Nicotine Addiction Treatment & Management

Tobacco use is the greatest potentially remedial problem throughout the world, and it is the number one preventable cause of death in the developed world. Clinicians have a particularly important role as patient advocates in health promotion, discouraging smoking initiation, encouraging and assisting smoking patients to quit, and participating in social efforts designed to curb smoking at various levels.

The gains in understanding the neuropathology of nicotine addiction have already opened new frontiers, including effective nicotine replacement therapy (NRT) and oral therapy. Greater therapeutic advances are anticipated in the years to come.

A critical component of treatment is educating patients about the benefits of smoking cessation and the cessation process. Provide a description of the expected withdrawal syndrome. Continue with a discussion of the possible cessation methods, which include counseling, NRT, antidepressant medications, behavioral training, group therapy, hypnosis, and quitting “cold turkey.” Successful cessation is confirmed by measuring cotinine or carbon monoxide levels.

More than 90% of patients who attempt to quit smoking stop cold turkey. Professional group therapy or counseling achieves an initial cessation rate of 60-100% and a 1-year cessation rate of approximately 20%. Hypnosis and acupuncture are popular programs that might encourage renewed attempts by people for whom other techniques have failed, but these modalities have not been shown to be any better than placebo.

The use of smokeless tobacco products constitutes a small but growing segment that requires special considerations in the design of treatment interventions. ^[31] NRT does not increase smokeless tobacco quit rates; however, of the pharmacologic options, varenicline shows early positive results.

Patients who quit smoking tend to gain weight; therefore, patients should be encouraged to follow a low-calorie diet and exercise regimen during and after cessation. In patients attempting smoking cessation, exercise has been shown to help curb long-term weight gain and to help alleviate nicotine withdrawal symptoms.

Interventions designed specifically for weight-concerned smokers (eg, an on-site exercise program) improved smoking abstinence rates and delayed weight gain. Cognitive-behavioral therapy to reduce weight concerns improved smoking cessation success and reduced weight gain.

Smoking may begin as a voluntary habit, but eventually it becomes an addiction. Health professionals can contribute powerfully to motivating their patients to attempt and sustain cessation by offering encouragement, advice, and assistance.

When patients are not yet ready to attempt quitting, such advice can move them further toward that point. Willingness to help and availability to provide assistance are very important in motivating cigarette smokers in attempting to quit. Reassurance that a knowledgeable health professional stands ready to offer guidance and support is immensely beneficial to individuals addicted to nicotine.

According to US Preventive Services Task Force (USPSTF) guidelines, clinicians should ask all adults about use of tobacco products and should provide cessation interventions to all current tobacco users. The guidelines advocate a “5-A” approach to counseling that includes the following ^[32] :

1. A sk about tobacco use

2. A dvise to quit through personalized messages

3. A ssess willingness to quit

4. A ssist with quitting

5. A rrange follow-up care and support

Brief behavioral counseling (ie, < 10 minutes) and pharmacotherapy are each effective when used alone, though they are most effective when used together. ^[33]

The task force also advises clinicians to ask all pregnant women, regardless of age, about tobacco use. Those who currently smoke should receive pregnancy-tailored counseling supplemented with self-help materials.

Understanding the benefits and limitations of the available medications provides an important foundation for a successful smoking cessation program.

Assess smoking history, level of addiction, and the health status of the patient (see the image below). After the assessment, intervene with education and advice. Patients may be referred for group therapy or behavioral counseling. If an affective disorder is suspected, evaluation by a psychiatrist may be indicated.

NRT works by making it easier to abstain from tobacco by partially replacing the nicotine previously obtained from tobacco. ^[3] There are at least 3 mechanisms by which NRT could be effective, as follows:

1. Reducing general withdrawal symptoms, thus allowing people to learn to get by without cigarettes

2. Reducing the reinforcing effects of tobacco-delivered nicotine

3. Exerting some psychological effects on mood and attention states

Nicotine replacement medications should not be viewed as standalone medications that make people stop smoking; reassurance and guidance from health professionals are still critical for helping patients achieve and sustain abstinence. There are 6 types of nicotine replacement products currently on the market, as follows:

1. Transdermal nicotine patch

2. Nicotine nasal spray

3. Nicotine gum

4. Nicotine lozenge

5. Sublingual nicotine tablet

6. Nicotine inhaler

The first type is intended for longer-term use, whereas the other 5 types are used for acute dosing. With the acute-dosing products, the amount and timing of nicotine delivery can be titrated by the user, allowing the use of these products as rescue medication for cravings.

Ongoing craving in a quitter is associated with acute episodes of more intense craving (ie, breakthrough craving). Provoked by situational stimuli, such as seeing someone smoke or experiencing emotional upset, such episodes are associated with a very high risk of relapse. Acute NRT approaches may also be used when a situation is expected to produce a craving (eg, a demanding meeting, rush-hour traffic, a long commute, or a social situation where cigarette smokers will be present).

Common adverse events that are common to all NRT products include dizziness, nausea, and headache.

Transdermal nicotine patch

Nicotine patches deliver nicotine through the skin at a relatively steady rate. ^[34] In general, they yield higher compliance rates than other NRT products do, but they may not adequately protect against craving provoked by smoking-related stimuli. For breakthrough cravings not adequately controlled by transdermal nicotine alone, acute therapies (see below) may be added.

Currently, 4 patch formulations are on the market; they vary widely with regard to design, pharmacokinetics, and duration of wear (eg, 16 or 24 hours). For some products, progressively lower doses may be given to allow weaning over a period of several weeks or longer so that the patient can gradually adjust to lower nicotine levels and ultimately to a nicotine-free state. Those who smoke more than 10 cigarettes per day should use the 21-mg/day patch for the first 6 weeks, the 14-mg/day patch for 2 weeks, and the 7-mg/day patch for the final 2 weeks.

Relapse is common and expected in the early stages of tobacco cessation treatment. A randomized, double-blind, placebo-controlled trial showed that active use of the nicotine patch (21 mg/day) by subjects who experienced a relapse during treatment significantly increased the likelihood of recovery from the relapse in comparison with those who received placebo. ^[35] Clinicians could encourage continued use of the nicotine patch during these relapses.

In a study testing the efficacy of nicotine patches in combination with behavioral therapy for the treatment of adolescent spit tobacco addiction, the spit tobacco cessation rate was 11.4% in the usual care group, 25% in the placebo patch group, and 17.3% in the active patch group. ^[36] The difference between the cessation rates for the last 2 groups was not significant, proving that behavioral intervention is twice as successful and that the nicotine patch did not offer additional improvement.

Nicotine nasal spray

Marketed as a prescription medication, the nasal spray delivers nicotine more rapidly than other NRTs and affords relief of acute cravings. The multidose bottle with a pump delivers 0.5 mg of nicotine per 50-µL squirt. Each dose consists of 2 squirts, 1 to each nostril. The dosage of nasal spray should be individualized for each patient according to the patient’s level of nicotine dependence. Most patients are started with 1 or 2 doses per hour, which may be increased up to the maximum of 40 doses per day.

Nicotine gum

First available in the 1980s, nicotine polacrilex (nicotine gum) is available without a prescription. ^[37] It is available in 2-mg and 4-mg doses, which deliver approximately 1 mg and 2 mg of nicotine, respectively.

Patients are instructed to use 1 piece of gum every 1-2 hours for the first 6 weeks and then reduce their use to 1 piece every 2-4 hours for the next 3 weeks and finally to 1 piece every 4-8 hours for the 3 weeks after that. In highly dependent smokers, the 4-mg gum is superior to the 2-mg gum. Because about 50% of the nicotine in gum is absorbed, a smoker who is on a fixed schedule of 10 pieces per day will receive a daily nicotine dose of about 10 mg with the 2-mg gum and 20 mg with the 4-mg gum.

Slow absorption of nicotine from gum doses will not produce extremely high levels of nicotine. Acidic beverages interfere with buccal absorption of nicotine; thus, patients should avoid acidic beverages (eg, soda, coffee, and beer) for 15 minutes before and during chewing gum. Nicotine gum chewing may cause jaw soreness; therefore, the smoker should chew the gum to release nicotine, then move the gum between the cheek and gum for a minute or so. Gum can also cause a mild burning sensation in the mouth and throat, which may be undesirable.

An open randomized trial of 314 daily smokers found that starting nicotine gum 4 weeks before the quit date did not yield higher smoking cessation rates than starting on the quit date. ^[38] At follow-up 8 weeks after the quit date, self-reported 4-week abstinence rates were 41.6% for the pre–quit date group and 44.4% for the usual care group. Biochemically verified cessation occurred at 1 year after the quit date for participants, and no significant difference was found between the 2 groups (20.8% for the first group, 19.4% for the second). ^[39]

Nicotine lozenge

The nicotine lozenge has been available in 2- and 4-mg formulations since 2002. Nicotine from the lozenge is absorbed slowly through the buccal mucosa. The lozenge should not be chewed, and the amount of nicotine absorbed per lozenge is somewhat higher than that absorbed from nicotine gum.

Sublingual nicotine tablet

A small nicotine tablet has been developed but is not yet available in the United States. The product is designed to be held under the tongue, where the nicotine in the tablet is absorbed sublingually. The levels of nicotine obtained by using the 2-mg tablet are comparable to those obtained by using the 2-mg nicotine gum. It is recommended that smokers use the sublingual tablet for at least 12 weeks, after which period the number of tablets used is gradually tapered.

Nicotine inhaler

Currently marketed as a prescription medication in the United States, the nicotine inhaler consists of a mouthpiece and a plastic cartridge containing nicotine. When the inhaler is “puffed,” nicotine is drawn into the mouth of the smoker; this satisfies a key behavioral aspect of smoking—namely, the hand-to-mouth ritual.

Each inhaler cartridge contains 10 mg of nicotine, of which 4 mg can be delivered; of the 4 mg delivered, 2 mg is absorbed. The nicotine is not delivered to the bronchi or lungs but is deposited and absorbed in the mouth, as with nicotine gum. Most people use between 6 and 16 cartridges a day. The recommended duration of treatment is 3 months, after which period patients may be weaned by gradual reduction over the following 6-12 weeks.

Efficacy of NRT

In a Cochrane meta-analysis of 132 trials involving the use of any type of NRT along with a placebo or non-NRT control group, the risk ratio (RR) of abstinence for any form of NRT relative to control was 1.58 (95% confidence interval [CI], 1.50-1.66). ^[3] The pooled RRs for each type were as follows:

• 1.43 (95% CI, 1.33 to 1.53; 53 trials) for nicotine gum

• 1.66 (95% CI, 1.53-1.81; 41 trials) for the transdermal nicotine patch

• 1.90 (95% CI, 1.36-2.67; 4 trials) for the nicotine inhaler

• 2.00 (95% CI, 1.63-2.45; 6 trials) for oral tablets or lozenges

• 2.02 (95% CI, 1.49-3.73, 4 trials) for the nicotine nasal spray

Thus, all of the commercially available forms of NRT increase the chances of successful smoking cessation. Overall, NRT increases the quit rate by 50-70%, and the increase appears to be independent of any additional support provided.

Piper et al conducted a randomized, placebo-controlled, double-blind trial of 5 smoking cessation pharmacotherapies. ^[40] The study population included 1504 adults who smoked at least 10 cigarettes daily for the previous 6 months and were motivated to quit smoking. Patients were randomly assigned to 1 of the following groups: nicotine lozenge, nicotine patch, sustained-release bupropion, nicotine patch plus nicotine lozenge, bupropion plus nicotine lozenge, or placebo.

All treatment groups had smoking cessation rates differing from those of the placebo group, but only the nicotine patch–plus–nicotine lozenge group showed significantly higher abstinence rates at 6 months after quitting in comparison with the placebo group. ^[40] The effects of the nicotine lozenge, bupropion, and bupropion plus lozenge were comparable with those reported in previous research.

A Canadian study, purported to be the first population-based longitudinal study using a representative sample of smokers, examined the association between duration of NRT use and smoking cessation (≥1 month). Results of the study support the recommendation to use NRT, particularly the patch, for 8–12 weeks in the clinical practice guideline by the US Public Health Service. ^{[41, 4]}

Long-term NRT

Smoking cessation treatments with NRT enable smokers to cease tobacco use and subsequently to withdraw from nicotine altogether. However, for some smokers, complete withdrawal from smoking may be difficult. In those individuals, it may be beneficial to continue NRT for longer periods, even indefinitely, to prevent relapse to smoking. This strategy is essentially the same as that currently used in methadone maintenance programs for heroin-dependent patients, where patients may be maintained on daily doses of methadone for years.

Although nicotine is not entirely without risk, nicotine maintenance is clearly safer than cigarette smoke–delivered nicotine, with its numerous accompanying toxins. Therefore, indefinite NRT to prevent resumption of smoking may be considered for some individuals.

Bupropion

Bupropion acts by alleviating some of the symptoms of nicotine withdrawal, which include depression. ^{[42, 43]} One clinical trial demonstrated that highly nicotine-dependent smokers who receive bupropion are more likely to experience a decrease in depressive symptoms during active treatment. Like NRT products, bupropion has been endorsed by the US Clinical Practice Guideline as a first-line therapy. ^[4]

Compared with placebo, bupropion approximately doubles smoking cessation rates, and it is equally effective for men and women. It may yield higher cessation rates when combined with NRT than when used alone. However, Planer et al found that bupropion was not effective in hospitalized patients with acute coronary syndrome (patients who are at high risk for subsequent ischemic events) despite continuous and intensive nurse counseling about smoking cessation. ^[44]

The recommended and maximum dosage of bupropion is 300 mg/day, given as 150 mg twice daily. Dry mouth and insomnia are the most common adverse events associated with use. A very small risk of seizure exists, which can be reduced by not prescribing the medication to persons with a history of seizure or a predisposition toward seizure.

Varenicline

Varenicline is a partial agonist that is selective for alpha-4, beta-2 nicotinic acetylcholine receptors (nAChRs). Its action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Its agonistic activity is significantly lower than that of nicotine. Varenicline helps smokers quit by preventing withdrawal symptoms while moderate levels of dopamine are maintained in the brain.

In a Cochrane meta-analysis including 5 trials of varenicline versus placebo (of which 3 also included bupropion as a comparator), the pooled odds ratio (OR) for continuous abstinence was 3.22 (95% CI, 2.43-4.27) for varenicline versus placebo at 12 months and 1.66 (95% CI, 1.28-2.16) for varenicline versus bupropion. ^[45] The main adverse effect of varenicline was nausea, which was mostly mild to moderate and usually subsided over time. Varenicline yielded a 3-fold increase in long-term smoking cessation rates compared with unassisted quit attempts.

In another Cochrane study, 11 randomized, controlled trials (with over 10,000 subjects) involving the use of nicotine receptor partial agonists for smoking cessation were reviewed, ^[45] and the pooled RR (for 10 trials with 4443 subjects; 1 trial that evaluated long-term safety was excluded) for continuous abstinence at 6 months or longer was 2.31 for standard-dosage varenicline versus placebo (95% CI, 2.01 to 2.66).

The main side effect remains nausea, which tends to diminish over time. Soon after the introduction of varenicline, scattered reports of an association between the medication’s use and depression and suicidal ideation arose. The results of the aforementioned review of 11 published studies suggest that any such association is likely to be weak ^[45] ; nevertheless, the possibility warrants further monitoring.

A systematic review and meta-analysis of 14 double-blind, randomized, controlled trials comprising more than 8000 tobacco users (including smokeless tobacco) who used varenicline found a 72% increased risk of serious adverse cardiovascular events in the varenicline group compared with the placebo group (1.06% vs 0.82%). ^[46]

In this review, serious adverse cardiovascular events were defined as myocardial infarction, unstable angina, coronary revascularization, coronary artery disease, arrhythmias, transient ischemic attacks, stroke, sudden death or cardiovascular-related death, or congestive heart failure. ^[46]

A meta-analysis reported by the FDA in 2012 also showed an increased risk of serious adverse cardiovascular events in patients receiving varenicline compared to those receiving placebo. Although the events were uncommon in both groups and the risk was not statistically significant, data analysis points to the drug as the likely cause. ^[47]

On the basis of study findings, extreme caution should be used when considering varenicline for patients with known cardiovascular problems.

Besides NRT products and bupropion, nortriptyline and clonidine are endorsed by the US Clinical Practice Guideline as second-line therapies.

Nortriptyline

Studies have demonstrated the potential efficacy of nortriptyline for smoking cessation in smokers without history of major depression. ^[42] Nortriptyline in combination with transdermal nicotine was also shown to enhance the cessation rates above levels seen with transdermal nicotine alone. The tricyclic antidepressant doxepin has also been shown in a small human study to improve cessation rates.

The most commonly encountered side effects associated with nortriptyline include fast heart rate, blurred vision, urinary retention, dry mouth, constipation, weight gain or loss, and low blood pressure on standing.

Nortriptyline is endorsed by the US Clinical Practice Guideline as a second-line therapy.

Clonidine

Clonidine, an alpha₂ -noradrenergic agonist used to treat hypertension, has been shown to diminish symptoms of both opiate and alcohol withdrawal symptoms. A study of heavy smokers who had failed in previous quit attempts found that those treated with clonidine had an abstinence rate double that seen in smokers treated with placebo at the end of the 4-week treatment period; this effect persisted for the 6-month follow-up period.

Although clonidine may be efficacious in the treatment of nicotine addiction, the conditions under which it is most appropriately used are not well defined. The most common side effects of clonidine are constipation, dizziness, drowsiness, dryness of mouth, and unusual tiredness or weakness.

Like nortriptyline, clonidine is endorsed by the US Clinical Practice Guideline as a second-line therapy.

To improve smoking cessation, medications can be combined. For example, passive nicotine delivery (eg, via a transdermal patch) may be used in conjunction with another medication that permits acute dosing (eg, gum, nasal spray, or inhaler). Combining the nicotine patch (which may prevent the appearance of severe withdrawal) with acute-dosing formulations (which can provide relief in trigger-to-smoke contexts) may provide an excellent treatment alternative to the use of either therapy alone. ^{[48, 49]}

Bupropion in combination with a nicotine patch appears to be more efficacious than a nicotine patch alone, possibly because the 2 medications act via different pharmacologic mechanisms. ^[50] Despite the possibility of increased efficacy, the US Clinical Practice Guideline recommends that such combination therapy be prescribed under the direction of an experienced clinician or a specialty clinic.

Novel therapies

In view of the rather limited success achieved with most pharmacologic and behavioral therapies is rather limited, there is clearly a need for other and better treatments. One novel approach is to immunize smokers against nicotine. The rationale is that antibodies induced by the vaccine should bind nicotine in the blood, thereby preventing it from reaching the nicotine receptors in the brain and breaking the cycle of nicotine addiction.

A prototype vaccine against nicotine was developed and studied in a randomized trial in which 229 subjects received 5 intramuscular injections of the nicotine vaccine and 112 placebo; the vaccine was safe and generally well tolerated, despite failure to increase continuous abstinence rates significantly, and results were significant in subgroup analyses. ^[51] Although more studies are needed, immunotherapy appears to have opened a new avenue to the treatment of nicotine addiction.

In a preliminary assessment of the first phase III trial, the nicotine vaccine NicVAX (Nabi Biopharmaceuticals, Rockville, MD) failed to meet the primary endpoint of abstinence from smoking at 12 months. ^[52] Results showed that subjects treated with NicVAX quit smoking at roughly the same rate (about 11%) as subjects who received placebo. A second phase III trial is under way.

Mecamylamine is a nicotine antagonist that—at least in principle—would seem capable of playing a role in smoking cessation. Much as opiate antagonists prevent opiate users from achieving a high, mecamylamine would prevent smokers from deriving any pleasurable affects from nicotine. The combination of mecamylamine with the nicotine patch increased successful quit rates. Routine clinical use of mecamylamine must await further research. ^[53]

More than 90% of first-time use of tobacco occurs before high school graduation. Because the average age at first use is 14.5 years, smoking prevention must start early. Because of their developmental stage, adolescents are more susceptible to social and environmental influences to use tobacco. ^[21] Approximately 40% of teenagers who smoke eventually become addicted to nicotine.

Social attitudes and policies toward smoking can have a major impact on smoking behavior. Healthcare associations, public health organizations, and consumer groups should lobby for the following:

• Restriction of access to tobacco products for minors

• Restriction of smoking in public places

• Restriction of advertisements

• Increased prices through taxation

• Increased awareness of the harmful health effects of smoking

Minimizing nicotine use among adolescents is an important social policy that can reduce adult addiction. Unfortunately, at the present time, no single clinical approach emerges as the best pathway. Clinical strategies that incorporate motivational interventions and cognitive-behavioral treatments show promise but await further research confirmation. ^[54]

Highly nicotine-dependent smokers may require initial therapy for 6 months or longer. Some individuals may require low-dose maintenance therapy for years.

Long-term follow-up is recommended because individuals who successfully quit smoking are at high risk for relapse. Relapse during the first year after achieving smoking cessation occurs in approximately 50% of patients, irrespective of therapeutic regimen. The changes in the central nervous system (eg, in neuron genetics, cell structure, and cell function) induced by smoking are not reversed by pharmacologic therapy.

The health care deliverer should make provisions for support, measurement of progress, and a mechanism to deal with relapse. For motivated patients who have failed smoking cessation, referral to an expert should be considered for treatment of a relapse. Controlled studies are required to help guide management of relapses and prolonged tapering periods. Immediately restarting nicotine medication might be helpful if a relapse occurs.