Cochrane Clinical Answers - Fulltext - How do bupropion, nicotine replacement therapy and varenicline for smoking cessation compare?

Question:How do bupropion, nicotine replacement therapy and varenicline for smoking cessation compare?

Clinical Answer:

When bupropion, varenicline and nicotine replacement therapy (NRT) were compared with each other in adolescent and adult smokers, varenicline was ranked the best treatment for efficacy. Withdrawals from varenicline due to nausea ranged from 0.6% to 7.6%, but most cases were mild to moderate and subsided over time.

When the antidepressant bupropion, the nicotinic receptor partial agonist varenicline, and nicotine replacement therapy (NRT; transdermal nicotine patch and other adjunctive short acting agents) were compared with each other in a network meta-analysis in adolescent and adult smokers, the probability of varenicline being ranked the best treatment for efficacy was 100%, with people more likely to quit smoking for at least 6 months with varenicline compared with both bupropion and NRT. The probability of the other interventions being ranked second best was 58% for NRT and 42% for bupropion.

The main adverse event associated with varenicline was nausea. Withdrawals due to nausea ranged from 0.6% to 7.6% across trials, but most cases were mild to moderate and subsided over time. Other adverse events included insomnia, abnormal dreams and headache. Two RCTs reported that 9.5% discontinued varenicline treatment, compared with an average of 14% with bupropion and 8% with placebo. The most common adverse events associated with bupropion were insomnia, dry mouth and nausea. Allergic reactions were scarce (1 to 3 per 1000 people). Withdrawals due to adverse events ranged from 7% to 12% across trials. The main side effects associated with nicotine gum were hiccoughs, gastrointestinal disturbances, jaw pain, and orodental problems. Nasal irritation and runny nose were the most commonly reported adverse events of nasal sprays. Skin sensitivity and irritation occurred in up to 54% of patch users, but was usually mild and rarely led to withdrawal.

Information about important clinical outcome such as reduction in craving, withdrawal symptoms and quality of life were not reported. There was no assessment of the impact of factors such as age, comorbidities, specific regimens within each intervention, or other situations (pregnancy).

Full outcome data is detailed below:

1.Bupropion, nicotine replacement therapy and varenicline compared with each other

  • Population, Intervention, Comparator

    Safety Alerts:

    Bupropion is not recommended for people with a history of seizures. The EMEA recommended strengthening warnings to clinicians on the possibility of hypersensitivity and of depression in patients taking bupropion for smoking cessation. Click here for more information.

    In 2008, the FDA required the manufacturers of varenicline to include a boxed warning on the packaging, to alert users and clinicians to the possibility of increased risks of behavior change, agitation, depressed mood, and suicidal ideation and behavior. Although warnings regarding these outcomes will be retained, according to the Pfizer website, the FDA committee voted to remove the boxed warning in Sept 2016. Click here and here for more information.

    Population:

    Trials were identified from 12 Cochrane Reviews. Most trials were conducted in adult smokers; two were conducted in adolescents

    Intervention:

    First-line pharmacological intervention: Bupropion, nicotine replacement therapy (NRT) or varenicline (specific regimens not reported)

    Comparator:

    Placebo (used as a common comparator in the network meta-analysis) or an alternative first-line therapy from the list above

  • OUTCOME 1.1: Sustained smoking cessation (for at least 6 months)

    Narrative result:

    182 pairwise comparisons were analyzed within a network meta-analysis; of these, 170 were comparisons of a first-line therapy with placebo, using placebo as the common comparator to make indirect comparisons. All dropouts were included in the analysis; it was assumed they continued to smoke (worst-case scenario).

    In terms of efficacy, the probability of varenicline being ranked the best treatment was 100%. The probability of NRT being ranked second best was 58%, and bupropion being ranked second best 42%.

    Reference:
    Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.1.1: Sustained smoking cessation – [subgroup Bupropion versus NRT]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding.

      Narrative result:

      Nine trials included in the network meta-analysis directly compared bupropion with NRT. Results from the network meta-analysis showed no statistically significant difference between groups when bupropion was compared with NRT.

      When a network meta-analysis was conducted with NRT split into four sub-groups (patch, gum, combination, ‘other’ [inhalers, sprays, tablets and lozenges]), there remained no statistically significant difference between groups.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (OR 0.99, 95% credible interval (CrI) 0.86 to 1.13). See Figure 2 from Cochrane review

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.1.2: Sustained smoking cessation – [subgroup Varenicline versus NRT]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding.

      Narrative result:

      No trials included in the network meta-analysis directly compared varenicline with NRT, therefore the estimate was via indirect comparisons only. Results from the network meta-analysis showed that people were more likely to quit smoking with varenicline compared with NRT.

      When a network meta-analysis was conducted with NRT split into four sub-groups (patch, gum, combination, "other" [inhalers, sprays, tablets and lozenges]), results for comparisons with gum, patch and ‘other’ NRT were similar to the main analysis; there was no statistically significant difference between groups when varenicline was compared with combination NRT.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of varenicline (OR 1.57, 95% CrI 1.29 to 1.91). See Figure 2 from Cochrane review

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.1.3: Sustained smoking cessation – [subgroup Varenicline versus bupropion]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding.

      Narrative result:

      Three trials included in the network meta-analysis directly compared varenicline with bupropion. Results from the network meta-analysis showed that people were more likely to quit smoking with varenicline compared with bupropion.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of varenicline (OR 1.59, 95% CrI 1.29 to 1.96). See Figure 2 from Cochrane review

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
  • OUTCOME 1.2: Adverse events

    Narrative result:

    No network meta-analysis was conducted for adverse events, therefore the results for each pharmacological intervention is reported separately. Click below for full details.

    Reference:
    Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.2.1: Adverse events – [subgroup: Bupropion]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), overall 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding. Of the 60 antidepressant trials, 48% were considered to be at a low risk of bias for randomization, and 50% at a low risk for blinding.

      Narrative result:

      The most common adverse events reported for bupropion were insomnia, dry mouth and nausea. Withdrawals due to adverse events ranged from 7% to 12%. Allergic reactions were also reported, including pruritus, hives, angioedema and dyspnea, at rates of about 1 to 3 per 1000. Two RCTs reported that 14% discontinued bupropion treatment, compared with an average of 9.5% discontinuing varenicline and 8% discontinuing placebo.

      Relative effect or mean difference:

      Studies were not combined in a meta-analysis, but reported narratively.

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.2.2: Adverse events – [subgroup: NRT]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), overall 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding. Of the 147 NRT trials, 25% were considered to be at a low risk of bias for randomization, and 33% at a low risk for blinding.

      Narrative result:

      The main adverse event usually reported with nicotine gum include hiccoughs, gastrointestinal disturbances, jaw pain, and orodental problems. The only adverse event that appeared to interfere with use of the patch was skin sensitivity and irritation (up to 54% of patch users), but it was usually mild and rarely led to withdrawal. Nasal irritation and runny nose were the most commonly reported adverse events of nasal sprays. Hiccoughs and throat irritation were the most commonly reported adverse events in people using oral sprays. Hiccoughs, burning/smarting sensation in the mouth, sore throat, coughing, dry lips and mouth ulcers were associated with nicotine sublingual tablets.

      No increased risk of adverse events was detected in reviews/trials measuring in people with cardiac disease or pregnant women. Fifteen RCTs reported that more people suffered chest pains and heart palpitations with NRT compared with placebo, however, this was an extremely rare event, occurring in 2.5% of people with NRT compared with 1.4% with placebo.

      Relative effect or mean difference:

      There was a statistically significant difference between groups in chest pains and heart palpitations, in favor of placebo (OR 1.88; 95% CI 1.37 to 2.57).

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.2.3: Adverse events – [subgroup: Varenicline]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), overall 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding. Of the 24 nicotinic receptor partial agonist trials, 66% were considered to be at a low risk of bias for randomization, and 58% at a low risk for blinding.

      Narrative result:

      The main adverse effect in people taking varenicline was nausea; this was generally mild to moderate and subsided over time. Withdrawal due to nausea ranged from 0.6% to 7.6%. Other adverse events included insomnia, abnormal dreams and headache. Two RCTs reported that 9.5% discontinued varenicline treatment, compared with an average of 14% discontinuing bupropion and 8% discontinuing placebo.

      Relative effect or mean difference:

      Studies were not combined in a meta-analysis, but reported narratively.

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
  • OUTCOME 1.3: Serious adverse events

    Narrative result:

    No network meta-analysis was conducted for serious adverse events, therefore the results for each pharmacological intervention is reported separately. Serious was defined as life-threatening or resulted in death, hospitalization, significant disability or birth defect. Click below for full details.

    Reference:
    Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.3.1: Serious adverse events – [subgroup: Bupropion]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), overall 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding. Of the 60 antidepressant trials, 48% were considered to be at a low risk of bias for randomization, and 50% at a low risk for blinding.

      Narrative result:

      21 trials with 7859 participants reported a marginal increase in the incidence of serious adverse events with bupropion compared with placebo. The event rates were 2.5% with bupropion and 2.2% with placebo. Four trials reported six seizures with bupropion; there were no seizures with placebo.

      When subgroup analyses were performed specifically for serious neuropsychiatric events (bupropion 0.8% versus placebo 0.9%), serious cardiovascular events (bupropion 0.3% versus placebo 0.5%), no statistically significant differences were detected.

      Relative effect or mean difference:

      There was a statistically significant difference between groups, in favor of placebo (RR 1.29; 95% CI 0.99 to 1.69).

      Neuropsychiatric events RR 0.88 (95% CI 0.31 to 2.50; six trials) and cardiovascular events RR 0.77 (95% CI 0.37 to 1.59; ten trials).

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.3.2: Serious adverse events – [subgroup: NRT]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), overall 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding. Of the 147 NRT trials, 25% were considered to be at a low risk of bias for randomization, and 33% at a low risk for blinding.

      Narrative result:

      Little or no information on SAEs was provided in the trial reports.

      Relative effect or mean difference:

      Little or no information was provided.

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
    • Subgroup analysis 1.3.3: Serious adverse events – [subgroup: Varenicline]
      Risk of bias of studies:

      The reviewers did not perform a GRADE assessment of the quality of the evidence. The risk of bias for the trials specifically included in the network meta-analysis is unclear. However, of the trials assessing NRT (147 trials), antidepressants (60 trials), and nicotinic receptor partial agonists (24 trials), overall 35% were considered to be at a low risk of bias for randomization, and 40% at a low risk for blinding. Of the 24 nicotinic receptor partial agonist trials, 66% were considered to be at a low risk of bias for randomization, and 58% at a low risk for blinding.

      Narrative result:

      14 RCT with 6333 participants reported no statistically significant difference between varenicline and placebo (event rate 2.1% and 2.0%, respectively).

      When subgroup analyses were performed specifically for serious neuropsychiatric events (varenicline 0.15% versus placebo 0.21%), serious cardiovascular events (varenicline 0.6% versus placebo 0.5%), no statistically significant differences were detected.

      Relative effect or mean difference:

      There was no statistically significant difference between groups (RR 1.06, 95% CI 0.72 to 1.55).

      Neuropsychiatric events RR 0.53 (95% CI 0.17 to 1.67) and cardiovascular events RR 1.26 (95% CI 0.62 to 2.56).

      Reference:
      Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]
  • OUTCOME 1.4: Reduction in withdrawal symptoms, Reduction in craving, Quality of life

    Narrative result:

    The overview identified no Cochrane Reviews/studies that assessed reduction in withdrawal symptoms or craving; the overview did not assess quality of life.

    Reference:
    Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]

    Additional Information:

    DOI

    10.1002/cca.1412

    Publication Dates

    1. Published Online: 30 MAR 2017

    CCA derived from

    Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2. [Review search date: November 2012]

    How to Cite

    How do bupropion, nicotine replacement therapy and varenicline for smoking cessation compare? Jane Burch (PhD) and Juliana Ester Martin-Lopez (PhD) (on behalf of Cochrane Clinical Answers Editors). Cochrane Clinical Answers 2016. DOI: 10.1002/cca.1412.

    Further Information

    • CCA Associate editor: Jane Burch (PhD), Editor, CEU, London, UK.
    • CCA Associate editor: Juliana Ester Martin-Lopez (PhD), Family physician and researcher, Andalusian Agency for Health Technology Assessment (AETSA), Seville, Spain.
    • CCA Editor: Karen Pettersen. Correspondence to kpettersen@wiley.com.