Pharmacotherapy of Tobacco Use Disorder

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 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 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 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 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).

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 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).