test

compound. A shift in convulsive threshold in the presence of treatment would

have to be on the order of sixfold to detect convulsions at the behavioral

ED50. Furthermore, assuming that the treatment doubles the sensitivity of the

subjects to convulsions (ED50 for convulsions now equals 3X, Rx 1 in figure 5),

administration of the behavioral or twice the behavioral ED50 of cocaine still

would not result in convulsions in any animal. However, since the slope of the

dose-response function for behavioral activity is less than that for convulsions,

55
FIGURE 5. Theoretical data illustrating dose-effect functions for the

behavioral effects of cocaine (e.g., with the range of abused

doses; curve at far left) and the convulsanf effects of cocaine

(curves at the far right). Also shown are hypothetical dose-effect

functions for interactions of cocaine with two hypothetical drug

abuse treatments.

large, behaviorally active doses of cocaine would result in convulsions in some

animals when given in combination with this treatment. For other toxic effects,

such as lethality, that occur at even greater cocaine doses, detection of toxicity

is even more difficult when examining behaviorally active cocaine doses in

combination with the treatment. However, if appropriate animal models could

predict toxicity from low doses of cocaine (e.g., cardiac arrhythmias, severe

blood pressure changes), this model of test drug evaluation could be very

useful. Thus, if the treatment interaction toxicity (Rx 2 toxicity) can be modeled

preclinically and validated as a predictor of clinical toxicity, then even small

56
changes in the toxicity of behaviorally active doses would be detected and

predictive of increased clinical risk.

Adequate safety evaluation can be achieved by examining the effects of lower

doses of cocaine in combination with the treatment, given adequate monitoring

of low-dose toxicity signs. In the absence of models predictive of toxicity from

low doses, direct observation of toxicity induced by cocaine alone and in the

presence of the treatment is needed. Appropriate toxicological assessment

requires more complete dose-effect analysis. Figure 5 shows theoretical doseeffect functions for convulsions alone and in the presence of a fixed dose of a

test compound (Rx 1 convulsions). In evaluating preclinical data of this nature,

the relationships among dose-effect curves are predictive of clinical toxicity.

Treatment 1 shifts the ED50 for convulsions to the left twofold. The degree of

that shift alone is probably not helpful in evaluating the magnitude of concern

over clinical toxicity. Instead, one must evaluate this shift relative to the ratio of

potencies of cocaine for inducing its behavioral effects and convulsant effects.

In this case, although only a twofold increase in sensitivity of cocaine is added

with the treatment, this is one-third of the original difference between behavioral

and toxic effects.

Furthermore, the toxicity and therapeutic potency of the treatment must

be known to evaluate its interactive effects with cocaine. Thus, if the

therapeutic dose of the treatment produces a shift of the convulsant effects of

cocaine to one-third of that of its behaviorally active dose range (e.g., range of

abused doses), the likelihood of clinical enhancement of convulsions is high.

Although safety evaluation should stay within the therapeutic dose range of

the treatment, this range is sometimes difficult to anticipate or to extrapolate.

Thus, the dose used preclinically relative to the therapeutic dose range may

not always be known. Under these conditions, interpretation of the dose-effect

curves can be made, given available information on the toxicity of the treatment

when given alone. For example, if the dose of the treatment is near its own

convulsant threshold, such a twofold shift in the cocaine dose-response function

is probably indicative of a minor clinical hazard since toxic doses of the

treatment would not realistically be within the clinically prescribed dose range.

Finally, it must be acknowledged that any preclinical safety data must be

considered as only a rough guideline for clinical investigation. A host of

differences between the effects of the test compound alone and in combination

with cocaine in experimental animals and humans necessitates the use of

carefully monitored clinical trials to ultimately establish safety of new

medications.

57
Mazindol

Mazindol was reported in open trials to reduce cocaine intake and craving for

cocaine in methadone maintenance patients (Berger et al. 1989). Given the

overlapping pharmacological profile of mazindol and cocaine, it was anticipated

that the two compounds may exacerbate the toxicity of one another. In mice,

mazindol has been shown to enhance both the convulsive and lethal effects of

cocaine at doses that are not toxic when given alone (figure 6). These data

have suggested caution in the use of mazindol in outpatient treatment (Jaffe et

al. 1989). However, the shifts in the dose-response functions were relatively

small (about twofold), and the dose of mazindol used in these experiments was

only one log-unit lower than the convulsant and lethal doses of mazindol. Since

the therapeutic dose range for mazindol would be estimated to be below that

used here, the potential for drug-interaction toxicity may be relatively small.

Tricylic Antidepressants

Although not without problems of compliance, side effects, and imperfect

overall treatment outcomes, desmethylimipramine is one of the most used

pharmacological treatments for cocaine abuse (Gawin et al. 1989; Johanson

and Fischman 1989; McElroy et al. 1990; O’Brien et al. 1988). Tricyclic

antidepressants might be anticipated to increase toxicity problems of cocaine

abuse, and cardiovascular toxicity has been noted (Fischman et al. 1990).

However, Jackson and coworkers (1990) noted that desmethylimipramine

afforded significant protection against the lethal effects of high doses of cocaine

in mice.

Opioids

The partial opioid agonist buprenorphine has been reported in both preclinical

studies and in open clinical trials to display efficacy in decreasing cocaine selfadministration (Kosten et al. 1989a, 1989b; Mello et al. 1989, 1990; Carroll and

Lac, in press; see Witkin, in press, for summary). Buprenorphine has been

shown to produce a dose-dependent protection against the lethal effects of

cocaine (Witkin et al. 1991b; figure 7, top panel). Although buprenorphine

protects against cocaine lethality, the convulsant effects of cocaine are

unaltered by buprenorphine treatment.

Further investigation suggested that the protection provided by buprenorphine

was due to μ-opioid agonist actions of buprenorphine. Other μ-opioids also

confer protection at relative potencies that are consistent with their affinities for

μ-opioid receptors. In addition, the unnatural (+)-enantiomer of buprenorphine

is devoid of activity; protection is blocked by relatively low doses of naloxone

58
FIGURE 6. Enhancement of the convulsant and lethal effects of cocaine by mazindol. Left panel: Effects of

increasing doses of mazindol against a fixed dose of cocaine (60 mg/kg) that was not lethal when given

alone. Right panels: Effects of cocaine alone and in the presence of 3 mg/kg mazindol on the

convulsant and lethal effects of cocaine. Mazindol alone did not induce convulsions or lethality at

doses below 30 mg/kg. Each point represents effects observed in at least eight male Swiss Webster

mice.
FIGURE 7. Top panel: dose-dependent protection against cocaine-induced

lethality by several μ-opioids, but not by (+)-buprenorphine,

which does not interact with opioid receptors. Respective

control effects of cocaine alone (75 mg/kg) are shown by the

60
unconnected points above C. Middle paneL: antagonism by

naltrexone of the protection against cocaine-induced lethality

conferred by buprenorphine. Unfilled bar: cocaine alone (75

mg/kg); solid bar: (-)-buprenorphine (1.0 mg/kg) administered 30

minutes before cocaine; striped bars: naltrexone (0.3 or 1.0

mg/kg) administered 15 minutes before (-)-buprenorphine, which

was given 30 minutes before cocaine. Bottom panel: lack of

effect of (-)-buprenorphine on cocaine-induced lethality in CXBK

mice, Unfilled bar: cocaine alone (100 mg/kg); solid bars:

(-)-buprenorphine (1.0 or 3.0 mg/kg) administered 30 minutes

before cocaine.

SOURCE: Witkin et al. 1991b. Copyright 1991 by Elsevier Scientific

Publishers Ireland Ltd. (Shannon).

(figure 7, middle panel); and buprenorphine does not induce protection in CXBK

mice, a recombinant inbred mouse strain relatively devoid of μ-opioid receptors

(figure 7, bottom panel).

Carbamazepine

Carbamazepine recently has received attention as a potential cocaine treatment

agent based on the preclinical observations of Post and Weiss (1989) and

the initial positive clinical findings of Halikas and coworkers (1989). Post and

Weiss (1989) drew parallels between the sensitization that develops to the

stimulatory, seizurogenic effects and mania induced by cocaine, as well as

manic-depressive psychosis. Since carbamazepine has been used in the

treatment of manic-depressive psychosis, these authors suggest it also may

be useful in the treatment of cocaine abuse. Data indicate that carbamazepine

can attenuate the development of cocaine-kindled seizures but not sensitization

to the locomotor stimulatory effects of cocaine in rats; however, carbamazepine

does not alter the convulsions induced by high doses of cocaine once kindling

has progressed (Post and Weiss 1989; Weiss et al. 1990). Substantial

differences in the degree to which carbamazepine confers protection against

both acute and kindled convulsions and lethality have been reported across

mouse strains (Marley and Goldberg 1991). The relevance of these

observations to an understanding of the mechanisms of action of

carbamazepine as a blocker of effects of cocaine will require further

detailed study.

61
ANTICONVULSANT DEVELOPMENT

Convulsions associated with cocaine abuse can be life threatening and

resistant to standard anticonvulsant drugs. In some models of cocaine

seizures, even high, incapacitating doses of diazepam are ineffective against

cocaine convulsions (Witkin and Tortella 1991). In this model, high doses

of cocaine (75 mg/kg, intraperitoneally [IP]) produced diazepam-insensitive

convulsions, whereas somewhat lower doses (60 mg/kg, IP) produced

diazepam-sensitive convulsions (see also Derlet and Albertson 1990b).

A host of other compounds are also inactive against diazepam-insensitive

cocaine convulsions. These compounds include the nonopioid antitussive

anticonvulsants (caramiphen, carbetapentane, and dextromethorphan), D1

dopamine receptor antagonists, noradrenergic antagonists, various opioids,

and 5-HT2 serotonin antagonists (Tortella et al., in press).

In contrast, noncompetitive N-methyl-D-aspartate (NMDA) antagonists dosedependently blocked the diazepam-insensitive convulsions (figure 8, left

panel). In addition, protection against diazepam-sensitive convulsions also

was conferred by antagonists that act competitively at the NMDA receptor.

Importantly, competitive antagonists generally have been found to be devoid

of the phencyclidine-like behavioral effects associated with the noncompetitive

antagonists (Willetts et al. 1990).

The relation of these data to the NMDA receptor is strengthened by

observations that drugs that act at other sites on the NMDA receptor complex

also modify the convulsant effects of cocaine. The NMDA receptor is coupled

allosterically to a strychnine-insensitive glycine receptor. An antagonist (7-

chlorkynurinic acid) and a partial agonist (ACPC) at this site also were

evaluated for anticonvulsant efficacy against cocaine since they attenuate the

convulsant and lethal effects of exogenously administered NMDA at doses well

below those producing behavioral incapacitation. Figure 8 (right panel) shows

that these compounds also produce protection against diazepam-sensitive

cocaine convulsions. Further results suggest that some of these compounds

may be useful adjuncts to standard anticonvulsant therapy. For example,

caramiphen and diazepam are devoid of activity against diazepam-insensitive

convulsions when given alone; in conjunction with low doses of diazepam,

caramiphen dose-dependently protected against diazepam-insensitive cocaine

convulsions (Tortella et al., in press).

ANTIPSYCHOTIC DEVELOPMENT

Compounds that bind to o-receptors are being developed as novel antipsychotic

agents that may be devoid of the side effects associated with conventional

62
FIGURE 8. Left panel: dose-dependent attenuation of the diazepam-insensitive convulsive effects of 75 mg/kg

cocaine by competitive (CPP, NPC 12626) and noncompetitive (MK-801, phencyclidine) NMDA

antagonists. Right panel: prevention of the convulsions induced by 60 mg/kg cocaine by diazepam and

two ligands of the strychnine-insensitive glycine site of the NMDA receptor/ion complex.

SOURCE: Witkin and Tortella 1991. Reprinted with permission from Life Sciences-Pharmacology Letters, vol. 48,

Witkin, J.M., and Tortella, F.C. Modulators of N-methyl-D-aspartate protect against diazepam- or

phenobarbital-resistant cocaine convulsions. Copyright 1991 by Pergamon Press plc (Elmsford, NY).
antipsychotics, such as haloperidol. The ability of the selective -ligands BMY

14802 and rimcazole to block the locomotor stimulant effects of cocaine was

compared with that of haloperidol and (+)-3-PPP, which have both dopamine

and receptor affinity, and the novel non antipsychotic clozapine. Each of

the selective ligands produced a significant shift in the cocaine dose-effect

functions at doses that did not have significant behavioral effects of their own.

In contrast, haloperidol, (+)-3-PPP, and clozapine were inactive as antagonists

of the locomotor stimulant effect of cocaine at doses that were behaviorally

inactive. At higher doses, all of these drugs except (+)-3-PPP also blocked the

locomotor stimulant effects of cocaine (Menkel et al. 1991). Interestingly, (+)-3-

PPP completely protected against the convulsant effects of cocaine, whereas

other ligands were only moderately effective, if at all (Tortella et al., in press).

The attenuation of the stimulant effects of cocaine by the selective

compounds suggests a novel approach to the development of drugs that may

be useful in the treatment of cocaine abuse and psychotic symptomatology.

The activity of these ligands against cocaine at doses without significant

behavioral activity of their own suggests that these compounds might

specifically block the psychotropic effects of cocaine without interfering with

ongoing behavior. The discovery and evaluation of other -site-selective

ligands will help clarify questions of mechanism and may foster development

of antagonists with therapeutic efficacy in the treatment of cocaine abuse and

toxicity.

CONCLUSIONS

The acute and chronic toxicity of cocaine is not fully understood. Treatment

strategies, although generally effective, remain imperfect. There are several

areas in which improved medications could be clinically useful. Preclinical drug

development efforts can increase understanding of the mechanisms underlying

cocaine toxicity, develop functional and predictive models, establish safety of

cocaine abuse treatments, and provide new leads in the development of more

effective medications to be used in the treatment of drug overdose toxicity and

drug abuse.

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ACKNOWLEDGMENTS

Data on the toxicity of higher doses of mazindol were obtained by Patrick

Hickey and Melissa Menkel. In conducting the research described in this

chapter, the authors adhered to the “Guide for the Care and Use of Laboratory

Animals,” as promulgated by the Committee on Care and Use of Laboratory

Animals of the Institute of Laboratory Animal Resources, Commission on Life

Sciences, National Research Council.

68
AUTHORS

Jeffrey M. Witkin, Ph.D.

Head

Drug Development Group

Psychobiology Laboratory

Jonathan L. Katz, Ph.D.

Chief

Psychobiology Laboratory

Preclinical Pharmacology Branch

Addiction Research Center

National Institute on Drug Abuse

P.O. Box 5180

Baltimore, MD 21224

69
The Cardiovascular Effects of

Cocaine—Update 1992*

Lewis R. Goldfrank and Robert S. Hoffman

INTRODUCTION/EPIDEMIOLOGY

In 1974 the National Institute on Drug Abuse (NIDA) estimated that 5.4 million

Americans had used cocaine at some time in their lives (Abelson and Miller

1985; Johnston et al. 1987). This number increased dramatically so that

by 1985 there were 25 to 40 million Americans who had used the agent, 3

million of whom could be considered cocaine dependent (Abelson and Miller

1985; Johnston et al. 1987). In 1988 there were 3.5 million Americans

between the ages of 18 and 25 who admitted to frequent use of cocaine

(National Institute on Drug Abuse 1989). Similar studies, including that of the

NIDA-sponsored Drug Abuse Warning Network (DAWN), have demonstrated a

tenfold to twentyfold increase in emergency department utilization for cocainerelated problems (Colliver 1987; National Institute on Drug Abuse 1987a,

1987b; Adams and Durell 1984; Jekel et al. 1986). Cocaine use is commonly

associated with the concomitant administration of other substances of abuse

such as ethanol, opioids (typically heroin), marijuana, and sedative hypnotics

(typically benzodiazepines). Current data suggest a marked increase in

cocaine use and complications. For example, in 1980 cocaine was the 10th

most commonly used drug in patients presenting to the Bellevue Hospital

Emergency Department; however, by 1989 it became the most commonly

used agent (unpublished data). As of 1986 cocaine use was the most frequent

drug-related cause of U.S. emergency department visits and ranked third

behind opioids and drugs combined with ethanol as the cause of drug-related

mortality (MacDonald 1987). Finally, between 1985 and 1988 cocaine-related

mortality increased from the fourth to the second most common cause of death

(accounting for more than 11.5 percent of the total fatalities) reported to the

American Association of Poison Control Centers National Data Collection

System (Litovitz et al. 1986, 1989).

*Part of this chapter was presented at the American College of Emergency

Physicians Winter Symposium in Tucson, AZ, March 1990, and part of it was

published in Goldfrank and Hoffman 1991 and is reprinted by permission.

70
The first systematic study designed to validate drug abuse mortality data,

from either national vital statistics (maintained by the Centers for Disease

Control’s National Center for Health Statistics [NCHS]) or DAWN, by

means of a comparison with a supplemental cause of death database was

undertaken between 1983 and 1988 in 25 metropolitan areas (Pollack et al.

1991). During this 6-year period, DAWN reported 6,057 cocaine-related

fatalities, and NCHS reported 3,466. Depending on the database utilized,

the differences in individual cities were as great as 600 percent. In addition,

Pollack and colleagues (1991) demonstrated that mortality rates exceeded the

number of deaths reported to NCHS in six of seven forensic case series

studied. When not attributed to trauma or human immunodeficiency virus

infection, the marked increase in fatalities described in all the current series is

ascribed to cardiovascular causes (National Institute on Drug Abuse 1987b).

Despite their limitations, these reports demonstrate evolving patterns of

utilization, showing that intranasal cocaine (insufflation), which was the

primary route of delivery in the early 1980s, was replaced largely by

intravenous (IV) cocaine in the mid-1980s and by smoking the alkaloid form

of cocaine known as “crack” in the late 1980s (Abelson and Miller 1985;

Johnston et al. 1987; Colliver 1987; National Institute on Drug Abuse 1987a,

1987b; Jekel et al. 1986). The myriad clinical manifestations of cocaine

intoxication include systemic complications such as malnutrition and exhaustion

as well as neurologic, psychiatric, cardiovascular, venous, musculoskeletal,

dermatologic, gastrointestinal, pulmonary, infectious, obstetrical, and neonatal

manifestations. There is no current evidence to suggest that the presence of

preexistent vascular disease or other abnormalities are essential prerequisites

for the development of a cocaine-related cardiovascular event. This chapter

emphasizes the cardiovascular and systemic vascular characteristics of

cocaine utilization and their therapeutic implications; it also attempts to

minimize reliance on the reported rates of cocaine drug use, complication,

and death due to the demonstrated unreliability of the current databases

(Kleber 1991; Schuster 1991; Weisman and Goldfrank 1991).

PHARMACOLOGIC PRINCIPLES

The white crystalline powder benzoylmethylecgonine (cocaine) is widely used

(by insufflation or IV route) as the highly water-soluble hydrochloride salt or (by

smoking) as the free base (or crack) form, which has limited water solubility but

is more volatile, vaporizable, and stable to pyrolysis when compared with the

hydrochloride salt. Cocaine’s pharmacologic effects are unusual in that it (1)

can inhibit the initiation or conduction of nerve impulses (anesthetic effect) and

(2) has both centrally and peripherally mediated vasoconstrictor effects (Ritchie

and Greene 1990). The pharmacologic effects of cocaine are discussed from a

71
theoretical perspective and often differ from the reported clinical responses.

Patients invariably utilize multiple other substances that alter the normal end

organ manifestations and potential adverse effects. The neuropharmacologic

drug interactions, the pharmacokinetic changes, and the development of new

metabolites have not been studied in detail.

Cocaine is a central nervous system (CNS) stimulant. Cocaine use is

associated with a general feeling of well-being, manifested by enhanced

alertness, self-confidence, reduction in social inhibitions, euphoria, and

dysphoria (Gawin 1991). The vasomotor center is initially stimulated producing

hypertension and tachycardia; however, later these same medullary centers

are depressed with the resultant development of respiratory depression and

possible death (Tseng et al. 1991). Small doses of cocaine slow the heart due

to a central vagally mediated effect (Ritchie and Greene 1990), whereas larger

doses produce tachycardia by direct central stimulation and also by increasing

peripheral catecholamine levels (Ritchie and Greene 1990). This latter effect

results from cocaine-induced blockade of norepinephrine reuptake, one of the

mechanisms normally responsible for limitation of peripheral catecholamine

effects. Cocaine also may alter neurotransmission of histamine, acetylcholine,

and phenylethylamine (Gawin 1991). Alternatively, cocaine’s stimulatory

effects may be mediated through the release of the excitatory amino acids

aspartate and glutamate (Rockhold 1991). Although cocaine also affects

the release and reuptake of serotonin and dopamine, which are the major

determinants of stimulant abuse, psychiatric complications, and withdrawal

manifestations (Gawin and Ellinwood 1988) this chapter does not focus on

these pharmacological effects. Possible alterations in plasma cholinesterase

(Van Dyke et al. 1978) (the major enzyme responsible for cocaine metabolism)

as well as the development of an incomplete form of tolerance (Ambre et al.

1988) play a role in the adaptive process. This adaptive process, which allows

for the euphoria and cardioacceleratory effects to diminish at a more rapid rate

than the plasma cocaine levels, has been demonstrated by several researchers

(Javaid et al. 1978; Zahler et al. 1982; Chow et al. 1985). That a second dose

of cocaine delivered within an hour of the initial dose induces a lesser response

is suggestive of highly effective homeostatic negative feedback mechanisms

or acute tolerance (Chow et al. 1985; Fischman and Schuster 1981).

The initial effect on blood pressure is directly related to sympathetically

induced tachycardia and vasoconstriction. A subsequent fall in blood pressure

may follow as massive cocaine doses probably result in direct toxic effects

on the myocardium. These manifestations of homeostasis, adaptation, and

tolerance play a substantial role in the diverse pathophysiologic characteristics

of cocaine toxicity, in addition to those that are specifically cardiovascular in

nature (Fischman and Schuster 1981).

72
Cocaine is absorbed by all sites (typically the mucous membranes but also the

respiratory, gastrointestinal, cutaneous, and genitourinary tract routes), and it

is absorbed whether in the hydrochloride or the free base form. The rapidity

of peak onset of action from the IV and inhalation routes are approximately

30 seconds to 2 minutes, whereas intranasally the peak effect may be

achieved within one-half hour. Gastrointestinal peak absorption may be

delayed for up to 90 minutes (Van Dyke et al. 1978). The duration of effect is

directly related to onset of effect and is approximately 15 to 30 minutes by IV

or inhalation route, 1 hour by intranasal exposure, and as long as 3 hours

after gastrointestinal absorption (Resnick et al. 1977). Following the IV or

inhalational administration of cocaine the plasma half-life approximates 60

minutes, but because of cocaine’s vasoconstrictor effect its absorption is

inhibited by the intranasal route, and the apparent half-life approaches 2 to

3 hours (Javaid et al. 1978; Zahler et al. 1982).

Cocaine is rapidly metabolized in great part by plasma (and somewhat by

hepatic) cholinesterases to an inactive metabolite, ecgonine methyl ester (Inaba

et al. 1978). Human and animal evidence suggests that an association exists

between the manifestations of cocaine intoxication and plasma cholinesterase

activity such that low plasma cholinesterase activity increases the risk for lifethreatening cocaine toxicity (Hoffman et al. 1991, 1992; Devenyi 1989).

Benzoylecgonine, the other major inactive metabolite of cocaine, is formed as

the result of nonenzymatic hydrolysis in the blood (Stewart et al. 1977, 1979).

Norcocaine, an active metabolite, is formed by an N-demethylation reaction

and usually represents less than 5 percent of the total quantity of cocaine

metabolites (Inaba et al. 1978). At most, 5 to 10 percent of the total cocaine

dose is excreted unchanged in the urine. Unmetabolized cocaine is not usually

present in the serum after 6 hours, whereas the metabolites can usually be

found for at least 48 hours (Verebey 1987). Actually, the ratio of cocaine to its

metabolites in the urine has been used to predict the time of exposure (Ambre

1985). Recently, benzoylecgonine has been detected in the urine as late as

22 days after the last intoxication in three asymptomatic patients with histories

of substantial cocaine use (Weiss and Gawin 1988). Although it is unclear

whether this is related to storage in body tissues or to abnormal metabolism,

this finding may have important clinical implications if active cocaine metabolites

may also be delayed in their metabolism and/or excretion.

CARDIOVASCULAR MANIFESTATIONS OF COCAINE

The toxic vascular effects of cocaine in humans are due largely to direct

stimulation of the central nervous, cardiovascular, and respiratory systems

Concomitant inhibition of catecholamine reuptake serves to amplify and

perpetuate these effects. Overstimulation and subsequent catecholamine

73
depletion may produce central nervous, cardiovascular, and respiratory system

depression. This section deals in greatest detail with the heart, great vessels,

and CNS but will also focus on the vascular effects of the pulmonary skeletal

musculature, dermatologic, gastrointestinal, uterine, placental, and fetal

systems. A summary of the vascular effects of cocaine can be found in table 1.

The Heart

There are now numerous reports documenting myocardial ischemia and

infarction during cocaine intoxication (Coleman et al. 1982; Kossowsky and

TABLE 1. Summary of vascular complications of cocaine toxicity

System Complication

Neurologic lntracerebral hemorrhage, cerebral

infarction, seizures, migraine headache,

vasculitis, blindness

Cardiac Myocardial infarction, myocardial ischemia,

coronary vasospasm, arrhythmias

myocarditis, cardiomyopathy

Great vessels

Gastrointestinal

Aortic dissection and rupture, hypertension

Mesenteric ischemia and infarction,

gastrointesinal perforation, hepatic

failure, splenic infarction

Pulmonary

Musculoskeletal

Dermatologic

Uterine, placental,

obstetrical, and

neonatal

Genitourinary

Pulmonary edema, infarction

Rhabdomyolysis

lschemia

Abruptio placentae, spontaneous abortion,

prematurity, developmental delays, growth

retardation, congenital abnormalities

Renal and testicular infarction,

myoglobinuric renal failure

Venous Vasculitis, superficial and deep venous

thrombosis and thrombophlebitis

SOURCE: Goldfrank and Hoffman 1991. Copyright 1991 by Annals of Emergency

Medicine (Dallas).

74
Lyon 1984; Schachne et al. 1984; Cregler and Mark 1985; Howard et al. 1985;

lsner et al. 1986; Pasternack et al. 1985; Mathias 1986; Simpson and Edwards

1986; Weiss 1986; Smith et al. 1987; Frishman et al. 1989; Stenberg et al.

1989; Amin et al. 1990; Minor et al. 1991; Zimmerman et al. 1991; Brody et

al. 1990a; Tokarski et al. 1990; Gitter et al. 1991) or withdrawal (Nademanee

et al. 1989). These case reports have demonstrated that infarctions frequently

occur in patients in the 19- to 40-year-old range without apparent massive

exposures (Schachne et al. 1984) to cocaine or without concurrent seizures

or agitation. Patients with cocaine-associated myocardial infarctions frequently

have either atypical chest pain, no chest pain, or chest pain delayed for

hours to days after their most recent use of cocaine (Amin et al. 1990;

Zimmerman et al. 1991; Brody et al. 1990a; Tokarski et al. 1990; Gitter et al.

1991). The electrocardiograms revealed abnormalities consisting of ST

segment elevation and T-wave inversions that persisted during hospitalization.

Electrocardiographic abnormalities were noted in many, but not all, patients

with acute myocardial infarctions (Amin et al. 1990; Tokarski et al. 1990). In

addition, no predeliction for a specific coronary artery distribution was shown,

and Q-wave or non-Q-wave infarctions were equally frequent (Amin et al.

1990). These researchers offer varying analyses of the pathogenesis of

these events. Mechanisms of pathogenesis under consideration include

tachyarrhythmias, systemic arterial hypertension, increased myocardial

oxygen demand, immediate or delayed coronary vasospasm, predisposition

due to underlying coronary artery stenosis, increased platelet aggregation,

and accelerated atherogenesis. There has been no evidence correlating

blood levels or route of administration to the development of cocaine-induced

myocardial ischemia or infarction (Mittleman and Wetli 1984). Autopsy and

angiographic studies have demonstrated myocardial infarction in the absence

of atherosclerotic disease and any other evidence of underlying heart disease

(Cregler and Mark 1985; Howard et al. 1985; lsner et al. 1986; Pasternack

et al. 1985; Minor et al. 1991). Minor and coworkers (1991) performed a

comprehensive review of all 35 reported cases of myocardial infarction

temporally related to the use of cocaine in the presence of normal coronary

arteries. These patients, with an average age of 32 years (range 21 to 60

years), experienced myocardial infarction involving the anterior left ventricular

wall 77 percent of the time, Focal coronary vasospasm was found in 2 cases,

and an intracoronary thrombus was found in 9 of 11 patients studied within 12

hours of infarction. Angiography done shortly after infarction has demonstrated

acute thrombotic occlusion, which, after being treated with thrombolytic agents,

has shown no underlying atheromatous disease (Smith et al. 1987). However,

in an autopsy study of 17 non-cocaine-related fatalities in young (average

age 32 years) cocaine abusers, coronary artery narrowing of greater than

75 percent of luminal diameter was found in approximately 50 percent of

cases (Dressler et al. 1990).

75
In 90 percent of patients with variant angina (Prinzmetal’s), ergonovine

challenge tests normally lead to a rise in systemic pressure, diffuse coronary

artery narrowing, and focal vasospasm (Isner et al. 1986). However,

administration of ergonovine in patients with cocaine-induced myocardial

infarctions uniformly fails to produce focal vasospasm (Howard et al. 1985;

lsner et al. 1986; Pasternack et al. 1985), although Chokshi and colleagues

(1989a) described a patient with a history of a cocaine-related ischemic

event who had a negative ergonovine provocation test and severe coronary

vasospasm when provoked with intranasal cocaine. Thus, the absence of

a response to standard testing techniques cannot be used to exclude the

possibility that cocaine-induced vasospasm occurred.

In the normal myocardium, increased oxygen demand stimulates coronary

vasodilation through an autoregulatory mechanism (Marcus 1983). In the

presence of cocaine and the marked increase in sympathetic activity, this

autoregulation may be lost and vasoconstriction may take precedence

(Mathias 1986) as has been noted in those with established atherosclerotic

lesions (Mudge et al. 1976). Although many of the patients studied also

smoked cigarettes and used other drugs as well as cocaine admixed with

numerous contaminants, these episodes have also occurred when cocaine

was smoked exclusively, which is usually considered to be a relatively pure

intoxication (Smith et al. 1987). The strongest correlation can be made in

individuals when there is a temporal relationship between the use of cocaine

and the myocardial infarction or the recurrent episode of ischemia.

Ventricular wall akinesis and dyskinesis have been demonstrated in the

distribution of the infarction. Infarctions have been anterior, inferior, and

anterolateral, with the left anterior descending coronary artery being most

frequently affected (Smith et al. 1987; Frishman et al. 1989). In many of the

affected individuals, ischemia recurred in those who continued to utilize cocaine

(Smith et al. 1987), with subsequent reinfarction (Simpson and Edwards 1986;

Weiss 1986) and death being described (Simpson and Edwards 1986). In

certain patients with cocaine-induced myocardial infarctions, normal stress

electrocardiograms and thallium studies have been subsequently documented

(Isner et al. 1986).

The sympathomimetic action of cocaine and the effects of epinephrine and

norepinephrine are postulated to initiate platelet adherence and aggregation

(Tonga et al. 1985). In cocaine-associated deaths some researchers (Tazelaar

et al. 1987) have demonstrated a marked increase (p<.001) in myocardial

contraction band necrosis (93 percent) at autopsy when compared with a

control population of sedative-hypnotic drug-associated deaths (45 percent).

However, Virmani and colleagues (1988) were unable to demonstrate any

76
statistically significant relationship, with a 25-percent incidence of contraction

band necrosis being found in those patients with cocaine-associated deaths

and a 41-percent incidence in those patients with sudden traumatic death.

Contraction band necrosis is pathologically defined by the hypercontracted

sarcomere and myofibrillar disruption commonly occurring in patients in the

presence of high catecholamine levels, such as with pheochromocytomas

(Rosenbaum et al. 1987; Reichenbach and Benditt 1970) or in the presence

of cocaine (Karch and Billingham 1986). Myocyte necrosis occurs, and this

tissue is ultimately replaced by fibrous tissue. Karch and Billingham (1986)

suggest that this myofibrillar degeneration may indicate reperfusion injury.

Direct cocaine-induced coronary vasospasm has been suggested in a human

angiography study with patients receiving 2 mg/kg cocaine intranasally (Lange

et al. 1989). In these patients with no prior use of cocaine, diffuse coronary

artery constriction occurred in the absence of associated chest symptoms

or pain. The heart rate and arterial blood pressure increased while the

coronary sinus blood pressure and the diameter of the left coronary artery

fell. All these parameters returned to normal when an intracoronary infusion

of the -adrenergic blocker phentolamine was given. Another study

demonstrated enhanced evidence of vasoconstriction at sites of significant

coronary artery stenosis (Flores et al. 1990). This vasospasm was exacerbated

by the administration of propranolol, which produced anginal symptoms and

ST-segment elevation in one of the study patients, Animal experimental models

that support the theory of cocaine-induced coronary vasospasm are reviewed

by lsner and Chokshi (1989).

Chronic alterations in catecholamine levels may produce coronary

vasospasm, thereby making the individual prone to ischemia and infarction

by simultaneously increasing myocardial oxygen demand and decreasing

oxygen supply. Nademanee and coworkers (1989) recently demonstrated

with ambulatory electrocardiographic monitoring that individuals had

spontaneous ischemic episodes during the first weeks of undergoing

withdrawal from cocaine. They postulate that patients in cocaine withdrawal

manifest a dopamine-depleted state, which results in intermittent coronary

spasm. Del Aguila and Rosman (1990) recently documented a myocardial

infarction that occurred 3 days after cocaine use in a 42-year-old male with

normal coronary arteries. The researchers postulated a state of increased

adrenergic receptor sensitivity and catecholamine replenishment during the

cocaine withdrawal period as an explanation for their findings. Further

understanding of the pharmacologic characteristics of cocaine withdrawal

may better explain these events.

77
Myocarditis

Although Virmani and colleagues’ (1988) study did not demonstrate myocardial

contraction band necrosis, it did demonstrate mononuclear myocarditis in

20 percent of those patients who died with detectable cocaine in body fluids,

whereas only 3.7 percent of those without cocaine who succumbed to a

traumatic death had similar findings. The study suggests that mononuclear

myocarditis may represent the result of microvascular injury. One of the

patients reported by lsner and colleagues (1986) also had myocarditis with a

characteristic eosinophilic leukocytic infiltration, as did two additional patients

in the Virmani group and several patients in other studies, suggesting a

hypersensitivity reaction to cocaine, its metabolites, or contaminants (Karch

and Billingham 1988).

Striking similarities have been noted in patients with ineffectively treated or

untreated pheochromocytomas or in animals exposed to norepinephrine.

Examination of the hearts of 26 patients who died with pheochromocytoma

demonstrated an active myocarditis in 58 percent, and two-thirds of these

patients died of left ventricular failure (Van Vliet et al. 1966). These researchers

characterized the focal degeneration and necrosis of myocardial fibers with foci

of histiocytes, plasma cells, and polymorphonuclear leukocytes as an “active

catecholamine myocarditis.” In a preliminary rat study, 40 percent of 60 rats

died within 72 hours after being given 1 to 2 subcutaneous injections of 2 mg

of norepinephrine per kilogram body weight (Van Vliet et al. 1966). All these

animals were found to have an active myocarditis; those rats sacrificed during

the first 5 days following the experiment also showed an active myocarditis,

whereas those that were sacrificed 3 to 8 weeks later showed myocardial

fibrosis.

Arrhythmias

Low-dose cocaine may result in bradycardias, whereas higher doses have

been associated with virtually all other arrhythmias. Sinus tachycardia, atrial

fibrillation, ventricular extrasystoles, accelerated idioventricular rhythms, and

ventricular tachycardia and fibrillation may follow exposure to cocaine and may

be directly related to increased catecholamine levels from effects on the central

and peripheral sympathetic nervous systems. In addition, cocaine-induced

myocardial ischemia or infarction may produce secondary cardiac arrhythmias

that are indistinguishable from those arrhythmias produced from atherosclerotic

heart disease. Recent work has concentrated on cocaine’s direct effects

on myocardial conduction and arrhythmogenesis. In dogs, Schwartz and

coworkers (1989) demonstrated that, although low doses of cocaine produced

increases in blood pressure, higher doses resulted in hypotension, infranodal

78
and interventricular conduction delays, and lethal ventricular arrhythmias. In

this study the QRS and QT intervals were markedly prolonged, and PR intervals

remained unchanged. Similar effects were noted by Parker and colleagues

(1989a), who suggested that cocaine demonstrated electrophysiologic

properties similar to type I antiarrhythmics, producing classic QRS and QT

prolongation. This probably occurs through blockade of sodium channels and

may help to explain why increasing doses of cocaine appear to have a direct

myocardial depressant effect (Perreault et al. 1989; Hale et al. 1989). Some

of these arrhythmias may lead to a cerebral hypoperfusion and a transient

loss of consciousness, a common finding in the cocaine-overdosed patient.

Clinically, this presentation must be differentiated from a seizure disorder or a

cerebrovascular catastrophe. A schematic representation of the mechanisms

that lead to myocardial ischemia or arrhythmias is shown in figure 1.

FIGURE 1. Mechanism of acute cocaine-induced arrhythmias and myocardial

ischemia

79
Cardiomyopathy

Long-term cocaine use predisposes to the development of a dilated

cardiomyopathy and recurrent myocardial infarction even in the absence

of atherosclerotic epicardial coronary artery disease. Although this form

of dilated cardiomyopathy may result from ischemia and the induction of a

“stunned” myocardium secondary to protracted coronary vasospasm (Weiner

et al. 1986), recent work has suggested that cocaine may have a direct

effect on contractility independent of its ischemic effects (Johnson et al.

1989). Chokshi and colleagues (1989b) described a patient who developed

a dilated cardiomyopathy temporally related to using free base cocaine.

With noninvasive studies, this patient’s left ventricular systolic function was

demonstrated to improve during a 2-week period of cocaine abstinence.

More recently, Van De Bor and associates (1990) demonstrated that infants

born to cocaine-using mothers had statistically lower cardiac outputs in the

first day of life when compared with control infants; the differences resolved

by the second day of life. These results are quite comparable with the

catecholamine-induced reversible cardiomyopathies reported to be

associated with pheochromocytomas (Imperato-McGinley et al. 1967)

and methamphetamine use (Hong et al. 1991).

Endocarditis and Endothellal Injury

An increased risk of upper extremity deep vein thrombosis (Lisse et al. 1989a,

1989b) and bacterial endocarditis (Chambers et al. 1987) has been noted to

be associated with IV cocaine use. This risk of endocarditis seems to be

higher than that for a similar population of IV heroin users and may result from

the increased frequency of injections in cocaine users or from direct effects of

cocaine on endovascular tissues and the immune system (Chaisson et al. 1989;

Weiss 1989). The normal functioning of the coronary artery endothelial cells is

dependent on the release of endothelium-derived releasing factor. This

agent is recognized as nitric oxide (Palmer et al. 1987) or another nitrosothiol

compound. Endothelial dysfunction has been noted in individuals with

coronary risk factors. Dysfunction also has been noted in humans who are

hypersensitive to catecholamines with vasoconstrictor properties such as

serotonin, which, in the presence of endothelial dysfunction, also causes

intense vasoconstriction of vascular smooth muscle, potentially resulting in

coronary vasospasm (Vanhoutte and Shimokawa 1989). Minor and coworkers

(1991) also suggest that an endothelial-derived contracting factor may play a

role in vasospasm. All these factors represent a potential for endothelial injury

and dysfunction, which may result in platelet-mediated vasoconstriction and

aggregation.

80
The Great Vessels

Several cases of cocaine-induced aortic dissection and rupture have been

reported (Tardiff et al. 1989; Barth et al. 1986; Gadaleta et al. 1989; Edwards

and Rubin 1987). In one pathologic report a medial dissection ruptured

proximally to the level of the aortic valve cusps in a man who had been smoking

free base cocaine (Barth et al. 1986). It is presumed that dissection and rupture

result from the increase in shear forces that result from cocaine-induced

hypertension and tachycardia. This is supported by the lack of pathological

correlates of aortic dissection (e.g., atherosclerotic aneurysms, syphilitic aortitis,

cystic medial necrosis, Marfan’s syndrome). To date, no cases of rupture of

abdominal aneurysms, which are typically atherosclerotic in nature, have been

reported to be associated with cocaine use.

Cerebral Vasculature

Cerebrovascular accidents, including subarachnoid hemorrhage (Lichtenfeld et

al. 1984; Schwartz and Cohen 1984), intracerebral hemorrhage (Wojak and

Flamm 1987), cerebral infarction (Seaman 1990; Brust and Richter 1977;

Levine et al. 1987, 1990; Golbe and Merkin 1986) transient ischemic attacks

(Mody et al. 1988), migraine-like headache syndromes (Satel and Gawin 1989),

seizures (Choy-Kwong and Lipton 1989a), cerebral vasculitis (Kaye and

Fainstat 1987), anterior spinal artery syndrome (Mody et al. 1988), and the

more common psychiatric manifestations (Lowenstein et al. 1987), have been

reported with increasing frequency. In all but one of these case reports or

series there was no correlation with the route of cocaine delivery, the amount

taken, or prior exposure (Levine et al. 1990). Levine and coworkers (1990)

found that ischemic and hemorrhagic strokes were reported with nearly equal

frequency in association with the use of alkaloidal cocaine, whereas cocaine

hydrochloride was associated with approximately 80 percent of the intracranial

hemorrhages, and in 50 percent of these cases ruptured cerebral saccular

aneurysms or vascular malformations were noted.

Although some patients have evidence of underlying cerebrovascular disease

such as rupture of preexisting unsuspected aneurysms or arteriovenous

malformations under the influence of cocaine-induced hypertension, reports

have failed to demonstrate underlying disease in most patients (Wojak and

Flamm 1987; Satel and Gawin 1989; Henderson and Torbey 1988). Other

mechanisms have been proposed for stroke associated with cocaine use and

include increased coagulability, impaired cerebrovascular autoregulation from

increased cerebrovascular resistance (Levine et al. 1987, 1990), vasospasm

(Golbe and Merkin 1986), embolism of particulate matter, and immunologically

mediated arteritis or vasculitis (Caplan et al. 1982; Krendel et al. 1990).

81
Recently, the finding of a high incidence of anticardiolipin antibodies in the

serum of cocaine users has led some researchers to conclude that the

immunologic mechanisms may play a greater role in cocaine toxicity than

previously assumed (Fritsma et al. 1991).

The visual system has also been affected by cocaine. Direct instillation into

the conjunctival sac denudes the corneal epithelium (Ravin and Ravin 1979).

Toxicity from particulates in smoke and irritation produce corneal abrasions

and ulcerations in a syndrome known as “crack eye” (McHenry et al. 1989).

Vascular effects, including central retinal artery occlusion (Devenyi et al. 1988)

and bilateral blindness from diffuse vasospasm (Reimer and Hoffman 1991)

have also been noted.

Pulmonary Vasculature

The possibility of a direct effect of cocaine on the pulmonary vasculature has

not been thoroughly evaluated. This is extremely important in view of the

highly concentrated heated cocaine alkaloid that is frequently used and directly

delivered into the pulmonary circulation. Ettinger and Albin (1989) suggest that

cocaine may induce an increase in systemic vascular resistance, with resultant

left ventricular dysfunction and pulmonary edema. Murray and colleagues

(1988a) have shown that pulmonary artery hypertrophy, in the absence of

foreign particle embolization, may occur with chronic cocaine use. Other

authors have described alveolar hemorrhage following the use of free base

cocaine, which may result from extreme vasoconstriction of the pulmonary

vasculature with ensuing tissue hypoxia (Godwin et al. 1989; Murray et al.

1988b). More recently, a clinical presentation of pulmonary embolus in

association with crack use was reported (Delaney and Hoffman 1991). After

all sources and common risk factors for pulmonary embolus were excluded, the

pulmonary infarction that resulted was presumed to be the consequence of in

situ vasospasm and thrombosis.

Skeletal Muscle Vasculature

Numerous recent reports of cocaine-related rhabdomyolysis involving all

routes of exposure have recognized the association with massive creatine

phosphokinase levels, acute renal failure, profound hypotension, and

hyperthermia (Roth et al. 1988; Merigian and Roberts 1987; Herzlich et al.

1988; Menashe and Gottlieb 1988; Anand et al. 1989; Pogue and Nurse 1989;

Rubin and Neugarten 1989; Singhal et al. 1989; Brody et al. 1990b; Welch

et al. 1991). However, seizures, hyperthermia, hypotension, or prolonged

unconsciousness were not requirements for the production of rhabdomyolysis

(Zamora-Querzada et al. 1988), which suggests that cocaine may act as a

82
direct muscle toxin. The mean serum creatine phosphokinase levels were

28,084 U/L in patients who subsequently developed renal failure. Fatalities

occurred in 6 of 13 patients with renal failure and 6 of 11 who developed

hepatic compromise. This high fatality rate may be related to concomitant

disseminated intravascular coagulation and severe, probably ischemic, hepatic

dysfunction seen in these patients (Roth et al. 1988). It was postulated that

rapid delivery of cocaine to the skeletal muscle vasculature led to arterial

vasoconstriction, tissue ischemia, and rhabdomyolysis (Roth et al. 1988).

Although rhabdomyolysis is often associated with myoglobinuric renal failure,

there is no evidence that cocaine has a direct renal toxic effect. However, it is

likely that cocaine’s vasoconstrictive effect would concomitantly impair renal

vasculature, thus altering renal hemodynamics and making myoglobinuric

renal failure more likely (Singhal et al. 1989). Additional suggestive data is

represented by the development of renal infarction in a 32-year-old male within

minutes after using IV cocaine (Sharff 1984). Sharff presumes that increased

adrenergic stimulation and a possible preexisting thrombus were responsible

for the patients infarction.

Uteroplacental Vasculature

Maternal cocaine use has recently been recognized as an increasing

problem for the successful continuation of the pregnancy (Cherukuri et al.

1988; Chasnoff et al. 1985; Acker et al. 1983; MacGregor et al. 1987; Barnwell

and Ramasastry 1983; Chouteau et al. 1988) as well as the subsequent fetal

growth and development (Chavez et at. 1989; Doberczak et al. 1988). An

increased incidence of spontaneous abortions, abruptio placentae, fetal

prematurity, and intrauterine growth retardation has been documented clearly.

Experimental evidence in pregnant ewes demonstrated dose-dependent

increases in maternal blood pressure with concomitant decreases in uterine

blood flow (Moore et al. 1986; Woods et al. 1987). Uterine vascular resistance

increased with increasing doses of cocaine. These vascular changes were

accompanied by marked fetal tachycardia, hypertension, and hypoxemia

(Woods et al. 1987). Direct administration of the cocaine into a fetal vein led

to smaller increments in pulse and blood pressure and no significant hypoxemia

and no effect on the mother (Woods et al. 1987). This study in ewes is based

on a single exposure and cannot replicate the exposure of the placenta and

fetus in a cocaine-dependent individual.

The increased incidence of spontaneous abortions and abruptio placentae with

cocaine use appears to relate directly to placental vasoconstriction decreasing

placental vascular supply and increasing uterine contractility. These factors,

in addition to the marked hypertension associated with cocaine use, may

precipitate abruptio placentae (Chasnoff et al. 1985; Acker et al. 1983). Chronic

83
exposure may result in decreased uteroplacental blood flow and uteroplacental

insufficiency. These factors all may play a role in limiting fetal intrauterine

growth and development (MacGregor et al. 1987). Cocaine’s effect on

placental function has been studied in vivo and in vitro, demonstrating

reduced vascular supply associated with vasoconstriction as well as limiting

cellular amino acid uptake independent of vascular distribution (Barnwell and

Ramasastry 1983).

Two cases of unruptured, incidentally diagnosed, ectopic pregnancies

developed acute abdominal pain 1 to 2 hours after using cocaine and were

found to have ruptured ectopic pregnancies on return to the hospital (Thatcher

et al. 1989). Ectopic pregnancies may rupture at any time, but in both these

instances the proximity of the abdominal pain and rupture to the use of cocaine

is highly suggestive.

Gastrointestinal, Splenic, and Hepatic Vasculature

The intestinal vasculature is highly sensitive to catecholamines due to the

wide distribution of adrenergic receptors in the intestinal wall. Acute mucosal

ischemia has been demonstrated in several case reports following cocaine use

by the oral, IV, or inhalational routes (Nalbandian et al. 1985; Freudenberger

et al. 1990; Mizrahi et al. 1988; Endress and Kling 1990; Garfia et al. 1990).

In one case report, transplacental cocaine absorption resulted in intestinal

ischemia in a term neonate (Telsey et al. 1988). Another syndrome consisting

of acute abdominal pain associated with diarrhea and occult blood positive or

grossly bloody stools has also been reported. On examination, superficial

ulcerations and diffuse areas of hemorrhage and necrosis have also been

noted, giving rise to the term “cocaine colitis” (Fishel et al. 1985). More

recently, Lee and coworkers (1990) demonstrated an association between

gastrointestinal perforations and crack cocaine use; they postulate acute

ischemia with subsequent tissue necrosis and perforation as a possible

etiology.

Splenic infarction has been reported in only one case; a 38-year-old black

woman with sickle cell trait developed left upper quadrant pain immediately

after the IV use of cocaine, pentazocine, and methylphenidate (Novielli and

Chambers 1991). Computerized tomography demonstrated a large posterior

splenic infarction. Although it is suprising that splenic infarction has not been

previously recognized, it must be remembered that this patient had numerous

potential etiologies for this event. However, clinicians should at least consider

this a potential cocaine complication.

84
In various mice experimental models, cocaine has been demonstrated to be

hepatotoxic, possibly through the formation of a reactive metabolite, norcocaine

nitroxide (Kloss et al. 1982, 1983; Gottfried et al. 1986; Kanel et al. 1990),

or alternatively through the creation of a futile redox cycle that results in

glutathione depletion (Kloss et al. 1984). This latter mechanism is of particular

interest because it suggests a mechanism for the protective effect of Nacetylcysteine in cocaine-induced mouse hepatotoxicity (Suarez et al. 1986).

Human reports have suggested a correlation between cocaine use and liver

function abnormalities in mixed drug dependency (Marks and Chapple 1967)

and nonparenteral cocaine use (Kothur et al. 1991). These studies are of

great importance because any cocaine effect on hepatic metabolism such as

the cytochrome p-450 system or the flavin adenine dinucleotide-containing

monooxygenase system may subsequently alter cocaine metabolism. Shunting

or delay of hepatic metabolism may alter the production of nontoxic metabolites

and could result in an increased or novel production of a toxic metabolite with

vasoactive characteristics.

The case of a 32-year-old male who died of massive hepatic failure

approximately 12 hours after using intranasal cocaine is of great interest

(Perino et al. 1987). The pathology was striking for the presence of periportal

and midzonal necrosis with the absence of centrilobular destruction. This

finding essentially excludes systemic shock, hypoxia, or hyperthermia as

etiologies for the hepatotoxicity. In a study of 39 patients with cocaine-related

rhabdomyolysis, liver function abnormalities were noted in 11 of 13 with renal

failure and in only 2 of 26 without renal failure (Roth et al. 1988). These

findings necessitate further investigation with regard to a direct vascular or

indirect hepatoxic effect.

EXPERIMENTAL BASIS FOR THE TREATMENT OF THE VASCULAR

MANIFESTATIONS OF COCAINE INTOXICATION

The pharmacologic and toxicologic properties that result in the cardiovascular

manifestations of cocaine toxicity have led to several consequential and at

times contradictory experimental studies (Catravas et al. 1978; Catravas and

Waters 1981; Derlet and Albertson 1989a, 1989b; Derlet et al. 1989; Spivey et

al. 1990; Mercuro et al. 1988; Trouve and Nahas 1986; Trouve et al. 1987;

Smith et al. 1991. Although many of these studies relate in particular to control

of neuropsychiatric manifestations, it is clear even from this conflicting database

that the cardiovascular and neuropsychiatric complications are inextricably

linked. A logical analysis of these studies is essential to propose an appropriate

clinical approach to the cocaine-intoxicated patient in general and the vascular

manifestations of cocaine-intoxication in particular.

85
In the dog model used by Catravas and coworkers (1978) and Catravas and

Waters (1981), cocaine-related increases in mean arterial pressure, heart rate,

cardiac output, rectal temperature, and systemic pH were studied. All animals

administered cocaine developed convulsions and died with a mean lethal dose

of 22 mg/kg. In the experimental design, pretreatment antidotal therapy was

administered. Although chlorpromazine demonstrated efficacy with regard to

vital sign abnormalities and lethality, all animals developed seizures. Pimozide,

a specific dopamine-2 (D2

) receptor antagonist and adrenergic blocking agent,

had no salutary effect on lethality or any other parameter. Although propranolol

was efficacious with regard to tachycardia and hypertension, it had an adverse

effect on the incidence of seizures and mortality. Pancuronium had no effect on

the cardiovascular manifestations but did prevent fatalities. Seizure activity was

not evaluated, but as expected, no motor activity occurred. Although sodium

bicarbonate corrected the metabolic acidosis associated with cocaine toxicity, it

had no effect on seizures or lethality. However, pretreatment with diazepam

decreased the cardiovascular manifestations, prevented seizures, and resulted

in no fatalities. The use of an ambient environment of -5 °C also led to a

diminished cardiovascular effect of the cocaine and the absence of seizures

and fatalities.

Derlet and Albertson (1989a) also demonstrated in a rat model that diazepam

was effective in preventing the tonic clonic manifestations of seizures and

death in spite of a continuum of convulsant-like electrical activity. Witkin

and colleagues (1989) further expanded investigations in search of a central

dopamine receptor blocking agent. Dopamine antagonists with varying

affinities for dopamine-1 (D1) and D2 receptor subtypes were utilized. When

the established rat model was pretreated with the D2

 antagonist haloperidol,

there was no alteration in the lethal effect of cocaine. When SCH 23390,

a D1

 antagonist, was utilized in pretreatment, the lethal dose was increased.

Unfortunately, when SCH 23390 was given 5 minutes after cocaine

administration, no appreciable benefits could be discerned.

A subsequent rat model study looked at the role of haloperidol in the treatment

of cocaine and amphetamine intoxication (Derlet et al. 1989). Haloperidol

was ineffective in preventing amphetamine-related seizures but did lower

mortality at most doses. When used for cocaine intoxication, there was a

decreased incidence of seizures at the highest doses of cocaine, but there

was no evidence of decreased mortality. More recently, when Spivey and

associates (1990) compared haloperidol and diazepam in a cocaine-toxic swine

model, they found that diazepam offered significant protection from cocaine

seizures and lethality, whereas haloperidol offered no protection from either of

these effects.

86
The role of the D2

 receptor has been studied by Mercuro and colleagues

(1988). When this receptor is activated by dopamine or its agonists, it inhibits

the sympathetic release of norepinephrine. Specifically, plasma norepinephrine

and epinephrine production was studied in human adult male volunteers while

at rest and during exercise (Mercuro et al. 1988). Plasma catecholamines

increased significantly at maximum exercise. Whereas administration of a

selective D2

 antagonist, domperidone, showed no modification of heart rate,

blood pressure, or catecholamine levels at rest, a significant increase in plasma

catecholamine levels was produced with exercise. The result was statistically

greater cardiovascular responses (heart rate, blood pressure, and rate pressure

product) and increased oxygen consumption. This study suggests that there

is a D2 antagonist-mediated increase in catecholamine release associated

with exercise. When these results are combined with an analysis of the

effects of chlorpromazine and another D2 antagonist, pimozide (Catravas et al.

1978), they suggest that currently available antidopaminergic agents such

as chlorpromazine (a D1 antagonist) and haloperidol (a D2 antagonist) may

not be efficacious and in fact may be deleterious in treating cocaine toxicity,

particularly when exercise (psychomotor agitation) is occurring. The routine

failure of D2 antagonists to treat experimental cocaine toxicity must be

considered when evaluating uncontrolled, anecdotal reports of response

in situations of mild and non-life-threatening poisoning.

Two models utilizing calcium channel blockers have resulted in divergent

analyses. Trouve and Nahas (1986) utilized nitrendipine, an experimentally

available calcium channel blocker, as an antagonist to cocaine’s cardiac

toxicity and as a potential antidote to the lethal effects. Arrhythmia suppression,

decreased convulsions, increased survival times, and an increased lethal dose

of cocaine were demonstrated in the rats administered nitrendipine. In a

second rat model, Trouve and coworkers (1987) compared propranolol to

nitrendipine. Propranolol was unable to prevent arrhythmias and decreased

coronary blood flow. In this model the calcium channel blocker appeared to

prevent the cardiac morphologic changes noted with high-dose cocaine.

In a rat model, Derlet and Albertson (1989b) demonstrated that animals

pretreated with intraperitoneal (IP) diltiazem, nifedipine, or verapamil

developed seizures more rapidly than did control animals. At any specific

dose the fatality rate was higher in the calcium channel blocker pretreatment

group. This potentiation of seizures and death was demonstrated at 2 mg/kg

nifedipine pretreatment doses with three variable cocaine doses. This study

suggests that all the currently available calcium channel blockers may increase

the risk and consequences of seizures associated with cocaine intoxication.

Derlet and Albertson (1989b) raise the concern of a potential hemodynamic

interaction between seizures and mortality in cocaine-intoxicated animals

87
pretreated with calcium channel blockers. The difference between these two

studies (Derlet and Albertson 1989b; Trouve et al. 1987) may reflect the

choice of calcium channel antagonists or other variations in experimental

design. In Trouve and colleagues’ study (1987), the calcium channel antagonist

was administered intravascularly, whereas Derlet and Albertson (1989b)

pretreated by the IP route. It is possible that IP pretreatment with calcium

channel antagonists produced local vasodilation, which increased cocaine

bioavailability when cocaine was subsequently administered by the IP route.

The pretreatment animals could have done as poorly as the control group

because the potential beneficial effects of the calcium antagonist might have

been masked by increasing the absorbed doses of cocaine.

Also in the rat, Smith and coworkers (1991) studied the effects of multiple

agents, including propranolol, labetalol, and verapamil, on survival following

an LD50 of cocaine. The ß-blocking agents were shown to adversely affect

outcome, whereas verapamil did not affect survival in this posttreatment model.

However, verapamil has been shown to increase the threshold for ventricular

fibrillation in cocaine-treated rats (Billman and Hoskins 1988). This might have

implications on the subset of patients whose manifestation of life-threatening

toxicity is ventricular arrhythmias.

Another model utilized anesthetized dogs that were pretreated with nifedipine

and then administered 10 mg/kg of cocaine by IV bolus (Hale et al. 1991).

Although the study demonstrated that nifedipine prevented cocaine-induced

decreases in coronary blood flow and improved left ventricular function and

ejection fraction, the use of sodium pentobarbital anesthesia limits the

importance of this study. When nifedipine administration followed cocaine

infusion, there was no improvement in left ventricular function or coronary

blood flow. This study suggests a direct negative inotropic effect of cocaine.

Vicaut and coworkers (1991) performed an in vivo study using a

videomicroscopy technique to evaluate the microvascular effects of cocaine

in rats. They demonstrated that 10 mg/kg of intraarterial cocaine induced a

maximal vasoconstriction of all arterioles studied and within 15 seconds

almost complete closure of the most distal arterioles. This vasoconstriction

was inhibited at all arteriolar levels by the intraarterial infusion of nitrendipine

Furthermore, although the intraarterial use of the angiotension-converting

enzyme inhibitor enalaprilat inhibited the vasoconstriction in the largest

vessels, it was not effective distally (Vicaut et al. 1991). These results offer

further experimental confirmation and theoretical explanation for the authors’

previous nitrendipine studies (Trouve and Nahas 1986).

88
The studies by Catravas and Waters (1981) and Derlet and Albertson (1989a)

suggest the importance of sedative-hypnotics such as diazepam, the utility of

paralyzing agents such as pancuronium, and the efficacy of ambient cooling in

the treatment of cocaine toxicity. The risks of currently available D1

 and D2

antagonists, a concern over the merits and risks of currently available calcium

channel blockers, and the lack of efficacy of a ß-adrenergic blocker such as

propranolol are also noteworthy in the varied experimental models. These

studies emphasize the need for further research directed toward defining the

effects of neurotransmitters, biogenic amines, sedative-hypnotics, specific D1

and D2 antagonists, and calcium channel and ß-adrenergic blockers (or, more

specifically, , ß1, and ß2-adrenergic receptor blockers) and the use of

thermoregulatory control. In spite of these controversial studies several

clinicians use haloperidol and 8-adrenergic blockers as therapeutic agents

for cocaine intoxication (Rappolt et al. 1976; Gay 1982; Sand et al. 1991).

ß-Adrenergic blockers have not been shown to be efficacious with regard to

mortality studies in either the Catravas and Waters (1981) or other experimental

designs. Although there have been frequent clinical papers supporting

propranolol use, actual use in emergency departments has been infrequent,

and the pharmacologic argument against propranolol use is strong. Recent

work by Lange and colleagues (1990) demonstrates that administration of

intracoronary propranolol to patients undergoing cardiac catheterization

potentiates cocaine-induced coronary vasoconstriction, decreased coronary

sinus blood flow, and increased coronary vascular resistance. Also, cocaine

has a stimulatory effect on the heart, increasing both inotropy and chronotropy.

Propranolol blocks ß1

-adrenergic receptors, decreasing contractile force and

heart rate, which, in the absence of cocaine, should allow for a fall in blood

pressure. However, because propranolol also inhibits the ß2-adrenergic

receptors, an unopposed adrenergic receptor stimulation ensues with

peripheral vasospasm and possibly a subsequent increase in blood pressure.

This theoretical exacerbation of hypertension would result from the markedly

elevated catecholamine levels present in the face of acute cocaine intoxication

(Olson and Benowitz 1987; Karch 1987). Unopposed adrenergic effect was

suggested in a case report by Ramoska and Sacchetti (1985) and supported

by some researchers (Dusenberry et al. 1987) but questioned by others

(Silverstein et al. 1987; Leikin et al. 1987; Karch 1988) as the cause for an

increase in blood pressure with concomitant resolution of the patient’s

tachycardia. Despite the elevated blood pressure, the increased afterload and

decreased inotropy might adversely affect blood flow and tissue perfusion.

Ramoska and Sacchetti (1985) and Dusenberry and coworkers (1987) suggest

that an agent such as labetalol with combined and ß-adrenergic blocking

effects or a long-acting agent such as metoprolol or the ultra-short-acting

esmolol (Kirshenbaum et al. 1988; Gray 1988; Pollan and Tadjziechy 1989)

with relative ß1-adrenergic antagonistic specificity might be more efficacious.

89
Esmolol was employed by Sand and coworkers (1991) as a possible antagonist

to the adverse cardiac effects of cocaine due to the fact that the drug is

delivered intravenously and would be metabolized within minutes, thereby

diminishing risks if any adverse effects developed. These researchers failed to

demonstrate any consistent benefit in control of their patients’ hypertension,

although heart rate decreased in some of their study patients. Although three of

seven patients showed resolution of their clinical symptoms, one hypertensive

patient had no fall in blood pressure, and two others showed further

exacerbation in hypertension. The remaining patient became significantly

hypotensive. In uncontrolled experiments such as this one, it is impossible to

distinguish between favorable drug effects and simple resolution of effects of

the short-acting agent cocaine.

Similarly, only case reports are offered as arguments in favor of the use

of labetalol (Dusenberry et al. 1987; Karch 1988; Gay and Loper 1988),

whereas no clinical studies on labetalol’s efficacy as an adrenergic blocker

have been presented. Labetalol has substantially greater nonselective

ß-adrenergic blockade that is quantitatively far more potent than the

a-adrenergic blocking effects (Sybertz et al. 1981). The ratio of -adrenergic

blocking to ß-adrenergic blocking potency is approximately 1:7. If the cocaineinduced catecholamine ratios are comparable with those produced in the

presence of a pheochromocytoma, then the result (a hypertensive crisis) would

be expected to be similar to that reported by Briggs and colleagues (1978)

when using labetalol for treatment of a pheochromocytoma. Furthermore,

evidence has already been given to suggest that propranolol has deleterious

effects on cocaine-induced coronary vasoconstriction, seizures, and mortality.

No experimental data exist to suggest that the addition of weak a-adrenergic

blockade to ß-adrenergic blockade is beneficial in this regard. In fact, in

Spivey and colleagues’ (1990) swine model that demonstrated the benefits

of diazepam administration, no protective effects of labetalol could be shown.

In Smith and coworkers’ study (1991) labetalol was also without efficacy. The

only advantage of labetalol is its theoretical advantage of protection against

unopposed a-adrenergic effects, which may in fact be inadequate.

The role, if any, for ß- and mixed and ß-adrenergic blockers in the presence

of cocaine remains ill defined. Experimental data in animals do not support

the use of ß-adrenergic blockers, and the controlled and uncontrolled clinical

experiences have been exceedingly limited. The use of nonselective

ß-adrenergic blockers has been restricted in most patients with cocaine

intoxication to those patients who have already been sedated and who have

isolated tachyarrhythmias. The choice of an antihypertensive agent that is

rapid acting and easily and reliably controlled leads to the use of vasodilating

agents such as nitroprusside or an a-adrenergic blocker such as phentolamine.

90
THERAPEUTIC PRINCIPLES FOR THE CARDIOVASCULAR

MANIFESTATIONS OF COCAINE INTOXICATION

Based on the direct pharmacologic and toxicologic relationship between

cocaine’s neuropsychiatric and cardiovascular complications, success in

management of the neuropsychiatric manifestations almost invariably has

a salutary impact on resolution of the cardiovascular abnormalities, at least

from an emergent or initial care perspective. Control of acute psychiatric

manifestations of cocaine intoxication should be based on supportive care

that minimizes risks to patients and staff and reduces external stimuli.

Evidence for the link between the CNS and cardiovascular effects of cocaine

intoxication is available in the animal model. Wilkerson (1988) demonstrated

in dogs that the site of action of cocaine-induced increases in sympathetic

activity is in the CNS, and he concluded that the cardiovascular effects of

cocaine can only be expressed fully when the central and peripheral nervous

systems are integrated. Similar differences between anesthetized and

unanesthetized animals have been described by Schwartz and colleagues

(1989). Studies mentioned previously by Catravas and Waters (1981) and

Derlet and Albetison (1989a) as well as another by Guinn and coworkers

(1980) all demonstrate that sedative-hypnotics are uniformly successful

agents for the treatment of cocaine toxicity and the prevention of lethality.

The model linking the CNS to the peripheral manifestations of cocaine

intoxication is demonstrated in figure 2. Using this model, one might predict

the failure of therapeutic interventions directed solely at ameliorating the

peripheral manifestations of cocaine toxicity. Thus, sedation with diazepam

is chosen due to its demonstrable experimental efficacy (Catravas and Waters

1981; Derlet and Albertson 1989a; Spivey et al. 1990; Guinn et al. 1980) and

the substantial experience in its use in other clinical states associated with

severe agitation and catecholamine excess, such as sedative-hypnotic or

ethanol withdrawal (Sellers et al. 1983; Thompson 1978).

Haloperidol is not recommended due to the lack of experimental support

(Catravas and Waters 1981; Spivey et al. 1990; Guinn et al. 1980) and

significant clinical difficulties in sedative-hypnotic withdrawal in humans

(Greenblatt et al. 1978) and animals (Blum et al. 1976), particularly when

treatment is initiated in the presence of agitation and hyperthermia. This

is of consequence because loss of thermoregulatory control is a common

complication in the acutely agitated or psychotic patient with cocaine

intoxication. Another argument against the use of haloperidol is the high

frequency of acute dystonic reactions associated with cocaine use (Merab

1988; Choy-Kwong and Lipton 1989b; Farrell and Diehl 1991). In addition,

Kumor and colleagues (1986) have noted a further increase in the incidence

of dystonic reactions in healthy cocaine addicts who were subsequently given

91
FIGURE 2. A pathophysiologic model for cocaine intoxication

SOURCE: Goldfrank and Hoffman 1991. Copyright 1991 by Annals of

Emergency Medicine (Dallas).

haloperidol. These dystonic reactions were often delayed and manifested by

torticollis, oculogyric crisis, or truncal or buccolingual symptoms.

Agitation and seizures are managed in the standard manner with a focus on

rapid control of motor activity while protecting the patient’s airway and

achieving adequate ventilation and oxygenation. Restraints should be applied

transiently to achieve an IV line. Ideally, if a restraining blanket is used, it

should be constructed as a strong netting or a mesh to avoid increasing

the patient’s temperature by preventing heat dissipation. Diazepam or

another benzodiazepine should be used for the initial management of

seizures. Although no studies exist that compare phenobarbital to phenytoin

for control of cocaine-induced seizures, phenobarbital may be preferable in

92
that it also produces CNS sedation. If these agents are not rapidly effective,

nondepolarizing neuromuscular blockade (e.g., with pancuronium) and

general anesthesia may be indicated. Succinylcholine use may be

contraindicated because of the risk of hyperkalemia with severe cocaineinduced rhabdomyolysis. It should also be noted that the enzyme plasma

cholinesterase is responsible for the metabolism of both succinylcholine and

cocaine, so that if these two agents are used simultaneously, prolonged

clinical effects of either or both agents might result.

Control of hyperthermia is best achieved by rapid cooling with an ice and

water bath or mist and fan technique. Conduction and evaporation prove

rapidly efficacious. Control of the associated agitation, psychosis, or seizures

is essential to achieve and maintain cooling while avoiding cerebral, hepatic,

and muscle cellular destruction. There is no evidence that other pharmacologic

agents (such as dantrolene) play a role in enhancing the cooling process in

these patients with life-threatening hyperthermia (Fox 1989). Once these

more generic approaches are initiated, most patients with cocaine-related

cardiovascular manifestations will have begun to improve. The premise chosen

is based on the experimental evidence presented above and the model for

cocaine intoxication described in figure 2.

Tachyarrhythmias of atrial origin that have not responded to control of the

central sympathetic stimulus and cooling should respond to verapamil, esmolol,

labetalol, or propranolol. Utilization of these agents in a previously sedated

individual limits the risks of unmasking adrenergic effects and theoretical

concerns associated with the risks of seizures when calcium channel or

ß-drenergic blockers are given in the animal model. Lidocaine may not be

the agent of choice for the treatment of ventricular arrhythmias that develop

immediately following cocaine use, such as in an individual with a ruptured bag

of cocaine in the gastrointestinal tract. These ventricular arrhythmias should be

presumed to occur from either catecholamine excess (in which case sedation

and cautious use of mixed -and ß-adrenergic blockade or calcium channel

blockade may be indicated) or from cocaine’s direct effect on the myocardium.

Since this latter effect may be due to cocaine’s type I antiarrhythmic properties,

the addition of a similar agent (lidocaine) may exacerbate cardiac conduction

abnormalities. Furthermore, lidocaine can lower the seizure threshold. The

combination of lidocaine and cocaine has been shown to increase the incidence

of seizures and death in a rat model (Derlet et al. 1991). Recent evidence

suggests that cocaine-induced wide-complex arrhythmias may respond to

administration of sodium bicarbonate, in a similar fashion to those arrhythmias

produced during intoxication with type IA and type IC antiarrhythmics (Parker

et al. 1989b). In an extension of this study, Beckman and colleagues (1991)

showed that cocaine-induced QRS prolongation was decreased approximately

93
to baseline, but no effect was noted on other electrocardiographic or

hemodynamic variables. In any other setting, ventricular arrhythmias

should be considered to be generated by an ischemic myocardium, and

standard management for ventricular arrhythmias (including lidocaine) is

indicated.

Initially, myocardial ischemia and infarction should be discriminated from

the other common causes of chest pain syndromes in cocaine users such as

pneumothorax, pneumomediastinum, dissecting aortic aneurysm, or septic

pulmonary emboli from endocarditis. Once myocardial ischemia or infarction

is suspected, these atypically young patients should be considered in the

same manner as anyone else who is presumed to be at risk for coronary artery

disease. The use of nitrates is indicated for cocaine-induced myocardial

ischemia, as in those patients with atherosclerotic heart disease. There is

substantial human evidence that nitroglycerin alleviates cocaine-induced

coronary vasoconstriction in both diseased and nondiseased segments

(Brogan et al. 1991). There is no clinical experience with calcium channel

blockers (diltiazem or verapamil) in humans with cocaine-related ischemia.

ß-Adrenergic blockers, such as propranolol, should not be utilized because

of the human data demonstrating enhanced vasospasm. Aspirin should be

administered, unless contraindicated, to reduce cocaine-mediated platelet

aggregation (Tonga et al. 1985). Thrombolytic therapy has been utilized in

spite of previous significant short-term hypertension but should therefore be

considered with extreme caution. It should be reserved for those patients

who do not respond rapidly to vasodilator therapy, have no suggestion of a

cerebrovascular catastrophe clinically, and have no risk of mycotic aneurysm

(Bush 1988).

Hypertension unresponsive to sedation should be managed with sodium

nitroprusside (0.5 to 10 mcg/kg/min) in a titrated fashion to achieve and

maintain a normal blood pressure. Phentolamine is also an effective

vasodilator at doses of 5 to 10 mg IV and may improve coronary perfusion

(Lange et al. 1989). Cocaine-intoxicated patients should be considered to

have an acute elevation in their blood pressure. Unless there is documentation

or clinical evidence of long-standing hypertension, there should be no concern

of cerebral hypoperfusion subsequent to an immediate lowering of the blood

pressure to a normal level.

The other cardiovascular end organ manifestations of cocaine intoxication

may necessitate specific intervention. The general strategies for managing

catecholamine excess, myocardial ischemia, and hypertension are summarized

below and allow for the case-specific approaches to complicated examples

such as aortic dissection, mesenteric ischemia, and abruptio placentae. Each

94
of these cases or the presentation of the patient in shock necessitates a critical

understanding of the risk/benefit ratios for pharmacologic, toxicologic, and

surgical or obstetrical interventions.

Hypertension

—Oxygenation

—Sedation (benzodiazepine)

—Vasodilators (nitroprusside or phentolamine)

—Hydralazine (if associated with pregnancy)

Myocardial ischemia

—Oxygenation

—Sedation (benzodiazepine)

—Nitrates

—Aspirin

—Calcium channel blockers

Myocardial infarction

—Oxygenation

—Sedation (benzodiazepine)

—Nitrates

—Aspirin

—Heparin

—Calcium channel blockers

—Opioids

—Consider thrombolytic therapy

Tachyarrhythmias

—Oxygenation

—Sedation (benzodiazepine)

—Atrial: Observation, cooling if febrile, consider calcium channel blocker.

Cautious use of mixed -ß-adrenergic blockade may be required.

—Ventricular: Consider lidocaine or sodium bicarbonate. Try to determine

etiology (ischemia vs. direct drug effect). Use standard Advanced Cardiac

Life Support approach if ischemia is suspected.

SOURCE: Goldfrank and Hoffman 1991. Copyright 1991 by Annals of

Emergency Medicine (Dallas).

95
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108
AUTHORS

Lewis Ft. Goldfrank, M.D.

Medical Director

New York City Poison Control Center

Director

Emergency Medical Services

Bellevue Hospital and New York University Medical Center

Robert S. Hoffman, M.D.

Associate Medical Director

New York City Poison Control Center

Director

Medical Toxicology Fellowship

New York City Poison Control Center

Attending Physician

Bellevue Hospital Emergency Medical Services

First Avenue and 27th Street

New York, NY 10016

109
Cocaine-Related Emergency

Department Presentations

Kathleen S. Schrank

INTRODUCTION

The 1980s saw a dramatic rise in cocaine use throughout the United

States. This trend was clearly reflected in emergency departments (EDs)

throughout the country, as cocaine became the leading cause of drug-related

presentations. The spectrum of emergency medical consequences of cocaine

use is quite broad, varying from cardiac arrest with dramatic hyperthermia to

relatively minor types of complaints. Fortunately, most medical problems

related to cocaine are of short duration and are not imminently life threatening.

Unfortunately, many aspects of understanding of this drug’s adverse effects

and of various treatment options remain ill defined. This chapter discusses

the major emergency medical conditions related to cocaine use and clinical

approaches and controversies.

PHARMACOLOGIC ASPECTS OF COCAINE USE

Cocaine hydrochloride is typically used intravenously or by nasal insufflation.

Intravenous (IV) use produces immediate clinical effects and peak blood levels;

both decline rapidly. Nasal cocaine produces peak blood levels after about 60

minutes, but clinical effects peak much earlier. The alkaloidal form of cocaine

(free base or crack) is smoked, with rapid peak effects only a few minutes later

than by IV route (Van Dyke and Byck 1982). Smoking crack cocaine is rapidly

increasing as the preferred route of ingestion by ED patients in many cities,

probably reflecting street popularity; however, this increase may suggest a

worrisome higher risk of medical complications. Cocaine also can be

administered orally, vaginally, rectally, or sublingually.

Cocaine is metabolized by plasma and liver cholinesterases to compounds,

including benzoylecgonine and ecgonine methyl ester, that are excreted by the

kidneys along with unmetabolized cocaine. The role of individual variability of

plasma cholinesterase activity in terms of risk of adverse reaction to this drug

merits further study.

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Concomitant use of other drugs along with cocaine is common, but

understanding of the ramifications of these mixtures is limited. Users

frequently take benzodiazepines to blunt the dysphoric effects of declining

cocaine levels. This practice also may serve to enhance respiratory depression

and prolong altered mental states but in fact may decrease the risk of seizures.

Indeed, animal data indicate a decreased risk of seizure or death if diazepam is

given prior to cocaine (Derlet and Albertson 1989a). The combination of alcohol

and cocaine also is frequent and may prove to significantly increase the risk

of certain adverse reactions. Available evidence shows that concurrent use

of ethanol and cocaine leads to hepatic production of a third compound,

cocaethylene, via transesterification. Cocaethylene can be measured in

blood, urine, and tissues, including brain (Hearn et al. 1991). In animal studies,

it appears even more potent than cocaine in lethality; in humans, preliminary

data suggest a relationship between cocaethylene and violent agitation (S.

Rose, personal communication, May 1991).

The role of adulterants in producing complications attributed to cocaine does

not appear significant, though it cannot be fully discounted. The more typical

contaminants include other local anesthetics, sugars, inert compounds, and

other stimulants. Strychnine, quinine, and hallucinogenic drugs have been

reported as well. The presence of adulterants is likely to vary geographically

along routes of distribution, but cocaine purity is generally very high, in contrast

to other illegal drugs such as opiates or hallucinogenics.

The primary actions of cocaine include central nervous system (CNS)

stimulation with increased dopaminergic effect, inhibition of catecholamine

reuptake with resultant generalized sympathetic stimulation, alteration of

serotonin release and reuptake, and local anesthesia via inhibition of sodium

current. Clinically, the adrenergic stimulation produces sinus tachycardia and

other arrhythmias, hypertension, hyperthermia, seizures, tremulousness,

mydriasis, and death. Sedation with diazepam clinically blunts tachycardia

and hypertension, suggesting central mediation of peripheral sympathetic

effects. Euphoria, agitation, delirium, insomnia, psychoses, stupor, and coma

are mediated through central dopaminergic pathways; effect on serotonin and

its significance is not well defined (Spivey and Euerle 1990).

CARDIOVASCULAR COMPLICATIONS

Cardiac Arrest

Cocaine may precipitate sudden death through acute cardiovascular,

respiratory, or neurologic events. Reported mechanisms of primary

cardiac deaths include catecholamine-induced tachyarrhythmias, ischemic

111
arrhythmias, bradycardias, myocardial depression, and aortic rupture (Gadaleta

et al. 1989). Any route of administration may lead to death, and many sudden

deaths do not appear to be due to an increased dose of this drug; indeed,

cocaine plasma levels in fatalities may be indistinguishable from those in mild

intoxications.

Detailed data on cocaine-induced cardiac arrest rhythms and management are

lacking. Ventricular fibrillation appears to be the most common rhythm (as in

arrests unrelated to drug use), but ventricular tachycardia, primary asystole,

bradycardias, and electromechanical dissociation also occur. Current medical

management follows standard Advanced Cardiac Life Support algorithms

published by the American Heart Association, but in the experience of the

author and other staff members at the University of Miami/Jackson Memorial

Medical Center, the prognosis is dismal, and modifications may be in order.

If the mechanism underlying ventricular fibrillation and ventricular tachycardia

(VFNT) is excessive catecholamine action, then the role of epinephrine in these

rhythms needs to be explored. Its peripheral vasoconstriction with shunting of

blood flow to the coronary and cerebral vessels during arrest remains desirable,

but perhaps receptors are already maximally stimulated by the cocaine, and

the direct cardiac effects of epinephrine may be more toxic than helpful in this

setting. Alternatively, if the mechanism producing VFNT is either ischemia or

direct myocardial depression from cocaine, then epinephrine is indicated. In

bradycardic or asystolic arrests, epinephrine remains a vital part of resuscitation

efforts.

The optimal antiarrhythmic agent for VFNT in these patients is also unclear;

each choice is controversial. Lidocaine generally is still used. However, arrest

may be due to a direct depressive effect of cocaine on the myocardium, an

effect similar to that of excess Type I antiarrhythmics; lidocaine in theory may

exacerbate this (Goldfrank and Hoffmann 1991). In one animal model, high

doses of lidocaine (30 or 40 mg/kg) given with cocaine significantly increased

the risk of seizures and death (Derlet and Albertson 1991), but extrapolation to

clinical dosage (total loading dose 1 to 3 mg/kg) is difficult. ß-Blockade would

seem pharmacologically effective if the rhythm is catecholamine induced.

However, propranolol is known to exacerbate coronary vasoconstriction

(Lange et al. 1990) and therefore decrease coronary blood flow, and P-blockade

results in decreased contractility. The majority of animal studies suggest that

P-blockade either does not change or may worsen outcome from toxic cocaine

doses (Smith et al. 1991), although Robin and colleagues (1989) did show

improved survival in one strain of mice given propranolol and massive doses

of cocaine. Alkalinization with sodium bicarbonate may be beneficial in VFNT,

though again supportive clinical studies are not available. Unfortunately,

attempts to provoke malignant arrhythmias by cocaine administration in animal

112
models have been unsuccessful (Isner and Chokshi 1991), underscoring the

limited knowledge base.

Sudden cardiac death is a rare though well-publicized consequence of cocaine

use. The vast majority of these deaths occur outside the hospital; arrest

following ED arrival with a pulse is extremely rare. Prediction of risk, other than

with massive ingestion, is ill defined, but patients who are hyperthermic and

whose behavior is agitated are more likely to suffer cardiac arrest. Restoration

of spontaneous circulation is uncommon, and the postresuscitation course may

be stormy (particularly in the hyperthermic patient) with myocardial failure,

hemodynamic instability, hepatic failure, renal failure, and coagulopathy.

Other Arrhythmias

Although cocaine may provoke a variety of rhythm disturbances, most are short

lived and do not require intervention. Sinus tachycardia is common and usually

merits only observation. Volume infusion is appropriate if blood pressure is low,

and benzodiazepine sedation is effective in the agitated tachycardic patient.

Supraventricular tachycardia is usually transient but may require treatment if

prolonged or if the patient has associated chest pain or hypotension. Sedation

of the agitated patient also may slow the rhythm. Electrical cardioversion is

preferred for the truly unstable patient. Caution must be exercised in the choice

of pharmacologic agent to avoid later bradycardia if the duration of action of the

treatment significantly exceeds that of cocaine. Therefore, adenosine may be

a logical choice, but clinical experience in this setting is minimal. Esmolol,

an “ultra” short-acting cardioselective ß-antagonist, also may be useful, but

hypotension is not uncommon as a side effect. Sand and colleagues (1991)

found no consistent benefit from esmolol in six patients with sinus tachycardia;

the one patient with supraventricular tachycardia became more hypotensive

without any effect on rhythm. Other risks of ß-antagonists were discussed

above. Also, ß-blockade allows the stimulation of cocaine to go unopposed,

with potentially dramatic hypertension. Calcium channel antagonists may be

useful but also are controversial. They may produce hypotension and act much

longer than the cocaine. Trouve and coworkers (1987) found that nitrendipine

appeared to have beneficial cardiovascular effects and improved outcome in an

animal model. However, Derlet and Albertson (1989b) found higher mortality

and seizure risk in animals that were pretreated with any of three other calcium

blockers.

Bradycardias in the absence of ventilatory problems have been reported,

perhaps related to lower doses of cocaine. The patient who is quite

symptomatic requires treatment. Temporary support with an external

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cardiac pacer is likely the safest approach; atropine also may be used. ED

patients who present with a chief complaint of palpitations should be asked

about cocaine use. Premature atrial and ventricular contractions are common

and rarely require therapy. Cocaine also may unmask underlying heart

conditions such as Wolff-Parkinson-White syndrome.

VT with a pulse requires an aggressive approach, but the current level of

knowledge does not lead to a clear-cut pharmacologic choice, as discussed

above. The unstable patient needed electrical conversion. Sodium bicarbonate

may be beneficial (Goldfrank and Hoffman 1991). In the setting of myocardial

ischemia, lidocaine is appropriate. Magnesium sulfate also may prove

beneficial in these patients, though experience is anecdotal.

Myocardial lschemia and Infarction

Cocaine’s ischemic effects are well documented and must be suspected in

patients of any age who complain of chest pain following drug use. Myocardial

ischemia and infarction may occur with or without preexisting atherosclerotic

vessels. Cocaine dramatically increases heart rate and blood pressure, is a

potent vasoconstrictor, and produces focal coronary vasospasm. Coronary

thrombosis may occur at a site of vasospasm, and cocaine-induced platelet

aggregation has been seen in vitro. Thus, oxygen demand is significantly

increased while coronary supply falls. Any of these actions may result in

ischemic damage (Isner and Chokshi 1991), and risk to patients with underlying

atherosclerosis is high. Evaluation for acute infarction may be a challenge.

Young patients often have repolarization changes that may resemble ischemia

and typically have no prior electrocardiograms (ECGs) for comparison.

Creatine kinase (CK) may be elevated from skeletal muscle rather than heart,

and percentage of MB fraction may be misleading in the patient with both

muscle and myocardial injury. lschemic symptoms may begin right after drug

use or may be delayed for hours to days.

Currently, anti-ischemic management parallels that for noncocaine users,

with supplemental oxygen, nitrates, opiates, benzodiazepine sedation, and

consideration of calcium channel or ß-receptor antagonists. The risk of the

latter two classes of drugs appears low, since the acute toxic effects of cocaine

are usually gone. Tachycardia and severe hypertension should be controlled

if present, but sedation and relief of pain may accomplish this without more

specific therapy. Patients with cocaine-caused infarcts are certainly candidates

for thrombolysis given early in their course. Available data do not yet allow

distinction from other myocardial infarction patients in terms of early or late

arrhythmias, prognosis, treatment, optimal window of time for thrombolysis,

or cardiac rehabilitation plans, Anecdotally, though, those patients without

atherosclerosis appear to do well if they remain abstinent.

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Given the widespread use of cocaine, routine queries as to drug use are in

order in all patients who come in with chest pain, angina, and infarctions,

and patients with known coronary disease should be cautioned against use.

Tokarski and colleagues (1990) looked further at cocaine-induced chest pain,

evaluating 42 patients with ECG and cardiac enzymes. All had normal or

nondiagnostic ECGs, but eight had elevated CK and cardiac isoenzyme on

arrival; two were diagnosed as acute infarctions based on serial enzymes.

Ten other patients had elevated total CK but no other evidence of cardiac

source. Zimmerman and coworkers (1991) also described cocaine-related

chest pain. Of 48 patients who were admitted to the hospital, 3 were confirmed

as acute infarcts. In this series, ECG abnormalities were quite common,

particularly significant repolarization abnormalities and T-wave inversions that

persisted on serial tracings. The temporal relationship between drug use and

onset of pain was variable.

Myocardial Disease

Cocaine acts acutely as a direct myocardial depressant, as shown in an

animal model by Fraker and coworkers (1990). Acute, slowly reversible

cardiomyopathy without infarction or myocarditis has been reported clinically

(Chokshi et al. 1989), suggesting direct myocardial depression. Chronic use

may lead to cardiomyopathy via recurrent infarctions, protracted vasospasm,

or chronic sympathetic stimulation. Contraction band necrosis may be seen in

some patients on postmortem histology; significance is unclear. Myocarditis

with inflammatory myocardial infiltration is reported from autopsy (Virmani et al.

1988) and biopsy specimens from cocaine users.

Acute Hypertension

Sudden, severe elevations of blood pressure may rapidly follow cocaine

taken via any route due primarily to the drug’s systemic vasoconstriction.

In most patients, pressure falls relatively rapidly to acceptable levels, and

no intervention is needed. Most hypertensive patients also are agitated

and thus respond well to benzodiazepine sedation. In very few cases the

sudden hypertension is severe enough to produce catastrophic results,

such as intracranial hemorrhage or thoracic aortic dissection/rupture. Severe

hypertension with acute end-organ compromise is best treated with a shortacting vasodilator, such as nitroprusside or phentolamine. IV labetalol has

been recommended because of its ß- and receptor antagonism. It may be

successful, but caution is advisable in that its action may not be strong

enough to overcome the stimulation of cocaine; an even higher pressure

may result, as with other ß-blockers.

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Shock

Rarely, cocaine use may be complicated by profound shock without an obvious

direct cause such as arrhythmia, infarction, or hemorrhage. The mechanism is

uncertain, and available information is anecdotal only. Cocaine “binges” lead

to poor oral intake plus increased insensible fluid losses; severe volume

depletion may result. Acute myocardial depression may contribute, but

absence of pulmonary congestion speaks against this. Vasodilation may occur

via atypical CNS effects of the drug. Management includes volume infusion

followed if necessary by pressor support, plus aggressive evaluation for a cause

(e.g., myocardial ischemia, unsuspected trauma, sepsis, aortic dissection, brain

stem infarction, gastrointestinal bleeding, pulmonary embolism, other toxins)

that may or may not be related to cocaine.

GASTROINTESTINAL COMPLICATIONS

Abdominal pain due to cocaine use is increasingly being recognized by

emergency physicians. Available literature is limited to case reports of the

more serious complications. In the experience of the author and colleagues

in Miami, however, most cases involve mild-to-moderate diffuse pain with

vomiting, lasting a few hours followed by spontaneous resolution; physical signs

and laboratory findings are generally nonspecific, and treatment is supportive.

Return visits for recurrent symptoms are rare. Etiology is uncertain, though it

likely represents mild intestinal ischemia. A minority of these patients present

with persistent rigidity and diffuse rebound tenderness; although mandated by

such findings, exploratory laparotomy may prove negative.

Cocaine clearly can precipitate severe mesenteric ischemia leading to bowel

infarction manifested by elevated white blood cell count, metabolic acidosis, and

shock. Presumably, cocaine acts as a potent vasoconstrictor in mesenteric

vessels. Other possible mechanisms of ischemic insult to the bowel include

focal vasospasm, intravascular thrombosis, or systemic hypotension due to

cardiac complications of the drug (Freudenberger et al. 1990).

Gastric ulcers with perforation also have been reported in association with

cocaine abuse. Here, too, the mechanism is uncertain but presumed to relate

to vascular compromise (Abramson et al. 1989).

These ED patients also must be evaluated for other forms of drug abuse. In

particular, alcohol use may precipitate abdominal problems such as gastritis

or pancreatitis.

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COCAINE PACKET INGESTION

ingestion of large quantities of cocaine packaged in small packets is a

smuggling technique of interest to medical personnel. These so-called “body

packers” or “mules” attempt to pass through customs. They may be brought

to the ED by customs agents because of suspected packet ingestion or may

present on their own due to a complication. Many deaths have occurred due to

massive cocaine poisoning from packet rupture, and standard recommendation

a decade ago was surgical removal of all packets. However, improvements

in the packaging materials and techniques, plus patients’ refusal of surgery,

have led to the conservative approach of observation. The presence of

packets can be confirmed by plain abdominal roentgenograms, contrast

studies, ultrasonography, rectal exam, or by observation for spontaneous

passage. Oral osmotic agents such as polyethylene glycol may safely be

used to speed evacuation of the packets. The patient must be observed

for evidence of packet leakage, often manifest initially by development of

tachycardia. Also, evacuated packets may be assessed for evidence of

breakdown. Cocaine intoxication may be seen even with intact packets,

however, depending on permeability of the material. The surgical approach

usually is reserved for patients who develop evidence of cocaine effect or

who develop bowel obstruction from the packets (Caruana et al. 1984;

McCarron and Wood 1983).

In the experience of the author and coworkers over the past 10 years, the

approach of observing body packers has proven quite safe, with rare

development of leakage, no ruptures, and one case of bowel obstruction.

Most of the packets seen at the University of Miami/Jackson Memorial

Medical Center were reportedly machine packaged.

These smugglers stand in contrast to the patient who swallows unpackaged

or poorly packaged cocaine hydrochloride to avoid imminent police arrest.

This latter type of patient is likely to develop symptoms of cocaine intoxication,

though fortunately the dose is often small. Experience with swallowed crack

cocaine is limited, but risk of symptoms appears to be much lower than with

the hydrochloride compound, due to crack’s limited solubility in water.

RESPIRATORY COMPLICATIONS

A variety of pulmonary complications have been described, primarily associated

with nasal or inhaled routes of exposure. The role of adulterants in some of

these conditions appears small but cannot be excluded.

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Pulmonary barotrauma may result from maneuvers meant to enhance

drug effect, such as Valsalva’s maneuvers or mouth-to-mouth breathing

with a partner. Paroxysmal coughing from smoke irritation also may

produce barotrauma. The sudden increase in airway pressure leads to

alveolar rupture, with free air then dissecting into the mediastinum, pleural

cavity, or subcutaneous tissues. There are numerous case reports of

pneumomediastinum, pneumothorax, and subcutaneous emphysema but

no reports of arterial air embolism. These patients present with chest pain

(typically pleuritic), dyspnea, and sometimes sore throat or hoarseness.

Examination may find subcutaneous crepitus but rarely reveals a Hamman’s

sign. Chest x-ray is diagnostic. The quantity of free air is generally small,

and spontaneous resolution during a short inpatient stay is the rule. The

possibility of esophageal rupture must be considered in pneumomediastinum,

particularly if the patient gives a history of vomiting.

Emergency visits for bronchospasm due to smoking crack cocaine are

increasingly noted, perhaps in part due to increased frequency of questioning

patients about recent cocaine use. Many but not all these patients have

a prior history of asthma. Most respond to standard ED bronchodilator

treatment, although a small percentage require intensive care with ventilatory

support. The transient tachycardic effect of cocaine usually is gone by the

time of presentation to the ED, so inhaled ß-agonists are quite safe. In most

cases, the smoke appears to act as a nonspecific airway irritant. In some

patients, bronchospasm occurs as part of an immunoglobulin-E-mediated

hypersensitivity reaction, as reviewed by Ettinger and Albin (1989).

Lobar and nonlobar pneumonias also are seen in crack smokers. Most are not

severely ill and are treated as outpatients with oral antibiotics for communityacquired organisms. Some of these cases may represent undiagnosed

hypersensitivity reactions manifested by fever, transient infiltrates, and

eosinophilia. Bronchiolitis obliterans also has been reported in association

with crack use; mild cases may go undiagnosed.

Tracheobronchitis with severe cough is well recognized in crack smokers.

Mild-to-moderate hemoptysis frequently accompanies the cough and is often

the symptom that prompts the patient to seek medical attention. Symptoms

resolve gradually with abstinence. Diffuse alveolar hemorrhage was reported

by Murray and colleagues (1988).

A moderate degree of pulmonary edema is a frequent finding at autopsy in

cocaine-related deaths but is an uncommon ED presentation. Although some

cases may be cardiogenic in origin, others are clearly noncardiogenic, with

lavage fluid consistent with increased pulmonary capillary permeability, The

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mechanism may be mediated by central adrenergic outflow or may represent

a direct effect on pulmonary vasculature (Ettinger and Albin 1989).

Intravenously, massive doses of cocaine have produced pulmonary edema in

mice (Robin et al. 1989); human cases of noncardiogenic pulmonary edema

appear to be caused more often by smoking the drug. Treatment includes

oxygen supplementation, assessment of cardiac function, and, if necessary,

ventilatory support. Fortunately, most reported cases improve spontaneously.

RENAL COMPLICATIONS

Acute rhabdomyolysis is a well-recognized consequence of cocaine use,

particularly in patients who develop agitation with excessive motor activity,

seizures, hyperthermia, coma (immobility), or hypotension. Since

rhabdomyolysis also is seen in patients with none of these other conditions,

this drug also may have a direct effect on myocytes or may cause ischemia to

skeletal muscle via vasospasm. Muscle necrosis may occur following any route

of exposure to cocaine. Myalgias or muscle tenderness are present in about

half the patients; some complain of chest pain from damage to chest wall

musculature.

The presence of rhabdomyolysis should be considered in cocaine-intoxicated

patients. In one study (Welch et al. 1991), 24 percent of all patients presenting

with a cocaine-related complaint were found to have rhabdomyolysis, defined

as a CK level at least five times normal. Most of these cases were mild and

asymptomatic. Myoglobinuria is another indicator of muscle necrosis, and

patients may be rapidly screened for this with a urine dipstick for occult blood

(detects hemoglobin or myoglobin); positive results necessitate assays for CK,

renal function, and electrolyte disturbances.

Milder cases should not lead to any significant renal or electrolyte problems.

Inpatient admission is unnecessary, but IV hydration in the ED over a few

hours is appropriate to minimize renal insult. It is important for the clinician to

consider the possibility of mild rhabdomyolysis as a confounding factor in the

interpretation of cardiac enzyme results on patients with chest pain.

The cocaine-intoxicated patient with toxic delirium, hyperthermia, multiple

seizures, coma, or shock must be considered a high risk for rhabdomyolysis

complicated by myoglobinuric renal failure (Brody et al. 1990a). The

hypotensive patient is also at risk for acute tubular necrosis. IV volume

infusion with isotonic fluids is appropriate early in the course of treatment

to maintain a urine output above 75 mL per hour; sodium bicarbonate infusion

also may be considered if CK is dramatically elevated. The comatose patient

should be turned periodically into different positions. Most of these patients

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do well even if renal failure ensues, but the patient with failure of other organs

(e.g., liver, heart) in addition to uremia carries a poor prognosis (Roth et al.

1988).

NEUROLOGIC COMPLICATIONS

The various neurologic sequelae from cocaine use may be acutely dramatic

and devastating or may develop much more chronically. Most do not appear to

be dose dependent, although higher doses clearly and significantly increase the

risk of seizures.

Seizures

Generalized tonic-clonic seizures have been recognized as a consequence

of cocaine intoxication for more than 70 years. These seizures usually occur

within minutes after IV, nasal, or inhaled routes of use; time of onset after oral

use is unpredictable. Although high doses of cocaine clearly increase the risk

of seizure, many patients deny intake greater than “usual,” and indeed a

kindling effect has been reported in animal studies with repetitive use of

smaller quantities of the drug.

Most seizures are single and short, without residual damage. However,

repeated seizures signal high risk of death from respiratory arrest and warrant

aggressive control. Airway maintenance and IV benzodiazepines are treatment

priorities. Diazepam given before or after onset of seizures appears to protect

against death from cocaine. In animal models, diazepam given prior to cocaine

administration also decreases the risk of seizures. Phenobarbital or phenytoin

may be tried if diazepam fails to control seizure activity. Neuromuscular

blockade and general anesthesia occasionally may be required. Complicating

factors such as hyperthermia, rhabdomyolysis, severe respiratory and lactic

acidoses, hypoglycemia, electrolyte disturbances, and trauma must be looked

for and treated in these patients. Once the patient has been stabilized,

emergency evaluation by computerized tomography (CT) is in order to look

for CNS hemorrhage, stroke, mass lesion, or trauma; selected situations (fever,

meningeal signs, prolonged altered mental status) may warrant lumbar

puncture or electroencephalogram. Toxicology screening for other drugs

(e.g., amphetamine, phencyclidine) is especially indicated if seizure activity is

prolonged. Cocaine use should be considered in the evaluation of ED patients

(including pediatric ages) who present with new onset of seizures. The patient

with an uncomplicated seizure who is found to have no underlying cause

beyond cocaine intake may be discharged safely with education on risks and

recommendation of abstinence, without long-term antiepileptic medication.

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Cerebrovascular lschemia and Hemorrhage

Other potential neurologic catastrophes include subarachnoid hemorrhage,

intracerebral bleeds, and ischemic strokes. Cocaine produces an intense,

short-lived burst of systemic hypertension that may lead to hemorrhage.

Subarachnoid hemorrhage (SAH) due to cocaine presents, as do nondrug-related SAHs, with severe headache, loss of consciousness, nausea/

vomiting, and/or neck stiffness. Of 27 reported cases reviewed by Green and

coworkers (1990), 78 percent were found to have an underlying predisposing

condition such as an aneurysm or arteriovenous malformation. Other forms

of intracranial hemorrhage due to cocaine present with headache, seizure,

altered sensorium, and/or lateralizing findings. Approximately half the reported

cases of intracerebral hemorrhage were found to have an underlying vascular

lesion (Green et al. 1990). Cocaine may induce a bleed due to its transient

hypertensive effect as in SAH or due to hemorrhage at a site of ischemia

produced by vasospasm. lschmic cerebrovascular accidents may occur as

often as hemorrhage in free base smokers (Levine et al. 1990), although both

are fortunately rare events. Cocaine-induced hypertension and vasospasm

appear to be the most likely mechanisms of ischemic stroke; thrombosis and

embolic phenomena (seen with arrhythmias and cardiomyopathies) are also

possible. Amphetamine-induced vasculopathy has been documented, but the

association of cocaine with vasculitis remains debated.

Transient ischemic symptoms have been reported with cocaine, probably

due to vasoconstriction. Management of these patients currently is identical

to management of these same CNS events unrelated to cocaine. Transient

syncope may be due to neurologic or cardiac effects of the drug; evaluation

is typically unrewarding if physical examination and ECG are normal.

Evidence from single photon emission CT studies now suggests that many

chronic cocaine users may have scattered deficits despite absence of

symptoms (Tumeh et al. 1990). The incidence and long-term consequences

of such damage are not yet known, although they may be found to contribute

to significant neurologic impairment.

Headache following cocaine use is a relatively common ED presenting

complaint among cocaine users. Most have no findings on exam but

present a challenge to the ED physician because of the possibility of

underlying hemorrhage. Thus, most are evaluated with at least an

emergent CT scan.

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Toxic Delirium

Cocaine produces an array of neuropsychiatric states, and the violently agitated

patient is perhaps the most dramatic ED presentation Caused by this drug.

This person typically arrives with a multitude of personnel who are attempting

physical control. There is an appearance of incredible strength, but this may

reflect an indifference to pain; the risk of physical harm to both caregivers and

the patient is significant. The patient is delusional, paranoid, and often overtly

psychotic. This state does not clearly relate to cocaine dosage, blood level

(Wetli and Fishbain 1985), route of administration, or frequency of use. It does

not seem to be precipitated by adulterants or concomitant use of other drugs,

with the possible exception of alcohol; the role of cocaethylene is under

investigation. Untreated, this confusional, agitated state may last for several

hours, far longer than cocaine’s other effects. It often is followed by a period

of complete exhaustion and obtundation.

In the ED, a rapid but systematic visual assessment should look for compromise

of airway or ventilation, for obvious trauma, and for obvious neurologic deficit.

Pulse rate and quality, pupillary reflexes, and skin temperature can be checked

quickly; more thorough examination often has to wait for sedation but must

not be neglected. ED personnel should be trained to act as a team to achieve

adequate physical control of these patients with minimal risk of injury. Physical

restraints may be required but must be checked often to minimize risk of

extremity ischemia or respiratory compromise; they should not inhibit heat

loss. More appropriately, parenteral pharmacologic sedation should be

instituted promptly. Diazepam or other benzodiazepines are the agents of

choice, with demonstrated efficacy, salutory effects on cardiovascular changes,

and apparent lowering of seizure risk and lethality. Haloperidol has been used

clinically with some success, but its use raises concerns in that it does not

protect against seizures, may adversely affect thermoregulation, and is less

well studied. A quiet environment and a calm approach are useful adjuncts.

As soon as possible, IV access should be established. Infusion of isotonic

fluids is recommended to replete volume and limit myoglobinuric renal damage.

Serial examinations are mandatory. A rather typical ED postsedation course

includes several hours of deep sleep, then gradual awakening of a calm patient

with little recollection of events.

Differential diagnoses of acute confusional states must be considered early.

Glucose and electrolytes should be checked. Examination must search for

evidence of head injury, intracranial hemorrhage, or thyrotoxicosis. Many

other agents can produce similar behavior, although most are uncommon.

Information from witnesses, friends, and family may be vital. In particular,

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anticholinergic poisoning requires consideration; anticholinergic drugs also

cause mydriasis but generally limit peristalsis, in contrast to the hyperactive

bowel sounds from cocaine. Amphetamine effects are difficult to rule out

clinically. Of course, toxicology testing is useful if diagnosis is unclear.

HYPERTHERMIA

Contributory mechanisms of cocaine-induced hyperthermia include sympathetic

discharge, excessive motor activity, seizures, increased metabolic rate,

vasoconstriction, and loss of thermoregulatory control. Toxic delirium often

is coupled with extreme hyperthermia, and these patients seem to be at high

risk of cardiovascular collapse. Sequelae include neurologic damage,

rhabdomyolysis, renal failure, coagulopathies, shock, and hepatic failure,

with similarities to heat stroke.

Aggressive cooling, with controlled application of ice packs, cool baths,

or cool water plus fans to increase evaporation, is vital. Core temperature

should be brought down to 102 °F; further cooling risks hypothermia due

to poor regulatory control. IV fluid support and, for the agitated patient,

benzodiazepine sedation also are indicated. Dantrolene does not appear

beneficial, since the underlying mechanism here is different from that of

malignant hyperthermia.

EMERGENCY DEPARTMENT DATA ON VISITS

Several authors have surveyed visits to busy, urban EDs for cocaine-related

medical problems. These data provide an important perspective on cocaine’s

side effects and the need for intervention and also emphasize the rarity of

catastrophic events.

Brody and colleagues (1990b) reviewed consecutive hospital visits by 233

patients over a 6-month period; 2 patients died (one death followed seizures,

one followed chest pain). Half the patients used the drug intravenously; 18

percent smoked alkaloidal cocaine. The majority had multiple complaints.

Fifty-six percent complained of cardiopulmonary symptoms; 36 percent

had psychiatric symptoms; and 39 percent had neurologic symptoms.

Pharmacologic intervention was deemed necessary in only 24 percent of

patients, and most treatments were nonspecific (e.g., naloxone, thiamine,

charcoal). Of admissions, 60 percent were related to direct drug effects,

whereas others were necessitated by complications of IV injection practices.

There were no documented myocardial infarctions on discharge diagnoses.

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Derlet and Albertson (1989c) reviewed all cocaine intoxications seen over

a 1-year period—137 patients, including one death. Thirty-four percent

used an IV route, whereas 18 percent smoked the drug. Neurologic and

psychiatric complaints accounted for the majority of visits (29 percent for

altered mental status, 8.8 percent for seizures, 9.5 percent for suicide attempts,

and 2.9 percent for transient ischemic symptoms). Chest pain prompted 15

percent of the visits; three patients were hospitalized for possible myocardial

infarctions, but none were later confirmed. In this series, 19 percent required

pharmacologic treatment, most frequently with diazepam, antipsychotic drugs,

nitroglycerin, nifedipine, phenytoin, and naloxone.

Rich and Singer (1991) evaluated 144 consecutive visits due to cocaine

effects seen over a 6-month period, including one death unrelated to the

drug’s presence. Routes of use were IV in 34 percent, nasal in 32 percent,

and smoked in 24 percent. Psychiatric symptoms accounted for 31 percent of

these visits, neurologic complaints for 17 percent, and chest pain/palpitations

for 16 percent. Chest symptoms were more common with nasal use.

Experience in the ED at the University of Miami/Jackson Memorial Medical

Center, a high-volume county hospital, parallels that of other metropolitan

hospitals. A brief (1 month) review of all emergency medical complaints due

to cocaine (41 patients; trauma and mild psychiatric complaints were excluded)

found that 46 percent of visits were due to cardiovascular symptoms, primarily

chest pain. There was one death in a cocaine user with known coronary

disease who suffered prehospital arrest. Eight patients had abdominal

complaints; seven were discharged; and one was admitted for pancreatitis

due to ethanol. Three patients presented with toxic delirium, one with seizures.

Significantly, the route of ingestion was by smoking in 83 percent of cases.

In all these series, the average patient age was about 30 years. A minority

(10 to 20 percent) required inpatient admission. Acute myocardial infarction,

intracranial hemorrhage, ischemic stroke, infarcted bowel, and pulmonary

barotrauma were not seen in the 555 cases described in this section. Deaths

were rare (four). The majority of patients (61 to 76 percent) were male. This

gender difference may well represent community patterns of use and is unlikely

to reflect any difference in risk of complications. In part, it also might reflect

interviewer bias; a past review of ED chart documentation by house staff on

all young adults with chest pain, palpitations, syncope, or new seizures

documented information on cocaine use (positive or negative history) in

most male patients but few females.

In these series, concurrent use of other drugs with the cocaine was commonly

reported (34 to 50 percent of patients), most frequently alcohol and opiates.

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Only a minority of patients required pharmacologic intervention for specific

cocaine effects, primarily benzodiazepines for agitation or seizures. Other

than the four cardiac arrests, no patients required treatment for arrhythmias.

In addition to the medical consequences of cocaine use, other ramifications,

especially use in obstetrical patients and those with trauma, must be

remembered. Although not discussed here, these do have an impact in the

ED. Neonatal effects of maternal drug use present a national health problem

now and for the foreseeable future. Cocaine is commonly present in patients

who arrive at the ED due to traumatic injury. Marzuk and coworkers (1990)

reported cocaine in 18.2 percent of autopsies on motor vehicle accident

victims, with similar percentages in drivers and passengers. Rich and Singer

(1991) found that 12 percent of cocaine-related ED visits were due to trauma.

In our institution in Miami, a busy urban Level One Trauma Center, evidence

of recent cocaine use is found in approximately 35 percent of major trauma

victims (all causes). Causative relationships to motor vehicle accidents and

effect on survivability from major trauma remain undefined.

SUMMARY

Cocaine use is related to a vast array of emergency medical conditions, and

emergency physicians throughout the United States are likely to be confronted

with these patients. Although catastrophic complications are well recognized,

they fortunately represent a very small fraction of cocaine sequelae. However,

a high index of clinical suspicion should be maintained to avoid misdiagnosis

of complications such as myocardial ischemia, significant rhabdomyolysis, or

small subarachnoid hemorrhage. Rapid intervention is crucial in patients

presenting with seizures, hyperthermia, lethal arrhythmias, or toxic delirium.

Most patients do well with ED evaluation and nonspecific supportive care, but

an understanding of this drug’s mechanisms of action and its interactions with

therapeutic interventions is vital in situations such as acute hypertension,

cardiac arrhythmias, or agitated states. Reliable animal models that closely

simulate human responses are not yet available. At this time, knowledge

remains limited, particularly as to optimal pharmacologic management of

specific cocaine effects. Further investigations into potentially adverse

consequences of commonly used medical regimens, such as p-receptor

antagonist, will be essential in guiding management of these cases.

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AUTHOR

Kathleen S. Schrank, M.D.

Associate Professor of Clinical Medicine

Section Chief, Emergency Medicine

Department of Medicine (R-60)

University of Miami School of Medicine

P.O. Box 016960

Miami, FL 33101

128
Cerebrovascular Complications From

Cocaine: Possible Long-Term

Sequelae

Bruce L. Miller, Frances Chiang, Lora McGill, Todd Sadow,

Mark A. Goldberg, and lsmael Mena

INTRODUCTION

The first report of cerebrovascular complications from cocaine was written by

Brust and Richter (1977). They described a man who developed aphasia and

hemiparesis 2 hours following an intramuscular injection of cocaine. Because

the subject was a polydrug abuser and because this complication had not

previously been reported, the authors cautiously stated that “. . . cocaine may

have contributed to the stroke.” However, with great foresight they concluded:

“If in fact cocaine played a causal role, we anticipate that more strokes will be

seen among the many abusers of this agent in American cities.”

Despite this prophecy there was scant literature on neurological sequelae from

cocaine abuse prior to 1984, and until recently, most reports on cocaine toxicity

focused on cardiac or respiratory symptoms. However, as predicted by Brust

and Richter, beginning in 1984 several investigators began to report on an

epidemic of cocaine-induced neurological problems. Mody and colleagues

(1987) described a group of 11 patients with neurological complications from

cocaine abuse, including transient ischemic attacks, ischemic spinal cord and

brain infarction, brain hemorrhage, and focal and generalized seizures. They

suggested that this epidemic of cocaine-induced stroke was due to the wide

availability of crack cocaine. More recently, a large multicenter study (Levine

et al. 1990) further delineated the extensive national presence of cocaineinduced stroke and confirmed that this epidemic was due to the use of crack

cocaine.

With the widespread availability of crack, it has become clear that cocaine is a

drug with serious and unpredictable effects on the brain. In fact, the authors’

experience suggests that crack is the most toxic of the street drugs abused

over the past three decades. One particularly disturbing feature of crack is that

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permanent neurological injury can occur with first-time use. For example, Mody

and coworkers (1988) reported on an 18-year-old man who developed a spinal

cord stroke with subsequent irreversible quadriplegia after smoking crack for

the first time. Of the 14 patients described in this study, 36 percent developed

neurological symptoms the first time that they used the drug. This “side effect”

of cocaine is not predictably dose related and occurs in patients without other

symptoms of cocaine intoxication. Therefore, unlike most other illicitly used

compounds, a single experimentation with cocaine can lead to irreversible

brain injury. This potential toxicity has been underreported and underestimated.

Until recently the mechanisms for cocaine-induced strokes were poorly

understood. For instance, some stroke patients in the authors’ early studies

had normal imaging studies of the brain, including computerized tomography

(CT), magnetic resonance imaging (MRI), and cerebral angiography. However,

with the use of single photon emission computerized tomography (SPECT) and

positron emission tomography (PET), the anatomical sites and physiological

mechanisms associated with cocaine-induced neurological and psychiatric

syndromes are becoming better understood.

This chapter briefly outlines the common neurological and neuropsychiatric

syndromes associated with cocaine abuse and summarizes the findings via

SPECT and PET in patients with acute and chronic cocaine intoxication. The

long-term sequelae of chronic cocaine abuse also are discussed.

COCAINE-INDUCED CEREBRAL HEMORRHAGE

Seven years after Brust and Richter (1977) predicted an epidemic of cocaine

strokes, various authors began to describe patients with cocaine-induced

cerebral hemorrhage. The first was a report on two patients who developed

cerebral hemorrhage associated with intranasal cocaine (Lichtenfeld et al,

1984). One patient had an anterior communicating artery aneurysm, and the

second had an arteriovenous malformation. Subsequently, Wojak and Flamm

(1987) described six patients who had brain hemorrhage associated with

cocaine abuse. Three of the six died; one was left in a vegetative state;

one had a fair outcome; and only one had a good recovery. Most had an

underlying vascular abnormality: Two demonstrated normal angiography;

two had cerebral aneurysms; one had an arteriovenous malformation; and

one had evidence for hemorrhage into a malignant brain tumor.

Jacobs and colleagues (1989) described 13 patients who developed

neurological deficits attributable to cocaine. Of these, 23 percent had

intracerebral hemorrhage; 23 percent had subarachnoid hemorrhage; and

54 percent showed evidence for ischemic brain infarction. Similarly, Mody

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and coworkers (1988) described three patients who developed brain

hemorrhage. Angiography was performed on each patient; in one an

arteriovenous malformation was present; a second showed evidence

for cerebral vasculitis; and the third had a normal angiogram. A typical

hemorrhage case is described below:

A 38-year-old man with a long history of cocaine abuse was

brought to hospital with new onset of right-sided paralysis

associated with loss of speech. The patient’s friends stated

that he had smoked crack shortly before developing his

paralysis. In hospital he was mute and could not follow simple

commands. He had a right homonymous hemianopsia and a

dense right-sided hemiparesis and sensory disturbance. CT

showed a large hyperdense hematoma in the left thalamus,

which extended to basal ganglia. SPECT showed profound

hypoperfusion in the left thalamus and basal ganglia with

hypoperfusion in the overlying left temporal-parietal cortex.

There was mild periventricular scalloping of perfusion. The

patient’s language and paralysis began to improve when he

checked himself out against medical advice.

The studies on brain hemorrhage associated with cocaine have shown a

remarkable consistency, with at least 50 percent of the patients demonstrating

an underlying abnormality in cerebral blood vessels, with arteriovenous

malformations and cerebral aneurysms accounting for most cases. Cocaineinduced hypertension leading to rupture of previously abnormal vessels is the

most likely explanation for hemorrhage in most individuals. However, in others

the angiogram is normal, or like the patient just described, the hemorrhage

occurs in regions that are commonly associated with hypertensive hemorrhage.

In these patients, the hypertension may cause the hemorrhage. Finally, it is

possible that in some patients a cerebral vasculitis weakens and eventually

leads to rupture of cerebral vessels. This issue is discussed in the section on

vasculitis.

In any patient with brain hemorrhage associated with cocaine, it is mandatory

that angiography be performed, as it often reveals an arteriovenous

malformation or an aneurysm that will require neurosurgical intervention.

Treatment for these patients is similar to the treatment of brain hemorrhage

that is unrelated to cocaine.

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TRANSIENT ISCHEMIC ATTACKS AND ISCHEMIC BRAIN INFARCTION

Beginning with Brust and Richter’s original report (1977), there has been

increasing evidence that transient ischemic attacks (TIAs) and ischemic

brain infarctions do occur in drug abusers, including those who abuse cocaine

(Caplan et al. 1982). Although clinical stroke is not a common sequela of

cocaine abuse, around 1987 numerous groups began to describe young

individuals with TIA and ischemic brain infarction secondary to cocaine abuse.

Golbe and Merkin (1986) described a single patient with a right middle cerebral

artery infarct; following this study, several groups reported on larger series of

patients with cocaine-induced stroke syndromes (Jacobs et al. 1989; Lowenstein

et al. 1987; Levine et al. 1987). In the study by Jacobs and colleagues (1989)

seven patients with ischemic stroke were reported. All were young (mean age

of 34) and there was a surprising predilection for small-vessel occlusions: Four

of their seven patients had lacunar strokes in a purely subcortical location; two

patients had middle cerebral branch occlusions; and one had a mixture of

cortical and subcortical stroke.

Similarly, Rowley and coworkers (1989) described three patients with a mean

age of 33 in whom strokes occurred in the rostral midbrain and thalamus.

These researchers noted that in a previous review of 25 subjects with thalamic

stroke, none of whom had abused cocaine, only 3 were younger than 50. They

concluded that the thalamic and midbrain strokes seen with cocaine abuse

occurred in an unusual location and that strokes occurring in this region in noncocaine abusers typically occurred in individuals age 50 and older. Also in the

report by Mody and colleagues (1988), the patients tended to have branch

occlusions, and none of the subjects had basilar or carotid artery occlusions.

In a multicenter study, Levine and colleagues (1990) described 28 patients

with cocaine-induced cerebrovascular complications; some had large-vessel

occlusions, and others had small-vessel occlusions.

WHY DOES ISCHEMIC STROKE OCCUR WITH COCAINE?

Often, individuals with cocaine-induced stroke are young without other

known risk factors for stroke. The time interval between cocaine use and

stroke has varied from minutes to many hours, but in some subjects it has

been hard to extract a reliable history, making it difficult to define precisely

a temporal relationship between abuse and stroke. The mechanism for

these events remains uncertain, and due to the young age of the patients,

atherosclerosis is not a likely explanation for most of the stroke syndromes.

Cocaine and some of its metabolites are potent vasoconstrictors: Lange

and coworkers (1989) have shown that intravenous (IV) cocaine produces

intense spasm of coronary arteries. Myocardial infarction can occur with

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excessive release of catecholamines, a major mechanism of action for cocaine.

Evidence that similar changes occur in cerebral vessels leading to stroke is now

beginning to emerge.

Some researchers suggest that the ischemic strokes seen with cocaine are

due to cerebral vasospasm caused by catecholamine release (Mody et al.

1988). However, angiographic findings have been variable, with only a few

cases demonstrating focal vasospasm. Similarly, Rowley and colleagues

(1989) have reported that the arterial branches supplying the thalamus and

midbrain, common locations for cocaine-stroke, are not heavily innervated with

noradrenergic fibers, making catecholamine-induced stroke as a mechanism

for cocaine far from certain. In these patients, angiography often shows either

branch vessel occlusions or normal angiography; only a few subjects show

“vasculitic” changes with angiography.

There are several explanations for the paucity of findings with angiography.

Most stroke subjects are many hours out (up to 24 or more hours) from their

dose of cocaine when they reach the hospital; by the time angiography is

completed, it is usually days after the acute event. Therefore, even if spasm

is the etiology for the stroke, the spasm might be gone by the time angiography

is performed. Also, with cocaine there is selective involvement of small- and

medium-size vessels, arteries that are not well resolved with angiography.

More research is needed to determine why some subjects develop ischemic

stroke, whereas most do not. The role of cocaine metabolites in stroke

has been incompletely investigated. Recent work shows that patients who

simultaneously abuse alcohol and cocaine metabolize cocaine to cocaethylene,

which is also centrally active (Hearn et al. 1991). It is possible that the

combination of alcohol and cocaine is particularly toxic. Accelerated

atherosclerosis is one possible explanation for ischemic stroke in chronic

abusers, although there is a paucity of information to support this concept.

Moreover, in Mody and colleagues’ (1988) study, many of the stroke patients

were first-time abusers, suggesting that certain individuals are particularly

prone to stroke when using cocaine. In these cases the cocaine may be just

one factor in the pathogenesis of the stroke syndrome. Two such patients with

multiple risk factors for ischemic stroke are described below:

A 17-year-old right-handed woman, G

2PoAb, was admitted to

labor and delivery with a 25-week pregnancy. She had a past

medical history significant for alcohol and polydrug abuse.

She was admitted for pre-eclampsia with mild hypertension.

Six days after admission, she had a generalized seizure,

which was treated with phenytoin (Dilantin). Subsequently,

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she delivered a small-for-gestational-age infant and her

hypertension resolved with delivery. Postpartum the phenytoin

was discontinued, but 3 days later a second generalized

seizure occurred and phenytoin was restarted. Two days later

she developed sudden onset right face and arm weakness

with dysarthria. A CT scan was normal, but MRI demonstrated

areas of hyperintensity in the left caudate and corona radiata

and in the right centrum semiovale. An echocardiogram was

normal, and serum studies revealed that antiphospholipid

antibody was present. Two days after the stroke, she

complained of acute onset of shortness of breath that was

associated with hypoxemia, and a pulmonary embolus was

diagnosed, for which she was started on heparin. She was

switched to sodium warfarin (Coumadin) and gradually

improved; after 2 weeks in hospital, she admitted to abusing

cocaine throughout the pregnancy.

This patient had multiple risks for stroke, including the pregnant state and

the presence of lupus anticoagulant (antiphospholipid antibody). Indeed,

she developed both venous thrombosis and brain infarction, a characteristic

of patients with this antibody. However, most pregnant women with lupus

anticoagulant do not have strokes, and it is possible that the combination of all

three risk factors-cocaine, antiphospholipid antibody, and pregnancy-led to

her cerebrovascular complications.

Another cocaine abuser with multiple risk factors for stroke

was a 56-year-old male admitted to hospital after developing

left-sided weakness associated with dysarthria and dysphagia.

Four days earlier he awakened unable to move his left arm or

leg, and when this did not improve, he came to hospital. On

examination, blood pressure was normal. He had mild

bradycardia but the electrocardiogram did not show left

ventricular hypertrophy. He was mentally slowed with slurred,

hypophonic output and had mild word-finding difficulty, a

memory disturbance, and a left hemiparesis. The clinical

diagnoses were mild dementia, pseudobulbar syndrome, and

left-sided hemiparesis due to multiple strokes, MRI showed

multiple lacunar strokes in the deep white matter, basal

ganglia, and internal capsule. SPECT showed bilateral

temporal and frontal hypoperfusion. Although he initially

denied cocaine abuse, urine toxicology was positive and he

eventually admitted to chronic cocaine use for up to 3 days

prior to his stroke. He left hospital after 4 days with little

clinical improvement.

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Despite the fact that this man had only mild hypertension and no history for

previous stroke, his MRI showed multiple ischemic white matter infarctions, and

clinically he had a dementia syndrome that was probably secondary to multiple

strokes. It is possible that hypertension alone caused the strokes, although he

was relatively young and blood pressure measured in the hospital was normal.

More likely, the combination of mild hypertension and chronic cocaine abuse

was responsible for the patient’s vascular dementia.

This is one of several patients the authors have seen who developed a

dementia syndrome associated with chronic cocaine abuse. One concern

with the current epidemic of cocaine abuse is whether chronic abusers will

develop a vascular dementia. Prospective neuropsychological and imaging

studies that longitudinally assess chronic cocaine abusers will be important.

Similarly, careful evaluation of other risk factors associated with stroke and

cocaine needs to be performed. It seems unlikely that a single mechanism

accounts for this phenomena and that the etiology for cocaine-induced

ischemic stroke and cocaine-induced vascular dementia is multifactorial.

VASCULITIS

One unresolved issue related to cocaine-induced stroke is whether it is due

to central nervous system (CNS) vasculitis. However, amphetamine, which

also boosts brain catecholamines, can cause a CNS vasculitis. Citron and

coworkers (1970) first described 14 polydrug abusers who developed

catastrophic systemic or neurological complications from a necrotizing

vasculitis. The common link among all was the use of amphetamine.

Subsequently, Rumbaugh and colleagues (1971a) showed that monkeys

given a single IV injection of methamphetamine developed changes in the

caliber of middle cerebral and lenticulostriate vessels. Although these changes

disappeared within 24 hours angiographically, postmortem evidence for

petechial hemorrhages and scattered areas of small infarction was found

throughout the brain. This has disturbing implications for chronic abusers.

Kaye and Fainstat (1987) described a patient who abused cocaine in whom a

diagnosis of vasculitis was made based on angiographic changes. However,

as noted by Levine and coworkers (1988), this case is controversial, because

the patient had a subarachnoid hemorrhage, which by itself could cause

angiographic findings that mimic vasculitis.

The diagnosis of vasculitis often depends on interpretation of cerebral

angiography, and the angiogram in patients with cocaine-associated stroke

most often shows occlusions or segmental stenoses of the vessels of the circle

135
of Willis, the supraclinoid internal carotid artery, and horizontal segments of

the anterior, middle, or posterior cerebral arteries. Areas of narrowing may be

multiple, focal, or diffuse. If stenoses involve the vessel walls uniformly, the

term “vasospasm” is used even though the findings may represent irreversible

changes, Less commonly, the vessels show a beaded appearance or

irregularly narrowed segments, which correlates with a vasculitis based on the

appearance of necrotizing angiitis in connective tissue diseases (Ferris 1974).

With cocaine, vessel “spasm” may involve the major branches of the

intracerebral arteries, particularly the sylvian branches of the middle cerebral

artery (Jacobs et al. 1989). These lesions can cause either ischemic infarcts

or intracranial hemorrhage (Klonoff et al. 1989). However, the numerous small

artery occlusions seen on angiography in amphetamine-associated vasculitis

(Rumbaugh et al. 1971b) are uncommon with cocaine abuse, and more

typically, the cerebral angiogram is completely normal, despite an ischemic

event. These patients most likely have true episodes of vasospasm that

subsequently reversed after causing ischemic injury. Described below is one

of the few cases that the authors have seen with a possible cocaine-induced

vasculitis:

A 36-year-old male was admitted to hospital with mental

decline and a pseudobulbar palsy. He had developed trouble

with speaking and swallowing over the previous 2 days. There

was a history of hypertension, but blood pressure was normal

on admission. On examination he had involuntary bursts of

laughter, bilateral facial weakness, an absent gag reflex, and

a spastic upper palate. Bilateral arm and leg weakness were

present. CT and MRI showed multiple small infarcts in the

corona radiata, basal ganglia thalamus, and pons (figure 1).

Angiography showed multiple areas of irregular narrowing in

branch vessels of the anterior, middle, and posterior cerebral

arteries (figure 2). SPECT showed small areas of

hypoperfusion in the frontal and temporal lobes.

This patient initially denied cocaine abuse but later admitted to episodic

use. A broad screen for an etiology of the patient’s strokes was negative,

including antinuclear and antiphospholipid antibody, hepatitis panel, human

immunodeficiency virus, protein electrophoresis, cerebrospinal fluid

examination, and erythrocyte sedimentation rate. A therapeutic trial with

prednisone and cyclophosphamide (Cytoxan) was unsuccessful. It is possible

that this man had multiple strokes on the basis of a primary CNS vasculitis

unrelated to cocaine. However, the history was highly suggestive for a cocaineinduced syndrome, and primary CNS vasculitis is rare. Biopsy-proven cases of

136
FIGURE 1. This T2-weighted MRI scan demonstrates multiple ischemic

infarctions in the corona radiata, thalamus, and basal ganglia.

137
FIGURE 2. This cerebral angiogram shows multifocal areas of cerebral

spasm in the patient.

cocaine vasculitis are rare, but Krendel and coworkers (1990) recently reported

a biopsy-proven case of granulomatous vasculitis in a cocaine abuser.

Although cocaine-induced cerebral vasculitis appears to be unusual, better

information should come from careful postmortem studies on the cerebral

blood vessels of patients who had a history of cocaine abuse. As described in

the next section, SPECT studies of cerebral blood flow appear to demonstrate

marked abnormalities in cerebral perfusion in both acute and chronic cocaine

abusers. Although in some cases this may be due to cerebral vasospasm, in

a few there may be a vasculitis.

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NEUROIMAGING STUDIES OF COCAINE NEUROPSYCHIATRIC

SYNDROMES

Techniques

During the past decade there have been significant advances in radiological

techniques that allow high-resolution imaging of both cerebral blood flow and

metabolism. With PET, the subject is injected with a radiolabeled compound

that emits positrons. These positrons are detected, and a three-dimensional

image of their distribution can be produced. It is possible to measure different

metabolic processes depending on the compound that is radiolabeled. For

example, with fluorodeoxyglucose an image of the brain’s glucose metabolism

is obtained. Conversely, with radiolabeled haloperidol one can obtain an image

that shows the distribution of the brain’s dopamine receptors.

Simultaneously, there have been significant advances with SPECT. Currently,

the lower resolution imaging agents such as 133Xenon are being augmented

with higher resolution compounds such as 99mtechnetium-hexamethyl-propyleneamine-oxime (HMPAO) (Neirinckx et al. 1981; Sharp et al. 1986). HMPAO

crosses the blood-brain barrier at a rate approximately equal to cerebral blood

flow. After reaching the brain, HMPAO is enzymatically converted and trapped,

allowing a high-resolution image of cerebral blood flow. Mena and coworkers

(1990) have utilized both 133Xenon, which gives absolute numbers for cerebral

perfusion, and HMPAO with its higher resolution capabilities to study cocaine

abuse.

The advantage of SPECT and PET is that they give information about brain

function independent of brain structure. For example, it is known that diffuse

metabolic disturbances, even those that lead to coma and death, do not

change the structural images of brain as shown by such techniques as MRI

and CT. However, even subtle disturbances in metabolic function will alter

functional brain images. Indeed, both PET and SPECT studies are beginning

to demonstrate subtle changes in brain metabolism and perfusion in cocaine

abusers with normal structural brain images. These studies are helping to

elucidate pathogenetic mechanisms associated with cocaine abuse.

SPECT Findings

For the past 2 years Miller and coworkers (1989) and Mena and coworkers

(1990) have utilized SPECT to evaluate patients with a variety of cocaineinduced neurological and psychiatric problems. These studies have shown a

sensitivity with SPECT that has exceeded that of CT and MRI. A recent study

(R. Giombetti et al., personal communication, August 1991) evaluated 14

139
consecutive patients with acute cocaine intoxication and neurological symptoms

with CT and SPECT. Symptoms included transient ischemic attacks, stroke,

seizures, and confusional states. Cerebral blood flow was imaged with HMPAO

and was measured using 133Xenon. Focal, multifocal, or diffuse areas of

hypoperfusion were found in all 14 patients with either HMPAO SPECT or

133Xenon. Multiple small superficial and deep areas of hypoperfusion causing

a “scalloped” appearance on SPECT were seen in 12 patients. This pattern

appeared to be characteristic of cocaine abuse in this population. Mean

cerebral blood flow measured with 133Xenon was slightly diminished at

43.6±3.4 mL/100 g/min compared with 55.1±1.4 mL/100 g/min in normals.

SPECT was valuable in studying these patients, and cortical and subcortical

vascular abnormalities, not seen on CT or MRI, were demonstrated with

SPECT. A typical patient in whom SPECT was valuable is described below:

A 25-year-old woman was admitted to hospital with a 3-day

history of left-sided weakness and a generalized seizure. She

had sudden onset of left arm and leg weakness that persisted

for 3 days. On the day of admission she had a generalized

seizure and was brought to the emergency room by friends.

There she admitted to a history of occasional cocaine abuse

but insisted that her last use had been more than 1 year ago.

However, her urine toxicology screen was positive for cocaine.

Neurologic exam showed mild left hemiparesis of arm and leg

with mildly decreased left-sided sensation. CT, EEG, lumbar

puncture, echocardiogram, and cerebral angiogram were

normal. SPECT showed areas of hypoperfusion in right

parietal, left temporal, and both frontal lobes. There was

scalloping in the periventricular region (figure 3). She was

admitted again 3 months later with increased left-sided

weakness and dysarthria. Her urine screen was again positive

for cocaine and this time she admitted to continued abuse.

She left hospital with a persistent left-sided neurologic deficit.

This patient is fairly representative of the cocaine-stroke population at HarborUCLA Medical Center. She was young and initially denied the importance of

her cocaine abuse as a factor in her stroke syndrome. Because cocaine

strokes often involve small-size vessels, CT and MRI can be normal, as was

the case in this patient. In contrast, SPECT often shows perfusion deficits in

the brain area appropriate to the clinical syndrome. SPECT also can show

other focal areas of hypoperfusion, which do not have clear clinical significance.

The most consistent abnormality has been the scalloping of cerebral perfusion

in the periventricular region, present in more than 80 percent of the acute

cocaine-abuse population (Mena et al. 1990). This appears to represent an

140
FIGURE 3. This SPECT demonstrates large right parietal areas of

hypoperfusion, diffuse small multifocal regions of cerebral

hypoperfusion, and periventricular scalloping.

area that is particularly vulnerable to the effects of cocaine, although the clinical

significance of this hypoperfusion remains to be determined. Also, many

cocaine abusers show multiple areas of cortical hypoperfusion, presumably

representing areas of focal vascular spasm or possibly stroke.

One intriguing aspect of the SPECT studies in cocaine abusers has been the

consistent demonstration that cerebral perfusion abnormalities may persist for

many months after the cocaine abuse has stopped. Recently, in a population

of chronic cocaine abusers, Holman and colleagues (1991) described focal or

deep areas of diminished cerebral perfusion with SPECT in 16 of 18 subjects.

Some of the subjects had abstained from cocaine for weeks prior to the study,

and all 18 subjects had at least mild neuropsychological deficits (13 mild and

18 moderate). In another study that suggests that chronic cocaine abuse may

cause permanent changes in brain structure and function, Pascual-Leone and

coworkers (1991) found that CT atrophy strongly correlated with the duration of

cocaine abuse.

141
Similarly, utilizing 133Xenon and HMPAO SPECT, Strickland and coworkers

(1991) described periventricular scalloping and multifocal perfusion deficits in

eight consecutive patients with a past history of cocaine abuse. All the subjects

were participating in a drug rehabilitation program, and all tested negative for

cocaine on repeated random screens. In addition to the SPECT findings, these

subjects had neuropsychological deficits. In this study of chronic cocaine

abusers, it appeared that chronic abuse led to longstanding (possibly

permanent) changes in cerebral perfusion.

In total, SPECT studies to date suggest that this technique may be exquisitely

sensitive to changes in cerebral perfusion associated with acute and chronic

cocaine abuse. The mechanisms for these changes await pathological studies

of cerebral blood vessels. Similarly, neuropsychological studies confirming

the clinical significance of these SPECT perfusion deficits will be important.

Finally, prospective studies on patients with cocaine-induced psychoses and

confusional states may help to define the vascular contribution to these

syndromes.

PET Findings

The most extensive PET studies of cocaine abusers have been done by

Volkow and coworkers (1988, 1991). The first study measured 15Oxygen

utilization in a group of chronic abusers and demonstrated modest decreases

in oxygen utilization in the frontal regions. Patients for that study were recruited

from a drug rehabilitation center, and unlike those that Mena and colleagues

(1990) reported, these subjects had no major medical or neurological problems.

In this study (Volkow et al. 1988), diffuse patchy areas of hypoperfusion

were observed, 15Oxygen metabolism in the prefrontal cortex was markedly

decreased, and repeat scans performed at 10 days revealed persistent deficits.

Volkow and colleagues (1991) also evaluated subjects during the first and

second weeks following withdrawal from cocaine. This second study utilized

fluorodeoxyglucose, and the researchers found increased metabolism of

glucose in the orbital-frontal cortex and basal ganglia during the first week of

cocaine withdrawal. In those subjects studied during the second week

following cocaine withdrawal, the metabolism in the frontal regions had

decreased. The researchers suggested that the findings might be related

to the effects of cocaine on dopamine, a compound with extensive projections

to the frontal lobes.

In contrast, London and coworkers (1990) found decreases in cerebral

glucose utilization in 26 of 29 brain regions in patients acutely exposed to

cocaine. Overall, these studies suggest that cerebral metabolism fluctuates

142
dramatically in cocaine abusers depending on whether the patient has acutely

abused cocaine or is in a state of withdrawal.

Like Volkow and colleagues, with SPECT, Mena and coworkers (1990) also

found a substantial group of patients with frontal hypoperfusion. It is hard to

know whether the changes in frontal glucose utilization precede or follow the

changes in blood flow shown with SPECT. They have seen some cocaine

abusers with behavioral disinhibition in whom there is concomitant frontal

hypoperfusion and have speculated that frontal ischemia induced by

vasospasm from cocaine may be the primary event responsible for these

patients’ behavioral changes. Another possible consideration is that frontal

hypoperfusion is a premorbid characteristic of the subjects who abuse cocaine.

A third possibility is that the hypoperfusion is secondary to a cocaine-induced

disturbance in neurotransmitters, which leads to hypometabolism and

subsequent hypoperfusion.

CONCLUSIONS

The recent epidemic of cocaine abuse has led to a variety of serious

neurological complications. Of great concern is the growing number of

cocaine-induced strokes in young healthy individuals. Many of these

subjects initially deny that they abuse cocaine, which often confounds

diagnosis. A particularly disturbing aspect of this epidemic is the SPECT

finding of persistent changes in cerebral perfusion many months after the

cocaine abuse has abated.

Some aspects of this epidemic have been incompletely studied and are

poorly understood. One important goal for researchers should be to

determine the neuropsychological and neuropathological substrate of these

changes. Careful prospective studies that utilize SPECT, PET, MRI, and

careful neuropsychological testing will help to determine the long-term toxicity

of cocaine. However, the long-term complications associated with cocaine

have been underestimated, and there is need for continued studies into the

toxicity of this compound.

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Caplan, L.R.; Hier, D.B.; and Banks, G. Stroke and drug abuse. Stroke

13:869-872, 1982.

Citron, B.P.; Halpern, M.; McCarron, M.; Lundberg, G.D.; McCormick, R.;

Pincus, I.J.; Tatter, D.; and Haverback, B.J. Necrotizing angiitis associated

with drug abuse. N Engl J Med 283:1003-1011, 1970.

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Skull and Brain: Angiography. St. Louis, MO: Mosby, 1974. pp. 2577-2597.

Golbe, L.I., and Merkin, M.D. Cerebral infarction in a user of free-base cocaine

(crack). Neurology 36:1602-1604, 1986.

Hearn, W.L.; Flynn, D.D.; Hime, G.W.; Rose, S.; Cofino, J.C.; Mantero-Atienza,

E.; Wetli, C.V.; and Mash, D.C. Cocaethylene: A unique cocaine metabolite

displays high affinity for the dopamine transporter. J Neurochem 56(2):1787-

1794, 1991.

Holman, B.L.; Carvalho, P.A.; Mendelson, J.; Teoh, S.K.; Nardin, R.; Hallgring,

E.; Hebben, N.; and Johnson, K.A. Brain perfusion is abnormal in cocainedependent polydrug users: A study using technetium-99m-HMPAO and

SPECT. J Nucl Med 32(6):1206-1210, 1991.

Jacobs, I.G.; Roszler, M.H.; Kelly, J.K.; Klein, M.A.; and Kling, G.A. Cocaine

abuse: Neurovascular complications. Radiology 170:223-227, 1989.

Kaye, B., and Fainstat, M. Cerebral vasculitis associated with cocaine abuse.

JAMA 258:2104-2106, 1987.

Klonoff, DC.; Andrews, B.T.; and Obana, W.G. Stroke associated with cocaine

use. Arch Neural 46:989-999, 1989.

Krendel, D.A.; Ditter, S.M.; Frankel, M.R.; and Ross, W.K. Biopsy-proven

cerebral vasculitis associated with cocaine abuse. Neurology 40:1092-1094,

1990.

Lange, R.A.; Cigarroa, R.G.; Yancy, C.W., Jr.; Willard, J.E.; Popma, J.J.; Sills,

M.N.; McBride, W.; Kim, A.S.; and Hillis, L.D. Cocaine-induced coronaryartery vasoconstriction. N Engl J Med 321:1557-1562, 1989.

Levine, S.R.; Brust, J.C.M.; Futtrell, N.; Ho, K.L.; Blake, D.; Millikan, C.H.;

Brass, L.M.; Fayad, P.; Schultz, L.R.; Selwa, J.F.; and Welch, K.M.A.

Cerebrovascular complications of the use of the “crack” form of alkaloidal

cocaine. N Engl J Med 323:1699-1704, 1990.

Levine, S.R.; Washington, J.M.; Jefferson, M.F.; Kieran, S.N.; Moen, M.; Feit,

H.; and Welch, K.M.A. “Crack” cocaine-associated stroke. Neurology

37:1849-1853, 1987.

Levine, S.R.; Welch, K.M.A.; and Brust, J.C.M. Cocaine vasculitis associated

with cocaine abuse or subarachnoid hemorrhage? JAMA 259(11):1648,

1988.

Lichtenfeld, P.J.; Rubin, D.M.; and Feldman, R.S. Subarachnoid hemorrhage

precipitated by cocaine snorting. Arch Neural 41:223-224, 1984.

London, E.D.; Cascella, N.G.; Wong, D.F.; Phillips, R.L.; Dannals, R.F.; Links,

J.M.; Herning, R.; Grayson, R.; Jaffe, J.H.; and Wagner, H.N. Cocaineinduced reduction of glucose utilization in human brain. Arch Gen Psychiatry

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Lowenstein, D.H.; Massa, S.; Rowbotham, M.; Collins, S.D.; McKinney, H.E.;

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Miller, B.L.; Garrett, K.; Leedom, L.; Djenderedjian, A.; and Mena, I.

Neurospect in cocaine abuse: rCBF and HMPAO findings. Clin Nucl Med

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Technetium-99m d, I-HMPAO: A new radiopharmaceutical for SPECT

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cocaine abusers: A planimetric CT study. Neurology 41:34-38, 1991.

Rowley, H.A.; Lowenstein, D.; Rowbotham, M.; and Simon, R.P.

Thalamomesencephalic strokes after cocaine abuse. Neurology 39:

428-430, 1989.

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Rumbaugh, C.L.; Bergeon, R.T.; Scanlan, R.I.; Teal, J.S.; Segall, H.D.; Fang,

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Technetium-99m HMPAO stereoisomers as potential agents for imaging

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Stroke 18:712-715, 1987.

145
ACKNOWLEDGMENT

Robert Giombetti, M.D., and Cyrus Mody, M.D., generated some of the original

research reported in this chapter.

AUTHORS

Bruce L. Miller, M.D.

Associate Professor

Department of Neurology, B-4

Frances Chiang, M.D.

Assistant Professor

Department of Radiology

Todd Sadow, M.D.

Assistant Professor

Department of Psychiatry

University of California, Los Angeles School of Medicine

Mark A. Goldberg, Ph.D., M.D.

Professor of Neurology and Pharmacology

UCLA School of Medicine

Chairman of Neurology

lsmael Mena, M.D.

Professor

Department of Radiology

UCLA School of Medicine

Chairman

Division of Nuclear Medicine

Lora McGill, M.D.

Neurology Fellow

Harbor-UCLA Medical Center

1000 West Carson Street

Torrance, CA 90509

146
Cocaine Levels and Elimination

in Inpatients and Outpatients:

Implications for Emergency

Treatment of Cocaine Complications

Michael C. Rowbotham

INTRODUCTION

Despite the large volume of published medical literature on cocaine, knowledge

of the pathophysiology of medical complications associated with its use remains

incomplete. Treatment of cocaine-associated medical illness is still empirical;

few emergency interventions have been tested prospectively in humans

specifically for treatment of cocaine-related complications. Those that have

been tested in animals may be ineffective, and some have been found harmful.

Although a portion of the medical complications of cocaine use represents a

sudden expression of previously silent anatomic abnormalities that put even a

first-time user at risk, most are related to compulsive, high-dose cocaine abuse.

Effective and well-tolerated pharmacological prevention of relapse in cocaine

abusers still awaits demonstration.

The time course of the physiological and subjective effects of a single dose of

cocaine is closely correlated with the route of administration and blood levels

achieved. An oral dose of 2 mg/kg produces peak effects in about 45 minutes

with easily demonstrable elevations in heart rate and systolic blood pressure,

a decrease in skin temperature, and an increase in pupil size. Administered

intravenously, intense effects can be achieved with doses one-fifth that

administered orally. When smoked, an intense and relatively brief mental

and physiologic state follows just one or two inhalations of cocaine, reflecting

a concentrated bolus delivered efficiently to the brain with only 8 seconds

of transit time. Intravenous (IV) infusion of lethal doses of cocaine in dogs

produces a predictable sequence of events culminating in generalized

convulsions and death (Catravas and Waters 1981). Heart rate, blood

pressure, cardiac output, and body temperature all rise, with blood

pH falling to near 7.0 as convulsions begin. Rapid administration of lethal

doses can produce apnea and cardiac arrest without generalized convulsions.

147
Observation of cocaine “body packers” (persons who smuggle cocaine by

ingesting many cocaine-filled balloons or condoms) in whom one or more

packets ruptured while hospitalized has confirmed this same sequence of

events in humans. Before the onset of generalized seizures, a toxic delirium

was observed. Cocaine blood levels of 2,000 to 5,200 ng/mL have been

reported in survivors.

The effects of repetitive administration of cocaine are more complex. In the

acute situation, tolerance to both the subjective and the cardiovascular effects

of cocaine occurs rapidly. Fischman and Schuster (1982) gave a group of

experienced human cocaine users the opportunity to self-administer repeated

bolus doses of cocaine, as often as every 10 minutes, in a tightly controlled

experimental situation. Even though blood levels continued to rise throughout

the experiment, the subjects could not discern any additional increase in effects

after the first few doses. The same effect was observed for doses administered

60 minutes apart.

Access to the drug is a critically important factor in understanding complications

of cocaine abuse. Under proper conditions, monkeys will self-administer the

same drugs taken illicitly by humans, a laboratory model used extensively in

research on psychoactive drugs. Animals will self-administer cocaine under

a broad range of conditions and by all routes. Cocaine has been a potent

reinforcer in all animal species tested so far, evidence that preexisting

psychopathology is not a prerequisite for cocaine addiction in humans. Once

self-administration has begun, the organism becomes totally preoccupied with

drug acquisition to the exclusion of food and socialization. Given unlimited

access, animals self-administer the drug in erratic bursts, similar to cocaine

binging seen in humans, with seizures or exhaustion terminating each binge. In

contrast, when access to cocaine is limited, animals self-administer cocaine in a

relatively regular manner with greatly reduced morbidity and mortality. With the

introduction of cheap cocaine in the smokable base form, extremely high blood

levels can be achieved almost instantaneously and replenished frequently over

longer periods, increasing the likelihood of behavioral and medical toxicity and

establishing an addictive pattern of use much more rapidly, sometimes within

weeks.

The role that drug metabolism and clearance play in the production of medical

complications has been studied little in the clinical setting. The available data

consist largely of single blood-level measurements in cocaine smugglers and

postmortem samples. At least three blood samples drawn within a few hours

time are needed to calculate an elimination drug half-life. In normal volunteers,

the average plasma half-life of cocaine ranges from 40 to 90 minutes. Cocaine

is metabolized primarily to ecgonine methyl ester (EME) and benzoylecgonine

148
(BE). EME is formed enzymatically via tissue and serum esterases, whereas

BE is formed partially if not entirely by nonenzymatic hydrolysis. It has been

hypothesized that low pseudocholinesterase activity may slow the metabolism

and thereby increase the risk for cocaine toxicity.

COCAINE ELIMINATION IN INPATIENTS WITH COCAINE-RELATED

NEUROLOGICAL ILLNESS

As part of ongoing studies at San Francisco General Hospital (SFGH), a

minimum of three blood samples were obtained for determination of cocaine

and BE levels from a group of 14 patients hospitalized for evaluation

and treatment of a cocaine-related neurological complication in 1989-90.

In addition, a blood sample was obtained for measurement of plasma

pseudocholinesterase activity. Three urine samples were collected within

the first 12 hours of hospitalization and analyzed for cocaine and BE. In

addition, a urine specimen was sent to the hospital toxicology laboratory for a

comprehensive drug screen. Blood was collected in tubes containing sodium

fluoride (to inhibit cocaine metabolism) and was immediately refrigerated.

Afler centrifugation, the plasma was frozen. Blood for pseudocholinesterase

measurement was collected in tubes containing ethylenediaminetetraacetic

acid and was refrigerated. Urine was collected in containers adjusted to a

pH of 3.0 to prevent hydrolytic degradation of cocaine and its metabolites and

was frozen. Plasma and urine samples were analyzed for cocaine and BE by

automated gas chromatography according to the method described by Jacob

and colleagues (1987, 1990). The lower limit of quantitation for this assay is 5

ng/mL for cocaine, although sensitivity for cocaine detection is 1 ng/mL. For

BE, the lower limit of quantitation is 10 ng/mL, with sensitivity for detection at 5

ng/mL. Plasma pseudocholinesterase activity was measured by a modification

of the Ellman method (George and Abernathy 1983).

Data on the 14 hospitalized patients are summarized in table 1. Nine patients

presented with seizures (one in status epilepticus), one with dystonic

movements of the head and arms, three with stroke, and one with

encephalopathy without focal neurologic deficits.

The route of cocaine administration was oral/nasal in three patients, combined

oral/nasal and smoked in two, smoked in six, and IV in three. The latency

between last cocaine use and the first blood sample (when known) ranged

between 1 and 20 hours and was less than 3 hours in four patients. In these

four patients, the maximum plasma cocaine level was 4,697 ng/mL, and the

average initial plasma cocaine level was 1,597 ng/mL (range 275 to 4,697

ng/mL). The average of the highest measured urine cocaine level in each of

these four patients was 28,995 ng/mL (range 13,879 to 61,656 ng/mL). In

149
TABLE 1. Patient summaries, drug levels, and cocaine plasma half-life

KEY: aC=cocaine: BE=benzoylecgonine; BZ=benzodiazepines; O=opioids; A=amphetamine; CZ=carbamazepine; BT=benztropine; OTC-nonprescription analgesics. decongestants.

or antihistamines; NA=no urine toxicology screen performed

b

o/n=oral/nasal; sm=smoked

cValue listed is maximum measured value. independent of time of maximum plasma cocaine level.

cBLQ=plasma cocaine levels at times of quantitation, precluding calculation of plasma hail-life
contrast, in the 10 remaining subjects in whom the latency either was not known

or was greater than 4 hours, the average initial plasma cocaine level was 317

ng/mL (range 7 to 1,358 ng/mL). The maximum urine cocaine levels in these

patients averaged 8,481 ng/mL (range 101 to 49,992 ng/mL). Maximum plasma

and urine BE levels are listed in table 1. Plasma pseudocholinesterase activity

was measured in nine patients and ranged from 1.7 to 3.6 U/mL, all within the

normal range for this assay.

Cocaine plasma half-lives could be calculated in 11 patients and averaged

137 minutes (median 132 minutes, range 60 to 197 minutes, range of sampling

period 120 to 1,850 minutes). The calculated half-life was greater than 100

minutes in 12 of the 14 patients and did not have any obvious relationship to the

highest measured cocaine level. Plasma cocaine half-life was not calculated in

the remaining three patients because there were not three cocaine levels above

20 ng/mL. In comparison, the terminal phase half-life in 10 healthy volunteer

subjects given 1.2 mg/kg cocaine by IV bolus followed by a 4-hour infusion of

1.2 mg/kg/hr was 95 minutes (median 86 minutes, range 62 to 176 minutes).

The difference in cocaine plasma half-life between the two groups is significant

(p=0.02, two-tailed unpaired t-test). The total dose of cocaine, the period over

which it was used, and the true latency from last use to first blood sample

cannot be known with any certainty. Therefore, it is not known what portion

of the curve of declining blood levels is being sampled. With the possible

exception of case DS and case CE, the peak blood level may have occurred

many hours before the first sample. The calculated half-lives cannot be

grouped together as representing a uniform portion of the elimination curve.

The nature of these data does not allow differentiation between dosedependent metabolism, an effect of chronicity of use, or a less specific effect

of acute medical illness in explaining the prolonged elimination half-life

observed.

OUTPATIENTS WITH COCAINE-RELATED NEUROLOGICAL SYMPTOMS:

COCAINE AND BE LEVELS

Another aspect of treatment of acute complications of cocaine abuse that

has received relatively little attention are the implications of both the delay in

seeking treatment and the magnitude of blood and urine levels of cocaine

and metabolites on clinical presentation for emergency treatment. To gain

perspective from the hospitalized group, a second group of 18 patients

presenting for emergency treatment at SFGH in 1990-91 who did not require

hospitalization was evaluated with three blood samples for cocaine and BE, a

blood cholinesterase level, a comprehensive urine toxicology screen, and one

urine sample for cocaine and BE level.

151
The ranges of values observed are shown in table 2. It is striking that 11 of

the 16 patients who provided information regarding latency from last use to

emergency room (ER) presentation had a latency of 4 hours or longer. Only

five patients in the entire group had a blood cocaine concentration higher than

100 ng/mL, although 14 of the subjects were using smoked cocaine. However,

the urine and plasma BE levels are probably the best index of total cocaine

dose over the previous 24 hours and were typically very high. Six patients had

urine BE levels exceeding 100,000 ng/mL, and only five patients had levels

below 20,000 ng/mL. Five patients had plasma BE levels above 2,000 ng/mL,

and only five had levels below 600 ng/mL.

By contrast, Jeffcoat and colleagues (1989) measured plasma BE levels of

approximately 600 ng/mL after a 100-mg intranasal dose, and Ambre (1985)

measured plasma BE levels of approximately 1,000 ng/mL afler 150 mg

administered intravenously over a 3-hour period. Ambre has estimated that

patients with urine BE levels of 100,000 to 200,000 ng/mL had consumed a

total dose approaching 500 mg. Using Ambre’s nomogram, which is based

on very limited data, the subject with a urine BE level of 621,000 ng/mL

probably used a total cocaine dose exceeding 1,000 mg (Ambre 1985).

IMPLICATIONS FOR DEVELOPMENT OF A COCAINE ANTAGONIST FOR

EMERGENCY USE

The experience at SFGH indicates that patients who present themselves for

emergency treatment in most cases have not used the drug for several hours

or more. On presentation, the peak plasma cocaine level almost certainly has

passed, especially when drug use is by the IV or smoked route. The range of

blood cocaine levels on presentation is quite broad, extending from near

unmeasurable to levels well into those reported postmortem. Although the

TABLE 2. Eighteen outpatients with cocaine-related neurological

complications

Measure Mean Minimum Maximum

Blood cocaine level 136 ng/mL 1 ng/mL

Blood BE level 2,209 ng/mL 6 ng/mL

Urine cocaine level 7,704 ng/mL 69 ng/mL

Urine BE level 118,591 ng/mL 107 ng/mL

Latency last use 312 min 60 min

to ER visit

1,700 ng/mL

15,149 ng/mL

56,546 ng/mL

621,251 ng/mL

760 min

152
elimination half-life may be prolonged compared with healthy volunteers,

plasma cholinesterase activity typically falls within the normal range.

The majority of acute complications of cocaine use can be tentatively

categorized as (1) unmasking a previously unsuspected abnormality such

as a cerebral arteriovenous malformation or aneurysm; (2) idiosyncratic

complications not clearly related to magnitude of drug use at any particular

time, such as headache, stroke, and myocardial infarction; (3) complex

interactions of multiple drug use that span the spectrum of reported

complications; and (4) complications that are dose related and mimic those

observed in experimental animals given lethal doses of cocaine, such as

multiple seizures, ventricular arrhythmias, agitated delirium, and hyperthermia.

This last category is potentially treatable by a medication that would antagonize

the effects of cocaine. However, despite the lack of proven medication

interventions, Brody and coworkers (1990) found an acute mortality rate of

less than 1 percent, and only 24 percent required any type of short-term

pharmacological intervention in a consecutive series of 233 hospital visits for

cocaine-related medical problems. In addition, by the time a patient has

survived long enough to present for treatment, the peak cocaine level has

passed (cocaine body packers may be an exception because of prolonged

absorption). The most difficult aspect of treatment of cocaine-related

complications are the secondary effects set in motion by cocaine intoxication.

A good example of the complexity of treating cocaine complications are

cocaine-induced seizures. Near total selective depletion of either brain

dopamine or norepinephrine has no effect on cocaine-induced seizures.

The convulsant effects of cocaine are most likely related to its local anesthetic

effects. Comparison studies of amphetamine, cocaine, and lidocaine in

kindling paradigms have shown that cocaine effects on brain electrical

activity are similar to lidocaine (Russell and Stripling 1985). Lidocaine is an

anticonvulsant at low doses but is a potent convulsant at doses similar to those

required to produce convulsions with cocaine. Two factors greatly reduce the

blood level of local anesthetic required for seizure production: elevated body

temperature and decreased blood pH. Both are produced in the course of

cocaine poisoning in dogs as observed by Catravas and Waters (1981).

Merely placing the animals in a cold room at the time of cocaine administration

prevented the hyperthermia, seizures, and death that otherwise would be

produced by cocaine. Once elevated body temperature and lowered pH are

established, seizure therapy must include correction of metabolic abnormalities

and elevated temperature to be maximally effective.

153
Paradigms widely used in animal studies of antagonists of cocaine toxicity

include pretreatment with the drug to be tested, coadministration of the

antagonist and cocaine, and in a few studies, administration of the antagonist

following a predetermined dose of cocaine but before the onset of toxicity.

In only one study has the drug antagonist under study been administered

after the onset of cocaine toxicity. Derlet and Albertson (1989) found diazepam

to be highly effective in preventing cocaine seizures and death when given

before or very shortly after cocaine. Once cocaine seizures began, efficacy in

preventing death was reduced significantly.

Simple measures such as preventing or correcting elevated body temperature

can be remarkably effective in preventing death from cocaine toxicity. In

addition, on emergency presentation the diagnosis of a cocaine-related

problem may be inferred based on history and examination, but nondrug

causes also must be excluded. Until remedies become available that have

been proven effective in animal studies that closely mimic the ER presentation

of cocaine toxicity, treatment recommendations should follow currently accepted

management guidelines based on presenting symptomatology.

REFERENCES

Ambre, J. The urinary excretion of cocaine and metabolites in humans: A

kinetic analysis of published data. J Anal Toxicol 9:241-245, 1985.

Brody, S.L.; Slovis, C.M.; and Wrenn, K.D. Cocaine-related medical problems:

Consecutive series of 233 patients. Am J Med 88:325-331, 1990.

Catravas, J.D., and Waters, I.W. Acute cocaine intoxication in the conscious

dog: Studies on the mechanism of lethality. J Pharmacol Exp Ther 217:350-

356, 1981.

Derlet, R.W., and Albertson, T.E. Diazepam in the prevention of seizures and

death in cocaine-intoxicated rats. Ann Emerg Med 18(5):542-546, 1989.

Fischman, M., and Schuster, C. Cocaine self-administration in humans.

Federations Proc 41:241-246, 1982.

George, P.M., and Abernathy, M.H. Improved Ellman procedure for erythrocyte

cholinesterase. Clin Chem 29:365-368, 1983.

Jacob, P. III; Elias-Baker, B.A.; Jones, R.T.; and Benowitz, N.L. Determination

of BE and cocaine in biological fluids by automated gas chromatography.

J Chromatogr 417:277-286, 1987.

Jacob, P. III; Lewis, E.; Elias-Baker, B.A.; and Jones, R.T. A pyrolysis product,

anhydroecgonine methyl ester, (methylecgonidine) is in the urine of cocaine

smokers. J Anal Toxicol 14:353-357, 1990.

Jeffcoat, A.R.; Perez-Reyes, M.; Hill, J.M.; Sadler, B.M.; and Cook, C.E.

Cocaine disposition in humans after intravenous injection, nasal insufflation

(snorting), or smoking. Drug Metab Dispos 17:153-159, 1989.

154
Russell, R., and Stripling, J. Monoaminergic and local anesthetic components

of cocaine’s effect on kindled seizure expression. Pharmacol Biochem

Behav 22:427-434, 1985.

ACKNOWLEDGMENTS

This chapter was prepared with support from National institute on Drug Abuse

grant DA-01696. Paula D. Mueller, M.D., Reese T. Jones, M.D., and Laura

Goldbaum, R.N., assisted with data collection and analysis.

AUTHOR

Michael C. Rowbotham, M.D.

Assistant Professor

Departments of Neurology and Anesthesia

University of California, San Francisco

M794, Box 0114

San Francisco, CA 94143

155
Potential Adverse Interactions of

Drugs With Cocaine

Paul R. Pentel and Timothy N. Thompson

INTRODUCTION

The purpose of this chapter is to consider some potentially toxic interactions

of cocaine with other drugs, focusing on drugs that are being evaluated as

treatments for chronic cocaine abuse. Acute cocaine toxicity is an important

clinical problem, but the opportunity to intervene medically is limited by the

brief duration of signs and symptoms. Many patients die prior to receiving

medical attention (see Wetli, this volume). In the emergency department,

toxicity typically resolves rapidly with supportive care. In patients with sequelae

such as myocardial infarction or stroke, these events usually have occurred

prior to medical intervention. Therefore, new treatments for acute cocaine

toxicity can be expected to have a limited impact on morbidity and mortality

and must necessarily be supplemented with preventive measures. One area

in which prevention could have an impact is the interaction of cocaine and

other drugs that may be chronically administered to cocaine abusers to help

maintain abstinence and prevent relapse. During inpatient studies, these

drugs often are coadministered with cocaine to determine their effects. During

outpatient studies or in clinical use, although abstinence is the goal, subjects

undoubtedly use cocaine at times, making it important to identify, understand,

and prevent any adverse interactions between cocaine and these drugs. This

chapter describes selected examples of potential interactions.

DRUGS THAT ACT ON DOPAMINERGIC NEUROTRANSMISSION

A variety of data suggest that dopamine is an important mediator of cocaine

self-administration and of its discriminative stimulus properties (Witkin et

al. 1991; Ritz et al. 1987). As a result, drugs that modify dopaminergic

neurotransmission are of interest as potential treatments for cocaine abuse.

Both agonists and antagonists have been studied in this regard-agonists

because they might mimic the effects of cocaine and act as a cocaine

substitute and antagonists because they might reduce cocaine’s reinforcing

effects. A few such drugs (bromocriptine, amantadine, flupenthixol) have been

156
studied in humans (Giannini and Billet 1987; Dackis et al. 1987; Gawin et al.

1989a). No important adverse effects have been noted; however, these

studies were designed primarily to test efficacy rather than toxicity, and

adverse interactions might not be detected for several reasons. First, the

numbers of patients and duration of these initial studies have been limited.

Second, in an outpatient setting it is not possible to monitor patients at the

time they use cocaine or to know how much cocaine they are using. An

exaggeration of cocaine’s effects (such as increased hypertension or

tachycardia) would be difficult or impossible to discern in this setting, and it

is likely that only a markedly symptomatic interaction would be detected.

An additional limitation of these trials is that any cocaine use that occurs

typically involves recreational doses. A clinically important adverse interaction

is presumably more likely if a large or toxic dose of cocaine is used. Because

the use of such large cocaine doses is less common than the use of recreational

doses, it is difficult to study the possibility of interactions involving high doses

of cocaine. Therefore, the lack of reported adverse interactions in these

studies is encouraging but should be considered preliminary.

Additional data from animal studies suggest that adverse interactions could

occur. In studies of rodents, the toxic end points most often used are seizures

and lethality; therefore, the doses of cocaine used are quite high. Whether the

results of such studies also would apply to the use of recreational doses of

cocaine as well is not clear. Nevertheless, these studies provide useful insights

into the types of interactions that might be expected and their mechanisms.

George and Ritz (in press) studied the lethality of cocaine and a variety of

structurally and behaviorally similar compounds in mice, as well as their binding

affinities for several neurotransmitters, receptors, and transporters. Lethality

was correlated significantly with binding affinity for the dopamine transporter,

suggesting that lethality in this paradigm is directly related to the synaptic

dopamine concentration (figure 1). If increasing the synaptic dopamine

concentration enhances the lethality of cocaine-like compounds, then dopamine

receptor agonists or antagonists might be expected to increase or decrease

(respectively) cocaine lethality. In support of this hypothesis, a protective effect

of pretreatment with the D1

 antagonist SCH 23390 has been demonstrated for

cocaine lethality in several studies of mice (George and Ritz, in press) and rats

(Derlet et al. 1990a; Witkin et al. 1989) (figure 2). In each case the protective

effect of SCH 23390 was modest, suggesting that mechanisms other than D1

agonist activity also contribute to lethality. However, D2 receptor antagonists

such as haloperidol or spiperone have not reduced the lethality of cocaine in

mice, rats, or dogs (Witkin et al. 1989; Derlet et al. 1989; Catravas and Waters

1981).

157
FIGURE 1. Relationship between the lethal potencies in mice of cocainerelated compounds and their affinities for 3H-mazindol binding

sites on dopamine transporters (p=0.03). The drugs represented

are (1) WIN 35,428, (2) (-)norcocaine, (3) (-)cocaine, (4) WIN

35,062-2, (5) procaine, (6) (+)pseudococaine, (7) tropococaine,

and (8) (-)pseudococaine.

SOURCE: George, F.R., and Ritz, M.C. Cocaine-induced lethality is

associated with interactions between dopamine transporters and

muscarinic and sigma receptors. J Pharmacol Exp Ther, in press.

Copyright 1992 by American Society for Pharmacology and

Experimental Therapeutics (Baltimore).

In contrast to their relationship to lethality, dopamine receptors did not

appear to be important mediators of cocaine-induced seizures. Ritz and

George (in press) found no correlation between the seizure ED, and the

dopamine transporter binding in mice of the same series of cocaine-like

compounds studied by George and Ritz (in press). Derlet and colleagues

(1990b) found a small protective effect of the D2

 antagonist haloperidol on

cocaine-induced seizures in rats, but others have found no protective effect

of either D1

 or D2 blockers in mice (Ritz and George, in press), rats (Witkin et al.

1989), or dogs (Catravas and Waters 1981). Thus, D1 or D2 blockers do not

appear to reduce cocaine-induced seizures in a variety of species, and the

158
FIGURE 2. The D1

 antagonist SCH 23390 prevented cocaine-induced

lethality in rats. The LD50 was increased from 79.7 to 100.1 mg/kg

(95-percent) confidence interval 91.5-109.5 mg/kg) in the presence

of 0.3 mg/kg SCH 23390. : effects of cocaine alone. : effects

of cocaine in SCH 23390-treated rats. Each point represents

effects in at least six animals.

SOURCE: Witkin, J.M.; Goldberg, S.R.; and Katz, J.L. Lethal effects of

cocaine are reduced by the dopamine-1 receptor antagonist SCH

23390 but not by haloperidol. Life Sci 44:1285-1291, 1989.

Copyright 1989 by Pergamon Press plc. (Elmsford, NY).

beneficial effect of D1

 blockers on cocaine lethality cannot be attributed to a

reduction in seizures.

The mechanism by which D1 antagonists reduce cocaine lethality is unclear.

In squirrel monkeys, SCH 23390 did not reduce cocaine-induced tachycardia

or hypertension. Haloperidol produced a small reduction in tachycardia, but

this did not appear to be mediated by dopaminergic blockade (Schindler et al.

1991). The D2

 antagonist pimozide did not reduce hypertension or tachycardia

due to cocaine in dogs (Catravas and Waters 1981). Thus, there are no data

to suggest a salutary cardiovascular effect of dopaminergic blockade as the

mechanism by which these drugs reduce cocaine’s lethality.

159
Also of interest are the potential interactions of cocaine with drugs that

might cause its behavioral effects, such as agitation or delirium. In humans,

behavioral toxicity is a major contributor to cocaine’s morbidity and mortality.

Drug interactions that increase the undesirable behavioral effects of cocaine

therefore could increase its overall toxicity. Behavioral toxicity is difficult to

study in animals because it is difficult to know whether an effect (such as a

change in locomotor activity) represents a desirable pleasant effect or an

undesirable toxic effect. It is reasonable to postulate, on the basis of clinical

observations, that the behavioral effects most likely to be toxic are those

associated with very high cocaine doses. Several animal studies are of

interest in this regard, as they demonstrate different behavioral effects of

cocaine at low and high doses. Katz and Witkin (1991) found that low cocaine

doses increased fixed-interval (FI) responding maintained under schedules

of electric shock presentation in squirrel monkeys, whereas high doses (1 to

3 mg/kg) decreased responding. The D1 antagonist SCH 23390 attenuated

both low- and high-dose responding, whereas the D2 antagonist haloperidol

reduced only the low-cocaine-dose response. Spealman (1990), using a

similar paradigm, reported similar results with the D, antagonist SCH 39166

but found that the D2 antagonist YM 09151-2 also decreased the high-dose

cocaine response. Thus, D1 and possibly D2 antagonists may decrease some

behaviors associated with high, potentially toxic doses of cocaine.

Taken together, these data generally support the hypothesis that dopaminergic

neurotransmission modulates cocaine lethality and some of its high-dose

behavioral effects and that decreasing dopaminergic stimulation is generally

protective. These data also suggest that increasing dopaminergic stimulation

might aggravate cocaine toxicity. This possibility is of concern because

dopaminergic agonists have been proposed and studied as treatments for

chronic cocaine abuse. Amantadine, bromocriptine, and flupenthixol have

been administered to outpatients (Giannini and Billet 1987; Dackis et al.

1987; Gawin et al. 1989a). No adverse effects were reported, but as noted

above, such events might not be detected in this type of outpatient study.

Few animal data are available. Howell and Byrd (1991) studied the effects

of the selective dopamine uptake inhibitor GBR 12909 in squirrel monkeys

using a paradigm similar to the study of Katz and Witkin (1991) described

above, which distinguishes low- and high-dose cocaine effects. GBR 12909

exaggerated the effects of high-dose cocaine on FI responding (figure 3). If

this behavior represents a toxic effect of cocaine, these data are consistent

with the hypothesis that dopamine uptake blockade aggravates cocaine’s

behavioral toxicity. In mice, the dopamine transporter inhibitor buproprion

has been reported to increase cocaine lethality, but only modestly (Ritz and

George 1992). These data are quite preliminary, but the possibility of a toxic

interaction between cocaine and dopaminergic agonists or transporter inhibitors

clearly warrants further study.

160
FIGURE 3. Effects of cocaine administered a/one (o) or in combination with

GBR 12909 (filled symbols) on mean (±SEM) rates of lever

pressing maintained by an FI-300 schedule in a group of three

monkeys. GBR 72909 exaggerated the effects of both low and

high doses of cocaine. The effects of the pretreatment drug

administered alone are shown with the filled symbols to the left

of the dose-effect curves. S=saline.

SOURCE: Howell, L.L., and Byrd, L.D. Characterization of the effects of

cocaine and GBR 12909, a dopamine uptake inhibitor, on behavior

in the squirrel monkey. J Pharmacol Exp Ther 258:178-185, 1991.

Copyright 1991 by American Society for Pharmacology and

Experimental Therapeutics (Baltimore).

DRUGS THAT ACT ON SEROTONERGIC NEUROTRANSMISSION

Drugs that modify serotonergic neurotransmission may alter the behavioral

effects of cocaine (Carroll et al. 1990a; Pollack and Rosenbaum 1991) and

are of interest as potential therapies for cocaine abuse. With regard to

toxicity, animal data suggest that serotonergic neurotransmission is related

161
to susceptibility to cocaine-induced seizures in mice. Ritz and George (in

press) found that the seizure ED, for a variety of cocaine-like compounds

was correlated significantly with their affinities for the serotonin transporter,

suggesting that seizures may be related to the synaptic serotonin concentration.

These data suggest that serotonergic antagonists might prevent seizures,

whereas serotonergic agonists might aggravate seizures. In support of this

hypothesis, administration of the serotonin transporter inhibitor fluoxetine

enhanced cocaine-induced seizures in mice, whereas the serotonin 5-HT2

receptor antagonist cinanserin reduced seizures (Ritz and George, in press).

However, Tortella and colleagues (1992) using Swiss Webster mice, found

no effect of cinanserin on cocaine-induced seizures, suggesting that strain

differences in this response may exist. It is clear that strain differences exert

a major influence on cocaine-kindled seizures and on seizures due to acute

cocaine administration (Marley et al. 1991; George 1991). These data illustrate

the problem of species or strain differences (see discussion of desipramine

below) in response to cocaine or cocaine-drug interactions and underscore the

importance of studying and comparing responses in different species or strains.

DESIPRAMINE

The tricyclic antidepressant desipramine has been studied as an adjunct to

reducing cocaine use in patients (Gawin et al. 1989b). Unlike many of the

drugs discussed above, desipramine has been in clinical use for decades. A

great deal is known about its pharmacology, some aspects of which suggest

that it could interact adversely with cocaine. Desipramine is an inhibitor of the

norepinephrine transporter. In humans, a therapeutic dose of desipramine

prolongs the plasma half-life of norepinephrine (Esler et al. 1981) and a

therapeutic dose of the closely related tricyclic antidepressant imipramine

exaggerates the tachycardia and hypertension produced by norepinephrine

or epinephrine (Boakes et al. 1973). Cocaine enhances sympathetic tone

and inhibits the norepinephrine transporter. On the basis of these actions,

even therapeutic doses of desipramine might be expected to exaggerate the

sympathomimetic effects of cocaine. In addition, toxic doses of desipramine

can cause seizures and tachycardia (Ellison and Pentel 1989), as can toxic

doses of cocaine. An adverse interaction of high doses of desipramine and

cocaine therefore might be expected as well.

A potentially adverse interaction between cocaine and desipramine

in humans has been observed by Fischman and colleagues (1990).

Desipramine was administered to cocaine abusers for 3 weeks at doses

sufficient to maintain therapeutic serum concentrations. Subjects were

allowed to self-administer intravenous (IV) cocaine before and after the 3

weeks of desipramine. Treatment with desipramine did not alter the amount

162
of cocaine self-administered but did exaggerate the maximum heart rate and

diastolic blood pressure observed at any dose (figure 4). This was caused

by both an increase in these parameters due to desipramine alone and

an additional increase due to the cocaine. Although these data clearly

demonstrate an interaction between cocaine and desipramine, its clinical

importance is not known. No untoward clinical events were observed in

this study despite the higher blood pressures and heart rates observed after

desipramine, but the cumulative cocaine doses administered were lower than

many cocaine abusers administer on their own. It would be of great interest to

know whether desipramine also exaggerates the effects of larger or potentially

toxic doses of cocaine, but this question is difficult to study in humans. Animal

data are limited. Jackson and colleagues (1990) reported a protective effect

of desipramine pretreatment on cocaine lethality in mice, whereas Ritz and

George (in press) noted an increase in lethality from cocaine after desipramine

pretreatment in C57BL mice. Blood pressure and heart rate were not monitored

in either study. Because these protocols used similar doses of desipramine and

cocaine, differing results could be due to the use of different strains of mice.

Taken together with the data from humans, these studies suggest that caution

should be observed with the concurrent use of desipramine and cocaine, but

the data do not allow an estimate of the risk posed by desipramine used in an

outpatient setting.

Desipramine also may exacerbate the behavioral toxicity of cocaine. In

Fischman and colleagues’ 1990 study (referred to above), ratings of cocaine’s

pleasant effects such as “positive mood” and “vigor” were decreased by

desipramine, whereas unpleasant effects such as “anxiety” and “anger” were

increased. Desipramine therefore shifted the profile of cocaine’s subjective

effects toward those that are less pleasant. The clinical consequences of this

effect are not known, but these observations do raise the question of whether

desipramine might increase undesirable or harmful behaviors due to cocaine.

CARBAMAZEPINE

The anticonvulsant carbamazepine is being evaluated as a treatment for

cocaine abuse. An adverse interaction with cocaine has not been noted

in outpatient trials (Halikas et al. 1991), but inpatient and animal studies

suggest that further study of this possibility is warranted. Like desipramine,

carbamazepine can reduce norepinephrine turnover in vitro (Waldmeier et

al. 1984), but it is probably less potent in this regard. Despite considerable

experience with its clinical use, adverse interactions between carbamazepine

and sympathomimetic amines have not been reported. Carbamazepine at

toxic doses can cause seizures or tachycardia (Sullivan et al. 1981), as can

163
FIGURE 4. Effects of desipramine pretreatment on responses to IV cocaine

in human subjects. Closed bars: before desipramine. Hatched

bars: during desipramine. Data are the mean percent of each

session that heart rate was above 137 (top panel), diastolic blood

pressure was above 100 mmHg (middle panel), and systolic blood

pressure was above 170 mmHg (bottom panel). Cocaine doses

represent the size of an individual dose for each multiple dose

session. Desipramine did not alter the total dose of cocaine

164
administered at each session but did increase the percent of

each session during which the heart rate and diastolic blood

pressure exceeded the specified values.

SOURCE: Fischman, M.W.; Foltin, R.W.; Nestadt, G.; and Pearlson, G.D.

Effects of desipramine maintenance on cocaine self-administration

by humans. J Pharmacol Exp Ther 253(2):760-770,1990.

Copyright 1990 by American Society for Pharmacology and

Experimental Therapeutics (Baltimore).

cocaine, so that an adverse interaction with excessive doses of both drugs

might be expected. However, at therapeutic doses of carbamazepine (and

recreational doses of cocaine), an adverse interaction would not be anticipated.

Nevertheless, one study of human subjects suggests that a therapeutic dose

of carbamazepine could exaggerate the blood pressure and heart rate effects

of cocaine. Hatsukami and coworkers (1991) administered carbamazepine

400 mg daily to subjects to achieve a therapeutic serum concentration of the

drug, or placebo, for 5 days. Subjects then received a single dose of smoked

cocaine (40 mg). Heart rate and diastolic blood pressure increased more after

carbamazepine than after placebo (figure 5). Although this study examined

only the short-term use of carbamazepine and a single dose of cocaine, it

suggests that blood pressure and heart rate should be monitored carefully

when carbamazepine and cocaine are coadministered. The potential use of

carbamazepine in an outpatient setting presents the same problem discussed

above regarding desipramine: Subjects might use much larger or toxic doses of

cocaine, and the interaction of these high doses of cocaine with carbamazepine

cannot be readily studied in humans.

In rats, both an increase and a decrease in cocaine-induced seizures have

been reported with carbamazepine. Weiss and colleagues (1990) found that

carbamazepine reduced kindled seizures produced by daily doses of cocaine

(40 or 50 mg/kg) and its associated lethality. This effect was observed,

however, only when carbamazepine was administered chronically prior to

cocaine. Intermittent dosing of carbamazepine had the opposite effect,

increasing seizures and lethality. An increase in cocaine toxicity during

carbamazepine treatment also has been noted by Carroll and coworkers

(1990b). In this study, rats were allowed to self-administer cocaine for 5

days and then were given carbamazepine. The introduction of carbamazepine

resulted in seizures and lethality. The toxic interaction was confined to those

groups of rats receiving the highest doses of cocaine and carbamazepine.

165
FIGURE 5. Effects of carbamazepine pretreatment (circles) vs. placebo

(squares) on responses to a single 40-mg dose of smoked

cocaine in human subjects. Heart rate, diastolic blood pressure,

and the rate-pressure product were significantly higher after

carbamazepine pretreatment (p<0.05).

SOURCE: Hatsukarni D.; Keenan, R.; Halikas, J.; Pentel, P.R.; and Brauer,

L.H. Effects of carbamazepine on acute responses to smoked

cocaine-base. Psychopharmacology 104:120-124, 1991. Copyright

1991 by Springer-Verlag (Heidelberg).

166
These data suggest that high doses of carbamazepine may increase the toxicity

of high doses of cocaine in rats but that the occurrence of this interaction may

depend on the manner and timing of carbamazepine administration. This

complexity illustrates the difficulty of extrapolating the results of such animal

studies to humans.

CONCLUSIONS

Predicting clinically important interactions between cocaine and potential drug

therapies for cocaine abuse is important but difficult for the following reasons.

1. Both animal and human data are limited. A few studies are available

regarding potentially toxic drug-cocaine interactions. Many small animal

studies use end points such as seizures or death that, although useful,

may not comment on the proximate mechanisms of toxicity (e.g.,

hypotension, arrhythmia, respiratory depression). Many animal studies

of cocaine toxicity involve short-term administration of very high doses

of the interacting drug. Whether these results also would apply to the

therapeutic use of the potentially interacting drug is not clear.

Studies of potential interactions in humans have inherent limitations. The

few inpatient studies available involved low doses of cocaine and only

therapeutic doses of the potentially interacting drug. Interactions reported

from such studies between cocaine and desipramine or carbamazepine

have been small in magnitude, and it is not clear whether they are of

clinical importance. The important question of whether larger doses of

cocaine would produce a greater interaction is difficult to study safely in

humans. The possibility of an adverse interaction due to an excessive

dose of the interacting drug, which must also be considered in the setting of

drug abuse, is likewise difficult to study.

Outpatient trials of drug treatments for cocaine abuse generally have few

subjects and have been of short duration, limiting their ability to detect

adverse events. Equally important in the outpatient setting, subjects

cannot be monitored at the time they are using cocaine.

2. Species or strain differences may exist. Contrasting reports of whether

desipramine enhances or reduces cocaine lethality in rats or whether

cinanserin inhibits cocaine-induced seizures in mice may be due in part

to strain differences. If this is the case, the choice of appropriate animal

models for such studies will be challenging.

167
3. Cocaine-drug interactions also may be dependent on the experimental

paradigm. For example, the opposite effects of carbamazepine on cocaineinduced seizures observed by Carroll and coworkers (1990b) and Weiss

and coworkers (1990) could be due to the order in which carbamazepine

and cocaine were administered or the chronicity of carbamazepine

administration.

Further study of potential drug-cocaine interactions is clearly needed, with

particular focus on the selection of appropriate animal models, comparisons of

different strains and species, attention to dose-response relationships for both

cocaine and the interacting drug, and the use of inpatient studies with human

subjects to supplement outpatient trials of drug treatment for cocaine abuse.

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ACKNOWLEDGMENT

The work described in this chapter was supported in part by National Institute

on Drug Abuse grant DA-05844.

170
AUTHORS

Paul R. Pentel, M.D.

Associate Professor of Medicine and Pharmacology

Department of Medicine

University of Minnesota Medical School

Hennepin County Medical Center

701 Park Avenue South

Minneapolis, MN 55415

Timothy N. Thompson, M.D.

Research Associate

Department of Psychiatry

University of Minnesota Medical School

Diehl 625

515 Essex Street Southeast

Minneapolis, MN 55455

171
The Pathology of Cocaine:

Perspectives From the Autopsy Table

Charles V. Wetli

INTRODUCTION

As a local anesthetic, cocaine has three unique side effects that account for the

majority of pathologic changes seen in individuals who have died from its toxic

effects. The first reaction is that of vasoconstriction. Initially, it was thought that

this phenomenon occurred only at the site of application of cocaine. However,

more recent evidence indicates that the vasoconstrictive properties of cocaine

are much more widespread: Coronary vasospasm has been demonstrated, and

cocaine also may cause cerebrovasospasm and cutaneous vasoconstriction.

The other two properties of cocaine that are responsible for fatal reactions

and sudden death are the sometimes unpredictable stimulation of the central

nervous system (CNS) and the cardiovascular system.

About 75 years ago, the adverse reactions attributed to cocaine included

perforations of the nasal septum, unpredictable psychotic reactions (often

violent), hyperthermia, convulsions, and sudden death by unknown

mechanisms. However, these effects were anecdotal and derived from

observations made at the turn of the century. Nonetheless, the overall

impression in the earlier part of this century was that cocaine was a dangerous

drug (McLaughlin 1973), which led to the passage of the Harrison Narcotics

Act in 1914. However, the early empirical observations by no means met the

scientific standards of the 1970s. Cocaine was presumed to be safe since

there was no current scientific evidence to show that it was dangerous.

Likewise, since cocaine use did not lead to “physical” dependency, it was

presumed to be nonaddictive. Consequently, the recreational use of cocaine

rapidly increased in the late 1970s and well into the 1980s. Therefore,

knowledge of the pathologic consequences of virtually unrestricted cocaine use

is derived from the relatively limited experience of the past 10 to 15 years.

The death rate in Dade County, FL, has increased steadily since the late

1970s (Mittleman and Wetli 1984). In 1980 the drug was relatively scarce

and selling for $100 to $125 per gram; it was approximately 15 percent pure.

172
In summer 1983 the death rate increased as the result of increased cocaine

production in South America. During that summer, the black market wholesale

price of cocaine dropped from $50,000 to $22,000 per kilogram. This resulted

in greater availability, lower price, and increased purity (approximately 35

percent), which in turn increased the death rate to approximately two per month.

This rate persisted until 1986, when the availability and purity of street cocaine

again increased and smokable “crack” cocaine became popular. The death rate

in Dade County increased to about one per week and, with some fluctuation,

has remained at about that level.

For the first half of the 1980s the vast majority of deaths due to cocaine toxicity

were from ingesting the hydrochloride salt of cocaine. However, since 1986,

increasing numbers of deaths have been associated with the use of free base

cocaine, commonly known as crack or “rock” cocaine. Those who died from the

use of cocaine hydrochloride often had blood levels of 3 to 5 mg/L at the time

of autopsy; with crack cocaine, deaths are associated with much lower blood

concentrations of cocaine, often less than 1 mg/L.

SNORTING COCAINE

In the late 1970s and early 1980s it was commonly believed that one could

not insufflate (“snort”) enough cocaine to die unless a tremendous quantity

was ingested. Indeed, there were occasions when individuals died with

obvious cocaine particles in their nose or moustache, and a few had a nasal

cavity completely packed with the drug. However, the more common scenario

involved an individual who was snorting cocaine, often in a party atmosphere,

who suddenly experienced a grand mal seizure that was followed rapidly by

respiratory collapse and death (Wetli and Wright 1979). The reaction often

occurred without warning about 25 to 30 minutes after the last line of cocaine

was snorted. The convulsions often were associated with severe bite marks

of the lower lip, the tongue, or the cheek. Prodromal symptoms sometimes

appeared (e.g., light sensitivity due to mydriasis, agitation, tactile and/or visual

hallucinations, hyperthermia). Cocaine-induced hyperthermia may be extreme

(108 °F or more), and at the scene of death there is sometimes evidence

that cold showers, wet towels, or ice were used in a frantic attempt to lower

the body temperature.

Early observations of deaths from snorting cocaine suggested that these

individuals did not necessarily die of a true overdose of the drug. When

information could be obtained, they appeared to have been snorting the

same amount of drug as they normally would. A possible explanation for

the death is provided by the theory of reverse tolerance or “kindling”: an

accentuated response to the usual dose of a drug.

173
The time delay of 25 to 30 minutes between the last dose of the drug and the

terminal seizure activity was thought to be related to the delayed absorption

of cocaine from the nasal passages. The initial effect of cocaine, besides

providing local anesthesia, is vasoconstriction, which limits the amount that

is absorbed. It was thought that an unexpected, sudden vasodilatation led

to a surge of cocaine into the blood and then into the CNS, initiating the

convulsions.

Perforations of the nasal septum frequently are observed at the time of autopsy.

Speculum examination of the nasal septum often discloses perforations that

range from only a few millimeters in diameter to complete erosion of the nasal

septum (figure 1). Three factors appear to be involved in these perforations of

the nasal septum. One is the intermittent vasoconstrictive effect, which limits

oxygen and nutrients to the area. Another contributory factor may be the

dissociation of cocaine hydrochloride into a weak base and a strong acid. The

third possibility (based on data from animal experiments), probably the most

relevant, is that cocaine is directly toxic to capillary endothelial cells; destruction

of the capillaries results in ischemia and tissue breakdown. Histologically, the

FIGURE 1. Perforation of the nasal septum from chronic nasal insufflation of

cocaine hydrochloride

174
margins of these perforations have the usual characteristics of a coagulation or

ischemic necrosis with a variable chronic inflammatory cell infiltrate.

COMPLICATIONS OF THE INTRAVENOUS USE OF COCAINE

Any intravenous (IV) drug abuser has the potential of contracting a variety

of diseases (e.g., local abscesses, bacterial endocarditis, malaria, acquired

immunodeficiency syndrome). However, unlike the heroin addict who develops

perivenous scars from the concomitant injection of excipients (starch or talc)

from oral medication, the IV cocaine user paradoxically develops subcutaneous

bleeding. The very fresh cocaine injection site appears as a needle puncture

mark surrounded by a halo of normal skin, which in turn is surrounded by a

very prominent ecchymosis. It is thought that this particular configuration is the

result of the vasoconstrictive property of cocaine creating the halo of normalappearing skin around the puncture mark with an acute backup of blood within

the capillaries causing their rupture and subsequent ecchymoses. In time, the

ecchymoses coalesce, and the blood pigment eventually breaks down and

disappears (like any other bruise) and does not leave a scar. The only scars

observed with chronic cocaine users are in individuals who never rotate

injection sites and repeatedly traumatize one area over a period of years.

Scars typical of those seen in heroin addicts have never been observed among

those who restrict their IV drug abuse to cocaine.

A curious observation made of IV cocaine users is the appearance of numerous

round and oval atrophic scars, often in sites of predilection for IV injection.

These seem to be associated almost exclusively with IV cocaine users. They

may be healed abscesses or healed areas of cutaneous gangrene (occurring

for basically the same reasons that individuals may get perforations of the nasal

septum from chronic nasal insufflation of cocaine). Cutaneous ulcers are seen

occasionally with pearly gray epidermal margins, indicative of attempts at repair.

This tends to support the theory of localized cutaneous gangrene. However,

sometimes these round and oval scars are in areas that would be unlikely,

or impossible, for a person to inject (such as the back). This suggests that

another possibility for the etiology of these scars is the lack of adequate healing

of unrelated local infections because of intermittent cocaine-induced peripheral

vasoconstriction. That is, intermittent vasoconstriction would delay the healing

of an infection by impeding the blood flow to the infected area. Prolonged

chronic inflammation then could lead to formation of the scars.

Another cutaneous reaction associated predominantly with IV use of

cocaine (and heroin users, if they also use cocaine) is the phenomenon of

necrotizing fasciitis (Wetli 1987). In these individuals, large areas of skin

slough from presumed injection sites. The area of skin slough may cover an

175
entire forearm or side of the lower extremity. The skin slough is usually full

thickness, and erosions down to the muscle and tendons are not unusual.

A cellulitis occasionally accompanies the process. For unknown reasons, the

necrotizing fasciitis often is associated with a rather pronounced lymphedema

of the affected extremity. Rarely, partial and complete autoamputations have

resulted from extensive and untreated necrotizing fasciitis.

ACUTE CARDIOVASCULAR EFFECTS OF COCAINE

It is now well recognized that cocaine, regardless of the route of administration,

can exacerbate any underlying cardiovascular abnormality, including

hypertension. The acute cardiovascular effects of cocaine are manifested

as ischemic damage to the myocardium, aortic dissections, and the rupture

of intracranial vascular malformations and saccular aneurysms. In cases

of apparent natural death where a contributory role of cocaine can be

demonstrated, cocaine is listed as a contributory cause of the death, and

the manner of death then becomes listed as accidental (Mittleman and Wetli

1987).

The mechanism for the ischemic damage to the myocardium is based on an

increased heart rate and, possibly, rhythm disturbances that could aggravate

any underlying arteriosclerotic coronary artery disease. However, cocaine

also has been demonstrated to directly constrict the coronary arteries and,

thus, may precipitate ischemic myocardial damage even in the face of

morphologically normal vessels (Lange et al. 1989).

Hypertensive crisis precipitated by cocaine may be quite dramatic and

associated with the various complications of hypertension, such as ruptured

vascular malformations. Should the individual survive for a period of time, he

or she may encounter renal failure from rhabdomyolysis (Roth et al. 1988),

most likely the result of increased muscular activity from convulsions and/or

hyperthermia.

CARDIOVASCULAR EFFECTS OF CHRONIC USE

Cumulative experience with the chronic, relatively unrestricted use of

cocaine has spanned approximately a decade. During this time, the scientific

community has had a growing suspicion that the chronic use of cocaine may

result in irreversible cardiovascular damage. Proposed mechanisms include

direct damage to the myocardial fibers by means of contraction-band necrosis

(catecholamine effect) (Karch and Billingham 1988) intimal proliferation due

to intermittent coronary vasospasm (Simpson and Edwards 1986), and

176
accelerated atherosclerosis (Langer et al. 1989). Reports also have linked

the use of cocaine to dilated cardiomyopathies (Duell 1987).

EFFECTS ON THE CENTRAL NERVOUS SYSTEM

The most frequent manifestation of cocaine use in the CNS is subarachnoid

hemorrhage (Nolte and Gelman 1989) due to ruptured vascular malformations

or saccular aneurysms. Although intracranial vasospasm may result in

ischemic changes (Rowbotham and Lowenstein 1990), these have not yet

been documented at the time of autopsy.

A rare complication that has been reported among IV cocaine and

amphetamine users is a very rapidly progressive, almost universally fatal,

primary fungal cerebritis (Wetli et al. 1984; Micozzi and Wetli 1985). The

organisms isolated from these individuals are generally opportunistic fungi

(e.g., Rhizopus species). The syndrome generally begins with nonspecific

but severe neurologic symptoms such as unsteady gait, double vision, or

slurred speech. This rapidly progresses to coma within approximately 24

hours, and death generally ensues within 48 to 72 hours. The victims do

not appear to have human immunodeficiency virus infection. Although the

etiology is not certain, one possibility is that frequent intermittent constriction

of the cerebral microvasculature may cause microscopic foci of necrosis of

the CNS that would provide the “fertile soil” for these opportunistic fungi.

PSYCHIATRIC COMPLICATIONS

It is well known that cocaine may exacerbate any underlying psychoneurotic

abnormality (Post 1975). Generally, however, these abnormalities disappear

as the blood level of cocaine diminishes. Morphologic expressions of these

psychiatric abnormalities are obviously indirect for the most part. Occasionally,

prominent scratches and abrasions from formication may be seen. Cocaineinduced paranoia has been known to include fatal, sometimes bizarre behavior:

Some individuals have run from a domicile only to drown in a canal or other

body of water; others have cringed in a closet while a small fire on the stove

generated enough carbon monoxide to kill them; and others have been

accidentally shot while fending off imaginary attackers.

The most serious psychiatric sequelae of cocaine abuse, however, is excited

delirium, which may be associated with sudden death (Wetli and Fishbain

1985). Cocaine-induced excited delirium generally is manifested as the sudden

onset of paranoia, followed shortly by violent activity generally directed toward

objects, particularly glass (windows, mirrors). Typically, the individuals will strip

off all their clothing and run through a neighborhood yelling, shouting, and

177
screaming. The bizarre and violent activity generally draws the attention of the

police who encounter somebody who is not only frankly psychotic but also has

a tremendous apparent increase in strength. After a fairly brief but extremely

violent struggle, the individual is restrained, Sudden death may occur moments

later or up to several minutes later. The mechanism of death is uncertain, but

in some cases electrocardiograms have revealed persistant cardiac electrical

activity but no pulse or blood pressure.

Sudden death from cocaine-induced excited deliruim presents problems from

two main perspectives. One is the perception of onlookers, including news

media, that the police are exerting unnecessary violence toward an individual.

The second is that once these people enter the emergency room, they pose a

threat of physical violence toward medical personnel. They must be restrained

and their symptoms treated. Most individuals will respond to symptomatic

treatment. However, hyperthermia appears to be a negative prognostic factor

and frequently is associated with sudden unexpected death (K. Schrank,

personal communication, July 1991).

In fatal cases, the autopsy findings are generally nonspecific and reveal only

injuries sustained during the struggle with the police officers and from fighting

against the restraints. Thus far, fatal injuries have not been reported with any

of these cases, although careful interpretation of the autopsy findings is often

necessary when extreme violence has been experienced (Mittleman and Davis

1991).

It is interesting to note that electrical stun gun devices and other injuries have

no significant effect on people in the throes of cocaine-induced excited delirium.

The presumption is that their sensation for pain is markedly diminished, a

phenomenon that also may account for their apparent increase in physical

strength.

CRACK COCAINE

Thus far, no physical abnormalities have been directly attributable to the use of

crack cocaine. However, in an indirect sense, the most prominent manifestation

of crack cocaine abuse is sudden death from violence, generally stemming from

attempts on the part of the crack cocaine addict to obtain sufficient funds for the

drug. Deaths include innocent victims, who are intentionally or unintentionally

killed during robbery attempts, and the addicts themselves. For example, crack

addicts have been electrocuted while stealing aluminum (to sell to recycling

plants) from electrical power plant substations.

178
EFFECTS ON THE FETUS AND NEWBORN

Although several anomalies have been associated with the maternal use

of cocaine, these may be coincidental. In the author’s experience at the

Dade County Medical Examiner’s office, the most common manifestation is

spontaneous abortion due to placental insufficiency or abruptio placentae at

approximately 28 weeks gestation. Autopsies of these fetuses thus far have

not revealed any consistent congenital anomalies.

THE BODY PACKERS

Ingesting packets filled with cocaine is a smuggling practice with intermittent

popularity. These individuals pack cocaine into a variety of containers,

including condoms or balloons. Each packet contains approximately 3 to

5 g of high-grade cocaine (figure 2). Up to .5 kg of cocaine has been

transported by this method. The individuals swallow the cocaine in a South

American country, generally Colombia, and board an airplane bound for the

United States. Prior to boarding the airplane, they generally have ingested

some sort of constipating agent, such as paregoric. The packets eventually

may break open because of poor packaging or may leak through the ties. Also,

the packaging material is often not waterproof, and consequently a dialysis

membrane is established: Water leaks into the packets, and the cocaine

dissolves and leaches out of the packet to be absorbed through

the gastrointestinal tract. The intent of the individuals is to clear customs

in the United States, find a hotel room, and pass the packets through the

gastrointestinal tract with the aid of laxatives, enemas, and fast foods

(usually hamburgers). However, cocaine toxicity may occur at any time,

and the smugglers suddenly may go into convulsions aboard the airplane,

in the customs area of the airport, or in the hotel room. After death, they

frequently have signs of terminal seizure activity (e.g., bite marks of the

lower lip) as well as hyperthermia (wet towels on their chest and postmortem

temperatures of more than 102 °F). Recently, there have been cases where

death resulted from the intestinal obstruction caused by these packets.

At autopsy, the packets may be retrieved from anywhere in the gastrointestinal

tract, especially the stomach and the cecum (Wetli and Mittleman 1981).

The mucosal lining of the gastrointestinal tract is frequently hemorrhagic

where it has come in contact with the drug. Most packets retrieved from these

individuals contain 3 to 5 g of cocaine compressed into a solid mass, wrapped

in plastic, and wrapped several more times with the tips of surgical gloves.

Some packets may be marked with “X’s,” possibly to denote various dealers

to whom the cocaine is to be delivered. In one recent case from Georgia, the

markings indicated which packets contained heroin and which contained only

cocaine (J. Burton, personal communication, May 1991).

179
FIGURE 2. These 76 packets of cocaine, totaling 429 g, were removed from

the gastrointestinal tract of a body packer. Each packet was

constructed with the tips of surgical gloves and tied with fishing

line. Some packets are darker colored due to staining with bile.

180
EMERGING PATTERNS

In 1980 a typical victim of cocaine toxicity was a 26-year-old white male who

died with grand mal seizure. At the autopsy table one might find a perforated

nasal septum, a bite mark of the tongue, and nonspecific change of asphyxia

(pulmonary edema, visceral petechiae) (Wetli and Wright 1979). Since then,

the view from the autopsy table has changed considerably (Mittleman and

Wetli 1991) as have the demographics of cocaine abuse (Escobeo et al. 1991).

More data are accumulating that strongly suggest the chronic use of cocaine

may result in permanent cardiovascular damage and, possibly, permanent

damage to the CNS. Whether this trend will manifest as premature, fatal,

cardiovascular catastrophes in the 1990s remains to be seen. Certainly, the

violent deaths related to cocaine addiction will be present for some time to

come.

REFERENCES

Duell, P.B. Chronic cocaine abuse and dilated cardiomyopathy. Am J Med

83:601, 1987.

Escobeo, L.G.; Ruttenber, A.J.; Agocs, M.M.; Anda, R.F.; and Wetli, C.V.

Emerging patterns of cocaine use and the epidemic of cocaine overdose

deaths in Dade County, Florida. Arch Pathol Lab Med 115:900-905, 1991.

Karch, S.B., and Billingham, M.E. The pathology and etiology of cocaineinduced heart disease. Arch Pathol Lab Med 112:225-230, 1988.

Lange, R.A.; Cigarroa, R.G.; Yancy, C.W.; Willard, J.E.; Pompa, J.J.; Sills,

M.N.; McBride, W.; Kim, A.S.; and Hillis, L.D. Cocaine-induced coronary

artery vasoconstriction. N Engl J Med 321:1557-562, 1989.

Langer, R.O.; Perry, L.E.; and Bement, C.L. Cocaine-induced blood vessel

injury in rabbits. Res Common Subst Abuse 10:209-223, 1989.

McLaughlin, G.T. Cocaine: The history and regulation of a dangerous drug.

Cornell Law Rev 58:537-573, 1973.

Micozzi, M.S., and Wetli, C.V. Intravenous amphetamine abuse, primary

cerebral mucormycosis, and acquired immunodeficiency. J forensic Sci

30:504-510, 1985.

Mittleman, R.E., and Davis, J.H. Death from custody? Am Soc Clin Pathol

Check Sample FP 91-2 30(2), 1991.

Mittleman, R.E., and Wetli, C.V. Death caused by recreational use-An update.

JAMA 252:1889-1893, 1984.

Mittleman, R.E., and Wetli, C.V. Cocaine and apparent “natural death.”

J Forensic Sci 32:11-19, 1987.

Mittleman, R.E., and Wetli, C.V. The pathology of cocaine abuse. Adv Pathol

4137-73. 1991.

181
Nolte, K.B., and Gelman, B.V. lntracerebral hemorrhage associated with

cocaine abuse. Arch Pathol Lab Med 113:812-814, 1989.

Post, R.M. Cocaine psychosis: A continuum model. Am J Psychiatry 132:225-

231, 1975.

Roth, O.; Alancor, F.J.; Fernandez, J.A.; Preston, R.A.; and Bourgoignie, J.J.

Acute rhabdomyolysis associated with cocaine intoxication. N Engl J Med

319:673-677, 1988.

Rowbotham, M.C., and Lowenstein, D.H. Neurological consequences of

cocaine use. Annu Rev Med 41:417-422, 1990.

Simpson, R.W., and Edwards, W.D. Pathogenesis of cocaine-induced ischemic

heart disease-Autopsy findings in a 21 -year-old man. Arch Pathol Lab Med

110:479-484, 1986.

Wetli, C.V. Fatal reactions to cocaine. In: Washton, A., and Gold, M., eds.

Cocaine-A Clinician’s Handbook. New York: Guilford, 1987. pp. 33-54.

Wetli, C.V., and Fishbain, D.A. Cocaine-induced psychosis and sudden death

in recreational cocaine users. J Forensic Sci 30:873-880, 1985.

Wetli, C.V., and Mittleman, R.E. The body packer syndrome-Toxicity following

ingestion and illicit drugs packaged for transportation. J Forensic Sci 26:492-

500, 1981.

Wetli, C.V.; Weiss, S.D.; Cleary, T.J.; and Gyori, E. Fungal cerebritis from

intravenous drug abuse. J Forensic Sci 29:260-268, 1984.

Wetli, C.V., and Wright, R.K. Death caused by recreational cocaine use. JAMA

241:2519-2522, 1979.

AUTHOR

Charles V. Wetli, M.D.

Deputy Chief Medical Examiner

Dade County Medical Examiner Department

One Bob Hope Road

Miami, FL 33136-1133

182
Summary Comments

Marian W. Fischman, Reese T. Jones, and James W. Cornish

A key question to be answered is whether there are sufficient untreated or

unresponsive cases of acute cocaine toxicity to warrant a National Institute

on Drug Abuse investment of funds and time. At present it appears that most

cases of cocaine-related toxicity seen in emergency rooms are treated

successfully. Only about one-quarter to one-third of the patients seen in

emergency rooms for acute cocaine toxicity are subsequently hospitalized.

For the most part these patients receive treatment directed at their presenting

symptom complexes (e.g., seizure, myocardial infarction, hyperthermia) and not

specific treatment for cocaine effects. In these cases, cocaine is the etiologic

agent that sets into motion a cascade of pathologic events that causes the

patient to seek medical care. Also, at times, it is very difficult to determine

whether a patient has taken cocaine prior to the medical emergency.

Some questions related to which currently used medications are most

efficacious remain to be studied, but overall, most acute cocaine toxicity

patients are successfully treated. It would be useful to disseminate emergency

medicine protocols that outline the current treatment approaches to patients

with acute cocaine toxicity.

The following are potential research areas:

1. Effects of other drugs in combination with cocaine

a. Other psychoactive substances

b. Potential treatment medications

c. Medications used to treat preexisting disorders

d. Order of drug interactions (precocaine, postcocaine, or together)

2. Animal models for cocaine toxicity

a. Determine which models are best to measure toxic effects

b. Study toxicity vs. route of administration

c. Evaluate genetic and strain differences for specific toxicities

183
d. Determine which models the Food and Drug Administration will need

in evaluating data for new medications in combination with cocaine

3. Long-term effects of chronic cocaine use

a. Cardiovascular

b. Central nervous system

c . Hormonal

4. Mechanisms of cocaine toxicity

a. Which physiological systems are affected?

b. Are there cocaine-specific symptom complexes?

c. What sets off the cascade of pathophysiological events?

AUTHORS

Marian W. Fischman, Ph.D.

Professor

Department of Psychiatry and Behavioral Sciences

Johns Hopkins University School of Medicine

600 North Wolfe Street

Baltimore, MD 21205

Reese T. Jones, M.D.

Professor of Psychiatry

University of California, San Francisco

Langley-Porter Psychiatric Institute

Box F 0984

401 Parnassus Avenue

San Francisco, CA 94143

James W. Cornish, M.D.

Research Assistant Professor

Department of Psychiatry

University of Pennsylvania

Director

Pharmacotherapy Division

Treatment Research Center

3900 Chestnut Street

Philadelphia, PA 19104-6178

184
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90 PROBLEMS OF DRUG DEPENDENCE 1988: PROCEEDINGS OF THE

50TH ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01362-5 $17

91 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

Steven W. Gust, Ph.D., and J. Michael Walsh, Ph.D., eds.

GPO Stock #017-024-01384-6 $10 NTIS PB #90-147257/AS $39

92 TESTING FOR ABUSE LIABILITY OF DRUGS IN HUMANS. Marian W.

Fischman, Ph.D., and Nancy K. Mello, Ph.D., eds.

GPO Stock #017-024-01379-0 $12 NTIS PB #90-148933/AS $45

93 AIDS AND INTRAVENOUS DRUG USE: FUTURE DIRECTIONS FOR

COMMUNITY-BASED PREVENTION RESEARCH. C.G. Leukefeld, D.S.W.;

R.J. Battjes, D.S.W.; and Z. Amsel, DSc., eds.

GPO Stock #017-024-01388-9 $10 NTIS PB #90-148941/AS $39

94 PHARMACOLOGY AND TOXICOLOGY OF AMPHETAMINE AND

RELATED DESIGNER DRUGS. Khursheed Asghar, Ph.D., and Errol De

Souza, Ph.D., eds.

GPO Stock #017-024-01386-2 $11 NTIS PB #90-148958/AS $39

95 PROBLEMS OF DRUG DEPENDENCE 1989: PROCEEDINGS OF THE

51 ST ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01399-4 $21 NTIS PB #90-237660/AS $67

96 DRUGS OF ABUSE: CHEMISTRY, PHARMACOLOGY, IMMUNOLOGY,

AND AIDS. Phuong Thi Kim Pham, Ph.D., and Kenner Rice, Ph.D., eds.

GPO Stock #017-024-01403-6 $8 NTIS PB #90-237678/AS $31

97 NEUROBIOLOGY OF DRUG ABUSE: LEARNING AND MEMORY. Lynda

Erinoff, Ph.D., ed.

GPO Stock #017-024-01404-4 $8 NTIS PB #90-237686/AS $31

98 THE COLLECTION AND INTERPRETATION OF DATA FROM HIDDEN

POPULATIONS. Elizabeth Y. Lambert, MS., ed.

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99 RESEARCH FINDINGS ON SMOKING OF ABUSED SUBSTANCES.

C. Nora Chiang, Ph.D., and Richard L. Hawks, Ph.D., eds.

GPO Stock #017-024-01412-5 $5 NTIS PB #91-141119 $23

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100 DRUGS IN THE WORKPLACE: RESEARCH AND EVALUATION DATA.

VOL. II. Steven W. Gust, Ph.D.; J. Michael Walsh, Ph.D.; Linda B. Thomas,

B.S.; and Dennis J. Crouch, M.B.A., eds.

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101 RESIDUAL EFFECTS OF ABUSED DRUGS ON BEHAVIOR. John W.

Spencer, Ph.D., and John J. Boren, Ph.D., eds.

GPO Stock #017-024-01426-7 $6 NTIS PB #91-172858/AS $31

102 ANABOLIC STEROID ABUSE. Geraline C. Lin, Ph.D., and Lynda Erinoff,

Ph.D., eds.

GPO Stock #017-024-01425-7 $8 NTIS PB #91-172866/AS $31

103 DRUGS AND VIOLENCE: CAUSES, CORRELATES, AND

CONSEQUENCES. Mario De La Rosa, Ph.D.; Elizabeth Y. Lambert, M.S.;

and Bernard Gropper, Ph.D., eds.

GPO Stock #017-024-01427-3 $9 NTIS PB #91-172841/AS $31

104 PSYCHOTHERAPY AND COUNSELING IN THE TREATMENT OF

DRUG ABUSE. Lisa Simon Onken, Ph.D., and Jack D. Blaine, M.D., eds.

GPO Stock #017-024-01429-0 $4 NTIS PB #91-172874/AS $23

105 PROBLEMS OF DRUG DEPENDENCE, 1990: PROCEEDINGS OF THE

52ND ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS

OF DRUG DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

GPO Stock #017-024-01435-4 $22

106 IMPROVING DRUG ABUSE TREATMENT. Roy W. Pickens, Ph.D.; Carl

G. Leukefeld, D.S.W.; and Charles R. Schuster, Ph.D., eds.

GPO Stock #017-024-01439-7 $12 NTIS PB #92-105873

Paperback $50 Microfiche $19

107 DRUG ABUSE PREVENTION INTERVENTION RESEARCH:

METHODOLOGICAL ISSUES. Carl G. Leukefeld, D.S.W., and William J.

Bukoski, Ph.D., eds.

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108 CARDIOVASCULAR TOXICITY OF COCAINE: UNDERLYING

MECHANISMS. Pushpa V. Thadani, Ph.D., ed.

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189
109 LONGITUDINAL STUDIES OF HIV INFECTION IN INTRAVENOUS DRUG

USERS: METHODOLOGICAL ISSUES IN NATURAL HISTORY RESEARCH.

Peter Hartsock, Dr.P.H., and Sander G. Genser, M.D., M.P.H., eds.

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110 THE EPIDEMIOLOGY OF COCAINE USE AND ABUSE. Susan Schober,

Ph.D., and Charles Schade, M.D., M.P.H., eds.

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Paperback $43 Microfiche $17

111 MOLECULAR APPROACHES TO DRUG ABUSE RESEARCH VOLUME I:

RECEPTOR CLONING, NEUROTRANSMITTER EXPRESSION, AND

MOLECULAR GENETICS. Theresa N.H. Lee, Ph.D., ed.

Not for sale at GPO NTIS PB #92-135743

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112 EMERGING TECHNOLOGIES AND NEW DIRECTIONS IN DRUG

ABUSE RESEARCH. Rao S. Rapaka, Ph.D.; Alexandros Makriyannis, Ph.D.;

and Michael J. Kuhar, Ph.D., eds.

GPO Stock #017-024-01455-9 $11

113 ECONOMIC COSTS, COST-EFFECTIVENESS, FINANCING, AND

COMMUNITY-BASED DRUG TREATMENT. William S. Cartwright, Ph.D.,

and James M. Kaple, Ph.D., eds.

Not for sale at GPO NTIS PB #92-155795

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114 METHODOLOGICAL ISSUES IN CONTROLLED STUDIES ON EFFECTS

OF PRENATAL EXPOSURE TO DRUG ABUSE. M. Marlyne Kilbey, Ph.D., and

Khursheed Asghar, Ph.D., eds.

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115 METHAMPHETAMINE ABUSE: EPIDEMIOLOGIC ISSUES AND

IMPLICATIONS. Marissa A. Miller, D.V.M., M.P.H., and Nicholas J. Kozel, M.S.,

eds.

GPO Stock #017-024-01460-5 $4

116 DRUG DISCRIMINATION: APPLICATIONS TO DRUG ABUSE

RESEARCH. Richard A. Glennon, Ph.D.; Torbjörn U.C. Järbe, Ph.D.; and

Jerry Frankenheim, Ph.D., eds.

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117 METHODOLOGICAL ISSUES IN EPIDEMIOLOGICAL, PREVENTION,

AND TREATMENT RESEARCH ON DRUG-EXPOSED WOMEN AND THEIR

CHILDREN. M. Marlyne Kilbey, Ph.D., and Khursheed Asghar, Ph.D., eds.

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118 DRUG ABUSE TREATMENT IN PRISONS AND JAILS. Carl G.

Leukefeld, D.S.W., and Frank M. Tims, Ph.D., eds.

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119 PROBLEMS OF DRUG DEPENDENCE 1991: 53RD ANNUAL

SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

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120 BIOAVAILABILITY OF DRUGS TO THE BRAIN AND THE BLOODBRAIN BARRIER. Jerry Frankenheim, Ph.D., and Roger M. Brown, Ph.D., eds.

121 BUPRENORPHINE: AN ALTERNATIVE TREATMENT FOR OPIOID

DEPENDENCE. Jack D. Blaine, Ph.D., ed.

122 RESEARCH METHODS IN WORKPLACE SETTINGS. Helen Axel, M.A.,

and Dennis J. Crouch, M.B.A., eds.

191
National Institute on Drug Abuse

NIH Publication No. 93-3498

Printed 1993