Consider drug treatment modalities for smoking cessation, including nicotine replacement, bupropion, and varenicline.

• Nicotine replacement therapy:
  • All currently evaluated forms of nicotine replacement therapy appear equally effective at increasing cessation rates by about 1.5- to 2-fold at 6 months among motivated persons, equivalent to a smoking cessation rate of 17%
  • The evaluated forms of nicotine replacement therapy include nicotine patch, nasal spray, inhaler, gum, sublingual tablet, and lozenge
  • Combination therapy with nicotine products may increase cessation rates over monotherapy, although insufficient evidence exists at this time to make a firm recommendation
• Antidepressant therapies including bupropion and nortriptyline:
  • Antidepressant therapies that are effective for smoking cessation include bupropion and nortriptyline, but there is a greater volume of evidence to support the use of bupropion
  • Therapy with bupropion or nortriptyline increases cessation rates by about 2-fold, or by approximately 15%, at 1 year among motivated persons
  • SSRIs do not appear effective for smoking cessation
• Nicotine receptor partial agonists (varenicline):
  • Therapy with varenicline increases cessation rates by about two-fold, or by approximately 15%, at 1 year among motivated persons
  • Varenicline may be more effective than bupropion, based upon results of two large randomized controlled trials and meta-analyses

Evidence:

• Nicotine Replacement Therapy
  • A Cochrane review of nicotine replacement therapy for smoking cessation observed a pooled OR of 1.74 (CI, 1.64 to 1.86) in favor of abstinence, equivalent to a cessation rate of 10% among controls and 17% among participants receiving nicotine replacement therapy (NNT 14). The benefit of nicotine replacement therapy was independent of whether the patch was worn for 16 hours or 24 hours, tapering vs. abrupt withdrawal of nicotine replacement therapy, and 8 weeks vs. a longer duration of therapy. The review found that all forms of nicotine replacement therapy were effective at increasing cessation rates. It also suggested that combination therapy may be superior to monotherapy (OR, 1.55 [CI, 1.17 to 2.05]), although substantial heterogeneity existed in the primary studies examining this question (42)
  • A separate RCT of combination therapy with nicotine patch and nasal spray showed this treatment regimen to be more effective than nicotine patch alone for smoking cessation at 1 year (11% vs. 27%, P = 0.001). There was also a trend towards increased cessation at 6 years (8% vs. 16%, P = 0.08) (43)
  • A pooled analysis of RCTs of nicotine replacement therapy showed the combined OR for increase in cessation with nicotine replacement therapy was 1.7 (CI, 1.6 to 1.8) (42)
  • A separate RCT of nicotine lozenges for smoking cessation demonstrated absolute increases in cessation rates of 8.3% and 8.7% respectively in low- and high-dependence participants at 52 weeks (44)
  • Only two small studies of the nicotine antagonist mecamylamine for smoking cessation were identified by a Cochrane review. There was some evidence that nicotine plus mecamylamine may be better than nicotine alone (45)
  • A follow-up study examined rates of smoking 8 years after enrollment in a RCT of the nicotine patch. The study found that 46% (CI, 38% to 54%) of those who had quit had relapsed. Relapse rates were similar in the treatment and control groups (46).
• Antidepressant Therapies Including Bupropion:
  • A Cochrane review of antidepressant therapy for smoking cessation found benefit for both bupropion and nortriptyline. Their efficacy appeared to be independent of their antidepressant activity. The data are inadequate to suggest that combining one of these medications with nicotine replacement therapy would be more efficacious. SSRI medications do not increase cessation rates (47; 48).
  • Two large randomized trials examined the effectiveness of bupropion for smoking cessation (49; 50). In one RCT, bupropion produced a 15% absolute increase in smoking cessation compared to placebo (NNT, 7), and a 14% absolute increase in smoking cessation compared to nicotine replacement therapy (NNT, 7) at 1 year. Combination therapy of bupropion and nicotine replacement therapy increased 1-year smoking cessation rates by 5% over bupropion alone but was not statistically significant (49)
  • A separate RCT of sustained-release bupropion vs. placebo in black Americans demonstrated an absolute increase in smoking cessation of 7.3% (CI, 1.0 to 13.7) at 26 weeks (51)
• Nicotine receptor partial agonists (varenicline):
  • Two large randomized trials examined the efficacy of varenicline for smoking cessation (52; 53). Both trials comprised three group studies that compared varenicline vs. placebo vs. bupropion. Compared to placebo, varenicline produced a 13% absolute increase in cessation (NNT, 8) at 1 year. One of two studies found a significant increase in cessation for varenicline compared to bupropion at 1 year (absolute increase 8.4%, NNT 12) (52). In the other study (53), the difference in cessation at 1 year was of marginal significance (varenicline 21.9% vs. bupropion 16.1%; P=0.057).
  • One large randomized trial examined the role of varenicline for relapse prevention (54). Individuals who were abstinent after 12 weeks of treatment with varenicline were randomly assigned to receive an additional 12 weeks (24 weeks total) vs. placebo. Cessation rates were higher at 1 year (absolute increase 7%, NNT 15).
  • Five studies have compared varenicline to placebo, and a meta-analysis found that varenicline increased the odds of continuous abstinence at 12 months by 3.22 [CI, 2.43 to 4.27] (55).
  • Three studies have compared varenicline vs. bupropion, and a meta-analysis found that varenicline increased the odds of continuous abstinence at 12 months by 1.66 [CI, 1.28 to 2.16] (55).

Comments:

• Few smoking cessation studies have evaluated the benefit of various therapies on cessation after 1 year. This fact is important to consider given the high rate of relapse after 1 year.
• Most smoking cessation studies recruited persons who were highly motivated to quit, which would limit the generalizability of their results.
• Biological verification of smoking cessation is important in assessing the validity of relevant studies, because there is a high rate of misrepresentation of smoking status by individuals enrolled in clinical trials (37).
• Bupropion is approved by the FDA for use in smoking cessation; nortriptyline has not received FDA approval.
• Varenicline is approved by the FDA for use in smoking cessation.
• Nausea is the most common side effect with varenicline (30%). Symptoms are generally mild and decrease with continued treatment (52; 53).
• Varenicline is excreted by the kidneys and should be used with caution in patients with renal failure. Doses should not exceed 0.5 mg twice daily in patients with substantial renal dysfunction (creatinine clearance <30 mL/min or 0.5 mg per day) in patients on hemodialysis (see manufacturer's label).
• To date, all trials of varenicline have been industry funded. Although these studies were methodologically rigorous, independent trials of varenicline are needed. Further trials comparing varenicline with nicotine replacement therapy, bupropion, and nicotine replacement plus bupropion are also needed to better establish relative efficacy of different treatments (55).
• Cytisine is a nicotine receptor agonist that has been used for smoking cessation in Eastern Europe. There have been few quality studies of cytisine. A meta-analysis (56) suggests possible benefit.