Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

Abstract

Back to table of contents Previous article Next article ArticleNo AccessHeavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment OptionsMichael Mirbaba, M.D., M.A., Ph.D.Michael MirbabaSearch for more papers by this author, M.D., M.A., Ph.D.Published Online:26 Apr 2017https://doi.org/10.1176/appi.ajp-rj.2016.110603AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Heavy-drinking smokers are a sizeable population with comorbid alcohol and tobacco use disorders requiring specific treatments tailored to both disorders. Heavy-drinking smokers are defined as women who drink >7 alcoholic beverages per week and >3 drinks on one occasion and men who drink >14 alcoholic beverages per week and >4 drinks on one occasion at least once weekly (in the past 30 days) and smoke at least 10 cigarettes daily (1). Though not formally recognized in DSM-5, heavy-drinking smokers are a distinct subpopulation identified in research studies, amounting to more than 6 million people in the United States who suffer greater risks of negative health consequences than those with either an alcohol use disorder or tobacco use disorder alone (2). Increased morbidity and mortality in heavy-drinking smokers are in part attributable to cardiopulmonary disease, malignancies, and hepatic disease. It is not surprising that alcohol and tobacco are the most commonly used legal substances of abuse given their widespread availability and lengthy market presence. Interestingly, use of either substance predisposes to use of the other: drinkers who have five or more drinks per week are 2.4 times more likely to smoke than those who have less than five drinks per year; smokers are three times more likely to engage in hazardous drinking than nonsmokers; during drinking episodes, abstinent smokers are five times more likely to have a tobacco relapse (3). In view of the staggering statistics that patients with mental illness consume 38% of all alcohol and 40% of all cigarettes and the fact that these substances cost society an estimated $550 billion annually, psychiatrists should be familiar with heavy-drinking smokers to provide evidence-based treatments (4).PathophysiologyAlthough the mechanism of the comorbidity between alcohol and tobacco use disorders remains unclear, there are shared genetic risk factors (polymorphisms), pharmacologic (cross-sensitization) and psychological (conditioning) changes, and common pathophysiology within mesolimbic dopaminergic, nicotinic, and opioid pathways that may contribute (5, 6). The role of nicotinic acetylcholine receptors (nAChRs) is of particular interest in understanding the co-use of alcohol and nicotine, as nAChRs are where both substances are believed to interact.nAChRs are ligand-gated ion channels that are highly prevalent throughout the CNS and consist of several subtypes with varying functions modulating excitatory neurotransmission. Research has focused primarily on two specific subtypes of nAChRs, α4β2 and α7, which are the most common subtypes. Nicotine binds the α4β2 subtype with higher affinity than the α7 subtype and causes the channels to open, leading to an influx of calcium and sodium ions that subsequently depolarize the neuron. Nicotine has a wide range of pharmacologic effects beyond its nAChR agonism, as it also causes release of dopamine, serotonin, norepinephrine, GABA, glutamate, and endogenous opioids, all of which have been implicated in its addictive potential. With chronic nicotine exposure, nAChRs become desensitized to its excitatory effects, particularly the α4β2 subtype whose expression increases over time (7).Beyond alcohol’s well-known agonist effects at GABA-A receptors and glutamatergic antagonism, it also exhibits agonism at α4β2 and antagonism at α7 nAChRs, the latter of which appears to be involved in protecting neurons from alcohol’s toxicity (8). Alcohol’s effects specifically on the α4β2 subtype may decrease the nicotine-induced desensitization of α4β2 nAChRs, thereby enhancing excitatory neurotransmission, which could in part contribute to the co-use of alcohol and nicotine. Furthermore, chronic use of alcohol has been shown not only to produce tolerance at GABA-A receptors, but it also alters the prevalence of nAChRs, and in doing so produces cross-tolerance to nicotine. Likewise, chronic nicotine exposure has been known to produce cross-tolerance to alcohol in animal models (9). Both of these processes may be mediated by genetic factors related to the expression of certain polymorphisms of the α4 and α7 nAChR subunits, which could explain individual differences in sensitivity to the effects of alcohol and nicotine (9). More recent research has shown that alcohol and nicotine co-use enhances ventral tegmental area glutamatergic AMPA receptor function via agonism at α6 nAChRs (10). This results in increased excitatory neurotransmission within mesolimbic dopamine pathways critical to addiction pathophysiology. Despite these putative mechanisms, pathophysiologic interactions between alcohol and nicotine at nAChRs and other key receptors are likely more complex and not entirely understood at this time.PharmacotherapiesThere are no Food and Drug Administration (FDA)-approved pharmacotherapies tailored to heavy-drinking smokers. Despite expert consensus that both disorders should be treated simultaneously, many heavy-drinking smokers receiving treatment for their alcohol use disorder are not offered treatment for their tobacco use disorder, even though up to 80% are interested in smoking cessation and effective tobacco use disorder treatments are easy to provide (11). This occurs in spite of the fact that tobacco use is the leading preventable cause of death in the United States, according to the Centers for Disease Control and Prevention (12). Furthermore, there is evidence that continued tobacco use represents a substantial risk for alcohol relapse and increases the likelihood of having an alcohol use disorder 3 years after treatment (odds ratio=2.30) (13). By providing interventions targeting both disorders, chances of successful treatment outcomes may improve.NaltrexoneOf the four FDA-approved pharmacotherapies for alcohol use disorder, only oral naltrexone has been shown to decrease smoking while decreasing alcohol use in recent clinical studies (14). Beyond blunting the rewarding and reinforcing properties of each substance, decreased tobacco use may also be a consequence of naltrexone acting to concomitantly decrease alcohol use, which in turn leads to less tobacco use, given their correlated co-use. Although there are no clinical studies investigating the effect of injectable extended-release naltrexone on smoking cessation in heavy-drinking smokers, it is not unreasonable to infer similar outcomes given their identical mechanisms of action. In fact, injectable extended-release naltrexone may have further advantages of improved treatment retention (see Table 1).TABLE 1. Potential Pharmacotherapies for Heavy-Drinking SmokersMedicationDosageMechanism of ActionCommon Side EffectsContraindications/CautionsOral naltrexone50 mg dailyMu-opioid receptor antagonism with kappa-opioid receptor partial agonismNausea, vomiting, headache, anorexia, fatigue, sedation, insomnia, anxiety, apathy, anhedonia, opioid withdrawal, dose-dependent hepatotoxicityRequires naloxone challenge/opioid abstinenceMaximum: 200 mg dailyBlocks rewarding effects of alcohol and nicotine in the nucleus accumbensHepatic or renal impairmentDepression, suicidal ideationInjectable extended-release naltrexone380 mg (IM) every 4 weeksSame as oral naltrexoneInjection site reactions, plus all others listed above for oral naltrexoneSame as oral naltrexoneVarenicline1 mg twice daily for up to 14 weeksPartial agonism of multiple nAChRs, including α4β2 and α6β2 Believed to reduce the ability of nicotine and alcohol to activate mesolimbic pathwaysNausea, vomiting, insomnia, headache, abnormal dreams, somnolence, xerostomia, constipation, diarrhea, flatulence, dysgeusia, dyspepsia, appetite changes, hostility, agitation, depression, suicidal ideationRenal impairment Psychiatric disorders or history Seizure disorder or risk Cardiovascular disease Alcohol use Patients <18 years old Safe in stable cardiovascular diseaseTopiramate200–300 mg daily Maximum: 400 mg dailyAntagonism of AMPA/kainate glutamatergic receptors Antagonism of voltage-dependent sodium channels Agonism of GABA-A receptors Inhibition of carbonic anhydraseNausea, diarrhea, somnolence, fatigue, cognitive impairment, dizziness, ataxia, anorexia, weight loss, paresthesias, nasopharyngitis, diplopia, glaucoma, metabolic acidosis, nephrolithiasis, depression, anxiety, suicidal ideationHepatic or renal impairment Depression, suicidal ideation Pregnancy Acute myopia and secondary angle closure glaucoma Hyperthermia Hyperammonemia EncephalopathyTABLE 1. Potential Pharmacotherapies for Heavy-Drinking SmokersEnlarge tableVareniclineVarenicline monotherapy has also been shown to decrease alcohol use and cravings in heavy-drinking smokers while decreasing smoking rates (15). This is hypothesized to be the result of varenicline’s partial agonism at multiple nAChRs, most notably the α4β2 subtype. Partial agonism at α4β2 nAChRs appears to blunt the effects of alcohol and nicotine on mesolimbic pathways. Specifically, varenicline’s partial agonism at α4β2 nAChRs likely decreases alcohol’s ability to activate α4β2 nAChRs, as any increased presence of activating ligands, such as alcohol, leads to competitive antagonistic effects from varenicline at this subunit. Moreover, recent research has identified that varenicline’s α6β2 partial agonism decreases the α6 nAChR activation induced by co-use of alcohol and nicotine, which in turn decreases AMPA receptor activation within the ventral tegmental area (10). By reducing the agonist effects of alcohol and nicotine on both α4β2 and α6 nAChRs, varenicline may indirectly decrease dopamine release within the nucleus accumbens when the substances are co-used, thereby reducing the rewarding and reinforcing properties of each (see Table 1).Varenicline Plus NaltrexoneGiven these putative effects of alcohol and nicotine on the endogenous opioid system and nAChRs, the combination of varenicline plus naltrexone is an appealing treatment for heavy-drinking smokers, since it targets two distinct but overlapping pathways that contribute to addiction pathophysiology. In a recent short-term clinical study involving heavy-drinking smokers, varenicline plus low-dose naltrexone (25 mg/day) acted synergistically to decrease use of both alcohol and tobacco more than placebo or either medication alone (16). These promising results require replication before consensus agreement on this particular combination pharmacotherapy. Of note, although the FDA issued a black box warning for varenicline regarding increased risks of adverse neuropsychiatric events, such as depression, suicidal ideation/behaviors, and suicide in patients with or without pre-existing psychiatric conditions, subsequent analyses have not found any evidence of these increased risks (17).TopiramateBeyond targeting the endogenous opioid system and nAChRs, there is growing evidence that off-label use of topiramate decreases both alcohol and tobacco use (18, 19). Topiramate has also been shown to decrease use of both substances in heavy-drinking smokers (20, 21). Topiramate acts by blocking AMPA/kainate glutamatergic receptors and facilitating GABA-A neurotransmission, the former of which may reduce the AMPA-mediated ventral tegmental area activation by alcohol and nicotine co-use (10). Though tolerability of topiramate represents a significant drawback, it offers another promising monotherapy for heavy-drinking smokers (see Table 1).Potential PharmacotherapiesPotential treatments that have yet to be studied in heavy-drinking smokers include the combination of varenicline plus oral naltrexone plus nicotine replacement therapy, varenicline plus injectable extended-release naltrexone with or without nicotine replacement therapy, varenicline plus topiramate with or without nicotine replacement therapy, and bupropion sustained release plus injectable extended-release naltrexone, acamprosate, or disulfiram with or without nicotine replacement therapy (see Table 1).ConclusionsTobacco use disorder is the leading preventable cause of death in the United States, and alcohol use disorder follows closely behind. Heavy-drinking smokers suffer from both conditions and are at risk for disproportionately more frequent negative health consequences. Furthermore, these disorders cost society hundreds of billions of dollars annually in health care expenditures and lost productivity. Currently, there are no FDA-approved pharmacotherapies for heavy-drinking smokers, but treatment of both disorders simultaneously has been shown to improve health outcomes for both disorders. Of the available FDA-approved pharmacotherapies for alcohol and tobacco use disorders, both varenicline and oral naltrexone independently decrease both alcohol and tobacco use as monotherapies. In combination, a recent study demonstrated promising results for enhanced efficacy compared to either medication alone in reducing both alcohol and tobacco use. This may result from synergistic mechanisms of action targeting two different foci of addiction pathophysiology: the mesolimbic endogenous opioid system and neuronal nAChRs. Off-label use of topiramate represents another promising monotherapy for heavy-drinking smokers, as it has also been shown to decrease use of alcohol and tobacco in heavy-drinking smokers. More clinical research is warranted to validate these findings and elucidate other potential pharmacotherapies to treat this sizeable population.Key Points/Clinical PearlsHeavy-drinking smokers are a sizeable population who face more frequent adverse health consequences than those with either alcohol use disorder or tobacco use disorder alone.Treatments targeting both alcohol and tobacco use disorders are necessary to improve health outcomes, but there are currently no FDA-approved treatments for heavy-drinking smokers.Combination pharmacotherapies for alcohol and tobacco use disorders targeting different foci of addiction pathophysiology, such as varenicline plus oral naltrexone, or off-label use of topiramate monotherapy, may improve treatment outcomes for heavy-drinking smokers, but further studies are warranted.Dr. Mirbaba is a fourth-year resident at UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles.