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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:
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1381-6128/11 $58.00+.00
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
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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.
Psychiatric comorbidities, somatic comorbidities, and concurrent substance dependence should be taken into consideration during the treatment of cocaine-dependent patients. CONFLICTS OF INTEREST None. REFERENCES
[1] [2]
[3]
[4]
[5] [6]
[7] [8] [9] [10] [11]
[12]
Part of information included in this article has been previously published in The International Journal of Neuropsychopharmacology (2008), 11: 425-438. Dackis CA, O'Brien CP. Cocaine dependence: a disease of the brain's reward centers. J Subst Abuse Treat 2001; 21(3): 111-7. EMCDDA.: European Monitoring Center for Drugs and Drug Abuse: annual report 2009: The state of the drug problem in Europe. (www.emcdda.europa.eu). 2010. EMCDDA.: European Monitoring Center for Drugs and Drug Abuse: annual report 2008: The state of the drug problem in Europe. (www.emcdda.europa.eu). 2009. Wagner FA, Anthony JC. From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology 2002; 26: 479-88. Dackis CA, Gold MS. Addictiveness of central stimulants. Adv Alcohol Subst Abuse 1990, 9(1-2): 9-26. Rohsenow DJ, Martin RA, Eaton CA, Monti PM. Cocaine craving as a predictor of treatment attrition and outcomes after residential treatment for cocaine dependence. J Stud Alcohol Drugs 2007; 68(5): 641-8. Dackis CA. Recent advances in the pharmacotherapy of cocaine dependence. Curr Psychiatry Rep 2004, 6(5): 323-31. Koob G, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. . Neuropsychopharmacology 2001; 24(2): 97-129. Nestler E. Molecular neurobiology of addiction. Am J Addict 2001; 10: 201-17. Cami J, Farre M. Drug addiction. N Engl J Med 2003; 349(10): 975-86. Lhuillier L, Mombereau C, Cryan JF, Kaupmann K. GABA(B) Receptor-Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine. Neuropsychopharmacology 2007; 32(2): 388-98. Arnold JC. The role of endocannabinoid transmission in cocaine addiction. Pharmacol Biochem Behav 2005; 81(2): 396-406.
Pharmacological Treatments for Cocaine Dependence [13]
[14] [15]
[16] [17]
[18]
[19]
[20]
[21]
[22]
[23] [24]
[25]
[26] [27] [28] [29] [30]
[31]
[32]
[33]
[34]
[35]
[36] [37]
[38]
Wiskerke J, Pattij T, Schoffelmeer AN, De Vries TJ. The role of CB1 receptors in psychostimulant addiction. Addict Biol 2008; 13(2): 225-38. Williams MJ, Adinoff B. The role of acetylcholine in cocaine addiction. Neuropsychopharmacology 2008; 33(8): 1779-97. Lee B, Tiefenbacher S, Platt DM, Spealman RD. Role of the hypothalamic-pituitary-adrenal axis in reinstatement of cocaineseeking behavior in squirrel monkeys. Psychopharmacology (Berl) 2003; 168(1-2): 177-83. Lingford-Hughes A, Nutt D. Neurobiology of addiction and implications for treatment. Br J Psychiatry 2003; 182: 97-100. Kalivas PW, Volkow N, Seamans J. Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 2005; 45(5): 647-650. Uys JD, LaLumiere RT. Glutamate: the new frontier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets 2008; 7(5): 482-91. Schmidt HD, Pierce RC. Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction. Ann N Y Acad Sci 2010; 1187: 35-75. Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002; 159(10): 1642-52. Howell LL, Votaw JR, Goodman MM, Lindsey KP. Cortical activation during cocaine use and extinction in rhesus monkeys. Psychopharmacology (Berl) 2009; 208(2): 191-9. Volkow ND, Wang GJ, Telang F, et al. Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues. Neuroimage 2008; 39(3): 1266-73. Uys JD, Reissner KJ. Glutamatergic neuroplasticity in cocaine addiction. Prog Mol Biol Transl Sci 2011, 98: 367-400. Hao Y, Martin-Fardon R, Weiss F. Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: factor in the transition to dependence. Biol Psychiatry 2010, 68(3): 240-8. Karila L, Gorelick D, Weinstein A, et al. New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 2008; 11(3): 425-38. Kampman KM. What's new in the treatment of cocaine addiction? Curr Psychiatry Rep 2010, 12(5): 441-7. Ross S, Peselow E. Pharmacotherapy of addictive disorders. Clin Neuropharmacol 2009; 32(5): 277-289. Kampman KM. New medications for the treatment of cocaine dependence. Ann Ist Super Sanita 2009; 45(2): 109-15. Preti A. New developments in the pharmacotherapy of cocaine abuse. Addict Biol 2007; 12(2): 133-51. Baker DA, McFarland K, Lake RW, et al. Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 2003; 6(7): 743-49. Baker DA, McFarland K, Lake RW, Shen H, Toda S, Kalivas PW. N-acetyl cysteine-induced blockade of cocaine-induced reinstatement. Ann N Y Acad Sci 2003; 1003: 349-51. Moussawi K, Pacchioni A, Moran M, et al. N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci 2009; 12(2): 182-9. Amen SL, Piacentine LB, Ahmad ME, et al. Repeated N-Acetyl Cysteine Reduces Cocaine Seeking in Rodents and Craving in Cocaine-Dependent Humans. Neuropsychopharmacology 2010. LaRowe SD, Mardikian P, Malcolm R, et al. Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. Am J Addict 2006; 15(1): 105-10. Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ. An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31(2): 389-94. LaRowe SD, Myrick H, Hedden S, et al. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 2007; 164(7): 1115-7. Arnulf I, Derenne JP. [Modafinil (Midiodal): wakefulness stimulant in narcoleptic patients]. Presse Med 2000, 29(20): 11312. Billiard M, Besset A, Montplaisir J, et al. Modafinil: a double-blind multicentric study. Sleep 1994, 17(8 Suppl): S107-12.
Current Pharmaceutical Design, 2011, Vol. 17, No. 14 [39] [40]
[41] [42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50] [51]
[52]
[53]
[54]
[55]
[56]
[57] [58]
[59]
[60]
[61]
[62]
1365
Laffont F, Mayer G, Minz M. Modafinil in diurnal sleepiness. A study of 123 patients. Sleep 1994, 17(8 Suppl): S113-5. Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 1988, 12(5): 695-700. Kumar R. Approved and investigational uses of modafinil : an evidence-based review. Drugs 2008; 68(13): 1803-39. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol 2000, 14(1): 53-60. Jasinski DR, Kovacevic-Ristanovic R. Evaluation of the abuse liability of modafinil and other drugs for excessive daytime sleepiness associated with narcolepsy. Clin Neuropharmacol 2000, 23(3): 149-56. Vosburg SK, Hart CL, Haney M, Rubin E, Foltin RW. Modafinil does not serve as a reinforcer in cocaine abusers. Drug Alcohol Depend 2010, 106(2-3): 233-6. Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. Jama 2009; 301(11): 1148-54. Rush CR, Kelly TH, Hays LR, Baker RW, Wooten AF. Acute behavioral and physiological effects of modafinil in drug abusers. Behav Pharmacol 2002; 13(2): 105-15. Rush CR, Kelly TH, Hays LR, Wooten AF. Discriminativestimulus effects of modafinil in cocaine-trained humans. Drug Alcohol Depend 2002; 67(3): 311-22. Dackis CA, Lynch KG, Yu E, et al. Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend 2003; 70(1): 29-37. Ballon JS, Feifel D. A systematic review of modafinil: Potential clinical uses and mechanisms of action. J Clin Psychiatry 2006; 67(4): 554-66. O'Brien CP, Dackis CA, Kampman K. Does modafinil produce euphoria? Am J Psychiatry 2006; 163(6): 1109. Donovan JL, DeVane CL, Malcolm RJ, et al. Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocainedependent volunteers. Clin Pharmacokinet 2005; 44(7): 753-65. Malcolm R, Swayngim K, Donovan JL, et al. Modafinil and cocaine interactions. Am J Drug Alcohol Abuse 2006; 32(4): 57787. Hart CL, Haney M, Vosburg SK, Rubin E, Foltin RW. Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 2008; 33(4): 761-8. 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(1): 205-11. Anderson AL, Reid MS, Li SH, et al. Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend 2009; 104(1-2): 1339. Castells X, Casas M, Perez-Mana C, Roncero C, Vidal X, Capella D. Efficacy of psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev 2010(2): CD007380. Sofuoglu M. Cognitive enhancement as a pharmacotherapy target for stimulant addiction. Addiction 2010, 105(1): 38-48. Muller U, Steffenhagen N, Regenthal R, Bublak P. Effects of modafinil on working memory processes in humans. Psychopharmacology (Berl) 2004, 177(1-2): 161-9. Turner DC, Robbins TW, Clark L, Aron AR, Dowson J, Sahakian BJ. Cognitive enhancing effects of modafinil in healthy volunteers. Psychopharmacology (Berl) 2003; 165(3): 260-9. Turner DC, Clark L, Dowson J, Robbins TW, Sahakian BJ. Modafinil improves cognition and response inhibition in adult attention-deficit/hyperactivity disorder. Biol Psychiatry 2004, 55(10): 1031-40. Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ. Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology 2004, 29(7): 1363-73. Morgan PT, Pace-Schott E, Pittman B, Stickgold R, Malison RT. Normalizing effects of modafinil on sleep in chronic cocaine users. Am J Psychiatry 2010, 167(3): 331-40.
1366 Current Pharmaceutical Design, 2011, Vol. 17, No. 14 [63]
[64]
[65]
[66] [67] [68]
[69]
[70]
[71] [72] [73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
Johnson BA. Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function. CNS Drugs 2005; 19(10): 873-96. 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(2): 132-5. Kampman KM, Pettinati H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 2004, 75(3): 233-40. Minozzi S, Amato L, Davoli M, et al. Anticonvulsants for cocaine dependence. Cochrane Database Syst Rev 2008(2): CD006754. Gass JT, Olive MF. Glutamatergic substrates of drug addiction and alcoholism. Biochem Pharmacol 2008; 75(1): 218-65. Kampman KM, Dackis C, Pettinati HM, Lynch KG, Sparkman T, O'Brien CP. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addict Behav 2010, 36(3): 217-21. Bisaga A, Aharonovich E, Cheng WY, et al. A placebo-controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-randomization lead-in period. Drug Alcohol Depend 2010, 111(1-2): 97-104. Cousins MS, Roberts DC, de Wit H. GABA(B) receptor agonists for the treatment of drug addiction: a review of recent findings. Drug Alcohol Depend 2002; 65(3): 209-20. Vocci F, Ling W. Medications development: successes and challenges. Pharmacol Ther 2005; 108(1): 94-108. Gorelick DA, Gardner EL, Xi ZX. Agents in development for the management of cocaine abuse. Drugs 2004, 64(14): 1547-73. Brodie JD, Figueroa E, Dewey SL. Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA. Synapse 2003; 50(3): 261-5. Fechtner R, Khouri A, Figueroa E, et al. Short-term treatment of cocaine and/or methamphetamine abuse with vigabatrin: ocular safety pilot results. Arch Ophthalmol 2006; 124: 1257-62. Brodie JD, Figueroa E, Laska EM, Dewey SL. Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction. Synapse 2005; 55(2): 122-5. Brodie JD, Case BG, Figueroa E, et al. Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry 2009; 166(11): 1269-77. Ling W, Shoptaw S, Majewska D. Baclofen as a cocaine anticraving medication: a preliminary clinical study. Neuropsychopharmacology 1998, 18(5): 403-4. Brebner K, Childress AR, Roberts DC. A potential role for GABA(B) agonists in the treatment of psychostimulant addiction. Alcohol Alcohol 2002; 37(5): 478-84. Haney M, Hart CL, Foltin RW. Effects of baclofen on cocaine selfadministration: opioid- and nonopioid-dependent volunteers. Neuropsychopharmacology 2006; 31(8): 1814-21. Shoptaw S, Yang X, Rotheram-Fuller EJ, et al. Randomized placebo-controlled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry 2003; 64(12): 1440-8. Kahn R, Biswas K, Childress AR, et al. Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug Alcohol Depend 2009; 103(1-2): 59-64. Winhusen TM, Somoza EC, Harrer JM, et al. A placebo-controlled screening trial of tiagabine, sertraline and donepezil as cocaine dependence treatments. Addiction 2005; 100 Suppl 1: 68-77. 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(11): 1625-32. 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 2007; 23; 87(1): 1-9.
Karila et al. [85]
[86] [87]
[88]
[89] [90] [91]
[92]
[93]
[94]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103]
[104]
[105] [106]
[107]
Winhusen T, Somoza E, Ciraulo DA, et al. A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence. Drug Alcohol Depend 2007; 91(2-3): 141-8. Williams E. Effects of alcohol on workers with carbon disulfide Jama 1937, 109: 1472-3. Gaval-Cruz M, Weinshenker D. mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse. Mol Interv 2009; 9(4): 175-87. Suh JJ, Pettinati HM, Kampman KM, O'Brien CP. The status of disulfiram: a half of a century later. J Clin Psychopharmacol 2006; 26(3): 290-302. O'Shea B. Disulfiram revisited. Hosp Med 2000, 61(12): 849-51. Barth KS, Malcolm RJ. Disulfiram: An Old Therapeutic with New Applications. CNS Neurol Disord Drug Targets 2010s; 9(1): 5-12. Gossop M, Carroll KM. Disulfiram, cocaine, and alcohol: two outcomes for the price of one? Alcohol Alcohol 2006; 41(2): 11920. Hart C, Jatlow P, Sevarino K, Cance-Katz E. Comparison of intravenous cocaethylene and cocaine in humans. . Psychopharmacology (Berl) 2000, 149: 153-62. Higgins ST, Budney AJ, Bickel WK, Hughes JR, Foerg F. Disulfiram therapy in patients abusing cocaine and alcohol. Am J Psychiatry 1993; 150(4): 675-6. Carroll KM, Nich C, Ball SA, McCance E, Rounsavile BJ. Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. Addiction 1998; 93(5): 713-27. Carroll KM, Nich C, Ball SA, McCance E, Frankforter TL, Rounsaville BJ. One-year follow-up of disulfiram and psychotherapy for cocaine-alcohol users: sustained effects of treatment. Addiction 2000; 95(9): 1335-49. Carroll KM, Fenton LR, Ball SA, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 2004, 61(3): 264-72. George TP, Chawarski MC, Pakes J, Carroll KM, Kosten TR, Schottenfeld RS. Disulfiram versus placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. Biol Psychiatry 2000, 47(12): 1080-6. Petrakis IL, Carroll KM, Nich C, et al. Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. Addiction 2000, 95(2): 219-28. Pettinati HM, Kampman KM, Lynch KG, et al. A double blind, placebo-controlled trial that combines disulfiram and naltrexone for treating co-occurring cocaine and alcohol dependence. Addict Behav 2008; 33(5): 651-67. Oliveto A, Poling J, Mancino MJ, et al. Randomized, double blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. Drug Alcohol Depend 2011, 113(2-3): 184-91. Malcolm R, Olive MF, Lechner W. The safety of disulfiram for the treatment of alcohol and cocaine dependence in randomized clinical trials: guidance for clinical practice. Expert Opin Drug Saf 2008; 7(4): 459-72. Rothman RB. High affinity dopamine reuptake inhibitors as potential cocaine antagonists: a strategy for drug development. Life Sci 1990, 46(20): PL17-21. Rau KS, Birdsall E, Hanson JE, et al. Bupropion increases striatal vesicular monoamine transport. Neuropharmacology 2005; 49(6): 820-30. Garrett BE, Rose CA, Henningfield JE. Tobacco addiction and pharmacological interventions. Expert Opin Pharmacother 2001; 2(10): 1545-55. Mooney ME, Sofuoglu M. Bupropion for the treatment of nicotine withdrawal and craving. Expert Rev Neurother 2006; 6(7): 965-81. Margolin A, Kosten TR, Avants SK, et al. A multicenter trial of bupropion for cocaine dependence in methadone-maintained patients. Drug Alcohol Depend 1995, 40(2): 125-31. Poling J, Oliveto A, Petry N, et al. Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population. Arch Gen Psychiatry 2006; 63(2): 219-28.
Pharmacological Treatments for Cocaine Dependence [108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
Shoptaw S, Heinzerling KG, Rotheram-Fuller E, et al. Bupropion hydrochloride versus placebo, in combination with cognitive behavioral therapy, for the treatment of cocaine abuse/dependence. J Addict Dis 2008; 27(1): 13-23. Grabowski J, Rhoades H, Silverman P, et al. Risperidone for the treatment of cocaine dependence: randomized, double-blind trial. J Clin Psychopharmacol 2000, 20(3): 305-10. Grabowski J, Rhoades H, Stotts A, et al. Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology 2004, 29(5): 969-81. Kampman KM, Pettinati H, Lynch KG, Sparkman T, O'Brien CP. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend 2003; 70(3): 265-73. Reid MS, Casadonte P, Baker S, et al. A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/Lcarnitine for the treatment of cocaine dependence. Addiction 2005; 100 Suppl 1: 43-57. Hamilton JD, Nguyen QX, Gerber RM, Rubio NB. Olanzapine in cocaine dependence: a double-blind, placebo-controlled trial. Am J Addict 2009; 18(1): 48-52. Loebl T, Angarita GA, Pachas GN, et al. A randomized, doubleblind, placebo-controlled trial of long-acting risperidone in cocaine-dependent men. J Clin Psychiatry 2008; 69(3): 480-6. Amato L, Minozzi S, Pani PP, Davoli M. Antipsychotic medications for cocaine dependence. Cochrane Database Syst Rev 2007(3): CD006306. Kennedy A, Wood AE, Saxon AJ, et al. Quetiapine for the treatment of cocaine dependence: an open-label trial. J Clin Psychopharmacol 2008; 28(2): 221-4. El-Sayeh HG, Morganti C, Adams CE. Aripiprazole for schizophrenia: Systematic review. Br J Psychiatry 2006; 189: 1028. Stoops WW, Lile JA, Glaser PE, Rush CR. A low dose of aripiprazole attenuates the subject-rated effects of d-amphetamine. Drug Alcohol Depend 2006; 84(2): 206-9. Stoops WW, Lile JA, Lofwall MR, Rush CR. The safety, tolerability, and subject-rated effects of acute intranasal cocaine administration during aripiprazole maintenance. Am J Drug Alcohol Abuse 2007; 33(6): 769-76. Beresford TP, Clapp L, Martin B, Wiberg JL, Alfers J, Beresford HF. Aripiprazole in schizophrenia with cocaine dependence: a pilot study. J Clin Psychopharmacol 2005; 25(4): 363-6. Vorspan F, Bellais L, Keijzer L, Lepine JP. An open-label study of aripiprazole in nonschizophrenic crack-dependent patients. J Clin Psychopharmacol 2008; 28(5): 570-2. Meini M, Moncini M, Cecconi D, et al. Safety, tolerability, and self-rated effects of aripiprazole and ropinirole treatment for cocaine dependence: a pilot study. Am J Addict 2011, 20(2): 17980. Haney M, Rubin E, Foltin RW. Aripiprazole maintenance increases smoked cocaine self-administration in humans. Psychopharmacology (Berl) 2011. Stoops WW, Blackburn JW, Hudson DA, Hays LR, Rush CR. Safety, tolerability and subject-rated effects of acute intranasal cocaine administration during atomoxetine maintenance. Drug Alcohol Depend 2008; 92(1-3): 282-5. Grabowski J, Shearer J, Merrill J, Negus SS. Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 2004; 29(7): 1439-64. Gorelick DA. The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv Pharmacol 1998, 42: 995-7. Grabowski J, Rhoades H, Schmitz J, et al. Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J Clin Psychopharmacol 2001; 21(5): 522-6. Shearer J, Wodak A, van Beek I, Mattick RP, Lewis J. Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction 2003; 98(8): 113741.
Current Pharmaceutical Design, 2011, Vol. 17, No. 14 [129]
[130]
[131]
[132]
[133]
[134]
[135]
[136]
[137]
[138]
[139] [140] [141]
[142]
[143]
[144]
[145] [146]
[147]
[148]
[149] [150] [151]
1367
Stoops WW, Vansickel AR, Lile JA, Rush CR. Acute d-amphetamine pretreatment does not alter stimulant self-administration in humans. Pharmacol Biochem Behav 2007; 87(1): 20-9. Rush CR, Stoops WW, Hays LR. Cocaine effects during Damphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol Depend 2009; 99(1-3): 26171. Czoty PW, Martelle JL, Nader MA. Effects of chronic damphetamine administration on the reinforcing strength of cocaine in rhesus monkeys. Psychopharmacology (Berl) 2010, 209(4): 37582. Castells X, Casas M, Vidal X, et al. Efficacy of central nervous system stimulant treatment for cocaine dependence: a systematic review and meta-analysis of randomized controlled clinical trials. Addiction 2007; 102(12): 1871-87. Schubiner H. Substance abuse in patients with attention-deficit hyperactivity disorder : therapeutic implications. CNS Drugs 2005; 19(8): 643-55. Volkow ND, Wang GJ, Tomasi D, et al. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers. PLoS One 2010, 5(7): e11509. Vansickel AR, Fillmorex MT, Hays LR, Rush CR. Effects of potential agonist-replacement therapies for stimulant dependence on inhibitory control in cocaine abusers. Am J Drug Alcohol Abuse 2008; 34(3): 293-305. Winhusen T, Somoza E, Singal BM, et al. Methylphenidate and cocaine: a placebo-controlled drug interaction study. Pharmacol Biochem Behav 2006; 85(1): 29-38. Collins SL, Levin FR, Foltin RW, Kleber HD, Evans SM. Response to cocaine, alone and in combination with methylphenidate, in cocaine abusers with ADHD. Drug Alcohol Depend 2006; 82(2): 158-67. White BP, Becker-Blease KA, Grace-Bishop K. Stimulant medication use, misuse, and abuse in an undergraduate and graduate student sample. J Am Coll Health 2006; 54(5): 261-8. Arria AM, Wish ED. Nonmedical use of prescription stimulants among students. Pediatr Ann 2006; 35(8): 565-71. Greenhill LL. The science of stimulant abuse. Pediatr Ann 2006; 35(8): 552-556. Somoza EC, Winhusen TM, Bridge TP, et al. An open-label pilot study of methylphenidate in the treatment of cocaine dependent patients with adult attention deficit/hyperactivity disorder. J Addict Dis 2004, 23(1): 77-92. Schubiner H, Saules KK, Arfken CL, et al. Double-blind placebocontrolled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 2002; 10(3): 286-94. 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 Alcohol Depend 2007; 87(1): 20-9. Moreno AY, Janda KD. Immunopharmacotherapy: vaccination strategies as a treatment for drug abuse and dependence. Pharmacol Biochem Behav 2009; 92(2): 199-205. Karila L, Reynaud M. [Therapeutic approaches to cocaine addiction]. Rev Prat 2009; 59(6): 830-4. Meijler MM, Matsushita M, Wirsching P, Janda KD. Development of immunopharmacotherapy against drugs of abuse. Curr Drug Discov Technol 2004, 1(1): 77-89. Orson FM, Kinsey BM, Singh RA, Wu Y, Gardner T, Kosten TR. The future of vaccines in the management of addictive disorders. Curr Psychiatry Rep 2007; 9(5): 381-7. Kantak KM, Collins SL, Lipman EG, Bond J, Giovanoni K, Fox BS. Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model. Psychopharmacology (Berl) 2000, 148(3): 251-62. Fox BS, Kantak KM, Edwards MA, et al. Efficacy of a therapeutic cocaine vaccine in rodent models. Nat Med 1996, 2(10): 1129-32. Heading CE. TA-CD. Xenova. IDrugs 2002; 5(11): 1070-1074. Kosten T, Rosen M, Bond J, et al. Human therapeutic cocaine vaccine: Safety and immunogenicity. Vaccine 2002; 20: 1196-204.
1368 Current Pharmaceutical Design, 2011, Vol. 17, No. 14 [152]
[153]
[154]
[155]
[156]
Martell BA, Mitchell E, Poling J, Gonsai K, Kosten TR. Vaccine pharmacotherapy for the treatment of cocaine dependence. Biol Psychiatry 2005; 58(2): 158-64. Haney M, Gunderson EW, Jiang H, Collins ED, Foltin RW. Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans. Biol Psychiatry 2009; 67(1): 59-65. Martell BA, Orson FM, Poling J, et al. Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Arch Gen Psychiatry 2009; 66(10): 1116-23. Hicks MJ, De BP, Rosenberg JB, et al. Cocaine Analog Coupled to Disrupted Adenovirus: A Vaccine Strategy to Evoke High-titer Immunity Against Addictive Drugs. Mol Ther 2011. Stitzer ML, Polk T, Bowles S, Kosten T. Drug users' adherence to a 6-month vaccination protocol: effects of motivational incentives. Drug Alcohol Depend 2010, 107(1): 76-9.
Received: February 1, 2011
Accepted: April 19, 2011
Karila et al. [157]
[158]
[159]
[160]
[161]
Alvarez Y, Farre M, Fonseca F, Torrens M. Anticonvulsant drugs in cocaine dependence: a systematic review and meta-analysis. J Subst Abuse Treat 2010, 38(1): 66-73. Soares BG, Lima MS, Reisser AA, Farrell M. Dopamine agonists for cocaine dependence. Cochrane Database Syst Rev 2003(2): CD003352. Silva de Lima M, Farrell M, Lima Reisser AA, Soares B. WITHDRAWN: Antidepressants for cocaine dependence. Cochrane Database Syst Rev 2010(2): CD002950. Winstanley EL, Bigelow GE, Silverman K, Johnson RE, Strain EC. A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients. J Subst Abuse Treat 2011. Potenza MN, Sofuoglu M, Carroll KM, Rounsaville BJ. Neuroscience of behavioral and pharmacological treatments for addictions. Neuron 2011, 69(4): 695-712.