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Review of Treatments for Cocaine Dependence

*J.K. Penberthy, N. Ait-Daoud, M. Vaughan, & T. Fanning

Department of Psychiatry & Neurobehavioral Sciences

University of Virginia Health System

Charlottesville, Virginia

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Abstract

Cocaine dependence is a complicated, destructive, and often chronic illness that is difficult to

treat. In this article we review the challenges in treating cocaine dependence, as well as recent

developments and future directions in psychosocial and pharmacological treatment relevant to

treatment of cocaine dependence. Cocaine is one of the most addictive drugs because of its immediate

and powerful rewarding effects. Often, cocaine dependent individuals experience difficulty abstaining

due to cognitive impairments from repeated cocaine use, strong use-related social and environmental

cues, and high levels of life stress. Cocaine use also affects areas of the brain related to motor function,

learning, emotion, and memory, further complicating the administration of effective interventions. In

addition, development of treatments for cocaine dependence has been complicated by the tendency for

abusers not to complete treatment programs and their propensity for relapse. Despite these challenges,

some treatment approaches, such as cognitive behavioral therapy [CBT] and medications have shown

promise in successfully treating cocaine dependence. However, individually, each of these treatments

exhibit weakness in longitudinal studies where long-term abstinence is the primary outcome of

interest. Although other treatments are being explored, thus far, the combination of CBT and

pharmacotherapy has elicited the best results for treating cocaine dependence with respect to patient

retention and relapse prevention following abstinence. No treatment method has yet been shown to

completely and effectively treat cocaine dependence. More research is necessary to test treatment

programs and garner further information in order to better understand and treat cocaine dependence.

Keywords: cocaine dependence, effective treatments, cognitive-behavioral therapy, topiramate, disulfiram

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Introduction

The 2007 National Survey on Drug Use and Health reports that 35.9 million Americans, 12

years and older, have used cocaine in their lifetime and that 5.7 million have used cocaine in the past

year. Cocaine is presently the most abused major stimulant in America [1]. Cocaine abuse is

characterized by a maladaptive pattern of use which results in one or more recurrent and significant

adverse events, such as difficulty fulfilling major role obligations at work, home or school, use in

physically hazardous conditions, legal problems stemming from using, or continued use despite

recurrent social/interpersonal problems caused by use. Cocaine is a powerful stimulant that when

abused, typically quickly leads to dependence. Cocaine dependence is characterized by the continued

use of cocaine despite significant substance-related problems. Specific criteria include manifesting

three or more significant impairments or signs of distress which must occur in the same 12 month time

period. These include: using more cocaine or over a longer period of time than intended; having a

persistent desire or failed efforts to reduce use; spending a great deal of time using, and thus reducing

other important social, occupational, or recreational activities to use; using despite physical or

psychological problems that are caused or worsened by use; and development of tolerance or

withdrawal. The fundamental mechanisms of cocaine dependence are not yet fully understood. Aside

from its high risk for abuse and dependency, cocaine use poses health risks that include respiratory

failure, cardiovascular complications, gastrointestinal problems, mental disturbances such as paranoia,

and other serious consequences that can lead to death [2]. In addition to these serious implications,

cocaine use has been found to have direct negative cognitive effects on the brain, affecting tasks

related to inhibition, memory, concentration, problem-solving, learning, planning, attention, and

discrimination [3].

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Cocaine is a crystalline tropane alkaloid that is extracted from the leaves of the coca plant [2].

It acts as a stimulant of the central nervous system, specifically as a dopamine reuptake inhibitor,

creating a feeling of euphoria and increased energy [2]. Cocaine is typically used in one of the

following three forms: hydrochloride salt, freebase cocaine, and crack cocaine. The hydrochloride salt

is a powder that is administered through snorting or dissolved in water and injected intravenously [1].

Freebase cocaine involves chemically treating the hydrochloride salt with a base, in order to smoke it,

generating a high within minutes [2]. Crack cocaine is processed from freebase cocaine using

ammonia and is left in a ‘rock’ form. When crack cocaine is smoked, it makes a distinct crackling

noise, hence the name [1, 2].

Two main challenges associated with treating cocaine dependence include treatment retention

and relapse [4]. The primary addictive triggers that instigate drug use are psychological or

physiological stresses, social and environmental cues, and the presence of cocaine itself [5]. Cocaine

directly affects neurological function, creating a conditioned response for use and pleasure, a pattern

that is difficult to break [6, 7].

Cocaine dependence is a problem to which there are few good treatment options. Research is

currently underway examining the role of medications including topiramate and disulfiram to combat

cravings [8, 9]. In addition, cognitive behavioral therapy [CBT], a psychotherapy treatment method

focused on changing problematic thoughts and behavioral patterns related to use, has been found to be

effective in treating both alcohol and cocaine dependence [10, 11]. While both pharmacotherapies

and behavioral therapies have strengths and weaknesses when used alone, they exhibit greater utility

and strength when used together to treat substance dependence [9].

Cocaine Dependence

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In cocaine-dependent individuals, many areas of the brain are impacted, making effective

treatment and patient retention difficult [12]. One of the areas affected by cocaine use is the frontal

lobe of the brain. The frontal lobe is associated with emotion, problem solving, memory, judgment,

impulse control, and spontaneity [6, 7, 13]. Cocaine use leads to hypofrontality, or reduced activity in

the frontal portions of the brain, and this negatively impacts effective decision making and lowers

motivation for goal directed activities [14].

Cocaine and the dependence pathway

Brain pathways involved in creating a stimulus-reward response for cocaine are natural

pathways that encourage certain appetitive and pleasurable behaviors such as eating and sex [2]. In

humans and other animals, these pathways promote engagement in and repetition of behaviors that are

rewarding. The stimulus-reward response creates pleasurable feelings that serve as positive

reinforcement for the behavior, leading to the likelihood that a given behavior will be repeated in an

attempt to recreate the feelings. Psychomotor stimulants, such as cocaine, in addition to healthier

behaviors, such as sex and eating, cause the release of dopamine in the nucleus accumbens, creating

feelings of pleasure [15] that serve to reward drug-taking behavior.

When cocaine is administered to the body it enters all parts of the brain, binding to specific

sites involved in reward and dependence: the ventral tegmental area [VTA], nucleus accumbens, and

caudate nucleus [3]. This activated pathway is known as the mesolimbic dopamine reward pathway

[15]. The VTA is connected to both the nucleus accumbens and the prefrontal cortex by the ‘pleasure

pathway’ and sends information to these cooperating structures via its neurons [3]. The neurons of the

VTA contain the neurotransmitter dopamine, which, when activated by a rewarding stimulus, is

released in the nucleus accumbens and the prefrontal cortex [3, 16]. Once inside the synaptic cleft,

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dopamine binds to the dopamine receptors, and then is released for reuptake, promoting pleasurable

sensations. [3].

Animal research suggest that cocaine may act as a dopamine transporter antagonist, blocking

dopamine from binding at the transporter site, and preventing the reuptake of dopamine [3]. This

function floods the synapse with dopamine and creates an extended state of euphoria, eventually

leading to dependence [3, 7, 17]. However, with long-term use of cocaine, the number of receptors

varies depending on the area of the brain as the nervous system tries to adapt to this high level of

dopamine. In rats, the density of dopamine receptor D1 in frontal cortex is either unchanged or

slightly increased 20 minutes after the last cocaine daily injection, but was decreased 2 weeks later. D1

sites in striatum are decreased both immediately and 2 weeks after the injection regimen. Decreases in

D1 binding site density in nucleus accumbens were observed only immediately after the last injection.

In contrast to these effects on D1 binding sites, D2 binding sites were decreased in striatum and frontal

cortex and increased in the nucleus accumbens 20 minutes after repeated cocaine, but were unaffected

2 weeks after repeated cocaine. Furthermore, cocaine caused opposite, transient effects on D1 and D2

site density in nucleus accumbens [New 18]. Consequently, the brain becomes more sensitive to and

reliant on the excess presence of dopamine, creating both a physical and psychological dependence

that leads to an intense desire to use cocaine again to attempt to re-experience the first initial “high”

[3]. Over time, the same amount of cocaine has a reduced effect. As a result, in many cases, the user

will only feel good, or “normal” by using cocaine [19]. After cocaine dependence has developed,

users often experience an inability to feel pleasure without cocaine, leading to depression, increases in

impulsive behavior, and further drug use [19].

Using positron emission tomography [PET] scans in humans, Volkow found that detoxified

cocaine abusers have fewer dopamine D2 receptors in the basal ganglia than normal controls [20].

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This deficit was long-lasting and persisted even as long as four months after detoxification. These

dopamine D2 receptors low densities were also associated with decreased metabolism in the

orbitofrontal cortex, an area associated with obsessive-compulsive disorder [OCD]. It is tempting to

conclude from these results that cocaine use may affect the brain in a way that makes drug taking a

compulsive behavior. One of the long-term effects of repeated cocaine use may be a state of relative

dopamine dysfunction. This dopaminergic activity downregulation may help explain the anhedonia

reported by cocaine users, and the fact that they use cocaine to reverse the negative emotional state in

an attempt to go back to normal mood and functioning.

Other areas of the brain impacted

Brain scans and medical studies show that certain areas of the brain of cocaine dependent

individuals are less active while other parts of the brain exhibit heightened activity [7]. Furthermore,

PET scans in cocaine dependent patients have indicated activation in the limbic and frontal structures

of the brain that is dissimilar from those of control subjects [7]. Specific structures involved in the

excitation include the amygdala, which functions in stimulus-reward associations and emotion, the sub

callosal gyrus and nucleus accumbens, which are associated with incentive motivation and pleasure,

and which helps to explain the underlying reinforcing effects of drug use. The anterior cingulate gyrus,

which is associated with anticipation, emotion, learning, memory, and controlling actions also exhibits

similar effects [7, 16, 21]

Another major brain system that has demonstrated differences in cocaine dependent individuals

is the white matter of the brain, composed of myelin, which increases impulse speed and through

which messages and nerve impulses pass. In cocaine users, the white matter content has been found to

be lower than in non-cocaine users [22]. The loss of this matter suggests that the users’ myelin

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production has decreased, a condition called demyelination, and which can lead to speech impairment,

memory loss, and decreased motor function [22].

As a dopamine transporter antagonist, cocaine eliminates the natural effects of dopamine

reuptake, therefore inducing a state of dopaminergic down regulation. In twenty-four cocaine-

dependent participants and an equal number of matched healthy subjects, cocaine dependence was

associated with a marked reduction in amphetamine-induced dopamine release in the striatum. Blunted

dopamine transmission in the ventral striatum and anterior caudate was predictive of the choice for

cocaine over money. This altered dopaminergic function may play a critical role in relapse [17]. The

decrease in dopamine in these previously identified brain regions could explain the difficulty that

people addicted to cocaine have in altering their habitual behavior. It may also explain their inability,

at times, to respond positively to therapy and different rewards to encourage healthier behaviors. In

cocaine dependent patients, the over stimulation of certain neural circuits may impair inhibitory

functions, which can then lead to lessened behavioral control and result in continued drug use, despite

efforts towards abstinence [6].

Brains scans of both cocaine dependent and control subjects show activity in the dorsal

striatum, involved in the selection and initiation of actions, reflexes and habits, as well as reward and

cue association [23]. This stimulation is implicated in habit formation as well as in the subjective

experience of “desire.” Identical neural activation is shown in images when both subjects are

prompted with images of food. In cocaine-dependent individuals, the same activation is evident when

subjects are shown images of cocaine, demonstrating that the same neural processes are activated for

natural rewards necessary for survival and for the drug of abuse [23].

Relapse and Retention

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Cocaine is a highly addictive substance that creates a high level of dependence and physical

harm [24]. Cocaine users often increase their dose in order to intensify and prolong the euphoric

effects created by cocaine [19]. Herein lays the danger of cocaine: because of its intense

psychological effects the user may pursue a more intense and enduring ‘high’ by increasing their

dosage. This increased dosage of cocaine ultimately may accommodate this excess by affecting the

brain’s dopaminergic function in key areas [3, 19].

The psychological and social aspects of cocaine dependence complicate its treatment, leading

to low rates of patient retention in treatment programs as well as high rates of patient relapse [25].

The main obstacles to retention include the often chaotic lifestyle and environment in which the

cocaine dependent patient lives, lack of motivation to change, and compromised cognitive functioning

of the patients, which affects their participation in treatment, and increases rates of relapse [4]. The

three major stimuli which trigger relapse are psychosocial stress, environmental and social cues, and

the presence of the drug itself [5]. These triggers are hypothesized to promote pleasant or rewarding

thoughts of use and promote permissive thoughts that encourage or allow use of the drug.

In addition, confounding issues associated with cocaine dependence include cognitive and

behavioral impairment, and co-morbid psychiatric disorders such as alcohol and drug abuse and

dependence, depression, Attention Deficit Hyperactive Disorder [ADHD], Obsessive Compulsive

Disorder [OCD], and Antisocial Personality Disorder [6]. Data show that cocaine abusers display

difficulty adapting their behaviors to environmental changes. They exhibit difficulty in functioning in

new and different situations or interacting with new people, and typically avoid deviating from their

established routines [6]. Studies show that early onset cocaine users exhibit impaired social skills

[26], which may be due to their developing cocaine-seeking behavior, or the effect of the interaction of

the drug with the frontal lobe in the brain, which is associated with emotional regulation.

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Further contributing to difficulties with treatment retention and relapse is the underlying issue

of cocaine’s prevailing effects on the brain. Long-term use is associated with deficits in performance

of neuropsychological tasks in memory, attention, learning, problem-solving, perceptual motor speed.

Neuroimaging studies have shown impairments of the frontal lobe function, which serves to regulate

behavioral control via suppression or termination of environmentally-triggered responses [6]. In

addition, data suggest repeated dopaminergenic activation by cocaine in neural circuits eventually

impairs inhibitory functions, resulting in a loss of control over behavioral impulses, including the

impulse to continue using cocaine [6].

Kelley found cognitive impairment pertaining to visuo-spatial tasks and concentration

developed in cocaine-dependent individuals under going acute withdrawal at 72 hours and up to 14 to

18 days [27]. These individuals recorded poor performance in tasks of cognitive flexibility, tasks

which are mediated by the anterior cingulate gyrus and the dorsal striatum in the frontal part of the

brain which, as was mentioned earlier, are activated by cocaine administration [7]. It appears that the

neural circuitry activated by cocaine use becomes somewhat deactivated in the absence of the drug.

Consequently, this mechanism contributes to abstinence becoming a major obstacle for addicts to

overcome, as they are forced to re-learn normal cognitive tasks in the absence of cocaine, and re-wire

their neural pathways to function normally without cocaine [7, 17, 22].

In research using cocaine-treated rats, Stalnaker attributed deficits in decision-making and

trouble with reversal-learning or unlearning certain behaviors to cue-selective neurons in the

basolateral amygdala [13]. The rats displayed a failure to change cue preference [choosing cocaine

over food for reward] during reversal learning, which researchers attributed to persistent encoding of

outdated associative information in the basolateral amygdala [13, 28]. Cocaine exposure and

associated cues affect behavioral flexibility [e.g. learning novel responses] related to the basolateral

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membrane and continues to affect behavior even in the face of negative consequences, contributing to

relapse and compulsive drug-seeking [5, 13, 28].

Stress and drug cue exposure increase perceived arousal and cocaine cravings, leading to

relapse [5, 25]. In attempting to abstain from cocaine use, individuals frequently experience

emotional, physical, and social stresses [19]. These stressors can arise from their social home

environment, if people they live with use or if they live in close proximity to where they can obtain

cocaine. Furthermore, removing cocaine from the brain exerts a physical stress on the neural circuitry,

as it has become reliant on cocaine to function normally to offset the dopaminergic dysfunction [25].

Cocaine exerts its primary rewarding effects on the stress-dependent mesolimic dopamine reward

pathway [15]. Studies show a positive correlation between stress and drug craving, implying

activation of the reward pathways following exposure to stressors as well as triggers and cues

associated with cocaine use [15]. Sinha found stress-induced cocaine cravings and action of the

hypothalamic-pituitary adrenal [HPA] axis, responsible for stress and craving, are positively

associated with cocaine relapse [25]. Data show a direct correlation between the elevation of the

stress hormones and the average cocaine use per occasion [25].

Cocaine administration, or the decision to use cocaine, has been associated with priming

effects, or triggers that initiate the desire to use [7, 28, 29]. Drug cues can be triggered by internal or

external experiences, activating the craving-related network of brain structures such as the amygdala,

nucleus accumbens, and anterior cingulate gyrus involved in stimulus-reward [7]. Priming effects

from cues can be moderated by the frequency and duration of cocaine use, environmental factors, and

drug availability [29]. Another possible factor related to cocaine dependence is the striatal dopamine

receptor availability in the brain [12]. With chronic cocaine use, the receptor availability may

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decrease, thus prompting a desire for the drug in the absence of the dopamine release achieved by

natural rewards [12].

Psychosocial/Behavioral Therapies

A number of psychosocial interventions based on cognitive-behavioral approaches have

received significant empirical attention in the literature on cocaine use disorders in the last two

decades [30, 31]. These standardized interventions have been tailored to the unique challenges

associated with cocaine use disorders. As described above, the neurobiology of cocaine addiction, the

environment in which the addiction occurs, and other resultant behavioral characteristics contribute to

particular difficulty in treating the cocaine addicted patient. Thus, the therapies developed to treat this

disorder address these challenges directly and include strategies to help patients clarify their

ambivalence about using [motivational interviewing/motivational enhancement therapy; MI/MET; 31,

32], cope more effectively without using cocaine [cognitive-behavioral therapy ; CBT; 9, 21, 22 26,

32, 33, 34, 35], think differently about their use behavior [cognitive therapy; CT; 31, 36], utilize

techniques to avoid/prevent triggers and/or the use behavior [CBT], change the reinforcing

contingencies in their environment [Contingency Management/The Community Reinforcement

Approach ; CM/CRA; 9, 26, 34, 37], and increase awareness of and detachment from sensations,

thoughts, and cravings that may lead to use, in order to prevent cocaine use [Meditation/Mindfulness

Therapies; MMT; 38, 39] . A recent meta-analysis of psychosocial interventions for substance use

disorders, Dutra and colleagues [30] found that these psychosocial interventions typically produce

moderate to large effect sizes, demonstrating their efficacy in treating cocaine use disorders. Below we

review and compare these psychosocial interventions, beginning with CBT then MI/MET, CM/CRT

and finally MMT.

Cognitive Behavioral Therapy [CBT]

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Clinical evidence indicates the efficacy of CBT in those trying to overcome cocaine

dependence [34, 31] as well as cigarette smoking, methamphetamine use, and alcohol use disorders

[10]. CBT has been found to be more effective than Interpersonal Therapy [IPT] in reducing frequency

of cocaine use [37]. Rohsenhow et al. [32] found that brief [6 session] coping skills training was more

effective than relaxation/meditation training in reducing cocaine use for up to 6 months, although these

effects did not persist at 7-9 month follow-up or 12 month follow-up.

Crits-Cristoph and colleagues [36] found that CT + group drug therapy [GDC] was no more

effective than GDC alone and was equivalent to other treatments [Supportive-Expressive Therapy] in

terms of promoting cocaine abstinence for 30 consecutive days during treatment, and 30, 60, and 90

day abstinence post-treatment. Rosenhow et al. [31] failed to find overall beneficial effects of coping

skills training vs. drug education, although women who received coping skills training were less likely

to resume cocaine use and more likely to maintain abstinence than women who received drug

education. Carroll and colleagues [9] found that CBT was no more effective than twelve-step

facilitation [TSF] in terms of reducing cocaine use or promoting abstinence, although Maude-Griffin

et al. [10] found that individuals who received CBT were more likely to be abstinent for cocaine for 4

consecutive weeks and through six-month follow-up than those who received a twelve step facilitation

[TSF] program.

Cognitive behavioral therapy [CBT] focuses on specific learning processes and teaching users

new skills to cope with high-risk situations in an effort to achieve abstinence. This treatment method

is goal-oriented, flexible, and individualized to meet the needs and schedule of the patient. The

interactive approach of CBT orients users to the program, asking them to create goals and set up a

cognitive baseline for themselves in terms of confidence and commitment. This information is also

useful to the therapist in matching therapeutic tasks to the specific needs of the patient. Looking at

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past, present, and future cocaine use associated habits, and triggers, the patient and the therapist

formulate effective coping strategies and emergency plans to mediate the impact of cocaine-related

stress situations in pursuit of abstinence. Utilizing principles of classical and operant conditioning, the

therapist works with the patient to customize a strategy to meet the goal of treatment: to unlearn old,

ineffective behaviors, and learn new ones [40].

Over the weeks of structured therapy, specific techniques are used in CBT to achieve and

maintain abstinence and program retention [40]. These techniques include developing problem-

solving skills, decision-making skills, improving social skills, and implementing thought management

and coping skills to support refusing use and managing cravings [40]. In CBT, a lapse is not

considered a failure, but rather an indication that the patient or user must further practice and rehearse

the skills learned in treatment to prevent the lapse from turning into a relapse [19].

CBT is intended for those committed to reducing or eliminating their use of harmful

substances. Empirical support for CBT shows that its effects appear to endure up to a year following

treatment and patients demonstrate higher post-treatment coping skills, compared to subjects receiving

other types of therapy [34, 41, 42].

Patient commitment is integral to the success of CBT. In fact, Carroll demonstrated that

participants who complete more homework assignments show significantly greater increases in the

effectiveness and quantity of their coping skills with respect to substance use, have greater treatment

Figure 1: Cognitive-Behavioral Therapy mediates individual thoughts, feelings, behaviors, and physical reactions as pertaining to a specific situation.

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adherence and use less cocaine during treatment and through a 1-year follow-up [41]. This

demonstrated commitment of subjects in an important factor to CBT’s efficacy. Indeed, completing

homework has been shown to be associated with more positive immediate and enduring outcomes

[41], and failure to participate and practice may result in less retention of skills and relapse [9, 41].

Contingency Management [CM] & The Community Reinforcement Approach [CRA]

A behavioral intervention utilizing the principles of operant conditioning, Contingency

Management [CM] and the Community Reinforcement Approach [CRA] involves rewarding

individuals for periods of abstinence [i.e. providing cocaine-free urine samples] with vouchers or

variable reinforcement methods [i.e. drawings from a prize bowl, lottery tickets: 43], often with

increasing rewards for longer periods of abstinence [37, 44, 45]. As part of CRA, CM techniques are

combined with counseling that integrates the behavioral aspects of CBT, offering individuals direct,

tangible incentives for their behavior designed to promote abstinence during treatment and experience

abstinence as rewarding [43]. Research on CRA for cocaine abuse and dependence has demonstrated

the efficacy of this method across different populations of individuals with cocaine dependence [37,

44, 46]. Prendergast and colleagues [47] in their meta-analysis on CRA for substance use disorders,

the authors found that use of vouchers in participants with cocaine dependence was associated with

medium effect sizes [d = 0.66].

CRA + vouchers has been found to more effective than other standard treatments including

methadone maintenance [34, 37] and TSF/standard drug counseling [45, 48, 49, 50, 51, 52, 53], even

after accounting for differential rates of attrition between groups. These results have persisted over

multiple follow-up points [37, 45]. In a series of studies conducted by Higgins and colleagues [49, 50,

51, 54, 55], this set of authors found that CRA + vouchers consistently produces higher rates of

retention over other treatments [48,51].

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Research examining the role of vouchers in CRA conducted by Higgins and colleagues [49,

56] found that CRA alone was less effective than CRA + vouchers with respect to promoting treatment

completion and abstinence. However, these differences were not maintained at follow-up in either

study, casting doubt on the long-term efficacy of CRA with vouchers in comparison to behavioral-

based counseling. In another study conducted by Higgins [51], CRA + vouchers was found to be

superior to three control conditions [one of which was CRA alone] in terms of abstinence in-treatment

and 6 month follow-up. However, the authors did not report if there were differences between specific

control conditions and the CRA+ vouchers condition, leaving questions about the long-term impact of

CRA + vouchers over CRA alone. In a series of studies exploring the impact of contingent

[abstinence-based] and non-contingent vouchers as part of CRA on treatment outcomes, Higgins and

colleagues [3, 50], found that CRA + vouchers was more effective than CRA with non-contingent

vouchers in terms of in-study abstinence and abstinence during the course of 6 and 18 month follow-

up, although one of these investigations included multiple conditions combined into the control group

[51]. In a comparable study by Jones [52], individuals who received both CBT and vouchers [CM]

were more likely to abstain from cocaine and obtain longer periods of abstinence than those who

received CBT and non-contingent vouchers, although follow-up data was not available.

In a recent investigation of the effects of different levels of vouchers as part of CRA, two sets

of authors [55, 57] investigated the role of low vs. high vouchers. Both studies found that participants

who received higher levels of vouchers were more likely to be abstinent during the study, with

medium-to-large effect size [57]. Differences between the voucher groups were not significantly

different during treatment in both studies and Higgins et al [55] found that differences between the

groups were not significant at the conclusion of treatment, although the high voucher group did

demonstrate somewhat higher rates of abstinence across the 18 month follow-up period. However,

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Garcia-Rodriguez and colleagues [57] did not provide follow-up data, leaving questions about the

long-term impact of CRA regardless of voucher level on long-term abstinence.

Combination of CBT and CM/CRA

Higgins and colleagues [58] compared the efficacy of a combination of coping skills training,

CRA and community reinforcement [CR; rewarding abstinence with prosocial activities with

friends/family] with standard individual/group drug counseling. They found that this combination of

behavioral interventions was superior to treatment as usual drug counseling in promoting and

maintaining abstinence over the 24 weeks of the program. In this study, 58% of the CRA + vouchers

participants completed the 24 weeks of therapy as compared to 11% of the drug counseling group [58],

with nearly half of the CRA + vouchers participants achieving 16 weeks of abstinence, but only 5% of

the drug counseling group achieving this goal. However, the researchers did not provide follow-up

data post-treatment and the differential rates of attrition between groups may account for some of the

differences between the groups.

Similar results were found by Carroll et al [42] in a recent study of computer-assisted CBT on

substance dependence vs. individual/group drug counseling in individuals with cocaine and other

substance dependence. They found that those who received CBT demonstrated lower levels of drug

use during the study and at follow-up, with a significant interaction between group and time, even

when controlling for treatment exposure. There was also a direct relationship between number of CBT

modules completed and maximum days of abstinence from drugs. These results indicate that CBT

may have a “sleeper effect” of CBT over time on substance dependence, promoting reductions in use

even after the completion of treatment [34, 42, 58, 59].

These results suggest that while skills learned in CBT may take time to be incorporated into

one’s behavior, the use of incentives in conjunction with CBT may be beneficial in establishing short-

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term gains [44]. Higgins found that of patients receiving vouchers for cocaine-free urine at their

scheduled CBT session, 75% competed 24 weeks of treatment as compared to 40% in the CBT-only

group [59]. Furthermore, the CBT+CRA group recorded significantly greater improvements of the

ASI scale and longer periods of abstinence during the study [44].

With respect to cocaine dependence, CBT demonstrates great utility [31, 34], and its efficacy

and durability has been tested and empirically supported [40]. Despite strong evidence for the efficacy

of CBT, this modality is not without its limitations. The positive benefits of CBT take time to

assimilate, requiring much practice and patience, often requiring weeks or months to show maximum

effectiveness. CBT is not for everyone. Subjects with low abstract reasoning skills may not receive

the full benefits of treatment [10]. This is problematic for individuals who use cocaine, as according

to a matched-pairs study by O’Malley using standardized neuropsychological assessment procedures,

50% of cocaine abusers, scored in the ‘impaired’ range on the summary index of the

Neuropsychological Screening Exam [60].

Messina et al. [26] found that CBT+CRA was no more effective than CRA or CBT alone in

producing cocaine-free urine samples during their study, although it was superior to MM. However,

over the course of 6 month and 12 month follow-up that those in the CBT+CRA group who did not

have antisocial personality disorder [ASPD] experienced declines in abstinence on par with those who

received CRA only, with CBT demonstrating greater efficacy than CBT+CRA over time. Individuals

with ASPD demonstrated fewer differences at follow-up, with CBT+CRA showing increases in

abstinence over time that surpassed CRA only at 1 year follow-up and were comparable to CBT only.

Rawson [34] found that the combination of CRA+CBT demonstrated greater effectiveness than MM in

producing cocaine-free and short-term abstinence and was superior to CBT alone during the study.

Those who received CRA+CBT also attended more sessions than those in CBT only. A 6 month

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follow-up, the CRA+CBT group was equivalent to CBT on outcome measures, although at 12 months,

individuals in the combined group were less successful than CBT only [and equivalent to CRA] in

reducing cocaine use. There was no evidence that CRA+CBT was superior over the long-term to either

CRA or CBT alone. Again, this demonstrates the enduring power of CBT and the fact that it may take

some time to be effectively incorporated into the recovering individuals’ daily behavioral and thought

patterns.

CM versus CBT

Rawson and colleagues [34] investigated the comparative efficacy of Contingency

Management [CM] and CBT (alone and in combination) vs methadone maintenance [MM].

Individuals who received CM (alone or with CBT) were more likely to maintain their abstinence in

treatment compared to the MM only group and CM only was superior to MM in promoting abstinence

at the end of treatment However, the superiority of CM dissipated over the 12 month follow-up

period. No significant differences between any of the groups were evident at 6 month follow-up and

CM and CM+CBT were found to be no more effective than MM at 12 month follow-up.

In a similar study conducted by Messina [26] on the comparative effectiveness of CBT, and

CM (alone and in combination) to MM in those with and without Antisocial Personality Disorder

[ASPD], the authors found no main effect of treatment condition on rates of abstinence overall,

although individuals with ASPD who received CM only, CBT only or CM+CBT were more likely to

be abstinent than those receiving MM only, and that CM only superior to CBT and MM and

equivalent to CBT+CM with respect to in-treatment abstinence. Over the course of 12 month follow-

up, individuals with ASPD in the CBT only and CM+CBT groups demonstrated increases in

abstinence, while those in the CM only condition demonstrate slight decreases in abstinence over time.

Although all three treatment conditions were superior to MM only, there were no statistically

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significant differences between groups at the 12 mo. follow-up point. Among those without ASPD,

those in the CM only and CBT+CM groups demonstrated increases in abstinence in the 6 months

following treatment vs. other groups. However, at 12 month follow-up, CBT only produced the

highest rates of abstinence and those who received CM-based therapies were the least likely to remain

abstinent of all four groups. These results suggest that individuals with ASPD may respond more

effectively to CM-based therapies over both the short and long-term, although in individuals without

ASPD, CBT alone may produce superior outcomes over time.

Overall, CRA-based interventions have demonstrated efficacy in promoting greater treatment

retention and abstinence during treatment. However, the mechanisms by which CRA works (including

the role of behavioral components of CRA) have received relatively little attention, creating challenges

in isolating the effective components of CRA. Differential retention rates across groups based on use

of vouchers may account for some differences in rates of abstinence between groups, making it

difficult to identify whether treatment retention may serve as a confounding variable in outcomes.

Methodological differences between studies regarding changes in the reinforcement schedule

regarding the value and type of vouchers [49, 50, 54, 55], as well as the use of supplemental vouchers

for providing urine samples regardless of condition or abstinence [54] may serve as additional

confounds in these studies regarding the influence of CM on cocaine use. The costs of the incentives

used in CM and CRA can be substantial even for short-term treatment, often with costs of $1,000 or

more per individual [26, 34, 50], although recent research has demonstrated that lower vouchers levels

may still be effective in promoting in-treatment abstinence [37, 55]. Given the lack of data on the

long-term efficacy of CM/CRA in comparison to other psychosocial treatments, CM only approaches

may be of limited efficacy in producing long-term abstinence, as individuals with cocaine dependence

may find themselves continuing to lack the skills and knowledge needed to promote long-term

21

changes in behavior unless they also receive therapy that teaches coping skills through cognitive

and/or behavioral strategies associated with CBT or CRA.

Motivational Enhancement/Motivational Interviewing

Motivational interventions, including motivational enhancement [ME] and motivational

interviewing [MI] focus on enhancing motivation to change long-standing drug use behaviors [61] and

has been widely applied to substance use disorders, demonstrating medium-sized effects in reducing

use [61]. ME/MI employs a directive, client-centered approach that focuses on expressing empathy,

developing discrepancy between current behavior and goals, rolling with resistance and supporting

self-efficacy [61] in an effort to explore and resolve resistance to making changes in use and use-

related behaviors. Stotts and colleagues [62] found that a brief [2 session] MI intervention promoted

the development of healthy coping skills and reduced cocaine use, with those low in initial motivation

to change were most likely to benefit from MI with respect to completing treatment. However,

Rosenhow et al. [33] failed to find any overall differences between MET and CST [coping skills

training] on cocaine-related outcomes, although MET was more efficacious for individuals low in

motivation to change than those high in motivation to change.

CBT versus MET/MI

McKee and colleagues [32] studied the additive effects of motivational enhancement therapy

[MET] to CBT in a study of individuals with cocaine abuse or dependence. They found no differences

in retention between groups, although those in the CBT+MET condition were more likely to seek out

further drug treatment after completion of the study. Those receiving CBT+MET also reported a

greater desire for abstinence and expectations for success, despite anticipating more challenges to their

long-term abstinence. However, these differences were not maintained during follow-up. In terms of

cocaine use, both CBT and CBT+MET had equivalent outcomes in terms of frequency and quantity of

22

use and number of cocaine-positive urines during treatment or at follow-up. Despite strong results and

corroboration by other studies, this study was limited by a small sample size.

The relatively small body of research on motivational-based interventions for cocaine

dependence preludes a definitive analysis of the effectiveness of MI or MET as stand-alone

interventions for cocaine dependence, with very limited evidence that MET may serve to promote

engagement in therapy and more positive attitudes about the change process when combined with

interventions such as CBT.

Meditation/Mindfulness-Based Therapies

So-called “third wave” behavioral therapies, including Acceptance and Commitment Therapy

[ACT], Dialectical Behavior Therapy [DBT], Mindfulness-Based Stress Reduction [MBSR] and

Transcendental Meditation [TM] thusfar received little empirical attention as treatments for reducing

use in individuals with cocaine dependence. Hypothesized to increase awareness of and detachment

from sensations, thoughts, and cravings that may lead to use, psychosocial interventions incorporating

mindfulness and/or meditation have been associated with reductions in substance use primarily among

non-abusing, non-dependent populations [63, 64, 65]. However, well-controlled studies investigating

the impact of meditation/mindfulness-based interventions for substance use disorders or comparing the

relative efficacy of these interventions to other psychosocial or pharmacotherapies are rare. Although a

small number of studies do exist [66, 67, 68], only two published studies [38 ,39] focus specifically on

cocaine dependence. Unfortunately, both of these studies used “meditation-relaxation” condition that

did not explicitly include meditation training or aspects of ACT or DBT. As such, there currently

exists a dearth of literature about the effectiveness of meditation and mindfulness-based therapies for

treatment of cocaine dependence.

23

Overview of Psychosocial Treatments Table

Strengths Weaknesses

CT/CBT Individualized to patient May be superior in promoting long-term decreases in use Focus on developing new skills andchanging problematic thoughts

Requires abstract reasoning skills Assumes motivation to change May require greater time to see full effects

CM/CRA May promote retention Evidence of immediate/short-term effects on use Easily used with other therapies

Costs may be significant No focus on changing underlying patternsleading to use Limited evidence of long-term efficacy

MI/MET Does not assume/require high motivation Very brief interventions May promote interest in seeking future treatment

Little research in cocaine-dependent populations

MM Promotes development of skills to cope with cravings

Very little research with cocaine-dependent populations

Pharmacotherapies

Topiramate

Formulated as an anticonvulsant to treat patients with epilepsy, topiramate has been found to

be superior to placebo in treating both early and late onset alcoholics [69], and has shown promise in

treating medical issues ranging from migraines, diabetic neuropathic pain, mood and anxiety disorders,

eating disorders and obesity [69, 70,71]. Topiramate is a sulphamate fructopyranose derivative,

thought to antagonize a drug’s rewarding effects by inhibiting mesocorticolimbic dopamine release via

the gamma amino-butyric acid [GABA] activity and inhibition of glutamate function after drug intake

[70, 72]. Through this activity, topiramate may decrease extracellular release of dopamine in the VTA

24

projecting to the nucleus accumbens. This action may mediate drug-seeking behaviors and craving by

reducing the rewarding effects associated with drug use [69, 70].

Promising topiramate doses range from 25mg to 300mg [8, 69]. However as the dose increases

beyond 100mg per day, so does the occurrence of adverse events. Most common adverse events

include: dizziness, parasthesia, psychomotor slowing, memory and concentration impairment and

weight loss. With a half life of 21 to 23 hours and at 80% bioavailability, a single daily dose of

topiramate is sufficient for treatment and remain active in the blood to enact its anti-craving effects

[70]. Results from a 12-week outpatient trial for cocaine dependent individuals, using varied, high and

low, doses of topiramate ranging from 25 to 100 mg daily, show a 57% compliance rate and 25% of

the sample reported a significant decrease in craving intensity and duration [8]. Two major limitations

to this study is that it is an open trial without placebo or control group and the small sample size [N=

28 males].

Researchers at the University of Pennsylvania School of Medicine tested topiramate 200mg

daily against placebo in 40 chronic, crack-cocaine-smoking outpatients for 13 weeks [73]. In nearly

every week of the study, compared to the placebo groups, more patients in the topiramate group

refrained from cocaine use and more exhibited 3 or more continuous weeks of abstinence [73]. Larger

placebo controlled randomized trials testing varied doses of topiramate are needed to learn more about

the effects of topiramate for the treatment of cocaine dependence.

Disulfiram

Disulfiram is a drug that inhibits aldehyde dehydrogenase, an enzyme necessary in alcohol

metabolism to convert acetaldehyde to acetate, and has been approved for the treatment of alcoholism

[70, 74, 75]. Haley showed that alcohol use in conjunction with disulfiram resulted in an adverse

physical reaction due to acetaldehyde accumulation in blood with symptoms including hypotension,

25

flushing, nausea and vomiting that discourage future use [70, 76]. In humans, disulfiram also inhibits

plasma and microsomal carboxylesterases and plasma cholinesterase [77, 78] that inactivate cocaine

systemically thereby increasing blood levels of cocaine [79]. This effect is believed to contribute to

disulfiram’s efficacy in treating cocaine addiction. Another important role is that disulfiram chelates

copper, and since copper is essential in the function of the dopamine beta-hydroxylase enzyme,

disulfiram inhibits the conversion of dopamine to norepinephrine [79]. Dopamine beta-hydroxylase

inhibition by disulfiram leads to decreases in peripheral and central norepinephrine and increases in

dopamine levels.

Disulfiram has also been studied as a treatment for cocaine dependence [76]. In a randomized,

double-blind, placebo-controlled study examining the interaction of disulfiram 62.5 or 250 mg/day

with intravenous cocaine, disulfiram was found to decrease self-reported 'high' and 'rush' associated

with cocaine use. The highest dose of disulfiram had a more significant reduction on the subjective

effects of cocaine with, the average cocaine ‘rush’ felt with a 62.5mg or 250mg dose of disulfiram

decreased 60% and 46%, respectively [76].

In a double blind randomized outpatient clinical trial conducted by Carroll et al, 121 cocaine

dependent patients were randomized to either disulfiram 250mg daily or placebo plus weekly therapy

[either CBT or Interpersonal Therapy; IPT] for 12 weeks [9]. Participants taking disulfiram

demonstrated greater reductions in cocaine use than those taking placebo or receiving IPT, with results

that were equivalent to CBT. Disulfiram was also associated with better patient retention and a longer

duration of abstinence from drug use [9].

Some studies with disulfiram in cocaine dependent population showed that higher doses [up to

3 gm loading dose, and up to 1 gm/day for maintenance] were associated with paranoid psychosis in

some patients [80], therefore limiting its use in certain patients. Overall, there is good evidence

26

indicating that disulfiram shows significant promise as a pharmacological treatment for cocaine

dependence. Future studies are needed to clarify the mechanisms involved, and the contributions of

other factors that may impact treatment response.

Ondansetron

Post-synaptic 5-HT3 receptors are located densely on the terminals of corticomesolimbic

dopamine containing neurons, where they promote DA release [New 81 Kilpatrick, New 82Oxford].

A primary effect of ondansetron a 5-HT3 antagonist is to decrease dopamine release, especially under

suprabasal conditions in these regions. In a human laboratory study of 12 cocaine-dependent

individuals, ondansetron pretreatment was associated with a significant dose-dependent decrease in

cocaine-induced positive subjective effects associated with its abuse liability and reinforcement [83].

Under a NIDA-directed and -sponsored contract, Johnson BA et al conducted a preliminary double-

blind, randomized, dose-ranging clinical trial to examine for a therapeutic signal, testing the efficacy

of ondansetron [0.25, 1.0, and 4.0 mg twice daily] vs. placebo as a treatment for cocaine dependence

among 63 male and female cocaine-dependent individuals. Ondansetron [4 mg twice daily] was

significantly more efficacious than placebo at increasing the weekly proportion of cocaine-free urine

specimens [p = 0.02] and was marginally significantly more efficacious at decreasing the urine

benzoylecgonine concentration [p = 0.07][84]. Important limitations of the study however, include the

small sample size and a higher than expected overall dropout rates.

Baclofen

Baclofen is a GABA B receptor agonist used to reduce muscle spasticity in different

neurological diseases. It is believed to modulate cocaine-induced dopamine release in the nucleus

accumbens [85]. In animal studies baclofen was found to reduce cocaine self administration,

reinstatement, and cocaine seeking behaviors in rats suggesting its potential utility as a medication for

27

treatment of cocaine addiction [86]. In humans, an open label study found that baclofen 20 tid

significantly reduced cocaine craving in cocaine-dependent subjects [87]. However, this trial had a

sample size of 10 and did not have a placebo arm. A randomized, double-blind clinical trial involving

70 cocaine-dependent treated with baclofen 60 mg/d or placebo found no statistically significant effect

for baclofen over placebo on measures such as treatment effectiveness and percent negative urines. A

secondary analysis of the same data found that baclofen significantly reduced cocaine use in the

subgroup of patients with the heaviest cocaine use only [88]. In a human laboratory study, baclofen 60

mg/d reduced cocaine self-administration in non-treatment seeking cocaine dependent volunteers who

were non-opioid dependent [89].

Modafinil

Modafinil, a functional stimulant, is FDA approved for the treatment of narcolepsy and

idiopathic hypersomnia. The mechanisms underlying modafinil’s therapeutic actions remain unknown.

It is believed to occupy both the dopamine and norepinephrine transporters consistent with a

stimulant-like effect but its affinity to these transporters is well below that of the antidepressant

buproprion [90, 91]. In addition, modafinil appears to increase release of the excitatory

neurotransmitter glutamate, and decrease the inhibitory neurotransmitter GABA, [92]. Modafanil is

usually well tolerated, although up to 3% of patients on modafanil experienced cardiovascular side-

effects such as hypertension, tachycardia, and palpitations. Because of its stimulant-like activity,

modafanil was suggested and later tested as a treatment for cocaine dependence. It was believed to

diminish not only the symptoms of cocaine withdrawal, but also act as a “substitution treatment” for

cocaine [93]. In animal studies, modafanil was found to have a weak cocaine-like reinforcement

effects [94]. In humans, modafinil did not appear to produce euphoria or evoke cocaine craving [91,

92], suggesting that it has low abuse potential and that is not an amphetamine like agent [95, 96].

28

Dackis et al conducted the first randomized, double-blind clinical trial testing the efficacy of

modafanil 400mg daily versus placebo in conjunction with CBT in 62 cocaine-dependent patients for

8 wk [97]. Patients in the active group had significantly less cocaine use compared to their placebo

counterpart. In a multi-site, controlled clinical trial of 210 cocaine-dependent patients who received

either modafinil [200 mg/d or 400 mg/d] or placebo, Modafinil significantly reduced cocaine use but

only in the subgroup of patients without alcohol dependence [98]. Additional clinical trials are needed

to evaluate the best clinical role of modafinil for the treatment of cocaine dependence.

Other Medications

Other medications that interact with GABA- or glutamate-mediated neuronal systems have

been tried as potential treatment for cocaine dependence. While there is preclinical evidence that

acamprosate can inhibit conditioned place preference to cocaine [99] and attenuates both drug- and

cue-induced reinstatement of cocaine-seeking behavior [100] there is to date, no clinical trial testing its

utility in treating humans with cocaine dependence.

In humans, several clinical trials have been conducted using carbamazepine to treat cocaine

dependence. A meta-analysis of 455 individuals enrolled in five different clinical trials conducted by

the Cochrane Database of Systematic Reviews concluded that there was no evidence supporting a

positive effect of carbamazepine in the treatment of cocaine dependence [101, 102].

Gabapentin is another gabanergic drug used to treat both epilepsy and neuropathic pain. Its

exact pharmacological mechanism remains unclear. Gabapentin has showed some promising results in

an open-label study and case series suggesting that it might have utility in the treatment of cocaine

dependence [103, 104]. Randomised, placebo-controlled, double-blind studies are needed to test its

efficacy.

29

There are encouraging preclinical data that support the utility of vigabatrin as a treatment agent

for cocaine dependence. Vigabatrin is another anticonvulsant that increases GABA neurotransmission

but this time by inhibiting GABA transaminase. In a preliminary open-label trial [n = 20], vigabatrin

was well tolerated and was associated with abstinence from cocaine in 75% of those who remained in

the study. Retention rate in this trial was low as only 40% of the enrolled participants completed the

trial [105]. It is a drug with great potentials but needs to be tested in adequately powered placebo

controlled randomized studies.

Tiagabine is yet another anticonvulsant that increases GABA neurotransmission by blocking

the presynaptic reuptake of GABA. In 2 randomized clinical trials involving cocaine dependent

patients who were maintained on methadone, tiagabine [12-24mg/day] was found to decrease cocaine

use compared with placebo [106, 107].

In a clinical trial conducted in cocaine dependents patients maintained on methadone for their

opioid dependence, buproprion [300mg/day], an antidepressant potentiated the effects of contingency

management in reducing cocaine, but did not have any effects in patients not assigned to contingency

management [108].

Finally, the use of stimulants has been tried for the treatment of cocaine dependence under the

premise of a drug substitution for a drug with slower onset formulation and less abuse liability.

Methylphenidate, a dopamine and nerepinephrine reuptake inhibitor used to treat attention deficit

hyperactivity disorders [ADHD] was found to be no better than placebo in the treatment of cocaine

dependent patients without comorbid ADHD [109]. However when used in a population with dual

diagnosis of cocaine dependence and ADHD, results from clinical trials were mixed. While a

controlled clinical trial using immediate release methylphenidate [90mg/day] found no difference

between the active drug and placebo groups [110], another trial using sustained release

30

methylphenidate [60mg/day], found significant improvement in ADHAD symptoms that were

associated with decrease in cocaine use compared with placebo [111].

Though medications such as those that facilitate gabanergic function, modulate dopaminergic

function or act as an agonist replacement therapy show promise in treating cocaine dependence, there

are certain drawbacks [70]. First, the majority of these drugs are still in their infancy stage with regard

to testing their clinical utility for the treatment of cocaine dependence, second, all drugs tested are

delivered orally, and those going through withdrawal may have trouble with ingestion due to vomiting

[70]. Other adverse side effects associated with the use of medications may affect compliance in

general. Some of the side effects associated with the use of anticonvulsant drugs include difficulty

with attention and concentration [112] which may increase craving to use more cocaine to offset those

undesirable side effects Furthermore, individuals prone to abuse may attempt to get a pleasurable

effect from taking more of the treatment drug than prescribed [19]. Current research using these

pharmacotherapies show great promise, but are largely based on small sample sizes, have limited

research control, and still have a relatively low rate of retention. Also, longitudinal data is lacking to

determine the enduring positive effects of the drugs due to patient displacement, convenience of

appointments, and budgets. While CBT has shown promise and some pharmacotherapies have shown

utility in treating cocaine dependence, neither have independently established solid effectiveness for

drug treatment.

Psychosocial Therapy plus Pharmacotherapy

Pharmacotherapies and behavioral therapy treatments have weaknesses when used alone, but

exhibit several strengths when used in combination [9]. Various substance abuse programs, ranging

from alcoholism and binge eating to cocaine dependence have successfully employed combination

therapies using CBT and medications [9, 84, 97, 106, 107, 113], and most randomized controlled trials

31

in these research field utilize a combination of psychosocial or behavioral therapies in conjunction

with the medication under investigation.

Exploring different treatment combinations, researchers have tested the efficacy of disulfiram

against a placebo in combination with different therapies including CBT, CRA, TSF, and IPT [9, 76].

Overall, those assigned to disulfiram significantly reduced their cocaine use compared to placebo

patients and participants assigned to CBT reduced their cocaine use significantly more than those

assigned to IPT [p<.01] for both [37, 76]. Participants in the therapies with disulfiram were retained

significantly longer compared to the placebo groups [8.4 versus 5.8 weeks, p<.05]. Examining the

specific treatment combinations, the CBT-disulfiram group recorded the highest retention rate

compared to CRA and TSF over a 12-week study period, at 8.8 weeks [9].

In a placebo-controlled study by Kampman et al, topiramate was delivered in conjunction with

CBT to 40 cocaine dependent study participants [73]. Treatment involved increasing dose of

topiramate up to 200mg/d, two CBT sessions a week, and biweekly urine test to verify cocaine

abstinence [73]. By the thirteenth week and conclusion of the study, nearly 60% of the patients taking

topiramate had achieved 3 or more weeks of continuous cocaine abstinence, compared to 26% of the

placebo patients [73]. Despite promising results, further evaluation of the drug in conjunction with

CBT needs to be conducted based on the homogeneity of the sample.

Other treatments

Emerging treatments to enhance recovery of cocaine dependence include improvements on

current methods and innovative options. Regarding CBT, treatment handbooks and workbooks are

being developed for patient use [19]. These manuals outline treatment protocols and provide

reminders on sessions, feedback, and contain homework assignments. Furthermore, providing this

material to the patients gives them a sense of control over their own recovery and can empower and

32

further motivate them to overcome their dependence. To provide better treatment at therapy centers,

the clinics should provide transportation, encourage patient feedback, praise attendance, update goals

weekly, chart progress visually, and provide positive reinforcement and encouragement for any

successes [41]. In addition, multiple medias [i.e., visual, auditory] should be utilized to reinforce

principles of treatment and strengthen messages via repetition [40].

Incorporation of technology into treatment methods is also being explored. Computer-assisted

therapies may offer more consistent and convenient delivery of instruction and reinforcement in

conjunction with CBT [42, 114]. Preliminary software has shown promise for treating simple phobias,

OCD, ADHD, panic disorder, depression and smoking [12].

An additional and innovative approach, to be used with a structured treatment program, is the

administration of a therapeutic cocaine vaccine. The vaccine is shown to inhibit the cocaine ‘high’

through antibodies binding to cocaine in the circulation and inhibiting entry to the brain [115, 116].

However, it does not stop drug cravings [114]. In addition, recent findings suggest that only those

subjects who attain high [> 43 ug/L] IgG anticocaine antibody levels benefited from significantly

reduced cocaine use. Unfortunately, only 38% of the vaccinated subjects achieved such high IgG

levels in this study.

Psychosocial therapy is still essential in medication and vaccine studies because the underlying

issues of the dependence and use behavior must be addressed or individuals may resort to another

drug. The intent of the vaccine is to immunize motivated patients as part of a comprehensive recovery

program and to inhibit the reinforcing activity of cocaine and decrease the likelihood of relapse [115].

Conclusion

There is strong evidence from controlled clinical trials that drugs that modulate the

dopaminergenic pathway, facilitate gabanergic function, or act as an agonist replacement therapy can

33

be efficacious medications for the treatment of cocaine dependence. Further evidence proves CBT is a

powerful therapy to manage cravings and stresses leading to use and may help prevent relapse. Used

concurrently, pharmacotherapy and CBT show promise as an effective treatment for cocaine

dependence. Nevertheless, much research and trials are still needed to assess the strength of new and

existing treatment modalities, and to evaluate exactly which treatment approaches work for which

individual. Further consideration of how therapies can be tailored to increase patients’ receptivity to

treatment, address the specific needs of the cocaine addicted individual, and improve retention in

treatment and prevent relapse need to be explored. In addition, future research should focus on

improving treatment accessibility for cocaine dependent individuals. This may include expanding

research on implementation of computer based interventions, peer facilitated treatments, and effective

treatments which can be administered by primary care providers.

34

Key learning objectives: This review presents an overview of the hypothesized mechanisms of cocaine dependence and combined treatment options. Key learning objectives include understanding pharmacological and psychosocial/ behavioral treatments for cocaine dependence, including their relevant strengths and weaknesses and benefits of combined treatments.

Future research questions: What combinations of pharmacotherapy and behavioral or psychosocial treatments work best in reducing cocaine use in addicted individuals? Are there combinations of medications and psychosocial treatments that work for specific individuals, such as heavy users, early-onset users, or users with co-occurring psychiatric disorders?

35

Reference List

1. NIDA Info Facts: Crack and cocaine. Bethesda, MD: NIDA [updated 2009 Jun; cited 2009 Aug]. Available from http://www.nida.nih.gov/Infofacts/cocaine.html

2. Gold M. Cocaine (and crack). 3rd ed. Baltimore (MD): Williams and Wilkins; 2007. 3. Harvey, JA. Cocaine effects on the developing brain: current status. Neurosci Biobehav

Rev 2004 Jan; 27 (8) 751-64. 4. O’Brien CP. Anticraving medication for relapse prevention: a possible new class of

psychoactive medications. Am J Psychiatry 2005; 162:1423-31. 5. DeVries TJ, Shaham Y, Homberg JR, et al. A cannabinoid mechanism in relapse to

cocaine seeking. Nat Med 2001; 7:1151-4. 6. Filmore MT, Rush, CR. Impaired inhibitory control of behavior in chronic cocaine users.

Drug Alcohol Depend 2002; 66:265-273. 7. Kilts CD, Schweitzer JB, Quinn CK, et al. Neural activity related to drug craving in

cocaine dependence. Arch Gen Psychiatry 2001; 58:334-41. 8. Reis AD, Castro LA, Faria R, Laranjeira R. Craving decrease with topiramate in

outpatient treatment for cocaine dependence: an open label trial. Rev Bras Psiquiatr 2008; 30:132-5.

9. Carroll KM, Nich C, Ball SA, McCance E, Rounsaville BJ. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Drug Alcohol Depend 1998; 93:713-28.

10. Maude-Griffin PM, Hohenstein JM, Humfleet GL et al. Superior efficacy of cognitive-behavioral therapy for urban crack cocaine abusers: main and matching effects. J Consult Clin Psychol 1998; 66:832-7.

11. Rawson R. Treatment of methamphetamine use disorders: an update. J Subst Abuse Treat 2002; 23:145-50.

12. Martinez D, Broft A, Foltin RW, et al. Cocaine dependence and d2 receptor availability in the functional subdivisions of the striatum: relationship with cocaine-seeking behavior. Neuropsychopharmacology 2004; 29:1190-202.

13. Stalnaker TA, Roesch MR, Franz TM et al. Cocaine-induced decision-making deficits are mediated by miscoding in basolateral amygdale. Nat Neurosci 2007; 10:948-51.

14. Dackis CA, O’Brien CP. Cocaine dependence: the challenge for pharmacotherapy. Curr Opin Psychiatr 2008; 118:454-61.

15. Cleck J, Blendy J. Making a bad thing worse: adverse effects of stress on drug dependence. J Clin Invest 2008; 118:454-61.

16. Schoenbaum G, Shaham Y. The role of orbitofrontal cortex in drug dependence: a review of preclinical studies. Biol Psychiatry 2007; 63:256-62.

17. Martinez D, Narendran R, Foltin RW, et al. Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer

cocaine. Am J Psychiatry 2007; 164:622-9 18. Kleven MS, Perry BD, Woolverton WL, Seiden LS: Effects of repeated injections of cocaine on D1 and D2 dopamine receptors in rat brain. Brain Res. 1990; 532(1-2]:265- 70. 19. Penberthy JK, Wartella J. Cognitive behavioral therapy and cocaine dependence: problems with treatment and retention. Charlottesville (VA): University of Virginia Center for Addiction Research and Education, 2007.

36

21. Grant S, London E, Newlin D. et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci 1996; 93(21):12040-5. 22. Moeller FG, Hasan KM, Steinberg JL et al. reduced anterior corpus callosum white matter integrity is related to increased impulsivity and reduced discriminability in cocaine-dependent subjects; diffusion tensor imaging. Neuropsychopharmacology 2005; 30:610-7. 23, Volkow ND, Wang GJ, Teland F. et al. Cocaine uses and dopamine in dorsal striatum: mechanism of craving in cocaine dependence. J Neurosci 2006; 26:6583-8. 24. Nutt D, King L, Saulsbury W, Blakemore C. Development of a rational scale to assess the harm of drugs of potential misuse. Lancet 2007; 36(9):1047-53. 25. Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ. Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arc Gen Psychiary 2006; 63:324-31. 26. Messina N, Farabee D, Rawson R. Treatment responsitivity of cocaine-dependent patients with antisocial personality disorder to cognitive-behavioral and contingency management interventions. J Consul Clin Psycho 2003; 71:320-9. 27. Kelley BJ, Yeager KR, Pepper TH, Beversdorf DQ. Cognitive impairment in acute cocaine withdrawal. Cogn Beh Neruol 2005; 18:108-12. 28. Stalnaker TA, Roesch MR, Calu DJ et al. Neural correlates of inflexible behavior in the orbitofrontal-amygdalar circuit after cocaine exposure. Ann N Y Acad Sci 2007; 31: 593- 9. 29. Mahoney JJ, Kalechstein AD, De La Garza R, Newton TF. A qualitative and quantitative review of cocaine-induced craving: the phenomenon of priming. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 593-9. 30. Dutra L, Stathopoulou G, Basden SL et al. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008: 165(2):179-87. 31. Crits-Cristoph P, Siqueland L, Blaine J et al. Psychosocial treatments for cocaine dependence: National Institute for Drug Abuse collaborative cocaine treatment study. Arch Gen Psychiatry 1999; 56:493-502. 32. McKee SA, Carroll KM, Sinha R et al. Enhancing brief cognitive-behavioral therapy with motivational enhancement techniques in cocaine users. Drug Alcohol Depend 2007; 91:97-101. 33. Rohsenow DJ, Colby SM, Monti PM et al. Predictors of compliance with naltrexone among alcoholics. Alcohol Clin Exp Res 2000; 24:1542-9. 34. Rawson RA, Huber A, McCann M, et al. A comparison of contingency management and cognitive behavioral approaches during methadone maintenance treatment for cocaine dependence. Arch Gen Psychiatry 2002; 59:817-824. 35. Carroll KM, Fenton LR, Ball SA et al. Efficacy of disulfiram and cognitive behavioral therapy in cocaine-dependent outpatients: a randomized placebo-controlled trials. Arch Gen Psychiatry 2004; 61:264-72. 36. Beck AT, Wright FD, Newman CF, Lies BS. Cognitive therapy for substance abuse. New York: Guilford Press; 1993. 37. Barry C, Sullivan B, Petry NM. Comparable efficacy of contingency management for cocaine dependence among African-American, Hispanic and White methadone maintenance clients. Psychol Addict Behav 2009; 23(1):168-74.

37

38. Rohsenhow DJ, Monti PM.; Martin RA. Brief coping skills treatment for cocaine abuse: 12-month substance use outcomes. J Consult Clin Psychol, 2000, 68(3): 515-52

39. Rohsenow DJ, Monti PM, Martin, RA et al. Motivational enhancement and coping skills training for cocaine abusers: Effects on substance use outcomes. Addiction 2004; 99(7): 862-874. 40. Carroll KM. A cognitive-behavioral approach: treatment of cocaine dependence. Rockville (MD): National Institute of Health, 1998. 41. Carroll KM, Nich C, Ball Sa. Practice makes progress? Homework assignments and outcome in treatment of cocaine dependence. J Consult Clin Psychol 2005; 73:749-55. 42. Epstein DH, Hawkins WE, Covi L, Umbricht A, Preston KL. Cognitive-behavioral therapy plus contingency management for cocaine use: findings during treatment and across 12-month follow-up. Psychol Addict Behav 2003; 17:73-82. 43. Meyers RJ, Squires DD. The community reinforcement approach. Albequerque (NM): University of New Mexico Center on Alcoholism, Substance Abuse and Addictions; 1995/2001. 44. DeRubeis RJ, Crits-Cristoph P. Empirically supported individual and group psychological treatments for adult mental disorders. J Consul Clin Psychol 198; 66:37- 52. 45. Petry NM, Martin B, Simcic F. Prize reinforcement contingency management for cocaine dependence: integration with group therapy in a methadone clinic. J Consul Clin Psychol 2005; 73(2):354-59. 46. Roozen HG, Boulogne JJ, van Tulder MW et al. A systematic review of the effectiveness of the community reinforcement approach in alcohol, cocaine and opoid addiction. Drug Alcohol Depend 2004; 74:1-13. 47. Prendergast M, Podus D, Finney J, Greenwell L, Roll J. Contingency management for the treatment of substance use disorders: a meta-analysis. Addiction 2006; 101:1546-1560. 48. Higgins ST, Budney AJ, Bickel WK et al. Achieving cocaine dependence with a behavioral approach. Am J Psychiatry 1993; 150(5):763-766. 49. Higgins ST, Budney AJ, Bickel Wk et al. Outpatient behavioral treatment for cocaine dependence: one-year outcome. Exp Clin Psychopharmacol 1995; 3(2):205-12. 50. Higgins, ST, Wong, CJ, Badger, DE et al. Contingent reinforcement increases cocaine abstinence during outpatient treatment and 1 year of follow-up. J Consult Clin Psychol 2000; 68(1):64-72. 51. Higgins ST, Badger, GJ, Budney, AJ. Initial abstinence in achieving longer term cocaine abstinence. Exp Clin Psychopharmacol 2000; 8(3):377-386. 52. Jones HE, Johnson RE, Bigelow GE. Safety and efficacy of L-tryptophan and behavioral incentives for treatment of cocaine dependence: A randomized clinical trial. Am J. Addict 2004; 13:421-427. 53. Secades-Villa R, Garcia-Rodriguez O, Higgins ST, Fernandez-Hermida JR, Carballo JL. Community reinforcement approach plus vouchers for cocaine dependence in a community setting in Spain: six month outcomes. J Subst Abuse Treat 2008; 34:202-207. 54. Higgins ST, Sigmon SC, Heil SH, et al. Community reinforcement therapy of cocaine- dependent outpatients. Arch Gen Psychiatry 2003; 60(10):1043-1052. 55. Higgins ST, Heil SH, Dantona R, et al. Effects of varying the monetary value of voucher- based incentives of abstinence achieved during and following treatment among cocaine- dependent individuals. Addiction 2006; 102:271-81.

38

56. Higgins ST, Budney AJ, Bickel WK, Foerg FE, Badger GJ. Incentives improve outcomes in outpatient behavioral treatment of cocaine dependence. Arc Gen Psychaitry 1994; 51(7):568-76. 57. Garcia-Rodriguez O, Secades-Villa R, Higgins ST et al. Effects of voucher-based intervention on abstinence and retention in an outpatient treatment for cocaine addiction: a randomized controlled trial. Exp Clin Psychopharmacol 2009; 17(3):131-8. 58. Higgins ST, Budney AJ, Bickel WK, et al. Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch Gen Psychiatry 1994; 51:568-576. 59. Carroll KM, Rounsaville BJ, Nich C et al. One year follow-up of psychotherapy and pharmacotherapy for cocaine dependency: Delayed emergence of psychotherapy effects. Arch Gen Psychiatry 1994; 51:989-97. 60. Aharonovich E, Nunes E, Hasin D. Cognitive impairment, retention and abstinence among cocaine abusers in cognitive-behavioral treatment. Drug Alcohol Depend 2003; 71:207- 61. Miller W, Rollnick S. Motivation interviewing: preparing people for change. New York: Guilford Press, 1991. 62. Stotts AL, Schmitz JM, Rhoades HM, Grabowski J. Motivational interviewing with cocaine dependent patients: a pilot study. J Consul Clin Psychol 2001; 69(5):858-62. 63. Aron, A, Aron, EN. The transcendental meditation program’s effect on addictive behavior. Addict Behav 1980; 5: 3-12.. 64. Genderloos P, Walton KG, Orme-Johnson DW, Alexander, CN. Effectiveness of the transcendental meditation program in preventing and treating substance misuse: A review. Intl J Addict 1991; 26(3):293-325. 65. Hawkins MA. Effectiveness of the transcendental meditation program in criminal rehabilitation and substance abuse recovery: a review of the research. J Offender Rehabilitation 2003; 36(1-4):47-65. 66. abuse: A pilot application to methamphetamine-dependent women with borderline

personality disorder. Cog Behav Prac 2000; 7(4):457-468.

67. Linehan MM, Demieff LA, Reynolds SK, et al. Dialectical behavior therapy versus comprehensive validation therapy plus 12-step for the treatment of opioid dependent women meeting criteria for borderline personality disorder. Drug Alcohol Depend 2002; 67(1):13-26. 68. Taub E, Steiner SS, Weingarten E, Walton KG. Effectiveness of broad spectrum approaches to relapse prevention in severe alcoholism: A long-term, randomized, controlled trial of transcendental meditation, EMG biofeedback and electronic neuropathy. Alcohol Treat Q 1994; 11(1-2):187-220. 69. Johnson BA, Roache JD, Ait-Daoud N et al. Effects of acute topiramate dosing on metamphetamine-induced subjective mood. Int J Neuropsychopharmacol 2007; 10:85-98. 70. Johnson BA. An overview of the development of medications including novel anticonvulsants for the treatment of alcohol dependence. Expert Opin Pharmacother 2004; 5:1943-55. 71. Yourick J, Faiman M. Comparative aspects of disulfiram and its metabolites in the disulfiram-ethanol reaction in the rat. Biochem Pharmacol 1989; 38:413-21. 72. Johnson BA, Ait-Daoud N, Bowdon C, et al. Oral topiramate for treatment of alcohol dependence: a randomized controlled trial. Lancet 2003; 361:1677-85.

39

73. Kampman KM, Pettinati H, Lynch KG et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 2004; 75:233-240. 74. Brien J, Loomis C. Pharmacology of acetaldehyde. J Physiol Pharmacol 1983: 61:1-22. 75. Haley TJ. Disulfiram (tetraethylthioperoxydicarbonic diamide): a reappraisal of its t oxicity and therapeutic application. Drug Metab Rev 1979; 9:319-35. 76. Baker JR, Jatlow P, McCance-Katz EF. Disulfiram: effects on responses to intravenous cocaine administration. Drug Alcohol Depend 2006; 87:202-9. 77. McCance-Katz EF, Price LH, McDougle CJ et al. Concurrent cocaine ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene. Psychopharmacology 1993; 11(1)39–46 78. McCance-Katz EF, Kosten TR, Jatlow P. Disulfiram effects on acute cocaine administration. Drug Alcohol Depend. 1998; 52(1)27–39. 79. Haile CN. Kosten TR. Kosten TA.: Pharmacogenetic treatments for drug addiction: cocaine, amphetamine and methamphetamine Am J Drug Alcohol Abuse. 2009; 35(3):161-77. 80. Martensen-Larsen O. Psychotic phenomena provoked by tetraethylthiuram disulfide. J Stud Alcohol. 1951; 12(2)206–16 81. Kilpatrick GJ, Jones BJ, Tyers MB. Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature 1987;330:746-748. 82. Oxford AW, Bell JA, Kilpatrick GJ, Ireland SJ, Tyers MB. Ondansetron and related 5- 83. Jasinski DR, Preston KL, Testa M, Sullivan JT. Evaluation of the 5HT3 antagonist ondansetron [O] for cocaine [C]-like activity and abuse potential. NIDA Res Monogr 1990;105:515. 84. Johnson BA, Roache JD, Ait-Daoud N, et al. A preliminary randomized, double-blind, placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence. Drug Alcohol Depend 2006;84:256-263. 85. Fadda P, Scherma M, Fresu A, Collu M, Fratta W. Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse 2003; 50, 1–6. 86. Roberts DC. Preclinical evidence for GABAB agonists as a pharmacotherapy for cocaine addiction. Physiology Behavior 2005; 86, 18–20 87. Ling W, Shoptaw S, Majewska D. Baclofen as a cocaine anti-craving medication: A preliminary clinical study. Neuropsychopharmacology 1998; 18(5), 403-404. 88. Shoptaw, S., 2000. Outcomes when using the GABA-B agonist baclofen in human cocaine users. In: Proc. 61st Annual Scientific Meeting. NIDA Res. Monogr. Ser.: 180, 42–43. 89. Haney M, Hart CL, Foltin RW [2006]. Effects of baclofen on cocaine self-administration: opioid- and nonopioid-dependent volunteers. Neuropsychopharmacology 31, 1814–1821. 90. Madras BK, Xie Z, Lin Z, et al. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Experim Therapeutics, 2006; 319, 561–569. 91. O’Brien CP, Dackis CA, Kampman K. Does modafinil produce euphoria? Am J Psychiatry 2006;163, 1109. 92. Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006; 67, 554–566.

40

93. Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: a double-blind, placebo- controlled drug interaction study. Drug Alcohol Depend 2003;70, 29–37. 94. Deroche-Gamonet V, Darnaudery M, Bruins-Slot L, et al. Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology 2002; 161, 387–395. 95. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharm 2000; 14, 53–60. 96. Jasinski DR, Kovacevic-Ristanovic R. Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy. Clin Neuropharmacology 2000; 23 149–156. 97. Dackis CA, Kampman KM, Lynch KG, Pettinati HM, O’Brien CP. A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 2005; 30, 205–211. 98. Elkashef A, Vocci JF. Promising medications for the treatment of cocaine addiction. Presented at American Psychiatric Association Annual Meeting, 2007. San Diego, CA. 99. McGeehan AJ. Olive MF. The anti-relapse compound acamprosate inhibits the development of a conditioned place preference to ethanol and cocaine but not morphine. Br J Pharmacol 2003;138: 9-12 100. Bowers MS. Chen BT. Chou JK et al. Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats. Psychopharmacology 2007; 195(3):397-406. 101. Johnson BA: Recent Advances in the Development of Treatments for Alcohol and Cocaine Dependence. CNS Drugs 2005; 19(10), 873 897. 102. Lima AR, Lima MS, Soares BG. et al. Carbamazepine for cocaine dependence. Cochrane Database Syst Rev 2000;2,CDO02023 103. Raby WN, Coomaraswamy S, Gabapentin reduces cocaine use among addicts from a community clinic sample, J Clin Psychiatry 2004; 65: 84-6 104. Myrick H, Henderson S. Brady KT, et al. Gabapentin in the treatment of cocaine dependence: a case series, J Clin Psychiatry 2001:62: 19-23 105. Brodie JD, Figueroa E. Dewey SL. Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA, Synapse 2(3) 261-5 106. Gonzalez G, Desai R, Sofuoglu M, et al. Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients. Drug Alcohol Depend 2006; 87, 1–9. 107. Gonzalez G, Sevarino K, Sofuoglu M, et al. Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study. Addiction 2003; 98, 1625–1632. 108. Poling J, Oliveto A, Petry N, et al. Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population. Archives Gen Psychiatry 2006; 63(2), 219-228. 109. Grabowski J, Roache JD, Schmitz JM et al. Replacement medication for cocaine dependence: Methylphenidate. J Clin Psychopharmacology 1997; 17(6), 485-488. 110. Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exper Clin Psychopharmacology 2002; 10, 286–294.

41

111. Levin FR, Evans SM, Brooks DJ, Garawi F. Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug and Alcohol Dependence 2007a; 87, 20–29. 112. Johnson BA, Rosenthal N, Capece JA et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007; 298:1641-51. population. Arch Gen Psychiatry 63, 219–228. 113. Claudino A, de Oliveira I, Appolinario J et al. Double-blind, randomized, placebo- controlled trial of topiramate plus cognitive-behavior therapy in binge-eating disorder. J Clin Psychiatry 2007; 68:1324-32. 114. Carroll KM, Ball SA, Martino S, et al. Enduring effects of a computer-assisted training program for cognitive behavioral therapy: A 6-month follow-up of CBT4CBT. Drug Alcohol Depend 2009; 100(1-2): 178-81. 115. Fox BS. Development of a therapeutic vaccine for the treatment of cocaine dependence. Drug Alcohol Depend 1997; 48:153-8 116. Martell BA, Mitchell E, Poling, J, et al. Vaccine Pharmacotherapy for the Treatment of Cocaine Dependence. Biol Psychiatry 2005; 58(2), 158-164.