Intervention
Number of studies
Estimated odds ratioa (95 % CI)
Estimated abstinence rate (95 % CI)
Total N
No intervention
–
–
3–5
–
Simple advice vs usual care
17
1.6 (1.4–1.9)
5.2 (3.2–6.5)
15,930
Patient-initiated telephone quit line@vs usual care
9
1.4 (1.2–1.5)
9.0 (8.5–14.1)
18,500
Placebo in medication trials
80
1.0
13.8
14,537
Single agents
Nicotine gum (6–14 weeks)
13
1.5 (1.2–1.7)
19.0 (16.5–21.9)
662
NRT vs placebo or no treatment
111
1.5 (1.5–1.6)
22.2 (18.7–24.8)
43,000
Nicotine patch (6–14 weeks)
31
1.9 (1.7–2.2)
23.4 (21.3–25.8)
16,625
Nicotine patch (>14 weeks)
6
1.9 (1.7–2.3)
23.7 (21.0–26.6)
5,939
Bupropion SR
45
2.0 (1.8–2.2)
24.2 (22.2–26.4)
13,182
Nicotine inhaler
4
2.1 (1.5–2.9)
24.8 (19.1–31.6)
3,282
Long-term nicotine gum (>14 weeks)
40
2.2 (1.5–3.2)
26.1 (19.7–33.6)
1,500
Nicotine nasal spray
4
2.3 (1.7–3.0)
26.7 (21.5–32.7)
1,126
Varenicline (2 mg/day)
14
3.1 (2.5–3.8)
33.2(28.9–37.8)
5,611
Combination therapy
Nicotine patch + inhaler
2
2.2 (1.3–3.6)
25.8 (17.4–36.5)
446
Nicotine patch + bupropion SR
6
2.5 (1.9–3.4)
28.9 (23.5–35.1)
1,106
Nicotine patch (>14 weeks) + nicotine@gum or spray
5
3.6 (2.5–5.2)
36.5 (28.6–45.3)
800
Although a broad literature exists guiding behavioral and pharmacological interventions in general surgical populations, there is relative paucity of data guiding medication choices in patients with malignancy [6]. There are only four studies that specifically evaluated the use of pharmacologic therapy among patients with cancer in the perioperative setting and only two were performed in patients with lung cancer. The other two studies were performed in patients with breast cancer. The study by Park et al. utilized a nonrandomized design to assign 49 smokers with suspected thoracic malignancy to either control group or a 12 week program consisting of varenicline and smoking cessation counseling [23]. Cotinine-confirmed 7 day point prevalence abstinence rates were 28.1 % in the intervention group versus 14.2 % in the control group at 2 weeks, and 34.4 % versus 14.3 % respectively at 12 weeks. Although these differences were not statistically significant in this small pilot study, these data suggest that a successful cessation intervention using varenicline can be delivered around the time of diagnosis and prior to therapy. In another small study of thoracic surgery patients, Kozower et al. described quit rates following a 10 min office-based intervention with a thoracic surgeon. The 40 participants were offered medication and instructed on use of a state-based quit line, used by 50 % and 7.5 % of the participants respectively. Biochemically confirmed abstinence rates at 3-month follow up were 35 %, suggesting that the surgery environment is a powerful place for effecting abstinence [24].
Nicotine Replacement Therapy
Nicotine replacement therapy products contain pure nicotine without other carcinogens and deliver 1/3–2/3 the concentration produced by cigarette smoking. Nicotine replacement therapy is based on the principle that nicotine is the dependence-producing constituent of cigarette smoking and that smoking cessation can be achieved by replacing nicotine without the toxins in cigarette smoke. Although NRT does not completely relieve the withdrawal symptoms, it makes the experience of stopping less unpleasant. All NRTs are nicotinic acetylcholine receptor agonists but compared with smoking a cigarette, the nicotine via NRT products is delivered to the brain much more slowly and at a lower dose. They do not reproduce the rapid and high levels of nicotine achieved through inhalation of cigarette smoke.
A Cochrane review of 132 trials with over 40,000 patients found that all forms of NRTs increase quit rates by one-and-a-half to twofold [25]. The efficacies of the various forms of NRT are generally similar but compliance may be the limiting factor. One study comparing four forms of NRT found comparable 12 week abstinence rates (20–24 %) but compliance varied: 11 % with the inhaler, 15 % with the nasal spray, 38 % with the gum, and 82 % with the patch. In nearly every randomized clinical trial performed to date, the nicotine patch has been shown to be effective compared with placebo, usually with a doubling of the smoking abstinence rate (Table 7.1) [19–22].
It seems possible to improve the efficacy of NRT by combining the transdermal patch (slow release) with an oral formulation (fast release) that permits ad libitum nicotine delivery. NRT is typically started the day of the quit date though pre-cessation treatment is considered safe and may be advantageous for smokers to try NRT prior to the stress of quitting to determine which agent or agents are preferable.
Most patients use NRT for 4–8 weeks but it is safe for longer use if needed to maintain smoking abstinence. The optimal length of treatment has not been determined but longer term treatment (more than 14 weeks) appears to provide benefit over standard lengths of treatment when combining nicotine patches and nicotine gum. Furthermore, long term treatment of up to 6 months with triple combination therapy (nicotine patches, Bupropion, and nicotine vapor inhaler) appears superior to standard dose nicotine patch therapy given over a 10 week period. For the best chance at success with these therapies, they may be used in combination and should be dose-appropriate based on the patient’s need.
Non-nicotine Medications
There are two non-nicotine medications which have been proven to be effective as smoking-cessation pharmacotherapy – bupropion and varenicline. Varenicline is considered more effective based on randomized trials. The U.S. Food and Drug Administration (FDA) has issued boxed warnings for both drugs due to reports of increased risks of psychiatric symptoms and suicide. Given the well-established link between smoking and psychiatric disease, there is no easy way to determine whether or not these adverse events are directly related to the medications. Unfortunately these warnings may deter clinicians from discussing or prescribing bupropion and/or varenicline.
Bupropion (Wellbutrin/Zyban)
Bupropion hydrochloride is an atypical slow-acting antidepressant recommended by the FDA as a first-line drug for the treatment of smokers. Bupropion is known to inhibit the reuptake of norepinephrine and dopamine in the nucleus accumbens, a key area for nicotine reinforcement. Additionally, bupropion antagonizes brain nicotine receptors and blocks the reinforcement effects of nicotine. It has been demonstrated to decreases craving and symptoms of withdrawal.
Since it takes up to 2 weeks to take effect, it is advised to establish a definitive quit date 2 weeks after beginning the medication. Bupropion has been shown to double the odds of cessation and appears to have similar effectiveness to NRT. In addition, studies have suggested that a combined approach with bupropion plus a nicotine patch may be even more effective. The dose of bupropion SR is 150 mg tablet per day, preferably upon waking, for 3 days, then increasing to one table twice daily. The doses should be separated by at least 8 h with the second dose as far away from bedtime as possible. The 2008 USPHS guideline recommends the combined use of bupropion SR and nicotine replacement therapy [19]. The length of recommended treatment is at least 3 months. In patients with depressive symptoms attempting to quit, bupropion should be considered in combination with NRT.
Varenicline
Varenicline is a partial nicotinic agonist; it binds to the nicotinic receptors, thereby preventing nicotine binding. This partial agonist activity induces receptor stimulation and reduces withdrawal symptoms during cessation. Varenicline also blocks the dopaminergic stimulation responsible for the reinforcement and reward associated with smoking. This action reduces the craving and the pleasure associated with cigarette smoking.
The effectiveness of varenicline in smoking cessation was demonstrated in six clinical trials. Five of the six studies were RCTs in which varenicline was shown to be superior to placebo in helping people quit smoking. In two of the five placebo controlled studies, varenicline-treated patients were more successful in giving up smoking than patients treated with bupropion [26, 27]. Evidence suggests that using varenicline can increase the chances of successful long-term smoking cessation between two-and threefold compared with pharmacologically unassisted quit attempts. In a 2009 meta-analysis of 101 studies of pharmacotherapy for smoking cessation, varenicline was found to be more effective than bupropion and NRT monotherapy in achieving continuous abstinence rates at 12 and 24 weeks [28]. In a more recent systematic review and multiple treatment meta-analyses, varenicline exhibited the largest and more sustained treatment effects compared to other pharmacotherapies [29]. A recent double-blind, randomized, placebo controlled trial of varenicline, demonstrated its effectiveness in the perioperative setting in patients undergoing a variety of non-thoracic surgical procedure [30]. Varenicline was also found to be slightly more effective than combination NRT and approximately triples the chances of long term abstinence versus placebo.
Varenicline is supplied in a “Starting Month Pack” and a “Continuing Month Pack”. Since it takes 1 week to take effect, it is advised to set the quit date 1 week after beginning the medication. The Starting Pack begins with 0.5 mg daily for 3 days, followed by 0.5 mg twice daily for 4 days. The target quit date is day 8 when the maintenance dose of 1 mg twice daily begins. The initial treatment period should be at least 12 weeks (one starting pack plus two continuing packs). The decision to continue past 12 weeks should be individualized, keeping in mind that higher quit rates are seen with longer duration of treatment. From a practical standpoint (as with any cessation medication), longer treatment can be recommended for abstinent smokers who are not secure and are concerned about smoking relapse.
Combination Pharmacotherapy
Data from RCTs suggest that certain combinations of first-line cessation medications are efficacious in promoting long-term abstinence. Improved cessation rates with combination therapy appear to be primarily due to greater craving suppression. As such, the 2008 USPHS clinical practice guideline considers the following regimens to be appropriate first-line therapy in patients attempting to quit smoking [19].
Combination NRT
Combination NRT involves the use of a long-acting formulation (patch) in combination with a short-acting formulation (gum, lozenge, inhaler, or nasal spray). The long-acting formulation, which delivers relatively constant levels of the drug, is used to prevent the onset of severe withdrawal symptoms, and the short-acting formulation, which delivers nicotine at faster rate, is used as needed to control withdrawal symptoms or cravings that may occur during potential relapse situations (for example, after meals, when under stress, or when around other smokers). A recent meta-analysis found that the combination of NRTs was significantly more effective than single agent NRT. The odds of long-term (>6 months) abstinence were 1.4 times better with the combination therapy compared to nicotine monotherapy [19].
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