Recent developments for smoking cessation and treatment of nicotine dependence

Nicotine is an addictive drug like heroin, amphetamine or cocaine. Addiction to tobacco leads to significant failure rates in programmes for smoking cessation. The alpha(4)beta(2) and alpha(7) nicotinic acetylcholine receptors (nAChRs) and CB1 cannabinoid receptors play an important role in nicotine addiction.

Varenicline, an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

A novel SNP in COMT is associated with alcohol dependence but not opiate or nicotine dependence: a case control study

Background It is well established that COMT is a strong candidate gene for substance use disorder and schizophrenia. Recently we identified two SNPs in COMT (rs4680 and rs165774) that are associated with schizophrenia in an Australian cohort. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. Association of both rs4680 and rs165774 with substance dependence, a common comorbidity of schizophrenia has not been investigated. Methods To determine whether COMT is important in substance dependence, rs165774 and rs4680 were genotyped and haplotyped in patients with nicotine, alcohol and opiate dependence. Results The rs165774 SNP was associated with alcohol dependence. However, it was not associated with nicotine or opiate dependence. Individuals with alcohol dependence were more than twice as likely to carry the GG or AG genotypes compared to the AA genotype, indicating a dominant mode of inheritance. The rs4680 SNP showed a weak association with alcohol dependence at the allele level that did not reach significance at the genotype level but it was not associated with nicotine or opiate dependence. Analysis of rs165774/rs4680 haplotypes also revealed association with alcohol dependence with the G/G haplotype being almost 1.5 times more common in alcohol-dependent cases. Conclusions Our study provides further support for the importance of the COMT in alcohol dependence in addition to schizophrenia. It is possible that the rs165774 SNP, in combination with rs4680, results in a common molecular variant of COMT that contributes to schizophrenia and alcohol dependence susceptibility. This is potentially important for future studies of comorbidity. As our participant numbers are limited our observations should be viewed with caution until they are independently replicated.

Improved treatment of nicotine addiction and emerging pulmonary drug delivery

Nicotine addiction remains the leading cause of death and disease in developed and developing nations and a major cause of mortality around the world. Currently, nicotine replacement therapies (NRTs), bupropion, and varenicline are approved by the regulatory agencies as first-line treatments for nicotine addiction. Emerging evidence indicates that varenicline and bupropion have some therapeutic limitations for treating nicotine addiction with oral route of administration. Thus, continued investigation of innovative drug delivery for nicotine addiction remains a critical priority. This review will discuss some novel strategies and future directions for pulmonary drug delivery, an emerging route of administration for smoking cessation. It is anticipated that the advancement of knowledge on pulmonary drug delivery will provide better management for nicotine addiction and other addictive disorders.

Nicotine Dependence and Smoking Behaviour : A genetic and epidemiological study

The worldwide health burden caused by the tobacco epidemic highlights the importance of study-ing determinants of smoking behaviour and key factors sustaining nicotine dependence. Despite vast-ranging preventive efforts, smoking remains one of the most deleterious health behaviours, and its genetic and environmental factors warrant continuous investigation. The heritability of smoking behaviour and nicotine dependence has been suggested to be relatively high. Earlier smoking behaviour, nicotine dependence, socio-economic position and demographic factors have all been shown to be associated with smoking cessation. This thesis aimed to examine various aspects of smoking behaviour and nicotine dependence from an epidemiological and genetic per-spective. Data for Studies I and IV were obtained from the Older Finnish Twin Cohort, a postal health sur-vey conducted in 1975, 1981 and 1990 on same-sexed pairs and in 1996-1997 on male-female adult pairs. The number of ever-smoking participants was 8941 in Study I and 3069 in Study IV. Data for Studies II and III came from the Family Study of Cigarette Smoking - Vulnerability to Nicotine Addiction. This study is linked to the Older Finnish Twin Cohort with new data collec-tion during 2001-2006 that focused on smoking twin pairs and their family members. The meas-ures included intensive telephone interviews, blood samples and additional postal questionnaires. The numbers of ever-smoking participants was 1370 in Study II and 529 in Study III. Study I examined whether a genetic component underlies smoking behaviour among Finnish adults. Genetic factors were important in the amount smoked and smoking cessation, with about half of the phenotypic differences explained by genetic variance. A novel finding was that genetic influences on amount smoked and smoking cessation were largely independent of genetic influ-ences on age at initiation. This result has implications for defining phenotypes in the search for genes underlying smoking behaviour. Furthermore, even if smoking initiation is postponed to a later age, potential vulnerability to subsequent nicotine dependence cannot be completely inhib-ited. Study II investigated the effect of genetic and environmental factors on nicotine dependence, as measured by the novel multidimensional Nicotine Dependence Syndrome Scale (NDSS). This scale was validated in the Finnish data. The NDSS correlated highly with other established nico-tine dependence scales (FTND and DSM-IV), suggesting that this new scale would be a feasible and valid measure for identifying nicotine-dependent smokers among the ever-smoking popula-tion. About one-third of the phenotypic variation in nicotine dependence in this sample was ex-plained by genetic influences. Study III aimed at identifying chromosomal regions harbouring genes that influence smoking be-haviour and nicotine dependence. Linkage analysis of family data revealed that for smoker and nicotine dependence phenotypes as well as for co-morbidity between nicotine dependence and alcohol use signals on specific chromosome regions (chromosomes 2q33, 5q12, 5q34 7q21, 7q31, 10q25, 11p15, 20p13) exist. Results further support the hypothesis that smoking behaviour phe-notypes have a genetic background. Study IV examined associations of smoking behaviour, socio-economic position and transition of marital status with smoking cessation. Indicators of socio-economic position were important pre-dictors of smoking cessation even when adjusted for previous smoking behaviour. Getting married was associated with an increased probability of cessation in men, a finding confirmed among dis-cordant twin pairs. Thus, having a partner appears to have a positive impact on smoking cessation. In conclusion, nicotine dependence and smoking behaviour demonstrate significant genetic liabil-ity, but also substantial environmental influences among Finnish adults. Smoking initiation should be prevented or at least postponed to a later age. Although genetic factors are important in nicotine dependence and smoking behaviour, societal actions still have a primary role in tobacco control and smoking prevalence. Future studies should examine the complex interactions between genetic and environmental factors in nicotine dependence.

Illicit drug use, alcohol use and nicotine dependence as predictors of antiretroviral adherence in a sample of HIV positive smokers

Objective. Predictors of non-adherence to antiretroviral medications in a population of low-income, multiethnic, HIV-positive smokers were investigated. ^ Methods. A secondary analysis was conducted using baseline data collected from 326 patients currently prescribed antiretrovirals enrolled in a randomized clinical trial assessing smoking outcomes. Variables evaluated included demographics, stress, depression, nicotine dependence, illicit drug use and alcohol use. ^ Results. The average age of participants was 45.9 years (SD=7.6). The majority of participants were male (72.1%), Black (76.7%), reported sexual contact as the method of HIV exposure (heterosexual (43%) and MSM (27%)) and were antiretroviral adherent (60.4%). Results from unadjusted analyses indicated depression (OR=1.02; 95% CI=1.00-1.04), illicit drug use (OR=2.39; 95% CI=1.51-3.79) and alcohol consumption (OR=2.86; 95% CI=1.79-4.57) were associated with non-adherence. Multivariate analyses indicated nicotine dependence (OR=1.13; 95% CI=1.02-1.25), illicit drug use (OR=2.10; 95% CI=1.27-3.49) and alcohol use (OR=2.50; 95% CI=1.52-4.12) were associated with nonadherence. ^ Conclusions. Illicit drug use, alcohol use and nicotine dependence are formidable barriers to antiretroviral adherence in this population. Future research is needed to assess how to address these variables in the context of improving antiretroviral adherence for individuals living with HIV/AIDS.^

A DRD2 and ANKK1 haplotype is associated with nicotine dependence

To test the importance of the dopamine D2 receptor (DRD2) region in nicotine dependence, 150 smokers and 228 controls were genotyped for the DRD2 C957T, -141delC and ANKK1 TaqIA polymorphisms (rs6277, rs1799732 and rs1800497, respectively). The -141delC SNP did not show any association but both the C957T and TaqIA SNPs showed association at the allele, genotype, haplotype and combined genotype levels. The 957C/TaqI A1 haplotype was more than 3.5 times as likely to be associated with nicotine dependence compared with the 957T/TaqI A1 haplotype (P = 0.003). Analysis of the combined genotypes of both SNPs revealed that individuals who were homozygous for the 957C-allele (CC) and had either one or two copies of the TaqI A1-allele were 3.3 times as likely to have nicotine dependence compared to all other genotype combinations (P = 0.0003) and that these genotypes accounted for approximately 13% of the susceptibility to nicotine addiction in our population. Our findings suggest that the DRD2 C957T polymorphism and the ANKK1 TaqIA polymorphism are key contributors to the genetic susceptibility to nicotine dependence.

Using virtual environments for trigger identification in addiction treatment

This paper presents a novel application of virtual environments to assist in encouraging behavior change in individuals who misuse drugs or alcohol. We describe the user-centered design of a series of scenes to engage users in the identification of triggers and to encourage discussions about relevant coping skills. Results from the initial testing of this application with six service users showed variation in user responses. Results also suggested that the system should encourage group discussion and that it was linked to a small improvement in users’ confidence in understanding and identifying triggers.

Association of smoking and nicotine dependence with pre-diabetes in young and healthy adults.

INTRODUCTION: Several studies have shown an increased risk of type 2 diabetes among smokers. Therefore, the aim of this analysis was to assess the relationship between smoking, cumulative smoking exposure and nicotine dependence with pre-diabetes. METHODS: We performed a cross-sectional analysis of healthy adults aged 25-41 in the Principality of Liechtenstein. Individuals with known diabetes, Body Mass Index (BMI) >35 kg/m² and prevalent cardiovascular disease were excluded. Smoking behaviour was assessed by self-report. Pre-diabetes was defined as glycosylated haemoglobin between 5.7% and 6.4%. Multivariable logistic regression models were done. RESULTS: Of the 2142 participants (median age 37 years), 499 (23.3%) had pre-diabetes. There were 1,168 (55%) never smokers, 503 (23%) past smokers and 471 (22%) current smokers, with a prevalence of pre-diabetes of 21.2%, 20.9% and 31.2%, respectively (p <0.0001). In multivariable regression models, current smokers had an odds ratio (OR) of pre-diabetes of 1.82 (95% confidential interval (CI) 1.39; 2.38, p <0.0001). Individuals with a smoking exposure of <5, 5-10 and >10 pack-years had an OR (95% CI) for pre-diabetes of 1.34 (0.90; 2.00), 1.80 (1.07; 3.01) and 2.51 (1.80; 3.59) (p linear trend <0.0001) compared with never smokers. A Fagerström score of 2, 3-5 and >5 among current smokers was associated with an OR (95% CI) for pre-diabetes of 1.27 (0.89; 1.82), 2.15 (1.48; 3.13) and 3.35 (1.73; 6.48) (p linear trend <0.0001). DISCUSSION: Smoking is strongly associated with pre-diabetes in young adults with a low burden of smoking exposure. Nicotine dependence could be a potential mechanism of this relationship.

Nicotine dependence and levels of depression and anxiety in smokers in the process of smoking cessation

Background: Depression and anxiety are psychiatric disorders that are related to tobacco use and associated with dependence, the process of cessation, lapses and relapses after quitting smoking. Objective: To analyze the association of nicotine dependence with the level of anxiety and depression in patients who are in the process of smoking cessation. Methods: Cross-sectional study conducted with patients who sought the smoking cessation program in Cuiabá/MT. All the smokers enrolled from May to August 2012, participated in this study. Four instruments were applied: Socio-demographic Questionnaire, Fagerstrom test, Beck Anxiety Inventory and Beck Depression Inventory. Following bivariate analysis, using the crude prevalence ratio, with level of significance lower than 5% (p < 0.05), having as variable outcome the nicotine dependence >= 5 (Fagerstrom). The associations with p < 0.20 were selected for robust Multiple Poisson Regression (RPa). Results: Associations of Fagerstrom >= 5 with the male sex (RP = 1.15 CI 95% 1.03-1.28); number of cigarettes/day (RP = 1,33; CI 95% 1.19-1.48); and moderate/severe level of depression (RP = 1.15; CI 95% 1.04-1.28) were found. In the final model (RPa), the following variables remained associated: male gender (RPa 1.12; CI 95% 1.01-1.24), number of cigarettes/day (RPa 1.28; CI 95% 1.15-1.43) and high level of depression (RPa 1.12; CI 95% 1.01-1.23). Discussion: High level of nicotine dependence was associated significantly with the level of depression, emphasizing the association between smoking and psychiatric comorbidities.

Safety and tolerability of slow-release oral morphine versus methadone in the treatment of opioid dependence

Opioid substitution treatment (OST) for opioid dependence may be limited by adverse events (AEs). Increasing the range of therapeutic options optimizes outcomes and facilitates patient management. An international, multi-center, two-phase study investigated the efficacy and safety of slow-release oral morphine (SROM) versus methadone in patients receiving methadone therapy for opioid dependence. In phase 1 (two way cross-over, 11 weeks each period) patients were randomized to SROM or methadone oral solution. In phase 2 (25 weeks), patients continued treatment with SROM (group A) or switched from methadone to SROM (group B). In total, 211 out of 276 completed phase 1 and 198 entered phase 2 (n = 95 group A, n = 103 group B). Treatment with both SROM and methadone was well tolerated. However, the mean QTc-interval associated with methadone was significantly longer than that under SROM. Higher treatment satisfaction, fewer cravings for heroin, and lower mental stress were reported with SROM. This study adds a significant further weight of evidence that SROM is an effective and well tolerated long-term maintenance treatment for opioid dependence with a beneficial risk profile compared to methadone regarding cardiac effects and supports its clinical utility.