Pharmacological Treatments for Cocaine Dependence - IngentaConnect

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Abstract: Introduction: There is no specific and approved treatment, by regulatory authorities, for cocaine dependence. Therefore, de- veloping new medications ...
Current Pharmaceutical Design, 2011, 17, 1359-1368

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Pharmacological Treatments for Cocaine Dependence: Is There Something New? Laurent Karila1,2,3, Michel Reynaud1,2,4, Henri-Jean Aubin1,2,4, Benjamin Rolland5, Dewi Guardia5, Olivier Cottencin5 and Amine Benyamina1,2,4 1 Addiction Research and Treatment Center, Paul-Brousse Hospital (Assistance Publique-Hôpitaux de Paris [AP-HP]), Villejuif, France, 2Paris-Sud University, 3CEA-INSERM U1000, 4INSERM U669, 5Addiction Center, CHRU Lille, Lille 2 University

Abstract: Introduction: There is no specific and approved treatment, by regulatory authorities, for cocaine dependence. Therefore, developing new medications for the treatment of this disease continues to be a research priority. Recent advances in neurobiology and brain imaging studies have suggested several promising pharmacological approaches. Materials and Methods: Literature searches were conducted for the period from January 1990 to February 2011 using PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov, which are the main electronic sources of ongoing trials. Results: Recent controlled clinical studies have highlighted some very promising medications, especially glutamatergic (NAcetylcysteine, modafinil, topiramate) and GABAergic (vigabatrin) agents, agonist replacement therapy (sustained-release methylphenidate, d-amphetamine) and dopamine agents (disulfiram). Additionally, immunotherapy is a new and promising pharmacological approach. Conclusion: Promising pharmacological approaches have emerged for the treatment of cocaine dependence, but larger, randomized, placebo-controlled studies are needed for some medications. Preclinical studies suggest new targets of interest in cocaine dependence. The optimal therapeutic platform is the combination of pharmacotherapies with behavioral therapies.

Keywords: Cocaine, dependence, addiction, pharmacotherapy, vaccine, immunotherapy, clinical trials. I. INTRODUCTION Cocaine is a crystalline alkaloid found in the Erythroxylum cocacoca and Erythroxylum novogranatense plant species. Cocaine hydrochloride is water soluble and is well absorbed by intranasal and intravenous routes (snorting is the most popular route). Before it can be smoked, cocaine hydrochloride must be converted into an alkaline form of either freebase or crack cocaine (different terms for the same chemical form). Intranasal cocaine powder requires 5 to 10 minutes to produce psychostimulant effects, whereas the effects of the smoked form are instantaneous [1]. This psychostimulant substance of abuse has become a noticeable part of the European drug scene and is the second most commonly used illicit drug after cannabis among the general population. Some European countries have seen rapid increases in cocaine use and cocaine-related seizures in recent years [2]. The European average for last year use of cocaine among young adults (15 to 34 years old) was estimated at 2.3 % (about 3 million) and for last month use at 0.9 % (1.5 million) in 2009 - a substantial increase over the past decade. As with most illegal drugs, the highest rates of cocaine use are among males aged 25 to 34 years [2]. The most dramatic increase in recent cocaine use in Europe occurred in the United Kingdom (last year prevalence: 6,2%; last month prevalence: 2,9%) and Spain (last year prevalence: 5,5%; last month prevalence: 1,9%) in 2009. Cocaine use tripled between 2005 and 2008, and 4% of 17-year-old males experimented with this psychostimulant drug in France in 2008 [3]. Furthermore, 5% of cocaine users will develop a substance dependence during the first year of use, and 20% of them will become long-term cocainedependent patients in North America [4]. In agreement with this epidemiological data, the number of patients entering drug treatment for primary cocaine use has been increasing in Europe for several years. *Address correspondence to this author at the Addiction Research and Treatment Center, Paul-Brousse Hospital (Assistance Publique-Hôpitaux de Paris [AP-HP]), Villejuif, France; Tel: 00 3 145 596 513; Fax: 00 33 145 593 863; E-mail: [email protected]

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Cocaine dependence is a multifactorial disorder that is variable in its manifestations. It comprises distinct clinical phenomena that include the following: cocaine-induced euphoria [5], acute withdrawal syndrome, cue-induced craving (people, places, things, cocaine paraphernalia) [6], loss of control with poor decision making and poor impulse control, cocaine-seeking behavior combined with taking multiple risks and cocaine administration [7]. This addictive disorder is a significant public health problem with psychiatric, somatic, legal and socio-economic complications. Cocaine increases synaptic levels of the monoamines (dopamine, serotonin and norepinephrine). Cocaine reward is attributable mostly to increased dopamine in the meso-cortico-limbic system (reward system) [8-10], although dopamine stimulation alone cannot explain the rewarding effects of stimulants. Other neurotransmitter systems, including GABA, acetylcholine, corticotrophinreleasing hormone and endocannabinoid are influenced by cocaine [11-15]. These systems interact with and modulate the reward, motivation, and memory systems in the brain [16, 17]. The glutamatergic system is critically involved in cocaine addiction. Glutamate levels in the nucleus accumbens increase during reinstatement, and glutamate receptor activation is necessary for reinstatement to drug-seeking behavior [18]. There is also evidence that repeated exposure to cocaine leads to profound changes in glutamate transmission in limbic nuclei [19]. Currently, there is no specific and approved treatment, by regulatory authorities, for cocaine dependence. Therefore, the development of new medications for the treatment of this disease continues to be a research priority. Recent advances in neurobiology and brain imaging studies have resulted in the identification of various neuronal mechanisms implicated in cocaine dependence [18, 20-24], and several promising pharmacological approaches have been suggested [25]. Current studies point to medications affecting the glutamatergic and GABAergic systems, agonist replacement therapy and immunotherapy as holding substantial promise [25]. Many reviews on pharmacological treatments for cocaine dependence have been written elsewhere [25-29], but this is an evolving area © 2011 Bentham Science Publishers Ltd.

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with new clinical trials being frequently published. This review will focus on medications that have been evaluated in clinical trials. Main outcomes measures such as cocaine use, craving, withdrawal, relapse, treatment retention were evaluated. We will not discuss the management of cocaine intoxication nor the treatment of cocaine dependence in patients with comorbid disorders. Literature searches were conducted for the period from January 1990 to February 2011 using PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov, which are the main electronic sources of ongoing trials. We used the following key words either alone or in combination: cocaine, dependence, addiction, pharmacotherapy, vaccine, immunotherapy, and clinical trials. II. GLUTAMATERGIC AGENTS II.1. N-acetyl-cysteine N-acetyl-cysteine (NAC), a mucolytic agent, is also available as a nutritional supplement. It is used in chronic pulmonary conditions, in cystic fibrosis and to treat paracetamol (acetaminophen) overdose. Acetyl cysteine, the N-acetyl derivative of the amino acid L-cysteine, has numerous mechanisms of action and is a major precursor of the antioxidant glutathione. Glutamate levels in the nucleus accumbens (NAcc) mediate reward-seeking behavior. Preclinical findings have shown that acute cocaine exposure increases extracellular levels of glutamate within the NAcc [18]. During cocaine withdrawal, extracellular levels of glutamate are decreased in this region relative to drugnaive animals. By providing a source of extracellular cysteine, which is converted to cystine, NAC can exchange extracellular cystine for intracellular glutamate. This restores basal levels of glutamate and prevents a further increase of these levels in the NAcc that are induced by a subsequent cocaine challenge. Finally, it produces a reduction of cocaine-seeking behavior [30, 31]. The ability to induce plasticity in cortico-accumbens circuitry is crucial for regulating motivated behavior. Moussawi and colleagues found that NAC can reverse cocaine-induced metaplasticity, which inhibits further induction of synaptic plasticity Moussawi et al. [32]. A recent study found that repeated NAC treatments lessened cocaineinduced increases in drug-seeking in rats without altering the reinforcing effects of cocaine in rats Amen et al. [33]. Regarding the translation of these findings from animal studies to the clinic, 4 human studies have been conducted. A double-blind, placebo-controlled, crossover inpatient safety and tolerability study was conducted in non-treatment-seeking, cocaine-dependent humans. Preliminary results suggest that NAC is well tolerated and may reduce cocaine-related withdrawal symptoms and cravings [34]. In a 4-week, open-label pilot study, the safety and tolerability of 3 doses of NAC (1200, 2400, and 3600 mg/day) were examined in 23 treatment-seeking, cocaine-dependent patients. All of the doses were safe and well tolerated. Treatment retention levels appeared to be greater for the two higher doses of medication. Sixteen subjects who completed the study either terminated the use of cocaine completely or significantly reduced their use of cocaine during treatment [35]. In a double blind, placebo-controlled crossover trial with NAC, 15 participants completed a cue-reactivity procedure that involved the collection of psychophysical and subjective data in response to slides depicting cocaine and cocaine use. NAC patients reported less desire to use and less interest in cocaine in response to cocaine images, and they watched cocaine slides for less time. NAC plays a role in the inhibition of cocaine cue reactivity [36]. Amen and colleagues recently showed that repeated administration (during 4 days) of NAC (1200–2400 mg/day) to cocaine-dependent human subjects produced a significant reduction in craving following an experimenter-delivered intravenous injection of cocaine (20 mg/70

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kg/60 s) [33]. Currently, an 8-week randomized controlled trial is actually being conducted. Participants in the NAC group will receive either 1200 or 2400 mg of the medication with cognitive behavioral therapy (CBT) throughout the study on a weekly basis (see clinicaltrials.gov). According to the definitions used by the United States Preventive Services Task Force (USPSTF), the recommendation grade of these studies is C (The USPSTF recommends against routinely providing the service. There may be considerations that support providing the service in an individual patient). II.2. Modafinil Modafinil, a wake-promoting agent, is chemically and pharmacologically distinct from amphetamine-like and other central nervous system stimulants. This non-amphetamine stimulant is approved for the treatment of sleep disorders, such as narcolepsy with or without cataplexy or idiopathic hypersomnia [37-40]. The precise neurobiological mechanism of action of this medication is complex. Its actions seem to be related to increased glutamate and decreased GABA levels; intact catecholamine (including dopamine) and serotonin systems are essential for modafinil’s effects on GABA. Serotonin and GABA seem to have an inverse relationship. Histaminergic and adrenergic systems appear to be important for the locomotion effects of modafinil. Until now, the interactions of modafinil with orexin neurons seemed complicated and unclear [41]. Modafinil has a low abuse potential [42, 43]. A recent double blind, randomized outpatient study evaluating the reinforcing and subjective effects of modafinil (200, 400, or 600 mg) in cocaine abusers found no abuse liability in this population [44]. However, caution is needed in interpreting these results. For example, a recent study utilized positron emission tomography with [(11)C]Raclopride and [(11)C]Cocaine to measure the effects of modafinil (200 or 400 mg given orally) on extracellular dopamine and on dopamine transporters in 10 healthy male participants. Volkow et al found that modafinil blocked dopamine transporters and increased dopamine in the human brain (including the nucleus accumbens). Drugs that increase dopamine in the NAcc are known to have the potential for abuse. Considering the increasing use of modafinil, the authors highlighted the need for a heightened awareness of potential abuse of and dependence on modafinil in vulnerable populations [45]. Modafinil has stimulant-like subjective effects in humans [46, 47]. It may decrease the cocaine withdrawal syndrome, including fatigue, depressed mood, cognitive impairment, increased appetite, sleep disorders (hypersomnia) [48], and cocaine craving. It does not appear to produce euphoria or evoke cocaine cravings [49, 50]. Human laboratory studies found no clinically significant adverse interactions between modafinil and cocaine [48, 51-53]. Modafinil emerges as a reasonable candidate for the pharmacological treatment of cocaine dependence based on increasing evidence from laboratory studies and clinical trials. A randomized, double-blind clinical trial involved 62 cocainedependent outpatients who received either modafinil 400 mg/day or placebo for 8 weeks in conjunction with CBT [54]. Patients taking modafinil had significantly less cocaine use (measured by urine drug testing) than did patients treated with placebo. No significant adverse effects were reported. A recently completed multi-site controlled clinical trial involved 210 cocaine-dependent outpatients who received either modafinil (200 or 400 mg daily) or placebo. Modafinil in combination with individual behavioral therapy was effective in increasing cocaine non-use days in participants without comorbid alcohol dependence and in reducing cocaine cravings [55]. In their meta-analysis evaluating the efficacy of psychostimulant drugs for the treatment of cocaine dependence, Castells et al found some interesting results; namely, the proportion of patients

Pharmacological Treatments for Cocaine Dependence

achieving sustained cocaine abstinence was higher with modafinil than with placebo [56]. A novel treatment strategy for cocaine dependence could be medications designed to enhance cognitive function and attenuate drug reward [57]. Dose-dependent cognitive benefits in terms of memory [58], motor, attention and executive function were reported with modafinil in healthy adult volunteers [59], in subjects suffering from attention deficit with hyperactive disorder (ADHD) and in schizophrenic patients [60, 61]. Sleep disturbances associated with cocaine withdrawal are more than symptomatic consequences of the illness and may provide a novel target for cocaine dependence. Cocaine users reported poor sleep and fatigue in the first three weeks of abstinence. Sleep architecture disorders include problems with nocturnal sleep latency, total sleep time, and daytime sleepiness. A 16-day inpatient, double-blind, randomized trial evaluating modafinil (400 mg) or placebo every morning at 7: 30 a.m. was conducted in 20 patients. Participants underwent polysomnographic sleep recordings, which were compared to those of 12 healthy subjects. Morningdosed modafinil promotes nocturnal sleep, normalizes sleep architecture, and decreases daytime sleepiness in abstinent cocaine users. Morgan et al suggested that sleep normalization by modafinil might actually improve the clinical outcome of cocaine-dependent patients. Hypersomnia during withdrawal syndrome might amplify stimulant-induced euphoria, which reinforces stimulant use and could increase the likelihood for relapse [62]. Double blind, placebo-controlled clinical trials of modafinil are ongoing at this time (see clinicaltrials.gov). According to the definitions used by the USPSTF, the recommendation grade of these studies is B (The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial). II.3. Topiramate Topiramate is an anticonvulsant that is also used to prevent migraine headaches. It may be a promising medication for relapse prevention based on its effects on glutamate and GABA neurotransmission. Topiramate was used for the first time in a 6-week open pilot study in six cocaine-dependent patients who were also alcohol users. Doses were gradually increased to 300 mg/day. All of the patients received weekly CBT. Urinary cocaine screening remained negative until the end of the study. Topiramate was also associated with reduced alcohol cravings and an absence of consumption during the study [63]. A 12-week, open-label pilot study that utilized increasing doses of topiramate (25 to 300 mg/day) for 6 weeks along with counseling in cocaine-dependent outpatients showed a significant reduction in craving intensity and duration in 25% of the sample group [64]. The first randomized, double-blind clinical trial was conducted in 40 cocaine-dependent outpatients who received either topiramate (up to 200 mg/day) or placebo for 13 weeks in conjunction with twice-weekly CBT. There was significantly less cocaine use in the topiramate group than in the placebo group, and 59% of the patients maintained continuous abstinence for at least 3 weeks [65]. Evidence for a beneficial role of topiramate in the treatment of cocaine is promising but is limited by small sample sizes [66]. More studies are currently underway. According to the definitions used by the USPSTF, the recommendation grade of these studies is C.

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II.4. Acamprosate Acamprosate is an effective pharmacological agent used in the treatment of alcohol dependence. It decreases glutamatergic activity via the antagonism of N-Methyl-D-Aspartate (NMDA) receptors or antagonism of type 5 metabotropic glutamate (MGluR5) receptors. Thus, it could impact abstinence in cocaine-dependent patients [67]. Kampmann et al conducted a 9-week, double-blind, placebocontrolled pilot trial of acamprosate (666mg 3 times daily) in 66 patients for the treatment of cocaine dependence. Although well tolerated, acamprosate was no more efficacious than placebo in promoting abstinence from cocaine in cocaine-dependent patients [68]. II.5. Memantine Memantine, used as a cognitive enhancer in Alzheimer disease, is an uncompetitive NMDA receptor antagonist. A 12-week, randomized, placebo-controlled trial involving 115 cocaine-dependent patients was conducted to evaluate memantine (40 mg/day) along with individual CBT. The trial began with a two-week placebo lead-in period with contingency management to induce abstinence. At the end of the trial, the efficacy of memantine was not supported. However, two subgroups of patients emerged: one that rapidly achieved sustained abstinence with contingency management and another that displayed persistent cocaine use and may need medications. This type of design could be a target of interest in the treatment of stimulant dependence [69]. III. GABA AGENTS The GABA system has received special attention concerning its potential as a pharmacological target in the treatment of cocaine dependence [70-72]. Among the existing GABAergic agents, vigabatrin is one of the most promising. Baclofen and tiagabine have been tested, but no evidence has been found for their use in the treatment of cocaine dependence. III.1. Vigabatrin (Gamma-Vinyl GABA) Vigabatrin (1.5-3 g/day), an atypical antiepileptic drug, was well tolerated in 3 open-label studies involving 78 stimulantdependent outpatients receiving medication for up to 9 weeks. It was associated with drug abstinence but the drop-out rate was about 50%. No ophthalmologic adverse effects were reported [73-75]. A 9-week randomized, double-blind, placebo-controlled trial with vigabatrin (1 to 3 g/day) was conducted with 103 cocainedependent, treatment-seeking Mexican parolees. The primary outcome was full abstinence for at least three weeks. Vigabatrin was well tolerated and safe. There was a retention rate of 62% of the vigabatrin group No differences between the two groups regarding drug craving, depression or anxiety were found. A higher rate of abstinence was achieved by the end of the trial in the vigabratin arm [76]. Therefore, this study showed evidence of the efficacy of vigabatrin in promoting short-term cocaine abstinence. According to the definitions used by the United States Preventive Services Task Force (USPSTF), the recommendation grade of these studies is B. III.2. Baclofen Baclofen is a GABAB receptor agonist that is used primarily to reduce muscle spasticity in patients with neurological diseases (e.g. multiple sclerosis, medullar lesions). A preliminary human clinical study showed the cocaine anti-craving properties of baclofen [77]. When cocaine-dependent patients received baclofen (20-40 mg/day), their cocaine craving decreased after 7 to 10 days [78]. A human laboratory study with baclofen (60 mg/day) showed a decrease of cocaine self-administration in non-opioid-dependent, nontreatment-seeking, cocaine-dependent patients [79]. Despite prom-

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ising findings, a 16-week, randomized, placebo-controlled, double blind clinical trial with baclofen (60 mg/day) in 70 cocainedependent outpatients found no significant overall difference between the two groups. A significant decrease of cocaine use was found in the subgroup of patients who had heavier cocaine use [80]. A recent multicenter, 8-week, randomized, placebo-controlled, double-blind clinical trial with baclofen (60 mg/day) in 160 cocaine-dependent outpatients yielded no significant difference between the two groups. According to the authors, there is a need to focus on severe cocaine-dependent patients and/or the need for a higher baclofen dose [81]. There is no evidence in support of baclofen use for the initiation of abstinence. Baclofen must be tested at higher doses to determine its efficacy in relapse prevention. III.3. Tiagabine Tiagabine is an anticonvulsant that acts on GABA neurotransmission. In a 10-week, screening, placebo-controlled trial, tiagabine (20 mg/day) showed a trend towards reduced cocaine use [82]. Two small, randomized, placebo-controlled clinical trials conducted with cocaine-dependent outpatients maintained on methadone to treat concurrent opiate dependence confirmed the efficacy of tiagabine (12 or 24 mg/day) along with weekly individual or group CBT [83] [84]. Therefore, tiagabine decreased cocaine use in this study. However, in a 12-week, double-blind, placebo-controlled outpatient trial in which 141 patients received either tiagabine (20 mg/day) or placebo along with one hour of manualized individual CBT on a weekly basis, no conclusive results were obtained. Tiagabine, at a dose of 20 mg/day, did not have a robust effect in decreasing cocaine use [85]. IV. DOPAMINE AGENTS IV.1. Disulfiram In 1937, disulfiram was reported as a potential treatment of alcoholism by Williams who, after accidentally exposing his laboratory assistants to this medication and then to alcohol, rendered them abstinent [86]. Disulfiram inhibits the enzyme acetylaldehyde dehydrogenase, which transforms acetaldehyde into acetate during alcohol metabolism, resulting in increased plasma concentrations of acetylaldehyde. Acetylaldehyde accumulation combined with ethanol causes adverse reactions in humans (i.e., flushing, sweating, headaches, nausea, tachycardia, palpitations, arterial hypotension and hyperventilation). Disulfiram could have a dopaminergic, agonist-like effect. It inhibits dopamine -hydroxylase (DBH), increases cerebral dopamine levels and decreases norepinephrine levels in the brain. This DBH inhibition could be a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence [87]. Furthermore, it has been shown that a disulfiram metabolite may block glutamatergic receptors [88]. There is evidence that disulfiram could be useful in the treatment of patients who have cocaine dependence alone or comorbid cocaine and alcohol dependence [89,90]. Up to 85% of comorbidity between cocaine and alcohol abuse or dependence have been found [71, 91]. Alcohol enables cocaine abusers or cocaine-dependent patients to manage their withdrawal syndrome when no more drugs are available. Alcohol may also disinhibit them and help them to avoid using cocaine. Cocaethylene, a metabolite resulting from the association of alcohol and cocaine, causes increased euphoria intensity and diminished effects of the withdrawal syndrome [25]. It has pharmacological actions similar to cocaine but may be longer acting [92]. Clinical trials have found significantly reduced cocaine and alcohol use with disulfiram 250-500 mg/day combined with CBT or a 12-step self-help program [93, 94]. Decreased cocaine use was still present one year after treatment [95]. In a 12-week, randomized, placebo-controlled trial with 4 treatment conditions, disulfiram (250 mg/day) seemed to exert a direct effect on cocaine use

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rather than through reducing concurrent alcohol use [96]. Disulfiram also showed a direct effect in reducing cocaine use in nonalcohol-abuse outpatients, opiate-dependents and those receiving opiate agonist maintenance treatment (methadone or buprenorphine) [97, 98]. An 11-week, double-blind, placebo-controlled trial evaluated the efficacy of disulfiram (250 mg/day), naltrexone (100 mg/day) and their combination in 208 patients with co-occurring cocaine and alcohol dependence. Patients taking disulfiram alone or in combination were more likely to achieve combined abstinence from cocaine and alcohol than placebo-treated patients [99]. A recent 14-week, double-blind, randomized, placebo-controlled clinical trial examined the dose-related efficacy of disulfiram (62.5, 125 or 250 mg/day) for treating cocaine dependence in 161 methadonestabilized, cocaine-dependent participants. Because the amount of cocaine-positive urines increased over time in the 62.5- and 125-mg disulfiram groups, it may be contraindicated for cocaine dependence at doses less than 250 mg/day. Studies with disulfiram at higher doses are needed to determine whether it is efficacious in reducing cocaine use in comorbid cocaine- and opioid-dependent individuals [100]. According to Malcom et al, disulfiram is rarely used in clinical settings because of safety concerns. Severe cardiovascular, hepatic, neurologic and psychiatric disorders have to be eliminated, and drug interactions (i.e. amitriptyline, warfarin, phenytoin, and some benzodiazepines such as chlordiazepoxide and diazepam) have to be evaluated. Studies showed that disulfiram has an acceptable side-effect profile for the treatment of cocaine dependence with or without alcohol dependence [101]. According to the definitions used by the USPSTF, the recommendation grade of these studies is B. IV.2. Bupropion Bupropion is a dopamine and norepinephrine reuptake inhibitor [102, 103]. It is an antidepressant approved as a treatment for smoking cessation [104, 105]. Bupropion (300 mg/day) along with individual counseling was not effective in reducing cocaine use in a 12week, multi-site, controlled clinical study of 149 outpatients who were methadone-maintained for the treatment of concurrent opiate dependence [106]. A significant beneficial effect in the patients with comorbid depression has been found in a post-hoc analysis of this study. In another study with the same design, bupropion at the same dosage potentiated the effect of contingency management in reducing cocaine use while having no effect on patients receiving non-contingent rewards [107]. A recent 16-week, randomized, double-blind, placebo-controlled trial in 70 outpatients failed to find an effect of bupropion relative to placebo when combined with CBT [108]. However, according to Castells et al, promising results of the efficacy of bupropion may exist for methadone-maintained, comorbid opiate- and cocaine-dependent patients. The proportion of patients achieving sustained cocaine abstinence was higher than with placebo [56]. IV.3. Conventional and Atypical Antipsychotics Several clinical trials found that neither risperidone (2-8 mg/day for 12 weeks or 2-4 mg/day for 26 weeks) [109, 110] nor olanzapine (10 mg/d for 8, 12 or 16 weeks) [111-113] along with CBT significantly decreased cocaine use in patients without psychiatric comorbidity. A 12-week, randomized, double-blind, placebocontrolled trial of intramuscular risperidone (25 mg every other week) was ineffective in 48 active cocaine users. It was associated with the worsening of depressive symptoms and weight gain [114]. A meta-analysis conducted by Amato et al found no evidence of beneficial effects from the use of antipsychotics (risperidone, haloperidol, olanzapine) in cocaine dependence [115]. The main outcomes were decrease of cocaine use, craving and side effects. A study utilizing an open-label treatment with quetiapine (300-600 mg/d) in 22 cocaine-dependent nonpsychotic men found that crav-

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ings were decreased and that some aspects of cocaine dependence were improved [116]. Aripiprazole is a potential candidate for the treatment of cocaine dependence. This pharmacological agent is an antipsychotic with partial agonist activity at D2 dopamine receptors [117]. Human laboratory studies have uncovered interesting results regarding aripiprazole. For example, it was suggested that 10 mg aripiprazole would be a reasonable starting dose for the treatment of stimulant abuse and dependence [118]. Aripiprazole altered temperatureincreasing and subject-rated effects of cocaine [119]. Aripiprazole is safe and tolerable when combined with cocaine [119]. Open label studies found decreased cocaine use and cravings in comorbid schizophrenic subjects [120]; in nonschizophrenic, crack-dependent patients [121]; and in cocaine-dependent patients [122]. A recent laboratory study found that aripiprazole could increase smoked cocaine self-administration to compensate for a blunted subjective cocaine effect [123]. According to the definitions used by the USPSTF, the recommendation grade of these studies is C. Randomized, placebocontrolled clinical trials are needed. V. AGONIST REPLACEMENT THERAPY Recent research indicates that agonist replacement may be an interesting option for the treatment of cocaine dependence [124]. Therapeutic programs are developed in several countries [25]. This pharmacological approach uses a drug from the same pharmacological family as the abused drug to suppress withdrawal and drug cravings [125, 126]. Clinical examples include the use of methadone or high-dose buprenorphine treatment for opiate dependence and nicotine gum, tablets or skin patches to treat nicotine dependence. Potential agonist medications include d-amphetamine, methylphenidate, modafinil and disulfiram [25]. We will focus on the first two cited medications. Dextro-amphetamine (15 to 60 mg/day sustained release formulation) in cocaine-dependent or in cocaine- and heroin-dependent patients showed decreased cocaine use at the higher doses (30-60 mg/day) in three double-blind, placebo-controlled studies [110, 127, 128]. A recent human study found that 15 mg oral d-amphetamine did not increase stimulant self-administration [129]. Another study showed that d-amphetamine attenuated some of the subjectrated effects of cocaine [130]. Czoty et al suggested that prolonged d-amphetamine treatment may be necessary to produce a sustained reduction in the reinforcing effects of cocaine [131]. Furthermore, secondary analyses provide some hopeful results that encourage further research regarding the use of d-amphetamine and modafinil for the treatment of cocaine dependence [132]. Up to 30% of cases, ADHD is a common psychiatric comorbidity among cocaine-dependent patients [133]. Because methylphenidate (MPH) is an effective treatment for ADHD, it was hypothesized that it might have a beneficial effect in cocaine users with this comorbid disorder [25]. A brain imaging study suggested that its use for the treatment of ADHD patients with comorbid cocaine abuse should not increase cravings [22]. Another study suggested that MPH's attenuation of brain reactivity to cocaine cues was distinct from that involved in cravings [134]. In a recent study, neither MPH nor modafinil impaired inhibitory control, but they produced prototypical subject-rated and cardiovascular effects. This suggests a beneficial use for these drugs as agonist-replacement therapies for cocaine dependence [135]. A placebo-controlled, cocaine-MPH interaction study suggested that MPH (60 or 90 mg) can likely be used safely in an outpatient setting with active cocaine users [136]. Another placebo-controlled crossover interaction study using sustained release (SR) oral MPH (40 or 60 mg) found similar results [137]. MPH immediate-release

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formulation has been found to have a potential for abuse [138] [139], while the sustained-release formulation has much less abuse potential [140]. A multi-site, open-label study of methylphenidate treatment found that only compliant cocaine-dependent patients with ADHD showed improvement [141]. MPH immediate-release formulation (90 mg/day) in 48 cocaine-dependent adults with comorbid ADHD was no better than placebo for treating cocaine use and cravings in a 12-week, double-blind, placebo-controlled trial of [142]. A 14-week, double-blind, placebo-controlled trial of sustained-release MPH (60 mg/day) in 106 cocaine-dependent outpatients with comorbid ADHD found a significant decrease in cocaine use [143]. These controlled clinical trials showed mixed results, but it was suggested that sustained-release MPH may have been more effective and had less potential for abuse than immediate-release MPH [138, 139]. The beneficial effect of MPH may be mediated in part by a reduction in ADHD symptoms. VI. IMMUNOTHERAPY Vaccines or passive administration of antidrug monoclonal antibodies are an innovative treatment strategy for drug addiction [144, 145]. Vaccines may be effective in blocking the effects of drugs of abuse [146] and have advantages over conventional medications such that they would have neither direct psychoactive effects nor abuse liability. Their effects may persist for months, thus improving patient adherence to treatment [147]. Animal studies showed that cocaine vaccines significantly reduced the behavioral effects of the drug [148, 149]. The goal of using cocaine-selective antibodies is to block the compound peripherally and to prevent it from crossing the blood–brain barrier. The TA-CD vaccine is a cocaine conjugate that stimulates the production of antibodies against cocaine [150]. This vaccine utilizes the cholera toxin B subunit as a carrier protein linked to norcocaine at the methyl ester group as an immunogen. A phase I randomized, double-blind, placebo-controlled trial of the vaccine in 34 cocaine abusers over 12 months found that cocaine-specific IgG cocaine antibodies were induced in a time- and dose-dependent manner. The vaccine was well tolerated with no serious adverse effects [151]. A 14-week, open label, dose-escalation study evaluating the safety, immunogenicity, and clinical efficacy of TA-CD in 18 cocaine-dependent patients was conducted. The vaccine was well tolerated, and cocaine-specific antibodies persisted for at least 6 months. There was decreased cocaine use in subjects who received the more intense vaccination schedule (2000 versus 400 g total dose group) [152]. A human laboratory study was conducted in 10 cocaine-dependent men not seeking cocaine. The TA-CD vaccine decreased the acute effects of smoked cocaine in subjects who generated a sufficient amount of antibody [153]. A 24-week, phase IIb, randomized, double-blind, placebo-controlled trial evaluated the immunogenicity, safety, and efficacy of this vaccine in 115 cocaine-dependent, methadone-maintained subjects. There was significantly reduced cocaine use in patients who attained high IgG anti-cocaine antibody levels (superior or equal to 43 mg/mL). One limitation of this study was that only 38% of the subjects reached these IgG levels. They had only two months of adequate cocaine blockade [154]. Improved vaccines and boosters are therefore needed. Recently, Hicks et al developed a new vaccine by covalently linking a cocaine analog to the capsid proteins of a noninfectious, disrupted adenovirus vector. There was preclinical evidence that high-titer, anti-cocaine antibodies were sufficient to completely reverse, on a persistent basis, intravenous cocaine-induced hyperlocomotor activity [155]. Another important point regarding immunotherapy is the challenges in medication adherence due to prolonged and administration schedules. Prize-based incentives on retention and medication adherence were efficacious among 26 cocaine users involved in a 6month hepatitis B vaccination series [156].

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Table 1.

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Recent Meta-analyses and Randomized Controlled Trials

Pharmacological Agents Anticonvulsant drugs

Design

Main Results

Systematic review and meta-analysis: 15 randomized, double-blind, placebo-controlled clinical trials involving 1236 patients

References

No evidence of the efficacy of anticonvulsant drugs

[157]

Anticonvulsant drugs

Meta-analysis: 15 studies involving 1066 patients

No efficacy of carbamazepine, gabapentin, lamotrigine, phenytoin and valproate

[66]

Psychostimulant drugs

Meta-analysis: 16 studies involving 1345 patients

No efficacy of mazindol, methamphetamine and selegiline

[56]

Dopamine agonists

Meta-analysis: 17 randomized, double-blind, placebocontrolled clinical trials involving 1224 patients

No efficacy of amantadine, bromocriptine, and pergolide

[158]

Antidepressants

Meta-analysis: 18 randomized, controlled studies involving 1177 patients

No efficacy of desipramine, imipramine, and fluoxetine

[159]

Fluoxetine

A 33-week, randomized, double-blind, placebo-controlled clinical trials involving 145 cocaine- and opioiddependent outpatients treated with methadone

No efficacy of fluoxetine

[160]

According to the definitions used by the USPSTF, the recommendation grade of these studies is B. VII. INEFFECTIVE MEDICATIONS: RESULTS OF RECENT STUDIES A number of other pharmacological agents tested for the treatment of cocaine dependence failed to prove any efficacy in clinical trials. We report here the main results of recent meta-analyses and randomized controlled trials that had an evidence-based medicine approach toward the pharmacological treatment of this addictive disorder. Table 1 summarizes the main results of these studies. VIII. CONCLUSION Cocaine dependence is an increasing public health problem in Europe. Despite many years of clinical research, no pharmacological treatment has proven to be effective. Recent literature have shown that the main identified pharmacological targets for addictive disorders were positive reinforcement (drug reward), negative reinforcement and individual vulnerabilities such as psychiatric comorbidity and cognitive deficits [161]. Additionally, various recent controlled clinical studies have highlighted some very promising medications, especially glutamatergic and GABAergic agents, which act on the various neurobiological circuits modified by chronic cocaine use. Immunotherapy is also a new and promising pharmacological approach. However, larger, randomized, placebocontrolled studies are needed. Preclinical studies suggest that the targets of interest in developing new treatments for cocaine dependence should also include acetylcholine, endocannabinoid systems, dual dopamine-serotonin releasers, corticotropin-releasing factor (CRF) receptor antagonists, neurokinin-1–receptor antagonists, and dopamine D3-receptor antagonists. Finally, the optimal therapeutic platform is the combination of medications for cocaine dependence with behavioral therapies, e.g., contingency management. This treatment modality has many advantages, such as enhancing compliance, fostering retention in treatment, abstinence initiation and increasing long-term abstinence. It will be also useful to outline profiles of responders according to the different dimensions of cocaine dependence such as craving, relapse prevention, rates of abstinence, withdrawal.

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Received: February 1, 2011

Accepted: April 19, 2011

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