Current Pharmaceutical Design - Volume 17, Issue 14, 2011

Addiction is a chronic, relapsing disorder characterized by compulsive substance seeking and substance use despite negative consequences [1]. This complex brain disease involves interactions between genetic components, individual and environmental factors (including familial, peer models, exposure to stressful factors, traumatic experiences, incarceration) [2]. Cognitive deficits (memory, learning, decision making, inhibitory control) also play a major role in the development and the persistence of this disease [3]. Many models, such as incentive salience [4], or a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement) [5] or reward deficiency [6] have been proposed for addictions. Across these models, motivational neurocircuitry, including dopaminergic systems, is dysregulated. Additionaly, brain imaging studies of dependent-patients have demonstrated brain structural abnormalities as well as changes in reward circuitry and neurotransmitter systems and metabolite changes [2]. Addictive disorders are a significant worldwide public health problem associated with somatic, psychiatric, socio-economic, and legal complications. Substantial advances have been made in pharmacological treatments for addictions due to the better understanding of the underlying neurobiology contributing to drug use and relapse [7, 8]. Many pharmacological agents have been evaluated for their effectiveness in improving alcohol or drug treatment outcomes. Various clinical trials and many meta-analyses in this area have been published. Two major goals are essential in the treatment of addictions: abstinence initiation and relapse prevention [9]. According to the recent literature, the main identified pharmacological targets for addictive disorders are 1) positive reinforcement (drug reward), 2) negative reinforcement and 3) individual vulnerabilities such as psychiatric comorbidity and cognitive deficits [9]. The agonist replacement therapy and antagonist agents are a pharmacological approach that targets drug reward. The first one uses a drug from the same pharmacological family as the abused drug to suppress withdrawal and drug craving. Clinical examples include the use of methadone or buprenorphine treatment for opiate dependence and varenicline or nicotine replacement therapy to treat nicotine dependence. Potential agonist medications for cocaine dependence include d-amphetamine, methylphenidate, modafinil and disulfiram [10]. Antagonist approach uses medications that block the effects of drugs. For example, naltrexone has been found to be effective for opioid and, more recently, alcohol addiction [9]. The recent development of immunotherapies is a more novel pharmacologic approach. Research on these agents is progressing rapidly and nicotine and cocaine vaccines have advanced to the level of human clinical trials [8]. Withdrawal symptoms, drug craving and negative mood states (i.e. anxiety, anhedonia, sadness) are the main negative reinforcing effects of abstinence that play a role in the maintenance of addictions. Pharmacological agents targeting glutamate, GABA, dopamine, norepinephrine systems may play a crucial role in developing new strategies to target negative reinforcement. Withdrawal symptoms, drug craving and negative mood states (i.e. anxiety, anhedonia, sadness) are the main negative reinforcing effects of abstinence that play a role in the maintenance of addictions. Pharmacological agents targeting glutamate, GABA, dopamine, norepinephrine systems may play a crucial role in developing new strategies to target negative reinforcement. In this Special Issue focusing on the pharmacological treatments of addictive disorders, international experts have made the state of the art of the question in many areas: tobacco [12], cannabis [13], alcohol [14-16], cocaine [17-20], opiates [21], eating disorders [22], pathological gambling [23]. We hope that these articles will contribute to help clinicians in their daily practice. Additional research efforts should be made to define novel targets for treatment.

Switching from the concept of substance or alcohol dependence to that of addiction has profoundly modified our ways of approaching, treating and organizing the care of this disease. This more complex and subtle approach gives less importance to the substance and its effects and focuses more on the initiation of pathological behavior. It is important to keep in mind that the addictive process associates a substance (more or less addictive), an individual (more or less vulnerable) and an environment (more or less condoning). Today, it is no longer possible to consider that a drug acts on only one receptor or one system. Current understanding of inner regulation mechanisms integrates the interactions between the various stimulated brain pathways. Addiction treatments which should benefit from advances in genetics, neuropsychology and neuroimaging could be increasingly individualized in the years to come. The “addictology” approach has triggered thinking about other therapeutic approaches such as modification of therapeutic objectives toward “risk reductions” or applying this model to behavioral addictions (food, sex, sport, gaming…) This conceptual shift seems to enrich clinical analysis, the therapeutic possibilities and the avenues for research.

Harmful alcohol use is a risk factor in more than 60 diseases and injuries resulting in approximately 2.5 million deaths per year worldwide. In the United States (US) and Europe, there are only a few medications approved for alcohol dependence (AD) however, these medications have only been moderately effective and there is a crucial need for more effective treatments. This review briefly summarizes research on currently approved medications for AD, as well as promising medications like topiramate, baclofen and ondansetron. Topiramate is likely the most promising new treatment for AD, however, further research is needed to determine the optimal dose and appropriate length of treatment. Baclofen, a GABAB agonist, is a promising medication as a treatment for AD, especially for patients with AD and severe liver disease. Ondansetron has shown promising results as a potential medication for AD, but only within a certain subtype of individuals. This review also discusses more recent findings on other potential pharmacotherapies for AD, such as serotoninspecific reuptake inhibitors (SSRIs; i.e. sertraline), aripiprazole and prazosin, as well as on some examples of other potentially interesting new neuropharmacological targets (i.e. cannabinoid receptors, CRF, NPY, ghrelin). Finally, the present review also discusses the attempts to personalize medication for AD treatment by alcohol typology and pharmacogenetics.

Binge Drinking (BD) is often considered to be recurrent alcohol abuse amongst adolescents and young adults. However, the close link between adolescence and impulsivity has led many authors to define BD as intoxication-seeking behaviour. Medications may sometimes be justified because of the major short-term and long-term risks that underlie the most severe BD-related behaviours. The most common consequences in the long run are the occurrence of alcohol dependence, psycho- and neurodevelopmental disruptions and alcohol liver disease. To understand the specificities of BD among other forms of alcohol addiction, this article is based on a two-headed conception of alcohol dependence: on one hand, psychological dependence, which refers to the behavioural habituation of alcohol intake, clinically results in craving and is neurobiologically supported by the reward system, particularly the dopaminergic mesolimbic pathway (MLP); on the other hand, physical dependence, which refers to the pharmacological tolerance induced by chronic alcohol intake, results in Alcohol Withdrawal Syndrome (AWS) and is neurobiologically supported by the imbalance between GABA and Glutamate-NMDA neurotransmission. Medications for psychological dependence include anticraving drugs, which all act by regulating MLP. Medications for physical dependence on alcohol include GABA-A and perhaps GABA-B agonists and some NMDA antagonists. In practice, many alcohol- dependence treatments seem to have a dual action. This article proposes an attempt to classify current and forthcoming medications for alcohol addiction based on this two-headed approach to treating alcohol dependence. Drawing from this classification, specific therapeutic schemes for treating BD are proposed, with currently approved alcohol medications and possible future treatments. These schemes are justified by recent literature on the subject and propose to prioritize pure anticraving medications, taking into account the clinical specificities of BD. Furthermore, these schemes also mention harm-reductive neuroprotective and hepatoprotective strategies, which could be included in the arsenal of possible medications for BD in the near future.

Tobacco dependence is a chronic disease that often requires repeated interventions and multiple attempts to quit. To date, three medications are FDA-approved for smoking cessation: nicotine replacement therapy, sustained-release bupropion, and varenicline. These treatments are effective across a broad range of populations, and are recommended for all smokers, including those with psychiatric or addictive comorbidity. Less is known however concerning the benefit-risk profile of these medications in pregnant women and adolescents. With these limitations in mind, clinicians should encourage and offer counseling and a prescription of pharmacotherapy to every patient willing to make a quit attempt. Despite the relative efficacy of first-line medications, many smokers relapse after one given quit attempt, and alternative pharmacotherapies are needed. Clonidine and nortriptyline have been proposed as second-line medications. In addition, this review identifies a series of promising drugs that hopefully will be available to complete our current armory.

Cannabis is the most frequently used illegal psychoactive substance in the world. There is a significant increase in the number of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis-dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population. So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, irritability), those that directly affect endogenous cannabinoid receptor function, and those that have shown efficacy in treatment of other drugs of abuse or psychiatric conditions. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. Results from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre-clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha7 receptor antagonists such as methyllycaconitine (MLA). Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications.

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.

Introduction: Cocaine has become a noticeable part of the European drug scene and is the second most commonly used illicit drug among the general population. Craving is a core issue in cocaine dependence and is strongly associated with lapse and/or relapse. However, no craving scale exists in French. The objective of our study was to assess the reliability and validity of a French language version of the 10-item Cocaine Craving Questionnaire-Brief (CCQ-Brief). Methods: A total of 131 individuals ranging in age from 18 to 65 years were enrolled in a 12-month outpatient treatment program in 2009. The participants were seeking treatment for cocaine dependence. They completed the Mini-International Neuropsychiatric Interview (MINI) and the French version of the CCQ-Brief. At the end of the interview, a Clinical Global Impression Scale (CGIS) was completed by a clinician blind to the subject's treatment group. We evaluated the internal consistency of the French CCQ-Brief using Cronbach's α coefficient and the correlation of each item with the total scale using the Pearson's coefficient. We conducted an exploratory factorial analysis followed by a scree test. Only items with factor loading >0.3 were retained. The convergent validity of the French CCQ-Brief was assessed using Pearson's correlation between the CCQ-Brief and the CGIS. Results: The mean (SD) score of the 10-item CCQ-Brief was 3.4 (1.5). Cronbach's α coefficient 0.88 and remained high even when an item was deleted (ranging from 0.86 to 0.88), indicating that this tool possesses a high internal consistency. Each item exhibited a strong correlation with the total score ranging from 0.62 to 0.83. All items presented factor loadings ranged from 0.47 to 0.83. The correlation between the CCQ-Brief and the CGIS was high (r=0.49, p<0.0001), indicating a sufficient convergent validity. Discussion: The French version of the CCQ-Brief is a reliable and valid instrument that can provide a comprehensive assessment of cocaine craving in treatment-seeking cocaine-dependent patients.

Background: Currently, there is no specific pharmacological therapy with established efficacy for the treatment of cocaine dependence. The aim of this study was to determine the safety, tolerability and the effects of aripiprazole and ropinirole in patients with cocaine dependence. Methods: This randomized clinical trial of 12-week duration was carried out on 28 consecutive patients with cocaine dependence presenting for treatment. The diagnostic assessment was performed using ICD-9-CM criteria and Mini International Neuropsychiatric Interview. The Clinical Global Impression Scale, a Visual Analogue Scale to assess craving and a self-report questionnaire on the use of cocaine were administered at baseline and then weekly throughout the study. Urinalyses were carried out three times per weeks to search for benzoylecgonine. Results: Of the 28 study participants, 14 completed the protocol. Treatment discontinuation was unrelated with side effects. One patient required a dosage reduction of ropinirole because of sleepiness and one patient assigned to aripiprazole who reported moderate akathysia had the dosage reduced to 5 mg/day. Routine blood works did not show significant changes from baseline and the overall proportion of positive urinalyses for benzoylecgnonine did not differ significantly between treatments. Using linear mixed-effect models a significant decrease in craving was found in the overall sample (p<0.001). The mean number of cocaine administrations exhibited a faster decrease with aripiprazole compared with ropinirole (p=0.009). Conclusions: Our pilot study indicates that cocaine craving decreases with both aripiprazole and ropinirole treatment but aripiprazole is more efficacious in reducing cocaine use.

Opiate substitution therapies have largely contributed to improving outcomes in opiate dependent patients. Their impact has significantly diminished HIV transmission rates, decreased incidence of overdose and reduced delinquency due to heroin trafficking. Since then, some advances have been made in the formulations and dosing regimen of these treatments. They have also largely facilitated opiate withdrawal. However, concerning the maintenance of opiate abstinence, very few new treatments have been proposed. Despite considerable advances in our knowledge of the neurobiological mechanisms of opiate dependence, few clinical trials have been proposed to test new molecules both in accompanying opiate substitution and in maintaining abstinence from illicit opiate use. The objective of this article is to examine the evidence concerning the treatment of opiate dependent patients, especially new treatments and to examine the eventual gaps between currently knowledge, available treatment and demands.

Given the rates of pathological gambling and its impact on affected individuals and their relatives, effective treatments are needed. There are, however, no approved pharmacological treatments for pathological gambling. This paper describes the development of pharmacological treatments for pathological gambling and is based on a review of the literature published in the past 10 years. Important studies were carried-out on antidepressants, mood stabilizers, and antipsychotic agents. In the absence of comorbid psychiatric disorder, these studies did not conclude to the efficacy of these psychotropic drugs. A possible efficacy of opiate antagonist treatment for pathological gambling has been replicated in a number of placebo-controlled studies. Preliminary results on N-acetyl cysteine, Memantine and Topiramate produced significant improvement for pathological gamblers and may open new avenues for treatment.

Lifetime prevalence estimates for binge eating disorder (BED) and bulimia nervosa (BN) are 3.5% and 1.5% among women and 2.0% and 0.5% among men, respectively. Night eating syndromes (NES) affect 1.1%-1.5% of the general population. All of these disorders induce an impaired quality of life and significant disability. Symptom overlaps are reported between substance use disorders and eating disorders such as BED, BN and NES. A growing body of evidence suggests that γ-amino-butyric acid (GABA) and glutamate modulation pathways might be useful targets in the treatment of alcohol and substance use disorders. Their involvement in the reward process and in the regulation of food intake could be the source of new pharmacological strategies for the treatment of eating disorders. We review published data on the efficacy and safety of drugs targeting the GABA and glutamate modulation pathways for the treatment of BED, BN and NES. Preliminary results indicate that baclofen and topiramate are effective in reducing binge eating, craving and weight gain. However, the potential clinical drug-placebo difference is not detected for acamprosate and lamotrigine. Limitations of these studies are discussed. In view of these data, first- and second-line pharmacological interventions are proposed.

Topiramate is one of the currently most promising compounds in the field of addiction medicine. This paper discusses its potential utility related to a phase model of addiction development, focusing on the assumption that addiction is a continuous process involving different neurobiological pathways, depending on the stage of addiction. A specific emphasis will be made on the development of dysfunctional automatic behaviors in the late stage of addiction and the central role of glutamate and AMPA receptors. The aim is to propose that if too broad an effect of anti-addiction medication is expected (such as anti-craving, anti-relapse and preventive effects), the results might be disappointing. The speculative specific efficacy of topiramate in addiction is described.