First-line pharmacotherapy options are medicines that have been shown to be effective and safe and are licensed for smoking cessation.1,11,12,13 In Australia, these medicines include NRT,11 varenicline and sustained-release preparations of bupropion hydrochloride. NRT is also licensed for smoking reduction as a step towards smoking cessation for people who are unable or not willing to stop smoking abruptly.
From current available evidence, varenicline is the most effective form of single pharmacotherapy (monotherapy) for smoking cessation.1,11,12,13 A Cochrane collaboration analysis concluded that combination NRT is as effective as varenicline and more effective than single types of NRT.11 Varenicline has been shown to be more effective than bupropion in a number of studies. Head-to-head comparisons between bupropion and NRT monotherapy have shown these medicines are equivalent to each other in efficacy.11
Efficacy of licensed smoking cessation medicine
All randomised controlled trials that examined and analysed smoking cessation pharmacotherapy include at least some behavioural support; for varenicline, this included intensive behavioural support (multiple sessions with at least two hours of total contact time).15
- Varenicline is effective, and can increase six- to 12-month continuous or sustained abstinence rates by 15% (95% confidence intervals [CI]: 13, 17) compared with placebo and 7% (95% CI: 4, 11) compared with bupropion. It is more effective than nicotine patches.11
- NRT is effective and can increase six- to 12-month continuous abstinence rates by
6% (95% CI: 6, 7) compared with placebo.
- Combining a nicotine patch with a faster-acting NRT (eg gum, lozenge) increases
six- to 12-month abstinence rates by 5% (95% CI: 3, 7) compared with single-form NRT.
- Bupropion is effective. Its use can increase six- to 12-month continuous abstinence rates by 7% (95% CI: 6, 9) compared with placebo.
- Bupropion appears to be as effective as NRT monotherapy, but evidence from three randomised controlled trials suggests that it is less effective than varenicline.
Reproduced from New Zealand Government Ministry of Health. New Zealand guidelines for helping people to stop smoking. Wellington: Ministry of Health, 2014 [Accessed 8 March 2018].
Long-term abstinence rates by treatment method16
The choice of pharmacotherapy most likely to assist people who are attempting to quit smoking is based on evidence of effectiveness (Figure 2.1), clinical suitability and patient choice (Figure 2.2). Considerations when helping an individual to select an appropriate form of pharmacotherapy to quit include:
- previous experience with pharmacotherapy
- cost and convenience
- adherence issues (eg individual preferences for a patch or gum, one or more forms of NRT, non-nicotine options)
- prescription medicine versus over-the-counter medicine
- potential for adverse events
- possible drug–drug interactions.
Patients who are quitting smoking using any method are at some risk of increased psychological stress during the process as a result of nicotine withdrawal symptoms, especially patients with a history of mental illness.12 Clinicians should alert patients to this possibility and encourage them to return promptly if they experience neuropsychiatry symptoms (eg anxiety, depression, behaviour changes, suicidality). Patients can also be encouraged to inform family members about this possibility so they can be alert to any concerning changes. People with mental illness are at higher risk of neuropsychiatric symptoms during smoking cessation and must be carefully monitored during treatment.
It is important on medication cessation to reinforce the quitting process to prevent relapse.17 Approximately 50% of those who have quit at the end of pharmacotherapy relapse to smoking;5 therefore, combining pharmacotherapy and behavioural intervention is important.
Recommendation 5 – In the absence of contraindications, pharmacotherapy (nicotine replacement therapy, varenicline or bupropion) is an effective aid when accompanied by behavioural support, and should be recommended to all people who smoke who have evidence of nicotine dependence. Choice of pharmacotherapy is based on efficacy, clinical suitability and patient preference.
Strong recommendation, high certainty
- Smoking cessation using NRT is always less harmful than continuing to smoke.
- When used correctly, all forms of NRT (at equivalent doses) are similarly effective in achieving long-term cessation.
- All forms of NRT monotherapy can increase the rate of quitting by 50–60%.
- More than one form of NRT (ie combination NRT) can be used concurrently with increased success rates and no greater safety risks.
- Higher dose forms of nicotine gum (4 mg) are more effective than lower dose forms (2 mg) for more people who smoke with nicotine dependence.
- Nicotine patches can be commenced several weeks before starting smoking cessation to help people who smoke prepare for quitting.
- NRT can be used by people with cardiovascular disease. Caution is advised for people in hospital for acute cardiovascular events, but NRT can be used under medical supervision if the alternative is active smoking.
- NRT may be considered in women who are pregnant if they were unsuccessful in stopping smoking without pharmacotherapy. If NRT is used, the benefits and risks should be explained carefully to the patient by a suitably qualified health professional. The clinician supervising the pregnancy should also be consulted.
- NRT accompanied by behavioural interventions can be used in those aged 12–17 years who smoke.
Nicotine is the main substance in tobacco that causes addiction as it makes people dependent on cigarettes. However, it is the other chemicals in combusted tobacco products that cause cancer, accelerate heart disease and affect other areas of health. While nicotine also has the potential for adverse effects in vulnerable developmental life stages, including pregnancy, childhood and adolescence,18,19,20 it is considered to be a safer alternative to tobacco smoking.
The aim of NRT is to reduce craving and withdrawal symptoms by providing some of the nicotine that would normally be obtained from cigarettes, without providing the harmful components of tobacco smoking. NRT provides lower doses of nicotine at a slower rate than tobacco smoking; none of the available forms of NRT (ie transdermal patch, gum, inhalator, lozenge, mouth spray) offer the same rapid nicotine delivery of a cigarette.21
GP, general practitioner; NRT, nicotine replacement therapy; OTC, over the counter; PBS, Pharmaceutical Benefits Scheme; PI, product information
Pharmacotherapy treatment algorithm
Nicotine patches are applied to the skin and deliver nicotine through the skin at a relatively steady rate, while other nicotine products are acute dosing forms of nicotine. Other nicotine products provide relief for general craving and breakthrough craving with faster release of nicotine than the patch. The main advantage of nicotine patches over acute NRT formulations is that patient adherence is simple despite its slow delivery.22 The advantage of acute-dosing NRT is that both the amount and timing of doses can be titrated by the person who smokes.
It is important to advise those who smoke on the correct use of the different forms of NRT and ensure an adequate dose is taken to relieve cravings and withdrawal symptoms (Figure 2.3).23,24 Under-dosing is a recognised problem with current NRT, whereby those who want to quit often do not use enough NRT to obtain the best clinical effect.25 Standard dosing references and product information guides for NRT tend to recommend more conservative doses.
Adapted with permission from Ministry of Health, New Zealand. Guide to prescribing nicotine replacement therapy (NRT). Wellington: Ministry of Health, 2014 [Accessed 9 September 2019].
NRT initial dosage guideline24
Patients should be reassured about the safety, efficacy and low addictive potential of NRT, as misinformed concerns are a major cause of poor adherence.23,26
Regular use of NRT beyond 12 months is not generally recommended as there is no evidence of efficacy beyond 24 weeks.27 At the 24-week point, the prospect of stopping NRT can be confronting for some who do not feel ready to stop treatment. An extended but not limitless period of treatment may be reasonable for such patients, although there are no data to support this approach. Current scientific evidence does not support an association between long-term NRT exposure and serious adverse health effects;25,28 a longer period of NRT may help some people remain abstinent29 and it is less harmful than tobacco smoking.
While there is evidence that NRT can increase quit rates with or without counselling,8,9 research suggests over-the-counter NRT appears to be associated with reduced success rates. More research is needed on the effectiveness of NRT in this context.7
Combining two forms of NRT (eg patch plus an acute form, such as spray, gum, inhalator or lozenge) has been shown to be more efficacious than a single form of nicotine replacement.11,30 The patch provides a steady background nicotine level while the oral forms provide additional protection for breakthrough cravings. Oral doses (eg gum, lozenge, inhalator, mouth spray) can be taken on a regular basis (eg hourly) in anticipation of triggers or when cravings occur. Combination NRT, rather than monotherapy, has been recommended for those who smoke and are nicotine dependent, including use of higher dose forms of oral products for those who need them.3
Combination NRT can be recommended:
- as first-line treatment for those who smoke and are nicotine dependent (Figure 2.3)4,5
- for those unable to quit using NRT monotherapy alone
- for those who experience cravings using NRT monotherapy alone.
The evidence review conducted by the Joanna Briggs Institute (JBI) on the use of combination NRT identified 12 randomised controlled trials with a total of 6318 participants. The relative effect was 1.28 (95% CI: 1.15, 1.42). The Expert Advisory Group (EAG) rated the certainty of the evidence as moderate. The EAG concluded that there is a small but not trivial improvement in smoking cessation for combination NRT compared with single NRT. The reviewed studies only included those who smoke with at least low-to-moderate nicotine dependence.
Recommendation 6 – Combination nicotine replacement therapy (NRT) (ie patch and oral form) accompanied by behavioural support is more effective than NRT monotherapy accompanied by behavioural support, and should be recommended to people who smoke who have evidence of nicotine dependence.
Strong recommendation, moderate certainty
Higher dose NRT
Higher dose oral NRT (ie 4 mg gum and lozenge) and higher dose patches (21 mg/24-hour patch and 25 mg/16-hour patch) are recommended for those who smoke with nicotine dependence. Higher dose NRT should also be considered for those who smoke with less nicotine dependence but who continue to report cravings when using the weaker form.31 Higher dose therapy with the patch is also possible by adding a second patch. While this approach seems to be safe, a Cochrane review of five randomised controlled trials found no clear evidence of superiority of dual patching over single patch (risk ratio [RR]: 1.09; 95% CI: 0.93, 1.29).32
Pre-cessation nicotine patch
There is evidence to support the use of nicotine patches before smoking cessation, commonly known as preloading. A meta-analysis found that nicotine patches used before quit day increased success rates when compared with standard therapy.33
A Cochrane review also found a 34% increase effect from the use of pre-cessation patches.3 The Therapeutic Goods Administration (TGA)-approved approach involves using either a 21 mg/24-hour patch or 25 mg/16-hour patch for two weeks before quitting, then continuing to use the nicotine patch in the usual way for the quit attempt and adding intermittent oral NRT if needed.
Reduce to quit
There is also evidence for the use of NRT to help those who are not willing to quit immediately to reduce their tobacco use and then progress to quitting.34 The TGA-approved approach (cut down then stop or reduce to quit) involves patients using NRT to prevent compensatory smoking (inhaling deeper on fewer cigarettes) when reducing the number of cigarettes they smoke before stopping completely within six months.35 A meta-analysis found that reducing cigarettes smoked before quit day versus quitting abruptly with no prior reduction produced comparable quit rates.32,36 Further research is needed to investigate those categories of people who smoke who would benefit the most from each approach.37
Tapering off NRT
Advice to wean off NRT over a period of weeks is included in the product information of NRT products, but it is not something that is supported by the evidence. The main issue is sufficient duration of NRT, not whether tapering occurs before the medicine is ceased.23
Longer treatment duration
There is limited evidence of benefit from longer term NRT. Two randomised controlled trials compared longer (up to 52 weeks) and standard courses (eight weeks) of NRT, but found no convincing effect from the longer course.25,38
Another use of longer term NRT is for relapse prevention in those who are abstinent at the end of a standard course of treatment or who have abstained unassisted. A systematic review of four trials found that prolonged NRT use was effective for the medium term (12- to 18-month follow-up).39 The evidence review conducted by JBI on the longer term NRT found only one trial that met inclusion criteria, which included abstinence confirmed by exhaled carbon monoxide concentration <8 ppm. The relative effect was 2.17 (95% CI: 0.85, 2.17). The EAG rated the certainty of the evidence as low. There was a lack of evidence on the rate or severity of adverse effects associated with longer term NRT.
Recommendation 7 – For people who have stopped smoking at the end of a standard course of nicotine replacement therapy (NRT), clinicians may consider recommending an additional course of NRT to reduce relapse.
Conditional recommendation for the intervention, low certainty
Contraindications and precautions
There is no safe level of smoking. Using therapeutic nicotine is always less harmful than continuing to smoke.
There are few contraindications associated with NRT use.23,33 These include:
- children aged <12 years
- people with known hypersensitivity to nicotine or any other component of the NRT product.
It is important to note that those weighing <45 kg can use NRT, but may require the lower dose (eg 14 mg/24-hour patch).
NRT should be used with caution for patients in hospital for acute cardiovascular events, but if the alternative is smoking, NRT can be used under medical supervision.
Minor side effects are common with NRT use.23,40 Common adverse effects with NRT depend on the delivery system. Patches can cause skin irritation, redness, itch and rash, which are usually mild but can be treated with 1% hydrocortisone cream if troublesome.23 It is important to rotate the application site each day to reduce irritation. Insomnia and vivid dreams can also occur.38 However, if irritation or sleep disturbance is severe, patients can remove the patch at bedtime or a couple of hours before and re-apply a new patch in the morning.23
For NRT gum and lozenges, minor side effects include dyspepsia and nausea; for NRT inhalator and mouth spray, mouth and throat irritation may occur.23,41
Use of NRT in cardiovascular disease
All forms of NRT can be used safely in stable cardiovascular disease;38,42 however, these should be used with caution in people with recent (six weeks) myocardial infarction, unstable angina, severe arrhythmias and recent cerebrovascular events. NRT can be used in this situation under medical supervision.39
Recommendation 8 –
a) Nicotine replacement therapy (NRT) is safe to use in patients with stable cardiovascular disease.
Strong recommendation, high certainty
b) NRT should be used with caution in patients who have had a recent myocardial infarction, unstable angina, severe arrhythmias or recent cerebrovascular events.
Strong recommendation, moderate certainty
Use of NRT in pregnancy
Given the importance of smoking cessation in pregnancy, every effort should be made to support the expectant mother to quit. Behavioural counselling is recommended as the first-line treatment for quitting smoking in pregnancy. Behavioural intervention can:43
- increase the proportion of women who stop smoking during pregnancy
- decrease the proportion of infants born with low birthweight
- increase smoking cessation after birth.
Refer to Chapter 4, ‘Smoking cessation for high-prevalence groups: Pregnant and breastfeeding women’ for more information.
Pregnant women should be encouraged to use Quitline. In some jurisdictions, there are special programs of support that extend into the postpartum period when risk of relapse to smoking is high.
There is inconclusive evidence of the effectiveness and safety of NRT during pregnancy, and other forms of pharmacotherapy are contraindicated.44,45 A Cochrane review and meta-analysis of eight studies and 2199 participants found that NRT as an adjunct to behavioural support was effective for smoking cessation in pregnancy (RR: 1.41; 95% CI: 1.03, 1.93). However, there was no significant difference in cessation rates in a sub-group analysis of placebo-controlled studies. Some observational studies suggest effectiveness in clinical practice.46,47 The modest effect of NRT could be due to inadequate dosing, as nicotine clearance is increased by 60% in pregnancy.48 Poor adherence is also likely to cause reduced cessation outcomes.49
Although nicotine has been linked to harmful effects on the fetus in animal studies, clinical trials have not reported adverse effects from NRT in humans. The Cochrane meta-analysis found no significant difference in health and safety outcomes in four studies.43 Several studies found no adverse effect on birth weight.46,50 One study found that infants born to mothers who received NRT had a significantly higher rate of unimpaired development when assessed two years after delivery.51 However, because of the small number of studies, further evidence is needed before firm conclusions on safety can be made.52,53
The evidence review conducted by JBI examined the outcome of smoking cessation in later pregnancy. This work by JBI focused on the studies within the Cochrane systematic review by Coleman and colleagues.45 Eight randomised controlled trials involving 2199 participants met entry criteria. The relative effect was 1.41 (95% CI: 1.03, 1.93), and the EAG rated the certainty of the evidence as low. The review found no evidence of an increase in adverse effects (ie miscarriage, stillbirth, pre-term birth, low birthweight, neonatal care unit admission, neonatal death) in women who used NRT during pregnancy. In fact, all comparisons found lower rates of these effects in the women who used NRT during pregnancy. However, it should be noted that the 95% CI for all RR were analysed to have no effect (ie RR: 1). On current evidence, the EAG concluded that there are important improvements in smoking cessation outcomes associated with use of NRT in pregnancy, while there does not appear to be an increase in harms.
Given this evidence, if quit attempts are unsuccessful without the use of pharmacotherapy, and the patient is motivated to quit:
- pharmacotherapy (usually oral forms of NRT) should be considered
- if NRT is used, the benefits and risks should be considered and explained carefully to the patient by a suitably qualified healthcare professional, and the clinician supervising the pregnancy should be consulted49,54,55
- intense behavioural support and close clinical surveillance of the pattern of any continuing smoking should be provided.
Recommendation 9 – For women who are pregnant and unable to quit smoking with behavioural support alone, clinicians might recommend nicotine replacement therapy (NRT), compared with no NRT. Behavioural support and monitoring should also be provided.
Conditional recommendation for the intervention, low certainty
Use of NRT in breastfeeding
Nicotine passes from the mother to child through breastmilk. Depending on the concentration of nicotine in the maternal blood, it is likely to be less harmful than continued smoking.56,57 NRT (ie patch, intermittent) is considered an option for breastfeeding mothers.58 Infant exposure to nicotine can be reduced further by taking intermittent NRT immediately after breastfeeding.
Women who smoke should be encouraged to continue breastfeeding and provided with strategies to minimise the potential harm to their child through breastmilk and second-hand smoke.52