About this course:
Therapies for patients with nicotine dependence
At the conclusion of this learning activity, the nurse should be able to:
- Recall the national statistics regarding tobacco dependence in the United States
- Briefly explain the deleterious effects of tobacco dependence and nicotine on the human body and the community
- Analyze the various treatments for tobacco dependence, including
- behavioral therapy
- nicotine replacement therapy
- pharmacology such as bupropion and varenicline
- electronic cigarettes
- legislative/community-wide efforts such as increased taxes or regulating decreased nicotine levels in cigarettes
- other alternatives such as financial incentives and meditation
According to The Health Consequences of Smoking- 50 Years of Progress (US Department of Health and Human Services [USDHHS], 2014) published by the Surgeon General, tobacco use and its ensuing dependence has resulted in over 20 million premature deaths in this country. They describe the tobacco industry as both aggressive and intentionally misleading the public for decades regarding the potential danger inherent in their products. While the number of cigarettes smoked each year in the United States has decreased steadily since the early 1980’s when it reached its zenith of over 600 billion, the number remains nearly 300 billion today. Roughly 18% of the US population still smokes cigarettes despite its well-known and now well-publicized deleterious health effects. This is due, in part, to a stabilization and even slight increase in the number of newly initiated smokers (2.3 million in 2012), which is now keeping up with the attrition of previous smokers quitting or dying. Most (88%) smokers start before the age of 18, including 3.5 million current smokers who are still in middle or high school. It is estimated that the current economic costs of smoking exceed $289 billion annually. The medical community stands in a key position to help the public manage this addiction and decrease the negative health consequences and financial cost for our country as a whole (USDHHS, 2014).
As research continues to elucidate the negative consequences of nicotine and tobacco products (see Figure 1 below), one of the recommendations that came from the Surgeon General’s report (USDHHS, 2014) included a national campaign to educate the public about all of the impacts of smoking.
Figure 1:The health consequences causally linked to smoking
The above figure does not include the effects of secondhand smoke such as stroke, lung cancer, coronary heart disease, and low birth weight (amongst pregnant women exposed to secondhand smoke) in exposed adults as well as middle ear disease, sudden infant death syndrome, and respiratory illness in exposed children (USDHHS, 2014). The Independent Scientific Committee on Drugs convened an international expert panel to rank 12 nicotine-containing products based on their relative harm using the multi criteria decision analysis (MCDA) approach. Their results state that cigarettes are by far the most harmful (score of 100 out of 100) both to oneself and to others based on 14 independent criteria. Nicotine replacement (NRT) products such as patches, nasal sprays, and oral products all received very low scores of 2, while small cigars (score 64), pipes (score 21), cigars (score 16), and water pipes (score 14) carried additional harm according to the committee. This committee credited the bulk of smoking’s harm to tobacco-specific nitrosamines (TSNAs), carbon monoxide (CO), and nitric oxide exposure (Nutt et al., 2014). A separate study of toxicant exposure in combustible tobacco products (CTPs) listed the primary toxins found in cigarette smoke to include TSNAs, metals such as lead and cadmium, polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs) (Goniewicz et al., 2018). Nicotine is considered a pregnancy category D substance with known negative effects on a developing fetus. Smoking during pregnancy increases the risk of low birth weight as well as peri- and postnatal complications (Drugs for Tobacco Dependence, 2016). Prenatal nicotine exposure has been shown to affect fetal lung development. Nicotine exposure in adolescents may increase the risk for future drug dependence (Dinakar & O’Connor, 2016). Kandel & Kandel (2014) cite both biological and psychological proof of the ability of prolonged nicotine exposure to act as a “gateway” for future drug use and addiction to cocaine.
Treatment Options for Tobacco Dependence
Regarding the treatment of tobacco dependence, there are multiple options currently available.
Table 1: Treatment options available for the treatment of tobacco dependence
|Drug||Some Available Formulations||Usual Adult Maintenance Dosage1||Cost2|
|Nicotinic Receptor Agonists|
|Nicotine transdermal patch3 - generic|
NicoDerm CQ (Sanofi)
7, 14, 21 mg/24 hr patches
|Nicotine nasal spray - Nicotrol NS (Pfizer)||200 sprays/10mL bottle|
|1 dose (2 sprays) 8-40x/d|
(max 5 doeses/hr)4,6
|Nicotin oral inhaler - Nicotrol (Pfizer)||10mg cartidges||4-16 cartridges/d|
(max 16 cartridges/d)4
|Nicotine polacrilex gum3 - generic|
Nicorette gum (GSK)11
|2, 4 mg/piece||8-24 pieces/d4,9|
|Nicotine polacrilex lozenge3 - generic|
Nicorette lozenge (GSK)11
|2, 4 mg/lozenge||8-20 lozenges/d4,10||$72.00|
|Doaminergic-Noradrenergic Reuptake Inhibitors|
|Bupropion SR - generic|
Wellbutrin SR (GSK)14
|100, 150, 200 mg SR tabs12|
150 mg SR tabs
|150 mg bid13||$27.00|
|Nicotinic Receptor Partial Agonist|
|Varenicline tartrate - Chantix (Pfizer)||0.5, 1 mg tabs||1 mg bid15||$157.50|
|1Dosage reduction may be needed for hepatic or renal impairment.|
2Approximate WAC for 30 days' treatment at the lowest usual maintenance dosage. WAC = wholesaler acquisition cost, or manufacturer's published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transational price. Source: AnalySource® Monthly. February 5, 2016. Reprinted with permission by First Databank, Inc. All right reserved. ©2016. www.fdbhealth.com/policies/drug-pricing-policy
3Available over the counter (OTC) for persons ≥18 years old. Patients should not eat or drink within 15 minutes of using a gum or lozenge.
4See specific label for instruction for dose titration
5Cost for 28 transdermal patches.
6One spray per nostril. Maximum of 40 doses/day. Should not be used for >3 months.
7Cost of 4 10-mL bottles
8Cost of 168 10-mg cartridges; each cartridge delivers 4 mg of nicotine.
9A second piece of gum can be used within one hour. Continuously chewing one piece after another is not recommended.
10Maximum of 5 lozenges in 6 hours or 20 lozenges/day. Do not use more than one lozenge at a time or continuously use one after another.
11Also available in a mini-lozenge.
12Only the generic 150-mg SR tablets are FDA-approved for this indication.
13Initial dosage is 150 mg once/d for 3 days.
14Not FDA-approved for this indication.
15INitial dosage is 0.5 mg once/d for 3 days, then bid for 4-7 days.
(Drugs for Tobacco Dependence, 2016)
Many research articles refer to a control comparison, termed “usual care” or similar. Typically, this involves informational support to the patient about the health risks of smoking and tobacco use, cessation guides including tips or strategies, as well as any local resources available such as support groups. In many studies, there is consistent behavioral or therpeutic support throughout the study. Hajek et al. (2019) refers to “weekly behavioral support” provided to all participants for a period of four weeks. The Study Evaluating the Safety and Efficacy of Varenicline and Bupropion for Smoking Cessation in Subjects With and Without A History of Psychiatric Disorders (EAGLES trial) (Anthenelli et al., 2016) included 10 minutes or less of “cessation counseling” at each appointment for each participant during their study. Baker et al. (2016) included six counseling sessions throughout their study, separate from other appointments. Cunningham et al. (2016) conducted their entire study remotely and thus chose to incorporate no behavioral support. Halpern et al. (2015) refers to usual care as consisting of pre-printed information on tobacco, a tobacco cessation guide, and behavioral modification therapy offered to the 41% of their study for whom this was covered by their medical insurance provider. Walker et al. (2014) provided behavioral support to all study participants via telephone calls, while Halpern et al. (2018) included motivational text messages via cell phone as a component of usual care. A study completed in Sweden amongst university students who smoked tested the use of text messaging as a critical component of a tobacco cessation treatment protocol. The intervention group received 157 therapeutic text messages over the course of 12 weeks, while the control group simply received a single text message every two weeks thanking them for participating in the study. Although the results were based on self-reporting only, the intervention group reported prolonged abstinence over 8 weeks in 25.9% of participants, while the control group reported only 14.6% (Müssener et al., 2016).
Nicotine Replacement Therapy
Nicotine replacement therapy (NRT) was first introduced in the late 1970’s to assist smokers with weaning gradually off nicotine, the most physically addicting component of cigarettes (Nutt et al., 2014). Options currently available for use in the United States include patches, gum, or lozenge over the counter for people 18+ or a nasal spray or inhaler with a prescription (see Table 1 above). NRT has been shown in studies to increase cessation rates by 50-70%. Combination therapy (the use of two or more NRT products, such as a patches and gum) has been shown to be more effective than monotherapy. The transdermal patch is the slowest and longest-acting option with serum concentration that peaks in 6-8 hours. The most commonly reported adverse effects include insomnia, abnormal dreams, and pruritus, but these are improved if the patch is removed overnight. The gum, lozenge, and inhaler peak in 20-60 minutes. Users of the nicotine gum most commonly report flatulence, indigestion, nausea, an unpleasant taste, hiccups, and a sore throat/mouth/jaw. Adverse effects related to the inhaler include mouth and throat irritation and a dry cough. The nasal spray has the fastest mechanism of action, most similar to the effect of smoking a cigarette, and peaks in the central nervous system in 5-20 minutes. NRT products are recommended for use for three months or less due to an increased risk for throat and nose irritation with prolonged use, and should be tapered off over several weeks (Drugs for Tobacco Dependence, 2016). NRT was shown to statistically improve confirmed abstinence rates among smokers compared to placebo in the very large EAGLES trial. In this trial involving over 8,000 adult smokers, the NRT group resulted in 23.4% and 15.7% abstinence rates at 12 and 24 weeks respectively, compared to just 12.5% and 9.4% in the placebo group (Anthenelli, 2016). Cunningham et al. (2016) mailed nicotine patches to 500 adults in Canada who smoked at least 10 cigarettes per day and compared their self-reported abstinence rates to 499 smokers who did not receive patches. At 30 days follow-up the study group self-reported a 7.6% abstinence rate, while the control group reported just 3%. Saliva samples to validate abstinence were returned by half of study participants and only 14 samples (2.8%) could be confirmed negative. Interestingly in this study, while 421 of 500 participants reported that they received the patches, only 246 reported they had used them, and only 46 reported having used all of the patches at the 8-week follow-up point (Cunningham et al., 2016). In a randomized trial involving 657 adult smokers in New Zealand, nicotine patches resulted in an abstinence rate of 5.8% and 7.3% when combined with electronic cigarettes (e-cigarettes). When NRT was studied in pregnant women, their use resulted in decreased smoking in the second trimester and better child development outcomes at two years (Dinakar & O’Connor, 2016).
Sustained-release bupropion (Zyban) and varenicline tartrate (Chantix) are both FDA-approved for smoking cessation in the US. They are both pregnancy category C medications. Bupropion (Zyban) is a norepinephrine and dopamine reuptake inhibitor that was primarily developed for the treatment of depression but was found to have nicotinic receptor blocking activity. It should be started 7-14 days prior to the target quit date (TQD) and has been shown to double abstinence rates in short term studies versus placebo, with roughly similar efficacy to NRT. Commonly reported adverse effects include insomnia, dry mouth, headache, nausea, and anxiety. The reported seizure incidence with bupropion use is 0.1%, and for this reason it is not recommended for use in patients with a history of seizures, stroke, brain tumor, brain surgery, or traumatic brain injury. It should not be used with monoamine oxidase inhibitors (MAOIs) (Drugs for Tobacco Dependence, 2016). Bupropion was shown to significantly improve abstinence rates among smokers compared to placebo in the EAGLES trial with 22.6% and 16.2% abstinence rates at 12 and 24 weeks respectively, compared to just 12.5% and 9.4% in the placebo group (Anthenelli, 2016).
Varenicline functions as a nicotinic receptor partial agonist by binding selectively to 𝛂2β4 nicotinic acetylcholine receptors to functionally decrease cravings and withdrawal symptoms. It should be started seven days prior to the TQD and has been shown in randomized trials to be more effective than NRT monotherapy or bupropion and roughly as effective as combination NRT. Common adverse effects include nausea, sleep disturbances, abnormal dreams, headache, constipation, vomiting, flatulence, and xerostomia (dry mouth secondary to reduced saliva production), with increased adverse effects reported when used in combination with NRT. Some observational studies have shown an increase in neuropsychological symptoms or exacerbations of previously-existing psychiatric illness, suicidal behavior, and an increased rate of cardiovascular events (Drugs for Tobacco Dependence, 2016). Despite this, the FDA-mandated EAGLES trial (Anthenelli, 2016) showed no statistically significant increase in moderate to severe neuropsychological adverse events in any treatment arm, including varenicline (#80), versus placebo (#74). This same trial showed statistically significant improvement in confirmed abstinence rates with varenicline at 12 and 24 weeks (33.5% and 21.8% respectively) compared to all other groups (Anthenelli, 2016). In a randomized trial involving over 900 adults who reported smoking at least 5 cigarettes per day, the use of varenicline was compared with a nicotine patch as well as a combination of patch and lozenge. After 12 weeks of treatment, the study showed no statistically significant difference in sustained confirmed abstinence or point prevalence (7 days) of confirmed abstinence. The varenicline group did report more common adverse effects, such as abnormal dreams, insomnia, nausea, sleepiness, constipation, and indigestion. The trial reported an overall adherence rate of only 43-49% (Baker et al., 2016).
As part of the aforementioned EAGLES trial (Anthenelli, 2016), a secondary analysis attempted to determine if any of the treatments tested worked better within specific participant subgroups. Just as a refresher, the EAGLES trial involved over 8,000 adult smokers in 16 countries to compare varenicline, bupropion, and NRT with placebo. They found that while there was no statistically significant variation by feature or treatment group, they did see improved abstinence across all treatment groups in patients that were not living in the US, of increased age, with increased BMI, Caucasian race, later age of smoking initiation, and those without a history of previous NRT use, psychiatric disorder or psychiatric medication use (West et al., 2018).
Cytisine, a partial agonist of nicotinic acetylcholine receptor 𝛂4β2 not currently approved for use in the United States but commonly used in Europe and elsewhere, has shown promising trial results. In a trial of over 1,300 motivated-to-quit adults in New Zealand, a free cytisine supply for 25 days was compared with vouchers for an eight-week supply of low-cost NRT products. At both time points, the reported abstinence rates among the intervention group was significantly higher than the NRT group (40% vs 31% at one month and 22% vs 15% at six months). Of note, the abstinence results were by self-report only, so they were not confirmed or verified, and the study was not double-blinded. The most commonly reported adverse effects in the trial included nausea, vomiting, and sleep disorders (Walker et al., 2014).
Electronic cigarettes (e-cigarettes) are not currently approved by the FDA for smoking cessation. They consist of a reservoir for liquid and a heating element (atomizer) that creates an aerosol from the liquid. The liquid is composed of a solvent (typically vegetable glycerin or propylene glycol) and may have added flavors and/or nicotine at various concentrations. While the solvents are considered safe for ingestion, their effects when vaporized are not as well known or studied. Analyses have shown, amongst other things, formaldehyde and acetaldehyde in e-cigarette vapor. E-cigarette use (called vaping) has increased quickly in the last decade, with just 1.8% of US adults reporting ever having used an e-cigarette in 2010, up to 13% in 2013. (Dinakar & O’Connor, 2016). Commonly reported adverse effects include mouth and throat irritation and dry cough, although lipoid pneumonia has also been reported. If nicotine is added, nicotine dependence is an expected risk of use. Regarding safety, many concerns exist regarding the long-term effects of e-cigarette use. An FDA analysis of two common brands showed impurities including PAHs and TSNAs, both of which are known carcinogens (Drugs for Tobacco Dependence, 2016). The Independent Scientific Committee on Drugs graded e-cigarettes a 4 out of 100 in terms of potential harm to self and others (Nutt et al., 2014). A direct comparison of nicotine and toxicant exposure between CTP and e-cigarette users was published in JAMA last year. They found that while the exposure from e-cigarettes was significantly lower than CTPs, it was not zero. The research found similar levels of most metals and three VOCs, but lower levels of nicotine, cadmium, all TSNAs, all PAHs and 17 VOCs. Dual users (those that smoke both CTP’s and e-cigarettes) were shown to have higher levels of nicotine metabolites, three TSNAs, two metals, five PAHs, and 13 VOCs when compared with participants who exclusively smoked CTPs. Their conclusion was that the exposure to toxicants was highest in dual users and was directly correlated with frequency of cigarette use (Goniewicz et al., 2018). One of the most troubling safety concerns that has presented itself in the last several years with e-cigarettes is their increased use amongst adolescents and young adults. In a study amongst over 2,500 high school students in Los Angeles, researchers sought to determine the association of e-cigarette use with later CTP use. They surveyed 2,530 9th grade students, 222 of which reported baseline use of e-cigarettes. In follow-up surveys at 6 and 12 months, they found reports of CTP use in 25-30% of baseline e-cigarette users versus just 8-9% of never-users (Leventhal et al., 2015). In a similar study, authors focused on 181 high school students throughout 10 high schools who reported the use of e-cigarettes. Six months later they found that the students who were using e-cigarettes with added nicotine at baseline had a significantly increased frequency of both smoking CTPs and vaping compared to those without added nicotine (Goldenson, Leventhal, Stone, McConnell & Barrington-Trimis, 2017).
The National Academies of Sciences, Engineering, and Medicine (NASEM) published a report on the public health consequences of e-cigarettes (NASEM, 2018). They cited the Family Smoking Prevention and Tobacco Control Act of 2009 which states that all nicotine and tobacco products introduced after February 15, 2007 must be shown to have a net positive health impact to both users and the community at large. Their expert panel concluded that while the vapor from e-cigarettes produced fewer and lower levels of toxicants than CTPs, the overall benefit to harm ratio would be determined by three factors: the effect of e-cigarettes on youth initiation of CTPs, the effect of e-cigarettes on adult cessation rates of CTPs, and their intrinsic toxicity. They noted that among youth and young adults, the reported use of e-cigarettes is now significantly higher than the reported use of CTPs and has increased from 2011 to 2015, with potential stabilization/decrease in 2016. They found the evidence as it exists currently allows for the following conclusive findings:
- Vaping increases the airborne particulate matter and nicotine in the indoor environment.
- Most e-cigarettes contain/emit numerous potentially toxic substances, including nicotine. Exposure is highly variable and depends on the device used, the liquid used, and how the product is operated.
- E-cigarette devices can explode, cause burns and other projectile injuries
- Intentional or accidental exposure to e-cigarette liquid (oral, eye contact, skin contact) can result in seizures, anoxic brain injury, vomiting, or lactic acidosis. Drinking or injecting e-cigarette liquid can be fatal.
- Complete replacement of CTPs with e-cigarettes decreases the individual’s exposure.
A number of other conclusions were made by the committee based on substantial or moderate evidence, as well as some matters that were only supported by limited, insufficient or no evidence. This includes substantial evidence that e-cigarette use among youth and young adults increases the risk of future CTP use and no evidence that long-term dual use affects morbidity and mortality (NASEM, 2018).
Regarding efficacy for smoking cessation, a small randomized trial of 300 smokers not-intending-to-quit found the use of an e-cigarette with 5.4 or 7.2 mg of added nicotine lead to significantly more reports of complete abstinence from cigarettes at 12 weeks follow-up compared to e-cigarettes without added nicotine. A larger randomized trial of over 650 smokers intending-to-quit compared NRT patches, an e-cigarette with 16 mg added nicotine, and a placebo e-cigarette. They showed no statistically significant difference between the groups at 6 months, with abstinence rates ranging from 4.1% (placebo group) to 7.3% (e-cigarette with nicotine). A meta-analysis of 38 trials of smokers who used e-cigarettes showed that those who used e-cigarettes were actually 28% less likely to quit smoking than those who did not use e-cigarettes (Drugs for Tobacco Dependence, 2016). The NASEM report (2018) concluded there was limited evidence that e-cigarettes may be an effective aid for smoking cessation. In a United Kingdom study involving over 800 adult smokers comparing e-cigarettes with any choice of NRT, the confirmed sustained abstinence rates at one year were significantly higher in the e-cigarette group (18%) compared with the NRT group (9.9%) (Hajek et al., 2019). In a small retrospective study of smokers diagnosed with COPD, chart review showed a significant decrease in cigarette consumption, along with decreased COPD exacerbations, COPD symptoms and an increase in physical ability in those patients using e-cigarettes. More than half had switched completely from cigarettes to e-cigarettes, while 46% remained dual users but with a significant decrease in the number of cigarettes per day (Polosa et al., 2016).
Legislative action and regulation are other alternatives to reduce smoking rates in the US. Chaloupka, Sweanor & Warner (2015) propose a federal relative harm tax. Based on a similar system in Sweden, all tobacco products would be taxed based on their relative harm (no tax on NRT products, a small tax on e-cigarettes, and a much larger tax on CTPs) (Chaloupka, Sweanor & Warner, 2015). Federal regulations regarding the amount of nicotine in cigarettes is also being explored. A randomized trial of reduced-nicotine cigarettes in 780 adults not-intending-to-quit showed that the low-nicotine groups (given cigarettes with just 0.4, 1.3 or 2.4 mg nicotine) were smoking an average of 14.9, 16.3 or 16.5 cigarettes per day respectively. These were statistically lower than the 15.8 mg nicotine group (21.3 cigarettes per day) and the control group allowed to smoke their usual brand (22.2 cigarettes per day) (Donny et al., 2015). A simulation model based on the opinions of eight experts was used to predict the public health effects of a federal regulation on nicotine in cigarettes. They predicted that initiation rates would steadily drop as cessation rates increased, and:
- Just 1.4% of the country would be smoking cigarettes by 2060 (currently 18%).
- Dual users would likely increase slightly in the first year or so.
- The rate of any tobacco use would gradually decrease to 11.6% by 2060.
- 16 million would-be smokers would be spared by 2060, and 33 million by 2100.
- 8.5 million tobacco-related deaths would be avoided by 2100 (Apelberg et al., 2018).
Other cessation treatments have been tried as well. A systematic review and meta-analysis on the effect of mindfulness meditation looked at ten randomized trials and found no statistically significant effect on abstinence rates or number of cigarettes per day (Maglione et al., 2017). A study of over a thousand adult smokers interested in quitting explored the effect of financial incentives. They were randomized to one of five groups:
- Usual care: pre-printed information on tobacco and a tobacco cessation guide; includes free behavioral therapy and NRT for some participants based on insurance coverage
- Usual care plus an individual reward group
- Usual care plus an individual deposit group
- Usual care plus a collective reward group
- Usual care plus a collective deposit group
Each group had a specific set of rules and requirements to achieve the monetary reward or to recuperate their initial financial deposit (plus additional reward) if abstinent at the two-week, 30-day, and six-month visits. At the six-month follow-up, all four financial incentive groups had statistically higher abstinence rates than the usual care group. Amongst the 41% of study participants with coverage, the free access to pharmaceutical cessation aids from their insurance providers did not lead to higher abstinence rates. There was not a significant difference in abstinence rates between the combined individual and collective groups. There were very few participants who willingly accepted assignment to one of the deposit groups (13.7%), but of those who accepted, their abstinence rates were over 50% at 6 months (Halpern et al., 2015). A similar study looked at financial incentives compared to e-cigarettes +/- NRT. Over 6,000 adult smokers were randomized to one of four groups:
- Usual care: free NRT or pharmaceuticals (with later offer of e-cigarette kit if desired)
- Free e-cigarette device kit
- Financial incentive program, reward-based
- Financial incentive program, deposit-based
Both financial incentive groups were also offered free NRT or pharmaceuticals with a secondary option of free e-cigarette if desired. The results showed only 80 confirmed cases of abstinence, although the rates were significantly higher in the financial incentive groups (2% and 2.9%) versus the usual care group (just 0.1%) (Halpern et al., 2018).
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- Baker, T. B., Piper, M. E., Stein, J. H., Smith, S. S., Bolt, D. M., Fraser, D. L., & Fiore, M. C. (2016). Effects of Nicotine Patch vs Varenicline vs Combination Nicotine Replacement Therapy on Smoking Cessation at 26 Weeks: A Randomized Clinical Trial. JAMA, 315(4), 371. doi: 10.1001/jama.2015.19284
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