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Alcohol consumption and smoking status: the role of smoking cessation
Biomedicine & Pharmacotherapy 58 (2004) 77–83 www.elsevier.com/locate/biopha
Dossier: Influence of alcohol consumption and smoking habits on human health
Alcohol consumption and smoking status: the role of smoking cessation Debra J. Romberger a,b,*, Kathleen Grant b a
Pulmonary and Critical Care Medicine Section, University of Nebraska Medical Center, 985300 Nebraska Medical Center, Omaha, NE 68198-5300, USA b Department of Veterans Affairs Medical Center, Omaha, NE, USA Received 28 October 2003
Abstract Cigarette smoking is common among persons with alcohol dependence or abuse with as many as 80% of persons who are alcohol dependent also being smokers. Not only is smoking common in persons with heavy alcohol consumption, but also nicotine dependence appears more severe in smokers with a history of alcohol dependence. This combined exposure to both tobacco smoke and alcohol results in major health consequences including additive risks for some diseases such as head and neck cancers. Although modest alcohol consumption has some positive health benefits, smoking typically negates these benefits. The cellular mechanisms impacted by combined smoking and alcohol exposure are poorly understood, but molecular epidemiology approaches are providing insights regarding the importance of effects on oxidant/antioxidant pathways and on metabolic pathways involving the cytochrome P450 system. Given the prevalence of smoking in the alcohol dependent population, smoking cessation in this group has the potential for tremendous impact. In recent years, smoking cessation approaches have been initiated in this population, but much work remains in order to define the optimal smoking cessation strategies for persons in alcohol treatment programs. © 2004 Elsevier SAS. All rights reserved. Keywords: Smoking cessation; Alcohol dependence; Substance abuse
1. Alcohol consumption and cigarette smoking and disease It has long been recognized that there is a strong association between heavy alcohol use and cigarette smoking. Approximately 80% of alcohol dependent patients are reported to smoke cigarettes [1–3]. Despite a decline of smoking in the US population in general, a recent study from a HMO (health maintenance organization) population seeking substance abuse treatment demonstrates that more than 60% of persons were active smokers [4]. Heavy cigarette use is a predictor of unrecognized alcohol abuse/dependence [5]. The prevalence of smoking among substance abusers is approximately two to three times that of the general population [1]. Alcoholism is estimated to be 10 times more common among smokers than among non-smokers [2]. In addition, nicotine dependence appears more severe in smokers with a history of alcohol dependence [6].
* Corresponding author. E-mail address: [email protected] (D.J. Romberger). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2003.12.002
The fact that heavy alcohol use and cigarette smoking frequently occur together has major impact on development of disease. The concomitant use of tobacco and alcohol contributes to an increased incidence of several malignancies, especially head and neck cancers [7–9]. Men who both smoke and drink are nearly 38 times more likely to develop head and neck cancers than men who do neither. This compares to non-smoking drinkers (average 30 drinks/week or greater) who are 5.8 times more likely to develop a head and neck cancer and non-drinking smokers (two packs/week or greater) who are 7.4 times more likely to develop such cancers [7]. Talamini et al. [10] recently observed a similar multiplicative risk for laryngeal cancer with combined alcohol and smoking exposure in European subjects. In addition, continued alcohol and smoking exposure augments the risk for a second primary tumor in patients with a previous upper aerodigestive tract tumor [11]. Alcohol consumption and tobacco smoking also contribute to pancreatic, esophageal, and hepatocellular cancers, although synergism between the two agents is not as pronounced as with head and neck cancer [12–14]. Interestingly, lung cancer is strongly associated with cigarette smoking,
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but is not consistently associated with alcohol consumption [15]. It is unclear why combined alcohol and smoking exposure appears to have a synergistic influence on biological processes leading to laryngeal cancer, but does not appear to have an identical influence on the processes leading to lung cancer even though both laryngeal and lung cancer can share common morphologic features. Non-malignant diseases are also influenced by combined alcohol and smoking exposure. There are reports of increased risk of cirrhosis of the liver, pancreatitis, and periodontal disease [8,16,17]. Cardiovascular disease is also influenced in that the worst triglyceride levels are associated with the combination of heavy smoking and heavy alcohol drinking in a Mediterranean population [18]. In this same study, smoking also interfered with positive health benefits associated with moderate alcohol consumption. Tobacco, not alcohol, has been shown to be the leading cause of death in persons previously treated for alcohol dependence [19]. This demonstrates the significance of the additional health risks of smoking even in persons who have experienced the negative effects of heavy alcohol consumption. The effect of combined alcohol and tobacco exposure on many diseases is complex and in some cases, poorly understood. Heavy alcohol consumption is associated with many disorders, whereas moderate alcohol intake has been shown to have positive health benefits. Cardiovascular disease, dementia, and hearing loss may be positively influenced by modest alcohol intake [20–23]. As noted previously, smoking interferes with the positive health effects of modest alcohol consumption on heart disease [18]. In contrast, the potential interactions between smoking and alcohol on dementia are not clearly defined [24–26]. Smoking appears to have a negative influence on hearing loss, but the interactions between alcohol and smoking are less clear [27,28]. In the lung, smoking is clearly associated with loss of lung function and pulmonary diseases such as emphysema and chronic bronchitis [29]. The alcohol effect on lung function is not clearly defined. In an epidemiological study of Scandinavian men, a J-shaped association between alcohol use and bronchitis was observed with the lowest prevalence of bronchitis seen with moderate alcohol consumption [30]. Similar results were reported by Tabak et al. [31] with the observation of a U-shaped relation between alcohol and chronic obstructive pulmonary disease mortality. Other reports have suggested both a positive and a negative influence of alcohol consumption on lung function [32–34]. It is likely that complex interactions occur in human lungs with smoking and varying levels of alcohol consumption. However, the importance of alcohol consumption on pulmonary response to injury has been clearly recognized in patients who develop acute respiratory distress syndrome (ARDS) in that persons with chronic alcohol abuse are at higher risk to both develop this disorder and to die related to complications of the disorder [35]. Given the fact that cigarette smoking occurs frequently in persons who consume excessive alcohol, it is important that
interactions between smoking and alcohol continue to be investigated. Much remains to be defined about how the combined exposure of these agents influences various organ systems as well as disease outcomes. The multiplicative risk with alcohol and smoking for certain diseases like head and neck cancer suggests possible synergism in the mechanisms of action of the agents regarding certain biological endpoints. With other processes, it appears clear that synergism does not occur. Thus, understanding how alcohol and smoking mediate cellular mechanisms responsible for biological responses is an exciting area of investigation. The next section will highlight some mechanistic observations made in the context of clinical disorders associated with combined alcohol and tobacco use.
2. Cellular mechanisms influenced by combined alcohol and cigarette smoke exposure Molecular epidemiology studies of malignancies with both alcohol and smoke exposure as risk factors provide some insights into possible genes modulated by the combined exposures. As previously noted, smoking and alcohol consumption are major risk factors for head and neck cancer [10]. Xenobiotic metabolizing enzymes are felt to be important in mediating cancer susceptibility. Polymorphisms of such enzymes including arylamine N-acetyltransferases (NAT1 and NAT2) genotypes have been associated with laryngeal cancer risk [36]. Specifically, significant overrepresentation of homozygous NAT2 genotypes coding for rapid acetylation were reported in association with laryngeal cancer. In non-small cell lung cancer, a role for alcohol augmenting the mutagenic effects of cigarette smoke has been suggested [37]. Mutations in the p53 gene were present more often in tumors from alcohol drinkers who smoked cigarettes (76% of the 105 patients studied) than in nondrinkers who smoked cigarettes (42% of the patients) or in nondrinkers who did not smoke (14% of patients). A role for p53 mutations in aerodigestive cancers in general has been suggested by others [38,39]. Oxidant injury and antioxidant defense systems are also influenced by combined alcohol and tobacco smoke exposure. The glutathione-S-transferases M1 (GSTM1) null genotype is associated with an increased odds ratio for esophageal cancer with a combined effect observed with smoking and the GSTM1 null genotype in a Chinese population study [40]. In a Swedish study, high alcohol consumption and smoking in combination with GSTM1 null genotype is associated with high titers of plasma autoantibodies against the oxidized DNA base derivative 5-hydroxymethyl2′-deoxyuridine that is used as a potential biomarker of cancer risk and oxidative stress [41]. In an animal model of combined exposure of alcohol and nicotine (as opposed to cigarette smoke), a 6 week exposure to alcohol and nicotine produced similar, and in some cases additive, oxidative tissue injuries in various organs in rats [42].
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Cytochromes P450 (CYP) are enzymes (mixed function oxidases) that are predominantly expressed in the liver and have long been recognized as central in metabolizing drugs, endogenous compounds, and environmental and dietary substances in humans. Specific CYP enzyme activities are influenced by both ethanol and smoking [43,44]. Howard et al. [45] have observed that low doses of nicotine and ethanol induce CYP2E1 in rat liver. These mechanisms may have relevance to cross-tolerance that is observed between smoking and drinking with chronic nicotine potentially increasing clearance of ethanol. Recently, Miksys et al. [46] have reported that another member of the cytochrome P450 family, CYP2B6, is increased in various regions of the brains of smokers and alcoholics with the potential role for the CC genotype contributing to the highest levels of CYP2B6 protein. Nicotine and alcohol interactions within both the developing and adult central nervous system (CNS) have been the subject of much investigation and are reviewed elsewhere [47–51]. Dopamine neurotransmission, particularly in the nucleus accumbens of the mesocorticolimbic system, is central to mechanisms regulating CNS effects of both nicotine and alcohol. Each substance works through different proteins and receptors (classically, nicotinic acetylcholine receptors or nAChRs for nicotine and N-methyl-D-aspartate or NMDA and g-aminobutyric acid or GABA receptors for alcohol) [49]. However, it is clear that ethanol also influences nAChR activation and that nicotine can mediate dopamine-activating properties of alcohol [51,52]. In addition, there is also a role for another important neurotransmitter, serotonin, in the interactions between nicotine and alcohol within the CNS [51,53,54]. It is anticipated that insights gained from genetic studies will further enhance our understanding of how smoking and alcohol interact to influence CNS activity [55].
3. Smoking cessation in the treatment of alcohol dependence Until recently, there has been reluctance within the alcohol treatment community in general to address cigarette smoking when treating alcohol abuse/dependence. In part, there has been a widely held belief that it is too difficult for persons to address both smoking cessation and alcohol abstinence [56]. The concern that discontinuation of smoking will result in a relapse of alcohol use also commonly exists [57]. Alcoholics anonymous, the support group many people use when discontinuing alcohol, avoids specific comment on tobacco smoking. In addition, the personnel of alcohol treatment programs are frequently recovering alcoholics who continue to smoke. Their continued use of nicotine makes it less likely that smoking cessation is addressed in the treatment of their patients. Bobo et al. [58] describe a survey of 771 professionals employed in alcohol treatment programs. About one third of respondents agreed that persons in active alcohol treatment should be urged to quit smoking. Those
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respondents who were currently smoking were one-half to one-third as likely to provide counseling on smoking cessation as those respondents who had never smoked. This demonstrates the fairly low priority that smoking cessation has been given in the past in treatment programs for alcohol addiction. In recent years, data has emerged to suggest that inclusion of smoking cessation programs does not interfere and may, in some instances, enhance the success of alcohol treatment. Interestingly, it has been observed that long-term (10 year) abstention from alcohol and smoking are highly correlated [59]. Initial work examining the relationship of smoking cessation to alcohol treatment programs focused on inpatient substance abuse programs. In this setting, smoking bans with and without counseling and nicotine replacement have been evaluated [60–62]. Importantly, these studies and others suggest that smoking cessation efforts during inpatient substance abuse treatment do not negatively impact abstinence from alcohol and other non-nicotine drugs of abuse and enhance smoking cessation [63]. Hurt et al. [60] demonstrated in a prospective trial involving 101 persons (50 controls, 51 in tobacco intervention group) that relapse rates for alcohol and other drugs were not different in the two groups while the smoking cessation rate at 1 year was 11.8% in the group given smoking cessation treatment and 0% in the control group. Bobo et al. [64] showed that simultaneous treatment of alcohol and tobacco in a residential setting did not jeopardize the participants’ recovery from alcohol. These studies and others suggests that smoking cessation efforts in inpatient and residential substance abuse treatment programs as well as the outpatient setting may be practical and not diminish the efficacy of the program in terms of alcohol abstinence [65,66]. There has been data suggesting that alcoholics who continue to smoke may be at increased risk for relapse. Stuyt [67] reported on a group of substance abusers that received inpatient addiction treatment and were followed for 1 year after completion of their treatment. No significant effect on length of sobriety after treatment was observed in regards to gender, race, or primary drug of abuse of participants. However, there was a significant difference in length of sobriety between tobacco users and non-tobacco users in that non-tobacco users (included those who were non-smokers at time of entry into inpatient treatment and those who elected to remain abstinent from cigarettes after treatment) had nearly twice the length of sobriety time compared to tobacco users. In contrast, Martin et al. [68] evaluated a group of recovering alcoholics (>3 months continuous abstinence) who were heavy smokers for the effect of a three different smoking cessation interventions and observed that length of alcohol abstinence was not associated with smoking cessation outcome. There are several differences in these two particular studies, specifically in the timing of smoking cessation with initial or more prolonged alcohol abstinence. However, such observations highlight the need to determine the most beneficial strategies to deal with treatment of persons with both addictions.
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There is currently increasing support for addressing smoking cessation in alcohol dependent persons, but the most efficacious strategies for smoking cessation in this population are not clear [69]. Many initial studies of various smoking cessation approaches excluded persons with alcohol dependence or a history of alcohol treatment. This is not surprising since it has been observed that alcohol use during smoking cessation efforts is associated with poorer smoking cessation rates [70]. Behavioral therapy strategies are clearly important in smoking cessation programs for the general population, but it appears that low-intensity programs are not effective in patients in alcohol treatment [64]. This is likely related, in part, to the observation that nicotine dependence is often more severe in persons with a history of alcohol dependence [6]. Behavioral therapy for smoking cessation that is more aligned to standard counseling approaches for alcohol dependence has been shown to be very effective at the end of end of treatment (60%) and to have quit rates sustained at 1 year that are comparable to persons without an alcohol addiction history at approximately 25% [68]. For the general population, a combined approach with behavioral therapy and pharmacological agents is recommended for smoking cessation [71]. For persons with alcohol dependence, a combined approach is also preferred. However, less is known about how alcohol dependent persons respond to the various pharmacologic agents available for smoking cessation [69]. The first-line pharmacologic agents for smoking cessation are nicotine gum, nicotine patches, nicotine nasal spray, nicotine vapor inhaler, and bupropion and the second-line agents are nortripyline and clonidine [71]. Nicotine replacement with gum and patches has been used in smoking cessation studies of alcohol dependent persons and there is data to suggest that nicotine patch may not be as effective in persons who are alcohol dependent [72]. However, this observation may be more related to a tendency to inadequate nicotine replacement in alcoholics. Recovering alcoholics have been observed to have significantly higher mean smoking rates in cigarettes per day, Fagerstrom scores (a measure of nicotine addiction) and baseline serum nicotine and cotinine than non-alcoholics [73]. Thus, nicotine replacement therapy (typically via a nicotine patch) that more closely mimics an individual’s usual nicotine intake may be particularly useful for persons who have been alcohol dependent. Such strategies have been studied in non-alcoholic persons [74] and found to be safe and well tolerated. The efficacy of giving higher doses than standard nicotine therapy for long-term smoking cessation has not yet been clearly established in heavily nicotine-addicted persons regardless of alcohol status. Additionally, it has been suggested that alcoholics may need nicotine replacement for longer periods of time than non-alcoholics because of the typical severity of their nicotine addiction [73]. Bupropion is a monocyclic anti-depressant that is a potent inhibitor of dopamine and noradrenaline reuptake. Since dopamine neurotransmission is central to mechanisms regu-
lating CNS effects of nicotine, the effect of bupropion on dopamine reuptake should make it a drug of value in smoking cessation. In addition, bupropion has also been shown to be a competitive inhibitor of nicotinic acetylcholine receptors [75], which also influence nicotine’s effects. Several studies have shown the efficacy of bupropion SR for smoking cessation in the general population [76–78]. Bupropion SR also appears to have efficacy for smoking cessation in persons with past alcoholism [79]. Studies are currently in progress at our institution and elsewhere directly examining the role of bupropion in alcoholic smokers for efficacy in smoking cessation and efficacy in preventing smoking relapse. Depression is fairly common in persons with alcohol dependence or abuse and bupropion is an anti-depressant. In addition, individuals with a combined history of alcoholism and major depression are observed to be at a high risk to use smoking as a means of mood enhancement [80]. Interestingly, the primary mechanism of action of bupropion in smoking cessation (or prevention of smoking relapse) is thought to be via the drug’s effect on dopamine neurotransmission and/or nicotinic acetylcholine receptors and not via its anti-depressant properties. It has also been suggested that bupropion can be given to an alcoholic smoker for smoking cessation while the patient is maintained on a previously prescribed serotonin reuptake inhibitor (SSRI) or tricyclic anti-depressant for depression treatment, as long as persons have no other contraindications for bupropion use such as history of seizure disorder [69]. Some other anti-depressants have been examined for their usefulness in smoking cessation in the general population, but not in persons with current or active alcohol abuse [81,82]. Of the anti-depressants investigated, nortripyline, a tricyclic anti-depressant, has documented smoking cessation efficacy, although it is associated with significant incidence of side effects such as dry mouth. Combination pharmacotherapy is advocated for smoking cessation in heavily nicotine addicted persons and thus, is appropriate for smoking cessation in those patients with current or past alcohol treatment [69,71]. Simultaneous use of more than one form of nicotine replacement therapy may be useful. Nicotine patch combined with nicotine gum or inhaler may provide nicotine replacement that helps persons deal with urges more effectively [83–85]. Combined nicotine replacement and bupropion use is also used, although it is has not been definitively shown that this therapy significantly enhances quit rates in the general population [86]. This combined therapy may be even more important for smoking cessation in patients in alcohol treatment, but the efficacy of the this approach has not yet been reported. Equally as important as the potential role of combined pharmacotherapy in smoking cessation in alcohol treatment is the importance of determining the best timing of initiating smoking cessation while treating alcohol dependence or abuse [87]. In a pilot study, concurrent initiation of smoking cessation (within 2 weeks) vs. delayed initiation (after 6 weeks) resulted in similar overall smoking cessation rates, but significantly fewer participants actually entered the de-
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layed smoking cessation program [88]. This would suggest that early smoking cessation therapy might be appropriate in order not to lose opportunities to provide persons in alcohol treatment with smoking cessation assistance. However, there has been some suggestion that early smoking intervention in alcohol treatment may impact alcohol abstinence and a recently completed National Institutes of Health (NIH) trial will provide insights into this (AM Joseph, personal communication). Additional pharmacotherapy approaches have been applied to smoking cessation in alcohol treatment including the use of naltrexone, an opiod antagonist. Naltrexone influences the mesolimbic pathways where nicotine and alcohol also act. An initial study showed that there is some reduction in number of cigarettes smoked, but there is no significant effect on smoking cessation [89]. There may still be an adjunct role for this agent in certain subsets of smokers in alcohol treatment, but this remains to be defined. Given the prevalence of cigarette smoking among patients in alcohol treatment programs and the significant impact of smoking-related diseases in these persons, it is clear that defining the optimal approaches to smoking cessation in alcohol treatment is of utmost important. Better understanding of the genetic and biochemical determinants of nicotine and alcohol addiction will substantially aid new approaches. Currently, additional studies are also required to improve understanding of the best combination and timing of existing therapies for smoking cessation in alcohol treatment. References [1]
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Dossier: Influence of alcohol consumption and smoking habits on human health
Alcohol consumption and smoking status: the role of smoking cessation Debra J. Romberger a,b,*, Kathleen Grant b a
Pulmonary and Critical Care Medicine Section, University of Nebraska Medical Center, 985300 Nebraska Medical Center, Omaha, NE 68198-5300, USA b Department of Veterans Affairs Medical Center, Omaha, NE, USA Received 28 October 2003
Abstract Cigarette smoking is common among persons with alcohol dependence or abuse with as many as 80% of persons who are alcohol dependent also being smokers. Not only is smoking common in persons with heavy alcohol consumption, but also nicotine dependence appears more severe in smokers with a history of alcohol dependence. This combined exposure to both tobacco smoke and alcohol results in major health consequences including additive risks for some diseases such as head and neck cancers. Although modest alcohol consumption has some positive health benefits, smoking typically negates these benefits. The cellular mechanisms impacted by combined smoking and alcohol exposure are poorly understood, but molecular epidemiology approaches are providing insights regarding the importance of effects on oxidant/antioxidant pathways and on metabolic pathways involving the cytochrome P450 system. Given the prevalence of smoking in the alcohol dependent population, smoking cessation in this group has the potential for tremendous impact. In recent years, smoking cessation approaches have been initiated in this population, but much work remains in order to define the optimal smoking cessation strategies for persons in alcohol treatment programs. © 2004 Elsevier SAS. All rights reserved. Keywords: Smoking cessation; Alcohol dependence; Substance abuse
1. Alcohol consumption and cigarette smoking and disease It has long been recognized that there is a strong association between heavy alcohol use and cigarette smoking. Approximately 80% of alcohol dependent patients are reported to smoke cigarettes [1–3]. Despite a decline of smoking in the US population in general, a recent study from a HMO (health maintenance organization) population seeking substance abuse treatment demonstrates that more than 60% of persons were active smokers [4]. Heavy cigarette use is a predictor of unrecognized alcohol abuse/dependence [5]. The prevalence of smoking among substance abusers is approximately two to three times that of the general population [1]. Alcoholism is estimated to be 10 times more common among smokers than among non-smokers [2]. In addition, nicotine dependence appears more severe in smokers with a history of alcohol dependence [6].
* Corresponding author. E-mail address: [email protected] (D.J. Romberger). © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2003.12.002
The fact that heavy alcohol use and cigarette smoking frequently occur together has major impact on development of disease. The concomitant use of tobacco and alcohol contributes to an increased incidence of several malignancies, especially head and neck cancers [7–9]. Men who both smoke and drink are nearly 38 times more likely to develop head and neck cancers than men who do neither. This compares to non-smoking drinkers (average 30 drinks/week or greater) who are 5.8 times more likely to develop a head and neck cancer and non-drinking smokers (two packs/week or greater) who are 7.4 times more likely to develop such cancers [7]. Talamini et al. [10] recently observed a similar multiplicative risk for laryngeal cancer with combined alcohol and smoking exposure in European subjects. In addition, continued alcohol and smoking exposure augments the risk for a second primary tumor in patients with a previous upper aerodigestive tract tumor [11]. Alcohol consumption and tobacco smoking also contribute to pancreatic, esophageal, and hepatocellular cancers, although synergism between the two agents is not as pronounced as with head and neck cancer [12–14]. Interestingly, lung cancer is strongly associated with cigarette smoking,
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but is not consistently associated with alcohol consumption [15]. It is unclear why combined alcohol and smoking exposure appears to have a synergistic influence on biological processes leading to laryngeal cancer, but does not appear to have an identical influence on the processes leading to lung cancer even though both laryngeal and lung cancer can share common morphologic features. Non-malignant diseases are also influenced by combined alcohol and smoking exposure. There are reports of increased risk of cirrhosis of the liver, pancreatitis, and periodontal disease [8,16,17]. Cardiovascular disease is also influenced in that the worst triglyceride levels are associated with the combination of heavy smoking and heavy alcohol drinking in a Mediterranean population [18]. In this same study, smoking also interfered with positive health benefits associated with moderate alcohol consumption. Tobacco, not alcohol, has been shown to be the leading cause of death in persons previously treated for alcohol dependence [19]. This demonstrates the significance of the additional health risks of smoking even in persons who have experienced the negative effects of heavy alcohol consumption. The effect of combined alcohol and tobacco exposure on many diseases is complex and in some cases, poorly understood. Heavy alcohol consumption is associated with many disorders, whereas moderate alcohol intake has been shown to have positive health benefits. Cardiovascular disease, dementia, and hearing loss may be positively influenced by modest alcohol intake [20–23]. As noted previously, smoking interferes with the positive health effects of modest alcohol consumption on heart disease [18]. In contrast, the potential interactions between smoking and alcohol on dementia are not clearly defined [24–26]. Smoking appears to have a negative influence on hearing loss, but the interactions between alcohol and smoking are less clear [27,28]. In the lung, smoking is clearly associated with loss of lung function and pulmonary diseases such as emphysema and chronic bronchitis [29]. The alcohol effect on lung function is not clearly defined. In an epidemiological study of Scandinavian men, a J-shaped association between alcohol use and bronchitis was observed with the lowest prevalence of bronchitis seen with moderate alcohol consumption [30]. Similar results were reported by Tabak et al. [31] with the observation of a U-shaped relation between alcohol and chronic obstructive pulmonary disease mortality. Other reports have suggested both a positive and a negative influence of alcohol consumption on lung function [32–34]. It is likely that complex interactions occur in human lungs with smoking and varying levels of alcohol consumption. However, the importance of alcohol consumption on pulmonary response to injury has been clearly recognized in patients who develop acute respiratory distress syndrome (ARDS) in that persons with chronic alcohol abuse are at higher risk to both develop this disorder and to die related to complications of the disorder [35]. Given the fact that cigarette smoking occurs frequently in persons who consume excessive alcohol, it is important that
interactions between smoking and alcohol continue to be investigated. Much remains to be defined about how the combined exposure of these agents influences various organ systems as well as disease outcomes. The multiplicative risk with alcohol and smoking for certain diseases like head and neck cancer suggests possible synergism in the mechanisms of action of the agents regarding certain biological endpoints. With other processes, it appears clear that synergism does not occur. Thus, understanding how alcohol and smoking mediate cellular mechanisms responsible for biological responses is an exciting area of investigation. The next section will highlight some mechanistic observations made in the context of clinical disorders associated with combined alcohol and tobacco use.
2. Cellular mechanisms influenced by combined alcohol and cigarette smoke exposure Molecular epidemiology studies of malignancies with both alcohol and smoke exposure as risk factors provide some insights into possible genes modulated by the combined exposures. As previously noted, smoking and alcohol consumption are major risk factors for head and neck cancer [10]. Xenobiotic metabolizing enzymes are felt to be important in mediating cancer susceptibility. Polymorphisms of such enzymes including arylamine N-acetyltransferases (NAT1 and NAT2) genotypes have been associated with laryngeal cancer risk [36]. Specifically, significant overrepresentation of homozygous NAT2 genotypes coding for rapid acetylation were reported in association with laryngeal cancer. In non-small cell lung cancer, a role for alcohol augmenting the mutagenic effects of cigarette smoke has been suggested [37]. Mutations in the p53 gene were present more often in tumors from alcohol drinkers who smoked cigarettes (76% of the 105 patients studied) than in nondrinkers who smoked cigarettes (42% of the patients) or in nondrinkers who did not smoke (14% of patients). A role for p53 mutations in aerodigestive cancers in general has been suggested by others [38,39]. Oxidant injury and antioxidant defense systems are also influenced by combined alcohol and tobacco smoke exposure. The glutathione-S-transferases M1 (GSTM1) null genotype is associated with an increased odds ratio for esophageal cancer with a combined effect observed with smoking and the GSTM1 null genotype in a Chinese population study [40]. In a Swedish study, high alcohol consumption and smoking in combination with GSTM1 null genotype is associated with high titers of plasma autoantibodies against the oxidized DNA base derivative 5-hydroxymethyl2′-deoxyuridine that is used as a potential biomarker of cancer risk and oxidative stress [41]. In an animal model of combined exposure of alcohol and nicotine (as opposed to cigarette smoke), a 6 week exposure to alcohol and nicotine produced similar, and in some cases additive, oxidative tissue injuries in various organs in rats [42].
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Cytochromes P450 (CYP) are enzymes (mixed function oxidases) that are predominantly expressed in the liver and have long been recognized as central in metabolizing drugs, endogenous compounds, and environmental and dietary substances in humans. Specific CYP enzyme activities are influenced by both ethanol and smoking [43,44]. Howard et al. [45] have observed that low doses of nicotine and ethanol induce CYP2E1 in rat liver. These mechanisms may have relevance to cross-tolerance that is observed between smoking and drinking with chronic nicotine potentially increasing clearance of ethanol. Recently, Miksys et al. [46] have reported that another member of the cytochrome P450 family, CYP2B6, is increased in various regions of the brains of smokers and alcoholics with the potential role for the CC genotype contributing to the highest levels of CYP2B6 protein. Nicotine and alcohol interactions within both the developing and adult central nervous system (CNS) have been the subject of much investigation and are reviewed elsewhere [47–51]. Dopamine neurotransmission, particularly in the nucleus accumbens of the mesocorticolimbic system, is central to mechanisms regulating CNS effects of both nicotine and alcohol. Each substance works through different proteins and receptors (classically, nicotinic acetylcholine receptors or nAChRs for nicotine and N-methyl-D-aspartate or NMDA and g-aminobutyric acid or GABA receptors for alcohol) [49]. However, it is clear that ethanol also influences nAChR activation and that nicotine can mediate dopamine-activating properties of alcohol [51,52]. In addition, there is also a role for another important neurotransmitter, serotonin, in the interactions between nicotine and alcohol within the CNS [51,53,54]. It is anticipated that insights gained from genetic studies will further enhance our understanding of how smoking and alcohol interact to influence CNS activity [55].
3. Smoking cessation in the treatment of alcohol dependence Until recently, there has been reluctance within the alcohol treatment community in general to address cigarette smoking when treating alcohol abuse/dependence. In part, there has been a widely held belief that it is too difficult for persons to address both smoking cessation and alcohol abstinence [56]. The concern that discontinuation of smoking will result in a relapse of alcohol use also commonly exists [57]. Alcoholics anonymous, the support group many people use when discontinuing alcohol, avoids specific comment on tobacco smoking. In addition, the personnel of alcohol treatment programs are frequently recovering alcoholics who continue to smoke. Their continued use of nicotine makes it less likely that smoking cessation is addressed in the treatment of their patients. Bobo et al. [58] describe a survey of 771 professionals employed in alcohol treatment programs. About one third of respondents agreed that persons in active alcohol treatment should be urged to quit smoking. Those
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respondents who were currently smoking were one-half to one-third as likely to provide counseling on smoking cessation as those respondents who had never smoked. This demonstrates the fairly low priority that smoking cessation has been given in the past in treatment programs for alcohol addiction. In recent years, data has emerged to suggest that inclusion of smoking cessation programs does not interfere and may, in some instances, enhance the success of alcohol treatment. Interestingly, it has been observed that long-term (10 year) abstention from alcohol and smoking are highly correlated [59]. Initial work examining the relationship of smoking cessation to alcohol treatment programs focused on inpatient substance abuse programs. In this setting, smoking bans with and without counseling and nicotine replacement have been evaluated [60–62]. Importantly, these studies and others suggest that smoking cessation efforts during inpatient substance abuse treatment do not negatively impact abstinence from alcohol and other non-nicotine drugs of abuse and enhance smoking cessation [63]. Hurt et al. [60] demonstrated in a prospective trial involving 101 persons (50 controls, 51 in tobacco intervention group) that relapse rates for alcohol and other drugs were not different in the two groups while the smoking cessation rate at 1 year was 11.8% in the group given smoking cessation treatment and 0% in the control group. Bobo et al. [64] showed that simultaneous treatment of alcohol and tobacco in a residential setting did not jeopardize the participants’ recovery from alcohol. These studies and others suggests that smoking cessation efforts in inpatient and residential substance abuse treatment programs as well as the outpatient setting may be practical and not diminish the efficacy of the program in terms of alcohol abstinence [65,66]. There has been data suggesting that alcoholics who continue to smoke may be at increased risk for relapse. Stuyt [67] reported on a group of substance abusers that received inpatient addiction treatment and were followed for 1 year after completion of their treatment. No significant effect on length of sobriety after treatment was observed in regards to gender, race, or primary drug of abuse of participants. However, there was a significant difference in length of sobriety between tobacco users and non-tobacco users in that non-tobacco users (included those who were non-smokers at time of entry into inpatient treatment and those who elected to remain abstinent from cigarettes after treatment) had nearly twice the length of sobriety time compared to tobacco users. In contrast, Martin et al. [68] evaluated a group of recovering alcoholics (>3 months continuous abstinence) who were heavy smokers for the effect of a three different smoking cessation interventions and observed that length of alcohol abstinence was not associated with smoking cessation outcome. There are several differences in these two particular studies, specifically in the timing of smoking cessation with initial or more prolonged alcohol abstinence. However, such observations highlight the need to determine the most beneficial strategies to deal with treatment of persons with both addictions.
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There is currently increasing support for addressing smoking cessation in alcohol dependent persons, but the most efficacious strategies for smoking cessation in this population are not clear [69]. Many initial studies of various smoking cessation approaches excluded persons with alcohol dependence or a history of alcohol treatment. This is not surprising since it has been observed that alcohol use during smoking cessation efforts is associated with poorer smoking cessation rates [70]. Behavioral therapy strategies are clearly important in smoking cessation programs for the general population, but it appears that low-intensity programs are not effective in patients in alcohol treatment [64]. This is likely related, in part, to the observation that nicotine dependence is often more severe in persons with a history of alcohol dependence [6]. Behavioral therapy for smoking cessation that is more aligned to standard counseling approaches for alcohol dependence has been shown to be very effective at the end of end of treatment (60%) and to have quit rates sustained at 1 year that are comparable to persons without an alcohol addiction history at approximately 25% [68]. For the general population, a combined approach with behavioral therapy and pharmacological agents is recommended for smoking cessation [71]. For persons with alcohol dependence, a combined approach is also preferred. However, less is known about how alcohol dependent persons respond to the various pharmacologic agents available for smoking cessation [69]. The first-line pharmacologic agents for smoking cessation are nicotine gum, nicotine patches, nicotine nasal spray, nicotine vapor inhaler, and bupropion and the second-line agents are nortripyline and clonidine [71]. Nicotine replacement with gum and patches has been used in smoking cessation studies of alcohol dependent persons and there is data to suggest that nicotine patch may not be as effective in persons who are alcohol dependent [72]. However, this observation may be more related to a tendency to inadequate nicotine replacement in alcoholics. Recovering alcoholics have been observed to have significantly higher mean smoking rates in cigarettes per day, Fagerstrom scores (a measure of nicotine addiction) and baseline serum nicotine and cotinine than non-alcoholics [73]. Thus, nicotine replacement therapy (typically via a nicotine patch) that more closely mimics an individual’s usual nicotine intake may be particularly useful for persons who have been alcohol dependent. Such strategies have been studied in non-alcoholic persons [74] and found to be safe and well tolerated. The efficacy of giving higher doses than standard nicotine therapy for long-term smoking cessation has not yet been clearly established in heavily nicotine-addicted persons regardless of alcohol status. Additionally, it has been suggested that alcoholics may need nicotine replacement for longer periods of time than non-alcoholics because of the typical severity of their nicotine addiction [73]. Bupropion is a monocyclic anti-depressant that is a potent inhibitor of dopamine and noradrenaline reuptake. Since dopamine neurotransmission is central to mechanisms regu-
lating CNS effects of nicotine, the effect of bupropion on dopamine reuptake should make it a drug of value in smoking cessation. In addition, bupropion has also been shown to be a competitive inhibitor of nicotinic acetylcholine receptors [75], which also influence nicotine’s effects. Several studies have shown the efficacy of bupropion SR for smoking cessation in the general population [76–78]. Bupropion SR also appears to have efficacy for smoking cessation in persons with past alcoholism [79]. Studies are currently in progress at our institution and elsewhere directly examining the role of bupropion in alcoholic smokers for efficacy in smoking cessation and efficacy in preventing smoking relapse. Depression is fairly common in persons with alcohol dependence or abuse and bupropion is an anti-depressant. In addition, individuals with a combined history of alcoholism and major depression are observed to be at a high risk to use smoking as a means of mood enhancement [80]. Interestingly, the primary mechanism of action of bupropion in smoking cessation (or prevention of smoking relapse) is thought to be via the drug’s effect on dopamine neurotransmission and/or nicotinic acetylcholine receptors and not via its anti-depressant properties. It has also been suggested that bupropion can be given to an alcoholic smoker for smoking cessation while the patient is maintained on a previously prescribed serotonin reuptake inhibitor (SSRI) or tricyclic anti-depressant for depression treatment, as long as persons have no other contraindications for bupropion use such as history of seizure disorder [69]. Some other anti-depressants have been examined for their usefulness in smoking cessation in the general population, but not in persons with current or active alcohol abuse [81,82]. Of the anti-depressants investigated, nortripyline, a tricyclic anti-depressant, has documented smoking cessation efficacy, although it is associated with significant incidence of side effects such as dry mouth. Combination pharmacotherapy is advocated for smoking cessation in heavily nicotine addicted persons and thus, is appropriate for smoking cessation in those patients with current or past alcohol treatment [69,71]. Simultaneous use of more than one form of nicotine replacement therapy may be useful. Nicotine patch combined with nicotine gum or inhaler may provide nicotine replacement that helps persons deal with urges more effectively [83–85]. Combined nicotine replacement and bupropion use is also used, although it is has not been definitively shown that this therapy significantly enhances quit rates in the general population [86]. This combined therapy may be even more important for smoking cessation in patients in alcohol treatment, but the efficacy of the this approach has not yet been reported. Equally as important as the potential role of combined pharmacotherapy in smoking cessation in alcohol treatment is the importance of determining the best timing of initiating smoking cessation while treating alcohol dependence or abuse [87]. In a pilot study, concurrent initiation of smoking cessation (within 2 weeks) vs. delayed initiation (after 6 weeks) resulted in similar overall smoking cessation rates, but significantly fewer participants actually entered the de-
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layed smoking cessation program [88]. This would suggest that early smoking cessation therapy might be appropriate in order not to lose opportunities to provide persons in alcohol treatment with smoking cessation assistance. However, there has been some suggestion that early smoking intervention in alcohol treatment may impact alcohol abstinence and a recently completed National Institutes of Health (NIH) trial will provide insights into this (AM Joseph, personal communication). Additional pharmacotherapy approaches have been applied to smoking cessation in alcohol treatment including the use of naltrexone, an opiod antagonist. Naltrexone influences the mesolimbic pathways where nicotine and alcohol also act. An initial study showed that there is some reduction in number of cigarettes smoked, but there is no significant effect on smoking cessation [89]. There may still be an adjunct role for this agent in certain subsets of smokers in alcohol treatment, but this remains to be defined. Given the prevalence of cigarette smoking among patients in alcohol treatment programs and the significant impact of smoking-related diseases in these persons, it is clear that defining the optimal approaches to smoking cessation in alcohol treatment is of utmost important. Better understanding of the genetic and biochemical determinants of nicotine and alcohol addiction will substantially aid new approaches. Currently, additional studies are also required to improve understanding of the best combination and timing of existing therapies for smoking cessation in alcohol treatment. References [1]
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