Nicotine Replacement Therapy

According to the Centers for Disease Control and Prevention, tobacco use is the leading preventable cause of death in the United States (1). The average lifespan of smokers is reduced by more than 10 years compared to individuals who have never smoked (2). Smoking cessation by age 40 reduces mortality by about 90% and cessation by age 60 reduces the loss by 40% (2). Some studies have found improvements in symptoms of depression and anxiety from smoking cessation with effect sizes comparable to those for antidepressants (3). The prevalence and mortality of smoking is so great among individuals with major psychiatric disorders that it is estimated that one-half of patients diagnosed with schizophrenia, bipolar disorder, and major depressive disorder will die of a tobacco-related illness (4). There is evidence that smoking cessation promotes abstinence from other substances in those with more than one substance use disorder (5, 6). As alcohol and tobacco together produce more than additive risks for cancer, treating tobacco and alcohol use together in particular can be more helpful than treating each in isolation (5).

Despite the high impact on health outcomes, there is a major discrepancy between the low rate of clinicians treating tobacco use disorder and the availability of effective treatment (7). Despite efficacy of treatment, up to two-thirds of smokers attempting to quit do not use any evidence-based treatment (8). Psychiatrists have the under-recognized opportunity and obligation to provide patients lifesaving and life-improving treatments for tobacco use disorder that are safe, effective, affordable, and often well received. Patients should be aware that under the Affordable Care Act, they are covered for smoking cessation treatment with no cost sharing. With the exception of unchanged plans grandfathered in before March 2010, health insurance providers are required to cover at least two tobacco cessation attempts annually, including four counseling sessions and 90 days of Food and Drug Administration (FDA)-approved smoking cessation medications (9). Nicotine replacement therapy products come in five forms: gum, inhalers, lozenges, nasal sprays, and transdermal patches (see Table 1). As applied in the present article, nicotine replacement therapy does not refer to smoked tobacco products, smokeless tobacco, or electronic cigarettes.

Mechanism of Action and Pharmacokinetics

Nicotine acts as a full agonist on nicotinic acetylcholine receptors in the autonomic ganglia and CNS. It has stimulant properties and enhances rewarding effects by increasing downstream release of dopamine in the ventral tegmentum of the midbrain (10). Additionally, nicotine’s desensitization of a6b2 nAChRs on cholinergic interneurons of the striatum slows dopamine depletion and enhances the contrast between dopamine release evoked by phasic and tonic firing of dopaminergic nerves in the striatum, leading to increased reward salience (11). Both positive reinforcement (e.g., heightened vigilance, improved mood, and weight loss) and negative reinforcement (alleviation of withdrawal symptoms, e.g., anxiety, irritability, impaired concentration, and increased appetite) mediate nicotine addiction (12). The pharmacokinetics of nicotine peak and fall quickly, contributing to their addictive potential. Nicotinic acetylcholine receptors become desensitized when nicotine levels in the brain are high and then resensitize, leading to withdrawal effects, as nicotine levels fall. Slower release nicotine delivery mechanisms are therefore less reinforcing both because nicotinic acetylcholine receptors cannot rapidly resensitize and because the user has less control in titrating the dose to receive a rewarding effect when desired (12). Furthermore, nicotine replacement therapy lacks additional potentially addictive compounds, such as menthol and acetaldehyde condensation products, which inhibit dopamine metabolism through monoamine oxidase inhibition (2, 10).

Nicotine inhaled from cigarette smoke is easily absorbed over the large surface area of the lungs and is transported directly to the brain via the pulmonary venous system in 10–20 seconds (13). Nicotine levels reaching the brain fall quickly as nicotine is redistributed in the body, largely to skeletal muscle (12, 13). Nicotine replacement therapies from gum, lozenges, inhalers, and nasal sprays are absorbed through oral or nasal mucosa and go into systemic venous circulation. These forms cause nicotine levels to peak on the order of minutes, while transdermal patches release nicotine even more gradually with peak concentrations within hours after application (13). Swallowed nicotine is absorbed poorly in the acidic stomach environment (2). Some is absorbed in the small bowel and is carried into the portal venous circulation where it undergoes first-pass hepatic metabolism, resulting in low (30%–40%) bioavailability. Ingestion of nicotine replacement therapy by swallowing gum or lozenges is therefore not recommended, but rather through buccal absorption. Elimination of nicotine is highly variable from person to person, with an average half-life of approximately 2 hours, primarily by CYP2A6 (10, 13). Nicotine has varying addictive potential depending on the mechanism by which it is administered (10, 13). The FDA recognizes that nicotine delivered via gum, lozenges, and patches has little potential for abuse or dependence and has approved these forms for over-the-counter sale (14). The pharmacokinetics of inhalers and nasal sprays may make them more habit-forming than other nicotine replacement therapies but less so than smoking (13). Nicotine replacement therapies assist with smoking cessation by stabilizing nicotine levels in the blood, thereby reducing both the positive and negative reinforcing effects of faster-acting nicotine delivery mechanisms such as cigarettes.

Drug-Drug Interactions

Nicotine has direct interactions with some drugs and also may indirectly affect hepatic metabolism of other drugs insofar as it offsets smoking, which induces hepatic enzymes. A randomized controlled study of 10 patients demonstrated that nicotine potentiates the effect of adenosine and that tachycardia is more likely to occur when both agents are combined (15). Cimetidine has been demonstrated to slow the elimination of nicotine, resulting in greater effect duration for the same dose (16). Cigarette smoke contains polycyclic aromatic hydrocarbons that are strong inducers of the hepatic enzymes CYP1A1, CYP1A2, and 2E1 (17, 18). Smoking tobacco accordingly decreases the serum levels of medications such as clozapine, olanzapine, imipramine, fluvoxamine, caffeine, theophylline, tacrine, propranolol, flecainaide, pentazocine, and erlotinib. However, nicotine itself is not responsible for these interactions. Clinicians must monitor levels and side effects of these medications closely if the patient’s smoking habits change, as levels can increase significantly with smoking cessation and nicotine replacement therapy.

Indications and Efficacy

The United States Public Health Service recommends the use of nicotine replacement therapy, bupropion, varenicline, or a combination for all patients attempting to quit smoking, except when medically contraindicated or for populations in which insufficient evidence for efficacy exists (pregnant women, adolescents, and smokeless tobacco users) (7). Nicotine replacement therapy increases the success rate of smoking quit attempts by 50%–80% and demonstrates similar efficacy to bupropion and varenicline (19–21). Combination treatment with both nicotine replacement therapy and bupropion is more effective than monotherapy with either (19). The most effective type of therapy is a combination of the transdermal patch and a faster-acting form, such as the lozenge or gum, for breakthrough cravings (12, 21). Although varenicline is more effective than any single form of nicotine replacement therapy, combination nicotine treatment can be equally effective (20). Additionally, nicotine replacement therapy-assisted smoking reduction has the benefit of promoting abstinence among smokers who are not ready to quit at the time therapy is started (22, 23).

Optimal clinical strategies for nicotine replacement therapy are subject to ongoing study and development. Evidence supporting the role of nicotine replacement therapy in adolescent and pregnant smokers is sparse, and different countries have conflicting recommendations on its use (8). Studies comparing nicotine replacement therapy regimens beginning 2 or 4 weeks before a quit attempt with therapy beginning at smoking cessation yield conflicting results and deserve further research (8, 19). Extended duration or maintenance treatment and high-dose nicotine replacement therapy (e.g., 42 mg daily transdermal vs. 21 mg daily transdermal) applied to study populations have only weak evidence of benefit (8). This does not mean that individual patients cannot benefit from these strategies. Some smokers do benefit from maintenance treatment with therapy, and long-term use is believed to be safe (13, 21). If decreasing intensity of nicotine cravings and diminishing medication adherence explain nonsuperiority of extended treatment in study populations, select patients with sustained cravings who can adhere to a prolonged therapy regimen might still benefit from extended treatment (8). The degree of nicotine dependence likely mediates optimal dosing for individual patients. Ongoing research may help guide individualized therapy regimens by phenotypes of nicotine dependence and nicotine metabolism and by genetic markers of nicotine metabolism, nicotine receptors, and dopamine receptors (8). New delivery mechanisms being developed include a nicotine inhalator, nicotine cannon, nicotine pouch, and rapid delivery gum, as well as an oral spray, all of which appear to control nicotine withdrawal at least as well as currently available therapies. Early evidence is mixed regarding the superiority versus equality of oral spray compared with standard therapy in maintaining abstinence from tobacco (8).

Nicotine replacement therapy can be used to alleviate the discomfort of nicotine withdrawal for individuals who are unable to smoke (e.g., while hospitalized). The importance of such symptomatic care is underlined by data showing that smokers with schizophrenia experiencing nicotine withdrawal in a psychiatric emergency department setting demonstrated less agitation when treated with therapy (24).

Adverse Effects

Cigarette smoking is known to precipitate acute cardiac events by at least three mechanisms, one of which involves nicotine. Nicotine’s hemodynamic effects include increasing heart rate and blood pressure and constricting coronary arteries, increasing myocardial work while decreasing blood flow to the myocardium. Unrelated to nicotine, cigarettes produce a hypercoagulable state, and carbon monoxide in smoke decreases oxygen delivery to the heart (25). Chronic use of nicotine replacement products in nonsmokers should theoretically increase the risk of acute cardiac events but to a much lesser degree than tobacco. No effect of increased risk of acute cardiac events is actually seen when nicotine replacement therapy is used by smokers. This is due to the following reasons: the hemodynamic effects of nicotine have a relatively flat dose-response relationship; cigarettes deliver nicotine more rapidly than gum or patches, resulting in more intense hemodynamic effects; and nicotine obtained from nicotine replacement products typically decreases nicotine intake from smoking even in people instructed to smoke ad libitum on nicotine replacement therapy (25). In the Lung Health Study, a multicenter trial following 5,887 middle-aged smokers over 5 years, two-thirds of participants had treatment for smoking cessation that often included nicotine gum. Smokers who quit with assistance from nicotine gum had fewer hospital admissions for cardiovascular events than either continuing smokers or those who quit without nicotine gum (26). Multiple clinical trials have failed to demonstrate increased risk of cardiovascular events with transdermal nicotine patches in current smokers with known cardiovascular disease (25).

Smokeless tobacco is associated with increased risk of pregnant women delivering infants that are small for gestational age and apnea in newborns, both of which might be mediated by effects of nicotine (2). Several studies have examined adverse effects of nicotine replacement products used for smoking cessation in pregnant smokers. No statistically significant differences were found between cohorts regarding outcomes such as preterm birth, placental abruption, or birth weight. Of five studies that compared birth weights and rates of preterm delivery, three found no differences in average birth weight and two found risk of higher-average birth weight with nicotine replacement therapy, one of which also found decreased incidence of low birth weight and preterm delivery with therapy (27). For pregnancy, transdermal nicotine is classified as FDA Category D, and shorter-acting therapies are classified as FDA Category C. Nicotine concentrates in breast milk, with a 2.9:1 ratio with maternal serum (28). Risks to breastfeeding infants are not well known (29).

Precaution should be taken for patients less than 18 years old, those with serious or worsening angina, those with myocardial infarction in the past 2 weeks, or those with serious arrhythmia. Nicotine gum and lozenges may cause hiccups, cough, and dyspepsia. Nicotine gum may also cause mouth/jaw soreness. With incorrect chewing technique, lightheadedness and nausea/vomiting may occur (21). Both lozenges and patches can cause sleep disturbances, and patches also may precipitate local skin reactions (19). Nasal sprays can cause tearing, sneezing, and rhinitis. All forms of nicotine replacement therapy have the potential to trigger headaches (21).

Key Points/Clinical Pearls