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2
Overview of the State of Scientific Knowledge
Concerning Drug Addiction
This chapter focuses on opiates and cocaine, the two classes of drugs
targeted by the National Institute on Drug Abuse (NIDA) Medications Develop-
ment Division (MDD), and begins with an overview of the various concepts of
addiction that influence not only the current addiction-treatment methods, but
also the scientific investigation of current and potential pharmacological
approaches to treatment. For each of the two drug classes, an overview of current
scientific knowledge is presented. The remainder of the chapter discusses the
MDD cocaine-medication screening program and other strategies for the
discovery of an anti-cocaine medication. Conclusions and recommendations are
presented with reference to the specific activities of MDD.
CONCEPTS OF DRUG ADDICTION
The initiating event leading to drug addiction is the administration of an
agent, such as heroin or cocaine, to obtain a pleasurable effect. Repeated
administration can result in addiction defined by compulsive drug-seeking
behavior, loss of control over drug use, return to drug use despite repeated efforts
to stop, interference with social functioning, and often, impairments to health.
Addiction can be associated with the presence of tolerance or sensitization to the
effects of the drug and/or dependence, as evidenced by withdrawal symptoms if
the drug is abruptly stopped. The two most important psychiatric diagnostic
classification schemes, Diagnostic and Statistical Manual (APA, 1987) and
International Classif cation of Diseases (ICD-10 draft; WHO, 1990), emphasize
43
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44
DEVELOPMENT OF MEDICATIONS
compulsive drug-seeking and drug-taking behavior, rather than tolerance,
dependence, and withdrawal (see Appendix C for diagnostic criteria). However,
pharmacological definitions used in the scientific literature require the latter
symptoms to be present, and most opiate-addicted patients (although not cocaine-
addicted patients) seeking treatment, in fact, exhibit these symptoms.
Drug addiction involves a complex interplay of psychological, physiological,
and social mechanisms, and various models have been put forward to account for
these mechanisms (Jaffe, 19921. Figure 2.1 presents the schematic model of drug
dependence ~ developed by the World Health Organization (WHO), which
emphasizes individual and social antecedents and consequences. Such a model
is extremely useful, in that it offers numerous points at which interventions can
be made to prevent the establishment or break the cycle of drug dependence
through both individual and social means. Jaffe (1992) found it useful to modify
this scheme in two ways to emphasize more clearly aspects that might affect the
urge to engage in use of addictive drugs and aspects that might underlie
successful treatment or cessation of drug addiction (Figures 2.2 and 2.39.
Although development of effective anti-addiction medications is only one
component of the multifaceted approach needed to develop an effective national
strategy for drug-addiction treatment, this report focuses on the development of
pharmacological interventions, so the models emphasizing biological factors are
presented here. An established working model to account for drug addiction is
the "brain-reward hypothesis" i.e., a neural network is responsible for the
subjective experience of pleasure (Koob, 1992; Wise and Hoffman, 1992), and
drugs are abused after initial exposure because they activate the brain's reward
system. The neurons in the brain, particularly those in the regions comprising the
mesolimbic dopamine system (so called because it uses the neurotransmitter
dopamine) are thought to be prominent in the rewarding actions of drugs (Koob,
1992~. It is likely that only a small subset of dopamine neurons are specialized
for carrying reward-relevant information. Different classes of abusable substances
appear to act on this dopamine reward system at different anatomical levels and
via different sites of action on or near the dopamine neurons. Activation of the
reward system by addictive drugs induces an immediate sense of euphoria or
pleasure similar to that obtained through activities that naturally produce rewards
such as sexual pleasure. This reward effect, termed positive reinforcement, leads
to compulsive drug use.
In support of this hypothesis, basic research has shown that addictive drugs
reinforce voluntary drug-taking behavior in humans and laboratory animals
(Deneau et al., 1969~. The development of techniques for studying the
reinforcing effects of cocaine and opiates has allowed researchers to establish and
validate laboratory models of critical features of drug addiction the chronic re-
lapsing behaviors of drug-seeking and drug- taking (Griffiths et al., 1980; Brady
and Lukas, 19841. Basic research in laboratory animals has shown that drug
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THE STATE OF SCIENTIFIC KNOWLEDGE
45
reinforced behaviors are influenced by multiple factors including the phannaco-
logical properties of a drug and its specific neuronal receptors and effecter
systems, the learned behaviors and cognitions established during repeated
episodes of drug use, arid the environmental cues that accompany drug-seeking
and drug-taking (Griffiths et al., 1980; Young and Herling, 1986; Katz, 1989~.
Furthermore, evidence is accumulating that the reinforcing effects of cocaine arid
opiates can be reduced by medications that alter their ability to activate the
brain's reward system (e.g., Bergman et al., 1990; Woolverton and Kleven,
1992~. In the case of opiates, preclinical studies of methadone, levo-alpha-
acetylmethadol (LAAM), naltrexone, and buprenorphine in the reinforcement
model have yielded results consistent with those from clinical studies demonstrat-
ing the potential effectiveness of these medications as treatment approaches
(reviewed bY Mello, 1991, 19921. In the case of cocaine, preliminary data
suggest a good concordance between results of animal studies in the reinforce-
ment model and preliminary human trials of potential medications (e.g.,
Fischman et al., 1990; Kosten et al., 1992a). As our understanding of the
mechanism of drug addiction continues to improve, development of medications
to treat drug addiction will be enhanced.
SOCIAL AND INDIVIDUAL ANTECEDENTS
l
SOCIAL
INDIVIDUAL
SOCIAL AND INDIVIDUAL CONSEQUENCES
.
r 4' ~
~1
IMMEDIATE T
ANTECEDENTS ANTECEDENTS ~ I
e e.g. AVOIDANCE
peer groups ~ licensing laws LEARNING
family interactions social pressures \ ~/
parental drug use ava' a 'ty
variables \ /
~ ~ ~ L
IDISPOSITION ~;: _
Lit UG
~ r ~ , Few \
ANTECI [A' IMME DIATE / ~ ~\ _
e e.9. / APPR ACH
early learning ~ mood states I LEAR NING I
drug experience withdrawal states .
genet~cen ment i n
developmenta expectato s
events
T
4, ' ,
AVERSIVE
CONSEQUENCES
e.g.
toxic effects
reduced snug effect
organic damage
psychosoc al
dysfunction
NEURO
ADAPTIVE
STATE
REINFORCING
CONSEQUENCES
erg.
mood enhancement
psyching
taalitation
avoidanos or relist
of withdrawal
symptoms
.
i,
~ 1
l
| TOLERANCE |
. I
Y WrrHDRAWAL I
SYMPTOMS I
WHO 81023
FIGURE 2.1 World Health Organization schematic model of drug use and dependence
(Edwards et al., 1981). Figures 2.2 and 2.3 represent modifications and elaborations of
Figure 2.1. Reproduced, by permission of WHO.
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46
a'
DEVELOPMENT OF MEDICATIONS
| Approach L6aming | ~
me_
_. ~ 1
_! _-1
_~ ~
-1
~. _ _
- ~^ ~ ~ ~
_n Urge Co5,nltlYe I
_~_ (Incilnat~on ~ Rlsk/~r - fit ~
~ _ r ~J AN __
1~51 ~ T y ~ ~
_
. -- ~.
_ .
.......... ........
. ~
...........................
....... .... _
Em_
Fir
is;
~=-
~ ~] Jobrance ~
Positive
I .. _ I ~ Consequence.
no
Drug U8O ~ ~ -- I
~ ~aUve _
Consequences _
I Avoidance Learning I ~_
FIGURE 2.2 Modification of the WHO model. This figure is a modification of Figure
2.1 that emphasizes that processes that subserve the urge to use drugs can be distinct from
processes that subserve cognitive risk-benefit analysis and that both can be influenced by
distinct factors. Note consequences of alternative drug-use or no drug-use decisions and
variety of factors shown by recent research to influence mood, urge to use drugs, and ca-
pacity (coping skills) to avoid drug use. Reprinted with permission of Raven Press from
Jaffe, 1992.
Compulsive drug use is a chronic relapsing disorder, focusing attention on
how the behavioral and physiological effects of drugs change over long periods
of repeated use. Depending on the particular drug involved and its specific
effects, tolerance might develop and be marked (e.g., Fischman et al., 1985~.
Thus, the user might require increasingly large doses of the drug to obtain the
same effects; indeed the initial euphoric effects of a person's first experience
with the drug are difficult to reproduce and in some cases are never achieved
again. Sensitization can also occur; that is, the person might experience greater
effects of the drug at a constant dose. The same drug can produce tolerance to
some of its effects and sensitization to others.
Psychological and physical dependence implies that a definable, reproducible,
and undesirable withdrawal syndrome will occur if the drug is abruptly stopped.
For many addictive drugs, there is a definable acute-abstinence syndrome that is
qualitatively and quantitatively different from protracted-abstinence syndrome.
Acute abstinence, usually lasting for several days or weeks, is more intense and
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THE STATE OF SCIENTIFIC KNOWLEDGE
47
uncomfortable than protracted abstinence. Protracted abstinence is associated with
more subtle symptoms, such as nervousness, insomnia, depression, craving, and
vague feelings of discomfort and dysphoria. Symptoms of protracted abstinence
can last for months to years and can increase the probability of relapse, a return
to the addictive substance. The biological basis of protracted symptoms and
craving is virtually unknown. Nevertheless, after extended drug use, withdrawal
discomfort or"craving" contributes to sustained, compulsive drug use.
The final stage in the cycle of addiction is relapse. Relapse can occur even
after medical treatment of acute withdrawal symptoms and psychosocial
treatment for psychological and social problems associated with the addictive
disorder. Relapse can be triggered by some of the same factors that initially led
to drug use, but it often seems unrelated to the original cause of the drug use.
Intelligence, motivation, and high socioeconomic class do not necessarily prevent
relapse. Athletes have terminated careers involving millions of dollars in salaries
by relapsing to cocaine use.
1 1
r~
97O~n" I
~_1
~ _ ~_ Confluence l l l
Urge Cogaltive
(IncilneVon ~ Rl~ne
fou-J 4_rnent ~I
- ~_,~ ~
~ ~ ''"''
~ _ it_ _ ~
..... ,. ~. :. _ 1
............................
',:::. Hi - :: ::
.. , , , , .: .
:'::': ::~;o;c - :,:: "':
:: :' Coste:': :
:: .:: :: :: . .: . :. :: : :.
, ~ p-4lw 1
I| Con~qwnc~. |
Con~quencee
F~ -~f/.
.~ in :::
..... :.,,,;,
:~.":2 ,.. - W:;':'..:".2.
::::: :: molt ::::
......................
...................
L
TREATMENTS
1
FIGURE 2.3 Model of drug use and dependence including amelioration influences. This
figure is a modification of Figure 2.2 that deletes (for visual clarity) some relationships
shown in Figures 2.1 and 2.2 and introduces some of the multiple influences (including
treatment) that can ameliorate patterns of harmful drug use (including dependence).
Reprinted with permission of Raven Press from Jaffe, 1992.
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48
DEVELOPMENT OF MEDICATIONS
After a person has become addicted to a drug, relapse appears at times to
take on an involuntary aspect; this problem has been extensively reviewed
(O'Brien et al., 19921. Several categories of variables can contribute to relapse.
One factor involves the presence of protracted withdrawal symptoms, most
extensively studied in opiate-addicted patients and alcoholics (Martin and
Jasinski, 19691. There is some evidence that long-term brain changes occur after
chronic cocaine use, and these might be associated with protracted withdrawal
symptoms in cocaine addicted individuals (Volkow et al., 1990~. Relapse is also
associated with the presence of psychiatric disorders in addition to the drug
addiction (McLellan et al., 1979; Rounsavilleet al., 1982; Khantzian, 19851.
Another class of variables that has been linked to relapse is conditioning
factors, that is, environmental factors and physiological states that become
associated with each other over time (Wikler, 1973; O'Brien, 1975~. Extensive
reports show that the rewarding effects of drug use can become associated with
particular settings or environments; when formerly addicted patients have been
detoxified and treated in a drugfree program, there is an increased probability of
relapse to drug use if they are returned to the environment in which they had
used drugs (Pratt, l991~. Laboratory studies have demonstrated autonomic
nervous system and subjective changes in formerly addicted patients presented
with videotaped cues specific to the drugs that they had used (Ehrman et al.,
19921. Even highly motivated patients report that these cues produce strong
craving for the drug. Accordingly, the use of medications that are effective in
reducing the symptoms of protracted abstinence will need to be coupled with
behavioral techniques to address conditioned responses.
Addiction is characterized by compulsive drug use, tolerance, dependence,
craving, and relapse. Key problems in addiction are: how to prevent the onset of
compulsive drug use and how to prevent relapse and the craving that leads to
relapse. In the past, much medical attention has been given to treatment
(detoxification) for the symptoms of acute abstinence. Acute abstinence
syndromes related to a wide array of abused substances can be treated reasonably
well with available medications; treatment usually does not even require
hospitalization (Hayashida et al., 19891. However, the most difficult problem is
preventing relapse to drug use, and relapse prevention is the focal point of much
current addiction research, and it is the proper focus of the MDD program. Yet,
knowledge about the pathophysiology of the syndromes of protracted abstinence
and conditioned withdrawal or relapse is still rudimentary and presents an
important challenge to development of anti-addiction medications.
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THE STATE OF SCIENTIFIC KNOWLEDGE
BIOLOGICAL CORRELATES AND
PSYCHOPHARMACOLOGY OF ADDICTION
Opiate Addiction
49
Opiates can be thought of as a category of plant-derived compounds that
happen to activate a major biological system in mammals, the endogenous opiate
system. This activation produces many important cardiovascular, endocrine,
immune, and neurophysiological effects including euphoria, analgesia, and
addiction. Heroin is a well-known example of this group of compounds. These
compounds in high doses can produce death from respiratory depression. They
also produce abnormalities in the endocrine system that are not easily reversible.
Since the 1960s, it has become clear that the effects of opiate drugs are
mediated through interaction with opioid receptors. Moreover, studies of the
binding of various related opiate compounds in the brain and other tissues
indicate the existence of a multitude of opioid-receptor types and subtypes
(Leslie, 1987; Terenius and O'Brien, 1992~. The brain contains three major
categories of receptors (mu, kappa, and delta), each with at least two subtypes.
An opiate drug can simultaneously interact with all three types and act as an
agonist (a compound that fully activates a receptor) or partial agonist at each.
Binding to the mu receptor, however, is generally considered to be the most
important with respect to the pathogenesis of opiate addiction.
The rewarding and subjective effects of opiates are mediated through actions
at mu opioid receptors (Holtzman and Locke, 1988; Woods et al., 1988, 1993),
and interference with actions at these receptors presents a rational strategy for
developing medications for opiate addiction. Specifically, medications that block
activation of mu opioid receptors (e.g., naltrexone and long-lasting partial
agonists) might reduce drug-taking by preventing or reversing the reinforcing or
subjective effects of opiates, whereas medications that produce long-lasting
receptor activation and tolerance (e.g., methadone and LAAM) might reduce
compulsive drug use by substituting at the receptor site of action and block
euphoria and withdrawal (reviewed by Preston and Bigelow, 1991; Mello and
Mendelson, 1992~. Research examining the effects of opiate maintenance or
antagonist treatments on voluntary drug-rewarded behaviors in laboratory animals
(e.g., Jones and Prada, 1977; Harrigan and Downs, 1978; Mello et al., 1981 ~ has
provided the framework for rational development of medications for opiate
addiction (Mello and Mendelson, 1992~.
Until very recently, attempts to characterize the opioid receptor at the
molecular level had been unsuccessful. However, in 1992 the delta receptor was
cloned and sequenced (Evans et al., 1992; Kieffer et al., 1992~; the mu and
kappa receptors were similarly cloned (Chen et al., 1993a,b; Li et al., 1993;
Meng et al., 1993; Wang et al., 1993; Yasuda et al., 1993~. It is now possible to
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so
DEVELOPMENT OF MEDICATIONS
express the individual types of receptor in isolated cells, making it easier to
characterize their specific properties in detail. Such molecular studies will
undoubtedly facilitate the unraveling of some of the complexities of opiate drug
use and possibly addiction. They will probably also aid in the further identifica-
tion and development of agonists and antagonists (compounds that block
activation of the receptor) that are specific for an individual type of receptor. In
turn, the availability of such selective chemical probes might provide new
mechanistic insights that can be applied to the development of medications to
treat the various aspects of opiate addiction.
As a result of the identification of the opioid receptors in the early 1970s
endogenous Jigands (peptides) for the receptor were isolated and characterized.
These function as neurotransmitters, neurotransmitter modulators, or neurohor-
mones. Three distinct families of peptides have been identified: enkephalins,
endorphins, and dynorphins (Simon and Hiller, 1994~. Considerable knowledge
has been obtained with respect to the physiological role of the endogenous opiate
peptides in normal physiological function. Although the endorphins bind to all
three opioid receptor types, they bind preferentially to the mu-receptor, whereas
the enkephalins interact with delta and, to a lesser extent, mu receptors, and
dynorphins appear to interact with the kappa receptor. Beta-endorphin is present
in circulating plasma and appears to function as an endocrine hormone. Its
release is therefore coupled with the release of adrenocorticotrophic hormone
(ACTH) and melanocyte-stimulating hormone (MSH). The feedback of systemic
cortisol and endogenous, as well as exogenous, opiates on the hypothalamus
inhibits the release of pro-opiomelanocortin (POMC) peptides. Thus, the function
of the hypothalamic-pituitary-adrenal axis is intimately tied to the physiology of
the endogenous opiate system. In contrast, the other endogenous opiates seem to
have more neurotransmitter or paracrine functions.
Despite the accumulation of considerable knowledge about the impact of
opioid-receptor activity on physiological and behavioral functioning, including
tolerance and dependence, the molecular mechanisms involved remain to be
defined. All opioid receptors appear to be coupled to molecular effector systems
involving so-called G-proteins. By analogy to similar types of receptors, it is
likely that opiates regulate signaling across cell membranes that requires a
complex interplay of molecules including adenylyl cyclase, protein kineses, and
various ion channels (K+, Ca2+) (North, 1979; Crain et al., 1986; Childers, 1991;
Harris and Nestler, 1993; Nestler and Greengard, 1994~. Presumably, opiate
inhibition of adenylyl cyclase results in alterations in the structure (via phos-
phorylation) of intracellular proteins that change their functioning and account
for many of the acute effects of opiates on neuronal function (Nestler, 1992~. It
appears that adaptations in some of the same intracellular signaling pathways
represent part of the molecular basis of opiate tolerance and dependence. Despite
considerable progress in recent years (Guitart and Nestler, 1989; Guitart et al.,
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TlIE STATE OF SCIENTIFIC KNOWLEDGE
51
1990), much more understanding is required at this mechanistic level before it
can be applied to the discovery and development of treatment medications.
Recent information shows that among the many effects of endogenous opiate
peptides and opiates on neurons are changes in gene expression. Such alterations
in gene expression are presumed to be important in drug addiction because of its
gradual and progressive development and the persistence of many of its features
long after discontinuation of drug exposure. Studies have demonstrated that
opiates can regulate some transcription factors that are important in neuronal
gene expression (Chang et al., 1988; Hayward et al., 1990; Guitart et al., 1992;
Nestler et al., 1993~. That could be important in the long-term adaptations
induced by opiates in the brain that ultimately lead to addiction. Many other
additional, and poorly understood, adaptive changes probably also contribute to
opiate reinforcement, tolerance, and dependence (Nestler, 1992; Nestler et al.,
1993).
Work to date suggests that use of opiate drugs can effect long-term changes
in the brain that can be successfully treated with medications. Although mu and
delta opioid receptors appear to play important roles in the development of opiate
tolerance and dependence, it has been difficult to relate reinforcement, tolerance,
or dependence to changes in these receptors themselves (Loin and Smith, 1990;
Nestler, 1992~.
The acute withdrawal of opiates from humans who are tolerant to and
dependent on those drugs produces a reproducible physiological syndrome. The
syndrome consists of yawning, lacrimation, rhinorrhea, perspiration, mydriasis,
tremor, gooseflesh, restlessness, myalgia, anorexia, nausea, vomiting, abdominal
cramps, diarrhea, fever, hyperpnea, hypertension, and, if prolonged, weight loss
(Kleber, 1981~. Many of these acute manifestations of opiate withdrawal
represent hyperactivity of the noradrenergic system, thought to be mediated by
the loss of opiate feedback inhibition to a specific brain region, the locus
ceruleus (Gold et al., 1979; Koob, 1992; Nestler, 1992~. The alpha-2-noradre-
nergic agonist clonidine reduces noradrenergic activity by autoreceptor activation
and can ameliorate many of the signs and symptoms of early withdrawal.
However, clonidine has proved to be of limited usefulness in the treatment of
opiate craving and in the prevention of relapse to addiction (Kleber et al., 1985;
Fraser, 1990~.
After acute withdrawal of opiates most drug-free formerly addicted patients
will still feel uncomfortable. Discomfort can take the form of quantifiable
symptoms such as restlessness, irritability, poor concentration, and sleep
disturbances which might persist for months or even years (Pratt, 1991~. Those
symptoms are not relieved by clonidine. Subjects on clonidine might also
complain of drug craving and engage in drug-seeking behavior and relapse to
drug use. However, methadone, a mu-receptor agonist, is capable of blocking the
euphoria of simultaneously administered opiates and inhibiting the symptoms of
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52
DEVELOPMENT OF MEDICATIONS
acute and chronic abstinence, including craving. Its clinical efficacy has been
shown to be dose-dependent and enhanced by the provision of ancillary
psychosocial services (McLellan et al., 1993~.
About 117,000 heroin-addicted individuals in the United States are being
treated with methadone and are able to perform normally in the workplace (see
Chapter 4 for discussion of the effectiveness of methadone maintenance
treatment). An additional benefit of methadone treatment is that it can give
opiate-addicted patients, who typically suffer from multiple medical problems,
access to other health-care services. A good methadone program can provide
medications for infectious diseases and treatment of psychiatric disorders and
other clinical problems that often accompany and aggravate opiate-addicted
patients' health status.
LAAM, another opiate agonist has recently been approved for use in the
treatment of opiate addiction, primarily because of MDD's efforts and those of
the Food and Drug Administration (FDA). LAAM is similar to methadone but
stays in the body longer and has active metabolites that persist for days, so it can
be taken as infrequently as three times per week. For some patients not having
to go to a clinic daily for medication removes a major disruption from their
lives.
Naltrexone, an antagonist, exploits the specificity of opiate binding to the mu
opioid receptor. Naltrexone binds preferentially to the mu receptor and so
prevents the binding of any opiate agonist. In animal studies, naltrexone acts to
block or reverse the rewarding and subjective effects of mu opiates, and in fact
its affinity for the mu receptor is 140 times greater than that of morphine
(Holtzman and Locke, 1988; Woods et al., 19931. Naltrexone is being used
clinically after detoxification and acute withdrawal to help patients stay off opiate
agonist by blocking their effects. Thus, patients taking naltrexone cannot achieve
euphoria if they take heroin, so the positive reinforcing effects of opiate
addiction are reduced or eliminated (Rose and Levin, 1992~. Naltrexone,
however, does not relieve all the symptoms of protracted abstinence. In
particular, craving, anxiety, and depression are still present, and a person being
treated with naltrexone can readily relapse if the naltrexone is stopped. For this
reason, naltrexone has proved most valuable in highly motivated addicted patients
who have a great socioeconomic risk or other risk associated with relapse, such
as medical personnel or parolees. MOD is developing an improved delivery
system for naltrexone that would reduce treatment failure due to noncompliance.
An implantable "depot" form of naltrexone, for example, that lasts 30~0 days
would help a patient who is ambivalent about remaining opiate-free.
Buprenorphine is another new medication for the treatment of opiate addic-
tion. It is a partial mu agonist; i.e., it can mimic the effects of agonists under
some conditions (especially conditions in which low doses of agonists are
effective) but antagonize effects of agonists under other conditions.
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THE STATE OF SCIENTIFIC KNOWLEDGE
New approaches to medications for opiate addiction might include
.
53
More effective forms of the above medications for example,
agents that selectively interact with the various opioid-receptor subtypes or
novel partial agonists that work at the mu opioid receptors.
A completely new category of medications, such as anticraving
compounds to reduce relapse in patients who have been detoxified from
opiates.
.
A wealth of scientific information and understanding of opiate effects,
ranging from the clinical to the molecular, has been obtained over the last several
decades. This information will continue to grow, especially at the molecular
level, primarily through NIDA-supported research. MDD should continue to
apply new fundamental knowledge to the study and development of potentially
more specific medications for opiate addiction. These might include delta
receptor agonists and antagonists or novel partial agonists. At the same time, the
clinical evaluation of new medications (such as buprenorphine) or delivery
systems (e.g., depot naltrexone) should be continued. Finally, a long-term
scientific program should be established with the focus of developing a
completely new category of medications based on their anticraving effects.
Cocaine Addiction
Cocaine addiction differs importantly from opiate addiction. Opiates produce
an initial calming effect, and dosing takes place two to four times per day. But,
cocaine is a stimulant that produces intense, brief euphoria, and dosing typically
takes place as often as every 15-30 minutes for hours or even days. Cocaine
users tend to use the drug intermittently in binges, rather than in relatively stable
daily doses. Cocaine can be taken by several routes; its toxicity depends on its
concentrations in the blood and brain. The euphoric effect of cocaine is a
function not just of the blood concentration, but of the rapidity and degree of rise
of that concentration. The faster the drug reaches the brain, the more euphoric
the effect; if the drug is taken intranasally, this takes 90 seconds, intravenously
or by smoking 15 seconds (as this involves no dilution with venous blood from
the rest of the body).
A major pharmacological effect of cocaine associated with its addictive
properties is on the dopaminergic system of the brain (Koob, 1992; Wise and
Hoffman, 1992~. Specifically, cocaine blocks the reuptake of dopamine in the
synaptic cleft by the dopamine transporter. That increases the amount of dopa-
mine available to dopamine receptors and leads to activation of dopaminergic
pathways. Although the brain contains several neural pathways rich in dopamine,
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THE STATE OF SCIENTIFIC KNOWLEDGE
63
Clinical Trials
In the absence of a clear understanding of the complexity of cocaine's
effects on the brain and lack of candidate compounds, there is an alternative
approach to identifying potentially useful medications for cocaine addiction:
evaluation of the efficacy of currently available psychopharmacological agents
to treat the various aspects of cocaine addiction. A number of drugs, approved
for indications other than treating drug addiction, have been clinically investi-
gated over the last several years. Many of these investigations have been investi-
gator-initiated and spontaneous (not necessarily funded by NIDA).
That strategy was taken with gepirone, a drug that facilitates serotonin
neurotransmission in the brain, and bupropion, an antidepressant with stimulant
properties. The findings were negative for both compounds. They were tested
initially in multiclinic trials, however, if gepirone and bupropion had first been
evaluated in more moderate-sized double-blinded trials, resources could have
been saved and the multiclinic strategy reserved for more promising medications.
Unfortunately, the typical history has been that open clinical trials of
potential medications have shown apparent effects but there has been failure to
confirm such effects consistently in carefully controlled studies. Even agents that
show effectiveness in double blind studies (e.g., desipramine in Gawin et al.,
1989) might not be effective for different populations such as cocaine-using
methadone patients, unless subpopulations are carefully analyzed; e.g., desipra-
mine showed effectiveness in the methadone studies if antisocial-personality
patients were removed from the analysis (Arndt et al., 1992; Arndt et al., in
press; Kosten et al., 1992b; Leal et al., in press).
The committee believes, however, that studies should be designed to take
full advantage of serendipity. The study design is critical; nonblinded and
uncontrolled studies should be avoided (Fraser, 1990~. Randomized controlled
trials with enough patients to ensure adequate statistical power are preferred. The
process by which subjects are selected for study should control for confounding
variables such as polydrug use; 20 percent of cocaine users self-medicate the
cocaine crash with ethanol; 50 percent of opiate users also use cocaine, and psy-
chiatric comorbidity must be controlled for because cocaine-addicted patients
with other diagnoses especially attention deficit disorder, major depression, and
bipolar disorders- respond differently to different medications (Metzger et al.,
19891. In addition, studies that include subjective ratings of craving should be
confirmed objectively, with a urine screen.
The committee believes that candidate compounds should be tested
in rigorously controlled, moderate-size trials and in a limited
number of sites; promising compounds can then be further
evaluated in multi-clinic settings.
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64
DEVELOPMENT OF MEDICATIONS
It has been shown that statistically significant results can often be achieved
when 20 to 30 individuals participate in a clinical trial in both the test and
placebo controlled groups (Alterman et al., 1992~. While the committee acknow-
ledges that the power analysis indicates that small effects will be missed, they
nonetheless believe that the ability to screen more substances for substantial
effects, with the given resources, is worth the risk of missing small effects.
Not only would that approach save resources, but moderate-sized studies can
often answer the questions being posed by the larger, multiclinic studies more
quickly. Finally, selection of compounds based on a systematic analysis of
chemical structure would be advantageous before selection of drugs for clinical
evaluation. Promising candidates might also be initially evaluated with
appropriate laboratory methods (Fischman and Foltin, 19921. MDD's focus on
evaluating multiple members of the same classes of compounds might be
questionable and could result in nonproductive, resource-intensive efforts for
many years.
The clinical evaluation of promising medications, whether derived from
screening procedures or from the armamentarium of currently approved drugs,
is resource-intensive, and the validity of the findings depends heavily on
appropriate experimental design.
Human Behavioral Models
Two test models that have been developed in human subjects are used to
screen potential medications for their efficacy in the treatment of cocaine addic-
tion (Fischman and Foltin, 1992; Robbins et al., 19921. These tests are conducted
in the laboratory and are completed more rapidly than long-term clinical trials.
They have not yet been sufficiently validated as to their predictive potential for
determining medications that are likely to be effective in clinical trials.
In the first model, volunteers are given the opportunity to take repeated
doses of cocaine, with doses and patterning approximating those reported in
natural settings (Fischman and Foltin, 19921. Separate measures are made of the
amount of drug taken, cardiovascular effects, subjective effects, and craving. The
results can be compared with the results measured when the volunteers are given
potential treatment medications. In addition, volunteers are given the opportunity
to choose between cocaine and nondrugs (a similarity to the ordinary setting,
where alternative reinforcers are available); this allows the investigator to deter-
mine how medications might interact with other behavioral treatment approaches
(Fischman and Foltin, 19921.
The second model evaluates human subjects' responses to cocaine-related
cues (Robbing et al., 19921. It relies on the conditioned effects of long-term
cocaine use. It has been noted that after detoxification cocaine-addicted patients
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THE STATE OF SCIENTIFIC KNOWLEDGE
65
with the determination to refrain from further cocaine use, regardless of the form
of psychotherapy, are likely to experience involuntary reactions (such as cocaine
craving and other psychological changes) when they return to areas in which they
previously used cocaine. Those reactions can also be produced by videotape or
other stimuli associated with cocaine even when presented to drugfree former
cocaine-addicted patients in the laboratory. A medication that dampens these cue-
elicited responses might have a protective value in the enhancement of cocaine
treatment programs.
Theoretically, a large number of compounds could be screened with the two
models, and those which seem to dampen drug-taking or the craving response
could be studied in clinical trials that are more time-consuming and costly.
CONCLUSIONS AND RECOMMENDATIONS
The initiation and maintenance of drug addiction are complex, involving
psychologic, physiologic, interpersonal, and social variables. Of particular focus
in the MDD program is development of refined medications to treat opiate-
addicted patients and the discovery of compounds that will be effective in
treating cocaine-addicted patients. The concept of using medications to help to
treat drug-addicted individuals is based on the physiological correlates of drug
addiction, and the strategy has been shown to be extremely useful as part of the
treatment of opiate addiction. Development of effective medications, however,
depends heavily on an adequate knowledge base derived from basic scientific
studies. Although the science base for opiates is rich, there are large gaps in
knowledge about cocaine. In addition, patterns of cocaine use differ greatly from
patterns of opiate use and the differences must be taken into account in
understanding the physiological underpinnings of the use of these drugs. The
largest gaps are related to craving, which likely represents the most important
factor in relapse to drug use once an addict is detoxified and enters treatment.
Emerging evidence suggests that chronic administration of both opiates and
cocaine produces adaptive responses in numerous behavioral and physiological
systems. Research on tolerance and sensitization suggests that chronic drug use
can change the neuronal systems with which addictive drugs interact, but only
rudimentary information is available on the cellular and molecular bases of these
changes for either opiates or cocaine. Moreover, treatment medications
themselves can have different effects in acute or repeated administration, and
relatively little is known about how chronic treatment with a medication can alter
the subjective or voluntary components of addiction. For those reasons, the
committee believes that it is imperative to foster NIDA's basic research efforts
in the mechanism of cocaine addiction and in the molecular, cellular, and
behavioral bases of chronic drug effects. Basic research to develop laboratory
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66
DEVELOPMENT OF MEDICA TIONS
models of critical behavioral characteristics of the addictive process is also
needed.
Current clinical understanding of the addictive process suggests that models
of drug-craving and relapse can be particularly important for medication
development. Animal studies exploring such processes as conditioned-stimulus
control of drug taking, incentive and motivational effects, and priming effects
have begun to identify potential targets for treatment medications. Identification
of such behavioral models must be followed by extensive pharmacological and
behavioral characterization to provide benchmarks for evaluation of potential
medications. A basic understanding of"craving" is also needed at both the
clinical and preclinical levels. Therefore, the committee strongly believes that
unless basic research is supported at an appropriate funding level, it will be
difficult to make important progress in the scientific knowledge base. The lack
of such knowledge would continue to hamper the private sector and MDD in the
development of a medication.
In relation specifically to MDD, the committee recommends two mechanisms
to address the critical issue of supporting basic science:
The committee recommends that MDD be given a high priority for
funding. Although MDD was authorized at $95 million in FY 1994,
its appropriation of $40 million has fallen far short of this mark
and is far below what is needed for research and development.
The committee is aware, however, of the budget constraints on the institutes
of the National Institutes of Health (NIH); as a possible mechanism for increased
support, the committee suggests the use of funds from the Special Forfeiture
Fund in the Office of National Drug Control Policy (ONDCP).2 Utilizing a
2The ONDCP Special Forfeiture Fund results from the transfer of money from the
Federal Asset Forfeiture Fund (described below). In FY 1990, the Federal Assets
Forfeiture Fund transferred $117 million to federal law-enforcement agencies. Deposits
of $17 million were also made to the Special Forfeiture Fund to supplement ONDCP
program resources and of $115 million to support Federal prison construction. The use
of the Special Forfeiture Fund is at the discretion of the director of ONDCP.
The Federal Asset Forfeiture Fund is a sum of money resulting from the sale of
assets used in criminal activity that have been seized by the government. In 1990 DEA
seized assets valued at more than $1 billion. About two-fifths of the assets seized by DEA
was currency valued at almost $364 million. In addition, DEA seized $346 million worth
of real property, 5,674 vehicles worth over $60 million, 187 vessels valued at over $16
million, and 51 airplanes worth over $25 million. Almost two-thirds of DEA's seizures
during 1990 resulted from cocaine investigations. DEA seizures that were ultimately
forfeited are valued at more than $427 million in 1990 (BJS, 1992~.
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THE STATE OF SCIENTIFIC KNOWLEDGE
67
portion of those funds for basic research not only would provide additional
money to MDD, but would demonstrate executive-branch support.
The committee recommends that NIDA designate national drug
abuse research centers, subject to congressional appropriations, as
described in the ADAMHA Reorganization Act [Public Law 102-
321, Section 464N (a)l, "for the purpose of interdisciplinary
research relating to drug abuse and other biomedical, behavioral,
and social issues related to drug abuse." These centers would be
engaged in and would coordinate all aspects of drug-abuse research,
treatment, and education.
The committee intends that the designation of such centers would serve as
focal points for all aspects of drug-abuse research and would have the added
benefit of encouraging new investigators to enter the field; they would also serve
as sites for clinical trials and for training clinicians (see Chapter 6 for additional
text and recommendations on comprehensive centers). The characteristics of the
centers should include the conduct of basic research, clinical research, high-
priority clinical trial research, and other applied research, drug abuse prevention,
training, information, and community service and outreach. One possible
mechanism for funding the centers could be through the use of core grants
(similar to those used by the National Cancer Institute) because they are designed
to bring together an institution's research efforts into a single administrative
structure. The grant provides funds for the operation of a centralized administra-
tive staff, resources, and services. It may also provide funding for newly
recruited investigators or investigators who have not previously been supported
by grants (Chapter 6~. By using the core grant mechanism the centers would have
the flexibility to explore new research leads. The core grants are not directly
designed to support laboratory and clinical research, but they do so indirectly.
Alternative funding mechanisms might include the use of contracts, CRADAs,
or cooperative agreements between NIDA and the designated center. It should be
noted that NIDA does have a number of specialized research centers, but they are
more narrowly focused and lack the flexibility of the centers suggested here.
With the designation of such centers, the committee believes that progress
will be made in basic, clinical, and other applied research in and treatment of
drug addiction. Furthermore, the paucity of basic knowledge in this field is best
approached through the coordinated effort that the centers are likely to achieve.
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Representative terms from entire chapter:
drug addiction
