Pharmacotherapy for smoking cessation

Three forms of medicine – NRT, varenicline and bupropion – are licensed and available in Australia to assist smoking cessation. These medicines have been shown to assist smoking cessation in meta-analyses of randomised clinical trials.^1,2,3,4

Pharmacotherapy should be recommended to all people who smoke with nicotine dependence.⁵ However, an individual’s choice to attempt to quit without assistance should be respected and supported.

The most successful quit approach for those who are nicotine dependent is behavioural support combined with first-line pharmacotherapy and follow-up.^5,6,7,8,9,10 Overall, varenicline or combination NRT almost triples the odds of quitting,¹¹ and bupropion and NRT alone almost doubles the odds of quitting versus placebo (dummy treatments plus brief counselling) at six months.^11,14

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.

Figure 2.1

Long-term abstinence rates by treatment method^₁₆ 

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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.

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

Figure 2.2

Pharmacotherapy treatment algorithm

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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.

Figure 2.3

NRT initial dosage guideline²⁴ 

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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

Combination NRT

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.

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.

Contraindications and precautions

There is no safe level of smoking. Using therapeutic nicotine is always less harmful than continuing to smoke.

Contraindications 

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.

Precautions

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.

Side effects

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

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 consulted^49,54,55
• intense behavioural support and close clinical surveillance of the pattern of any continuing smoking should be provided.

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

Varenicline was developed specifically for smoking cessation. It acts at the nicotinic acetylcholine receptors (nAChRs) in the reward centre in the brain. Varenicline binds with high affinity at the alpha-4 beta-2 (α4β2) nAChRs, where it acts as a partial agonist to alleviate symptoms of craving and withdrawal. If a cigarette is smoked, the varenicline prevents inhaled nicotine from activating the α4β2 nAChRs agonist activity, and so blocks the pleasure and reward response. This mechanism may explain why quitting can occur later in a course of treatment with varenicline.

Efficacy

At the standard dose, varenicline can more than double the chances of successful long-term smoking cessation when compared with pharmacologically unassisted quit attempts.⁵⁹ A Cochrane meta-analysis of 27 trials of varenicline found it more than doubled sustained abstinence rates at six-month follow-up.¹ Varenicline monotherapy was also more effective than NRT monotherapy at 24 weeks;¹ however, it was of similar efficacy to combination NRT (patch and oral form).¹¹ Varenicline improves smoking cessation rates two-fold over bupropion and is well tolerated.^60,61

Two randomised controlled trials have examined varenicline as an aid to relapse prevention in those who smoked and had successfully quit on varenicline.^62,63 One study continued treatment for an additional 12 weeks,⁶³ the other for an additional 40 weeks.⁶² There was a modest benefit in favour of extended treatment compared to the placebo groups.^62,63 The benefit appears to be maintained only for the period of use of varenicline.

The evidence review conducted by JBI on this question examined the two trials^62,63 which, combined, involved 1297 participants that met entry criteria (including that smoking cessation of study participants was biochemically confirmed). The relative effect was 1.23 (95% CI: 1.08, 1.41). The EAG rated the certainty of the evidence as low.

Combination varenicline and other pharmacotherapy for smoking cessation

Varenicline in combination with NRT patch results in significantly higher abstinence rates than varenicline alone.^64,65 A systematic review aggregated the reported number of adverse events from these studies, and generated a pooled odds ratio (OR) with a fixed-effect model.⁶⁶ Compared with varenicline monotherapy, participants receiving combination varenicline and NRT reported increased incidence of:

• nausea (28.4% versus 25.7%; OR: 1.15; 95% CI: 0.85, 1.56)
• insomnia (18.7% versus 15.4%; OR: 1.27; 95% CI: 0.89, 1.80)
• abnormal dreams (13.6% versus 10.7%; OR: 1.20; 95% CI: 0.78, 1.84).

Frequency of headaches was similar between groups (7.1% versus 7.8%; OR: 1.01; 95% CI: 0.60, 1.72). Koegelenberg and colleagues reported that skin reactions (of any type) were more prevalent in the combination therapy group (14.4% versus 7.8%; p = 0.03).⁵⁹

The evidence review conducted by JBI on this question found two trials involving 787 participants that met entry criteria (including biochemically confirmed cessation). The relative effect was 1.62 (95% CI: 1.18, 2.23). The EAG rated the certainty of the evidence as moderate, and concluded that, on current evidence, there is a small but not trivial improvement in smoking cessation for people taking varenicline in addition to NRT, compared to NRT alone.

There is no clinical study of varenicline combined with oral NRT. However, in clinical practice, this combination is sometimes used together. Varenicline helps to relieve background cravings and reduce the stimulatory effects of smoking, and oral NRT products alleviate cue-induced triggers.

There is a lack of evidence of the effectiveness of combination varenicline plus bupropion. One study found a benefit at 26 weeks, but not at 52 weeks; a more recent study found no benefit at either of these follow-up points.^67,68

There is increasing evidence of the efficacy of varenicline in sub-populations of patients who smoke.

Sub-populations of patients who smoke

People with mental illness

Psychiatric comorbidity is common in those who smoke, and varenicline has been found to be safe and effective in those with stable mental illness or a past history of mental illness.⁶⁹ There is also evidence that varenicline is safe and effective to assist cessation in people with schizophrenia.^70,71

Women

Varenicline is more effective than other cessation monotherapies, but the difference is relatively greater for women. Women have lower quit rates with NRT and bupropion compared with men, but the same response to varenicline.⁷²

People who smoke and drink heavily

Varenicline reduces alcohol cravings and overall alcohol consumption in those who drink heavily, and may have a role in the concurrent treatment of alcohol and nicotine dependence, especially in men.^73,74,75

Varenicline and mental illness

After initial marketing of varenicline, there were concerns about an association between varenicline and mood changes, depression, behaviour disturbance and suicidal ideation. Subsequent meta-analyses of randomised controlled trials^76,77 and observational studies^72,78,79 have not supported a causal link. The large randomised controlled trial, EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study), has given further reassurance.⁶⁴ In those with or without stable mental illness, the study did not find a significant increase in the rates of moderate-to-severe neuropsychiatric adverse events in those taking varenicline, compared with those using placebo, bupropion or nicotine patch. As expected, those with mental illness in all treatment groups had higher rates of neuropsychiatric adverse events than those without mental illness.

Patients quitting smoking with any method are at some risk of increased psychological stress, especially those with a history of mental illness. Clinicians should monitor all patients with follow-up for neuropsychiatric changes associated with withdrawals, whether taking varenicline or not, and should promptly report any adverse events.

Cardiovascular safety of varenicline

Safety data from more than a dozen recent randomised controlled trials, including one conducted in the highest‐risk patient population studied to date, examined the use of varenicline and cardiovascular events. These randomised controlled trials found that cardiovascular events are rare and not likely to be increased with the use of varenicline.⁸⁰ The findings are consistent with the results of several large cohort studies, which found no increased risk of cardiovascular adverse events between varenicline and bupropion for smoking cessation.^81,82 There appears to be no substantive evidence to suggest that varenicline increases the risk of cardiovascular adverse events.^39,75

It is important to note that smoking is a major risk factor for cardiovascular disease, and the health benefits of quitting smoking are immediate and substantial.⁸³

Pregnancy and varenicline

Due to the limited efficacy and pregnancy safety data, varenicline is not recommended as a smoking cessation aid for pregnant or breastfeeding women.⁸⁴

Side effects

Nausea is the most common adverse effect of varenicline, and was reported in studies of almost 30% of those who are attempting to quit, although less than 3% discontinued treatment due to nausea.^57,58 There is some evidence that nausea can be minimised by taking tablets with food, titration and self-regulation of varenicline (0.5–2 mg/day).^85,86 Lower doses of varenicline are also effective if the full dose cannot be tolerated.¹

Sleep disturbance and abnormal dreams were more common in the varenicline group (13.1%) than the bupropion (5.9%) or placebo groups (3.5%).^57,58

Other less common side effects include drowsiness, headache, constipation, dizziness and flatulence.

No clinically meaningful drug interactions have been identified.

Varenicline is excreted almost entirely by the kidneys. For people with creatinine clearance below 30 mL/min, the recommended daily dosage is 1 mg/day (0.5 mg/day for three days then increasing to 1 mg/day). Avoid varenicline in those with end-stage renal failure in favour of other approaches to smoking cessation. Dose adjustment is not routinely required in older people or in people with hepatic impairment.⁸⁷

Bupropion reduces the urge to smoke and reduces symptoms from nicotine withdrawal.

Efficacy

Bupropion significantly increases the long-term cessation rate by about 60%, compared with placebo over 12 months.²

Bupropion has been shown to be effective in a range of patient populations, including those with depression, cardiac disease and respiratory diseases (eg chronic obstructive pulmonary disease [COPD]).⁸⁸ It has also been shown to improve short-term abstinence rates for people with schizophrenia.^89,90 In comparison with NRT, varenicline and placebo, bupropion has not been shown to cause an increase in neuropsychiatric adverse events, including in people with a history of mental health disorders.⁶⁴

Clinical trials have shown that bupropion is not as effective as varenicline for smoking cessation.^1,91 However, bupropion is a useful option in cases where varenicline is not appropriate (eg patient choice, side effects).

Combination bupropion and other pharmacotherapy for smoking cessation

The combination of NRT and sustained-release bupropion has not shown an additive benefit.² As previously stated, there is a lack of evidence of effectiveness of the combination of bupropion plus varenicline.^62,63

Safety

Bupropion is contraindicated in patients with a history of seizures, eating disorders and those currently or recently (within the last 14 days) taking monoamine oxidase inhibitors.⁹² The current recommendation is that it should be used with caution in people taking medications that can lower seizure threshold (eg antidepressants, antipsychotics, anti-malarials, oral hypoglycaemic agents).^2,92 Alcohol consumption should be minimised or avoided completely when taking bupropion, as alcohol can alter the threshold at which bupropion induces seizures. A sudden decrease in alcohol consumption can also alter the seizure threshold, and alternative medication should be considered in these situations.⁹²

Caution is needed if there is concomitant use of bupropion with certain drugs (eg tricyclic antidepressants, selective serotonin reuptake inhibitors [SSRIs]). These drugs should be initiated at the lower end of the dosage range while the individual is taking bupropion. In the more common situation where bupropion is initiated for a person already taking these drugs, these may need to be decreased. Bupropion should not be used in patients taking monoamine oxidase inhibitors, including moclobemide.

A 14-day washout is recommended between completing monoamine oxidase inhibitors and starting bupropion. Consultation with a psychiatrist may be considered for advice on co-prescribing bupropion with other antidepressants.^93,94

There is no evidence that the use of bupropion for smoking cessation increases the risk of serious cardiovascular adverse events during or after treatment.³⁹ Due to the limited efficacy and pregnancy safety data, bupropion is not recommended as a smoking cessation aid for women who are pregnant or breastfeeding.⁷⁹

Side effects

Seizures are the most clinically important adverse effect (0.1% risk) with the use of bupropion for smoking cessation, and fatalities have been previously been reported.⁹² Therefore, bupropion should not be prescribed to patients with a current seizure disorder or a previous history of seizures. Common adverse effects are insomnia, headache, dry mouth, nausea, dizziness and anxiety. If bupropion is used in combination with NRT, blood pressure should be monitored.⁸³

Availability of smoking cessation medicines on the Pharmaceutical Benefits Scheme

Health professionals should check for updated Pharmaceutical Benefits Scheme (PBS) listings.

Nicotine patches (eg 25 mg/16 hours, 15 mg/16 hours, 5 mg/16 hours, 21 mg/24 hours, 14 mg/24 hours, 7 mg/24 hours) are listed on the PBS for use as an aid to quitting for people who participate in a support and counselling program. The subsidised patches are not available at the same time as other PBS-subsidised smoking cessation therapies (ie varenicline, bupropion), but those who are unsuccessful at quitting using the nicotine patches are able to access PBS-subsidised medicines during that same 12-month period.

Oral forms of NRT subsidised on the PBS are gum and lozenges for use as the sole PBS-subsidised therapy. This means combination NRT is not currently PBS subsidised.

Under PBS rules, a maximum 12 weeks of PBS-subsidised NRT is available per 12-month period.

All forms of NRT are available over the counter in pharmacies and supermarkets in Australia.

Aboriginal and Torres Strait Islander peoples

Aboriginal and Torres Strait Islander peoples qualify for a PBS-restricted benefit listing, which provides up to two courses of nicotine patches per year, each a maximum of 12 weeks. Under this listing, participation in a support and counselling program is recommended but not mandatory. Nicotine gum (2 mg and 4 mg doses) and lozenge (2 mg and 4 mg doses) are also available on the PBS for Aboriginal and Torres Strait Islander peoples. The PBS listing does not cover two forms of NRT at once (ie no combination therapy). Access to NRT for Aboriginal and Torres Strait Islander peoples can be facilitated through the Closing the Gap PBS co-payment measure (refer to Chapter 4, ‘Smoking cessation for high prevalence groups: Closing the Gap PBS co-payment measure’).

Availability of varenicline on the PBS

Varenicline is available on the PBS as a short-term adjunctive therapy for nicotine dependence. It can be prescribed as a streamlined authority prescription for up to 24 weeks of continuous therapy for smoking cessation. Eligibility requirements include enrolling in a support and counselling program, and abstinence at 12 weeks. Making use of the Closing the Gap PBS co-payment can further reduce the cost for Aboriginal and Torres Strait Islander peoples.

The first script is a starter pack that lasts for four weeks (including dose titration), followed by a continuation batch for eight weeks of treatment. A third prescription is required for the final 12 weeks of treatment, but only for those who respond to the first 12 weeks. Under PBS rules, a maximum of 24 weeks of PBS-subsidised treatment with this drug is permitted per 12-month period.

Availability of sustained-release bupropion on the PBS

Sustained-release bupropion is available on the PBS as a streamlined authority prescription for a short-term course of treatment (nine weeks) for nicotine dependence, with a comprehensive support and counselling program. Making use of the Closing the Gap PBS co-payment can further reduce the cost for Aboriginal and Torres Strait Islander peoples.

Bupropion is available as a starter pack of 30 tablets and a continuation pack of 90 tablets. The dose of bupropion is 150 mg/day for the first three days, then increased to 150 mg twice per day. The patient should stop smoking in the second week of treatment. Under PBS rules, a maximum of nine weeks of PBS-subsidised treatment with this drug is permitted per 12-month period.

Nortriptyline is a tricyclic antidepressant that has been shown in a relatively small number of trials to significantly increase long-term cessation when used as the sole pharmacotherapy.^2,56 A systematic review found that the use of nortriptyline for smoking cessation resulted in higher prolonged abstinence rates after at least six months, compared with placebo treatment.⁹⁵ The efficacy of nortriptyline does not appear to be affected by a past history of depression, but it is limited in its application by its potential side effects, including dry mouth, constipation, nausea, sedation and headaches, and a risk of arrhythmia in patients with cardiovascular disease. Nortriptyline can be dangerous in overdose.

Nortriptyline is not registered for smoking cessation in Australia.

The dose of nortriptyline used for smoking cessation is approximately 75 mg/day for 12 weeks. Further information about nortriptyline for smoking cessation can be obtained from the New Zealand smoking cessation guidelines.¹⁶

Note: ”Heated tobacco products” are not nicotine vaping products.

Electronic cigarettes, often referred to as e-cigarettes, are a diverse range of battery-powered devices that deliver nicotine aerosol without tobacco or smoke.⁹⁶ E-cigarettes were invented in the 2000s and have since been rapidly changing. The vaping device heats an e-liquid – also known as the nicotine vaping product (NVP) – into an aerosol for inhalation.

Beside nicotine, the e-liquid usually contains propylene glycol and glycerol, with or without flavours. Nicotine in e-liquid can be in free-base (original) or salt form. In both cases the active ingredient is nicotine. The free-base form at concentration >20 mg/mL causes adverse effects including throat irritation and therefore higher concentrations need to be diluted before use. The nicotine salt is associated with less throat irritation allowing for higher concentrations of nicotine to be used. The pharmacokinetics of nicotine delivery, which includes rapidity of onset and peak nicotine levels, is variable and is a function of the form of the nicotine, NVP concentration, the vaping device, and inhalation technique.

There is a broad range of vaping devices, which can be open or closed systems, and refillable or non-refillable.^{96, 97, 98, 99} Open system devices are those that need to be manually filled with e-liquid before use. Closed system devices include prefilled cartridges, pods or other disposables where the e-liquid is enclosed in a sealed container.⁹⁹ Disposable devices cannot be refilled with e-liquid and are non-rechargeable. ⁹⁷

Change to regulation of nicotine from 1 October 2021

Under existing state and territory laws, the domestic sale of NVPs to consumers without a prescription is illegal throughout Australia. Additionally, the possession or use of these products without a prescription is illegal in all states and territories. From 1 October 2021, consumers will also require a valid Australian medical prescription to import NVPs (Schedule 4). This means that from 1 October 2021, consumers will require a prescription for all purchases of all NVPs, regardless of where they are sourced from.

Australia’s approach to only have NVPs available on prescription is currently unique around the world. The regulatory arrangements for NVPs vary considerably within and across countries, ranging from prohibition to minimal or no regulation. In Australia, NVPs are regulated under various regulatory frameworks that apply to tobacco products, poisons, medicines and consumer products.⁹⁹

Nicotine vaping products are not currently approved therapeutic goods

There are currently no TGA-approved NVPs registered in the Australian Register of Therapeutic Goods (ARTG). Medicines that are not in the ARTG are known as ‘unapproved’ medicines. There are established pathways for consumers to legally access unapproved NVPs, with a valid prescription. Further details about these pathways are provided below. However, it is important to note that unapproved medicines have not been assessed by the TGA for safety, quality and efficacy.

The TGA has released a product standard for NVPs, which sets out the minimum safety and quality requirements for NVPs supplied in Australia. The Therapeutic Goods (Standard for Nicotine Vaping Products) (TGO 110) Order 2021 (TGO 110) comes into effect on 1 October 2021.

The TGO 110 requirements for NVPs include:

• labelling requirements – ingredient list, nicotine concentration (mg/mL) and warning statements (can be on either the actual product or on an accompanying information sheet). Note that the currently required warning statements do not include the warnings against the risk of ingestion.
• child-resistant packaging¹
• ingredient requirements – including the prohibition of other active ingredients besides nicotine. Note that TGO 110 allows a maximum nicotine concentration of up to 100 mg/mL. This does not mean that products with a nicotine concentration of 100 mg/mL are safe or appropriate (See Dosing considerations).
• restriction on certain ingredients that are known to have potential for toxicity
• record-keeping obligations.

Importantly, the TGO 110 labelling and packaging requirements do not apply to NVPs imported by a consumer for their personal use, which is why the Personal Importation Scheme is not a recommended prescribing pathway (See Prescribing pathways and TGA table "TGO 110 Requirement").

Minimising risk

The recommended first-line smoking cessation support includes TGA-approved pharmacotherapies and behavioural support. NVPs are NOT first-line treatments for smoking cessation. NVPs may be considered with ongoing behavioural support for people who have tried to achieve smoking cessation with TGA-approved pharmacotherapies combined with behavioural intervention but failed and are still motivated to quit smoking.

Given there is not as yet a TGA-approved NVP, this guidance seeks to provide advice to clinicians on how to minimise risk to the person trying to quit smoking and society in general, and maximise benefit. The risks of NVPs include: ^{100, 101}

• unknown long-term health effects
• intentional and accidental poisoning
• acute nicotine toxicity, injuries, burns and lung injury
• dual use with continued smoking ¹⁰²
• greater long-term exposure to nicotine than the use of other smoking cessation measures ¹⁰³
• diversion leading to use by non-smokers
• acting as a gateway to tobacco use
• the potential to promote nicotine use and re-normalise smoking among those who do not smoke, especially young people ¹⁰⁴
• Nicotine exposure can harm adolescent brain development ¹⁰⁴
• potential medicolegal risks for prescribers.

* Child fatalities have occurred following ingestion of liquid nicotine.⁹⁶

Nicotine vaping products and smoking cessation: Efficacy and safety

There is a lack of well conducted randomised controlled trials comparing NVPs with TGA-approved pharmacotherapies, such as bupropion and varenicline. ⁹⁸

An updated evidence review conducted by the Australian National University (ANU) compared nicotine e-cigarettes (nicotine concentration >0.01 mg/mL) versus nicotine replacement therapy. The review identified two randomised controlled trials that met inclusion criteria with a total of 1468 participants. The relative effect was 1.67 (95% CI: 1.21 to 2.28). The RACGP Expert Advisory Group (EAG) concluded there is a small benefit in smoking cessation in the clinical setting for NVPs compared with NRT although the certainty of the evidence is low. The evidence from good quality randomised trials has not improved since the review conducted for the RACGP by the Joanna Briggs Institute in 2019 and there remains limited evidence that NVPs are an effective aid for quitting smoking compared with NRT or usual care. ¹⁰³

The most commonly reported acute adverse effects in a recent Cochrane review were throat irritation, headache, cough and nausea.⁹⁷ The ANU also reviewed the available evidence on short- and long-term adverse effects of NVPs. Based on the evidence, the EAG assessed the overall magnitude of acute adverse effects in the clinical setting as small but there may be other short-term effects that have not become evident. The effects of NVPs on other clinically important short- and long-term health outcomes are unknown. (See the Appendix for the evidence-to-decision framework).

Navigating prescribing pathways

There are three main prescribing pathways for NVPs with the first two being preferred: (see NPS figure in the Appendix)

1. Authorised Prescriber Scheme – The medical practitioner applies to the TGA for authority to prescribe NVPs directly for patients under their immediate care without requiring separate approval for individual patients. The number of patients treated every 6 months must be reported to the TGA. (See the TGA infographic on becoming an Authorised Prescriber for NVPs)
2. Special Access Scheme – The medical practitioner applies to the TGA for approval to prescribe an NVP for a single patient on a case-by-case basis.
3. Personal Importation Scheme – The medical practitioner supplies a script for the patient to import the product (up to 3 months’ supply) for their personal use. The medical practitioner does not need TGA approval or authority.

Supply of NVPs through Australian pharmacies using either the Authorised Prescriber or Special Access Scheme pathways (apply online) is recommended.

Use of the Personal Importation Scheme is not recommended to minimise the risk of the patient receiving imported products that do not meet the full TGO 110 requirements. This is because TGO 110 labelling (ingredient list, nicotine concentration in mg/mL and warning statements), and packaging requirements apply only to NVPs supplied in Australia and not to products imported via the Personal Importation Scheme.

Medical practitioners can choose to take the following steps to minimise the risk of patients using their prescription supplied under the Authorised Prescriber or Special Access Scheme to purchase NVPs through the Personal Importation Scheme:

1. Supply the prescription directly to the patients nominated pharmacy
2. Endorse the prescription “For local supply only” to indicate dispensing within Australia

Note: NVPs are currently under consideration for inclusion in real-time prescription monitoring systems in Australia.

Prescribing

The recommendations depend on whether the patient is new to using NVPs for smoking cessation or is an experienced user of NVPs.

• It is recommended that new users only use devices with closed systems, such as cartridges and pods, to reduce the risk of poisoning and the addition of other potentially toxic substances to the e-liquid. The majority of available closed systems deliver nicotine salt.
• Experienced users may have preferences with regards to type of vaping device and e-liquid, which can be taken into account but are not determinative.

Writing prescriptions

NVP prescriptions should specify the following:

• nicotine concentration (in mg/mL)
• recommended daily dose
• quantity ­– The EAG recommends limiting the quantiaty provided per prescription to a maximum 3 months’ supply. Consider aligning the duration of supply with the timing of follow-up.

In addition, since different NVP brands have different nicotine concentrations, prescribers may have to specify product brands to reduce confusion or uncertainty during dispensing. Therefore, prescribers will likely need to be aware of product availability. At the time of writing, the specific products that will be available in Australian pharmacies is not known. Besides consideration of open or closed systems, other issues to consider when choosing a product include certification of adherence to Good Manufacturing Practices and whether the manufacturer provides product liability insurance.

Dosing considerations

The EAG noted it is not possible to provide definitive advice on dosing as there is no clear evidence and no guidelines on dosing exist at this time. In addition, the dose of nicotine received by the person can vary by the type of vaping device (including the electrical power of the device), concentration of nicotine, and inhalation technique.

The evidence shows:

• The amount of nicotine inhaled from NVP can be very variable – between 0.5 and 4 mg with 15 puffs (in comparison, the amount of nicotine per combustible cigarette is 0.5 to 1.5 mg) ¹⁰⁵
• Blood concentrations similar to or greater than combustible cigarettes are attainable with liquid nicotine concentrations of ≤20 mg/mL. ^{105, 106}

There is currently only limited guidance from the literature on NVP dosing with the free-base nicotine.

The two trials demonstrating significant NVP efficacy, which were included in the ANU review, used a nicotine free-base concentration of ≤20 mg/mL.^{107, 108} One trial involved participants receiving a starter pack of 18 mg/mL liquid nicotine and subsequently choosing their own nicotine concentration up to 20 mg/mL. The other trial, which allowed participants to choose their own nicotine concentration up to 20 mg/mL, reported use of a median of 10 mg/mL initially and 6 mg/mL at 6 months.

It is important to note that there are currently no trials of the efficacy of nicotine in salt form to assist smoking cessation.

The higher-concentration nicotine salt have potential advantages and disadvantages. Potential advantages are that their pharmacokinetics more closely replicate nicotine from smoking, which may facilitate people transitioning away from combustible tobacco.¹⁰⁹ Also, the consumption of e-liquid is reduced, which may result in reduced exposure to toxic compounds (including volatile aldehydes) and flavouring molecules with unknown toxicity.^{109, 110, 111} Along with the lack of evidence of efficacy in smoking cessation, an important disadvantage is the concerning level of uptake of high concentration nicotine salt products in non-smokers including young people. This has been a particular feature in countries with consumer availability such as the United States and Canada. ^{112, 113} Therefore, risk of diversion needs to be considered and minimised.

While acknowledging the lack of evidence, the EAG provided the following suggestions to assist in making prescribing decisions:

• When prescribing for new users to support smoking cessation, choose a starting dose based on the patient’s level of nicotine dependence (See Assess Nicotine Dependence in Chapter 1 Introduction to smoking cessation). If using nicotine free-base a reasonable starting strength for less dependent smokers is 6–12 mg/mL. Higher concentrations (18–20 mg/mL) may be needed for more dependent smokers. If using nicotine salt pods, a reasonable starting strength is 18–30 mg/mL for less dependent smokers. Higher concentrations (>30 mg/mL) may be needed for more dependent smokers.
• Current users of NVPs will likely have their own preferences of concentration, device, and daily use. If the patient is currently using an open system device and moderate to high nicotine concentration, recommend changing to nicotine free-base concentration ≤20mg/mL and/or a closed system device to reduce risk of poisoning.

Device considerations

Premixed ‘closed’ systems are recommended to avoid the following risks:

• inappropriate or incorrect dilution of liquid nicotine (the dilution process is not straightforward and relies on adequate product labelling)
• intentional or accidental ingestion or exposure through skin or eyes
• addition of potentially toxic or illegal substances, or contamination

Therapeutic guidelines on nicotine toxicity state the potentially lethal oral exposure dose is 5 mg/kg.¹¹⁴ Therefore, about 4 mL of a 100 mg/mL NVP is potentially fatal for an adult and <1 mL is potentially fatal for the average 2-year-old.

The risk of addition of toxic substances was demonstrated by the occurrence of E-cigarette or Vaping-Associated Lung Injury (EVALI), a severe respiratory illness first identified in the United States in early 2019. Investigations by the US Centers for Disease Control found that in the majority of EVALI cases the e-liquids used contained tetrahydrocannabinol (THC) and that vitamin E acetate, an additive that was much more common in THC-containing vaping products, was strongly linked to the EVALI outbreak. However, 1 in 8 cases are reported in use of nicotine-only products.¹¹⁵

Flavourings

Flavouring chemicals can reduce the harshness of nicotine, increase the appeal and reduce the perceived risk of NVPs.⁹⁸ Fruit and sweet (dessert) flavours are popular with young people and encourage uptake in non-smokers. ^{112, 116} Though it is not essential for prescribers to specify the flavour on the prescription, ideally avoiding flavours or limiting to only tobacco flavour may reduce this risk.

The TGA’s TGO 110 prohibits certain ingredients being added to NVPs but does not assess the safety of ingredients used in unregistered NVPs. There is limited evidence about the long-term safety of inhaled flavourings. Flavouring chemicals may be safe to consume as food or medication but may not be safe to inhale.^{96, 117}

To minimise risk, the EAG strongly recommends the use of devices with closed systems as users cannot purchase and add their own flavours, and to avoid open systems.

Use in people with chronic illnesses

There is a lack of high-quality evidence for the use of NVPs in people with chronic illnesses. The risk of using NVPs needs to be weighed against the risk of long-term smoking in people who have not been able to quit with first-line treatments (TGA-approved pharmacotherapies and behavioural support).

Pregnant or breastfeeding women

NVPs are not recommended in pregnant or breastfeeding women. NVPs are not approved for use in pregnancy and their effects on foetal development and obstetric outcomes are not known. For further information about smoking cessation in this group, refer to Chapter 4: ‘Pregnant or breastfeeding women’.

Adolescents

NVPs are not recommended in people under 18 years oldFor further information about smoking cessation in this group, refer to Chapter 4: ‘Adolescents and other young people’.

Aboriginal and Torres Strait Islander peoples

Currently there is no evidence on the effectiveness of NVPs to assist quitting in Aboriginal and Torres Strait Islander peoples. For further information about smoking cessation in this population, refer to Chapter 4: Aboriginal and Torres Strait Islander peoples. The use of specific culturally safe resources, such as Tackling Indigenous Smoking and the Aboriginal Quitline is recommended.

Aboriginal and Torres Strait Islander people are more likely than non-Indigenous people to live in households with children present ¹¹⁹ and to experience mental health illness. ¹²⁰ Both can increase the risk of accidental and intentional poisoning related to NVPs. Particular care should therefore be taken to avoid prescription of high nicotine concentration liquids and open systems, and to advise on appropriate storage of NVPs, including keeping them out of reach of children.

People with mental illness

Smoking is highly prevalent in people with mental illness, especially those with severe illness. If people with mental illness have not been able to quit with first line treatment, consideration of NVPs in combination with behavioural support may be of value, although evidence specific to this group is currently lacking. People with mental illness are likely to be at greater risk of intentional poisoning from NVPs. Therefore, particular caution should be taken to avoid prescription of high nicotine concentration liquids and open systems. (For further information about smoking cessation in this population, refer to Chapter 4: People with mental illness).

Monitoring NVP use and follow-up

As with any intervention for smoking cessation, follow-up visits to discuss progress and provide support is recommended. Arrange follow-up starting within a week of the quit day (refer to Chapter 1 “Arrange follow-up”). Note that dose titration may be needed with regular follow-up and should be discussed with the patient. Follow-up will also support managing and reporting (to the TGA) any adverse effects associated with NVP use. Encourage complete transition to NVPs and cessation of combustible tobacco.

After this initial phase, it is reasonable to review at least every 3 months, which is consistent with prescribing of PBS-subsidised smoking cessation therapy.

There is currently a lack of evidence about the optimal length of use or how to titrate NVPs down to achieve nicotine cessation. A suggested approach would be to attempt weaning or cessation of NVPs after 12 weeks of use. Transfer to NRT is an option for transitioning from NVPs to a form of nicotine less associated with long-term use. Other approved smoking cessation pharmacotherapies may have a role; however, there is a need for further research.

A maximum duration of 12 months’ use of NVPs is a reasonable consideration.

NVPs in combination with other smoking cessation pharmacotherapy options

There is currently limited evidence for combination use involving NVPs. The ANU review included one published RCT on the combination of NVPs with NRT, which had a GRADE rating of very low certainty.¹⁰³ According to a 2021 UK briefing paper on NRT combination therapy, there may be benefit from the rapid delivery of nicotine from NVPs alongside steady state nicotine from NRT patches. ¹²¹

Tobacco relapse prevention

Cessation of both tobacco smoking and use of other forms of nicotine is always the preferred option. However, there may be instances in selected patients where the doctor and patient agree that a longer term use of NVP is needed to avoid a relapse to tobacco use. Dual use should be avoided. If considering ongoing use of NVPs, counsel the patient on the risks and benefits versus re-trying other approved smoking cessation pharmacotherapies. This discussion includes that the long-term safety of NVPs is unknown, that there is a lack of high quality evidence of the health benefit from a tobacco harm reduction approach using NVPs, and that people who use NVPs have an approximately double the risk of relapse to combustible tobacco smoking compared with non-NVP users. ¹²² Regular follow-up, monitoring and consideration of re-trialling other first-line interventions over time is recommended.

Based on a small number of trials, clonidine has been found to be more effective than placebo in promoting smoking cessation.¹⁰⁶ Prominent side effects for the use of clonidine include postural hypotension, extreme drowsiness, fatigue and dry mouth, which limit the usefulness of clonidine for smoking cessation.¹⁰⁷

Clonidine is not registered for smoking cessation therapy in Australia.

A number of other tobacco cessation therapies are available or in development, as described below.^108,109

Cytisine is a naturally occurring substance, chemically related to varenicline, that has been used for smoking cessation for decades in parts of Eastern Europe.¹¹⁰

A Cochrane meta-analysis concludes that cytisine increases the chances of quitting, although absolute quit rates in two recent trials were modest.¹ A New Zealand study found that cytisine combined with brief behavioural support was superior to NRT in helping people who smoke to quit, but it was associated with a higher frequency of self-reported adverse events.¹¹¹

Cytisine is not currently approved by the TGA or available in Australia.

Anti-nicotine vaccines have been in development for a number of years. The rationale for immunisation against nicotine is to induce antibodies that bind nicotine in the blood, thereby preventing it from crossing the blood–brain barrier.¹⁰⁹ It is postulated that with less nicotine reaching the brain immediately after smoking, the vicious cycle between smoking and nicotine-related gratification will be broken. The vaccines must be administered regularly to maintain long-term protection. Early pre-clinical trials evaluating different vaccines were encouraging, but to date no study has detected a statistically significant difference in long-term cessation between vaccines and placebo.¹¹² Nicotine vaccines are not yet licensed anywhere in the world for use as an aid to smoking cessation or relapse prevention.¹¹

Given that the current available first-line medications are all efficacious, and non-drug factors make a substantial contribution to the likelihood of quitting successfully,⁸ choice should be based on overall evidence of relative efficacy, clinical suitability and patient preference (Figure 2.2).