Pharmacotherapy of Tobacco Use Disorder
Tobacco use is the leading cause of preventable mortality worldwide (1). Over one-half of all persistent smokers will eventually die of a tobacco-related disease (1).
The primary addictive substance in tobacco is nicotine. Cigarette smoking facilitates the rapid absorption of nicotine via pulmonary circulation into the brain within seconds. Nicotine binds to α4β2 nicotinic acetylcholine receptors (nAChRs) and causes the release of dopamine, norepinephrine, glutamate, serotonin, beta-endorphins, and other neurotransmitters. These nicotinic receptors are pentameric in nature and are made up of α and β subunits. The α subunit occurs in nine different isoforms (α2–α10), while the β subunit occurs in three different isoforms (β2–β4). Nicotinic receptors containing the α4 and β2 subunits (α4β2*nAChRs) are the most prevalent in the brain and are thought to play the largest role in nicotine’s reinforcing effects (2). Repeated exposure to nicotine causes upregulation of α4β2 nicotinic acetylcholine receptors, leading to an increase in their numbers, which subsequently reinforces the addiction (3). Although debate regarding the mechanism of upregulation continues to exist, proposed mechanisms include conformation changes of low-affinity receptors to high-affinity states, as well as decreased cell surface receptor degradation secondary to nicotine exposure (4).
The reinforcing effects of nicotine are primarily tied to its stimulatory effect on the mesoaccumbens dopamine pathway, which consists of dopamine projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc). Nicotine’s action at α4β2*nAChRs in the VTA is thought to be the primary role behind nicotine’s reinforcing effects; however, other subtypes, such as α6*nAChRs heavily located in the VTA and NAcc, are important as well. The α7*nAChRs are also important, as they are thought to play a role in regulating nicotine intake (25). Tobacco dependence also has a genetic component. Two single-nucleotide polymorphisms in CHRNA4 (the gene coding for the α4 subunit of nAChRs) are biologically functional and associated with tobacco dependence phenotypes (5).
Pharmacotherapies are effective treatments for tobacco dependence and are recommended by the United States Public Health Service to be provided in conjunction with behavioral therapy (6) (Tables 1 and 2). Nicotine replacement therapy, such as the nicotine patch, acts mainly at the α4β2*nAChRs, while buproprion is an antagonist at nAChRs. Varenicline is a partial agonist at α4β2*nAChRs, as well as a full agonist at α7*nAChRs (2). The present article focuses primarily on first-line pharmacotherapies for tobacco dependence (7).
| Drug | Mechanism of Action | Usual Dose | Side Effects | Cautions | Drug-Drug Interactions |
|---|---|---|---|---|---|
| Nicotine gum (over the counter) | Intermediate nicotine absorption, nicotine delivery through oral mucosa, full agonist, reduces cravings and withdrawal | 2 mg or 4 mg | Hiccups, gastrointestinal side effects, jaw discomfort | Pregnancy or breastfeeding; history of systemic rash with nicotine replacement therapy; less than 18 years of age; temporomandibular joint disease; dental or oral problem | None |
| Nicotine lozenge (over the counter) | Intermediate nicotine absorption, nicotine delivery through oral mucosa, full agonist, reduces cravings and withdrawal | 2 mg or 4 mg | Hiccups, oropharyngeal irritation, dry lips, oral ulcers | Pregnancy or breastfeeding; history of systemic rash with nicotine replacement therapy; less than 18 years of age | None |
| Nicotine patch (over the counter) | Slow nicotine absorption; nicotine delivery through skin; full agonist; reduces cravings and withdrawal | 7 mg, 14 mg, or 21 mg/24 hours | Mild skin irritation, nightmares | Pregnancy or breastfeeding; history of systemic rash with nicotine replacement therapy; less than 18 years of age; certain skin conditions | None |
| Nasal spray (prescription) | Fast nicotine absorption; rapidly reduces cravings and nicotine withdrawal | 1 or 2 doses/hour but should not be >5 doses/ hour or 40 doses/day | Mild irritation in nasal mucosa | Pregnancy or breastfeeding; history of systemic rash with nicotine replacement therapy; less than 18 years of age; skin conditions; rhinitis; nasal polyps; sinusitis | None |
| Nicotine Inhaler (prescription) | Intermediate nicotine absorption; nicotine delivery through oral mucosa; full agonist; reduces cravings and withdrawal | 6 to 16 cartridges/day | Oropharyngeal irritation, cough | Pregnancy or breastfeeding; history of systemic rash with nicotine replacement therapy; less than 18 years of age; hypersensitivity to menthol | None |
| Bupropion sustained-release | Norepinephrine and dopamine reuptake inhibition; competitive inhibition of nAChR; reduces nicotine craving; withdrawal, and reinforcement | 150 mg twice daily | Insomnia, dry mouth | Liver disease, renal impairments; seizure disorder in personal and/or family history or with concomitant medications that lower seizure threshold; eating disorders; head trauma with loss of consciousness; pregnancy or breast feeding; less than 18 years of age; taking medications for Parkinson’s disease; history of depressive disorders, bipolar disorders, or schizophrenia; prior adverse reaction with bupropion | Increase risk of seizure with tramadol; can increase tricyclic antidepressant levels. Can be fatal with monoamine oxidase inhibitors via CYP 2D6 inhibition; can interfere with analgesic actions of codeine; can increase plasma levels of some beta-blockers and atomoxetine; can increase concentrations of thioridazine and cause cardiac arrhythmias |
| Varenicline | Partial agonist at α4β2 nAChR; mitigates nicotine craving; withdrawal, and reinforcement | Dose titrated to 1 mg twice daily | Mild nausea, insomnia, nightmares, constipation, possible neuropsychiatric changes (behavioral changes, depressed mood, self-injurious thoughts or behaviors, “boxed warning”); cardiovascular side effects, decreased tolerance to alcohol, rare risk of seizure | Pregnancy or breast feeding; less than 18 years of age; history of depressive disorders, bipolar disorders, or schizophrenia; prior adverse reaction with varenicline | Does not inhibit hepatic enzymes or renal transport proteins; is not hepatically metabolized-unlikely to be affected by other drugs |
TABLE 1. First-Line Pharmacotherapies of Tobacco Dependence
| Drug | Mechanism of Action | Study Conclusion |
|---|---|---|
| Clonidine | Alpha2-adrenergic receptor agonist | Small benefit for smoking cessation |
| Nortriptyline | Tricyclic antidepressant | Demonstrated efficacy for long-term abstinence (>6 months) but no statistically significant benefits in adding nortriptyline to nicotine replacement therapy. |
| Cytisine | Nicotine receptor partial agonist | Used for smoking cessation in Europe and Russia. Data are favorable in achieving smoking cessation up to 6 months compared with placebo. |
| Mecamylamine | Ganglionic blocker and noncompetitive antagonist of α4β2 nAChRs | Nicotine patch in combination with transdermal mecamylamine patch or placebo did not demonstrate statically significant improvement in abstinence. |
TABLE 2. Pharmacotherapies for Tobacco Dependence Not Approved by the Food and Drug Administrationa
Nicotine Replacement Therapy
All nicotine replacement therapy products are recommended as first-line agents to treat tobacco dependence (6, 7) (Table 1). Nicotine replacement therapies deliver nicotine via oral or nasal mucosa, thus reducing the severity of withdrawal symptoms and cravings associated with tobacco use cessation (6, 7). A Cochrane meta-analysis of 150 trials demonstrated that nicotine replacement therapy increases long-term smoking abstinence compared with placebo or controls without nicotine replacement therapy (relative risk=1.60; 95% confidence interval [CI]=1.53–1.68) (7).
Nicotine Gum
Nicotine gum is available over the counter in 2-mg or 4-mg dose forms and increases smoking abstinence rates at 12 months compared with a control intervention (relative risk=1.43; 95% CI=1.31–1.56; 32 studies) (7). As monotherapy, standard dosing for highly dependent smokers is 4 mg, as this dose showed higher abstinence rates compared with the 2-mg dose (4, 5). Nicotine gum side effects include hiccups, gastrointestinal upset, and jaw discomfort associated with chewing (7).
Nicotine Lozenges
Nicotine lozenges are available over the counter in 2-mg or 4-mg dose forms, and a meta-analysis demonstrated their efficacy in increasing abstinence rates at 6 months compared with placebo (relative risk=1.90; 95% CI=1.36–2.67; four trials) (7). Lozenges provide at liberty dosing in response to cravings and release 25% more nicotine than an equal dose of gum. The lozenge is placed in the buccal cavity, allowing for nicotine absorption through the oral mucosa. It may be preferable to gum for patients with oral problems (8).
Nicotine Patches
Nicotine patches are available over the counter in various formulations and dosing schedules (i.e., 15 mg/16 hours; 7 mg, 14 mg, and 21 mg/24 hours). The nicotine patch is neither designed to alleviate acute cravings nor replace the behavioral activities of smoking in comparison to other types of nicotine replacement therapy (6). Nicotine patches provide slow, transdermal nicotine delivery over 16–24 hours and have been shown to significantly increase sustained 12-month abstinence rates (relative risk=1.51; 95% CI=1.35–1.70; 21 trials), with the most common side effect being mild skin irritation at the application site (7). Highest dose should be started in individuals smoking 10 or more cigarettes per day (3). In a preference trial comparing nicotine replacement therapy products, smokers preferred nicotine patches the most (8).
Nasal Sprays
Nasal sprays are available through prescription and deliver nicotine through nasal mucosa. One spray through each nostril constitutes a dose. Patients can initially use 1 or 2 doses/hour but should not exceed 5 doses/hour or 40 doses/day (9). Nasal sprays deliver nicotine faster than gum, patches, or inhalers but less rapidly than cigarettes (9). Nasal sprays increase smoking abstinence at 6 months greater than placebo (relative risk=2.02; 95% CI=1.49–2.73; four trials) (7). Side effects include rhinorrhea and nasal irritation (7).
Nicotine Inhalers
Nicotine inhalers require a prescription and deliver nicotine into the oropharynx where it is absorbed across the buccal mucosa (7). It addresses the sensory and ritualistic aspects of smoking behavior (10). Nicotine inhalers increase long-term abstinence compared with placebo (relative risk=1.90; 95% CI=1.36–2.67; four trials) (11). The most common side effects reported are oropharyngeal irritation and cough (7).
No nicotine replacement therapy product delivers an equivalent dose of nicotine as quickly as cigarette smoking (7). Consequently, they have a limited ability to consistently and effectively counter the addictive appeal of smoking in tobacco-dependent individuals (7).
Evidence recommends combination use of nicotine replacement therapy products that provide both continuous and at-liberty dosing (6, 7).
Pharmacotherapy Not Containing Nicotine
Bupropion Sustained-Release
Bupropion sustained-release is the first non-nicotine prescription drug to be Food and Drug Administration (FDA)-approved as a first-line agent for tobacco dependence (6). Bupropion mediates its effect on the brain’s reward centers through norepinephrine and dopamine reuptake inhibition, as well as through competitive inhibition on nAChRs (12). A network meta-analysis showed that bupropion significantly increased the odds of quitting as monotherapy (odds ratio=1.82; 95% CI=1.60–2.06) and demonstrated comparable efficacy with nicotine replacement therapy (13). There was no significant difference in abstinence based on gender or dosing bupropion at 150 mg or 300 mg (relative risk=1.08, 95% CI=0.93–1.26) (14). Bupropion has been shown to decrease withdrawal symptoms, cigarette craving, and improve mood during smoking cessation (15). Additionally, bupropion has benefits in limiting postcessation weight gain at the end of treatment (mean weight loss=–1.12 kg; 95% CI=–1.47 to –0.77 kg), although results beyond 6 months did not demonstrate persistence of effect (16). Bupropion was found to be safe and effective in smoking cessation in patients with schizophrenia (17). The “target quit date” is typically set on the eighth day of bupropion treatment when the bupropion level reaches a steady-state concentration.
Common side effects include insomnia and dry mouth (14). Bupropion should be used with caution in patients with liver disease or renal impairment and is contraindicated in those with a history of seizure, eating disorders, or head trauma with loss of consciousness or those using medications that lower seizure threshold (6). Bupropion was associated with a seizure rate of 1:1500 but had no excess neuropsychiatric or cardiovascular events compared with placebo across all trials (13).
Varenicline
Varenicline was FDA approved as a first-line agent for smoking cessation in 2007 (5). Varenicline’s novel therapeutic effect is through its partial agonist activity and competitive inhibition with nicotine at the α4β2 receptor, which in turn affects central mesolimbic dopamine release. As a result, varenicline mitigates symptoms of craving, withdrawal, and the reward reinforcement mechanism of nicotine (18).
A meta-analysis concluded that varenicline was the most effective treatment, nearly tripling the odds of quitting compared with placebo (odds ratio=2.88; 95% CI=2.40–3.47) (11). Varenicline was more effective than nicotine replacement therapy (odds ratio=1.57; 95% CI=1.29–1.91) and bupropion (odds ratio=1.59; 95% CI=1.29–1.96) but not more effective than combination nicotine replacement therapy (odds ratio=1.06; 95% CI=0.75–1.48) (13). Efficacy regarding the combination of varenicline and nicotine replacement therapy is unclear and not currently recommended by United States Public Health Service guidelines (6). A multicenter randomized clinical trial demonstrated that combination varenicline and bupropion increased prolonged abstinence at 12 and 26 weeks compared with varenicline alone (19). A randomized clinical trial also demonstrated that among cigarette smokers not willing or able to quit within the next month, but willing to reduce cigarette consumption and make a quit attempt at 3 months, use of varenicline for 24 weeks compared with placebo significantly increased smoking cessation rates at the end of treatment and also at 1 year (20). A recent multicenter randomized clinical trial showed that those who had a normal nicotine metabolite ratio had significantly higher quit rates after receiving varenicline for 11 weeks compared with those receiving a nicotine patch (21).
Varenicline is titrated to a dose of 1 mg twice daily for 12 weeks and has been shown to reduce relapse rates in abstinent smokers when given for an additional 12 weeks (22). The most common adverse effect associated with varenicline is mild nausea (7). Postmarketing surveillance raised concerns regarding neuropsychiatric and cardiovascular adverse events of varenicline. This prompted the FDA to issue a black box warning in 2008 regarding risks of behavioral change and suicidal ideation. A 2013 meta-analysis demonstrated no increased risk of serious adverse events with varenicline compared with placebo (relative risk=1.06; 95% CI=0.72–1.55) (13). Subgroup analysis additionally found no difference in risk of neuropsychiatric (relative risk=0.53; 95% CI=0.17–1.67) or cardiovascular events (relative risk=1. 26; 95% CI=0.62–2.56) between varenicline and placebo (13). However, these results are inconclusive and are included in the most updated FDA warning on varenicline (23). The FDA also changed the labeling regarding possible risk of decreased tolerance to alcohol (increased drunkenness, unusual behavior or memory loss) and rare risk of seizures within the first month of starting varenicline in patients who had either no history of seizures or had a seizure disorder that had been well controlled (23).
Conclusions
The two most effective tobacco pharmacotherapies are varenicline and combination nicotine replacement therapy, with a recent meta-analysis suggesting varenicline plus combination nicotine replacement therapy being superior to varenicline alone (24). Additional research is underway to determine novel targets, effective pharmacotherapy combinations, optimal duration, relapse prevention strategies, and genetic determinants that improve pharmacotherapeutic efficacy (21).
Key Points/Clinical Pearls
People with mental illness are more likely to use tobacco and therefore more likely to suffer from tobacco-related illness and death compared with people without prior history of mental illness.
Tobacco dependence is due to complex and insidious effects of nicotine through nicotinic acetylcholinergic receptors on physiologic processes and neural reward pathways in the brain leading to long-term habituation.
Pharmacotherapies are effective treatments for tobacco dependence and are recommended by the United States Public Health Service to be provided in conjunction with behavioral therapy.
All Food and Drug Administration-approved pharmacotherapies have demonstrated benefits in promoting abstinence, but relapse rates remain high.
1. : Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004; 328:1519 Crossref, Google Scholar
2. : Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions. Nicotine Tob Res 2012; 14:1300–1318 Crossref, Google Scholar
3. : Nicotine addiction. N Engl J Med 2010; 362:2295–2303 Crossref, Google Scholar
4. : Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol 2009; Oct 78:756–765 Crossref, Google Scholar
5. : CHRNA4 and tobacco dependence: from gene regulation to treatment outcome. Arch Gen Psychiatry 2007; 64:1078–1086 Crossref, Google Scholar
6.
7. : Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev 2012; 11:CD000146 Google Scholar
8. : Individual differences in preferences for and responses to four nicotine replacement products. Psychopharmacology (Berl) 2001; 153:225–230 Crossref, Google Scholar
9. : Recent advances in the pharmacotherapy of smoking. JAMA 1999; 281:72–76 Crossref, Google Scholar
10. : The nicotine inhaler: clinical pharmacokinetics and comparison with other nicotine treatments. Clin Pharmacokinet 2001; 40:661–684 Crossref, Google Scholar
11. : Successful treatment with a nicotine lozenge of smokers with prior failure in pharmacological therapy. Addiction 2004; 99:83–92 Crossref, Google Scholar
12. : A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997; 337:1195–1202 Crossref, Google Scholar
13. : Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2013; 5:CD009329 Google Scholar
14. : Antidepressants for smoking cessation. Cochrane Database Syst Rev 2007; 1:CD000031 Google Scholar
15. : Effect of stress and bupropion on craving, withdrawal symptoms, and mood in smokers. Nicotine Tob Res 2011; 13:492–497 Crossref, Google Scholar
16. : Interventions for preventing weight gain after smoking cessation. Cochrane Database Syst Rev 2012; 1:CD006219 Google Scholar
17. : Interventions for smoking cessation and reduction in individuals with schizophrenia. Cochrane Database Syst Rev 2013; 2:CD007253 Google Scholar
18. : Varenicline: an alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005; 48:3474–3477 Crossref, Google Scholar
19. : Combination varenicline and bupropion sr for tobacco-dependence treatment in cigarette smokers: a randomized trial. JAMA 2014; 311:155–163 Crossref, Google Scholar
20. : Effect of varenicline on smoking cessation through smoking reduction: a randomized clinical trial. JAMA 2015; 313:687–694 Crossref, Google Scholar
21. : Use of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2015; 3:131–138 Crossref, Google Scholar
22. : Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA 2006; 296:64–71 Crossref, Google Scholar
23.
24. : Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: a systematic review and meta-analysis of randomized controlled trials. BMC Public Health 2015; 15:689 Crossref, Google Scholar
25. : Emerging drugs for the treatment of tobacco dependence: 2014 update. Expert Opin Emerg Drugs 2014; 19:243–260 Crossref, Google Scholar
