Jason M. Jerry, MD, FAPA

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Most people assume that electronic cigarettes (e-cigarettes) are safer than conventional tobacco products. Nevertheless, we should not encourage addicted smokers to try “vaping” as an alternative to nicotine replacement therapy, and we should discourage never-smokers from taking up vaping as vigorously as we try to discourage them from taking up smoking.

This article examines the prevailing assumptions and the evidence regarding the safety of e-cigarettes and traditional nicotine replacement therapy.

SMOKING IS DECLINING BUT FAR FROM GONE

While smoking rates have been declining over the past 50 years, the burden of disease attributable to tobacco use remains high. In the United States, it is estimated that nearly 6 million of those currently under the age of 18 will die of tobacco-related illnesses.¹ In the 50 years since the US surgeon general first reported on the health concerns related to tobacco, smoking has claimed the lives of nearly 21 million Americans¹ and continues to kill more than 400,000 every year.²

Even though the risks of smoking are well known, smoking remains one of the most difficult habits to quit. Indeed, about half of all smokers attempt to quit each year, but very few succeed.³

NICOTINE REPLACEMENT: GUM, PATCHES…E-CIGARETTES?

Smoking continues to kill more than 400,000 Americans every year

Nicotine replacement therapy was born out of the thought that, though nicotine is responsible for tobacco’s addictive quality, most tobacco-related disease is attributable to the 7,000 other substances found in tobacco smoke.⁴ Nicotine polacrilex gum was approved by the US Food and Drug Administration (FDA) in 1984, and nicotine transdermal film was approved in 1991.⁵

Nicotine replacement therapy, in the form of patches and gum, has been shown to improve the odds of successfully quitting smoking by a factor of nearly 1.5 to 2.⁶ Nicotine patches and gum were initially prescription medications but became available over the counter in 1996.⁷ They quickly became first-line agents for smoking cessation, and their over-the-counter availability softened any potential concerns about the possible deleterious health consequences of nicotine itself.

E-cigarettes—devices that generate a nicotine vapor that can be inhaled in a fashion that mimics the experience of smoking—were introduced in China in 2004.⁸ By 2012, sales of these devices in the United States had reached $500 million and in 2013 were expected to top $1 billion.^9,10

E-cigarette manufacturers make no therapeutic claims about their products, thus allowing them to escape regulation by the FDA as nicotine replacement therapy. A recent FDA proposal, however, is likely to change their “protected” status.¹¹ Despite the lack of regulation up to this point, patients generally assume that e-cigarettes are just another form of nicotine replacement therapy, even though they contain substances other than nicotine.

WHAT’S IN E-CIGARETTES?

Nicotine, which is bad in itself

E-cigarettes contain nicotine in varying amounts (some cartridges contain none at all). Though nicotine replacement therapy is less harmful than tobacco, nicotine by itself is associated with its own health problems, notably cancer, cardiovascular disease, birth defects (possibly), and poisoning.

Carcinogenesis. Nicotine plays a direct role in carcinogenesis through a variety of mechanisms, including increasing the activity of tumor growth-promoting transcription factors, decreasing apoptosis, and increasing angiogenesis in tumors.¹² Additionally, specific types of nicotinic acetylcholine receptors— eg, alpha 7 receptors, which are stimulated by nicotine—are found in many malignant tumors and are thought to play a role in tumor progression.¹² Blockade of alpha 7 nicotinic acetylcholine receptors has been shown to decrease the growth of certain cancers.¹²

However, these findings were from in vitro studies, and the concerns they raised have not been reflected in in vivo studies. Despite having been on the market for 30 years, nicotine replacement therapy has as yet not been associated with any “real world” increase in cancer risk.

Smoking is one of the leading risk factors for cervical cancer, and nicotine itself may play a contributing role. Nicotine has been shown to increase cellular proliferation in cervical cancer.¹³ Some evidence suggests that it may also play a role in the lymphogenic metastasis of cervical cancer.¹³

Cardiovascular disease. Nicotine has been linked to cardiovascular disease. It directly affects the heart’s rate and rhythm via nicotinic acetylcholine receptors in the peripheral autonomic nervous system. It impairs endothelial-dependent dilation of blood vessels in response to nitric oxide, and this inhibition in the coronary arteries may contribute to smoking-related heart disease.^14,15 Nicotine has also been shown to raise serum cholesterol levels, increase clot formation, and contribute to plaque formation by increasing vascular smooth muscle.¹⁴

Possible teratogenic effect. There is some theoretical concern regarding exposure to nicotine in utero, as nicotinic acetylcholine receptors develop before neurons, and nicotine may therefore interfere with the natural influence of acetylcholine on the development of this system.¹⁴

Consuming one vial of e-cigarette fluid could be fatal

Direct toxicity. Nicotine is toxic at high levels. The overdose potential associated with nicotine is particularly worrisome with e-cigarettes, as the nicotine solution they use is typically supplied in 5-mL, 10-mL, or 20-mL vials that range in concentration from 8.5 to 22.2 mg of nicotine per mL.¹⁶ The fatal single dose range of nicotine has been reported at 30 to 60 mg in adults and 10 mg in children and can be achieved by oral, intravenous, or transdermal absorption,¹⁶ so one vial, if consumed orally, could be fatal.

The number of calls to US poison control centers regarding e-cigarettes has increased, closely paralleling their rise in popularity. In 2010, there were only 30 e-cigarette related calls to poison control centers; in 2011 the number increased to 269, and in 2012 it had reached 459 and included one fatality that was deemed a suicide.^17–19 Even though such toxic nicotine overdoses are rare, physicians should exercise caution and avoid recommending e-cigarettes to individuals with mental confusion, psychotic disorders, or suicidality, who might consume an entire vial.

Possible positive effects? Smoking is one of the worst things that people can do to their body, but the picture is complicated by a few possible positive effects. In the brain, although smoking increases the risk of Alzheimer disease, it is associated with a lower risk of Parkinson disease. In the bowel, it increases the risk of Crohn disease but may decrease the risk of ulcerative colitis. Gahring and Rogers²⁰ pointed out that neuronal nicotinic receptors are present in nonneuronal cells throughout the body and proposed that expression of these receptors may play a role in mediating the consequences of nicotine use, both good and bad. The lesson may be that nicotine is very active in the body, its effects are complicated and still incompletely understood, and therefore we should not encourage people to inhale nicotine products ad lib.

Additives

E-cigarettes typically contain propylene glycol, flavorings, and glycerine. One study that analyzed the additive contents of e-cigarettes found that propylene glycol accounted for 66% of the fluid, glycerine 24%, and flavorings less than 0.1%.²¹ Propylene glycol is the substance typically used in theater fog machines and is used to generate the vapor in e-cigarettes. Other substances such as tobacco-specific nitrosamines and diethylene glycol have also been found in e-cigarettes in small amounts.²²

Propylene glycol, ‘generally recognized as safe’

Propylene glycol has been used in theater fog machines for years—think Phantom of the Opera. It is also widely used as a solvent in many consumer products and pharmaceuticals. The FDA classified it as “generally recognized as safe” on the basis of one study conducted in rats and monkeys over 60 years ago.²³ As other authors have noted, however, a major manufacturer of propylene glycol recommends that exposure to propylene glycol mist be avoided.^24,25 Potential concern over propylene glycol mist was heightened when it was discovered that of all industries, the entertainment business ranked first in terms of work-related asthma symptoms and had the fifth-highest rate of wheezing.^26,27

Studies conducted over the last several decades have raised numerous health concerns about the safety of propylene glycol (Table 1).^26,28–36 The studies of propylene glycol fog are particularly important, as they most closely resemble the route of exposure in e-cigarette users.

Wieslander et al²⁸ exposed 27 volunteers to propylene glycol mist for 1 minute in an aircraft simulator under training conditions. Exposures were high, ranging from 176 to 851 mg/m³ (mean = 309 mg/m³). Four volunteers who developed a cough exhibited evidence of airway obstruction as indicated by a 5% decrease in forced expiratory volume in 1 second (FEV₁), while the rest did not exhibit any change in FEV₁.

Moline et al²⁹ conducted a non-peer-reviewed study for the Actors Equity Association and the League of American Theaters and Producers of 439 actors exposed to theater fog. They found statistically significant evidence of throat and vocal cord inflammation with prolonged peak exposure to glycols and recommended that actors not be exposed to glycol concentrations exceeding 40 mg/m³.

Varughese et al²⁶ conducted a study in 101 volunteers at 19 sites. The mean concentration of glycol-based fog was much lower than that in the studies by Wieslander et al²⁸ and Moline et al,²⁹ at 0.49 mg/m³ (the maximum was 3.22 mg/m³). The investigators concluded that glycol-based fog was associated with deleterious respiratory effects and that employees’ exposure should be limited.

The health issues related to propylene glycol are unique to e-cigarettes compared with nicotine replacement therapy. Unfortunately, the most applicable data available are from studies of persons exposed to theater fog, which involved periodic exposure and likely do not emulate the deep inhalation, multiple times daily, of propylene glycol by e-cigarette smokers. A 2014 review of the chemistry of contaminants in e-cigarettes³⁷ concluded that estimated levels of propylene glycol exposure in e-cigarette users come close to the threshold limit value set by the American Conference of Governmental Industrial Hygienists, and should merit concern.

These studies and real-life experience in the theater, while limited in scope, should give physicians pause and should cause increased awareness of the possibility of e-cigarette-induced pulmonary and upper airway complications. If such complications should occur, discontinuation of vaping should be advised.

Contaminants

The issue of adulterants is common to both e-cigarettes and nicotine replacement therapy. Several unlisted substances have been found in analyzed samples of e-cigarette fluid, including tobacco-specific nitrosamines (TSNAs), diethylene glycol (found in only one e-cigarette cartridge), cotinine, anabasine, myosmine, and beta-nicotyrine.²² The tobacco-specific nitrosamines N´-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N-nitrosoanabasine, and nitrosoanatabine have been found in five e-cigarette cartridge samples from two manufacturers in amounts similar to those found in nicotine replacement products.²²

Goniewicz et al³⁸ tested the vapor generated by 12 e-cigarette brands and found trace amounts of TSNAs. NNN was present in the vapor of eight of the samples in concentrations ranging from 0.8 to 4.3 ng per 150 puffs, and NNK in the vapor of nine of the samples in concentrations ranging from 1.1 to 28.3 ng per 150 puffs. Neither NNN nor NNK was found in blank samples nor with the Nicorette inhalator tested in the same study.³⁸

Because TNSAs can be formed from nicotine and its metabolites, there is also concern that cancer-causing nitrosamines may be formed from nicotine after it is absorbed into the body (ie, endogenously). While endogenous formation of NNK from nicotine has never been demonstrated, endogenous formation of NNN has been seen in some nicotine patch users.³⁹ The presence of these nitrosamines has raised concern that e-cigarettes and nicotine replacement therapy may have carcinogenic potential. The amounts of tobacco-specific nitrosamines found in e-cigarettes are also found in some nicotine replacement products.⁴⁰

Investigators have examined a possible connection between e-cigarettes and potentially carcinogenic carbonyl compounds, including formaldehyde, acetaldehyde, and acrolein. Formaldehyde (a known carcinogen) and acetaldehyde (a potential carcinogen) have been detected in e-cigarette cartridges and vapor.^38,41–43 Acrolein, a mucosal irritant, has been found in e-cigarette vapor.^38,43 Goniewicz et al³⁸ suggested that acrolein may be formed by the heating of the glycerin contained in the e-cigarette solution.

An extensive review of the studies of possible contaminant exposures (including polycylic aromatic hydrocarbons, TSNAs, volatile organic compounds, diethylene glycol, and inorganic compounds) with e-cigarette use according to occupational hygiene standards concluded that there was no cause for concern about increased health risk.³⁷ The study by Goniewicz et al also concluded that using e-cigarettes instead of traditional cigarettes may significantly reduce exposure to some tobacco-specific toxins.³⁸

E-CIGARETTES VS NICOTINE REPLACEMENT

Traditional nicotine replacement therapy products are regulated by the FDA and therefore standardized in terms of their contents. E-cigarettes, on the other hand, are unregulated vehicles for supplying nicotine, and may pose other health risks. One such risk is related to exposure to propylene glycol, which has never been studied under conditions (in terms of mode of delivery, frequency of dosing, and total duration of exposure) that approximate the exposure associated with e-cigarettes. Furthermore, the high concentration of nicotine in e-cigarette fluid poses a real risk of toxicity and potentially fatal overdose.

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine

Nicotine replacement therapy and e-cigarettes both maintain addiction to nicotine if used in a harm-reduction strategy as a maintenance medication. Whether the ongoing nicotine addiction makes it more likely that individuals would switch back and forth between nicotine replacement and tobacco-based products is not clear. Also not known is whether e-cigarettes may serve as the “gateway drug” by which teens enter into nicotine addiction, but we believe that the potential exists, as these products are potentially more appealing in terms of the lack of pungent smell, the perception of safety, and the variety of flavors of e-cigarettes.

The efficacy of nicotine replacement therapy in improving smoking cessation has been reviewed extensively elsewhere³⁷ and is beyond the scope of this article. E-cigarettes may be appealing to many cigarette smokers because they deliver smokeless nicotine, and they more closely emulate the actual experience of smoking compared with traditional nicotine replacement therapy. Though some evidence suggests that e-cigarettes may be modestly effective in helping tobacco smokers quit nicotine, they are not FDA-approved for smoking cessation and are not marketed for that indication.⁴⁴ Medical practitioners should see them for what they are: a new nicotine product with a novel delivery system that is not approved as treatment. Because of the inherent risks involved with e-cigarettes, medical practitioners are best advised to remain neutral on the relative value of e-cigarettes and should continue to motivate patients to discontinue nicotine use altogether.

Tobacco is a dirty weed,
I like it.
It satisfies no normal need,
I like it.
It makes you thin, it makes you lean,
It takes the hair right off your bean.
It’s the worst darn stuff I’ve ever seen.
I like it.

Graham Lee Hemminger. The Penn State Froth, November 1915: 19. Courtesy of Paul J. Dzyak, Jr., Paterno Library, Pennsylvania State University, State College, PA.

All physicians recognize the harm in tobacco smoking and try to convince patients to quit for health reasons, but quitting is challenging and frustrating for both doctor and patient. Physicians can improve quitting outcomes by applying their knowledge of the physiologic basis of nicotine addiction and newer tools that are making a real difference in smoking cessation.

THE NO. 1 PREVENTABLE CAUSE OF DEATH

Tobacco use remains the single largest preventable cause of death and disease in the United States: 443,000 US adults die of smoking-related illnesses each year, or one every 8 seconds.¹ Tobacco smoking is currently responsible for 18% of all deaths and 37% of all preventable deaths. One-third of all smokers die early, with men losing 13 years of life and women losing 15 years. (See The rise and partial fall of smoking for a historical overview.)

Smoking, the leading cause of lung cancer, is also implicated in cancers of the mouth, larynx, esophagus, stomach, kidney, bladder, and cervix and has been linked to leukemia. (Though nicotine is responsible for the addictive properties of tobacco, it does not cause cancer itself: other substances in tobacco smoke, many of them byproducts of combustion, are carcinogenic.)

Running a close second to cancer as a smoking-related cause of death is cardiovascular disease, including stroke, myocardial infarction, microvascular dementia, peripheral vascular disease, and aortic aneurysm. Pulmonary and respiratory diseases, including chronic obstructive pulmonary disease, pneumonia, and asthma, are the third most common fatal smoking-related ailments.

Other medical consequences include erectile dysfunction, infertility, pregnancy complications, and low birth weight. Smoking also causes adverse surgical outcomes, poor wound healing, hip fractures, low bone density, peptic ulcer disease, and cataracts.

Smoking is estimated to cost the United States $96 billion in direct medical expenses and $97 billion in lost productivity annually.²

On the positive side, quitting smoking has health benefits at any age, and smokers who quit before age 35 have death rates similar to those in people who have never smoked.^1,3

WHY IS IT SO HARD TO QUIT?

Most smokers want to quit, and many try to—but few succeed. In the 2010 National Health Interview Surveys, 68.8% of adult smokers said they wanted to stop smoking, and 52.4% had tried to in the past year, but only 6.2% had succeeded.⁴ Many recovering alcoholics and drug addicts say that quitting tobacco was much harder than abstaining from other substances of choice.

Why is it so hard to quit?

Smoking is a classic addiction

Addictions are usually diagnosed by behavioral signs, and nicotine addiction has many of the clinical hallmarks, eg:

• Tolerance, with a trend toward increasing the potency of the dose and the frequency of smoking over time
• Mental preoccupation with smoking, as it often becomes woven into one’s daily schedule and is associated with almost everything the smoker does throughout the day. Having no cigarettes in the house can generate anxiety that is relieved only by obtaining more
• Squandering scarce financial resources on nicotine products, over time amounting to substantial sums, and since smoking rates are higher in poor people than in the affluent, these are people who can least afford it
• Withdrawal symptoms, characterized by jitteriness, irritability, headache, insomnia, anxiety, and increased appetite.

People continue to smoke despite adverse consequences such as falling asleep while smoking and setting fire to the bed or to the house, or losing digits to peripheral vascular disease. Being unable to quit and to stay off smoking is a hallmark of tobacco dependence. Relapses are often triggered by being near other smokers or seeing a billboard advertising cigarettes. Eventually, the nicotine addict comes to value and crave nicotine more than health or life itself.

Nicotine stimulates ‘reward’ centers in the brain

Nicotine is an alkaloid found in many plants (including potatoes) but in especially high concentrations in tobacco. In mammals, it is a stimulant, rapidly producing dependence and addiction.

Inhaled by smoking, nicotine is absorbed across the large alveolar surface, avoids first-pass metabolism, and is transported rapidly to the brain (Figure 1). In fact, nicotine reaches the brain less than 20 seconds after inhalation, which is slightly faster even than when drugs are injected intravenously.⁵

Tobacco smoke contains approximately 4,800 compounds, many of which activate neurotransmitter systems such as dopamine, norepinephrine, acetylcholine, glutamate, serotonin, beta-endorphin, and gamma-aminobutyric acid. The most significant of these is the dopamine reward system known as the mesoaccumbens pathway. This system is activated within seconds of smoking and produces a sense of pleasure.

Nicotine binds to nicotinic acetylcholine receptors, primarily to alpha-4, beta-2 receptors in the ventral tegmental area of the midbrain. Once this binding occurs, a neurochemical message is conveyed to the nucleus accumbens via the release of dopamine in the mesoaccumbens pathway—the final common reward pathway triggered by all drugs of abuse. Since these structures and pathways of the brain are anatomically central, the addiction is driven by the basal ganglia and midbrain, the phylogenetically oldest parts of the brain. Nicotine therefore drives its addicts to continue smoking by producing strong neurochemical rewards and by causing strongly negative reactions when discontinued.

Genetically mediated susceptibility probably contributes to addiction. People whose neurochemical pathways are easily stimulated by this drug are probably at far greater risk of addiction. Paradoxically, people who are rapid metabolizers of nicotine are at greater risk than slow metabolizers.⁶ (Nicotine is metabolized by cytochrome P450 2A6 in the liver.)

Tolerance and withdrawal

Tolerance develops with long-term use, mediated by up-regulation (increased numbers) of alpha-4, beta-2 cholinergic receptors in the ventral tegmental area. Any reduction in nicotine level causes distress because receptors are unoccupied; with more receptors, nicotine intake must increase to keep physiologic balance and avoid withdrawal. Since the half-life of nicotine is only about 2 hours, the smoker must smoke almost constantly to satisfy receptors hungry for the stimulating drug. If drug levels drop, withdrawal occurs very quickly.

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal. The cycle of pleasure, eventual tolerance, withdrawal, craving, and compulsion is biologically driven, like the drives of thirst, reproduction, and hunger. Nicotine hijacks species-sustaining reward mechanisms, leading to the malignant, compulsive disease of nicotine addiction.

Treatment doomed to fail?

Because nicotine addiction involves the midbrain, cessation strategies that rely on higher cerebral function are not likely to succeed. Counseling, common sense, and willpower simply cannot overcome the dopaminergic stimulating power or assuage the withdrawal sickness of nicotine dependence. Telling patients that smoking is bad for them misses the mark in most cases. Patients want to quit, but the drive to smoke is too powerful. Attempts to cut down rather than abstain from smoking also fail.

Nicotine is a formidable adversary for the patient and for the doctor or other health professional. Until recently, treatment was usually ineffective.

So, what does work against nicotine addiction?

PHARMACOTHERAPIES FOR SMOKING CESSATION

Nicotine replacement therapy

The oldest of the pharmacotherapies for nicotine addiction is nicotine replacement, in the form of patch, gum, lozenge, or nasal spray.

Advantages:

• Nicotine replacement therapy eliminates exposure to the other harmful compounds in tobacco, with few to none of the health risks associated with smoking.
• By delivering nicotine by a different route, nicotine replacement therapy breaks the association between smoking and feeling good. The addict is already dopamine-stimulated before putting a cigarette in the mouth, merely by association and suggestion. Using a different route of nicotine administration avoids that associative stimulation from the act of smoking, so that quitting becomes easier.
• The dose of nicotine is lower with replacement therapy than with smoking. The cigarette is the most efficient delivery mechanism for getting nicotine into the body. A smoked cigarette produces a rapid spike in plasma nicotine levels, far higher and faster than nicotine gum, nasal spray, or transdermal patch. Peak levels of plasma nicotine from nicotine replacement therapy are only 30% to 50% as high as those achieved by smoking.^7–9
• It is inexpensive.

Disadvantages:

• Nicotine replacement therapy maintains the addiction to nicotine, with its neurophysiologic distortions.
• Some patients continue nicotine replacement therapy for years.

Use of nicotine gum can be a problem because of the need for frequent administration. The gum is chewed until the user feels a tingling or peppery taste in the mouth, after which the gum must be placed inside the cheek to allow for maximal absorption of the nicotine. Once the tingling has faded, the user is to chew another piece and repeat the cycle as long as craving is perceived. On the other hand, the nicotine patch is applied once daily. Both of these products are available over-the-counter.

Caution is indicated when starting nicotine replacement therapy in those with recent myocardial infarction, angina, or arrhythmia.

Effectiveness. Nicotine replacement therapy has been shown to be as effective as bupropion (see below) but not as effective as varenicline when used in single administration form (patch, gum, lozenge, or inhaler alone). The four single-administration forms of nicotine replacement therapy are all equally efficacious. Combinations of nicotine replacement formulations have been reported to be as effective as varenicline and superior to single formulations.10

How about electronic cigarettes? Electronic cigarettes, or e-cigarettes, supply nicotine in a noncombustion vapor and are advertised as an alternative to smoking. No claim is made for reducing smoking, so the products, including the liquids involved, are not regulated by the US Food and Drug Administration (FDA). Controversy exists as to whether they actually increase the number of smokers by introducing young people to “vaping” to get nicotine. Since nicotine is still inhaled, the addictive potential remains unabated. E-cigarettes are unregulated vehicles for supplying nicotine and may pose other health risks, and there is very limited evidence to support the efficacy of e-cigarettes as aids to smoking cessation. Since no controlled study has demonstrated successful cessation of smoking with e-cigarettes, they are best regarded for now as merely another way to introduce nicotine into the body.

Bupropion

Bupropion, an antidepressant also sold as Wellbutrin SR, was approved in 1997 for use in smoking cessation under the trade name Zyban. The manufacturer, Glaxo SmithKline, learned serendipitously that depressive patients taking bupropion were able to quit smoking. After some field trials, this “new” medication was born. It was the first nonnicotine drug for tobacco dependence to gain FDA approval.

Its mechanism of action in combating smoking is unknown but is thought to be related to mild inhibition of dopamine re-uptake in the midbrain.

The drug is approved for smokers over age 18 who are smoking at least nine cigarettes daily. It requires a prescription, and the typical dose is 150 mg twice daily for 8 to 12 weeks, up to 12 months. Smoking is allowed for the first 7 days of drug use.

Contraindications include a history of seizures, concurrent use of bupropion, bulimia, anorexia, detoxification from alcohol or sedatives, use of monoamine oxidase inhibitors, and allergy to bupropion. Warnings are noted for diseases of heart, liver, or kidney; for use with selective serotonin reuptake inhibitors or tricyclic antidepressants; for pregnancy; and for adolescents because of heightened suicide risk.

Side effects. Seizure risk has been estimated at 1 in 1,000 bupropion users at dosages of up to 300 mg daily and is 10 times greater at dosages of 450 to 600 mg/day.¹¹

The most common side effect reported is insomnia, which occurs in about one-third of people who take the medication. Less common side effects include dry mouth, anxiety, and hypertension. Pretreatment screening should include a history of seizure, closed head trauma, brain surgery, stroke, and the eating disorders anorexia nervosa and bulimia. The FDA has required a boxed warning regarding the association of bupropion with psychiatric symptoms.¹²

Effectiveness. Compared with placebo, bupropion reduces withdrawal symptoms such as irritability, frustration, anger, restlessness, depression, craving, poor concentration, and urge to smoke. Bupropion SR, 150 or 300 mg per day, has been reported to lead to substantial abstinence rates when used with intensive telephone counseling. In a randomized trial,¹³ side effects were common, especially at the higher dose, but there were no serious adverse effects such as deaths or seizures.¹³

Buproprion has been found to be as efficacious in improving the odds of quitting as single forms of nicotine replacement therapy, but not as efficacious as nicotine replacement therapy forms used in combination. Bupropion does not appear to be as effective as varenicline.⁹ US Public Health Service guidelines since 2000 have included nicotine replacement therapy and sustained-release bupropion in combination.

Disadvantages. Bupropion is significantly more expensive than nicotine replacement therapy, but it is often covered by insurance when it is used for smoking cessation. Bupropion has many contraindications, produces drug-drug interactions, is often poorly tolerated, and has many side effects. Some deaths have been reported. Zyban is available by prescription only, an indicator of its relative risk, with the added drawback of higher cost to patients.

Varenicline

Varenicline (Chantix, Champix) was granted a priority review by the FDA in 2005, as it showed significantly better results than other current therapies. It was approved in 2006 and added as a first-line agent in the 2008 guidelines.¹²

Mechanism of action. A synthetic “designer” drug made for its specific purpose, the varenicline molecule is a modified version of cytisine, a naturally occurring alkaloid previously marketed as Tabex in Eastern Europe. Cytisine is a selective alpha-4, beta-2 nicotinic acetylcholine receptor partial agonist. The high-affinity alpha-4, beta-2 nicotinic acetylcholine receptors exist in the mesolimbic dopaminergic system, the reward center of the brain.¹⁴

Telling patients that smoking is bad for them usually misses the mark

Varenicline has the same mechanism of action as cytisine but penetrates the central nervous system better. This mechanism of action allows varenicline to block the attachment of the nicotine molecule to this receptor, preventing nicotine’s dominant effect. Varenicline, however, is a partial agonist, so that when it attaches itself to the receptor, it causes a partial agonist effect, which is an opening of the receptor channel to sodium ions, causing partial stimulation of the cells in the ventral tegmental area, and ultimately causing a mild release of dopamine in the nucleus accumbens.^15,16 Thus, varenicline effectively stimulates the receptor partially, while at the same time blocking the effects of nicotine.

Pharmacokinetics. After oral intake, the maximal plasma concentration of varenicline is reached in 3 to 4 hours. Food does not inhibit absorption. There is minimal hepatic metabolism, with 92% of the drug excreted unchanged in the urine. There are no known drug-drug interactions. The 24-hour half-life of varenicline allows for once-daily dosing.

Effectiveness. Several phase 2 and phase 3 studies compared varenicline with placebo and other drugs in terms of efficacy, dosing, and safety in 3,600 smokers. The initial phase 2 study, lasting 7 weeks, showed a 4-week abstinence rate of 48% with varenicline compared with 17% with placebo.¹⁷

Two phase 3 trials with 2,052 participants demonstrated that, at 12 weeks, abstinence rates were 44% with varenicline, 17% with bupropion, and 17% with placebo. At the end of 1 year, those groups again demonstrated significant differences in nicotine abstinence—22% in the varenicline group vs 15% with bupropion and 9% with placebo. Also, varenicline was superior to bupropion and placebo in reducing craving.^18,19 For those who were nicotine-free after 12 weeks of treatment, continuing varenicline for another 12 weeks boosted nicotine abstinence rates from 36% to 44% at 1 year.²⁰

Though varenicline produces a mild physiologic dependence, it is not addictive and does not produce tolerance to itself. There is no need to increase the dose over time. Three percent of patients have reported mild irritability on stopping varenicline.

In sum, varenicline has been shown to be more effective than bupropion and any of the four single formulations of nicotine replacement when they are used alone. It has not been shown to be more effective than combinations of nicotine replacement therapy.¹⁰

Safety considerations with varenicline. Psychiatric adverse events associated with varenicline have included severe depression, agitation, and suicidal behavior—including completed suicide. Motor vehicle accidents and erratic behaviors have led to a ban on varenicline use by airline pilots, truck drivers, and maritime workers. Skin rashes (including Stevens-Johnson syndrome), renal failure, and cataracts have also been reported. Safety has not been established with schizophrenia, bipolar disorder, or major depression. The physician should ask about prior psychiatric history, illnesses, and reactions before prescribing varenicline. Generally, it is prudent to avoid varenicline in patients with a significant psychiatric history.

Nausea and sleep disturbances such as vivid dreams and insomnia are the most frequently reported side effects.

Black box warnings with bupropion and varenicline. In July 2009, the FDA issued boxed warnings for bupropion SR and for varenicline for smoking cessation because of reports of neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, attempted suicide, and completed suicide.²¹ These can occur in people with or without a history of mental illness, and whether the patient has stopped smoking or not. Providers should inform patients, family members, and caregivers about the potential for these symptoms and what to do if symptoms develop—ie, stop the medication immediately and contact the health care provider.

Patients should also be told  to use caution when driving, operating machinery, or performing hazardous activities until they know how the medication will affect them.²¹

When prescribing varenicline. Advise patients to set a “quit date” 7 days after starting varenicline—they can continue smoking for the first 7 days on the drug. The starter packet for varenicline comes as 0.5 mg daily for 3 days, then twice daily for 2 days; the dose increases to 1 mg twice daily thereafter. Smokers report that it is much easier to quit after 7 days on varenicline.

Combinations of nicotine replacement are as effective as varenicline and are superior to single formulations

Maintenance packs are available for 1 month of daily dosing. Generally, one starter pack is prescribed, with a second prescription for continuing packs for 2 to 5 more months. Varenicline is best taken with a full glass of water. If the smoker abstains for the first 3 months of therapy, it is best to prescribe an additional 3 months of medication to improve long-term abstinence from nicotine. With nausea or renal disease, lower the dose. Avoid prescribing varenicline for the elderly, teens, and pregnant women.

Varenicline is available only by prescription, and no generic equivalent is available.

WHEN IT’S TIME TO QUIT

A useful prescribing plan is:

• For most people, begin with nicotine patches plus gum
• If nicotine replacement therapy fails, prescribe varenicline
• Prescribe bupropion for patients with depression or if varenicline fails.

According to the US Public Health Service guideline,¹² in a meta-analysis comparing various tobacco cessation medications with placebo and nicotine patch, the combination of nicotine patch (> 14 weeks) plus gum was 3.6 times as effective as placebo and 1.9 times as effective as nicotine patch alone. Varenicline at 2 mg per day was 3.1 times as effective as placebo and 1.6 times as effective as nicotine patch alone. Therefore, the combination of nicotine patch and gum is an inexpensive yet effective way to begin a course of smoking cessation therapy.

Behavioral counseling

Timing is important to successful quitting. Patients generally know when it’s a good time to quit—and when it’s not. Avoid trying to get patients to quit when they are stressed, overly busy, fatigued, or anxious. Try to get the patient to set a time to quit that’s ideal, and then encourage the patient to stick to it. For example, scheduling the quit day on a celebration, anniversary, or birthday gives that date added significance and enhances motivation. Follow the patient frequently for 6 to 12 months with intense monitoring and encouragement, and to assess for any adverse effects of medication.

In July 2009, the FDA issued boxed warnings for bupropion SR and for varenicline because of neuropsychiatric symptoms

The 2008 update to the Public Health Service Clinical Practice Guidelines on treating tobacco use and dependence concludes that counseling and medication are each effective alone in increasing smoking cessation and are even more effective when used together.¹² Even very brief, 3-minute discussions and encouragement have been shown to be helpful. The Public Health Service evidence-based clinical practice guideline on cessation states that brief advice by medical providers to quit smoking is an effective intervention.¹²

Doctors who show great interest in smoking cessation seem to be more effective in persuading patients to quit. They should take note of smoking rather than ignoring it. A modified version of the CAGE questionnaire to assess problem drinking is recommended as a tool to assess patients’ smoking behavior and initiate a discussion about it (Table 1).²² Emphasize the health and financial costs to the patient. Try to form a therapeutic alliance with the patient against smoking: “Let’s see what we can do about this problem.” Be positive and optimistic in offering help with counseling, support, and medications.

Caution smokers against switching to “light” tar and nicotine cigarettes, as controlled experiments have failed to show consistent reductions in the amounts of tar and nicotine these products deliver into the lungs. Smokers also appear to compensate or adapt their smoking habits to increase the yield from these products. There is insufficient evidence to support the supposed health benefits of such low-yield smoking products.²³

Always refer the patient for counseling with the pharmaceutical company help line or with a supported quit line. Some manufacturers of smoking cessation medications offer counseling or web-based support for patients trying to quit. For example, patients who are prescribed varenicline are offered the GETQUIT Plan, a free program that includes online education, tracking of progress, and “check-ins with slip-up support.” These services are often underused yet represent a ready source of helpful support.

If relapses occur, encourage the patient to keep trying again and again, as it may take several attempts to succeed.

Quit lines

To help smokers and other tobacco users quit, all states now have a toll-free cessation quit line, a telephone service accessible through a national toll-free number (1-800-QUIT-NOW). Quit lines also can be a referral source for health care providers who might not have the time or staff to provide all of the steps in the recommended “five-A” cessation counseling model,¹² ie:

• Ask about tobacco use
• Advise to quit
• Assess willingness to make a quit attempt
• Assist in quit attempt
• Arrange follow-up.

Quit lines have been shown to improve outcomes when compared with people trying to stop on their own.¹² Quit line services have evolved from their modest beginnings as providers of information and counseling to a level at which  in many states, evidence-based medications are provided through quit lines.^13,24 Medication use, coupled with quit line counseling intervention, increases the likelihood of tobacco abstinence and is consistent with US Public Health Service guideline recommendations that all tobacco users should be offered at least one medication as part of their quit attempt.¹²

WOMEN SMOKERS HAVE UNIQUE HEALTH RISKS

Women have unique health risks arising from smoking: low-birth-weight babies, sudden infant death syndrome, cervical cancer, and an increasing rate of lung cancer. In general, women have poorer responses to nicotine replacement therapy, are more concerned about gaining weight after quitting, and demonstrate more mood lability after quitting. Women seem more energized by the taste, smell, and overall sensations involved in smoking.

Weight gain will occur when quitting smoking; this is hard to overcome. More exercise may help, and a trial of bupropion with nicotine replacement therapy may mitigate weight gain.

Women who are pregnant present a special challenge when it comes to weighing the benefit of medications against continued smoking. For pregnant women who want to quit smoking, the best treatment is counseling without nicotine replacement or other pharmacotherapy. There are inadequate data for the use of varenicline or bupropion in pregnancy. If medication is needed, start nicotine replacement therapy early in pregnancy, as its risk is the same as or less than the smoking risk to the fetus.

Smokers say it is much easier to quit after 7 days on varenicline

The US Public Health Service guideline provides a useful discussion and bibliography related to this topic.¹² All of the FDA-approved medications for tobacco cessation carry an FDA pregnancy category designation of C or D—ie, not recommended for use by pregnant women. These designations are not absolute contraindications and do allow for use in life-threatening situations or when other treatment modalities have failed. Some clinicians and their patients may decide that the potential for fetal harm, including fetal death, with continued smoking is high enough to warrant use of medications.

A careful and thorough discussion of the risks and benefits is recommended between the patient and her physician regarding this issue.

A CALL TO ARMS

The statistics are incontrovertible but do not tell the whole story. The day-to-day practices of physicians bear witness to the suffering that compulsive smoking creates for the smoker. As in all addictions, those around the addict suffer as well, from secondary smoke but also from fear and anxiety about premature loss of their loved ones. Smoking causes suffering and early death, and it is vitally important that doctors—the front-line troops—take up the fight against it as America’s number-one preventable cause of health problems and death.

To be effective champions in the public health fight against smoking, doctors must develop an understanding of compulsive smoking as a biologically driven process of addiction. The smoker attempting to quit is literally in the fight of his or her life and needs emotional support, cognitive-behavioral tools, and state-of-the-art pharmacology to overcome the slow destruction caused by the “dirty weed.”

Tobacco is a dirty weed,
I like it.
It satisfies no normal need,
I like it.
It makes you thin, it makes you lean,
It takes the hair right off your bean.
It’s the worst darn stuff I’ve ever seen.
I like it.

Graham Lee Hemminger. The Penn State Froth, November 1915: 19. Courtesy of Paul J. Dzyak, Jr., Paterno Library, Pennsylvania State University, State College, PA.

All physicians recognize the harm in tobacco smoking and try to convince patients to quit for health reasons, but quitting is challenging and frustrating for both doctor and patient. Physicians can improve quitting outcomes by applying their knowledge of the physiologic basis of nicotine addiction and newer tools that are making a real difference in smoking cessation.

THE NO. 1 PREVENTABLE CAUSE OF DEATH

Tobacco use remains the single largest preventable cause of death and disease in the United States: 443,000 US adults die of smoking-related illnesses each year, or one every 8 seconds.¹ Tobacco smoking is currently responsible for 18% of all deaths and 37% of all preventable deaths. One-third of all smokers die early, with men losing 13 years of life and women losing 15 years. (See The rise and partial fall of smoking for a historical overview.)

Smoking, the leading cause of lung cancer, is also implicated in cancers of the mouth, larynx, esophagus, stomach, kidney, bladder, and cervix and has been linked to leukemia. (Though nicotine is responsible for the addictive properties of tobacco, it does not cause cancer itself: other substances in tobacco smoke, many of them byproducts of combustion, are carcinogenic.)

Running a close second to cancer as a smoking-related cause of death is cardiovascular disease, including stroke, myocardial infarction, microvascular dementia, peripheral vascular disease, and aortic aneurysm. Pulmonary and respiratory diseases, including chronic obstructive pulmonary disease, pneumonia, and asthma, are the third most common fatal smoking-related ailments.

Other medical consequences include erectile dysfunction, infertility, pregnancy complications, and low birth weight. Smoking also causes adverse surgical outcomes, poor wound healing, hip fractures, low bone density, peptic ulcer disease, and cataracts.

Smoking is estimated to cost the United States $96 billion in direct medical expenses and $97 billion in lost productivity annually.²

On the positive side, quitting smoking has health benefits at any age, and smokers who quit before age 35 have death rates similar to those in people who have never smoked.^1,3

WHY IS IT SO HARD TO QUIT?

Most smokers want to quit, and many try to—but few succeed. In the 2010 National Health Interview Surveys, 68.8% of adult smokers said they wanted to stop smoking, and 52.4% had tried to in the past year, but only 6.2% had succeeded.⁴ Many recovering alcoholics and drug addicts say that quitting tobacco was much harder than abstaining from other substances of choice.

Why is it so hard to quit?

Smoking is a classic addiction

Addictions are usually diagnosed by behavioral signs, and nicotine addiction has many of the clinical hallmarks, eg:

• Tolerance, with a trend toward increasing the potency of the dose and the frequency of smoking over time
• Mental preoccupation with smoking, as it often becomes woven into one’s daily schedule and is associated with almost everything the smoker does throughout the day. Having no cigarettes in the house can generate anxiety that is relieved only by obtaining more
• Squandering scarce financial resources on nicotine products, over time amounting to substantial sums, and since smoking rates are higher in poor people than in the affluent, these are people who can least afford it
• Withdrawal symptoms, characterized by jitteriness, irritability, headache, insomnia, anxiety, and increased appetite.

People continue to smoke despite adverse consequences such as falling asleep while smoking and setting fire to the bed or to the house, or losing digits to peripheral vascular disease. Being unable to quit and to stay off smoking is a hallmark of tobacco dependence. Relapses are often triggered by being near other smokers or seeing a billboard advertising cigarettes. Eventually, the nicotine addict comes to value and crave nicotine more than health or life itself.

Nicotine stimulates ‘reward’ centers in the brain

Nicotine is an alkaloid found in many plants (including potatoes) but in especially high concentrations in tobacco. In mammals, it is a stimulant, rapidly producing dependence and addiction.

Inhaled by smoking, nicotine is absorbed across the large alveolar surface, avoids first-pass metabolism, and is transported rapidly to the brain (Figure 1). In fact, nicotine reaches the brain less than 20 seconds after inhalation, which is slightly faster even than when drugs are injected intravenously.⁵

Tobacco smoke contains approximately 4,800 compounds, many of which activate neurotransmitter systems such as dopamine, norepinephrine, acetylcholine, glutamate, serotonin, beta-endorphin, and gamma-aminobutyric acid. The most significant of these is the dopamine reward system known as the mesoaccumbens pathway. This system is activated within seconds of smoking and produces a sense of pleasure.

Nicotine binds to nicotinic acetylcholine receptors, primarily to alpha-4, beta-2 receptors in the ventral tegmental area of the midbrain. Once this binding occurs, a neurochemical message is conveyed to the nucleus accumbens via the release of dopamine in the mesoaccumbens pathway—the final common reward pathway triggered by all drugs of abuse. Since these structures and pathways of the brain are anatomically central, the addiction is driven by the basal ganglia and midbrain, the phylogenetically oldest parts of the brain. Nicotine therefore drives its addicts to continue smoking by producing strong neurochemical rewards and by causing strongly negative reactions when discontinued.

Genetically mediated susceptibility probably contributes to addiction. People whose neurochemical pathways are easily stimulated by this drug are probably at far greater risk of addiction. Paradoxically, people who are rapid metabolizers of nicotine are at greater risk than slow metabolizers.⁶ (Nicotine is metabolized by cytochrome P450 2A6 in the liver.)

Tolerance and withdrawal

Tolerance develops with long-term use, mediated by up-regulation (increased numbers) of alpha-4, beta-2 cholinergic receptors in the ventral tegmental area. Any reduction in nicotine level causes distress because receptors are unoccupied; with more receptors, nicotine intake must increase to keep physiologic balance and avoid withdrawal. Since the half-life of nicotine is only about 2 hours, the smoker must smoke almost constantly to satisfy receptors hungry for the stimulating drug. If drug levels drop, withdrawal occurs very quickly.

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal. The cycle of pleasure, eventual tolerance, withdrawal, craving, and compulsion is biologically driven, like the drives of thirst, reproduction, and hunger. Nicotine hijacks species-sustaining reward mechanisms, leading to the malignant, compulsive disease of nicotine addiction.

Treatment doomed to fail?

Because nicotine addiction involves the midbrain, cessation strategies that rely on higher cerebral function are not likely to succeed. Counseling, common sense, and willpower simply cannot overcome the dopaminergic stimulating power or assuage the withdrawal sickness of nicotine dependence. Telling patients that smoking is bad for them misses the mark in most cases. Patients want to quit, but the drive to smoke is too powerful. Attempts to cut down rather than abstain from smoking also fail.

Nicotine is a formidable adversary for the patient and for the doctor or other health professional. Until recently, treatment was usually ineffective.

So, what does work against nicotine addiction?

PHARMACOTHERAPIES FOR SMOKING CESSATION

Nicotine replacement therapy

The oldest of the pharmacotherapies for nicotine addiction is nicotine replacement, in the form of patch, gum, lozenge, or nasal spray.

Advantages:

• Nicotine replacement therapy eliminates exposure to the other harmful compounds in tobacco, with few to none of the health risks associated with smoking.
• By delivering nicotine by a different route, nicotine replacement therapy breaks the association between smoking and feeling good. The addict is already dopamine-stimulated before putting a cigarette in the mouth, merely by association and suggestion. Using a different route of nicotine administration avoids that associative stimulation from the act of smoking, so that quitting becomes easier.
• The dose of nicotine is lower with replacement therapy than with smoking. The cigarette is the most efficient delivery mechanism for getting nicotine into the body. A smoked cigarette produces a rapid spike in plasma nicotine levels, far higher and faster than nicotine gum, nasal spray, or transdermal patch. Peak levels of plasma nicotine from nicotine replacement therapy are only 30% to 50% as high as those achieved by smoking.^7–9
• It is inexpensive.

Disadvantages:

• Nicotine replacement therapy maintains the addiction to nicotine, with its neurophysiologic distortions.
• Some patients continue nicotine replacement therapy for years.

Use of nicotine gum can be a problem because of the need for frequent administration. The gum is chewed until the user feels a tingling or peppery taste in the mouth, after which the gum must be placed inside the cheek to allow for maximal absorption of the nicotine. Once the tingling has faded, the user is to chew another piece and repeat the cycle as long as craving is perceived. On the other hand, the nicotine patch is applied once daily. Both of these products are available over-the-counter.

Caution is indicated when starting nicotine replacement therapy in those with recent myocardial infarction, angina, or arrhythmia.

Effectiveness. Nicotine replacement therapy has been shown to be as effective as bupropion (see below) but not as effective as varenicline when used in single administration form (patch, gum, lozenge, or inhaler alone). The four single-administration forms of nicotine replacement therapy are all equally efficacious. Combinations of nicotine replacement formulations have been reported to be as effective as varenicline and superior to single formulations.10

How about electronic cigarettes? Electronic cigarettes, or e-cigarettes, supply nicotine in a noncombustion vapor and are advertised as an alternative to smoking. No claim is made for reducing smoking, so the products, including the liquids involved, are not regulated by the US Food and Drug Administration (FDA). Controversy exists as to whether they actually increase the number of smokers by introducing young people to “vaping” to get nicotine. Since nicotine is still inhaled, the addictive potential remains unabated. E-cigarettes are unregulated vehicles for supplying nicotine and may pose other health risks, and there is very limited evidence to support the efficacy of e-cigarettes as aids to smoking cessation. Since no controlled study has demonstrated successful cessation of smoking with e-cigarettes, they are best regarded for now as merely another way to introduce nicotine into the body.

Bupropion

Bupropion, an antidepressant also sold as Wellbutrin SR, was approved in 1997 for use in smoking cessation under the trade name Zyban. The manufacturer, Glaxo SmithKline, learned serendipitously that depressive patients taking bupropion were able to quit smoking. After some field trials, this “new” medication was born. It was the first nonnicotine drug for tobacco dependence to gain FDA approval.

Its mechanism of action in combating smoking is unknown but is thought to be related to mild inhibition of dopamine re-uptake in the midbrain.

The drug is approved for smokers over age 18 who are smoking at least nine cigarettes daily. It requires a prescription, and the typical dose is 150 mg twice daily for 8 to 12 weeks, up to 12 months. Smoking is allowed for the first 7 days of drug use.

Contraindications include a history of seizures, concurrent use of bupropion, bulimia, anorexia, detoxification from alcohol or sedatives, use of monoamine oxidase inhibitors, and allergy to bupropion. Warnings are noted for diseases of heart, liver, or kidney; for use with selective serotonin reuptake inhibitors or tricyclic antidepressants; for pregnancy; and for adolescents because of heightened suicide risk.

Side effects. Seizure risk has been estimated at 1 in 1,000 bupropion users at dosages of up to 300 mg daily and is 10 times greater at dosages of 450 to 600 mg/day.¹¹

The most common side effect reported is insomnia, which occurs in about one-third of people who take the medication. Less common side effects include dry mouth, anxiety, and hypertension. Pretreatment screening should include a history of seizure, closed head trauma, brain surgery, stroke, and the eating disorders anorexia nervosa and bulimia. The FDA has required a boxed warning regarding the association of bupropion with psychiatric symptoms.¹²

Effectiveness. Compared with placebo, bupropion reduces withdrawal symptoms such as irritability, frustration, anger, restlessness, depression, craving, poor concentration, and urge to smoke. Bupropion SR, 150 or 300 mg per day, has been reported to lead to substantial abstinence rates when used with intensive telephone counseling. In a randomized trial,¹³ side effects were common, especially at the higher dose, but there were no serious adverse effects such as deaths or seizures.¹³

Buproprion has been found to be as efficacious in improving the odds of quitting as single forms of nicotine replacement therapy, but not as efficacious as nicotine replacement therapy forms used in combination. Bupropion does not appear to be as effective as varenicline.⁹ US Public Health Service guidelines since 2000 have included nicotine replacement therapy and sustained-release bupropion in combination.

Disadvantages. Bupropion is significantly more expensive than nicotine replacement therapy, but it is often covered by insurance when it is used for smoking cessation. Bupropion has many contraindications, produces drug-drug interactions, is often poorly tolerated, and has many side effects. Some deaths have been reported. Zyban is available by prescription only, an indicator of its relative risk, with the added drawback of higher cost to patients.

Varenicline

Varenicline (Chantix, Champix) was granted a priority review by the FDA in 2005, as it showed significantly better results than other current therapies. It was approved in 2006 and added as a first-line agent in the 2008 guidelines.¹²

Mechanism of action. A synthetic “designer” drug made for its specific purpose, the varenicline molecule is a modified version of cytisine, a naturally occurring alkaloid previously marketed as Tabex in Eastern Europe. Cytisine is a selective alpha-4, beta-2 nicotinic acetylcholine receptor partial agonist. The high-affinity alpha-4, beta-2 nicotinic acetylcholine receptors exist in the mesolimbic dopaminergic system, the reward center of the brain.¹⁴

Telling patients that smoking is bad for them usually misses the mark

Varenicline has the same mechanism of action as cytisine but penetrates the central nervous system better. This mechanism of action allows varenicline to block the attachment of the nicotine molecule to this receptor, preventing nicotine’s dominant effect. Varenicline, however, is a partial agonist, so that when it attaches itself to the receptor, it causes a partial agonist effect, which is an opening of the receptor channel to sodium ions, causing partial stimulation of the cells in the ventral tegmental area, and ultimately causing a mild release of dopamine in the nucleus accumbens.^15,16 Thus, varenicline effectively stimulates the receptor partially, while at the same time blocking the effects of nicotine.

Pharmacokinetics. After oral intake, the maximal plasma concentration of varenicline is reached in 3 to 4 hours. Food does not inhibit absorption. There is minimal hepatic metabolism, with 92% of the drug excreted unchanged in the urine. There are no known drug-drug interactions. The 24-hour half-life of varenicline allows for once-daily dosing.

Effectiveness. Several phase 2 and phase 3 studies compared varenicline with placebo and other drugs in terms of efficacy, dosing, and safety in 3,600 smokers. The initial phase 2 study, lasting 7 weeks, showed a 4-week abstinence rate of 48% with varenicline compared with 17% with placebo.¹⁷

Two phase 3 trials with 2,052 participants demonstrated that, at 12 weeks, abstinence rates were 44% with varenicline, 17% with bupropion, and 17% with placebo. At the end of 1 year, those groups again demonstrated significant differences in nicotine abstinence—22% in the varenicline group vs 15% with bupropion and 9% with placebo. Also, varenicline was superior to bupropion and placebo in reducing craving.^18,19 For those who were nicotine-free after 12 weeks of treatment, continuing varenicline for another 12 weeks boosted nicotine abstinence rates from 36% to 44% at 1 year.²⁰

Though varenicline produces a mild physiologic dependence, it is not addictive and does not produce tolerance to itself. There is no need to increase the dose over time. Three percent of patients have reported mild irritability on stopping varenicline.

In sum, varenicline has been shown to be more effective than bupropion and any of the four single formulations of nicotine replacement when they are used alone. It has not been shown to be more effective than combinations of nicotine replacement therapy.¹⁰

Safety considerations with varenicline. Psychiatric adverse events associated with varenicline have included severe depression, agitation, and suicidal behavior—including completed suicide. Motor vehicle accidents and erratic behaviors have led to a ban on varenicline use by airline pilots, truck drivers, and maritime workers. Skin rashes (including Stevens-Johnson syndrome), renal failure, and cataracts have also been reported. Safety has not been established with schizophrenia, bipolar disorder, or major depression. The physician should ask about prior psychiatric history, illnesses, and reactions before prescribing varenicline. Generally, it is prudent to avoid varenicline in patients with a significant psychiatric history.

Nausea and sleep disturbances such as vivid dreams and insomnia are the most frequently reported side effects.

Black box warnings with bupropion and varenicline. In July 2009, the FDA issued boxed warnings for bupropion SR and for varenicline for smoking cessation because of reports of neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, attempted suicide, and completed suicide.²¹ These can occur in people with or without a history of mental illness, and whether the patient has stopped smoking or not. Providers should inform patients, family members, and caregivers about the potential for these symptoms and what to do if symptoms develop—ie, stop the medication immediately and contact the health care provider.

Patients should also be told  to use caution when driving, operating machinery, or performing hazardous activities until they know how the medication will affect them.²¹

When prescribing varenicline. Advise patients to set a “quit date” 7 days after starting varenicline—they can continue smoking for the first 7 days on the drug. The starter packet for varenicline comes as 0.5 mg daily for 3 days, then twice daily for 2 days; the dose increases to 1 mg twice daily thereafter. Smokers report that it is much easier to quit after 7 days on varenicline.

Combinations of nicotine replacement are as effective as varenicline and are superior to single formulations

Maintenance packs are available for 1 month of daily dosing. Generally, one starter pack is prescribed, with a second prescription for continuing packs for 2 to 5 more months. Varenicline is best taken with a full glass of water. If the smoker abstains for the first 3 months of therapy, it is best to prescribe an additional 3 months of medication to improve long-term abstinence from nicotine. With nausea or renal disease, lower the dose. Avoid prescribing varenicline for the elderly, teens, and pregnant women.

Varenicline is available only by prescription, and no generic equivalent is available.

WHEN IT’S TIME TO QUIT

A useful prescribing plan is:

• For most people, begin with nicotine patches plus gum
• If nicotine replacement therapy fails, prescribe varenicline
• Prescribe bupropion for patients with depression or if varenicline fails.

According to the US Public Health Service guideline,¹² in a meta-analysis comparing various tobacco cessation medications with placebo and nicotine patch, the combination of nicotine patch (> 14 weeks) plus gum was 3.6 times as effective as placebo and 1.9 times as effective as nicotine patch alone. Varenicline at 2 mg per day was 3.1 times as effective as placebo and 1.6 times as effective as nicotine patch alone. Therefore, the combination of nicotine patch and gum is an inexpensive yet effective way to begin a course of smoking cessation therapy.

Behavioral counseling

Timing is important to successful quitting. Patients generally know when it’s a good time to quit—and when it’s not. Avoid trying to get patients to quit when they are stressed, overly busy, fatigued, or anxious. Try to get the patient to set a time to quit that’s ideal, and then encourage the patient to stick to it. For example, scheduling the quit day on a celebration, anniversary, or birthday gives that date added significance and enhances motivation. Follow the patient frequently for 6 to 12 months with intense monitoring and encouragement, and to assess for any adverse effects of medication.

In July 2009, the FDA issued boxed warnings for bupropion SR and for varenicline because of neuropsychiatric symptoms

The 2008 update to the Public Health Service Clinical Practice Guidelines on treating tobacco use and dependence concludes that counseling and medication are each effective alone in increasing smoking cessation and are even more effective when used together.¹² Even very brief, 3-minute discussions and encouragement have been shown to be helpful. The Public Health Service evidence-based clinical practice guideline on cessation states that brief advice by medical providers to quit smoking is an effective intervention.¹²

Doctors who show great interest in smoking cessation seem to be more effective in persuading patients to quit. They should take note of smoking rather than ignoring it. A modified version of the CAGE questionnaire to assess problem drinking is recommended as a tool to assess patients’ smoking behavior and initiate a discussion about it (Table 1).²² Emphasize the health and financial costs to the patient. Try to form a therapeutic alliance with the patient against smoking: “Let’s see what we can do about this problem.” Be positive and optimistic in offering help with counseling, support, and medications.

Caution smokers against switching to “light” tar and nicotine cigarettes, as controlled experiments have failed to show consistent reductions in the amounts of tar and nicotine these products deliver into the lungs. Smokers also appear to compensate or adapt their smoking habits to increase the yield from these products. There is insufficient evidence to support the supposed health benefits of such low-yield smoking products.²³

Always refer the patient for counseling with the pharmaceutical company help line or with a supported quit line. Some manufacturers of smoking cessation medications offer counseling or web-based support for patients trying to quit. For example, patients who are prescribed varenicline are offered the GETQUIT Plan, a free program that includes online education, tracking of progress, and “check-ins with slip-up support.” These services are often underused yet represent a ready source of helpful support.

If relapses occur, encourage the patient to keep trying again and again, as it may take several attempts to succeed.

Quit lines

To help smokers and other tobacco users quit, all states now have a toll-free cessation quit line, a telephone service accessible through a national toll-free number (1-800-QUIT-NOW). Quit lines also can be a referral source for health care providers who might not have the time or staff to provide all of the steps in the recommended “five-A” cessation counseling model,¹² ie:

• Ask about tobacco use
• Advise to quit
• Assess willingness to make a quit attempt
• Assist in quit attempt
• Arrange follow-up.

Quit lines have been shown to improve outcomes when compared with people trying to stop on their own.¹² Quit line services have evolved from their modest beginnings as providers of information and counseling to a level at which  in many states, evidence-based medications are provided through quit lines.^13,24 Medication use, coupled with quit line counseling intervention, increases the likelihood of tobacco abstinence and is consistent with US Public Health Service guideline recommendations that all tobacco users should be offered at least one medication as part of their quit attempt.¹²

WOMEN SMOKERS HAVE UNIQUE HEALTH RISKS

Women have unique health risks arising from smoking: low-birth-weight babies, sudden infant death syndrome, cervical cancer, and an increasing rate of lung cancer. In general, women have poorer responses to nicotine replacement therapy, are more concerned about gaining weight after quitting, and demonstrate more mood lability after quitting. Women seem more energized by the taste, smell, and overall sensations involved in smoking.

Weight gain will occur when quitting smoking; this is hard to overcome. More exercise may help, and a trial of bupropion with nicotine replacement therapy may mitigate weight gain.

Women who are pregnant present a special challenge when it comes to weighing the benefit of medications against continued smoking. For pregnant women who want to quit smoking, the best treatment is counseling without nicotine replacement or other pharmacotherapy. There are inadequate data for the use of varenicline or bupropion in pregnancy. If medication is needed, start nicotine replacement therapy early in pregnancy, as its risk is the same as or less than the smoking risk to the fetus.

Smokers say it is much easier to quit after 7 days on varenicline

The US Public Health Service guideline provides a useful discussion and bibliography related to this topic.¹² All of the FDA-approved medications for tobacco cessation carry an FDA pregnancy category designation of C or D—ie, not recommended for use by pregnant women. These designations are not absolute contraindications and do allow for use in life-threatening situations or when other treatment modalities have failed. Some clinicians and their patients may decide that the potential for fetal harm, including fetal death, with continued smoking is high enough to warrant use of medications.

A careful and thorough discussion of the risks and benefits is recommended between the patient and her physician regarding this issue.

A CALL TO ARMS

The statistics are incontrovertible but do not tell the whole story. The day-to-day practices of physicians bear witness to the suffering that compulsive smoking creates for the smoker. As in all addictions, those around the addict suffer as well, from secondary smoke but also from fear and anxiety about premature loss of their loved ones. Smoking causes suffering and early death, and it is vitally important that doctors—the front-line troops—take up the fight against it as America’s number-one preventable cause of health problems and death.

To be effective champions in the public health fight against smoking, doctors must develop an understanding of compulsive smoking as a biologically driven process of addiction. The smoker attempting to quit is literally in the fight of his or her life and needs emotional support, cognitive-behavioral tools, and state-of-the-art pharmacology to overcome the slow destruction caused by the “dirty weed.”

Tobacco is a dirty weed,
I like it.
It satisfies no normal need,
I like it.
It makes you thin, it makes you lean,
It takes the hair right off your bean.
It’s the worst darn stuff I’ve ever seen.
I like it.

Graham Lee Hemminger. The Penn State Froth, November 1915: 19. Courtesy of Paul J. Dzyak, Jr., Paterno Library, Pennsylvania State University, State College, PA.

All physicians recognize the harm in tobacco smoking and try to convince patients to quit for health reasons, but quitting is challenging and frustrating for both doctor and patient. Physicians can improve quitting outcomes by applying their knowledge of the physiologic basis of nicotine addiction and newer tools that are making a real difference in smoking cessation.

THE NO. 1 PREVENTABLE CAUSE OF DEATH

Tobacco use remains the single largest preventable cause of death and disease in the United States: 443,000 US adults die of smoking-related illnesses each year, or one every 8 seconds.¹ Tobacco smoking is currently responsible for 18% of all deaths and 37% of all preventable deaths. One-third of all smokers die early, with men losing 13 years of life and women losing 15 years. (See The rise and partial fall of smoking for a historical overview.)

Smoking, the leading cause of lung cancer, is also implicated in cancers of the mouth, larynx, esophagus, stomach, kidney, bladder, and cervix and has been linked to leukemia. (Though nicotine is responsible for the addictive properties of tobacco, it does not cause cancer itself: other substances in tobacco smoke, many of them byproducts of combustion, are carcinogenic.)

Running a close second to cancer as a smoking-related cause of death is cardiovascular disease, including stroke, myocardial infarction, microvascular dementia, peripheral vascular disease, and aortic aneurysm. Pulmonary and respiratory diseases, including chronic obstructive pulmonary disease, pneumonia, and asthma, are the third most common fatal smoking-related ailments.

Other medical consequences include erectile dysfunction, infertility, pregnancy complications, and low birth weight. Smoking also causes adverse surgical outcomes, poor wound healing, hip fractures, low bone density, peptic ulcer disease, and cataracts.

Smoking is estimated to cost the United States $96 billion in direct medical expenses and $97 billion in lost productivity annually.²

On the positive side, quitting smoking has health benefits at any age, and smokers who quit before age 35 have death rates similar to those in people who have never smoked.^1,3

WHY IS IT SO HARD TO QUIT?

Most smokers want to quit, and many try to—but few succeed. In the 2010 National Health Interview Surveys, 68.8% of adult smokers said they wanted to stop smoking, and 52.4% had tried to in the past year, but only 6.2% had succeeded.⁴ Many recovering alcoholics and drug addicts say that quitting tobacco was much harder than abstaining from other substances of choice.

Why is it so hard to quit?

Smoking is a classic addiction

Addictions are usually diagnosed by behavioral signs, and nicotine addiction has many of the clinical hallmarks, eg:

• Tolerance, with a trend toward increasing the potency of the dose and the frequency of smoking over time
• Mental preoccupation with smoking, as it often becomes woven into one’s daily schedule and is associated with almost everything the smoker does throughout the day. Having no cigarettes in the house can generate anxiety that is relieved only by obtaining more
• Squandering scarce financial resources on nicotine products, over time amounting to substantial sums, and since smoking rates are higher in poor people than in the affluent, these are people who can least afford it
• Withdrawal symptoms, characterized by jitteriness, irritability, headache, insomnia, anxiety, and increased appetite.

People continue to smoke despite adverse consequences such as falling asleep while smoking and setting fire to the bed or to the house, or losing digits to peripheral vascular disease. Being unable to quit and to stay off smoking is a hallmark of tobacco dependence. Relapses are often triggered by being near other smokers or seeing a billboard advertising cigarettes. Eventually, the nicotine addict comes to value and crave nicotine more than health or life itself.

Nicotine stimulates ‘reward’ centers in the brain

Nicotine is an alkaloid found in many plants (including potatoes) but in especially high concentrations in tobacco. In mammals, it is a stimulant, rapidly producing dependence and addiction.

Inhaled by smoking, nicotine is absorbed across the large alveolar surface, avoids first-pass metabolism, and is transported rapidly to the brain (Figure 1). In fact, nicotine reaches the brain less than 20 seconds after inhalation, which is slightly faster even than when drugs are injected intravenously.⁵

Tobacco smoke contains approximately 4,800 compounds, many of which activate neurotransmitter systems such as dopamine, norepinephrine, acetylcholine, glutamate, serotonin, beta-endorphin, and gamma-aminobutyric acid. The most significant of these is the dopamine reward system known as the mesoaccumbens pathway. This system is activated within seconds of smoking and produces a sense of pleasure.

Nicotine binds to nicotinic acetylcholine receptors, primarily to alpha-4, beta-2 receptors in the ventral tegmental area of the midbrain. Once this binding occurs, a neurochemical message is conveyed to the nucleus accumbens via the release of dopamine in the mesoaccumbens pathway—the final common reward pathway triggered by all drugs of abuse. Since these structures and pathways of the brain are anatomically central, the addiction is driven by the basal ganglia and midbrain, the phylogenetically oldest parts of the brain. Nicotine therefore drives its addicts to continue smoking by producing strong neurochemical rewards and by causing strongly negative reactions when discontinued.

Genetically mediated susceptibility probably contributes to addiction. People whose neurochemical pathways are easily stimulated by this drug are probably at far greater risk of addiction. Paradoxically, people who are rapid metabolizers of nicotine are at greater risk than slow metabolizers.⁶ (Nicotine is metabolized by cytochrome P450 2A6 in the liver.)

Tolerance and withdrawal

Tolerance develops with long-term use, mediated by up-regulation (increased numbers) of alpha-4, beta-2 cholinergic receptors in the ventral tegmental area. Any reduction in nicotine level causes distress because receptors are unoccupied; with more receptors, nicotine intake must increase to keep physiologic balance and avoid withdrawal. Since the half-life of nicotine is only about 2 hours, the smoker must smoke almost constantly to satisfy receptors hungry for the stimulating drug. If drug levels drop, withdrawal occurs very quickly.

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal

Eventually, smokers use nicotine less for pleasure and more as a way to avoid withdrawal. The cycle of pleasure, eventual tolerance, withdrawal, craving, and compulsion is biologically driven, like the drives of thirst, reproduction, and hunger. Nicotine hijacks species-sustaining reward mechanisms, leading to the malignant, compulsive disease of nicotine addiction.

Treatment doomed to fail?

Because nicotine addiction involves the midbrain, cessation strategies that rely on higher cerebral function are not likely to succeed. Counseling, common sense, and willpower simply cannot overcome the dopaminergic stimulating power or assuage the withdrawal sickness of nicotine dependence. Telling patients that smoking is bad for them misses the mark in most cases. Patients want to quit, but the drive to smoke is too powerful. Attempts to cut down rather than abstain from smoking also fail.

Nicotine is a formidable adversary for the patient and for the doctor or other health professional. Until recently, treatment was usually ineffective.

So, what does work against nicotine addiction?

PHARMACOTHERAPIES FOR SMOKING CESSATION

Nicotine replacement therapy

The oldest of the pharmacotherapies for nicotine addiction is nicotine replacement, in the form of patch, gum, lozenge, or nasal spray.

Advantages:

• Nicotine replacement therapy eliminates exposure to the other harmful compounds in tobacco, with few to none of the health risks associated with smoking.
• By delivering nicotine by a different route, nicotine replacement therapy breaks the association between smoking and feeling good. The addict is already dopamine-stimulated before putting a cigarette in the mouth, merely by association and suggestion. Using a different route of nicotine administration avoids that associative stimulation from the act of smoking, so that quitting becomes easier.
• The dose of nicotine is lower with replacement therapy than with smoking. The cigarette is the most efficient delivery mechanism for getting nicotine into the body. A smoked cigarette produces a rapid spike in plasma nicotine levels, far higher and faster than nicotine gum, nasal spray, or transdermal patch. Peak levels of plasma nicotine from nicotine replacement therapy are only 30% to 50% as high as those achieved by smoking.^7–9
• It is inexpensive.

Disadvantages:

• Nicotine replacement therapy maintains the addiction to nicotine, with its neurophysiologic distortions.
• Some patients continue nicotine replacement therapy for years.

Use of nicotine gum can be a problem because of the need for frequent administration. The gum is chewed until the user feels a tingling or peppery taste in the mouth, after which the gum must be placed inside the cheek to allow for maximal absorption of the nicotine. Once the tingling has faded, the user is to chew another piece and repeat the cycle as long as craving is perceived. On the other hand, the nicotine patch is applied once daily. Both of these products are available over-the-counter.

Caution is indicated when starting nicotine replacement therapy in those with recent myocardial infarction, angina, or arrhythmia.

Effectiveness. Nicotine replacement therapy has been shown to be as effective as bupropion (see below) but not as effective as varenicline when used in single administration form (patch, gum, lozenge, or inhaler alone). The four single-administration forms of nicotine replacement therapy are all equally efficacious. Combinations of nicotine replacement formulations have been reported to be as effective as varenicline and superior to single formulations.10

How about electronic cigarettes? Electronic cigarettes, or e-cigarettes, supply nicotine in a noncombustion vapor and are advertised as an alternative to smoking. No claim is made for reducing smoking, so the products, including the liquids involved, are not regulated by the US Food and Drug Administration (FDA). Controversy exists as to whether they actually increase the number of smokers by introducing young people to “vaping” to get nicotine. Since nicotine is still inhaled, the addictive potential remains unabated. E-cigarettes are unregulated vehicles for supplying nicotine and may pose other health risks, and there is very limited evidence to support the efficacy of e-cigarettes as aids to smoking cessation. Since no controlled study has demonstrated successful cessation of smoking with e-cigarettes, they are best regarded for now as merely another way to introduce nicotine into the body.

Bupropion

Bupropion, an antidepressant also sold as Wellbutrin SR, was approved in 1997 for use in smoking cessation under the trade name Zyban. The manufacturer, Glaxo SmithKline, learned serendipitously that depressive patients taking bupropion were able to quit smoking. After some field trials, this “new” medication was born. It was the first nonnicotine drug for tobacco dependence to gain FDA approval.

Its mechanism of action in combating smoking is unknown but is thought to be related to mild inhibition of dopamine re-uptake in the midbrain.

The drug is approved for smokers over age 18 who are smoking at least nine cigarettes daily. It requires a prescription, and the typical dose is 150 mg twice daily for 8 to 12 weeks, up to 12 months. Smoking is allowed for the first 7 days of drug use.

Contraindications include a history of seizures, concurrent use of bupropion, bulimia, anorexia, detoxification from alcohol or sedatives, use of monoamine oxidase inhibitors, and allergy to bupropion. Warnings are noted for diseases of heart, liver, or kidney; for use with selective serotonin reuptake inhibitors or tricyclic antidepressants; for pregnancy; and for adolescents because of heightened suicide risk.

Side effects. Seizure risk has been estimated at 1 in 1,000 bupropion users at dosages of up to 300 mg daily and is 10 times greater at dosages of 450 to 600 mg/day.¹¹

The most common side effect reported is insomnia, which occurs in about one-third of people who take the medication. Less common side effects include dry mouth, anxiety, and hypertension. Pretreatment screening should include a history of seizure, closed head trauma, brain surgery, stroke, and the eating disorders anorexia nervosa and bulimia. The FDA has required a boxed warning regarding the association of bupropion with psychiatric symptoms.¹²

Effectiveness. Compared with placebo, bupropion reduces withdrawal symptoms such as irritability, frustration, anger, restlessness, depression, craving, poor concentration, and urge to smoke. Bupropion SR, 150 or 300 mg per day, has been reported to lead to substantial abstinence rates when used with intensive telephone counseling. In a randomized trial,¹³ side effects were common, especially at the higher dose, but there were no serious adverse effects such as deaths or seizures.¹³

Buproprion has been found to be as efficacious in improving the odds of quitting as single forms of nicotine replacement therapy, but not as efficacious as nicotine replacement therapy forms used in combination. Bupropion does not appear to be as effective as varenicline.⁹ US Public Health Service guidelines since 2000 have included nicotine replacement therapy and sustained-release bupropion in combination.

Disadvantages. Bupropion is significantly more expensive than nicotine replacement therapy, but it is often covered by insurance when it is used for smoking cessation. Bupropion has many contraindications, produces drug-drug interactions, is often poorly tolerated, and has many side effects. Some deaths have been reported. Zyban is available by prescription only, an indicator of its relative risk, with the added drawback of higher cost to patients.

Varenicline

Varenicline (Chantix, Champix) was granted a priority review by the FDA in 2005, as it showed significantly better results than other current therapies. It was approved in 2006 and added as a first-line agent in the 2008 guidelines.¹²

Mechanism of action. A synthetic “designer” drug made for its specific purpose, the varenicline molecule is a modified version of cytisine, a naturally occurring alkaloid previously marketed as Tabex in Eastern Europe. Cytisine is a selective alpha-4, beta-2 nicotinic acetylcholine receptor partial agonist. The high-affinity alpha-4, beta-2 nicotinic acetylcholine receptors exist in the mesolimbic dopaminergic system, the reward center of the brain.¹⁴

Telling patients that smoking is bad for them usually misses the mark

Varenicline has the same mechanism of action as cytisine but penetrates the central nervous system better. This mechanism of action allows varenicline to block the attachment of the nicotine molecule to this receptor, preventing nicotine’s dominant effect. Varenicline, however, is a partial agonist, so that when it attaches itself to the receptor, it causes a partial agonist effect, which is an opening of the receptor channel to sodium ions, causing partial stimulation of the cells in the ventral tegmental area, and ultimately causing a mild release of dopamine in the nucleus accumbens.^15,16 Thus, varenicline effectively stimulates the receptor partially, while at the same time blocking the effects of nicotine.

Pharmacokinetics. After oral intake, the maximal plasma concentration of varenicline is reached in 3 to 4 hours. Food does not inhibit absorption. There is minimal hepatic metabolism, with 92% of the drug excreted unchanged in the urine. There are no known drug-drug interactions. The 24-hour half-life of varenicline allows for once-daily dosing.

Effectiveness. Several phase 2 and phase 3 studies compared varenicline with placebo and other drugs in terms of efficacy, dosing, and safety in 3,600 smokers. The initial phase 2 study, lasting 7 weeks, showed a 4-week abstinence rate of 48% with varenicline compared with 17% with placebo.¹⁷

Two phase 3 trials with 2,052 participants demonstrated that, at 12 weeks, abstinence rates were 44% with varenicline, 17% with bupropion, and 17% with placebo. At the end of 1 year, those groups again demonstrated significant differences in nicotine abstinence—22% in the varenicline group vs 15% with bupropion and 9% with placebo. Also, varenicline was superior to bupropion and placebo in reducing craving.^18,19 For those who were nicotine-free after 12 weeks of treatment, continuing varenicline for another 12 weeks boosted nicotine abstinence rates from 36% to 44% at 1 year.²⁰

Though varenicline produces a mild physiologic dependence, it is not addictive and does not produce tolerance to itself. There is no need to increase the dose over time. Three percent of patients have reported mild irritability on stopping varenicline.

In sum, varenicline has been shown to be more effective than bupropion and any of the four single formulations of nicotine replacement when they are used alone. It has not been shown to be more effective than combinations of nicotine replacement therapy.¹⁰

Safety considerations with varenicline. Psychiatric adverse events associated with varenicline have included severe depression, agitation, and suicidal behavior—including completed suicide. Motor vehicle accidents and erratic behaviors have led to a ban on varenicline use by airline pilots, truck drivers, and maritime workers. Skin rashes (including Stevens-Johnson syndrome), renal failure, and cataracts have also been reported. Safety has not been established with schizophrenia, bipolar disorder, or major depression. The physician should ask about prior psychiatric history, illnesses, and reactions before prescribing varenicline. Generally, it is prudent to avoid varenicline in patients with a significant psychiatric history.

Nausea and sleep disturbances such as vivid dreams and insomnia are the most frequently reported side effects.

Black box warnings with bupropion and varenicline. In July 2009, the FDA issued boxed warnings for bupropion SR and for varenicline for smoking cessation because of reports of neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, attempted suicide, and completed suicide.²¹ These can occur in people with or without a history of mental illness, and whether the patient has stopped smoking or not. Providers should inform patients, family members, and caregivers about the potential for these symptoms and what to do if symptoms develop—ie, stop the medication immediately and contact the health care provider.

Patients should also be told  to use caution when driving, operating machinery, or performing hazardous activities until they know how the medication will affect them.²¹

When prescribing varenicline. Advise patients to set a “quit date” 7 days after starting varenicline—they can continue smoking for the first 7 days on the drug. The starter packet for varenicline comes as 0.5 mg daily for 3 days, then twice daily for 2 days; the dose increases to 1 mg twice daily thereafter. Smokers report that it is much easier to quit after 7 days on varenicline.

Combinations of nicotine replacement are as effective as varenicline and are superior to single formulations

Maintenance packs are available for 1 month of daily dosing. Generally, one starter pack is prescribed, with a second prescription for continuing packs for 2 to 5 more months. Varenicline is best taken with a full glass of water. If the smoker abstains for the first 3 months of therapy, it is best to prescribe an additional 3 months of medication to improve long-term abstinence from nicotine. With nausea or renal disease, lower the dose. Avoid prescribing varenicline for the elderly, teens, and pregnant women.

Varenicline is available only by prescription, and no generic equivalent is available.

WHEN IT’S TIME TO QUIT

A useful prescribing plan is:

• For most people, begin with nicotine patches plus gum
• If nicotine replacement therapy fails, prescribe varenicline
• Prescribe bupropion for patients with depression or if varenicline fails.

According to the US Public Health Service guideline,¹² in a meta-analysis comparing various tobacco cessation medications with placebo and nicotine patch, the combination of nicotine patch (> 14 weeks) plus gum was 3.6 times as effective as placebo and 1.9 times as effective as nicotine patch alone. Varenicline at 2 mg per day was 3.1 times as effective as placebo and 1.6 times as effective as nicotine patch alone. Therefore, the combination of nicotine patch and gum is an inexpensive yet effective way to begin a course of smoking cessation therapy.

Behavioral counseling

Timing is important to successful quitting. Patients generally know when it’s a good time to quit—and when it’s not. Avoid trying to get patients to quit when they are stressed, overly busy, fatigued, or anxious. Try to get the patient to set a time to quit that’s ideal, and then encourage the patient to stick to it. For example, scheduling the quit day on a celebration, anniversary, or birthday gives that date added significance and enhances motivation. Follow the patient frequently for 6 to 12 months with intense monitoring and encouragement, and to assess for any adverse effects of medication.

In July 2009, the FDA issued boxed warnings for bupropion SR and for varenicline because of neuropsychiatric symptoms

The 2008 update to the Public Health Service Clinical Practice Guidelines on treating tobacco use and dependence concludes that counseling and medication are each effective alone in increasing smoking cessation and are even more effective when used together.¹² Even very brief, 3-minute discussions and encouragement have been shown to be helpful. The Public Health Service evidence-based clinical practice guideline on cessation states that brief advice by medical providers to quit smoking is an effective intervention.¹²

Doctors who show great interest in smoking cessation seem to be more effective in persuading patients to quit. They should take note of smoking rather than ignoring it. A modified version of the CAGE questionnaire to assess problem drinking is recommended as a tool to assess patients’ smoking behavior and initiate a discussion about it (Table 1).²² Emphasize the health and financial costs to the patient. Try to form a therapeutic alliance with the patient against smoking: “Let’s see what we can do about this problem.” Be positive and optimistic in offering help with counseling, support, and medications.

Caution smokers against switching to “light” tar and nicotine cigarettes, as controlled experiments have failed to show consistent reductions in the amounts of tar and nicotine these products deliver into the lungs. Smokers also appear to compensate or adapt their smoking habits to increase the yield from these products. There is insufficient evidence to support the supposed health benefits of such low-yield smoking products.²³

Always refer the patient for counseling with the pharmaceutical company help line or with a supported quit line. Some manufacturers of smoking cessation medications offer counseling or web-based support for patients trying to quit. For example, patients who are prescribed varenicline are offered the GETQUIT Plan, a free program that includes online education, tracking of progress, and “check-ins with slip-up support.” These services are often underused yet represent a ready source of helpful support.

If relapses occur, encourage the patient to keep trying again and again, as it may take several attempts to succeed.

Quit lines

To help smokers and other tobacco users quit, all states now have a toll-free cessation quit line, a telephone service accessible through a national toll-free number (1-800-QUIT-NOW). Quit lines also can be a referral source for health care providers who might not have the time or staff to provide all of the steps in the recommended “five-A” cessation counseling model,¹² ie:

• Ask about tobacco use
• Advise to quit
• Assess willingness to make a quit attempt
• Assist in quit attempt
• Arrange follow-up.

Quit lines have been shown to improve outcomes when compared with people trying to stop on their own.¹² Quit line services have evolved from their modest beginnings as providers of information and counseling to a level at which  in many states, evidence-based medications are provided through quit lines.^13,24 Medication use, coupled with quit line counseling intervention, increases the likelihood of tobacco abstinence and is consistent with US Public Health Service guideline recommendations that all tobacco users should be offered at least one medication as part of their quit attempt.¹²

WOMEN SMOKERS HAVE UNIQUE HEALTH RISKS

Women have unique health risks arising from smoking: low-birth-weight babies, sudden infant death syndrome, cervical cancer, and an increasing rate of lung cancer. In general, women have poorer responses to nicotine replacement therapy, are more concerned about gaining weight after quitting, and demonstrate more mood lability after quitting. Women seem more energized by the taste, smell, and overall sensations involved in smoking.

Weight gain will occur when quitting smoking; this is hard to overcome. More exercise may help, and a trial of bupropion with nicotine replacement therapy may mitigate weight gain.

Women who are pregnant present a special challenge when it comes to weighing the benefit of medications against continued smoking. For pregnant women who want to quit smoking, the best treatment is counseling without nicotine replacement or other pharmacotherapy. There are inadequate data for the use of varenicline or bupropion in pregnancy. If medication is needed, start nicotine replacement therapy early in pregnancy, as its risk is the same as or less than the smoking risk to the fetus.

Smokers say it is much easier to quit after 7 days on varenicline

The US Public Health Service guideline provides a useful discussion and bibliography related to this topic.¹² All of the FDA-approved medications for tobacco cessation carry an FDA pregnancy category designation of C or D—ie, not recommended for use by pregnant women. These designations are not absolute contraindications and do allow for use in life-threatening situations or when other treatment modalities have failed. Some clinicians and their patients may decide that the potential for fetal harm, including fetal death, with continued smoking is high enough to warrant use of medications.

A careful and thorough discussion of the risks and benefits is recommended between the patient and her physician regarding this issue.

A CALL TO ARMS

The statistics are incontrovertible but do not tell the whole story. The day-to-day practices of physicians bear witness to the suffering that compulsive smoking creates for the smoker. As in all addictions, those around the addict suffer as well, from secondary smoke but also from fear and anxiety about premature loss of their loved ones. Smoking causes suffering and early death, and it is vitally important that doctors—the front-line troops—take up the fight against it as America’s number-one preventable cause of health problems and death.

To be effective champions in the public health fight against smoking, doctors must develop an understanding of compulsive smoking as a biologically driven process of addiction. The smoker attempting to quit is literally in the fight of his or her life and needs emotional support, cognitive-behavioral tools, and state-of-the-art pharmacology to overcome the slow destruction caused by the “dirty weed.”

In Reply: We thank Dr. Chandiramani for his thoughtful comments.

Only four cases of seizure-like activity associated with synthetic cannabinoids have been reported in the literature. In addition to the case reported in our paper,¹ there was another in which a 19-year-old had two seizures soon after smoking a spice product, and the second seizure was witnessed by paramedics on the way to the hospital.² Though this patient’s urine was not analyzed for synthetic cannabinoids, the spice product that was reportedly smoked by the patient was later sent to a laboratory for analysis and was found to contain four synthetic cannabinoids: JWH-018, JWH-081, JWH-250, and AM-2201.

In another case,³ seizure occurred after use of an incense product called “Spicy XXX,” but neither the incense sample nor the patient’s urine was tested for synthetic cannabinoids.

The final case reported in the literature involved a 25-year-old man who was brought to an emergency department by coworkers who had witnessed seizure-like activity.⁴ He was reported to have smoked an incense product about “45 minutes prior to presentation,”⁴ indicating that the seizure-like activity happened within that time frame. Two synthetic cannabinoids (JWH-018 and JWH-073) were detected in the patient’s urine.

In the case by Lapoint et al¹ that we referred to in our paper,¹ seizure activity recurred in the hospital and was successfully treated with lorazepam. The case reported by Schneir and Baumbacher² described treatment of the second seizure with intranasal midazolam, with no recurrence of seizure activity.

In summary, the literature on seizure activity related to synthetic cannabinoids is sparse. When the time course has been documented in these few cases, seizures seem to occur “soon” after using these products,² or from 45 minutes to 1 hour after use.^1,4 Although benzodiazepines have been used to treat seizure activity, there have been no published reports of using medications to prevent seizures in individuals who have been using spice products. Furthermore, the routine employment of seizure prophylaxis of any kind would probably be premature at this point given the uncertainty of the actual seizure risk among all synthetic cannabinoid users. We would consider giving a benzodiazepine to prevent possible seizures after drug ingestion in cases in which prior seizures have occurred, in cases of extreme excitement or agitation, or in those with marked alterations of mental state.

In Reply: We thank Dr. Chandiramani for his thoughtful comments.

Only four cases of seizure-like activity associated with synthetic cannabinoids have been reported in the literature. In addition to the case reported in our paper,¹ there was another in which a 19-year-old had two seizures soon after smoking a spice product, and the second seizure was witnessed by paramedics on the way to the hospital.² Though this patient’s urine was not analyzed for synthetic cannabinoids, the spice product that was reportedly smoked by the patient was later sent to a laboratory for analysis and was found to contain four synthetic cannabinoids: JWH-018, JWH-081, JWH-250, and AM-2201.

In another case,³ seizure occurred after use of an incense product called “Spicy XXX,” but neither the incense sample nor the patient’s urine was tested for synthetic cannabinoids.

The final case reported in the literature involved a 25-year-old man who was brought to an emergency department by coworkers who had witnessed seizure-like activity.⁴ He was reported to have smoked an incense product about “45 minutes prior to presentation,”⁴ indicating that the seizure-like activity happened within that time frame. Two synthetic cannabinoids (JWH-018 and JWH-073) were detected in the patient’s urine.

In the case by Lapoint et al¹ that we referred to in our paper,¹ seizure activity recurred in the hospital and was successfully treated with lorazepam. The case reported by Schneir and Baumbacher² described treatment of the second seizure with intranasal midazolam, with no recurrence of seizure activity.

In summary, the literature on seizure activity related to synthetic cannabinoids is sparse. When the time course has been documented in these few cases, seizures seem to occur “soon” after using these products,² or from 45 minutes to 1 hour after use.^1,4 Although benzodiazepines have been used to treat seizure activity, there have been no published reports of using medications to prevent seizures in individuals who have been using spice products. Furthermore, the routine employment of seizure prophylaxis of any kind would probably be premature at this point given the uncertainty of the actual seizure risk among all synthetic cannabinoid users. We would consider giving a benzodiazepine to prevent possible seizures after drug ingestion in cases in which prior seizures have occurred, in cases of extreme excitement or agitation, or in those with marked alterations of mental state.

In Reply: We thank Dr. Chandiramani for his thoughtful comments.

Only four cases of seizure-like activity associated with synthetic cannabinoids have been reported in the literature. In addition to the case reported in our paper,¹ there was another in which a 19-year-old had two seizures soon after smoking a spice product, and the second seizure was witnessed by paramedics on the way to the hospital.² Though this patient’s urine was not analyzed for synthetic cannabinoids, the spice product that was reportedly smoked by the patient was later sent to a laboratory for analysis and was found to contain four synthetic cannabinoids: JWH-018, JWH-081, JWH-250, and AM-2201.

In another case,³ seizure occurred after use of an incense product called “Spicy XXX,” but neither the incense sample nor the patient’s urine was tested for synthetic cannabinoids.

The final case reported in the literature involved a 25-year-old man who was brought to an emergency department by coworkers who had witnessed seizure-like activity.⁴ He was reported to have smoked an incense product about “45 minutes prior to presentation,”⁴ indicating that the seizure-like activity happened within that time frame. Two synthetic cannabinoids (JWH-018 and JWH-073) were detected in the patient’s urine.

In the case by Lapoint et al¹ that we referred to in our paper,¹ seizure activity recurred in the hospital and was successfully treated with lorazepam. The case reported by Schneir and Baumbacher² described treatment of the second seizure with intranasal midazolam, with no recurrence of seizure activity.

In summary, the literature on seizure activity related to synthetic cannabinoids is sparse. When the time course has been documented in these few cases, seizures seem to occur “soon” after using these products,² or from 45 minutes to 1 hour after use.^1,4 Although benzodiazepines have been used to treat seizure activity, there have been no published reports of using medications to prevent seizures in individuals who have been using spice products. Furthermore, the routine employment of seizure prophylaxis of any kind would probably be premature at this point given the uncertainty of the actual seizure risk among all synthetic cannabinoid users. We would consider giving a benzodiazepine to prevent possible seizures after drug ingestion in cases in which prior seizures have occurred, in cases of extreme excitement or agitation, or in those with marked alterations of mental state.