The pharmacotherapy of smoking cessation

In Australia, cigarette smoking is the most significant cause of avoidable health harm. To reduce this, individual clinicians should follow the so-called five A's — Ask about smoking; Advise quitting; Assess current willingness to quit; Assist in the quit attempt; and Arrange timely follow-up.1 While this review focuses on the forms of drug therapy that assist cessation, these treatments should be coordinated with the general and specific support and counselling strategies that are also of proven benefit.2

The great majority of regular smokers are dependent on cigarette smoking, and not simply addicted to nicotine.3 Smoking is highly contextual and associated with certain rituals. These start with the opening of a packet, followed by the lighting process and then the sight and smell of smoke. After inhaling smoke from a modern cigarette, arterial nicotine levels increase markedly within 15 seconds.4 This bolus of nicotine activates the brain-reward system by increasing dopamine release.5 This brain reward system is a common pathway for pleasurable activities (sexual activity, eating) and most drugs of addiction.6

This peak in plasma nicotine level, and the transient activation of the reward system, is followed by a gradual fall in nicotine levels into a state of withdrawal7 that is, in turn, relieved by the next cigarette. Dependence arises from the temporal association of the rituals and sensory inputs with the repeated stimulation and relief of withdrawal.2 This required association explains why nicotine replacement therapy (NRT) products, that deliver nicotine slowly and do not produce high plasma nicotine levels, have minimal addictive potential.8

There is now quite extensive evidence that NRT is safe in patients with stable cardiac disease such as angina pectoris (E1)10,11 (for an explanation of level-of-evidence codes, see Box 1). Evidence is lacking in acutely unstable patients, but NRT would produce lower peak and cumulative nicotine exposure levels than smoking, without delivering the increased carboxyhaemoglobin and the many other vasoactive compounds in smoke. The issue of NRT use in pregnancy is a vexed one. In one randomised study, NRT by patch did not increase cessation during pregnancy, but did increase birthweight, perhaps by reducing total smoke exposure.13 The second issue is safety. Prenatal exposures to nicotine have important developmental effects, but, as total nicotine levels are lower with NRT than smoking, if the alternative is active smoking NRT is almost certainly safe in pregnancy.14

Because of residual safety concerns, use of NRT in pregnant women should be aimed at those who are moderately or highly dependent and have been unable to quit by other means.13 NRT is most likely to be effective if combined with high-intensity counselling. Careful supervision of NRT could include monitoring of urinary cotinine levels and use of non-continuous treatment — gum, spray and 16-hour, rather than 24-hour, patches. A key message here is that women contemplating pregnancy should try to quit beforehand, as pregnancy is not a time during which smoking cessation is easy to achieve.15

Bupropion was developed and first marketed as an anti-depressant. Although it is an effective antidepressant,16 it is not marketed for this purpose in Australia. Anecdotal observation of spontaneous smoking cessation in depressed smokers17 led to its further evaluation as an aid to smoking cessation,18 and the later development of the sustained-release form presently marketed as Zyban (GlaxoSmithKline). The suggested mechanism of action is inhibition of neural reuptake of dopamine or noradrenaline, but this may be simplistic.19 Bupropion is not related to other classes of antidepressants presently in clinical use. With the exception of nortryptiline, which has a weak effect, these other antidepressants do not increase rates of smoking cessation.1 There is no evidence that the antidepressant activity of bupropion contributes to its efficacy in smoking cessation.

In counselling smokers about the optimal means to achieve cessation, clinicians should make an assessment of dependence. Box 2 shows the Fagerström test for nicotine dependence, which may be useful and is simple to administer.23 If there is not the opportunity to apply the Fagerström test, the number of cigarettes smoked daily and the interval between waking and first cigarette will give a rough guide to the degree of dependence. Some long-term smokers do have minimal dependence. They typically smoke small numbers of cigarettes, and may cease smoking for short or longer periods without withdrawal symptoms. This group is worth identifying, as such smokers should be able to quit without pharmacological assistance.

Drug treatments address some of the biochemical aspects of smoking, but are most effective when counselling or behavioural programs are used to redress the associated contextual and ritual elements (E1).2 The effectiveness of programs and products for smoking cessation needs to be judged against the "natural" rate of smoking cessation that is in the range of 1.5%–3% per year.24,25 Placebo success rates in all published drug treatment trials are typically higher, about 10%–15% at end of treatment and 5%–10% after one year, as participants are self-selected as interested in quitting and receive at least a minimum level of counselling.

Other than those who are minimally dependent, all smokers trying to quit should be advised to use one of the range of safe, effective treatments available (E1).1,2 All forms of NRT about double the chance of successful cessation (E1).26 The number of patients needed to treat to achieve one extra successful quitter is about 10. Patients report a preference for patches over gums, sprays or the inhaler and tend to use patches nearer to the fashion recommended, but these differences do not affect cessation rates.27

If the initial treatment is a nicotine patch, 16-hour and 24-hour patches are equally effective (E1). There is a modest increase in success for increases in delivered dose above 20 mg (E1).28 There is no need to adjust patch dose based on smoking level before cessation.29 Treatment periods should be at least eight weeks. There is no medical need to taper treatment, but the process of tapering is reassuring to some patients. Smoking while using patches has a trivial safety risk, but above all predicts a very low chance of successful cessation. If a patient is still smoking after seven days, the quit attempt should be terminated, with the intention of trying again at a later time.

If gum is used, 4 mg doses are associated with greater chance of cessation in smokers with higher dependency.30,31 Other than those who are minimally dependent, smokers should be advised to use 4 mg pieces (E1). Tapering to 2 mg doses later is intuitively logical, but of unproven benefit. If the nicotine inhaler is chosen, at least six cartridges should be used initially. Tapering the dose is recommended after three months without evidence to support this.

A range of studies have shown that bupropion increases the chance of success 2.1-fold, with the number needed to treat to achieve an extra successful quitter being 7.5.1 The one comparative study published found that bupropion (150 mg twice daily) produced a higher cessation rate than nicotine patch alone (E2).32 However, the quit rate with NRT in this study was lower than that generally found in other studies. In a second study, bupropion and NRT by patch were compared for their effect on late quitting from Week 4 onwards.20 Late quitting was more common with bupropion than NRT but this could be predicted from other studies. The likelihood of successful cessation with bupropion is not reduced in patients previously treated with bupropion.33

The choice of recommending NRT or bupropion will rest on individual patient characteristics and preferences. At present, in Australia, cost is an issue. Bupropion has an advantage in terms of ease of use and is the only smoking cessation agent currently subsidised under the Pharmaceutical Benefits Scheme (some forms of NRT are available on the Repatriation Pharmaceutical Benefits Scheme). Although this presents an economic advantage for the patient, contraindications should never be discounted.

Current product information advises against concurrent use of different NRT formulations. However, higher abstinence rates are achieved when a patch is combined with ad libitum use of either 2 mg gum34,35 or nasal spray.36 Although there has been no direct comparison, the benefit derived from combination NRT is greater than that seen with higher-dose patches alone.37,38 Intuitively, this strategy should be employed in highly dependent smokers, but there is not yet evidence to support this. At present, the use of combination NRT is reasonable in moderate or highly dependent smokers who have failed cessation with monotherapy, particularly if withdrawal symptoms were prominent. The addition of nicotine patches to bupropion has not increased rates of cessation.32

Extension of treatment with bupropion to one year in those abstinent during Week 7 of initial treatment increases abstinence during treatment and delays relapses, but smoking rates are similar one year later (E2).39 Until there is more evidence, extended therapy should not be prescribed. Many patients who use NRT do so beyond the usual treatment periods. This is unlikely to be harmful, but no benefit has been shown (E1).2 Generally, smokers should be encouraged to use treatments for 8–12 weeks.

At any one time, most smokers are not committed to quitting. If prompt cessation is impossible, the principle of harm reduction is to use treatment that may reduce the total number of cigarettes smoked and lead the way to future cessation. The extent to which smoking fewer cigarettes reduces harm is uncertain. In smokers who were also using nicotine sprays, the number of cigarettes smoked was reduced but adverse biomarker exposure was not.40 Bupropion also reduced smoking in uncommitted quitters with17 and without41 depression. In conjunction with counselling support, it may be reasonable to recommend bupropion to the uncommitted quitter.

Smokers are, on average, underweight. Weight gain is a feature of successful cessation and few smokers will ever return to their precessation weight. Median weight gain is about 2 kg, but around 10% have very large weight increases (more than 12 kg).42 Despite its intuitive attractiveness, strict dietary restriction reduces cessation rates and should not be initiated during a cessation attempt.43 Use of NRT or bupropion delays, but does not prevent, weight gain.44,45 For smokers with particular concerns or who are overweight, it may be better to combine cessation with exercise,46 and any attempt at weight control by dietary means should be delayed until cessation is consolidated.

Patients with all major forms of mental illness, particularly major psychoses or those in institutions, have high rates of smoking.47,48 It has been estimated that just under half of all cigarettes smoked in the United States are smoked by individuals with mental illness.49 This complex area has recently been reviewed in some detail.50 There is an incorrect but prevalent view that attempts at controlling smoking in these patients are futile. Bupropion increased cessation rates in a small study of patients with post-traumatic stress disorder (E2),51 and group therapy with NRT52 or bupropion53 has reasonable efficacy in patients with schizophrenia (E2). Patients with depression are as likely as others to quit with NRT54 or bupropion.55 There is a risk of relapse of major depression if abstinence is achieved, and these patients should be closely observed (E2).56 Patients with well controlled major depression should not be switched from an effective therapy to bupropion for the purpose of achieving cessation.