Although rates of smoking have declined in recent years, there are still around 2.8 million Australians who smoke.1 Of all the behavioural risk factors associated with poor health, smoking is the leading cause of preventable disease and premature death.

Most smokers want to quit, and with increases in the tobacco excise, quitting may become an even more important financial consideration for many smokers.2 However, for the proportion of smokers who are dependent on nicotine, unassisted attempts to quit will usually be unsuccessful.

Pharmacological intervention may help smokers who want to quit to do so successfully. However, of the three agents approved for use in Australia — nicotine replacement therapy, varenicline and bupropion — which one makes the most difference to smokers?

A 2013 Cochrane meta-analysis may provide some clarity on which agent is the most effective in helping people quit smoking.

Practice points

  • Smoking cessation is an essential public health intervention. All health professionals should be engaging smoking-cessation interventions at every patient encounter.3
  • Smoking-cessation therapy success depends on individual patient factors. Tailor interventions to the individual person, taking into account their dependence on nicotine and the psychosocial context of smoking.
  • Pharmacological intervention may be necessary. People who are dependent on nicotine may require pharmacological intervention to help them quit smoking.
  • Varenicline is more effective than single-agent nicotine replacement therapy (NRT) or bupropion. Be aware of potential adverse events when prescribing any pharmacological treatment for smoking cessation.
  • A combination of NRT agents appears to be as effective as varenicline. For people who choose NRT, a combination of NRT agents for first-line therapy may be advisable.

Intervening in nicotine dependence

Nicotine is now acknowledged to be as addictive as heroin or cocaine.4,5 Of all the people who start smoking, around one-third will become addicted to nicotine.6

Smoking is responsible for the deaths of over 15,000 Australians each year6 and is strongly related to many chronic diseases, including coronary artery disease, chronic obstructive pulmonary disease and osteoporosis.7 Smoking is also responsible for 20% of cancer-related deaths in Australia.8

Interventions work

Smoking cessation is one of the most cost-effective and clinically effective preventive health measures.6 However, some health professionals may harbour beliefs that can be significant barriers to smoking cessation,6,9 such as a perception that patients lack motivation to quit or that cessation interventions are ineffective.9

Nearly all smokers are interested in quitting and nearly half will attempt to quit each year.6,10 However, as few as 3% of unaided cessation attempts result in complete abstinence at 6–12 months,10,11 indicating a need for more effective interventions.

Health professionals can play an important part in encouraging and assisting smoking-cessation efforts.9 It has been shown that health-professional intervention can substantially increase abstinence rates and deliver significant public health benefits.6,12 Even brief advice can lead to significantly improved smoking-cessation rates.6,12

All health professionals should identify smokers, assess smoking status and offer advice and cessation treatment at every opportunity.3,6 Interventions to encourage smoking cessation can include:6

  • brief advice to quit
  • assessing a patient's readiness to quit
  • offering counselling and pharmacotherapy
  • providing self-help material
  • referral to intensive quit programs such as Quitline and other local and State programs.

Assess for dependence

Assess people for their dependence on nicotine before embarking on a smoking-cessation strategy.4,6

People who need to smoke within 30 minutes of waking, those who smoke more than 10 cigarettes a day, and those who have a history of withdrawal symptoms in previous quit attempts, may be nicotine dependent.13

In these cases pharmacological intervention may improve their chances of successful cessation.13

Pharmacological intervention

The success of any smoking-cessation intervention will depend on patient-specific factors.

Smoking dependence is a complicated process involving not only addiction to nicotine but is reinforced by the context in which smoking occurs, including the rituals and sensory stimuli.6

Nicotine delivered by smoking a cigarette reaches the brain within seconds of inhalation, triggering reward systems that reinforce the psychosocial context in which the cigarette is smoked.6

Available treatments to assist with smoking cessation relieve the symptoms of withdrawal by either supplying nicotine without the other toxic chemicals associated with smoking, or by targeting the biochemical reward pathways, blunting the effects of nicotine.6

While treatments have different mechanisms of action, there are three basic underlying principles that determine their efficacy:5

  • mitigating craving and withdrawal symptoms
  • reducing the reward supplied by smoking
  • delivering positive reinforcement by means other than a cigarette.

Clearing the air — an analysis of efficacy

There are three pharmacological interventions available in Australia to assist in smoking cessation — NRT, varenicline and bupropion.4,6

All three have been shown to be effective in supporting smoking cessation in clinical trials.6 However, there is current uncertainly about their relative efficacies.6

A network meta-analysis of Cochrane systematic reviews on pharmacological interventions for smoking cessation provides further information on the relative efficacies of these treatments.5

The study design

Network meta-analysis allows for the indirect comparison of treatments not previously compared, leading to a much broader comparison of efficacies.5

The primary efficacy outcome of the 12 included reviews was abstinence of smoking for at least 6 months. This was based on sustained or continuous abstinence over point prevalence, determined by biochemically confirmed findings rather than self-report.

In total 267 studies were included in this analysis involving over 100,000 participants.5

Comparative efficacy

This network meta-analysis found that NRT, bupropion and varenicline all significantly increased the odds of complete abstinence at 6 months compared with placebo.5

NRT and bupropion almost doubled the chances of quitting, while varenicline nearly tripled the chances.5 This means that for every 10 people who quit with placebo, 18 would be expected to quit with NRT and 28 with varenicline.

When compared against each other:

  • single-agent NRT (such as, nicotine patch, oral spray, inhaler or chewing gum) and bupropion had similar efficacy
  • combination NRT (nicotine patch plus inhaler or lozenge) performed better than single-agent NRT or bupropion
  • varenicline performed better than single-agent NRT or bupropion
  • varenicline and combination NRT were equally effective.


The meta-analysis also analysed the safety of individual agents by observing the rate of adverse events reported in the individual trials. The analysis found that overall the three agents for smoking cessation were associated with a low risk of harm.5

Nicotine replacement therapy

NRT was associated with local effects of treatment in the form of site irritation.

Although chest pains and heart palpitations have been reported among users of NRT compared with placebo groups,14 few or no serious adverse events were reported in the trials included in the present review.5


The most common adverse events associated with bupropion were insomnia (30–40% of patients), dry mouth and nausea. The main serious adverse effect of bupropion therapy was seizures, which can occur at a rate of 1:1000 users.

The number of seizures was tallied across the trials included in the meta-analysis but overall there were too few recorded incidences of seizure to be analysed meaningfully.5


Although trial data for varenicline use did not indicate any excess in serious adverse events,5 postmarketing surveillance of varenicline has raised concerns regarding neuropsychological effects and risk of cardiovascular events.

In response to concerns about possible cardiovascular risk, the FDA requested the US sponsor of varenicline 'to conduct a large, combined analysis (meta-analysis) of randomized, placebo-controlled trials'.15

This meta-analysis found a small but non-significant effect, although it was observed that the data were analysed many different ways and consistently showed a higher occurrence of events in patients using varenicline.

The FDA concluded it was more likely that the effect was related to the drug and not purely a chance finding.15

However, as smoking is a strong independent risk factor for cardiovascular disease, it is important for clinicians to weigh the small potential risk of varenicline-induced cardiovascular events against the considerable health benefits of cessation of smoking, which are immediate and substantial.15

Despite earlier data indicating a risk of serious psychiatric adverse events with varenicline,16,17 the current meta-analysis did not indicate any significantly raised incidence of depression or suicidal ideation or behaviour.5

However, be aware of the potential for patients to experience psychological distress, including suicidal ideation while undertaking pharmacologically assisted smoking cessation.6

For more information see NPS RADAR articles: 

Limitations of the study

This analysis was limited to Cochrane reviews and was essentially a meta-analysis of meta-analyses, which may have introduced bias and error through omission of studies. In addition, three of the authors of this review were also involved in most reports included in the analysis.5

Attempts were made to ensure objectivity through the use of independent assessment tools and criteria, but bias cannot be ruled out.5

In terms of safety, the analysis was limited to safety reports from clinical trials. This would not have included various postmarketing safety signals for varenicline, although the authors acknowledged these limitations in their discussion.

More research needed

While these results indicate that either varenicline or combination NRT may be more effective smoking-cessation interventions than single-method NRT or bupropion, more research is needed before recommending one over another.

In particular, direct comparisons between varenicline and combination NRT are required. Further postmarketing surveillance of the adverse effects of varenicline are also required to provide more certainty of the magnitude of risk for cardiovascular events or psychiatric effects.

Change to practice?

It is clear that NRT, bupropion and varenicline all improve the chances of a person successfully quitting smoking.5

The Cochrane review also suggests that combination NRT and varenicline are equally effective quitting aids, and that an acceptable level of adverse events is associated with their use.5 However, should this new information change clinical practice?

In light of the results from this latest Cochrane review it may be advisable to recommend a combination of NRT agents for patients who are considering NRT therapy.

However, current guidelines suggest that a trial of single-agent NRT be used first line, and additional agents added to a single-agent regimen if a smoker is unable to maintain abstinence, or is still experiencing withdrawal symptoms.4

Also consider varenicline as a first-line therapy for smoking cessation.

Current RACGP guidelines for smoking cessation recommend pharmacological treatment for all patients deemed to be nicotine dependent.6,13 However, they do suggest that the choice of pharmacotherapy be driven by clinical suitability and patient choice.6

NRT, for example, can be used safely in all smokers, but caution is advised in pregnant women and patients with unstable cardiovascular disease.

Use varenicline with caution in patients with significant intercurrent psychiatric or psychological disorders and in those with cardiovascular disease or in pregnant women.6,13

Patients may also be more comfortable with a particular method because of past experience, which can influence treatment choice.6,13


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