Opioid -Related Disorders

More than 20 chemically distinct opioid drugs are in clinical use throughout the world. In the
developed countries, the opioid drug must frequently associated with abuse and dependence is
heroin—a drug that is not used for therapeutic purposes in the United States. Dependence on
opioids other than heroin is seen mostly in persons who have become dependent in the course
of medical treatment, among health care professionals who have easy access to such drugs, and
in those who use drugs that are diverted from medical providers and treatment programs.
Virtually all of the opioid dependence and abuse seen clinically is associated with prototypical
μ-agonist uploads, and all μ-agonists produce similar subjective effects. However, the patterns
of use and some aspects of opioid toxicity are powerfully influenced by the route of
administration and the metabolism of the specific opioid, as well as by the social conditions
that determine its price and purity and the sanctions attached to nonmedical use.

DEFINITIONS

The revised fourth edition of the Diagnostic and Statistical Manual of Mental disorders (DSM-
IV-TR) divides opioid-related disorders into disorders (opioid abuse and opioid dependence) and
nine other opioid-induced disorders (e.g., intoxication and withdrawal).

Opioid dependence is a cluster of physiological, behavioral, and cognitive symptoms, which,

taken together, indicate repeated and continuing use of opioid drugs despite significant
problems related to such use. Drug dependence in general has also been defined by the World
Health Organization (WHO) as a syndrome in which the use of a drug or class of drugs takes
on a much higher priority for a given person than other behaviors that once had a higher
value. These brief definitions each have as their central features an emphasis on the drug-
using behavior itself, its maladaptive nature, and on how the choice to engage in that behavior
has shifted and becomes constrained as a result of interaction with the drug over time.
Opioid abuse is a term used to designate a pattern of maladaptive use of an opioid drug leading
to clinically significant impairment or distress
and occurring within a 12-month period, but one in which the symptoms have never met the
criteria for opioid dependence. The opioid-induced disorders as defined by DSM-IV-TR
include such common phenomena as opioid intoxication, opioid withdrawal, opioid-induced
sleep disorder, and opioid-induced sexual dysfunction. Opioid intoxication delirium is
occasionally seen in hospitalized patients. Opioid-induced psychotic disorder, opioid-induced
mood disorder, and opioid-induced anxiety disorder, by contrast, are quate uncommon with μ-
agonist opioids but have been seen with certain mixed agonist-antagonist opioids acting at other
receptors. DSM-IY-TR also includes opioid-related disorder not otherwise specified for
situations that do not meet the criteria for any of the opioid-related disorders.

COMPARATIVE NOSOLOGY
The DSM-IV-TR criteria for opioid dependence are the same generic criteria as are applied to
other psychoactive drugs. The notion of a generic concept of dependence is shared with the
tenth revision of the International Statistical Classification of Diseases and Related Health
Problems (ICD-10). In the diagnosis of opioid dependence, there generally is a high level of
agreement between DSM-IV-TR and ICD-10: They use similar concepts (the dependence
syndrome varying in degree of severity), although the wording of the criteria for determining
the presence and severity of the syndrome differs. Both require that three elements of the
syndrome occur within a 12-month period.
A major difference between DSM-IV-TR and ICD-10 lies in how sasiv fe&ns& s\fty&a&£&.
'dfcw&t.\CXW^ tots mV \>&t ^wt \srrcv abuse. Instead, it includes a category of harmful use that
is substantially different from the concept of abuse in DSM-IV-TR. However, the concept of
harmful use is limited to physical and mental health (e.g., hepatitis, overdose, and skin abscess)
and specifically excludes social impairments. ICD-10 states: "Harmful patterns of use are often
criticized by others and frequently associated with adverse social consequences of various
kinds. The fact that a pattern of use or a particular substance is disapproved of by another
person or by the culture, or may have led to socially negative consequences such as arrest or
marital arguments is not in itself evidence of harmful use."
DSM-IV-TR and ICD-10 also have distinctly different coding systems. ICD-10 separates for
record-keeping purposes mental and behavioral disorders due to use of opioids from those
caused by other categories of drugs. DSM-IV-TR limits the number of distinct drug-induced
syndromes that can be recorded (except under the categories other and unspecified) as disorders
induced by opioids.
 ETIOLOGY
Opioid dependence is currently seen as a biopsychosocial disorder in which multiple
factors interact to influence initiation of use, continued use, and relapse after periods of
abstinence.. Those factors—pharmacological, social, environmental, personality,
psychopathology, genetic, and familial—are the same ones that must be considered
when loocing at abuse and dependence on other categories of drugs. What changes . in the case
of the opioids is the balance of the various factors. For opioids, as for most substances, it is
largely social and cultural factors that influence availability and initial use. In the case of
OPIOID DRUGS, however, pharmacological factors—the initial effects and their
consequences—are believed to play important roles in the perpetuation of use and of
progression to dependence. Opioids have potent mood-elevating and euphorigenic actions
in humans and are powerful reinforcers in animal models. This is particularly true when
the effects are rapid in onset, such as when the opioids are injected or inhaled . Perhaps
more than any other category of drugs, the opioids can induce long-lasting alterations in
the nervous system. Some of these changes are responsible for the physical dependence that
causes an aversive withdrawal syndrome when central nervous system (CNS) opioid levels
decline. Other drug-induced changes that may persist for some time after withdrawal include
a hyperresponsiveness to stress and reduced responsivity for ordinary pleasurable events
(hypophoria) It is not clear whether these changes should be considered part of protracted
withdrawal syndrome or whether they represent distinct phenomena.

DIAGNOSIS AND CLINICAL FEATURES

Opioid Intoxication

DSM-IV-TR Diagnostic Criteria for Opioid intoxication

 A. Recent use of an opioid.
B. Clinically significant maladaptive behavioral or psychological
changes (e.g., initial euphoria followed by apathy dysphoria,
psychomotor agitation or retardation, impaired judgment, or
impaired social or occupational functioning) that developed during
, or shortly after, opioid use.
C. Pupillary constriction (or pupillary dilation due to anoxia from
severe overdose) and one (or more) of the following sings, developing
during, or shortly after, opioid use:
(1) Drowsiness or coma
(2) Slurred speech
(3) Impairment in attention or memory
D. The symptoms are not due to a general medical condition are
not better accounted for by another mental disorder
Specify if:
With perceptual disturbances.

Opioid Withdrawal

The opioid withdrawal syndrome can vary greatly in intensity, depending primarily on
the level of physical dependence (i.e., the chronic dose of the opioid used), the degree to
which the opioid effects on the CNS were continuously exerted, the duration of use, and the
rate at which the opioid is removed from the receptors. These generalizations appear to
apply as well to other categories of drugs, such as barbiturates and benzodiazepines. The
DSM-IV-TR diagnostic criteria for opioid withdrawal are shown in

Although there are numerous signs and symptoms associated with opioid withdrawal, not
all are uniformly present across withdrawal episodes—there can be considerable variability
between persons in the particular cluster of symptoms exhibited during opioid withdrawal.
 DSM-IV-TR Diagnostic Criteria for Opioid Withdrawal

A. Either of the following:

(1) Cessation of (or reduction in) opioid use that has been heavy
and prolonged (several weeks or longer).
(2) Administration of an opioid antagonist after a period of opioid
use.

B. Three (or more) of the following, developing within minutes to

several days after Criterion A:

(1) Dysphoric mood

(2) Nausea or vomiting

(3) Muscle aches

(4) Lacrimation or rhinorrhea

(5) Pupillary dilation, piloerection, or sweating

(6) Diarrhea

(7) Yawning

(8) Fever

(9) Insomnia

C. The symptoms in Criterion B cause clinically significant distress or

impairment in social, occupational, or other important areas of
functioning.

D. The symptoms in Criterion are not due to a general medical condition

and are not better accounted for by another mental disorder
Opioid Abuse and Opioid Dependence
Opioid abuse is a pattern of maladaptive use of an opioid drug leading to clinically significant
 impairment or distress and occurring within a 12-month period, but one in which the
symptoms have never met the criteria for opioid dependence.
Opioid dependence is inferred from behaviors that indicate some decrease in volitional
control over the use of an opioid drug. DSM-IV-TR specifies the criteria to be used by the
clinician to decide whether the patient exhibits such a decrease in volitional control. These
criteria are not specific for opioids but are believed to apply for all psychoactive agents. DSM-
IV-TR does not require that any single criterion be met, and none is given special weight.
Thus, the presence of tolerance and physical dependence (withdrawal) is not required.
However, according to DSM-IV-TR, if tolerance and physical dependence are present, they
should be noted specifically. Because tolerance develops to many of the actions of opioid
drugs after long-term use, opioid effects are not readily detected by even the careful observer.
Patients maintained on large oral doses of methadone function quite normally. Physicians,
nurses, and other medical personnel who use opioids, even by injection, may go undetected by
their colleagues for months or years. Thus, a candid history obtained from the patient or a
reliable informant is needed to make a diagnosis of dependence, although evidence of recent
and long-term use can be developed by testing urine or hair for the presence of opioids.

Opioid Intoxication Delirium

Opioid intoxication delirium is most likely to happen when opioids are used in high doses,
are mixed with other psychoactive compounds, or are used by a person
with preexisting brain damage. Certain opioids, such as meperidine, have toxic metabolites
that can accumulate, causing delirium and sometimes causing seizures. Impaired renal
function increases the likelihood of accumulation.

Opioid-lnduced Psychotic Disorder

Opioid-induced psychotic disorder can begin during opioid intoxication. The DSM-IV-TR
diagnostic criteria are contained in the section on schizophrenia and other psychotic disorders.
Clinicians can specify whether hallucinations or delusions are the predominant symptoms and
whether the onset occurs during intoxication or withdrawal.
Opioid-induced Mood Disorder

Opioid-induced mood disorder can begin during opioid intoxication or withdrawal and can
result from chronic use. Opioid-induced mood disorder symptoms may be of a manic,
depressed, or mixed nature. A person coming to psychiatric attention with opioid-induced mood
disorder usually has mixed symptoms, combining irritability, expan-siveness, and depression.
Some degree of depressed mood (hypophoria) typically occurs during and for several weeks
after opioid withdrawal. Opioid-induced mood disorder should not be diagnosed after opioid
withdrawal unless the severity of mood disturbance exceeds what is normally encountered or
persists for more than a few weeks and is of sufficient intensity to warrant independent clinical
attention

Opioid-induced Sleep Disorder and Opioid-induced Sexual Dysfunction

Opioid-induced sleep disorder and opioid-induced sexual dysfunction are diagnostic categories
in DSM-IV-TR. Hypersomnia is likely to be a more common sleep disorder among those
given opioids therapeutically, but disturbed sleep (insomnia) is a common complaint of patients
maintained on opioid agonists such as methadone. The most common sexual dysfunction is
likely to be impotence, but patients maintained on methadone may complain of inability to
achieve orgasm, rather than impotence

Opioid-Related Disorder Not Otherwise Specified

DSM-IV-TR includes diagnoses for opioid-related disorders with symptoms of delirium,

abnormal mood, psychosis, abnormal sleep, and sexual dysfunction. Clinical situations that do
not fit into these categories are examples of appropriate cases for the use of the DSM-IV-TR
diagnosis of opioid-related disorder not otherwise specified
DSM-IV-TR Diagnostic Criteria for Opioid-Related
Disorder Not Otherwise Specified

The opioid-related disorder not otherwise specified category is for

disorders associated with the use of opioids that are not
classifiable as opioid dependence, opioid abuse, opioid
intoxication, opioid withdrawal, opioid intoxication delirium,
opioid-induced psychotic disorder, opioid-induced mood disorder,
opioid-induced sexual dysfunction, or opioid-induced sleep
disorder.
 PATHOLOGY AND LABORATORY EXAMINATION

In opioid abuse and opioid dependence, there may be no abnormal laboratory findings at all.
Standard urine tests for heroin actually test for its main metabolite, morphine, and can usually
detect morphine (heroin) for 12 to 36 hours after use. A urine test that is positive for morphine
can also be caused by therapeutic doses of codeine or by the ingestion of modest amounts of
poppy seeds (of the type and amount used to flavor bagels and other breads and pastries).
Potent opioids, such as fentanyl (Actiq), may not be detected by standard opioid urine screens.
If it is suspected that a specific opioid is being abused, it can be useful to check with a
laboratory to ensure that the proper urine test is obtained, as not all opioids react with the test
for morphine (e.g., methadone). Opioids with longer half-lives, such as methadone, may be
detected for longer periods (4 or more days in the case of methadone) on a urine screen that
tests specifically for such medications. Analysis of hair samples can provide information on
drug use over the preceding 2 to 3 months. Samples of oral fluids can detect recent opioid use
with approximately the same sensitivity as urine testing.
Persons who have shared injection implements often test positive for hepatitis (B and C) and
for HIV. Liver enzyme tests may be elevated if there is active hepatitis. There may be
positive and false-positive tests for syphilis. Chest X-rays may show evidence of
pulmonary fibrosis if the person has been using injection materials contaminated with
microcrystalline talc or cotton particulates. During withdrawal, white blood cell counts and
Cortisol levels may be elevated. Physical findings may be unremarkable if opioids are
ingested orally; snorting (insufflation) of heroin may irritate nasal membranes. Drug
injectors, however, may show widespread evidence of having used unsterile injection
equipment. There may be needle tracks over veins on the arms, legs, and, in some cases, the
backs of the hands and the femoral and jugular veins. Infections and venous scleroses and
lymph obstruction may lead to severe edema of the hands and feet. There may be skin
abscesses or scars on accessible skin surfaces as a result of unsterile subcutaneous injections
(Fig. 11.10-3). There may be rock-like hardening of subcutaneous and muscle tissue as a
result of repeated IM injections of meperidine (often seen among health professionals).
Endocarditis may produce fever and heart murmurs. In addition, a variety of neurological
sequelae of IV heroin use may be detected.
TREATMENT
Treatment of Opioid Intoxication (Overdose)
Overdose with an opioid agonist can produce respiratory depression and is therefore a
medical emergency. The first task is to ensure an adequate airway. Tracheopharyngeal
secretions should be aspirated; an airway may be inserted. The patient should be ventilated
mechanically until an opioid antagonist can be administered. There are two approved opioid
antagonists (naloxone, nalmefene [Revex]) that can be administered parenterally for reversal of
an opioid overdose. Naloxone has a relatively short half-life (60 to 90 minutes) and must be
repeatedly administered in patients who have overdosed on an opioid with a longer half-life
(e.g., methadone). Initial IV naloxone dosing is approximately 0.8 mg per 70 kg of body
weight. Signs of improvement—increase in respiratory rate and pupillary dilation— should
occur promptly. If there is no response to the initial dosage, naloxone may be repeated after
intervals of a few minutes. Nalmefene has a longer duration of action (its half-life is
approximately 10 hours), and a single dose of nalmefene may be sufficient to produce sustained
reversal for the duration of the effects of the opioid agonist overdose. Nalmefene's onset of
effects typically occurs within minutes after IV administration, and the usual initial dose is 0.5
to 1.0 mg.
In opioid-dependent patients, too much naloxone or nalmefene may produce signs of
withdrawal (precipitated opioid withdrawal), as well as reversal of overdosage. In some
instances, patients may become agitated owing to precipitated withdrawal symptoms. A relative
advantage of naloxone is that precipitated withdrawal effects—if they occur—are of relatively
short duration. In contrast, nalmefene-precipitated withdrawal can last for hours.
In the past, it was thought that, if no response was observed after administering naloxone or
nalmefene, then CNS depression was probably not solely due to opioids. However,
buprenorphine is difficult to reverse with opioid antagonists, and higher doses of naloxone and
nalmefene may be required for an overdose of buprenorphine. (However, the risk of respiratory
depression from an overdose of buprenorphine is uncommon, as reviewed later in this chapter.
 Cocaine-Related Disorders

Few public health issues attracted as much media attention in the United States during the
1980s and early 1990s as the problems resulting from the use of cocaine and "crack."
Although the intranasal use of cocaine hydrochloride in the early 1980s was associated with
high-income, "jet-set" users, smokable "crack” cocaine has become an endemic drug
problem in the inner cities across the United States. Epidemiological evidence has
documented that the peak of this epidemic has passed in the United States, but available data
indicate that rates of cocaine use are increasing in a number of European countries.
There is a wealth of new information on the neurobiology of cocaine and cocaine
dependence, treatment research efforts have been extensive, and progress has been made in
identifying behavioral-psychosocial treatments. However, in spite of well-funded research,
there are still no clinically useful pharmacotherapies for the treatment of cocaine-related
disorders.

D EF E N IT IO N S

Substance use may be associated with a number of distinct disorders, of which _dependence
and abuse are but two. In the case of cocaine, the revised fourth edition of the Diagnostic and
Statistical Manual of Mental Disorders (DSM-IV-TR) describes ten other substance-related
disorders. Cocaine dependence is defined in DSM-IV-TR as a cluster of physiological ,
behavioral, and cognitive symptoms that, taken
Together, indicate that the person continues to use cocaine despite significant
problems related to such use. With cocaine dependence, individuals find
it increasingly difficult to resist using cocaine whenever it
is a available. It is defined in the tenth revision of the International Statistical
Classification of Diseases and Related Health Problems (ICD-10) as a
cluster of physiological, behavioral, and cognitive phenomena
in which the use of cocaine takes on a much higher priority for a given .individual than do other
behaviors that once had a greater value. Central
to these definitions is the emphasis placed on the drug-using
behavior, its maladaptive nature, and how, over time, the voluntary
choice to engage in that behavior shifts and becomes constrained as a result of
interactions with the drug..
Cocaine abuse is a term used in DSM-IV-TR to categorize a pattern of
maladaptive cocaine use leading to clinically significant impairment or distress within a
12-month period but one in which the symptoms have not met criteria for cocaine
dependence. Specifically, when there is evidence of tolerance, withdrawal, or compulsive
behavior associated with obtaining or administering cocaine, a diagnosis of dependence
rather than abuse should be used. ICD-10 does not use the term.
Other cocaine-related disorders include cocaine intoxication, .cocaine
withdrawal, cocaine-induced psychotic disorder with delusions or with hallucinations,
cocaine intoxication delirium, cocaine -induced mood disorder, cocaine-induced anxiety
disorder, cocaine-induced sleep disorder, cocaine-induced sexual dysfunction, and cocaine-
related disorder not otherwise specified. The DSM-IV-TR coding scheme provides distinct
code numbers for cocaine dependence and cocaine abuse.

DSM-IV-TR Cocaine-Related Disorders

Cocaine use disorders Cocaine dependence

Cocaine abuse Cocaine-induced disorders
Cocaine intoxication Specify if:
With perceptual disturbances Cocaine withdrawal Cocaine
intoxication delirium Cocaine-induced psychotic disorder
with delusions Specify if:
With onset during intoxication
Cocaine-induced psychotic disorder with hallucinations
Specify if:
With onset during intoxication Cocaine-induced
mood disorder Specify if:
With onset during intoxication With onset during
withdrawal Cocaine-induced anxiety disorder
Specify if:
 With onset during intoxication With onset during
withdrawal Cocaine-induced sexual dysfunction
Specify if:
With onset during intoxication Cocaine-induced
sleep disorder Specify if:
With onset during intoxication With onset during withdrawal
Cocaine-related disorder not otherwise specified

ETIOLOGY

Substance dependence is currently viewed as the result of a process

In which social, psychological, cultural, and biological factors influence substance
-using behavior. The actions of the drug are seen as
critical, but is recognized that not everyone who becomes dependent
experiences the effects of a given drug in the same way. Further,
depending on the individual, different factors may be more or less
important at deferent stages of the process, even with the same class
of pharmacological agents.

Social and cultural factors largely influence the availability and initial use of cocaine and other
substances. In the case of cocaine, pharmacological factors are believed important in
perpetuating useand progression to dependence. Cocaine has potent mood-elevating and
euphorigenic actions, especially when its effects have rapid onset, as when cocaine is
injected or inhaled. Although some physical dependence develops, a physically
uncomfortable, aversive withdrawal syndrome probably is less prominent in perpetuating
cocaine use than that of opioids and sedatives.

Comorbidity Additional psychiatric diagnoses are quite common among cocaine-

dependent patients. It is not always evident how this comorbidity is linked etiologically to
cocaine, but the epidemiological evidence clearly shows that the presence of a psychiatric
disorder not related to substance abuse (e.g., mood disorders, schizophrenia, and antisocial
personality disorder) substantially increases the odds of developing substance abuse and
dependence. For some people, cocaine may serve to alleviate various psychiatric disorders or
 dysfunctional states. Some users, for example, may find relief from dysthymic disorder. Others
may find that cocaine facilitates sexual activity, permits extended socializing, or counteracts
the sedative effects of alcohol. However, although factors may explain substance use on
more than one occasion, they do not account for progression to dependence or abuse.
Genetic Factors The most convincing evidence to date of a genetic influence on cocaine
dependence comes from studies of twins, ale twins. A study of male who served in the U.S.
military between 1965 and 1975 found higher concordance rates for stimulant dependence
( cocaine, amphetamines, and amphetamine-like drugs) among monozygotic than
dizygotic twins. The analyses indicated that genetic factors and unique (unshared)
environmental factors contributed approximately equally to the development of stimulant
dependence. A study of male twins in Virginia found a common genetic factor exerted a strong
influence on risk for illicit use and abuse/dependence for six distinct classes of drugs.
Environmental factors were the major determinant of whether a particular class of drugs are
used by predisposed individuals. Other studies have shown genetic contributions to attention- deficit/
hyperactivity disorder (ADHD), conduct disorder, and antisocial personality disorder. Because
these disorders are important risk i drug use and dependence, these findings also support
genetic involvement in the etiology of drug dependence in general.
In animal models, it is interesting to note that laboratory animal _strains differ greatly in
their willingness to self-administer psychoactive drugs including cocaine, and that strains
that differ even more markedly can be developed.

Other Factors Social, cultural, and economic factors are powerful

determinants of initial use, continuing use, and relapse. Excessive use is far more likely in
countries in which cocaine is readily available.
Different economic opportunities may influence certain groups more
than others to engage in selling illicit drugs, and selling is more likely to be carried out in
familiar communities than in those in which the seller runs a high risk of arrest.
Because in both human and animal studies alternative positive
reinforcers compete with drugs as reinforcers, the absence of such
nondrug alternatives can be seen as a causal factor for use, especially
when drugs are available and the social pressures against using them
are not strong. Alternative positive reinforcers are not limited to
material rewards but include psychological rewards associated with
satisfying interpersonal relationships and the self-esteem that derives
from achievements in socially acceptable roles. In animal models,
chronic stress mediated by high levels of Cortisol increases sensitivity to the reinforcing effects
of cocaine and induces relapse to drug self-administration in withdrawn animals.

DIAGNOSIS AND CLINICAL FEATURES

Patterns of Use and Abuse

Vhere are several patterns of cocaine use and abuse. For example, the indigenous people of the
Andes chew coca leaves daily, but apparently very few progress to excessive use or toxicity.
Although some people can use cocaine intermittently without becoming dependent, it is not
clear how long such intermittent, nondependent use can continue and for what proportion of
users. Cocaine use that does not cause problems for the user does not meet the DSM-IV-TR
criteria for either dependence or abuse.

Among people seeking treatment for cocaine dependence (unlike opioid dependence), daily
use of the drug is not the most common pattern. Instead, use may be intermittent. Intermittent
use consists of episodes or binges of use, often starting on weekends and paydays and lasting
until the drug supply is exhausted or toxicity develops The runs, or binges, during which the
drug may be used every 15 to 30 minutes, can last 7 or more consecutive days but typically are
shorter. Although there appears to be little tolerance between binges, changes in the response
to the drug occur during the binge. Euphoric effects seem less prominent, and anxiety, fatigue,
irritability, and depression increase. Any pause in the drug use causes blood concentrations to
drop; typically, there is dysphoria rather than a return to normal mood. If cocaine is still
available, it is used to dispel the dysphoria. When the binge is interrupted or supplies have
been depleted, a cocaine "crash" quickly follows. Patients report the sense of needing more
cocaine to get the same effect (tolerance) more commonly than the experience of pronounced
withdrawal. Some users distinguish between a brief crash and withdrawal. A substantial
proportion of cocaine users seeking treatment report daily or almost daily use, often associated
with daily heroin use. A small percentage
of patients report using high doses for a few days a month over a long period; such people
may still meet the criteria for dependence.
 In the early stages, cocaine use may cause little interference with normal activities. Some
people may even find that the sense of energy and heightened sense of self-confidence facilitate
productive activity. Others may find that the cocaine facilitates social interaction, particularly
enhancing sexual arousal and enjoyment, at least initially. The development of sexual dysfunction
later in the course of use is better documented than is the enhancement.
In addition to feelings of euphoria, cocaine use may also induce concurrent feelings of anxiety,
irritability, and suspiciousness. Users may commit crimes to obtain money to buy cocaine, and
such crimes may involve violence. In addition, cocaine can induce paranoid ideation, and there are
reports of homicide and attempted homicide during such cocaine-induced toxic states.

Cocaine abusers frequently use sedatives or opioids to modulate the stimulant and toxic effects
of the cocaine, a practice that can lead to concurrent dependence on sedatives or opioids.
Sometimes an opiate, such as heroin, and cocaine are injected intravenously simultaneously; the
mixture (speedball) is reportedly especially euphorigenic. Similar synergistic effects are seen
when cocaine and buprenorphine (Buprenex, Subutex) are taken simultaneously. Alcohol is
probably the substance most commonly used in conjunction with cocaine, and its use may
become associated with cocaine use and can trigger cocaine craving in former users trying to
abstain from cocaine.
 Cocaine Dependence As drug use progresses, greater priority is often given to
obtaining and using cocaine than to meeting other social obligations or avoiding toxicity or
arrest. The user may engage in illegal activities to raise money for cocaine or trade sex for it.
At this stage, the use of cocaine is considered maladaptive and probably meets the DSM-IV-
TR criteria for cocaine abuse or dependence. The DSM-IV-TR criteria for cocaine
dependence are the same generic criteria applied to other substances (Table 11.1-3). A
diagnosis of dependence requires a maladaptive drug use pattern that leads to clinically
significant impairment or distress, as indicated by at least three of seven criteria presented in
the table. DSM-IV-TR instructs the clinician to specify whether physiological dependence is
present (i.e., evidence of either tolerance or withdrawal as defined in the diagnostic criteria).
Drug use to prevent withdrawal is not as dominant with cocaine dependence as with opioid
dependence. However, the other criteria for dependence are common among heavy users of
cocaine. Tolerance to some drug actions (e.g., euphorigenic effects) can coexist with
increased sensitization to other actions (e.g. anxiogenetic and psychotogenic effects).

Cocaine Abuse Some cocaine users develop problems or adverse effects related to their
drug use (i.e., their maladaptive) even though such use does not meet the three-criteria
requirement for the diagnosis of dependence. Examples of such recurrent maladaptive
patterns include use that leads to multiple legal problems ; inability to meet major social,
school, or work-related obligations; and continued use despite social or vocational
difficulties caused by, or aggravated by, cocaine use. When one more such substance-
related problems occur in a 12-month period, but the pattern has never met the criteria for
dependence, the diagnosis of cocaine abuse (Table 11.1-8) should be made.

Cocaine Intoxication Delirium and cocaine-Induced Psychotic Disorder

Whereas some paranoia or
hypervigilance is typical of cocaine intoxication, and tactile and other hallucinations may also
occur, cocaine use can also induce a toxic delirium and a more persistent toxic psychotic
disorder characterized by suspiciousness, paranoia, visual and tactile hallucinations, and loss of
insight. The hallucination of bugs (cocaine bugs) or vermin crawling under the skin
(formication) is sometimes reported and is often with associated excoriation of the skin. A
paranoid syndrome can develop within 24 hours after the beginning of a cocaine binge. When
the syndrome develops in the presence of a clear sensorium, and the person retains insight into
the drug-induced nature of the symptoms, it is called cocaine intoxication, even when there are
hallucinations. When insight is lost, but the sensorium is clear, the syndrome is called cocaine-
induced psychotic disorder with delusions or with hallucinations. If consciousness is disturbed
(i.e., the ability to focus, sustain, or shift attention is reduced), and deficits in memory and
orientation exits, the diagnosis is cocaine intoxication delirium.

Cocaine Intoxication

A. Recent use of cocaine,

B. Clinically significant maladaptive behavioral or psychological

e.g., euphoria or affective blunting; changes in sociability ; hypervigilance;
interpersonal sensitivity; anxiety, tension, or anger; stereotyped behaviors; impaired
judgment; or impaired social or occupational functioning) that developed during, or
shortly after, use of cocaine.
C. Two (or more ) of the following, developing during, or shortly after cocaine
use:
(1) Tahycardia or bradycardia
(2) Pupillary dilation
(3) Elevanted or lowered blood pressure
(4) Perspiration or chills
(5) Nausea or vomiting
(6) Evidence of weight loss
(7) Psychomotor agitation or retardation
(8) Muscular weakness, respiratory depression, chest pain, or cardiac atrhythmias
(9) Confusion, seizures, dyskinesias, dystonias, or coma
 D. The symptoms are not due to a general medical condition and are not better
accounted for by another mental disorder.
Specify if:
With perceptual disturbances

Cocaine Withdrawal Cocaine withdrawal phenomena have not been as thoroughly studied
as those associated with opioids or alcohol. No experimental studies have been conducted in
which patient with known baseline characteristics have been stabilized solely on large
doses of cocaine and then abruptly withdrawn. Consequently, most data have been derived from
interviews and patients' recollections or from observations of hospitalized patients whose
level of drug ingestion and prior baseline characteristics can only be estimated. During the
cocaine epidemic of the 1980s, approximately 50 percent of cocaine users reported
experiencing some type of withdrawal when drug use was interrupted.
An early description of withdrawal based on interviews of outpatients described a three-phase
syndrome in which the first phase, the crash, was characterized by agitation, depression,
anorexia, and high cocaine craving. This cluster of symptoms was followed by a decrease
in cocaine craving, fatigue, depression, and a desire for sleep, followed in turn by
exhaustion and hypersomnia, with intermittent awakening, and hyperphagia. The second
phase was reported to be heralded by normalized sleep, improved mood, and low levels of
craving, but that relatively benign phase was succeeded by a return of anergia, anhedonia,
anxiety, and increased cocaine craving, especially in response to stimuli previously associated
with cocaine use. A third phase, extinction (which appears to represent a period of extended
vulnerability to relapse rather than a phase of an extended withdrawal syndrome) was also
described.
Others who have observed cocaine-dependent patients admitted to clinical and research
units have not reported seeing such a complex phasic withdrawal. Instead, symptoms of
depression and craving for cocaine declined steadily over several weeks. After 3 weeks, sleep,
weight, and appetite were mostly comparable to those of normal controls on the same unit.
Hypersomnia, disturbed sleep, hyperphagia, and excessive weight gain were not seen, nor
was a severe crash observed. The phases and fluctuations in craving previously reported
might have been related to environmental stimuli, j
Some of the inconsistencies in the findings and symptoms associated with cocaine cessation
are probably attributable to differences in the dose and duration of use and to vulnerability
factors. In interviews with almost 400 cocaine abusers, including approximately 100 who
were not seeking treatment, some 83 percent reported tolerance to cocaine effects (needing
more to get the same effect), and 52 percent reported having undergone some type of
withdrawal. Those seeking treatment were more likely to report experiencing withdrawal.
Available data show no convincing evidence that a protracted cocaine withdrawal syndrome
follows resolution of the signs and symptoms associated with abrupt cessation. However,
abnormalities of brain function appear to persist for at least 12 weeks, and, possibly, subtle
withdrawal phenomena increase vulnerability to relapse.
Although not commonly observed during recent clinical studies, severe depression,
sometimes associated with suicidal ideation, is reported in the older literature on cocaine
withdrawal and in occasional contemporary clinical reports. Emil Erlenmeyer reported in
1886 that depression was likely to be seen when cocaine was stopped. Maier (Der
Kokainismus, 1926) noted that depression and apathy appeared on cessation of cocaine. To
what degree the more severe depressive features are a part of withdrawal or represent the
emergence of primary mood disorder is unclear.
vjhe DSM-IV-TR diagnostic criteria for cocaine withdrawal (Table 11.6-3) specify that the
syndrome follows the cessation (or reduction) of heavy, prolonged cocaine use. Further, the
dysphoric mood and other symptoms (e.g., fatigue and sleep disturbances) must be intense
enough to cause significant distress or impairment. Thus, the criteria are structured so that the
brief dysphoria and fatigue (crash) that follow a single short binge by an occasional user do not
lead to a diagnosis of withdrawal. Drug craving, often a part of cocaine withdrawal, is not
included among DSM-IV-TR diagnostic criteria.

Table 11.6-3
DSM-IV-TR Diagnostic Criteria for Cocaine Withdrawal
 A. Cessation of (or reduction in) cocaine use that has been heavy
and prolonged.
B. Dysphoric mood and two (or more) of the following physiological
changes, developing within a few hours to several days after Cri
terion A:
(1) Fatigue
(2) Vivid, unpleasant dreams /
(3) Insomnia or hypersomnia
(4) Increased appetite
(5) Psychomotor retardation or agitation
C. The symptoms in Criterion B cause clinically significant distress
or impairment in social, occupational, or other important areas of
functioning.
D. The symptoms are not due to a general medical condition and are
not better accounted for by another mental disorder.

Other Cocaine-Induced Disorders Other psychiatric syndromes that may develop in the
ourse of cocaine use include cocaine-induced mood disorder, cocaine-induced anxiety disorder,
nd cocaine-induced sleep disorder. With each of those disorders, the clinician should specify whether
he onset occurred during intoxication or during withdrawal. DSM-IV-TR also describes cocaine-
nduced sexual dysfunction and a category of cocaine-related disorder not otherwise specified.
ocaine-induced mood disorder can occur during use, intoxication, or withdrawal. During use and
ntoxication, the disorder is more likely to simulate a manic, hypomanic, or mixed episode; during
thdrawal, it is more likely to involve a depressed mood. Such diagnoses are difficult to make during
eriods of active drug use or during the first week or two of withdrawal. Because sexual dysfunction,
anxiety, and disturbed sleep are seen so commonly during cocaine use and withdrawal, the
iagnoses should be made only when the disturbances or dysfunctions are judged to be in excess of
that usually associated with intoxication and withdrawal and only when severe enough to require
ndependent treatment or attention. Panic episodes that develop during cocaine use may persist for
many months after cessation. Lasting vulnerability to panic attacks may be linked to sensitization
 phenomena.
TREATMENT
Selection of Treatment Setting
eneral principles of treatment for cocaine dependence do not differ much from those for other
eties of drug dependence. Patient heterogeneity requires careful assessment of the patient and
ghtful selection among alternative treatment approaches. Cocaine dependence severe enough to
ire formal treatment is often associated with other psychiatric diagnoses. Not all cocaine users
ire extensive treatment; some who are not severely dependent respond to external pressures, as
n employers insist on carefully monitoring substance use. Among the factors influencing selection
THE SEVERITY of dependence, other drugs being used concurrently, comorbid medical and
hiatric disorders, and the preferences of the patient and the alternatives available. Availability, in
is often influenced by the policies of managed care companies, the patient's resources, and
ypes of therapy provided locally.
ong the few reliable predictors of treatment response number of cocaine use days within the past
t the time of treatment admission and route of cocaine administration. There is considerable
ence that individuals who use cocaine on a daily or near-daily frequency or use cocaine by the
ction route, or both, are more difficult to engage in outpatient treatments, are retained in treatment
horter durations, and have poorer outcomes. These data suggest that the use of more intensive
ment (e. g. residential or inpatient settings) is preferable for individuals with these pretreatment
profiles.
In general, treatment can be initiated in intensive outpatient settings, although often third-
party payers do not authorize and public sector programs cannot provide the duration of
treatment or the intensity shown to be most effective. Research on treatment outcome has
consistently demonstrated that individuals who are retained in outpatient treatments for
longer durations (typically 90 days or more) have better outcome than those who are
retained for shorter durations. In addition, in a prospective study in which cocaine-
dependent individuals were randomly assigned to to receive 30 days or 120 days of thrice-
weekly, manualized outpatient treatment, there was a significantly superior outcome
associated with the longer treatment episode. A study using random assignment found that at
4 months, working-class veterans treated in a day hospital program were about as successful
in reducing their cocaine use and improving social functioning as those treated in a 28-day
inpatient program. However, a somewhat higher proportion of those assigned to the inpatient
setting completed the 28-day program. Currently, severe depression with suicidal ideation,
psychosis, or substance use that has repeatedly failed to respond to outpatient efforts are the
indications for hospitalization. A retrospective study of individuals treated : for cocaine
dependence in various settings found no advantage in outcome for inpatient treatment lasting
more than 2 weeks.

In many instances, neither the patient nor the c selection of the setting and type of
treatment. Patients are often referred (mandated) to treatment by the criminal justice often
prefers long-term residential programs (therapeutic). The intensity and specificity of services
for panics (i.e., medical, psychiatric, and vocational) are now considered determinants of
outcome in the specific problem areas.

Detoxification The cocaine withdrawal syndrom is distinct from the opioid, alcohol, or sedative-hypnotic withdrawal syndrome
in that there are no physiological disturbances that necessitate inpatient or residential drug withdrawal. Thus, it is generally
possible to engage in a therapeutic trial of outpatient withdrawal before deciding whether a more intensive or controlled setting is
required for patients unable to stop without help in limiting their access to cocaine. Patients withdrawing from cocaine typically
experience fatigue, dysphoria, disturbed sleep, and some craving; some may experience depression. No pharmacological agents
reliably reduce the intensity of withdrawal, but recovery over a week or two is generally uneventful. It may take longer, however,
for sleep, mood, and cognitive function to recover fully.