Promising Medications for Cocaine Dependence ... - IngentaConnect

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Recent Patents on CNS Drug Discovery, 2011, 6, 146-160

Promising Medications for Cocaine Dependence Treatment Lorenzo Somaini1, Claudia Donnini2, Maria A. Raggi3, Mario Amore4, Roberto Ciccocioppo5, Maria A. Saracino3, Marsida Kalluppi5, Marco Malagoli2, Maria L. Gerra4 and Gilberto Gerra6,* 1

Addiction Treatment Centre, Local Health Unit SERT Cossato, Biella, Italy, 2Department of Genetics, Biology of Microorganisms, Anthropology and Evolution, University of Parma, Parma, Italy, 3Laboratory of PharmacoToxicological Analysis, Department of Pharmaceutical Sciences, University of Bologna, Bologna, Italy, 4Department of Neurosciences, Division of Psychiatry, University of Parma, Parma, Italy, 5Department of Experimental Medicine and Public Health, University of Camerino, Camerino, Italy, 6Drug Prevention and Health Branch, United Nations Office on Drugs and Crime, Vienna, Austria Received: May 2, 2011; Accepted: May 17, 2011; Revised: May 19, 2011

Abstract: Cocaine dependence is characterized by compulsive drug seeking and high vulnerability to relapse. Overall, cocaine remains one of the most used illicit drugs in the world. Given the difficulty of achieving sustained recovery, pharmacotherapy of cocaine addiction remains one of the most important clinical challenges. Recent advances in neurobiology, brain imaging and clinical trials suggest that certain medications show promise in the treatment of cocaine addiction. The pharmacotherapeutic approaches for cocaine dependence include medications able to target specific subtypes of dopamine receptors, affect different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways), and modulate neurological processes. The systematic reviews concerning the pharmacological treatment of cocaine dependence appear to indicate controversial findings and inconclusive results. The aim of future studies should be to identify the effective medications matching the specific needs of patients with specific characteristics, abandoning the strategies extended to the entire population of cocaine dependent patients. In the present review we summarize the current pharmacotherapeutic approaches to the treatment of cocaine dependence with a focus on the new patents.

Keywords: Cocaine, dependence, promising medications treatments. INTRODUCTION Cocaine dependence is a chronic, relapsing disorder characterized by compulsive drug-seeking and drug use despite adverse consequences and continues to be a significant worldwide public health problem with medical, psychological, and legal aspects, including the spread of infectious diseases (e.g. AIDS, hepatitis and tuberculosis), crime, violence and prenatal drug exposure [1]. The European Monitoring Centre for Drugs and Drug Abuse (EMCDDA) estimates that over 3.5 million Europeans used cocaine at least once during the past year. Cocaine has become the third commonest reason, after opiate and cannabis use, for patients in the European Union to enter drug abuse treatment [2]. The US situation is quite similar with 2.4 million or more Americans aged 12 or older as current users of cocaine [3]. Although, effective pharmacotherapy is available for alcohol and heroin dependence, no approved drugs currently exist for cocaine dependence despite two decades of clinical trials involving different types of medications. The medical field has been trying to come up with a satisfactory treatment for cocaine dependence for almost as long as the drug has been available in Europe and the United States [4]. More than sixty medications have been investigated over the past *Address correspondence to this author at the Drug Prevention and Health Branch, Division for Operations, United Nations Office on Drugs and Crime, P.O. Box 500, 1400 Vienna, Austria; Tel: (+43-1) 26060-4123; Fax: (+43-1) 26060-74123; E-mail: [email protected] 1574-8898/11 $100.00+.00

thirty years as treatments for cocaine use or dependence [5] but none have shown adequate effectiveness. However, the search continues because, although non-pharmacologic treatment options remain the treatment of choice for cocaine dependence [6, 7], many cocaine-dependent patients do not adequately respond or are unable to maintain abstinence after treatment. Moreover, changes in brain function due to chronic drug use do not revert to normal when patients are detoxified from drug. Thus, long-term pharmacological treatment beyond detoxification is necessary in the context of psychotherapy and counselling. The new neurobiological knowledge of how the brain is changed by chronic use of cocaine has led to the discovery of promising medications that have already shown encouraging results in some controlled clinical trials. Recent clinical studies have tested some of these drugs, which act on the various neurobiological circuits modified by cocaine use and clinically improve patient’s symptoms [8]. It is well known that cocaine is able to affect different neurotransmitter systems. Initially, it was hypothesized that cocaine could cause only a dysregulation of the corticomesolimbic dopaminergic system, but recent experimental data are evidencing that cocaine can induce widespread effects on different neurotransmitter systems. In fact, norepinephrine, serotonin, glutamate, gamma-aminobutyric acid (GABA), endocannabinoid neurotransmissions are all affected by chronic cocaine use [2]. As a result, multiple mechanisms can be targeted for the development of © 2011 Bentham Science Publishers

Cocaine Dependence Treatment

innovative pharmacotreatments for cocaine addiction. These include modulation of: i) specific dopamine receptor subtypes; ii) different neurotransmitter systems (i.e. noradrenergic, serotonergic, cholinergic, glutamatergic, GABAergic and opioidergic pathways); iii) neuronal excitability (i.e. anticonvulsant). Alternative approaches consist in the use of immunotherapies aimed at the stimulation of antibodies against cocaine to reduce its ability to cross the blood brain barrier. In general, goals for the treatment of addiction include preventing withdrawal symptoms, reducing drug craving, normalizing the different physiological functions that are disrupted by drug use and targeting the treatment agent to the specific site of action/s or neurotransmitter system/s that is/are altered by the drug of abuse [9]. Ideally, medications for the treatment of cocaine dependence should reduce cocaine use and withdrawal symptoms, blunt cocaine euphoria, decrease cocaine reinforcing effects and prevent cocaine relapse. Recent reviews on pharmacotherapy for cocaine have been published [2-10] but this is a very fast evolving area with new clinical trials and preclinical findings being reported frequently. This paper intends to provide an overview about recent developments in cocaine pharmacotherapy, focusing on medications that showed promising clinical results. NEUROBIOLOGICAL CORRELATES Cocaine hydrochloride is well absorbed following intranasal administration and its effects last for about 30-45 minutes. Oral consumption is also possible but the slow absorption rate makes it less attractive for users. Absorption is very rapid if the cocaine is taken by inhalation as a free base (crack) through the smoke; this route allows for the achievement of peak blood concentrations of the drug higher than that obtained following consumption of intranasal cocaine hydrochloride. Intravenous administration of the drug is also possible. This route is often used when cocaine is co-administered with heroin (speedball). The short halflife of cocaine contributes to development of a typical pattern of consumption characterized by repeated dosing over a short period of time (binge) leading to repeated drug “on-off” in the brain. Following acute administration cocaine causes an increase in the synaptic availability of serotonin, dopamine, and noradrenaline. These actions depend upon the ability of cocaine to block catecholamine reuptake mechanisms. Cortico-mesolimbic dopamine neurons originating from the ventral tegmental area (VTA) are known to be particularly sensitive to this action due to the ability of cocaine to block the dopamine transporter (DAT). Evidence for this includes data in a mutant mouse line with a cocaine-insensitive DAT. In these animals, cocaine is unable to evoke conditioned place preference, suggesting that it is no longer rewarding [11]. Blockade of DAT by cocaine leads to changes in both tonic and phasic activity of DA neurons and this is thought to also affect salience attribution to secondary stimuli (cue) associated to drug reward [12].

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Protracted cocaine use results in a series of neuroadaptive changes within the cortico-mesolimbic DA system leading to its hypofunction. This shift in DA activity may explain why animals trained to long access cocaine self-administration escalates cocaine intake and at the same time show an upward shift of the hedonic set point as measured by intracranial self-stimulation [13]. Overall, increased dopaminergic neurotransmission subsequent to acute cocaine administration appears responsible for the state of excitement, euphoria and motor hyperactivity observed after consumption of the substance, while the catecholaminergic system hypoactivity that develops after prolonged cocaine use seems to be responsible for many negative symptoms associated with drug abstinence [14]. Using brain imaging techniques, adaptive changes in the cortico-mesolimbic DA system have been also evidenced in humans. Positron Emission Tomography (PET) studies showed, for example, that compared to healthy controls, active cocaine users had reduced extracellular DA levels measured as in [11C]-raclopride displacement study while showing an increased DA response following presentation of cues reminiscent of cocaine use [15]. In chronic cocaine users hypoactivity of frontocortical areas has been also documented [15]. Since these structures exert inhibitory action over striato-pallidal outputs, hypofunction of frontocortical areas may result in disinhibition of motor planning actions and goal directed behaviors linked to activation of medium spine neurons (MSNs), the most largely represented cell type in the nucleus accumbens. Following cocaine use, significant neuroadaptive changes in glutamate neurotransmission accumbal MSNs have been also widely described. These involve impaired glutamate reuptake, leading to decreased extra synaptic glutamate levels, changes in AMPA receptor density and alteration in intrinsic membrane excitability. These changes are thought to mediate several behavioral outcomes associated with repeated cocaine experiences such as locomotor sensitization, increased seeking behavior and, as mentioned above, reduced cortical control over motor planning and goal-directedbehavior. These changes in glutamate activity become progressively more pronounced during withdrawal thus offering a neurochemical mechanism for the augmented cocaine seeking during protracted abstinence [16, 17]. Several lines of evidence suggest that protracted cocaine use is also associated with neuroadaptive dysregulation of stress-responsive circuitry. Such disturbances are hypothesized to underlie symptoms of anxiety, irritability, autonomic arousal and exaggerated responsiveness to anxiogenic stimuli that emerge when cocaine use is discontinued. For example, detoxified cocaine addicts exhibit increased panic and anxiety, with at least some cases thought to result directly from prior cocaine use. Notably, anxiety and other “protracted withdrawal” symptoms, such as cocaine craving, sleep dysregulation and somatic symptoms predict poor clinical outcome. A logical candidate for the neuroadaptive mechanism that may contribute to protracted withdrawal and vulnerability to relapse is dysregulation of the stress-regulatory neuropeptide corticotropin-releasing factor (CRF). CRF integrates behavioural, endocrine, and autonomic responses to stress [18].

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Hypothalamic CRF, via its hormonal action, is the primary activator of the HPA “stress” axis. Accordingly, acute cocaine induces HPA-activation through potentiation of CRF activity in rats, nonhuman primates and humans [19]. However, inhibitory adaptations of the CRF system (i.e. downregulation of anterior pituitary CRF1 receptor binding levels) are seen during chronic administration. These changes may account for the blunted pituitary-adrenal response to protracted cocaine use. Overall, these findings demonstrate neuroadaptation in stress-responsive CRF systems consequent to chronic cocaine exposure. Increased vulnerability to relapse associated to cocaine withdrawal and stress exposure were originally linked to their common ability to cause the activation of the HPA axis through the CRF [20]. However, mounting evidence indicates that the pivotal role in the regulation of these mechanisms is played by the extrahypothalamic, non-neuroendocrine CRF neurotransmission in the extended amygdala, a neuroanatomical structure comprising the central amygdala, the bed nucleus of the stria terminalis and the nucleus accumbens shell [18]. These findings clearly point to the possibility that targeting the stress system may represent an additional strategy to control cocaine seeking especially for relapse prevention. PHARMACOLOGICAL INTERVENTIONS COCAINE DEPENDENCE

FOR

N-acetylcysteine N-Acetylcysteine (NAC) is the N-acetyl derivate of the naturally occurring amino acid cysteine. It is approved for the treatment of pulmonary complications of cystic fibrosis and chronic obstructive lung disease as a mucolytic agent [21]. Because it is a precursor of glutathione synthesis and forms complexes with toxic reactive metabolites of acetaminophen, which prevents hepatic cell necrosis, it has been used for many years as an antidote to treat paracetamol overdose [22]. In the 2004, Food and Drug Administration approved the intravenous form of NAC to treat acetaminophen poisoning. However, research has demonstrated that NAC may be useful for other clinical conditions. In fact, NAC has been shown to be useful in preventing X-ray contrast nephropathy and in improving cognitive function in patients with dementia [23]. Chronic cocaine use reduces basal levels of glutamate in rats [24] and drug-induced plasticity in central glutamate function has been implicated in the process of cocaine addiction and relapse [25]. The impaired ability of cocaine addicts to regulate drug seeking is thought to be rooted in long term neuroadaptations of glutamatergic input in different areas of the central nervous system (i.e. prefrontal cortex, basal ganglia). The cysteine prodrug NAC has been shown to restore basal glutamate levels and prevent increased glutamate during reinstatement of cocaine seeking by reversing glutamate dysregulation after cocaine self administration [26, 27]. NAC treatment prevents relapse both in animal models and in humans by activating cysteineglutamate exchange and thereby stimulating extra synaptic metabotropic glutamate receptors (mGluR). NAC is metabolized by the body to form cysteine, a pharmacologically active compound-that may normalize a cocaine-induced glutamate imbalance without influencing behavioural res-

ponse for natural rewards [25]. These data implicate NAC as a possible pharmacotherapy for relapse prevention in cocaine addiction. Acute administration of NAC in animal models prevents cocaine-induced increases in extinguished drug seeking [28, 29]. Chronic administration of NAC given during cocaine self administration does not modify cocaine intake in animals with daily 2 hour access conditions, rather, it reduces the escalation of intake in extended access conditions (over 6 hours) [28, 29]. These data indicate that NAC does not change the reinforcing mechanism associated with cocaine, but instead prevents drug seeking by a reduction of the development of plasticity necessary for cocaine-induced reinstatement [26]. Recently, the use of different cysteine and cysteine prodrugs for the treatment drug addiction has been extensively explored and new patents have been published disclosing the use of these agents in the treatment of cocaine dependence and psychiatric conditions [30]. A double-blind, placebo-controlled, cross-over trial was conducted to assess the safety and tolerability of NAC in healthy and in 13 cocaine dependent subjects. In this study NAC was well tolerated, with some evidence of reduced cocaine craving as well as withdrawal symptoms [31]. Another study examined the dose related efficacy of NAC for treating cocaine dependence in 23 treatment seeking cocaine dependent outpatients and revealed that NAC at the range of concentration from 1200 to 3600 mg/day was safe and well tolerated [32]. In this study, the majority of subjects reduced cocaine use and the retention in treatment was higher at the two highest dose groups. Similar results were obtained from another double blind, placebo-controlled clinical trial conducted on 15 participants receiving NAC or placebo during 3-day hospitalization. In this study subjects were crossed over to receive the opposite condition on a second, identical 3-day stay occurring 4 days later. At the end of the study, while taking NAC, participants reported less desire to use cocaine, and less interest in response to cocaine slides wathing the slides for less time [33]. Recently, Amen et al. [34] investigated the impact of repeated NAC on reinstatement in rodents and on craving in cocaine dependent humans. Interestingly, repeated administration of NAC for 7 days induced a significant reduction in cocaine reinstatement even though rats were tested 24 hours after the last administration of NAC. Similarly, repeated administration of NAC for 4 days in the dose range of 1200 and 2400mg/day to cocaine-dependent humans produced a significant reduction of craving following an experimenterdelivered IV injection of different doses of cocaine. Modafinil Modafinil is a novel, non amphetamine psychostimulant, approved by US Food and Drug Administration in 1998 for treatment of narcolepsy or idiopathic hypersomnia. For more than two decades psychiatrists have known about and have promoted the use of modafinil to increase wakefulness in the case of excessive sleepiness and also to enhance cognitive functions and mood [35, 36]. Modafinil has also shown efficacy in the treatment of child and adult attention deficit hyperactivity disorder [37].


Despite the fact that modafinil use dates back twenty years, its main neurochemical mechanisms remain elusive. Different preclinical studies have shown that modafinil is able to affect both the dopamine and norepinephrine transporters [38]. In addiction, modafinil appears to activate Central Nervous System (CNS) excitatory neurotransmission by increasing the release of glutamate and reducing the release of GABA [39]. Furthermore, its action on the hypocretin/orexin system could help the recovery of the homeostasis disrupted by the use of cocaine. Recently, the hypocretin/orexin system represents the target of different new compounds that could be useful in the treatment of cocaine dependence [40]. Group II metabotropic glutamate receptors (mGlu2/3R) have been suggested as a new therapeutic target for drug addiction. Recent preclinical studies have revealed a novel mechanism for modafinil actions, a role for mGLU2/3R in reinstatement of opiate seeking and a new therapeutic option for the treatment of opiate relapse [41]. The clinical effects of modafinil may reduce the symptoms of cocaine withdrawal, which often include hyperinsomnia, anergia, dysphoric mood, cognitive impairment and hyperphagia consequently reducing the need to use cocaine [42]. Interestingly, modafinil has weak cocaine like reinforcing effects in animals and stimulant-like subjective effects in humans. Furthermore, modafinil does not appear to induce euphoria or evoke cocaine craving [43] suggesting that it has a low abuse potential [44]. Of note, cocaine users are capable of discriminating between cocaine and modafinil effects [45, 46]. Different preclinical studies have reported that modafinil could be beneficial in reducing some withdrawal symptoms [47] and in attenuating subjective responses to cocaine [42]. Additionally, modafinil appears to blunt cocaine euphoria and to reduce cocaine priming. The first randomized, double blind clinical trial was conducted by Dackis et al. [48]. In this trial, patients receiving modafinil had significantly less cocaine use, with increased rate of cocaine-free urines with rates of 45% for modafinil compared to 20% for placebo. In a multi site clinical study the efficacy of different doses of modafinil (200 mg/day and 400 mg/day) were evaluated on 210 cocaine dependent outpatients receiving either modafinil or placebo [49]. Modafinil significantly reduced cocaine use only in the subgroup of patients without alcohol dependence. Similarly and more recently, Anderson et al. [50] tested the efficacy of modafinil on 210 cocaine treatment seekers, in a double blind, placebo controlled study with 12 weeks of treatment and a 4-week follow-up. Modafinil in combination with individual behavioural therapy was effective in reducing cocaine craving and in increasing cocaine non- use days only in subjects without concomitant alcohol dependence. Human laboratory studies have reported no clinically significant adverse interactions between cocaine and modafinil [51] and post marketing surveillance studies have not evidenced a significant abuse liability for this drug [52]. Methylphenidate Preclinical studies suggest that the reinforcing effect of cocaine which promotes its abuse is mediated by blockade of


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the pre-synaptic dopamine transporter, with increased dopamine activity in the cortico-mesolimbic reward system [53, 54]. For this reason, development of new medications to treat cocaine dependence has focused on the manipulation of this dopaminergic mechanism. Methylphenidate, as a dopamine uptake inhibitor, has been studied in experimental animals to investigate its possible interactions with cocaine and its potential role in the treatment of cocaine abuse [55]. To this purpose, methylphenidate has been reported to decrease cocaine-maintained responding in the rat [56], supporting the hypothesis of a reinforcing effect modulation. Following this line, methylphenidate has been repeatedly tested in the treatment of cocaine dependence [57]. Sustained-release formulations of this stimulant have shown promise in a substitution approach [54]. In particular, methylphenidate treatment has been experimented in combination with cognitive behavioural therapy and has yielded encouraging results [58]. Accordingly, more recent controlled clinical trials have highlighted the effectiveness of agonist replacement therapy with methylphenidate and d-amphetamine in the treatment of cocaine dependence [59]. In particular, methylphenidate has been found effective in the treatment of cocaine dependent patients with adult attention-deficit hyperactivity disorder (ADHD): the trial demonstrated that improvement in ADHD symptoms among those patients receiving methylphenidate, but not placebo, was associated with a reduction in cocaine use [60]. In agreement with these results, subsequent studies confirmed the effectiveness of methylphenidate in the treatment of cocaine dependence when it is associated with attention-deficit/hyperactivity disorder. This may indicate the capacity of this psychostimulant to replace cocaine when it is used for self-medication purposes [61]. Different methylphenidate analogues are now under development for the treatment of drug addiction. Particular attention has been devoted to methylphenidate extended release formulations that may offer advantages over the original product [62]. Pharmacogenetic studies suggest that clinical outcome for methylphenidate in cocaine addiction is influenced by DAT genotype. In fact, 10/10 repeat DAT gene variant has been reported to respond poorly to methylphenidate pharmacotherapy and the 9/9 DAT1 variant showed blunted euphoria and physiological response to amphetamines [63]. In contrast with the studies investigating specific subgroups of cocaine addicted patients, Cochrane review found that the evidence of the efficacy of psychostimulants, such as methylphenidate, for cocaine dependence was inconclusive. However, the review evidenced that psychostimulants were able to increase the proportion of patients achieving sustained cocaine and heroin abstinence amongst methadone maintained dual heroin-cocaine addicts [64]. The role of methylphenidate in the treatment of cocaine addiction should be investigated with further studies, considering the practical implication of recent laboratory evidence obtained with brain imaging techniques. In fact, oral methylphenidate was found to normalize cingulate activity in cocaine addiction during salient cognitive tasks [65] and to attenuate limbic brain inhibition after cocainecues exposure in cocaine abusers [66].


Topiramate Topiramate has been used as an anticonvulsant for over a decade and has more recently been approved for the treatment of migraine. It has also been prescribed for psychiatric conditions such as bipolar disorder and post-traumatic stress disorder without consolidated evidence about treatment outcome. Several recent clinical trials indicated a potential role of topiramate in the pharmacological treatment of substance use disorders. Topiramate was found to attenuate alcohol craving and alcohol consumption, and to promote abstinence from cocaine, nicotine and MDMA [67, 68]. Like many anticonvulsant drugs, topiramate has multiple mechanisms of action, including inhibition of voltage-gated Na+ and Ca2+ channels and activation of GABAA receptors [68]. Enhancing GABA action at the GABA A receptor level, topiramate has been found to cause a general increase in brain GABA activity [69-71]. In addition, topiramate has been demonstrated to antagonize glutamate transmission by blocking GluR5- containing AMPA receptors [72, 73]. Both GABAergic and glutamatergic neurons appear to be important modulators of the brain reward system. For this reason, medications that affect GABA and glutamatergic neurotransmission may reduce the rewarding properties of cocaine and help to control cocaine craving [74]. Several evidence have suggested that GABAergic neurons function as modulators, particularly those of the mesocorticolimbic dopamine system and play an important role in mediating the reinforcing effects of cocaine [75, 76]. Accordingly, GABAergic medications have been found to reduce the self-administration of cocaine in various animal models [77, 78]. For example, gamma-vinyl-GABA (GVG), a selective and irreversible inhibitor of GABA-transaminase (GABA-T), was reported to significantly attenuate cocaineinduced increases in neostriatal synaptic dopamine in the brain of non-human primates, as assessed by PET, and to abolish both the expression and acquisition of cocaineinduced conditioned place preference [75]. Glutamatergic neurons located in the prefrontal cortex have been demonstrated to innervate the nucleus accumbens and to play a critical role in cocaine-reinforced behaviour [79]. In an animal model, Cornish and Kalivas [80] found that the microinjection of an AMPA glutamate receptor antagonist into the nucleus accumbens was able to block the reinstatement of addictive behaviour by all compounds, whereas dopamine receptor antagonists were effective only in blocking reinstatement by dopamine administration. To this purpose, glutamate receptor activation seems to be an essential step in cocaine-induced relapse to drug-seeking behaviour. On the basis of this neuropharmacological evidence, a double-blind, placebo-controlled study conducted in cocainedependent patients showed that those treated with topiramate, 200 mg/day, had higher cocaine abstinence rates than the placebo group (59% vs 26%). A post hoc analysis showed that topiramate also helped those who had stopped using cocaine to remain abstinent, which suggests that this

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medication could be used as a potential cocaine relapse prevention pharmacotherapy [74]. Accordingly, an open trial study suggested the capacity of topiramate to reduce craving intensity in patients with cocaine dependence [81]. Recent reviews indicate that GABA agents such as topiramate, tiagabine, baclofen and vigabatrin seem to be among the most promising medications in the treatment of cocaine dependence [82-84]. On one hand, topiramate’s unique pharmacodynamic profile offers a promising theoretical rationale for its use across multiple substance-related disorders. On the other, heterogeneity both across and within these disorders may limit topiramate’s broad applicability in the control of addictive behaviour [85]. Considering a possible subgroup of patients characterized by concomitant mental health disorders, topiramate obtained encouraging results also in the treatment of co-morbid cocaine dependence in schizophrenia [86]. Confirmatory clinical studies are necessary to replicate the initial efficacy findings for topiramate and the other anticonvulsant medications. More research is needed in both cocaine and cocaine-alcohol dependent populations. Once confirmatory studies have been carried out, testing of rational medication combinations with different behavioural therapies is an obvious next step to increase the ability to manage cocaine dependence [87]. Baclofen Baclofen (p-chlorophenyl gamma-amminobutyric acid) is an analog of the inhibitory neurotransmitter (GABA), the main inhibitory neurotransmitter in the CNS. Specifically, baclofen is a GABAB receptor agonist with skeletal muscle relaxant and sedative properties. For this reason it has been used for the treatment of spasticity in neuromuscular disorders [88-92]. Various preclinical studies in rats have demonstrated that baclofen (and other GABAB receptor agonists) decreases intravenous cocaine self-administration under various schedules of reinforcement. In particular, baclofen, examined under fixed ratio (FR) or progressive ratio (PR) schedules, dose-dependently reduces self-administration of cocaine, but the effect depends on the dose of self-administered cocaine [93-97]. The effects of baclofen compared on cocaine and foodreinforced responding have demonstrated that baclofen attenuation of cocaine self-administration is not the result of a non specific disruption in responding caused by locomotor impairment or sedation suggesting that baclofen specifically reduces the motivation to respond for cocaine [96-98]. In addition, baclofen pretreatment dose dependently reduces the cocaine priming injection effects in a rat model of relapse [95]. Similarly, the reinstatement of cocaine-seeking produced by priming doses of cocaine is attenuated by low doses of baclofen in baboons [99]. However baclofen does not suppress cocaine self-administration in rhesus monkeys [100]. In an open-label trial and in a double-blind placebo controlled trial, cocaine dependent subjects were treated with baclofen (20 mg, t.i.d.) in conjunction with weekly cognitive behavioral group counseling demonstrating that baclofen


associated with counseling reduces cocaine craving [101103]. One of these studies also provides indications about baclofen-cocaine interaction: no adverse effects were attributable to drug combination [101]. The safe and beneficial use of baclofen has been demonstrated in a patient with cocaine dependence and schizoaffective disorder [104] but not in opioid-dependent cocaine users [105]. However, recent results do not replicate this beneficial effect with nonabstinent cocaine patients with severe cocaine dependence [106]. CGP 56433A, a specific GABA B antagonist, has been reported to attenuate baclofen’s effect on cocaine selfadministration under FR1 and PR schedules of reinforcement [107] suggesting that baclofen’s effect on cocaine reinforcement is mediated by GABAB receptor activation. Moreover, intracerebral injections in rats have been used to study the baclofen’s site of action in cocaine reinforcement suppression and this demonstrated that the greatest effect on cocaine self-administration was seen when baclofen was injected into the VTA [94, 97]. Baclofen and GABAB receptor agonists attenuate cocaine-reinforcing effect by modulating the dopaminergic transmission, specifically by reducing the activity of the mesolimbic dopamine system [108, 109]. After baclofen administration, brain imaging analyses during exposure to cocaine-related videos of cocaine dependent subjects show a pattern of limbic activation comparable to that of non cocaine users suggesting for baclofen a role as an anti-relapse agent [110, 111]. Baclofen also reduces symptoms of alcohol and opiate withdrawal syndrome and nicotine abuse [112-115]. Recently, two patent applications have been published by Olivier Ameisen, Paris (FR). [116,117]. The first patent is directed to prevent relapse in a patient being treated for substance and behavioral addiction using baclofen and to treating depression or other psychological conditions. The second patent is directed to the treatment of addiction and particularly to addictions with a chemical dependency component. Atomoxetine Atomoxetine is a selective norepinephrine reuptake inhibitor that is not classified as a stimulant and is approved for the treatment of ADHD [118]. It is known to improve response inhibition in humans and to decrease impulsivity in animals [119]. Atomoxetine produces pharmacological and behavioral effects that are similar to those observed with prototypical stimulants [120, 121], but atomoxetine appears not to have reinforcing properties and therefore has less abuse potential [122, 123]. Economidou et al. [124, 125] have demonstrated in rats that treatment with atomoxetine can decrease cocaine and heroin seeking and significantly attenuates relapse to cocaine-seeking after abstinence, especially in highly impulsive rats that show the increased propensity to relapse. The effect of atomoxetine is not due to its anti-impulsivity property because it has no significant effect on locomotor activity [125]. The effect of atomoxetine on cocaine seeking and relapse could be due to an extracellular increase of norepinephrine and dopamine induced by atomoxetine in the prefrontal cortex (PFC) of rats [121] which is in agreement


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with the demonstration that manipulation of PFC areas influences drug seeking behavior [126] and vulnerability to relapse [127, 128]. On the other hand, hypoactivity of the PFC is typical of cocaine, heroin, and other drugs of addiction in humans [129, 130]. However, an open-label preliminary trial to assess the utility and tolerability of atomoxetine in the treatment of ADHD in cocaine dependent subjects has shown that atomexitine in conjunction with cognitive-behavioral therapy reduced ADHD symptoms in actively using cocaine dependent individuals but does not influence cocaine use. In contrast, in ADHD patients with comorbid alcohol abuse, treatment with atomoxetine leads to a reduction of cumulative heavy drinking days as well as improving ADHD symptoms [131]. Also, treatment with atomoxetine attenuates some of the subjective effects of dextroamphetamine [132] including the rating of “good drug effects” and “high” that are predictive of reinforcing effects from amphetamines [133]. Ondansetron Ondansetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist that has been introduced into clinical practice as therapy of choice for nausea and vomiting evoked by chemotherapy, radiotherapy and anesthesia. Animal and human research have suggested its possible novel application in the treatment of substance use disorders and related addictive conditions such as alcoholism, cocaine addiction, opioid withdrawal syndrome, anxiety, gastrointestinal motility disorders and Tourette’s syndrome [134]. Ondansetron is a potent, highly selective, competitive antagonist at 5-HT3 receptors. Although, it has demonstrated some affinity to other receptor subtypes including 5-HT1B, 5HT1C, 5-HT4 receptors, opioid receptors, and alpha-1adrenergic receptors [135], ondansetron has strong (1000:1) selectivity toward 5-HT3 receptors [136]. The 5-HT3 receptor is a serotonin-gated ion channel selectively permeable to Na+, K+, and Ca2+ ions, which are involved in the process of depolarization. High concentrations of 5-HT3 receptors have been found in the central nervous system as well as in the peripheral nervous system [134]. While all mechanisms of ondansetron’s effects are not fully understood, it is likely to inhibit 5-HT3 receptors in different brain regions, including the area postrema, nucleus tractus solitarius, amygdala and dorsal raphe nucleus, and, with the mediation of the serotonin system, to reduce dopamine release in the nucleus accumbens. Considering that cortico-mesolimbic dopamine neurons mediate the reinforcing effects of cocaine that are associated with its abuse liability [137] and that 5-HT3 receptors have been found to be involved in dopamine release in this area [138], 5-HT3 receptor antagonists may exert a potential role in modulating cocaine rewarding effects. To this purpose, ondasentron has been found to reduce the reinforcing effects of a variety of abused drugs including alcohol and amphetamines [139-141], presumably by attenuating the suprabasal release of cortico-mesolimbic dopamine. In animal models, research has evidenced that continuous cocaine administration results in behavioral tolerance,


whereas intermittent daily injections of cocaine result in behavioral sensitization [142]. Ondansetron was reported to block the development of both behavioral sensitization and tolerance [143, 144] with a long lasting activity [145]. In addiction, Davidson et al. [146-148] demonstrated that ondansetron was able to inhibit cocaine self-administration and sensitization during the acute cocaine withdrawal period in the experimental animals, suggesting ondansetron as a possible pharmacotherapy in cocaine abuse. Human studies utilizing the 5HT3 antagonist ondansetron also evidenced promising results. In a pilot randomized, double-blind, 10-week controlled trial, 63 treatment-seeking, cocaine-dependent subjects received ondansetron (0.25mg, 1.0mg, or 4.0mg twice daily) or placebo. The ondansetron 4.0mg group had the lowest dropout rate among all treatment groups and a greater rate of improvement in terms of percentage of participants with a cocaine-free week compared with the placebo group [149]. Given the high prevalence of HIV infection among cocaine users, ondansetron has also been proposed as a good alternative for treating not only cocaine addiction, but also the nausea and vomiting associated with HIV infection or its therapy [150]. Further studies are needed to establish and extend these findings and to better delineate the subpopulation for which 5-HT3 antagonists may provide the maximum effect. Buprenorphine Buprenorphine, a partial mu-opioid agonist and kappaopioid antagonist, has been found to significantly reduce cocaine self-administration in non-human primates without interfering with appetitive behaviours such as eating [151153]. Chronic treatment with the mu-opioid receptor partial agonist, buprenorphine, has been found to reduce cocaineinduced behaviours in rats with a history of cocaine selfadministration. The mechanisms underlying these actions of buprenorphine remain unclear [154]. Buprenorphine may block the expression of cocaine sensitization and other cocaine-related behaviors by increasing basal levels of glutamate in the nucleus accumbens, which could serve to decrease the effectiveness of cocaine or cocaine-associated cues. Replications of these effects in humans have obtained uncertain results. In some human laboratory studies, buprenorphine was able to reduce self reported cocaine craving and cocaine self-administration; other studies have failed to replicate those results [155-158]. In some clinical trials with opiate dependent subjects, buprenorphine treatment has been associated with a reduction in cocaine use [159] whereas other trials have found no evidence of efficacy [160, 161]. More recently, a sublingual buprenorphine high dose preparation solution was found effective in reducing both opiate and cocaine use in heroin addicts, with a therapeutic action on cocaine use that appeared independent of that on opiates [162]. Our previous studies indicated the combination of naltrexone and buprenorphine to be more effective than naltrexone alone in the treatment of opioid dependence and

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concomitant cocaine use, with a significant decrease in the rate of positive urinalyses for cocaine metabolites [163]. This observational study evidenced a potential action of buprenorphine on cocaine craving that is not directly related to the mu-opioid effects of the medication. To explain the possible mechanism of action of buprenorphine in reducing cocaine craving and consumption, the role of kappa receptor antagonists has been considered. Research efforts in this area focused on the modulation of kappa opioid receptors, with some evidence in experimental animals [164, 165]. Kappa agonists have been found to decrease cocaine self-administration [166] and the reinstatement of cocaine place-conditioning has been reported to be prevented by kappa-opioid antagonists, suggesting a potential use of drugs acting on this system in the treatment of cocaine abuse [165]. Accordingly, mixed-action kappa/mu opioids appear to affect cocaine self-administration without altering cocaine's discriminative stimulus effects [167] and a kappa opioid mechanism has been repeatedly hypothesized to underlie the attenuation of cocaine induced reinstatement in non-human primates [168, 169]. The interpretation of the potential efficacy of buprenorphine in the control of cocaine-induced compulsory behaviour could be also referred, at high dosage, to its agonist effects on orphanin receptors (NOP). In fact, the efficacy of buprenorphine in attenuating alcohol consumption in alcohol-preferring animal models, at higher doses, has been attributed to its partial agonist activity at the NOP receptors [170]. These studies suggested that NOP receptor agonists may have potential as drug abuse medications. Further research is needed to clearly establish how NOP agonists may attenuate the addictive process [171] and eventually provide therapeutic benefits also in the treatment of cocaine dependence. This possibility is well supported by preclinical evidence showing that central administration of nociceptin, the endogenous ligand for NOP receptors, reduces cocaine sensitization and cocaine -induced DA release in the nucleus accumbens [171]. Of note is also the finding that NOP activation prevents morphine from eliciting conditioned place preference suggesting that NOP agonism may represent a promising strategy for the treatment of addiction in general [171]. Bupropion Bupropion (1-(3-chlorophenyl)-2-[(1,1-dimethylethyl) amino]-1-propanone, BPP,) is a drug of the aminoketone class, similar in chemical structure to stimulants cathinone, diethylpropion and phenethylamines. Initially marketed for treating depression [172], BPP was subsequently approved by FDA as a smoking cessation drug in combination with motivational support therapies in nicotine-dependent patients [173]. The neurochemical action of BPP is still not welldefined: its primary action is thought to be norepinephrinedopamine reuptake inhibition with a little effect on serotonin reuptake [174]. It binds selectively to the dopamine transporter [175], but its behavioural effects have often been attributed to its inhibition of norepinephrine reuptake [174] and also to the more potent norepinephrine reuptake


inhibition by its active metabolite, S,S-hydroxybupropion. BPP is extensively metabolized by the cytochrome P450 system and three metabolites have been shown to be active: hydroxybupropion and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion. The efficacy of BPP rests upon its ability to support positive mood by inhibiting the reuptake of dopamine (as antidepressant and smoking cessation aid) and the same mechanism has been proposed in easing the negative mood symptoms of methamphetamine withdrawal. Moreover, it may be an effective treatment for cocaine dependence due to its ability to reverse deficits in dopaminergic functioning that occurs in chronic cocaine users. However, clinical trials showed mixed results. In two preliminary studies, Margolin et al. found that BPP at a daily dose of 300 mg, administered to five cocaine dependent methadone-maintained patients substantially reduced self-reported craving for cocaine [176], while Hollister et al. reported no effect for BPP over placebo in cocaine-dependent, non-opiate addicted patients [177]. A test of BPP in a full-scale, randomized clinical trial in a methadone-maintained patient population suggested a medical effect only for patients with depression [178]. In subsequent clinical studies there were no statistically significant differences between BPP and placebo in treatment outcomes and cocaine craving ratings also when BPP was combined with standard cognitive behavioural therapy [179, 180]. Conversely, the combined contingency management and BPP administration in methadone-maintained patients for the cocaine dependence significantly improved outcomes relative to BPP alone [181]. One systematic review reports other clinical trials conducted in methadone maintained opioid-cocaine dependent patients, in which drugs with CNS stimulating effects (specifically, BPP and dexamphetamine) showed promising results in reducing cocaine use and increasing sustained cocaine abstinence [182]. Thus, the existence of an underlying interaction between opioids and psychostimulants was hypothesised. A recent meta-analysis is not fully supportive of BPP (and other psychostimulants) for cocaine dependence, but dual opioid-cocaine dependent patients seem to be the most suitable candidates for agonist therapy with this drug [183]. In animal pharmacology studies, BPP stimulates locomotor activity [184], and is self-administered by both rats and nonhuman primates; this is in line with its DA activating properties. A recent study using dopamine transportercocaine insensitive knock-in mice, a mutant line with increased striatal extracellular DA and basal motor hyperactivity, showed that BPP reverts motor hyperactivity through its ability to increase striatal dopaminergic transmission [185, 186]. The exact mechanism of action of BPP is not completely defined yet; it is a weak DA reuptake inhibitor and has been shown to increase dopamine transmission in both the nucleus accumbens and the prefrontal cortex [187]. Moreover, PET imaging studies showed that administration of BPP results in relatively low dopamine transporter occupancy [175, 188]. In general, BPP may represent a promising medication for cocaine dependence, being also well-tolerated and presenting minor side effects (insomnia, agitation, and dry mouth); its new analogues, synthesised and studied by


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Carroll et al. seem to possess increased dopaminergic properties and are able to reverse dopaminergic deficits in chronic cocaine users better than BPP [189]. These novel compounds may offer additional benefits compared to BPP. In 1999, an invention related to BPP in a pharmaceutical composition for treating nicotine, cocaine and alcohol addiction appeared with the aim to ameliorate withdrawal symptoms and the effects associated with drug withdrawal [190]. The composition of the formulation comprised a therapeutically effective combination of a nicotine receptor antagonist (i.e. mecamylamine) and either an antidepressant or an anti-anxiety drug (i.e. BPP). The methods of delivery and dosages administered for treatment of cocaine addiction and alcohol dependence may be similar to those suggested for treatment of nicotine addiction. Each agent of the pharmaceutical composition had a unique mechanism of action and when administered simultaneously, the combined drugs provided unexpected advantages over existing therapies. Disulfiram Disulfiram (tetraethylthiuram disulphide, DSF), a thiuram derivative, was first discovered as a potential treatment for alcoholism in 1937 when it was observed that a group of DSF-exposed workers experienced unpleasant physiological symptoms (flushing of the face, shortness of breath, tachycardia, headache and nausea) after drinking alcohol, thus becoming ‘‘involuntary total abstainers’’[191]. In the 1951 FDA approved DSF (as Antabuse®) to support the treatment of chronic alcoholism. The DSF-ethanol reaction depends on the inhibition of the aldehyde dehydrogenase enzyme (ALDH), which is responsible for converting acetaldehyde to acetate in metabolizing alcohol; the accumulation of acetaldehyde the main alcohol metabolite produces the unpleasant symptoms that deter alcohol drinking [192]. Alcohol and cocaine are frequently co-abused because their simultaneous use limits the negative symptoms associated to cocaine (i.e. anxiety) while potentiating its rewarding effect. Due to concomitant use of alcohol and cocaine while DSF was being used to treat alcoholism, it was possible to observe its effects on cocaine [192]. These preliminary observations suggested the potential efficacy of DSF in the treatment of cocaine addiction. [193]. At present, the potential usefulness of DSF in cocainism is supported by several preclinical and clinical studies [194]. The first published study by Higgins et al. [195] showed that DSF significantly decreased both cocaine and alcohol use in comorbid abusers, even if the effect on cocaine use was attributed to behavioural therapy. In the same year, some research groups compared the effects of DSF to those of naltrexone with or without cognitive behavioural therapy (CBT) in patients with joint alcohol-cocaine dependence [196-198]. DSF proved to be more effective than the other treatments and the results obtained led to further investigations to find out the direct involvement of DSF in each of these outcomes. In 2000, two trials evidenced the efficacy of DSF in the reducing cocaine use in patients who were addicted to both


cocaine and opiates (but not to alcohol) and were maintained on methadone and buprenorphine [199, 200]. A breakthrough was reached in 2004 when a systematic study confirmed that DSF curbed cocaine intake in a manner independent of its action in reducing alcohol intake [201]. Several other randomized controlled trials showed the efficacy of DSF in treating cocaine dependence [202, 203] with significantly better outcomes in men than those found in women [204]. A recent meta-analysis [205] included seven studies of those reported in the literature, selected according to pre-established criteria. However, according to Pani et al. the heterogeneity of included studies limits the possibility to draw conclusions on the efficacy and safety of DSF for the treatment of cocaine addiction because selected studies differ in design, quality, and characteristics of patients, services and treatments delivered [205]. Moreover, these studies did not investigate the potential toxicity arising from the interaction between DSF and cocaine in addition to the other DSF related adverse effects, such as hepatotoxicity, cardiovascular and psychiatric complication. Another recent study examined the dose-related efficacy of DSF for treating cocaine dependence in methadone-stabilized cocaine dependent participants and revealed that DSF may be contraindicated for cocaine dependence at doses