Home » Chapter 7: Cessation » 7.16 Pharmacotherapies for smoking cessation

7.16 Pharmacotherapies for smoking cessation

Last updated: May 2021

Suggested citation: Greenhalgh, EM., Dean, E., Stillman, S., & Ford, C. 7.16 Pharmacotherapies for smoking cessation. In Greenhalgh, EM, Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2021. Available from: http://www.tobaccoinaustralia.org.au/chapter-7-cessation/7-16-pharmacotherapy

Note: This section is intended for health professionals. People who smoke tobacco and are interested in quitting can find information at: https://www.quit.org.au/

The development and introduction of pharmacotherapies has provided much-needed assistance for those people who smoke tobacco and are trying to quit, particularly for more dependent smokers. Pharmacotherapies for cessation primarily aim to reduce withdrawal symptoms and block the reinforcing effects of nicotine. A substantial body of research has demonstrated the effectiveness of such therapies for increasing smoking abstinence rates. In 2020, the US Surgeon General concluded that cessation medications are independently effective in increasing smoking cessation, and are more effective than self-help materials or no treatment.¹ First-line treatments are those that have been shown to be effective and safe and are licensed for smoking cessation. These include nicotine replacement therapy (NRT), bupropion, and varenicline, all of which increase smoking cessation. Varenicline has generally been shown to be superior to bupropion and single forms of NRT, but equally effective as combination NRT (i.e., faster-acting plus longer-acting form). Table 7.16.1 shows the findings of recent Cochrane reviews examining the effectiveness of each first-line pharmacotherapy.

Table 7.16.1 Effectiveness of pharmacotherapies for smoking cessation

Pharmacotherapy	Relative effect (95% CI)
Nicotine replacement²
Any form versus placebo/control	1.55 (1.49 to 1.61); i.e., users of NRT were 1.55 times more likely to successfully quit than placebo/control
Nicotine gum versus placebo/control	1.49 (1.40 to 1.60)
Nicotine patch versus placebo/control	1.64 (1.53 to 1.75)
Oral tablets^/lozenges versus placebo/control	1.52 (1.32 to 1.74)
Nicotine inhalator versus placebo/ control	1.90 (1.36 to 2.67)
Nicotine nasal spray^ versus placebo/ control	2.02 (1.49 to 2.73)
Mouth spray versus placebo/control	2.48 (1.24 to 4.94)
Bupropion³
Versus placebo/control	1.64 (1.52 to 1.77)
Versus NRT (patch, lozenge, or a choice)	0.99 (0.91 to 1.09)
Versus varenicline	0.71 (0.64 to 0.79)
Varenicline⁴
Versus placebo/control	2.24 (2.06 to 2.43)
Versus NRT	1.25 (1.14 to 1.37)
Versus bupropion	1.39 (1.25 to 1.54)
Combination therapies
Combination NRT (faster-acting form + patch) versus single form⁵	1.25 (1.15 to 1.36)
Combination NRT versus varenicline⁶	1.06 (0.75 to 1.48)
Bupropion + NRT versus NRT alone³	1.19 (0.94 to 1.51)
Bupropion + varenicline versus varenicline alone³	1.21 (0.95 to 1.55)

Note: Italics indicate interventions for which there was no benefit over comparison group.
^ No longer available in Australia

Surveys in the US, UK, Canada, and Australia show that the self-reported use of any stop smoking medication has increased significantly over the 2000s. The most-used medication is NRT, with use of varenicline increasing significantly. Greater use of any medication is related to being female, white, and having a higher education level.^{7, 8}

Choice of pharmacotherapy should take into account potential adverse effects as well as benefits.⁹ When pharmacotherapy combinations or dosages beyond those contained in product information and consumer medicines information are used, medical recommendation is necessary.

Cost is also taken into account by the Australian government in deciding which pharmaceuticals to subsidise under the Pharmaceutical Benefits Scheme (PBS) and the Repatriation Pharmaceutical Benefits Scheme (RPBS). Nicotine patches were listed on the RPBS in August 1994 and December 1995 and then made available under the PBS for Indigenous smokers from 2009.^{10, 11} Availability was extended to all smokers in January 2011. In April 2014, the 25 mg/16 hours patch was also added—see Section 7.16.1.6 for further details on medicines listed. Bupropion and varenicline are Schedule 4 in Australia so that they are available only on prescription,¹² and have been available on Australia’s PBS since 2001 and 2008 respectively. Since January 2021, the dispensed price for subsidised medicines is up to $6.60 for people with a concession card and up to $41.30 for other patients.¹³ Subsidy of medicines in Australia has clearly been associated with increased use.

Figure 7.16.1 shows the annual total number of prescriptions for each of the available anti-smoking medications and in total in Australia from 2001 to 2020.

Figure 7.16.1 Annual total number of prescriptions for anti-smoking medications, Australia, 2001 to 2020: bupropion, varenicline, and NRT

Source: Pharmaceutical Benefits Scheme database statistics http://medicarestatistics.humanservices.gov.au/statistics/pbs_item.jsp

Notes: Total number of prescriptions includes second and subsequent prescriptions for all classes of patients (general), those with concession cards and those covered by Repatriation Pharmaceutical Benefits Scheme) and some patients may have used more than one medicine over the 10-year period. NRT figures do not include over-the-counter sales of NRT.

This section summarises research on the use, effectiveness and safety of:

7.16.1 Nicotine replacement therapy

7.16.2 Bupropion and other anti-depressants

7.16.3 Varenicline and other nicotinic receptor partial agonists

7.16.4 Vaccines

7.16.5 Combination treatments (drug combinations, and drugs + behavioural support), and

7.16.6 Other medications that might increase quitting

It also examines:

7.16.7 The effects of dispensing arrangements and subsidies, and

7.16.8 Methodological and ethical issues in smoking cessation trials

7.16.1 Nicotine replacement therapy

Nicotine is the drug in tobacco that causes dependence.¹⁴ It is the decrease in nicotine levels that is mainly responsible for withdrawal symptoms after stopping smoking.¹⁴ NRT aims to temporarily replace some of the nicotine from cigarettes, in turn reducing motivation to smoke and nicotine withdrawal symptoms, and easing the transition from smoking to abstinence.⁹ By replacing only nicotine, the many thousands of other chemicals produced when tobacco is smoked that are largely responsible for tobacco-related disease are avoided. Hence NRT is sometimes thought of as ‘clean nicotine’.¹⁵

NRT products are either long-acting dosing forms or faster-acting forms.¹⁶ There are advantages and disadvantages associated with each form of NRT. Nicotine patches are simple to use and the adherence rate tends to be higher than other forms of NRT.^{17, 18} Patches deliver nicotine more slowly than other products and when used alone, may not adequately protect against increased cravings from smoking-related stimuli. Users of the faster-acting forms have greater control over the amount and timing of the dose, and these forms are better suited to respond to sudden increases in cravings.¹⁸ However, some people only use faster-acting NRT forms in response to cravings. Underdosing is a common problem, where people don’t use enough to obtain the best clinical effect.¹⁸ Nicotine delivered via a mouth spray is absorbed faster than nicotine delivered via gum or lozenge.^{19, 20} There is robust evidence showing that combination NRT (long-acting plus faster-acting) is more effective than single‐form NRT⁵ (see Section 7.16.1.2.2, below).

E-cigarettes can provide users with inhaled doses of aerosolised nicotine. There is currently widespread debate within the public health community regarding the use and regulation of these products.²¹ From the 1^st of October 2021, consumers will require a doctor's prescription to legally access nicotine e-cigarettes and liquid nicotine in Australia—both domestically and when importing the products from overseas.²² See InDepth Section 18B for a detailed discussion.

7.16.1.1 Mechanisms and pharmacokinetics of NRT

Several mechanisms have been proposed by which NRT may assist smoking cessation. First, NRT decreases the intensity of cravings and withdrawal symptoms, enabling people to function effectively while dealing with the social and psychological aspects of their dependence. NRT does not completely eliminate all withdrawal symptoms because the available delivery systems do not replicate the rapid and high levels of nicotine that result from smoking a cigarette.²³ Second, it may reduce the reinforcing effects of tobacco-delivered nicotine. Third, it may provide some of the perceived effects for which the smoker previously relied on cigarettes, such as sustaining desirable mood, coping with stressful situations, and maintaining concentration.^{18, 24, 25} The nicotine inhalator is designed to mimic the hand-to-mouth ritual of smoking.

7.16.1.2 Efficacy and effectiveness of NRT

A Cochrane review published in 2018 concluded that NRTs increase the rate of quitting by 50 to 60%, and all of the commercially available forms can help increase the chances of a quit attempt being successful.² However, some have suggested that this effect size may be an overestimate.^26-28 Another review concluded that given the quality of research and the lack of serious adverse effects, NRT appears to be a safe and effective option for current smokers who wish to quit.²⁹ A 2021 meta-analysis concluded that single-form NRT increases the odds of six-month abstinence by 2.2 times compared with placebo.³⁰ Studies with long-term follow-up have found that the impact of a single course of NRT persists over time, with NRT users about twice as likely to not be smoking four years later than those who quit without using NRT.³¹

7.16.1.2.1 Dosage and mode of delivery

Some evidence suggests that dosage and speed of delivery has an impact on outcomes.^32-35 A review of high-dose transdermal NRT (patches) for smoking cessation published in 2014 concluded that there is insufficient evidence to support the safety and efficacy of this approach, and called for more robust trials.³⁶ More recently, a 2019 Cochrane review found that people were more likely to quit successfully if they used higher‐dose compared with lower-dose nicotine patches or nicotine gum.⁵

7.16.1.2.2 Combination NRT therapy (longer-acting and faster-acting form)

In 2006, the Therapeutic Goods Administration (TGA) approved combination therapy for the concurrent use of the 15 mg 16-hour patch with 2 mg gum. There is robust evidence that combining a longer-acting form (e.g., patch) with a faster-acting form (e.g., lozenge) is more effective than single form NRT and is safe.^{9, 37-42} A 2013 Cochrane review found that, comparable with varenicline, combination NRT (e.g., patch plus inhalator) was the most effective available pharmacological intervention for achieving smoking cessation,⁶ and a 2019 Cochrane review similarly concluded that using combination NRT versus single‐form NRT can increase the chances of successfully stopping smoking.⁵ In 2020, the US Surgeon General concluded that combination NRT increases smoking cessation compared with using single forms of NRT.¹ A 2021 meta-analysis found that compared with placebo, people given combination NRT were 2.6 times more likely to successfully quit.³⁰

Overall, researchers suggest that combination NRT likely represents the most promising smoking cessation strategy moving forward.⁴³ Some have recommended that NRT labelling allow for combined use of faster-acting NRT forms with nicotine patch,³⁷ and The Royal Australian College of General Practitioners has called for combination NRT to be subsidised under the PBS.⁴⁴ The mechanisms underlying the effectiveness of combination NRT may include the higher percentage of nicotine substitution, more effective relief of cravings, and the sensory effects of different forms.^{9, 18}

7.16.1.2.3 NRT combined with behavioural support

NRT works with or without behavioural support, however behavioural support further increases the odds of success.^45-47 Although a combination of NRT and behavioural support is a well-established cessation method, one study found that self-reported abstinence rates were significantly higher among participants who were sent nicotine patches compared with a control group, supporting the effectiveness of NRT in isolation.⁴⁸ Smokers making self-initiated quit attempts without formal behavioural support tend to have lower long-term success rates, but the relative effect of NRT is similar to the effects in other settings, offering significant improvement over unaided quitting.^{9, 49-51}

7.16.1.2.4 Duration of use

An important factor affecting success rates appears to be the duration of NRT use. Pre-quit nicotine patch use appears to increase quit rates⁵ and may engage additional smokers who are unwilling to quit.³⁷ The US Surgeon General’s report in 2020 found that pre-loading (e.g., initiating cessation medication in advance of a quit attempt), especially with the nicotine patch, may increase smoking cessation.¹ The manufacturer’s recommended period of use for NRT forms substantially varies, often with provision for a gradual reduction of dosage levels to avoid withdrawal effects at the end of the period.⁵² However, research indicates that eight weeks of patch use is as effective as longer courses, and there is no evidence that tapered therapy is better than simply stopping after using the higher dose.⁹ Highly dependent smokers who still have cravings and withdrawal symptoms eight weeks after quitting may benefit from longer use.^{18, 53, 54} Short courses of NRT, for example four weeks, may not be effective in the long term.⁵⁵ Longitudinal research in Canada found that compared with unassisted quitting, using NRT for less than 4 weeks was associated with a lower likelihood of quitting; however, using NRT for 4 weeks or longer was associated with a higher likelihood of cessation.⁵⁶ After quitting, extended use of NRT may be beneficial for lapse recovery and relapse prevention in some smokers.³⁷ Findings from a 2019 Cochrane review showed that while extended NRT use did not show a benefit in preventing relapse in assisted abstainers, extended use in unassisted abstainers did suggest a benefit. However, the evidence was of low certainty.⁵⁷ Continued use of NRT and tobacco during a lapse or relapse does not appear harmful and could enhance quitting outcomes.⁵⁸ For example, one study found that if people continue to use a nicotine patch ( after a lapse they are 4–5 times more likely to quit.⁵⁹ The Royal Australian College of General Practitioners has recommended that a second 12-week round of NRT be subsidised under the Pharmaceutical Benefits Scheme within a 12-month period, to allow for extended use to prevent relapse.⁴⁴

7.16.1.2.5 Factors affecting use and adherence

The widespread availability and promotion of NRT forms has led to increased use, however there are concerns that use of the products in the community appears to be more haphazard and less effective than among participants in research trials. A meta-analysis found poor adherence to NRT among participants of population-based studies, with only about one in four people taking it as directed.⁶⁰ A population-based study in England found that smokers attempting to reduce their cigarette intake are often underusing NRT, which may explain why real-world studies often report less success with NRT than clinical trials.⁶¹ A study in New South Wales found that more than 40% of people who had used NRT in their most recent quit attempt had no instruction from a doctor or pharmacist on how to use the product, 61% used it for less than two weeks, and for about one-third of people, use was concurrent with smoking.¹⁷

Research suggests that many smokers have misperceptions about the health risks of NRT, which makes them less likely to use the NRT or use it correctly.^{34, 47, 62} Smokers tend to use less than the recommended dose or not complete the full course of treatment.^{63, 64} Treatment adherence has been found to significantly increase abstinence rates.^{60, 65} Using more doses of nicotine gum, nicotine lozenges and nicotine inhalator, increases quit rates.^{66, 67} For example, one study found that for each additional lozenge used, the odds of successful quitting increase by 10%.⁶⁸ Approaches to increase smokers’ willingness to use—and correct use of—NRT include addressing their expectations of its effectiveness, explaining clearly how it works, tailoring treatment plans, and addressing barriers to use.⁶⁹ Clear and accurate information regarding the safety of NRT from health professionals can increase use and adherence.⁷⁰ The literacy levels of packaging and instructions have been assessed as being above the reading levels recommended to ensure maximum comprehension.⁷¹ There is some evidence that enabling smokers to sample the NRT forms prior to use may result in more realistic choice of NRT and better compliance.⁷²

The use of NRT for a reason other than quitting, including temporary abstinence or reducing consumption, appears to be common. A review of NRT products available in Canada found that while more robust studies are needed to test newer products (such as a nicotine mouth spray or mini lozenges), NRT appeared to be effective in smoking reduction for those smokers who did not want to quit, failed from previous NRT, or intended to quit smoking gradually.⁷³ Such usage is associated with higher education level, heavier smoking, no intention to quit, no quit attempts in the past year and the type and availability of the product used. These patterns of use may help to explain why significant benefits of NRT use are not easily detected in population studies.⁷⁴

7.16.1.3 Safety of NRT

In general, NRT is considered to be safe for most users. Discontinuation because of adverse reactions is relatively low.⁹ Using NRT to quit is always safer than continuing to smoke.⁷⁵ When used as directed, users of NRT typically absorb a lower daily dose of nicotine than they would get from smoking a pack of cigarettes per day.^{18, 76} While there has been concern about the potential for symptoms of nicotine overdose, studies of higher dose products and combination of NRT products have found no evidence of harm from moderate increases in nicotine intake.^{75, 77, 78} Further, research suggests that using faster-acting NRT forms alongside smoking does not appear to increase average nicotine levels, although smoking while using the nicotine patch does.⁷⁷ Smoking while using NRT does not significantly increase the risk of a heart attack or other cardiovascular events.^{9, 75} No serious adverse effects have been reported in studies of concomitant smoking and NRT use, although one study reported that nausea and vomiting were more common in the active than the placebo group.^{18, 77} Other potential symptoms of nicotine overdose include pallor, sweating, tachycardia, agitation, and a number of less common symptoms.⁵²

All NRT products have a low addictive potential.⁷⁹ Addictive potential is strongly influenced by speed and method of delivery of nicotine.^{75, 80} When smoking a cigarette, peak blood nicotine levels are achieved within seconds, taking only 10–19 seconds for nicotine absorbed from the lungs to reach the brain, after which time it declines rapidly.⁷⁵ In contrast, it can take more than 30 minutes to reach the peak blood nicotine level when using faster-acting forms of NRT,^81-84 with effects of nicotine evident within 15–20 minutes.¹⁸ When using the patch, it takes four to nine hours (depending on the patch) to reach peak blood nicotine level, which then remains constant while wearing the patch.⁷⁶

A paper examining the first 20 years of NRT use reported no serious adverse effects of either short or long-term use.⁵⁴ The most common side effects of the patch are skin rashes where it is applied and sleep disturbance. Common side effects for the faster-acting forms include irritation of the mouth or throat, headaches, hiccups, indigestion, nausea and coughing.^{9, 52, 76, 85, 86} These are relatively minor for most users, and NRT is generally rated as safe compared to other medications.^{9, 54} Although such use is uncommon, extended duration NRT is safe, and is at least as effective as short courses.^{37, 87}

While NRT has the potential for adverse effects in vulnerable developmental stages (such as during adolescence, pregnancy, and breastfeeding), it is considered to be safer alternative to smoking and can be considered under medical supervision.^{88, 89} NRT is safe to use in people with stable cardiovascular disease, including angina and previous heart attack.^{9, 75} Nicotine does have some effects on the cardiovascular system, such as increased heart rate and blood pressure, however it is not the major cause of increased cardiac risk due to smoking.⁷⁵

Many smokers believe that nicotine causes cancer, since it is equated with tobacco;^{75, 90} however, the US Surgeon General’s 2014 report concluded that there is insufficient data to conclude that nicotine causes or contributes to cancer.⁹¹ It appears to be the other carcinogens in tobacco smoke that are responsible for smoking-related cancers.^{92, 93}

7.16.1.4 Using NRT to ‘cut down to quit’

Many smokers find it very difficult to stop using tobacco abruptly even using NRT. In 2007, the TGA approved the use of the ‘cut down and stop method’, where smokers using NRT (inhalator, mouth spray, lozenge or gum) reduce the amount they smoke over a six-week period before stopping completely. Research suggests that the addition of this method to the approved uses of NRT may increase the numbers of smokers who quit altogether.⁹⁴ Pre-quit nicotine patch use appears to increase quit rates and may engage additional smokers compared with starting the patch on quit day.^{37, 77, 95, 96}

There has been discussion about offering NRT to smokers not wanting to quit but who are interested in reducing their level of smoking. The rationale is that once reduced, they may decide to quit altogether. Studies of smokers cutting down while using NRT have found that while blood nicotine levels generally remain stable or slightly higher, carbon monoxide readings decreased.^97-99 Research is limited but trials indicate that NRT can achieve sustained smoking abstinence in this group. However, most trials also provided some type of behavioural support.^{100, 101} Evidence suggests that use of NRT to ‘cut down to quit’ is effective and cost effective compared to no quit attempt.¹⁰²

7.16.1.5 Scheduling and subsidy of NRT

In Australia, NRT is available in the form of a patch, gum, lozenge, mini-lozenge, mouth spray, and inhalator. The gum and lozenge come in 4 mg and 2 mg strengths, while the inhalator comes in a 15mg strength. The mini lozenges come in strengths of 4mg and 1.5mg. A mouth spray delivers 1 mg per spray, while the dose from an inhaler is similar to that of the 2 mg gum. There are two types of patches, each with three strengths: the 24-hour patch 21 mg, 14 mg and 7 mg strengths, and the 16-hour patch 25mg, 15 mg, and 10 mg strengths.¹⁰³ Nicotine chewing gum first became available on prescription in Australia in 1984, followed by the patch in 1993.¹⁰⁴ The 2 mg gum became available over-the-counter without prescription (i.e., became unscheduled) in pharmacies in 1988, and the 4 mg gum and patches in late 1997.¹⁰⁵ The nicotine inhaler, lozenges and sublingual tablets were introduced as over-the-counter products in 1999, 2002 and 2003 respectively.^{82, 83, 85} In 2005, NRT products started to appear in supermarkets. Direct advertising to the public of NRT began in 1998, which markedly increased sales.¹⁰⁶

Subsidised nicotine patches have also been available since 1994 to patients eligible for repatriation benefits and to patients who identify as Aboriginal or Torres Strait Islander since January 2009. Access to nicotine patches under the PBS was extended to all smokers in February 2011, and lozenges and gum were also added to the PBS in 2018. A condition for the subsidy is that the smoker participates in cessation counselling. If a patient is unsuccessful in quitting using NRT, they can access other smoking cessation therapies on the PBS (bupropion and varenicline) during that 12-month period.

As of April 2021, there were 11 nicotine replacement products available on the PBS and/or RPBS, including patches, gum, and lozenges. For details about each of the products, see here.

7.16.2 Bupropion and other anti-depressants

Bupropion is a non-nicotine medication that is approved for use as an aid to smoking cessation. Originally developed as an antidepressant, early users reported that they had less urge to smoke, and further research demonstrated that it was useful as an aid to quitting.

7.16.2.1 Mechanisms and pharmacokinetics of bupropion

The active ingredient is bupropion hydrochloride. The tablets are ‘sustained release’ which mean the buproprion is released slowly and absorbed,¹⁰⁷ While the exact mechanism by which bupropion supports smoking cessation is unknown, its action is likely mediated through the noradrenergic and/or dopaminergic pathways.¹⁰⁸ It relieves withdrawal symptoms and may reduce depressed mood,^{107, 109-111} and symptoms of depression.¹¹² Use of bupropion is associated with improved ability to resist cravings that result from ‘cues’ to smoke.¹¹³ Bupropion appears to reduce the weight gain that occurs after quitting, but the effect does not last beyond treatment.¹⁰⁷

7.16.2.2 Efficacy of bupropion

A Cochrane review published in 2020 concluded that there is high quality evidence that bupropion increases the likelihood of long-term smoking cessation. People who use bupropion are about 60% more likely to achieve long-term cessation (vs. placebo/control), which is similar to that for single-form NRT, but lower than when using varenicline.³ A 2021 meta-analysis concluded that bupropion increased the odds of six-month abstinence by 2.1 times compared with placebo.³⁰ The Cochrane review did not find any evidence that the efficacy of bupropion depended on the level or type of additional behavioural support, or whether people had a psychiatric condition.³ There is some evidence that positive beliefs and attitudes about bupropion are associated with being positive about quitting, better compliance, and potentially better outcome.¹¹⁴ One study found that extended use of bupropion prior to a quit attempt reduced smoking behaviour during the pre-quit period and improved short-term abstinence rates.¹¹⁵ A 2019 Cochrane review concluded that extended treatment with bupropion did not appear to help prevent relapse; however uncertainty in the data meant that the authors could not rule out such a benefit.⁵⁷ People with certain genetic variants appear to have lower success rate with bupropion, highlighting the potential for genetic markers to guide individualised pharmacotherapy.¹¹⁶

7.16.2.3 Use of bupropion in Australia

Bupropion was introduced into Australia in 2000 and listed on the PBS in February 2001, sold as 30 x 150 mg tablets (code 8465M), since February 2001 and 90 x 150 mg tablets (code 8710K), since February 2004.

It is available only on prescription, and one nine-week course per year is subsidised under the PBS on condition that users participate in a comprehensive counselling program such as with the Quitline. Since changes to the authority conditions in 2004, smokers wishing to use bupropion must visit a doctor for the initial 30-tablet prescription, and then make a second visit to receive the second prescription for the remaining 90 tablets.

7.16.2.4 Adverse events associated with bupropion

The most common side effects of bupropion use are sleeping difficulties, dry mouth, headache, dizziness, anxiety and nausea.^{112, 117} A small number of allergic reactions to bupropion have been reported, including skin rashes or breathlessness, and, less frequently, fever, muscle and joint pain.^{107, 117} Overdosing can cause serious side effects, including vomiting in children, rapid heartbeat in teenagers and adults and seizures. Other effects of overdose include lethargy, confusion and tremors.¹⁰⁷ The most serious side effect is a risk of seizure, estimated to occur in 1 in 1000 patients.¹¹² One review found that cardiovascular events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion compared with placebo.¹¹⁸ While a large randomised trial found that use of bupropion did not appear to increase the risk of neuropsychiatric adverse events,¹¹⁹ a 2020 Cochrane review found high‐certainty evidence that participants randomised to bupropion were more likely to report psychiatric adverse events. This along with other side effects resulted in more trial dropouts. However, there was insufficient evidence regarding whether participants taking bupropion were more likely than those taking placebo to report serious adverse events, such death or hospitalisation.³ Bupropion is contraindicated for smokers who are allergic to bupropion, who are pregnant or breastfeeding, who are less than 18 years of age, who have a current or previous history of seizures or eating disorders, who are currently or recently (within last 14 days) taking monoamine oxidase inhibitors, who have any tumours of the central nervous system or severe liver disease, or who are undergoing abrupt withdrawal from alcohol or benzodiazepines.^{120, 121} There is also an increased risk of seizures occurring with bupropion in the presence of predisposing risk factors which lower the seizure threshold.¹⁰⁸

7.16.2.5 Other antidepressants

A number of other antidepressants have been investigated for smoking cessation. A 2020 Cochrane review³ and a 2021 meta-analysis³⁰ both concluded that the antidepressant nortriptyline approximately doubles the odds of six-month abstinence compared with placebo. The side effects of this medication include dry mouth, constipation, nausea, and sedation, and it can be dangerous in overdose. Like bupropion, the likelihood of quitting using nortriptyline appears to be similar to that for NRT, but lower than when using varenicline. Selective serotonin reuptake inhibitor antidepressants (for example, fluoxetine), monoamine oxidase inhibitors (for example, selegiline), and the antidepressant venlaxafine have not been shown to help smoking cessation, nor has the herbal therapy St John's wort, or S-Adenosyl-L-Methionine (SAMe), a dietary supplement that is thought to have antidepressant properties.^{3, 112}

None of these drugs are currently licensed for smoking cessation in Australia; however, nortriptyline is licensed for smoking cessation in New Zealand³ and is sometimes prescribed ‘off-label’ in Australia for people trying to quit.¹²²

7.16.3 Varenicline and other nicotinic receptor partial agonists

Varenicline is derived from cystine, a similar drug that has been used to assist cessation in central and eastern European countries for several decades. The active ingredient is varenicline tartrate.¹²³ An extensive body of evidence supports the use of varenicline as a smoking cessation medication in a broad range of tobacco users with medical, behavioural, and diverse demographic characteristics.¹²⁴

7.16.3.1 Mechanisms and pharmacokinetics of varenicline

Varenicline is a nicotinic receptor partial agonist (i.e., it binds to nicotinic acetylcholine receptors), which maintains moderate levels of dopamine to reduce withdrawal symptoms and the urge to smoke. It also acts as an antagonist by blocking nicotine binding to specific receptors, which may reduce the rewarding effects of smoking and reduce reactivity to smoking cues.^{4, 123, 125-127} Recent research also suggests that varenicline's reduction of reward anticipation in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, can independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation.¹²⁸ Some evidence suggests that varenicline improves cognitive performance among highly dependent smokers using the medication to quit.¹²⁹

7.16.3.2 Efficacy of varenicline

A robust body of evidence supports the efficacy of varenicline as a smoking cessation medication. A 2016 Cochrane review concluded that varenicline increased the chances of successful long-term cessation between two- and three-times compared to attempts with no medication. It may also help to prevent relapse.⁴ A 2021 meta-analysis concluded that nicotine receptor agonists increased the odds of six-month abstinence by 2.7 times compared with placebo.³⁰ A ‘real-world’ study found that the continuous abstinence rate of varenicline users was 44.4%, with no significant gender or age differences. For every day that varenicline was taken, abstinence increased by an average of 6.6 days.¹³⁰ For smokers ‘cutting down to quit’, a randomised clinical trial found that use of varenicline significantly increased smoking cessation rates at the end of treatment (6 months), and also at 1 year.¹³¹

A number of international studies have shown that varenicline is well tolerated and can be regarded as a cost-effective cessation treatment in smokers willing to quit, including users of smokeless tobacco.^132-145 It also appears to be equally effective for light and heavy smokers.¹⁴⁶ Varenicline has been found to be effective and safe in those with stable mental illness or a past history of mental illness.¹⁴⁷ There is also evidence that varenicline is effective and safe for smoking cessation in people with schizophrenia.^{148, 149}

Varenicline has generally been shown to be superior to bupropion and NRT.^{109, 119, 140, 150-155} For example, one ‘real world’ study found that varenicline users were 3.83 more likely to be abstinent than users of NRT following a quit attempt,¹⁵⁶ and several Cochrane reviews have also concluded that varenicline is more effective than bupropion or NRT.^{3, 4} A double-blind randomised trial found that varenicline, compared with nicotine patch, more than doubled the odds of end-of-treatment abstinence among a sample of women smokers, although this diminished somewhat at post-treatment follow-up.¹⁵⁷ On the other hand, a randomised clinical trial published in 2016 that compared the efficacies of 12 weeks of treatment with varenicline, combination NRT (patch + lozenge), or the nicotine patch alone found no significant differences in rates of abstinence at 26 weeks, indicating that all three treatments were equally effective.¹⁵⁸ One meta-analysis similarly concluded that combination NRT and varenicline are equally effective for quitting.⁶

Extended use of varenicline may also be effective.^159-161 Limited data indicates that smokers using varenicline who have an initial delay in quitting have increased risk of relapse and may benefit from extended use of the medication.¹⁶² A 2019 Cochrane review similarly found that extended treatment with varenicline can help to prevent relapse.⁵⁷ Initiating varenicline use several weeks prior to quitting, known as preloading, may also increase cessation rates.¹⁶³ A study examining the efficacy and safety of retreatment with varenicline concluded that the medication is efficacious and well tolerated in smokers who have previously taken it. Abstinence rates were comparable to those reported for varenicline-naive smokers.¹⁶⁴ Lower doses are also beneficial while lessening the incidence of adverse events.⁴ One study found that increasing varenicline dose in smokers with low response to the drug had no significant effect on nicotine withdrawal symptoms or smoking cessation.¹⁶⁵ Although some studies have shown compliance to be an issue,¹⁶⁶ varenicline appears to be effective in increasing cessation at 12 months even when compliance with the medication is not 100%.¹⁶⁷ Certain genotypes also appear to be associated with higher odds ratio for success in individuals on varenicline therapy.¹⁶⁸

7.16.3.3 Use of varenicline in Australia

Varenicline was introduced into Australia as Champix® on 1 January 2008, as a prescription medicine available on the PBS to smokers enrolled in a smoking cessation counselling program.¹⁶⁹ It is available in three different configurations:

56 x 1 mg tablets (1 pack/12 week course: code 5469W, 2 packs/24 week course: code 9129L)
11 x 0.5 mg tablets and 14 x 1 mg tablets in the first pack and 42 x 1 mg tablets in the second pack (code 9128K)

Varenicline is not suitable for pregnant women, children under 18 years of age, or people allergic to varenicline tartrate.^{123, 170} The manufacturers’ list of illnesses for which medical advice may be needed includes having a mental illness or a history of mental illness, renal impairment, and history of seizures or other conditions potentially lowering the seizure threshold.¹⁷¹ Caution is recommended when operating vehicles or heavy machinery.¹⁷²

Data from a number of countries show that since being introduced, varenicline has become the second most used cessation medication, behind NRT, including in Australia. Between 2006 and 2008 varenicline use rates increased from 0.0 to 14.5%. The findings suggest that varenicline did not simply gain market share at the expense of other medications, but led to an increase in smokers using evidence-based treatment.⁷ In the US, the introduction of varenicline coincided with a net increase in attempts to quit smoking and, among these, a net increase in use of stop-smoking medications.¹⁷³ Canadian research concluded that both standard and extended courses of varenicline are cost-effective treatment regimens compared with alternative smoking cessation interventions.¹⁷⁴

7.16.3.4 Adverse events associated with varenicline

Varenicline is well tolerated by most people who use it.^{123, 172, 175} The main side effect of varenicline is mild to moderate nausea, affecting about 3 out of 10 people.^{4, 123} There is some evidence that nausea can be minimised by taking with food, titration and self-regulation of varenicline (0.5-2mg/day).¹⁷⁶ Other side effects include stomach or bowel problems (e.g. constipation, gas, dry mouth, vomiting, indigestion), headache, dizziness, sleeping problems, unusual dreams, feeling tired, increased appetite and changes in taste.¹²³ These side effects are usually mild to moderate and decrease over time.^{4, 123, 155, 175} Side effects usually occur in the first week of taking the medicine.¹²³ There is some evidence of adverse gastrointestinal effects when varenicline is used at maintenance dose.¹⁷⁷ In the US, the FDA have noted a number of adverse reactions in patients drinking alcohol while being treated with varenicline, including increased intoxication, loss of memory, and aggressive or uncharacteristic behaviour. It recommends reducing alcohol consumption until the patient knows to what extent the medication affects their capacity to tolerate alcohol.¹⁷⁸

Varenicline may cause other, less common side effects.¹²³ Serious side effects are rare and estimated to affect up to 1 in 1000 people (0.1%).¹⁵⁵ Very serious side effects that require urgent medical attention or hospitalisation may affect up to 1 in 10,000 people (0.01%).¹²³ Safety warnings and revised labels have been issued in response to serious side effects from overdosing.¹²³ Although there have been ongoing concerns about a possible association between varenicline and heart attack or stroke, a retrospective cohort study in England found that neither bupropion nor varenicline showed an increased risk of any cardiovascular event compared with NRT.¹⁷⁹ A meta-analysis also found no increase in the risk of all cardiovascular disease events with bupropion or varenicline.¹⁸⁰ A review paper concluded that there is sufficient evidence to suggest that benefits of using cessation pharmacotherapies outweighs the low risk of serious adverse cardiovascular events associated with their use, particularly in light of the high cardiovascular risk from continued smoking.¹⁸¹

Some people report experiencing psychiatric symptoms when they start taking the varenicline, such as depression, agitation, aggression, thoughts of self-harm, self-harm, thinking about suicide, suicidal behaviour, and hallucinations.^{4, 123} However, a 2016 Cochrane review concluded that recent observational cohort studies and meta-analyses have not confirmed fears of a causal link between varenicline and psychiatric symptoms, including depressed mood, agitation, and suicidal behaviour. However, the evidence was not conclusive in people with past or current psychiatric disorders.⁴ Another 2016 systematic review and meta-analysis, this time of varenicline for smoking cessation and reduction in people with severe mental illnesses, concluded that varenicline appears to be significantly more effective than placebo for helping people with severe mental illness to reduce or quit smoking, with no clear evidence of increased risks or adverse events.¹⁸² Results of a large-scale randomised controlled trial similarly found that there was not a significant increase in neuropsychiatric adverse events attributable to varenicline.¹¹⁹ A large cohort study in the US found no increased risk of cardiovascular or neuropsychiatric hospitalisations in varenicline users compared with those who used NRT,¹⁸³ while a British study found that varenicline was associated with a decreased risk of death, serious cardiovascular events, and neuropsychiatric events compared with NRT.¹⁸⁴

7.16.3.5 Other nicotinic receptor partial agonists

Cytisine is a nicotinic acetylcholine receptor partial agonist.¹⁸⁵ A systematic review and meta-analysis published in 2013 concluded that cytisine is an effective treatment for smoking cessation with efficacy comparable to that of other currently licensed treatments,¹⁸⁶ and another more recent review similarly concluded that cytisine is a low-cost medication that can increase the likelihood of smoking cessation.¹⁸⁷ The US Surgeon General concluded in 2020 that cytisine may increase smoking cessation.¹ In comparing the effectiveness of cytisine with NRT for smoking cessation, New Zealand researchers found that when combined with brief behavioural support, cytisine was superior to NRT in helping smokers quit. Although it was associated with a higher frequency of self-reported adverse events, only 5% of people stopped taking it because of them. It is also low-cost compared with many other pharmacotherapies, potentially making it more accessible to low income people and countries.¹⁸⁸ One evaluation estimated that cytisine is both more clinically effective and cost-effective than varenicline.¹⁸⁹

7.16.4 Vaccines

In recent years, researchers have been attempting to develop vaccines that create antibodies that bind to nicotine in the bloodstream and prevent it from entering the brain, thus reducing the rewards of smoking and promoting cessation.^{16, 190} ^{191, 192} Despite promising preclinical trials,¹⁹³ clinical trials have not supported the efficacy of the products,^194-196 and none are yet approved cessation aids. Nonetheless, researchers have suggested that there is good reason for continued optimism,¹⁹⁶ and that next-generation immunotherapies are likely to be substantially more effective than first-generation vaccines.¹⁹⁷ For example, some studies have found that subjects with high anti-nicotine antibody levels demonstrate higher quit rates after receiving nicotine vaccines.^198-202 Therefore, vaccines that consistently generate higher antibody levels could be effective therapies.¹⁹⁷ Another study has identified which of two types of nicotine is the best to target when developing nicotine vaccines.²⁰³

7.16.5 Combination treatments

7.16.5.1 Drug combinations

Combining approved medications is one approach to potentially improving cessation outcomes. There is robust evidence that combining a longer-acting form of NRT (e.g., patch) with a faster-acting form (e.g., lozenge) is more effective than single-form NRT and is safe⁹—see Section 7.16.1.2.2.

Drugs with different mechanisms and pharmacokinetics may also be combined. Most of these combinations are yet to be approved but some show promise.⁶⁵ A systematic review and meta-analysis found that combination therapy of varenicline with NRT patch is better than varenicline alone.²⁰⁴ A systematic review published in 2016 concluded that combination bupropion and varenicline appears to have greater efficacy in smoking cessation than varenicline alone.²⁰⁵ A meta-analysis published in 2021 found that the most effective combination of cessation medications for achieving six-month abstinence was a nicotinic receptor agonist with NRT. Compared with placebo, smokers given this combination were 4.4 times more likely to successfully quit. Those given bupropion with a nicotinic receptor agonist were four times more likely to quit for six months, and bupropion and NRT 3.8 times more likely, compared with placebo.³⁰

7.16.5.2 Drug plus non-drug therapies

A ‘real-world’ population study in England found that smokers who use a combination of behavioural support and pharmacotherapy in their quit attempts have almost three times the odds of success than those who use neither pharmacotherapy nor behavioural support.²⁰⁶ In a systematic review published in 2015, the US Preventive Services Task Force found that combined behavioural and pharmacotherapy interventions increased cessation by 82% compared with minimal intervention or usual care.²⁰⁷ A 2016 Cochrane review concluded that combining pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. The authors did not find evidence that offering more intensive behavioural support was associated with larger treatment effects.²⁰⁸ Another Cochrane review published in 2019 concluded that providing behavioural support in person or via telephone for people using pharmacotherapy to stop smoking increases quit rates. Increasing the amount of behavioural support is likely to increase the chance of success by about 10% to 20%.²⁰⁹ The US Surgeon General concluded in 2020 that while behavioural counselling and cessation medications are independently effective in increasing smoking cessation, they are even more effective when used in combination.¹ A review of combination therapies found that varenicline combined with behavioural therapy appears to be more effective than other pharmacotherapies combined with behavioural therapy.⁴²

7.16.6 Other medications that might increase quitting

Many pharmaceutical companies and research institutions are investigating the potential for developing smoking cessation products that interfere with mechanisms involved in nicotine addiction.^{16, 23, 65, 192, 210} Drugs that target the cannabinoid receptor system have also been investigated.²¹¹ Rimonabant is used predominantly for treating obesity, but some thought it would also be useful for smoking cessation, particularly for smokers concerned about weight gain.^{18, 212} Early clinical trials suggested a benefit for long-term smoking cessation and reduction of weight gain, especially in overweight or obese individuals.²¹³ However, increased psychiatric side effects appeared in clinical trials.¹⁶ In October 2008 the manufacturer discontinued development of the drug.¹⁹²

A pilot study based on evidence that glutamate transmission plays an important role in relapse examined a cysteine pro-drug, N-acetylcysteine (NAC) and concluded the results were encouraging.²¹⁴ However, a subsequent systematic review did not support its use for aiding cessation.²¹⁵ Methoxsalen blocks the enzyme that breaks down nicotine in the body, slowing elimination, thus potentially postponing the onset of withdrawal symptoms and making cessation easier.²¹⁶ Initial research in mice suggests that combining the drug with NRT may have a beneficial role in treating nicotine dependence.^{217, 218}

Topiramate is an anticonvulsant medication that may be effective as a treatment for alcohol and cocaine addiction, which has been proposed as a potential cessation aid.^219-222 A pilot randomised controlled trial in 2014 found that topiramate, alone or in combination with NRT, resulted in a higher quit rate than placebo and decreased weight.²²³ However, a meta-analysis published in 2020 investigating the effectiveness of topiramate in smoking cessation found insufficient evidence for its use.²²⁴

Although naltrexone has been used to successfully treat opioid and alcohol dependence,^{225, 226} a 2013 Cochrane review concluded that there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, and a 2014 systematic review and meta-analysis arrived at similar conclusions.^{227, 228} An Australian drug company has reported findings from a clinical trial showing that smokers administered the respiratory drug INV102 (nadolol) were more likely to stop smoking completely, or dramatically reduce the number of cigarettes smoked. The drug may also be useful for treating epithelial damage (i.e., damage to the tissues that line the blood vessels and organs) caused by smoking.²²⁹ A 2004 Cochrane review found low-quality evidence that the blood pressure medication clonidine may increase smoking cessation.²³⁰ Side effects include postural hypotension, extreme drowsiness, fatigue and dry mouth, which limit its usefulness.¹⁷⁶

Silver acetate was marketed in the 1970s and 1980s as smoking deterrents or aversion therapy, because it produced an unpleasant taste when smoking. A 2012 Cochrane review concluded that existing trials show little evidence for a specific effect of silver acetate in promoting smoking cessation, and any effect of this agent is likely to be smaller than NRT.²³¹

New research focusing on pharmacogenetics is emerging, based on the discovery of genetic properties influencing the pharmacokinetics and pharmacodynamics of nicotine.⁶⁵ Genetic-based methods may be useful in predicting response to pharmacotherapy for sub-groups of smokers and assist the personalisation of treatments.^{55, 232-236} See Section 7.7.1.4 for a detailed discussion.

7.16.7 Effects of dispensing arrangements and subsidies

Research in the Netherlands found that a national reimbursement policy for smoking cessation treatment that is accompanied by media attention can increase cessation.²³⁷ Canadian research also found that the adoption of a smoking cessation medication coverage drug policy was an effective intervention to improve quit rates, the advantages of which were lost once coverage was discontinued.²³⁸ A Cochrane review similarly concluded that the provision of financial assistance for smokers trying to quit increase the proportion of smokers who attempt to quit, use smoking cessation treatments, and succeed in quitting.²³⁹

Since February 2011, Australian smokers have been able to access a 12-week supply of nicotine patches under the PBS as long as they have a medical prescription.²⁴⁰ Data from the Australian National Drug Strategy Household Survey show that among adult regular smokers, past year use of NRT (gum, patches, or inhalers) increased significantly from 14.9% in 2010 to 16.7% in 2013 (controlling for age and sex), after this change was implemented.²⁴¹ Similarly, Australian research has found that reported use of prescription medication to quit smoking rose sharply with the addition of varenicline to the PBS.²⁴²

In the US, Quitlines often provide free NRT to callers. Evaluations have found that such programs increased the number of callers, in some cases quite dramatically, and most found that access to free NRT improved long-term quit rates.^243-254 One US study also reported that the majority of recipients of their program were from disadvantaged groups.²⁵⁵ One study in which GPs gave a personalised letter to patients who smoke that encouraged them to quit and offered free NRT increased the number of smokers making a supported quit attempt.²⁵⁶ Another found that providing free NRT samples engaged both motivated and unmotivated smokers into the quitting process and produced positive changes in smoking outcomes.²⁵⁷

7.16.8 Methodological and ethical issues in smoking cessation trials

Clinical research is increasingly being sponsored by companies that make the products under investigation, either because the companies directly perform the studies, or fund them.²⁵⁸ Potential ways that industry sponsors can influence the outcome of a study include the framing of the question, the design of the study, the conduct of the study, how data are analysed, selective reporting of favourable results, and ‘spin’ in reporting conclusions.²⁵⁸ A meta-analysis published in 2007 concluded that NRT trials with pharmaceutical industry funding tend to show higher success rates than those independently funded.²⁵⁹ The authors suggest that one possible reason for this difference may be greater resources in industry-sponsored trials, leading to higher treatment compliance and therefore greater efficacy.²⁵⁹ A follow-up study in 2010 found that the differential efficacy of NRT between industry-sponsored and non-industry trials may be caused by differences in the quit rate among those in the placebo condition, perhaps due to characteristics of participants recruited (in particular heaviness of smoking or level of tobacco dependence), the exclusion of participants with confounding comorbidity (such as psychiatric disorder) or the number of study sites.²⁶⁰ A 2012 Cochrane review concluded that sponsorship of drug and device studies by the manufacturing company leads to more favourable results and conclusions than sponsorship by other sources.²⁵⁸ Such trials may receive more scientific attention than trials with unfavourable findings, resulting in an overestimation of effectiveness.⁶⁵

Although there is robust evidence from clinical trials for the effectiveness of pharmacotherapies and behavioural interventions for quitting, population-based or ‘real-world’ studies have produced mixed results, with some reporting less successful quit rates. Randomised controlled trials that enrol highly motivated smokers who are carefully followed up and who receive higher intensity behavioural support than is usually provided may report higher cessation rates than would occur in general population use of the medications.⁶⁵ Several papers have raised concerns that strict selection criteria in cessation trials mean that many smokers are excluded from such trials, and therefore the findings may not be valid or generalisable.^{261, 262} Further, more dependent smokers may be more likely to use some form of treatment, but with less success, and this may artificially lower success rates.⁹⁴ Researchers have argued that real-world studies of cessation treatments have often failed to adequately control for the fact that smokers who use these medications are more dependent upon cigarettes. Nonetheless, after adjusting for major confounding variables such as tobacco dependence, findings from population studies in England support the efficacy of combined behavioural therapy and pharmacotherapy for tobacco dependence treatment, thus supporting their use in the real world.^{206, 263}

A recent review has also highlighted that using a consistent definition of abstinence in smoking cessation clinical trials is crucial to both comparing results across clinical trials and for including the data in meta-analyses. It concludes that defining abstinence requires specification of which products a user must abstain from (i.e., combustible tobacco, smokeless tobacco, and/or alternative products such as e-cigarettes), the type of abstinence (i.e., point prevalence or continuous), and the duration of abstinence (end of treatment, ≥3 months after the end of treatment, and ≥6 months post-quit or post-treatment initiation).²⁶⁴ Another review notes that biochemical verification of tobacco use and abstinence (see also Section 18.1.3) increases scientific rigour and validity compared to self-reported cessation, but should be considered in light of its costs and limitations, including the cost of the assays, the feasibility of sample collection, the ability to draw clear conclusions based on the duration of abstinence, and the variability of the assay within the study population.²⁶⁵

Another important methodological consideration in cessation studies is the extent to which smokers’ compliance with directions for using and taking smoking cessation medications affects outcomes.⁶⁵ There is evidence that the majority of smokers using stop-smoking medications do not complete the recommended course of treatment.^{60, 63} Reasons for premature discontinuation of medication include relapse back to smoking, reported side effects and the perception that the medication has worked for the user and is no longer needed.⁶³ Smokers may have unreasonable expectations of how effective stop-smoking medications are likely to be for them.⁶³ One trial showed that good adherence to varenicline was associated with a two-fold increase in six-month quit rates compared with poor adherence.²⁶⁶ While higher levels of adherence to cessation medications increase the likelihood of sustained smoking cessation, many smokers use them at a lower dose and for less time than is optimal.²⁶⁷ A Cochrane review published in 2019, which assessed the effectiveness of interventions aiming to increase adherence to cessation medications, concluded that there is moderate‐certainty evidence that enhanced behavioural support focusing on adherence to medications can modestly improve adherence. However, the authors only found weak evidence that this may slightly improve the likelihood of cessation in the shorter or longer‐term.²⁶⁸

Smokers’ beliefs about a particular treatment may influence their choice of a particular medication as well as their medication experience.²⁶⁹ A perceived lack of need for cessation aids and beliefs that cessation aids do not help with cessation are consistently associated with medication nonadherence.²⁷⁰ One study found that positive medication expectancies in smokers may contribute to better treatment response, and the authors suggest that assessing treatment expectations and attempting to maintain or improve them may be important for the delivery, evaluation, and targeting of smoking cessation treatments.²⁷¹ Similarly, participants’ perception of treatment assignment (i.e., their beliefs about whether they have been assigned to receive a medication or a placebo) can also affect treatment outcomes. Participants’ expectancies may therefore influence treatment outcome despite use of placebo-controlled designs. Researchers suggest that inclusion of no-treatment control groups or use of active placebos may be warranted. ²⁷²

A common ethical concerns about smoking cessation and other randomised controlled trials is whether it is ethical to assign participants to a non-active control condition, thereby denying some participants treatment.²⁷³ In a paper addressing such concerns, the authors argue that it is ethical to randomise when it is uncertain whether a new intervention is superior to an older one after benefits, risks, and costs have been taken into account. Other ways of overcoming this problem include a phased study in which all participants received the program eventually; trials with two distinct interventions, each of which serves as the other’s control; trials that allocate high- and low-intensity interventions; and trials that randomise to wait lists.²⁷⁴ A 2020 review also highlighted that interventions provided to comparator/control groups in smoking cessation trials vary substantially which can lead to very different apparent success rates. This makes some cessation interventions appear much more effective than others, whereas the differences in results may be due to a more vs. less effective/intensive comparator group intervention.²⁷⁵ In many health systems, patients seeking clinical care are only offered tobacco treatment if, in the opinion of the clinician, they express a desire to quit smoking or are perceived as ‘ready to quit’. Researchers have proposed that, because only a minority of tobacco users will say they are ready to quit at any given time, all tobacco users should be offered evidence-based care, without being screened for readiness as a precondition for receiving treatment. That is, receiving treatment for tobacco dependence should be ‘opt-out’ rather than ‘opt-in’. They argue that most tobacco users want to quit, there is little to no evidence supporting the utility of assessing readiness to quit, and an opt-out default is more ethical.²⁷⁶ Others have suggested that while this approach may be warranted, a better understanding of its effectiveness and its impact on clinician–patient relationships is needed as a first step.²⁷⁷

Relevant news and research

For recent news items and research on this topic, click here. ( Last updated November 2022)

References

1. US Department of Health and Human Services. Smoking cessation. A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, 2020. Available from: https://www.hhs.gov/sites/default/files/2020-cessation-sgr-full-report.pdf.

2. Hartmann-Boyce J, Chepkin SC, Ye W, Bullen C, and Lancaster T. Nicotine replacement therapy versus control for smoking cessation. Cochrane Database of Systematic Reviews, 2018; 5:CD000146. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29852054

3. Howes S, Hartmann-Boyce J, Livingstone-Banks J, Hong B, and Lindson N. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews, 2020; 4:CD000031. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32319681

4. Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, and Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews, 2016; 5(5):CD006103. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27158893

5. Lindson N, Chepkin SC, Ye W, Fanshawe TR, Bullen C, et al. Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews, 2019; 4(4):CD013308. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30997928

6. Cahill K, Stevens S, Perera R, and Lancaster T. Pharmacological interventions for smoking cessation: An overview and network meta-analysis. Cochrane Database of Systematic Reviews, 2013; 5(5):CD009329. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23728690

7. Fix BV, Hyland A, Rivard C, McNeill A, Fong GT, et al. Usage patterns of stop smoking medications in Australia, Canada, the United Kingdom, and the United States: Findings from the 2006-2008 international tobacco control (ITC) four country survey. International Journal of Environmental Research and Public Health, 2011; 8(1):222-33. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21318025

8. Narayanan S, Ebbert JO, and Sood A. Gender differences in self-reported use, perceived efficacy, and interest in future use of nicotine-dependence treatments: A cross-sectional survey in adults at a tertiary care center for nicotine dependence. Gender Medicine, 2009; 6(2):362-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19682663

9. Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews, 2012; 11:CD000146. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23152200

10. Pharmaceutical Benefits Advisory Committee. March 2008 meeting, positive recommendations. 2008. Available from: http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar08-positive.

11. Pharmaceutical Benefits Advisory Committee. Letter concerning listing of NRT patches for Indigenous smokers, The Cancer Council Australia, Editor 2008: Sydney.

12. Australian Government Department of Health. Australian register of therapeutic goods, medicines 2019. Available from: https://www.ebs.tga.gov.au/.

13. Australian Government Department of Health. Pharmaceutical benefits scheme – what are the current patient fees and charges? 2020. Available from: http://www.pbs.gov.au/info/about-the-pbs#What_are_the_current_patient_fees_and_charges.

14. US Department of Health and Human Services. The health consequences of smoking: Nicotine addiction. A report of the Surgeon General. Rockville, Maryland: US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Health Promotion and Education, Office on Smoking and Health, 1988. Available from: https://stacks.cdc.gov/view/cdc/22014/cdc_22014_DS1.pdf.

15. Hughes JR. The future of smoking cessation therapy in the United States. Addiction, 1996; 91(12):1797-802. Available from: https://www.ncbi.nlm.nih.gov/pubmed/8997761

16. Fant RV, Buchhalter AR, Buchman AC, and Henningfield JE. Pharmacotherapy for tobacco dependence. Handbook of Experimental Pharmacology, 2009; (192):487-510. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19184660

17. Paul C, Walsh R, and Girgis A. Nicotine replacement therapies over the counter: Real life use in the Australian community. Australian and New Zealand Journal of Public Health, 2003; 27(5):491–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14651392

18. Henningfield JE, Fant RV, Buchhalter AR, and Stitzer ML. Pharmacotherapy for nicotine dependence. CA: A Cancer Journal for Clinicians, 2005; 55(5):281-99; quiz 322-3, 5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16166074

19. Kraiczi H, Hansson A, and Perfekt R. Single-dose pharmacokinetics of nicotine when given with a novel mouth spray for nicotine replacement therapy. Nicotine and Tobacco Research, 2011; 13(12):1176-82. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21849415

20. Hansson A, Hajek P, Perfekt R, and Kraiczi H. Effects of nicotine mouth spray on urges to smoke, a randomised clinical trial. BMJ Open, 2012; 2(5):e001618. Available from: https://bmjopen.bmj.com/content/bmjopen/2/5/e001618.full.pdf

21. Lindblom EN. Effectively regulating e-cigarettes and their advertising—and the first amendment. Food and Drug Law Journal, 2015; 70:57–94. Available from: http://www.law.georgetown.edu/oneillinstitute/news/documents/March10-LindblomFDLJ_001.pdf

22. Therapeutic Goods Administration. Nicotine e-cigarettes. Australian Government Department of Health, 2021. Available from: https://www.tga.gov.au/nicotine-e-cigarettes.

23. Polosa R and Benowitz NL. Treatment of nicotine addiction: Present therapeutic options and pipeline developments. Trends in Pharmacological Sciences, 2011; 32(5):281-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21256603

24. World Health Organization. Tools for advancing tobacco control in the xx1st century: Policy recommendations for smoking cessation and treatment of tobacco dependence. Tools for public health. Geneva: World Health Organization, 2003. Available from: http://www.wpro.who.int/NR/rdonlyres/8D25E4D3-BB81-479E-8DF5-7BAF674DB104/0/PolicyRecommendations.pdf.

25. Beaver JD, Long CJ, Cole DM, Durcan MJ, Bannon LC, et al. The effects of nicotine replacement on cognitive brain activity during smoking withdrawal studied with simultaneous fmri/eeg. Neuropsychopharmacology, 2011; 36(9):1792-800. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21544072

26. Stanley TD and Massey S. Evidence of nicotine replacement's effectiveness dissolves when meta-regression accommodates multiple sources of bias. Journal of Clinical Epidemiology, 2016; 79:41-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27079846

27. Hughes JR, Fanshawe TR, and Stead LF. Is nicotine replacement really ineffective? A reply to stanley and massey. Journal of Clinical Epidemiology, 2017; 81:143-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27663610

28. Stanley TD. Yes, nicotine replacement therapy's effectiveness is much lower than often reported. Journal of Clinical Epidemiology, 2017; 81:144-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27650384

29. Green G. Nicotine replacement therapy for smoking cessation. American Family Physician, 2015; 92(1):24A-B. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26132134

30. Mishra A, Maiti R, Mishra BR, and Jena M. Comparative efficacy and safety of pharmacological interventions for smoking cessation in healthy adults: A network meta-analysis. Pharmacological Research, 2021; 166:105478. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33549729

31. Etter JF and Stapleton JA. Nicotine replacement therapy for long-term smoking cessation: A meta-analysis. Tobacco Control, 2006; 15(4):280-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16885576

32. Shiffman S. Effect of nicotine lozenges on affective smoking withdrawal symptoms: Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial. Clinical Therapeutics, 2008; 30(8):1461-75. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18803988

33. Pack QR, Jorenby DE, Fiore MC, Jackson T, Weston P, et al. A comparison of the nicotine lozenge and nicotine gum: An effectiveness randomized controlled trial. WMJ, 2008; 107(5):237-43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18777992

34. Shiffman S, Ferguson SG, Rohay J, and Gitchell JG. Perceived safety and efficacy of nicotine replacement therapies among US smokers and ex-smokers: Relationship with use and compliance. Addiction, 2008; 103(8):1371–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18855827

35. Perkins KA, Briski J, Fonte C, Scott J, and Lerman C. Severity of tobacco abstinence symptoms varies by time of day. Nicotine and Tobacco Research, 2009; 11(1):84-91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19246445

36. Brokowski L, Chen J, and Tanner S. High-dose transdermal nicotine replacement for tobacco cessation. American Journal of Health-System Pharmacy, 2014; 71(8):634-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24688036

37. Fucito LM, Bars MP, Forray A, Rojewski AM, Shiffman S, et al. Addressing the evidence for FDA nicotine replacement therapy label changes: A policy statement of the association for the treatment of tobacco use and dependence and the society for research on nicotine and tobacco. Nicotine and Tobacco Research, 2014; 16(7):909-14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24919399

38. Schneider NG, Cortner C, Gould JL, Koury MA, and Olmstead RE. Comparison of craving and withdrawal among four combination nicotine treatments. Human Psychopharmacology, 2008; 23(6):513-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18438964

39. Piper ME, Smith SS, Schlam TR, Fiore MC, Jorenby DE, et al. A randomized placebo-controlled clinical trial of 5 smoking cessation pharmacotherapies. Archives of General Psychiatry, 2009; 66(11):1253-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19884613

40. Gonzales D. Nicotine patch plus lozenge gives greatest increases in abstinence from smoking rates at 6 months compared with placebo; smaller effects seen with nicotine patch alone, bupropion or nicotine lozenges alone or combined. Evidence-Based Medicine, 2010; 15(3):77-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20522682

41. Prochazka AV. Acp journal club. Nicotine patch plus nicotine lozenges increased smoking cessation rate more than placebo. Annals of Internal Medicine, 2010; 152(10):JC5-2. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20479019

42. Windle SB, Filion KB, Mancini JG, Adye-White L, Joseph L, et al. Combination therapies for smoking cessation: A hierarchical bayesian meta-analysis. American Journal of Preventive Medicine, 2016; 51(6):1060-71. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27617367

43. Carpenter MJ, Jardin BF, Burris JL, Mathew AR, Schnoll RA, et al. Clinical strategies to enhance the efficacy of nicotine replacement therapy for smoking cessation: A review of the literature. Drugs, 2013; 73(5):407-26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23572407

44. The Royal Australian College of General Practitioners. A bold plan to help more Australians to quit smoking. RACGP, 2020. Available from: https://www.racgp.org.au/gp-news/media-releases/2020-media-releases/january-2020/a-bold-plan-to-help-more-australians-to-quit-smoki

45. Le Foll B and George T. Treatment of tobacco dependence: Integrating recent progress into practice. Canadian Medical Association Journal, 2007; 177(11):1373–80. Available from: http://www.cmaj.ca/cgi/content/full/177/11/1373

46. Fiore MC, Jaén M, Carlos Roberto, Baker TB, Bailey WC, Benowitz NL, et al. Treating tobacco use and dependence. Clinical practice guidelines. Rockville, MD: US Department of Health and Human Services, 2008. Available from: http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/tobacco/clinicians/update/index.html.

47. Ferguson SG and Shiffman S. Effect of high-dose nicotine patch on the characteristics of lapse episodes. Health Psychology, 2010; 29(4):358-66. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20658822

48. Cunningham JA, Kushnir V, Selby P, Tyndale RF, Zawertailo L, et al. Effect of mailing nicotine patches on tobacco cessation among adult smokers : A randomized clinical trial. JAMA Internal Medicine, 2016; 176(2):184–90. Available from: http://dx.doi.org/10.1001/jamainternmed.2015.7792

49. Hughes JR, Shiffman S, Callas P, and Zhang J. A meta-analysis of the efficacy of over-the-counter nicotine replacement. Tobacco Control, 2003; 12(1):21-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12612357

50. West R and Zhou X. Is nicotine replacement therapy for smoking cessation effective in the 'real world'? Findings from a prospective multinational cohort study. Thorax, 2007; 62(998-1002). Available from: http://www.ncbi.nlm.nih.gov/pubmed/17573444

51. Schnoll RA, Patterson F, Wileyto EP, Heitjan DF, Shields AE, et al. Effectiveness of extended-duration transdermal nicotine therapy: A randomized trial. Annals of Internal Medicine, 2010; 152(3):144-51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20124230

52. Zwar N, Richmond R, Borland R, Stillman S, Cunninghan M, et al., Smoking cessation guidelines for Australian general practice: Practice handbook. Vol. 4 July 2004.Canberra: Department of Health and Ageing; 2004. Available from: http://www.health.gov.au/pubhlth/publicat/document/smoking_cessation.pdf.

53. Shiffman S, Khayrallah M, and Nowak R. Efficacy of the nicotine patch for relief of craving and withdrawal 7-10 weeks after cessation. Nicotine and Tobacco Research, 2000; 2(4):371-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11197318

54. Hajek P, McRobbie H, and Gillison F. Dependence potential of nicotine replacement treatments: Effects of product type, patient characteristics, and cost to user. Preventive Medicine, 2007; 44(3):230-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17207524

55. Berrettini WH and Lerman CE. Pharmacotherapy and pharmacogenetics of nicotine dependence. American Journal of Psychiatry, 2005; 162(8):1441-51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16055765

56. Zhang B, Cohen JE, Bondy SJ, and Selby P. Duration of nicotine replacement therapy use and smoking cessation: A population-based longitudinal study. American Journal of Epidemiology, 2015; 181(7):513-20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25740789

57. Livingstone-Banks J, Norris E, Hartmann-Boyce J, West R, Jarvis M, et al. Relapse prevention interventions for smoking cessation. Cochrane Database of Systematic Reviews, 2019; 2(2):CD003999. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30758045

58. Zapawa LM, Hughes JR, Benowitz NL, Rigotti NA, and Shiffman S. Cautions and warnings on the US otc label for nicotine replacement: What's a doctor to do? Addictive Behaviors, 2011; 36(4):327-32. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21220188

59. Ferguson SG, Gitchell JG, and Shiffman S. Continuing to wear nicotine patches after smoking lapses promotes recovery of abstinence. Addiction, 2012; 107(7):1349-53. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22276996

60. Mersha AG, Eftekhari P, Bovill M, Tollosa DN, and Gould GS. Evaluating level of adherence to nicotine replacement therapy and its impact on smoking cessation: A systematic review and meta-analysis. Arch Public Health, 2021; 79(1):26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33663575

61. Beard E, Bruguera C, McNeill A, Brown J, and West R. Association of amount and duration of NRT use in smokers with cigarette consumption and motivation to stop smoking: A national survey of smokers in England. Addictive Behaviors, 2015; 40:33-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25218069

62. Borland R, Cooper J, McNeill A, O'Connor R, and Cummings KM. Trends in beliefs about the harmfulness and use of stop-smoking medications and smokeless tobacco products among cigarettes smokers: Findings from the ITC four-country survey. Harm Reduction Journal, 2011; 8:21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21859499

63. Balmford J, Borland R, Hammond D, and Cummings KM. Adherence to and reasons for premature discontinuation from stop-smoking medications: Data from the ITC four-country survey. Nicotine and Tobacco Research, 2011; 13(2):94-102. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21147894

64. Burns E and Levinson A. Discontinuation of nicotine replacement therapy among smoking-cessation attempters. American Journal of Preventive Medicine, 2008; 34(3):212–5. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18312809

65. Raupach T and van Schayck CP. Pharmacotherapy for smoking cessation: Current advances and research topics. CNS Drugs, 2011; 25(5):371-82. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21476609

66. Shiffman S, Rolf CN, Hellebusch SJ, Gorsline J, Gorodetzky CW, et al. Real-world efficacy of prescription and over-the-counter nicotine replacement therapy. Addiction, 2002; 97(5):505-16. Available from: https://pubmed.ncbi.nlm.nih.gov/12033652/

67. Tonnesen P, Nørregaard J, Mikkelsen K, Jorgensen S, and Nilsson F. A double-blind trial of a nicotine inhaler for smoking cessation. JAMA, 1993; 269(10):1268-71. Available from: https://doi.org/10.1001/jama.1993.03500100066029

68. Shiffman S. Use of more nicotine lozenges leads to better success in quitting smoking. Addiction, 2007; 102(5):809-14. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1360-0443.2007.01791.x

69. Vogt F, Hall S, and Marteau TM. Understanding why smokers do not want to use nicotine dependence medications to stop smoking: Qualitative and quantitative studies Nicotine and Tobacco Research, 2008; 10(8):1405–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18686189

70. Campbell K, Coleman-Haynes T, Bowker K, Cooper SE, Connelly S, et al. Factors influencing the uptake and use of nicotine replacement therapy and e-cigarettes in pregnant women who smoke: A qualitative evidence synthesis. Cochrane Database of Systematic Reviews, 2020; 5:CD013629. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32441810

71. Weiss SM and Smith-Simone SY. Consumer and health literacy: The need to better design tobacco-cessation product packaging, labels, and inserts. American Journal of Preventive Medicine, 2010; 38(3 Suppl):S403-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20176315

72. Schneider N, Cortner C, Justice M, Gould J, Amor C, et al. Preferences among five nicotine treatments based on information versus sampling. Nicotine and Tobacco Research, 2008; 10(1):179–86. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18188758

73. Canadian Agency for Drugs and Technologies in Health. Nicotine replacement therapy for smoking cessation or reduction: A review of the clinical evidence. CADTH Rapid Response Reports, 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24741730

74. Hammond D, Reid JL, Driezen P, Cummings KM, Borland R, et al. Smokers' use of nicotine replacement therapy for reasons other than stopping smoking: Findings from the ITC four country survey. Addiction, 2008; 103(10):1696–703. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18821877

75. Zwar N, Bell J, Peters M, Christie M, and Mendelsohn C. Nicotine and nicotine replacement therapy – the facts. Australian Pharmacist, 2006; 25(12):969–73. Available from: www.psa.org.au/site.php?id=1458

76. Fant RV, Owen LL, and Henningfield JE. Nicotine replacement therapy. Primary Care, 1999; 26(3):633-52. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10436291

77. Stead LF and Lancaster T Interventions to reduce harm from continued tobacco use. Cochrane Database of Systematic Reviews, 2007 DOI: 10.1002/14651858.CD005231.pub2. Available from: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005231/frame.html

78. Stepanov I, Carmella S, Han S, Pinto A, Strasser A, et al. Evidence for endogenous formation of n'-nitrosonornicotine in some long-term nicotine patch users. Nicotine and Tobacco Research, 2009; 11(1):99–105. Available from: http://ntr.oxfordjournals.org/cgi/content/full/ntn020v1

79. Etter JF. Addiction to the nicotine gum in never smokers. BMC Public Health, 2007; 7(147):159. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17640334

80. Perkins KA. Nicotine self-administration. Nicotine and Tobacco Research, 1999; 1 Suppl 2(suppl. 2):S133-7; discussion S9-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11768171

81. Pharmacia Australia. Product information. Nicorette chewing gum. 2mg & 4mg. [leaflet], July 2003, Pharmacia Australia Pty Limited: Rydalmere, NSW.

82. Pharmacia Australia. Product information. Nicorette inhaler. [leaflet] July 2003, Pharmacia Australia Pty Limited: Rydalmere, NSW.

83. Pharmacia Australia. Product information. Nicorette microtab. 2mg sublingual tablets. [leaflet], October 2003, Pharmacia Australia Pty Limited: Rydalmere, NSW.

84. Shiffman S, Dresler CM, Hajek P, Gilburt SJ, Targett DA, et al. Efficacy of a nicotine lozenge for smoking cessation. Archives of Internal Medicine, 2002; 162(11):1267-76. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12038945

85. GlaxoSmithKline. Nicobate cq lozenges 2/4mg. [leaflet]. January Ermington NSE: GlaxoSmithKline, 2002.

86. Mills EJ, Wu P, Lockhart I, Wilson K, and Ebbert JO. Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta-analysis of one hundred and twenty studies involving 177,390 individuals. Tob Induc Dis, 2010; 8(1):8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20626883

87. Agboola S, McNeill A, Coleman T, and Leonardi Bee J. A systematic review of the effectiveness of smoking relapse prevention interventions for abstinent smokers. Addiction, 2010; 105(8):1362-80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20653619

88. England LJ, Aagaard K, Bloch M, Conway K, Cosgrove K, et al. Developmental toxicity of nicotine: A transdisciplinary synthesis and implications for emerging tobacco products. Neuroscience and Biobehavioral Reviews, 2017; 72:176-89. Available from: https://pubmed.ncbi.nlm.nih.gov/27890689

89. McEvoy CT and Spindel ER. Pulmonary effects of maternal smoking on the fetus and child: Effects on lung development, respiratory morbidities, and life long lung health. Paediatric Respiratory Reviews, 2017; 21:27-33. Available from: https://pubmed.ncbi.nlm.nih.gov/27639458

90. Bansal MA, Cummings KM, Hyland A, and Giovino GA. Stop-smoking medications: Who uses them, who misuses them, and who is misinformed about them? Nicotine and Tobacco Research, 2004; 6 Suppl 3(suppl. 3):S303-10. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15799593

91. US Department of Health and Human Services. The health consequences of smoking: 50 years of progress. A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014. Available from: http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf.

92. Zheng Y, Ritzenthaler J, Roman J, and Han S. Nicotine stimulates human lung cancer cell growth by inducing fironectin expression. American Journal of Respiratory Cell and Molecular Biology, 2007; 28. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17600315

93. Wong H, Yu L, Lam E, Tai E, Wue W, et al. Nicotine promotes colon tumour growth and angiogenesis through beta-adrenergic activation. Toxicological Sciences, 2007; 97(2):279–87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17369603

94. Shiffman S. Nicotine replacement therapy for smoking cessation in the "real world". Thorax, 2007; 62(11):930–1. Available from: http://thorax.bmj.com/cgi/content/full/62/11/930

95. Shiffman S and Ferguson SG. Nicotine patch therapy prior to quitting smoking: A meta-analysis. Addiction, 2008; 103(4):557-63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18339101

96. Shiffman S, Ferguson S, and Strahs K. Quitting by gradual smoking reduction using nicotine gum: A randomized controlled trial. American Journal of Preventive Medicine, 2009; 36(2):96–104.e1. Available from: http://www.ajpm-online.net/article/S0749-3797(08)00891-X/fulltext

97. Dalack GW and Meador-Woodruff JH. Acute feasibility and safety of a smoking reduction strategy for smokers with schizophrenia. Nicotine and Tobacco Research, 1999; 1(1):53-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/11072388

98. Bolliger CT, Zellweger JP, Danielsson T, van Biljon X, Robidou A, et al. Smoking reduction with oral nicotine inhalers: Double blind, randomised clinical trial of efficacy and safety. BMJ, 2000; 321(7257):329-33. Available from: https://www.ncbi.nlm.nih.gov/pubmed/10926587

99. Fagerstrom KO, Tejding R, Westin A, and Lunell E. Aiding reduction of smoking with nicotine replacement medications: Hope for the recalcitrant smoker? Tobacco Control, 1997; 6(4):311-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9583629

100. Moore D, Aveyard P, Connock M, Wang D, Fry-Smith A, et al. Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: Systematic review and meta-analysis. BMJ, 2009; 338:b1024. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19342408

101. Etter JF and Laszlo E. Postintervention effect of nicotine replacement therapy for smoking reduction: A randomized trial with a 5-year follow-up. Journal of Clinical Psychopharmacology, 2007; 27(2):151-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17414237

102. Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, et al. 'Cut down to quit' with nicotine replacement therapies in smoking cessation: A systematic review of effectiveness and economic analysis. Health Technology Assessment, 2008; 12(2):1–135. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18093448

103. Quit Victoria. Nicotine replacement products. 2016. Available from: http://www.quit.org.au/preparing-to-quit/choosing-best-way-to-quit/nicotine-replacement-products

104. Winstanley M, Woodward S, and Walker N, Tobacco in Australia; facts and issues 1995; 2nd edition. Vol. 2.Carlton South: Victorian Smoking and Health Program; 1995. Available from: http://www.quit.org.au/quit/FandI/welcome.htm.

105. Carter S, Borland R, and Chapman C. Finding the strength to kill your best friend–smokers talk about smoking and quitting. Sydney: Australian Smoking Cessation Consortium and GlaxoSmithKline Consumer Healthcare, 2001. Available from: http://tobacco.health.usyd.edu.au/site/supersite/resources/pdfs/killbestfriend.pdf.

106. Chapman S, Relapse and other realities: An update on smoking cessation rates in Australia. SmithKline Beecham; (World No Tobacco Day) 2000.

107. Richmond R and Zwar N. Review of bupropion for smoking cessation. Drug and Alcohol Review, 2003; 22(2):203-20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12850907

108. Therapeutic Goods Administration. Australian product information: Zyban sr (bupropion hydrochloride) sustained release tablets. 2021. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01138-1.

109. Lancaster T, Stead L, and Cahill K. An update on therapeutics for tobacco dependence. Expert Opinion on Pharmacotherapy, 2008; 9(1):15-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18076335

110. Kotlyar M, Drone D, Thuras P, Hatsukami DK, Brauer L, et al. Effect of stress and bupropion on craving, withdrawal symptoms, and mood in smokers. Nicotine and Tobacco Research, 2011; 13(6):492-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21378081

111. Paterson NE. Behavioural and pharmacological mechanisms of bupropion's anti-smoking effects: Recent preclinical and clinical insights. European Journal of Pharmacology, 2009; 603(1-3):1-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19101536

112. Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, and Lancaster T. Antidepressants for smoking cessation. Cochrane Database of Systematic Reviews, 2014; 1(1):CD000031. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24402784

113. Culbertson CS, Bramen J, Cohen MS, London ED, Olmstead RE, et al. Effect of bupropion treatment on brain activation induced by cigarette-related cues in smokers. Archives of General Psychiatry, 2011; 68(5):505-15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21199957

114. Fucito LM, Toll BA, Salovey P, and O'Malley SS. Beliefs and attitudes about bupropion: Implications for medication adherence and smoking cessation treatment. Psychology of Addictive Behaviors, 2009; 23(2):373-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19586156

115. Hawk LW, Jr., Ashare RL, Rhodes JD, Oliver JA, Cummings KM, et al. Does extended pre quit bupropion aid in extinguishing smoking behavior? Nicotine and Tobacco Research, 2015; 17(11):1377-84. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25589680

116. Tomaz PR, Santos JR, Issa JS, Abe TO, Gaya PV, et al. Cyp2b6 rs2279343 polymorphism is associated with smoking cessation success in bupropion therapy. European Journal of Clinical Pharmacology, 2015; 71(9):1067-73. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26153084

117. Zwar N, Nasser A, Comino E, and Richmond R. Short-term effectiveness of bupropion for assisting smoking cessation in general practice. Medical Journal of Australia, 2003; 177(5):277–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12197829

118. Kittle J, Lopes RD, Huang M, Marquess ML, Wilson MD, et al. Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort. Clinical Cardiology, 2017; 40(10):899-906. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28605035

119. Anthenelli RM, Benowitz NL, West R, St Aubin L, McRae T, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (eagles): A double-blind, randomised, placebo-controlled clinical trial. Lancet, 2016; 387(10037):2507-20. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27116918

120. Holmes S, Zwar N, Jimenez-Ruiz C, Ryan P, Browning D, et al. Bupropion as an aid to smoking cessation: A review of real-life effectiveness. International Journal of Clinical Practice, 2004; 58(3):285−91. Available from: http://www3.interscience.wiley.com/journal/118807867/abstract

121. Roddy E. Bupropion and other non-nicotine pharmacotherapies. BMJ, 2004; 328(7438):509-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/14988194

122. McDonough M. Update on medicines for smoking cessation. Aust Prescr, 2015; 38(4):106-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26648633

123. Pfizer Australia Pty Ltd. Product information champix® (varenicline as tartrate) pfpchamt10108. Canberra 2008. Available from: http://www.pbs.gov.au/pi/pfpchamt10108.pdf.

124. Williams JM, Steinberg MB, Steinberg ML, Gandhi KK, Ulpe R, et al. Varenicline for tobacco dependence: Panacea or plight? Expert Opinion on Pharmacotherapy, 2011; 12(11):1799-812. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21644843

125. Brandon TH, Drobes DJ, Unrod M, Heckman BW, Oliver JA, et al. Varenicline effects on craving, cue reactivity, and smoking reward. Psychopharmacology, 2011; 218(2):391-403. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21559801

126. Faessel HM, Obach RS, Rollema H, Ravva P, Williams KE, et al. A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation. Clinical Pharmacokinetics, 2010; 49(12):799-816. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21053991

127. Franklin T, Wang Z, Suh JJ, Hazan R, Cruz J, et al. Effects of varenicline on smoking cue-triggered neural and craving responses. Archives of General Psychiatry, 2011; 68(5):516-26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21199958

128. Fedota JR, Sutherland MT, Salmeron BJ, Ross TJ, Hong LE, et al. Reward anticipation is differentially modulated by varenicline and nicotine in smokers. Neuropsychopharmacology, 2015; 40(8):2038-46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25742873

129. Loughead J, Ray R, Wileyto EP, Ruparel K, Sanborn P, et al. Effects of the alpha4beta2 partial agonist varenicline on brain activity and working memory in abstinent smokers. Biological Psychiatry, 2010; 67(8):715-21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20207347

130. Pascual FP, Fontoba Ferrandiz J, Gil Sanchez MC, Ponce Lorenzo F, and Botella Estrella C. Two-year therapeutic effectiveness of varenicline for smoking cessation in a real world setting. Substance Use and Misuse, 2016; 51(2):131-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26829065

131. Ebbert JO, Hughes JR, West RJ, Rennard SI, Russ C, et al. Effect of varenicline on smoking cessation through smoking reduction: A randomized clinical trial. JAMA, 2015; 313(7):687-94. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25688780

132. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: A randomized controlled trial. JAMA, 2006; 296(1):47-55. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16820546

133. Howard P, Knight C, Bolar A, and Baker C. Cost-utility analysis of varenicline versus existing smoking cessation strategies using the benesco simulation model: Application to a population of US adult smokers. Pharmacoeconomics, 2008; 26(6):497–511. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18489200

134. Annemans L, Nackaerts K, Bartsch P, Prignot J, and Marbaix S. Cost effectiveness of varenicline in belgium, compared with bupropion, nicotine replacement therapy, brief counselling and unaided smoking cessation: A benesco markov cost-effectiveness analysis. Clinical Drug Investigation, 2009; 29(10):655-65. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19715382

135. Bae JY, Kim CH, and Lee EK. Evaluation of cost-utility of varenicline compared with existing smoking cessation therapies in South Korea. Value in Health, 2009; 12 Suppl 3:S70-3. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20586986

136. Bolin K, Mork AC, and Wilson K. Smoking-cessation therapy using varenicline: The cost-utility of an additional 12-week course of varenicline for the maintenance of smoking abstinence. Journal of Evaluation in Clinical Practice, 2009; 15(3):478-85. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19536915

137. Igarashi A, Takuma H, Fukuda T, and Tsutani K. Cost-utility analysis of varenicline, an oral smoking-cessation drug, in Japan. Pharmacoeconomics, 2009; 27(3):247-61. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19354344

138. Jimenez-Ruiz C, Berlin I, and Hering T. Varenicline: A novel pharmacotherapy for smoking cessation. Drugs, 2009; 69(10):1319-38. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19583451

139. Keiding H. Cost-effectiveness of varenicline for smoking cessation. Expert Review of Pharmacoeconomics and Outcomes Research, 2009; 9(3):215-21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19527093

140. Fagerstrom K and Hughes J. Varenicline in the treatment of tobacco dependence. Neuropsychiatr Dis Treat, 2008; 4(2):353-63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18728741

141. Fagerstrom K, Nakamura M, Cho HJ, Tsai ST, Wang C, et al. Varenicline treatment for smoking cessation in asian populations: A pooled analysis of placebo-controlled trials conducted in six asian countries. Current Medical Research and Opinion, 2010; 26(9):2165-73. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20666691

142. Ebbert JO, Croghan IT, North F, and Schroeder DR. A pilot study to assess smokeless tobacco use reduction with varenicline. Nicotine and Tobacco Research, 2010; 12(10):1037-40. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20724382

143. Ebbert J, Montori VM, Erwin PJ, and Stead LF. Interventions for smokeless tobacco use cessation. Cochrane Database of Systematic Reviews, 2011; 2(2):CD004306. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21328266

144. Bolliger CT, Issa JS, Posadas-Valay R, Safwat T, Abreu P, et al. Effects of varenicline in adult smokers: A multinational, 24-week, randomized, double-blind, placebo-controlled study. Clinical Therapeutics, 2011; 33(4):465-77. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21635992

145. Boudrez H, Gratziou C, Messig M, and Metcalfe M. Effectiveness of varenicline as an aid to smoking cessation: Results of an inter-European observational study. Current Medical Research and Opinion, 2011; 27(4):769-75. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21294601

146. Ebbert JO, Croghan IT, Hurt RT, Schroeder DR, and Hays JT. Varenicline for smoking cessation in light smokers. Nicotine and Tobacco Research, 2016; 18(10):2031-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27117285

147. Anthenelli RM, Morris C, Ramey TS, Dubrava SJ, Tsilkos K, et al. Effects of varenicline on smoking cessation in adults with stably treated current or past major depression: A randomized trial. Annals of Internal Medicine, 2013; 159(6):390–400. Available from: http://dx.doi.org/10.7326/0003-4819-159-6-201309170-00005

148. Williams JM, Anthenelli RM, Morris CD, Treadow J, Thompson JR, et al. A randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of varenicline for smoking cessation in patients with schizophrenia or schizoaffective disorder. Journal of Clinical Psychiatry, 2012; 73(5):654-60. Available from: https://pubmed.ncbi.nlm.nih.gov/22697191/

149. Pachas GN, Cather C, Pratt SA, Hoeppner B, Nino J, et al. Varenicline for smoking cessation in schizophrenia: Safety and effectiveness in a 12-week, open-label trial. Journal of Dual Diagnosis, 2012; 8(2):117-25. Available from: https://pubmed.ncbi.nlm.nih.gov/22888309

150. Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: A randomized controlled trial. JAMA, 2006; 296(1):56-63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16820547

151. Potts LA and Garwood CL. Varenicline: The newest agent for smoking cessation. American Journal of Health-System Pharmacy, 2007; 64(13):1381-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17592002

152. Aubin H, Bobak A, Britton J, Oncken C, Billing C, et al. Authors’ reply. Thorax, 2008; 63:752–3 Available from: http://thorax.bmj.com/cgi/content/full/63/8/752

153. Nides M, Glover ED, Reus VI, Christen AG, Make BJ, et al. Varenicline versus bupropion sr or placebo for smoking cessation: A pooled analysis. American Journal of Health Behavior, 2008; 32(6):664-75. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18442345

154. Hind D, Tappenden P, Peters J, and Kenjegalieva K. Varenicline in the management of smoking cessation: A single technology appraisal. Health Technology Assessment, 2009; 13 Suppl 2( Suppl 2):9-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19804684

155. Cahill K, Stead L, and Lancaster T. A preliminary benefit-risk assessment of varenicline in smoking cessation. Drug Safety, 2009; 32(2):119-35. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19236119

156. Kotz D, Brown J, and West R. Prospective cohort study of the effectiveness of varenicline versus nicotine replacement therapy for smoking cessation in the "real world". BMC Public Health, 2014; 14:1163. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25392075

157. Gray KM, McClure EA, Baker NL, Hartwell KJ, Carpenter MJ, et al. An exploratory short-term double-blind randomized trial of varenicline versus nicotine patch for smoking cessation in women. Addiction, 2015; 110(6):1027-34. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25727442

158. Baker TB, Piper ME, Stein JH, Smith SS, Bolt DM, et al. Effects of nicotine patch vs varenicline vs combination nicotine replacement therapy on smoking cessation at 26 weeks: A randomized clinical trial. JAMA, 2016; 315(4):371-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26813210

159. Lee JH, Jones PG, Bybee K, and O'Keefe JH. A longer course of varenicline therapy improves smoking cessation rates. Preventive Cardiology, 2008; 11(4):210-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19476573

160. Keating GM and Lyseng-Williamson KA. Varenicline: A pharmacoeconomic review of its use as an aid to smoking cessation. Pharmacoeconomics, 2010; 28(3):231-54. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20108995

161. Burke MV, Hays JT, and Ebbert JO. Varenicline for smoking cessation: A narrative review of efficacy, adverse effects, use in at-risk populations, and adherence. Patient Prefer Adherence, 2016; 10:435-41. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27099479

162. Hajek P, Tonnesen P, Arteaga C, Russ C, and Tonstad S. Varenicline in prevention of relapse to smoking: Effect of quit pattern on response to extended treatment. Addiction, 2009; 104(9):1597-602. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19686530

163. Bohadana A, Freier-Dror Y, Peles V, Babai P, and Izbicki G. Extending varenicline preloading to 6 weeks facilitates smoking cessation: A single-site, randomised controlled trial. EClinicalMedicine, 2020; 19:100228. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32055787

164. Gonzales D, Hajek P, Pliamm L, Nackaerts K, Tseng LJ, et al. Retreatment with varenicline for smoking cessation in smokers who have previously taken varenicline: A randomized, placebo-controlled trial. Clinical Pharmacology and Therapeutics, 2014; 96(3):390-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24911368

165. Hajek P, McRobbie H, Myers Smith K, Phillips A, Cornwall D, et al. Increasing varenicline dose in smokers who do not respond to the standard dosage: A randomized clinical trial. JAMA Intern Med, 2015; 175(2):266-71. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25545858

166. Jung JW, Jeon EJ, Kim JG, Yang SY, Choi JC, et al. Clinical experience of varenicline for smoking cessation. Clinical Respiratory Journal, 2010; 4(4):215-21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20887344

167. Grassi MC, Enea D, Ferketich AK, Lu B, Pasquariello S, et al. Effectiveness of varenicline for smoking cessation: A 1-year follow-up study. Journal of Substance Abuse Treatment, 2011; 41(1):64-70. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21349681

168. Rocha Santos J, Tomaz PR, Issa JS, Abe TO, Krieger JE, et al. Chrna4 rs1044396 is associated with smoking cessation in varenicline therapy. Front Genet, 2015; 6:46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25774163

169. Pharmaceutical Benefits Scheme. Varenicline. Available from: https://www.pbs.gov.au/medicine/item/5469W-9128K-9129L

170. Zwar N, Richmond R, Borland R, Peters M, Stillman S, et al. Smoking cessation pharmacotherapy: An update for health professionals. Melbourne: Royal Australian College of General Practitioners, 2007. Available from: http://www.treatobacco.net/en/uploads/documents/Treatment%20Guidelines/Australia%20treatment%20guidelines%20-%20pharmacotherapy%20in%20English%202007.pdf.

171. Therapeutic Goods Administration. Australian product information - champix®. 2021. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06102-3.

172. Garrison GD and Dugan SE. Varenicline: A first-line treatment option for smoking cessation. Clinical Therapeutics, 2009; 31(3):463-91. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19393839

173. Kasza KA, Cummings KM, Carpenter MJ, Cornelius ME, Hyland AJ, et al. Use of stop-smoking medications in the United States before and after the introduction of varenicline. Addiction, 2015; 110(2):346-55. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25331778

174. von Wartburg M, Raymond V, and Paradis PE. The long-term cost-effectiveness of varenicline (12-week standard course and 12 + 12-week extended course) vs. Other smoking cessation strategies in Canada. International Journal of Clinical Practice, 2014; 68(5):639-46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24472120

175. Galanti LM. Tobacco smoking cessation management: Integrating varenicline in current practice. Vasc Health Risk Manag, 2008; 4(4):837-45. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19066000

176. The Royal Australian College of General Practitioners, Supporting smoking cessation: A guide for health professionals. 2nd edn edEast Melbourne, Vic: RACGP; 2019. Available from: https://www.racgp.org.au/getattachment/00185c4e-441b-45a6-88d1-8f05c71843cd/Supporting-smoking-cessation-A-guide-for-health-professionals.aspx.

177. Leung LK, Patafio FM, and Rosser WW. Gastrointestinal adverse effects of varenicline at maintenance dose: A meta-analysis. BMC Clinical Pharmacology, 2011; 11:15. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21955317

178. McIntosh J. Chantix could affect patients' alcohol tolerance, warn FDA. Medical News Today, 2015. Available from: http://www.medicalnewstoday.com/articles/290654.php?tw

179. Kotz D, Viechtbauer W, Simpson C, van Schayck OC, West R, et al. Cardiovascular and neuropsychiatric risks of varenicline: A retrospective cohort study. Lancet Respir Med, 2015; 3(10):761-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26355008

180. Mills EJ, Thorlund K, Eapen S, Wu P, and Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: A network meta-analysis. Circulation, 2014; 129(1):28-41. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24323793

181. Sharma A, Thakar S, Lavie CJ, Garg J, Krishnamoorthy P, et al. Cardiovascular adverse events associated with smoking-cessation pharmacotherapies. Current Cardiology Reports, 2015; 17(1):554. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25410148

182. Wu Q, Gilbody S, Peckham E, Brabyn S, and Parrott S. Varenicline for smoking cessation and reduction in people with severe mental illnesses: Systematic review and meta-analysis. Addiction, 2016; 111(9):1554-67. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27043328

183. Carney G, Bassett K, Maclure M, Taylor S, and Dormuth CR. Cardiovascular and neuropsychiatric safety of smoking cessation pharmacotherapies in non-depressed adults: A retrospective cohort study. Addiction, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32077187

184. Carney G, Maclure M, Malfair S, Bassett K, Wright JM, et al. Comparative safety of smoking cessation pharmacotherapies during a government-sponsored reimbursement program. Nicotine and Tobacco Research, 2020. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32484873

185. Etter JF, Lukas RJ, Benowitz NL, West R, and Dresler CM. Cytisine for smoking cessation: A research agenda. Drug and Alcohol Dependence, 2008; 92(1-3):3-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17825502

186. Hajek P, McRobbie H, and Myers K. Efficacy of cytisine in helping smokers quit: Systematic review and meta-analysis. Thorax, 2013; 68(11):1037-42. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23404838

187. Tutka P, Vinnikov D, Courtney RJ, and Benowitz NL. Cytisine for nicotine addiction treatment: A review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Addiction, 2019; 114(11):1951-69. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31240783

188. Walker N, Howe C, Glover M, McRobbie H, Barnes J, et al. Cytisine versus nicotine for smoking cessation. New England Journal of Medicine, 2014; 371(25):2353-62. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25517706

189. Leaviss J, Sullivan W, Ren S, Everson-Hock E, Stevenson M, et al. What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. Health Technology Assessment, 2014; 18(33):1-120. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24831822

190. Hatsukami DK, Jorenby DE, Gonzales D, Rigotti NA, Glover ED, et al. Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic. Clinical Pharmacology and Therapeutics, 2011; 89(3):392-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21270788

191. Cerny EH and Cerny T. Vaccines against nicotine. Human Vaccines, 2009; 5(4):200-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19276649

192. Casella G, Caponnetto P, and Polosa R. Therapeutic advances in the treatment of nicotine addiction: Present and future. Ther Adv Chronic Dis, 2010; 1(3):95-106. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23251732

193. Escobar-Chavez JJ, Dominguez-Delgado CL, and Rodriguez-Cruz IM. Targeting nicotine addiction: The possibility of a therapeutic vaccine. Drug Design, Development and Therapy, 2011; 5:211-24. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21607018

194. Havermans A, Vuurman EF, van den Hurk J, Hoogsteder P, and van Schayck OC. Treatment with a nicotine vaccine does not lead to changes in brain activity during smoking cue exposure or a working memory task. Addiction, 2014; 109(8):1260-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24894701

195. Tonstad S, Heggen E, Giljam H, Lagerback PA, Tonnesen P, et al. Niccine(r), a nicotine vaccine, for relapse prevention: A phase ii, randomized, placebo-controlled, multicenter clinical trial. Nicotine and Tobacco Research, 2013; 15(9):1492-501. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23471101

196. Fahim RE, Kessler PD, and Kalnik MW. Therapeutic vaccines against tobacco addiction. Expert Review of Vaccines, 2013; 12(3):333-42. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23496672

197. Pentel PR and LeSage MG. New directions in nicotine vaccine design and use. Advances in Pharmacology, 2014; 69:553-80. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24484987

198. Hatsukami DK, Rennard S, Jorenby D, Fiore M, Koopmeiners J, et al. Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clinical Pharmacology and Therapeutics, 2005; 78(5):456-67. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16321612

199. Maurer P and Bachmann MF. Vaccination against nicotine: An emerging therapy for tobacco dependence. Expert Opinion on Investigational Drugs, 2007; 16(11):1775-83. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17970637

200. Cerny EH and Cerny T. Anti-nicotine abuse vaccines in the pipeline: An update. Expert Opinion on Investigational Drugs, 2008; 17(5):691-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18447595

201. Cornuz J, Zwahlen S, Jungi WF, Osterwalder J, Klingler K, et al. A vaccine against nicotine for smoking cessation: A randomized controlled trial. PLoS ONE, 2008; 3(6):e2547. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18575629

202. Fattom AI, Hohenboken M, and Kalnik M, Nicvax®, a nicotine conjugate vaccine, aids smokers to quit smoking and stay quit: Animal and human data in support of a proposed mechanism of action. The eleventh annual conference on vaccine research Baltimore, MD 2008. Available from: http://www.nfid.org/pdf/conferences/vaccine08abstracts.pdf.

203. Lockner JW, Lively JM, Collins KC, Vendruscolo JC, Azar MR, et al. A conjugate vaccine using enantiopure hapten imparts superior nicotine-binding capacity. Journal of Medicinal Chemistry, 2015; 58(2):1005-11. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25493909

204. Chang PH, Chiang CH, Ho WC, Wu PZ, Tsai JS, et al. Combination therapy of varenicline with nicotine replacement therapy is better than varenicline alone: A systematic review and meta-analysis of randomized controlled trials. BMC Public Health, 2015; 15(1):689. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26198192

205. Vogeler T, McClain C, and Evoy KE. Combination bupropion sr and varenicline for smoking cessation: A systematic review. American Journal of Drug and Alcohol Abuse, 2016; 42(2):129-39. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26809272

206. Kotz D, Brown J, and West R. 'Real-world' effectiveness of smoking cessation treatments: A population study. Addiction, 2014; 109(3):491-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24372901

207. Patnode CD, Henderson JT, Thompson JH, Senger CA, Fortmann SP, et al. Behavioral counseling and pharmacotherapy interventions for tobacco cessation in adults, including pregnant women: A review of reviews for the u.S. Preventive services task force. Annals of Internal Medicine, 2015; 163(8):608-21. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26389650

208. Stead LF, Koilpillai P, Fanshawe TR, and Lancaster T. Combined pharmacotherapy and behavioural interventions for smoking cessation. Cochrane Database of Systematic Reviews, 2016; 3:CD008286. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27009521

209. Hartmann-Boyce J, Hong B, Livingstone-Banks J, Wheat H, and Fanshawe TR. Additional behavioural support as an adjunct to pharmacotherapy for smoking cessation. Cochrane Database of Systematic Reviews, 2019; 6:CD009670. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31166007

210. Rose JE. Disrupting nicotine reinforcement: From cigarette to brain. Annals of the New York Academy of Sciences, 2008; 1141:233-56. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18991961

211. Butler K and Le Foll B. Novel therapeutic and drug development strategies for tobacco use disorder: Endocannabinoid modulation. Expert Opin Drug Discov, 2020:1-16. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32425077

212. Siu EC and Tyndale RF. Non-nicotinic therapies for smoking cessation. Annual Review of Pharmacology and Toxicology, 2007; 47:541-64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17209799

213. Cahill K and Ussher M Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation. Cochrane Database of Systematic Reviews 2007 DOI: 10.1002/14651858.CD005353.pub3. Available from: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005353/frame.html

214. Schmaal L, Berk L, Hulstijn KP, Cousijn J, Wiers RW, et al. Efficacy of n-acetylcysteine in the treatment of nicotine dependence: A double-blind placebo-controlled pilot study. European Addiction Research, 2011; 17(4):211-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21606648

215. Asevedo E, Mendes AC, Berk M, and Brietzke E. Systematic review of n-acetylcysteine in the treatment of addictions. Braz J Psychiatry, 2014; 36(2):168-75. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24676047

216. Frishman WH, Mitta W, Kupersmith A, and Ky T. Nicotine and non-nicotine smoking cessation pharmacotherapies. Cardiology in Review, 2006; 14(2):57-73. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16493243

217. Bagdas D, Muldoon PP, Zhu AZ, Tyndale RF, and Damaj MI. Effects of methoxsalen, a cyp2a5/6 inhibitor, on nicotine dependence behaviors in mice. Neuropharmacology, 2014; 85:67-72. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24859605

218. Alsharari SD, Siu EC, Tyndale RF, and Damaj MI. Pharmacokinetic and pharmacodynamics studies of nicotine after oral administration in mice: Effects of methoxsalen, a cyp2a5/6 inhibitor. Nicotine and Tobacco Research, 2014; 16(1):18-25. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23884323

219. Sofuoglu M, Poling J, Mouratidis M, and Kosten T. Effects of topiramate in combination with intravenous nicotine in overnight abstinent smokers. Psychopharmacology, 2006; 184(3-4):645-51. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16432681

220. Anthenelli RM, Blom TJ, McElroy SL, and Keck PE. Preliminary evidence for gender-specific effects of topiramate as a potential aid to smoking cessation. Addiction, 2008; 103(4):687–94. Available from: http://www.blackwell-synergy.com/doi/abs/10.1111/j.1360-0443.2008.02148.x

221. Arbaizar B, Gomez-Acebo I, and Llorca J. Decrease in tobacco consumption after treatment with topiramate and aripiprazole: A case report. J Med Case Rep, 2008; 2:198. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18547425

222. Khazaal Y and Zullino DF. Topiramate for smoking cessation and the importance to distinguish withdrawal-motivated consumption and cue-triggered automatisms. Journal of Clinical Psychopharmacology, 2009; 29(2):192-3; author reply 3-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19512990

223. Oncken C, Arias AJ, Feinn R, Litt M, Covault J, et al. Topiramate for smoking cessation: A randomized, placebo-controlled pilot study. Nicotine and Tobacco Research, 2014; 16(3):288-96. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24057996

224. Lotfy N, Elsawah H, and Hassan M. Topiramate for smoking cessation: Systematic review and meta-analysis. Tob Prev Cessat, 2020; 6:14. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32548351

225. Byars JA, Frost-Pineda K, Jacobs WS, and Gold MS. Naltrexone augments the effects of nicotine replacement therapy in female smokers. Journal of Addictive Diseases, 2005; 24(2):49-60. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15784523

226. David S, Lancaster T, Stead LF, and Evins AE Opioid antagonists for smoking cessation. Cochrane Database of Systematic Reviews 2006 DOI: 10.1002/14651858.CD003086.pub2. Available from: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003086/frame.html

227. David SP, Chu IM, Lancaster T, Stead LF, Evins AE, et al. Systematic review and meta-analysis of opioid antagonists for smoking cessation. BMJ Open, 2014; 4(3):e004393. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24633528

228. David SP, Lancaster T, Stead LF, Evins AE, and Prochaska JJ. Opioid antagonists for smoking cessation. Cochrane Database of Systematic Reviews, 2013; 6(6):CD003086. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23744347

229. Invion. Invion successfully completes phase 2 study of inv102 (nadolol) to aid smoking cessation. 2015. Available from: http://inviongroup.com/invion-successfully-completes-phase-2-study-of-inv102-nadolol-to-aid-smoking-cessation/

230. Gourlay SG, Stead LF, and Benowitz NL Clonidine for smoking cessation. Cochrane Database of Systematic Reviews 2004 DOI: 10.1002/14651858.CD000058.pub2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15266422

231. Lancaster T and Stead LF. Silver acetate for smoking cessation. Cochrane Database of Systematic Reviews, 2012; 9(9):CD000191. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22972041

232. Drgon T, Johnson C, Walther D, Albino AP, Rose JE, et al. Genome-wide association for smoking cessation success: Participants in a trial with adjunctive denicotinized cigarettes. Molecular Medicine, 2009; 15(7-8):268-74. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19593411

233. David SP, Johnstone EC, Churchman M, Aveyard P, Murphy MF, et al. Pharmacogenetics of smoking cessation in general practice: Results from the patch ii and patch in practice trials. Nicotine and Tobacco Research, 2011; 13(3):157-67. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21330274

234. Sturgess JE, George TP, Kennedy JL, Heinz A, and Muller DJ. Pharmacogenetics of alcohol, nicotine and drug addiction treatments. Addiction Biology, 2011; 16(3):357-76. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21362114

235. Saccone NL, Baurley JW, Bergen AW, David SP, Elliott HR, et al. The value of biosamples in smoking cessation trials: A review of genetic, metabolomic, and epigenetic findings. Nicotine and Tobacco Research, 2018; 20(4):403-13. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28472521

236. Salloum NC, Buchalter ELF, Chanani S, Espejo G, Ismail MS, et al. From genes to treatments: A systematic review of the pharmacogenetics in smoking cessation. Pharmacogenomics, 2018; 19(10):861-71. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29914292

237. Nagelhout GE, Willemsen MC, van den Putte B, de Vries H, Willems RA, et al. Effectiveness of a national reimbursement policy and accompanying media attention on use of cessation treatment and on smoking cessation: A real-world study in the Netherlands. Tobacco Control, 2015; 24(5):455-61. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24842854

238. Selby P, Brosky G, Oh P, Raymond V, Arteaga C, et al. A pragmatic, randomized, controlled study evaluating the impact of access to smoking cessation pharmacotherapy coverage on the proportion of successful quitters in a Canadian population of smokers motivated to quit (accessation). BMC Public Health, 2014; 14:433. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24885542

239. Reda AA, Kotz D, Evers SM, and van Schayck CP. Healthcare financing systems for increasing the use of tobacco dependence treatment. Cochrane Database of Systematic Reviews, 2012; (6):CD004305. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22696341

240. Department of Health, The extension of the listing of nicotine patches on the pharmaceutical benefits scheme from 1 February 2011. Australian Government; 2013. Available from: http://www.pbs.gov.au/info/publication/factsheets/shared/Extension_of_the_listing_of_nicotine_patches.

241. Australian Institute of Health and Welfare. National Drug Strategy Household Survey, 2013 [computer file], 2015, Australian Data Archive, The Australian National University: Canberra.

242. Cooper J, Borland R, and Yong HH. Australian smokers increasingly use help to quit, but number of attempts remains stable: Findings from the international tobacco control study 2002-09. Australian and New Zealand Journal of Public Health, 2011; 35(4):368-76. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21806733

243. An LC, Schillo BA, Kavanaugh AM, Lachter RB, Luxenberg MG, et al. Increased reach and effectiveness of a statewide tobacco quitline after the addition of access to free nicotine replacement therapy. Tobacco Control, 2006; 15(4):286–93. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16885577

244. Grigg M and Glasgow H. Subsidised nicotine replacement therapy. Tobacco Control, 2003; 12(2):238-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12773740

245. Tinkelman D, Wilson SM, Willett J, and Sweeney CT. Offering free NRT through a tobacco quitline: Impact on utilisation and quit rates. Tobacco Control, 2007; 16 Suppl 1(suppl. 1):i42-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18048631

246. Maher JE, Rohde K, Pizacani B, Dent C, Stark MJ, et al. Does free nicotine replacement therapy for young adults prompt them to call a quitline? Tobacco Control, 2007; 16(5):357-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17897996

247. Hollis JF, McAfee TA, Fellows JL, Zbikowski SM, Stark M, et al. The effectiveness and cost effectiveness of telephone counselling and the nicotine patch in a state tobacco quitline. Tobacco Control, 2007; 16 Suppl 1(suppl. 1):i53-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18048633

248. Cummings KM, Fix B, Celestino P, Carlin-Menter S, O'Connor R, et al. Reach, efficacy, and cost-effectiveness of free nicotine medication giveaway programs. Journal of Public Health Management and Practice, 2006; 12(1):37-43. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16340514

249. Cummings KM, Hyland A, Fix B, Bauer U, Celestino P, et al. Free nicotine patch giveaway program 12-month follow-up of participants. American Journal of Preventive Medicine, 2006; 31(2):181-4. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16829336

250. Bauer JE, Carlin-Menter SM, Celestino PB, Hyland A, and Cummings KM. Giving away free nicotine medications and a cigarette substitute (better quit) to promote calls to a quitline. Journal of Public Health Management and Practice, 2006; 12(1):60–7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16340517

251. Alberg AJ, Stashefsky Margalit R, Burke A, Rasch KA, Stewart N, et al. The influence of offering free transdermal nicotine patches on quit rates in a local health department's smoking cessation program. Addictive Behaviors, 2004; 29(9):1763-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15530720

252. O'Dea D. An economic evaluation of the quitline nicotine replacement therapy (NRT) service. June 28, 2004. Available from: http://www.ndp.govt.nz/moh.nsf/pagescm/1007/$File/economicevaluationquitline.pdf.

253. Bush TM, McAfee T, Deprey M, Mahoney L, Fellows JL, et al. The impact of a free nicotine patch starter kit on quit rates in a state quit line. Nicotine and Tobacco Research, 2008; 10(9):1511-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19023843

254. Walker N, Howe C, Bullen C, Grigg M, Glover M, et al. Does improved access and greater choice of nicotine replacement therapy affect smoking cessation success? Findings from a randomized controlled trial. Addiction, 2011; 106(6):1176-85. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21371155

255. Miller N, Frieden TR, Liu SY, Matte TD, Mostashari F, et al. Effectiveness of a large-scale distribution programme of free nicotine patches: A prospective evaluation. Lancet, 2005; 365(9474):1849-54. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15924980

256. Watson D, Bullen C, Clover M, McRobbie H, Parag V, et al. Impact on quit attempts of mailed general practitioner 'brief advice' letters plus nicotine replacement therapy vouchers. Journal of Primary Health Care, 2010; 2(1):4-10. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20690396

257. Jardin BF, Cropsey KL, Wahlquist AE, Gray KM, Silvestri GA, et al. Evaluating the effect of access to free medication to quit smoking: A clinical trial testing the role of motivation. Nicotine and Tobacco Research, 2014; 16(7):992-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24610399

258. Lundh A, Sismondo S, Lexchin J, Busuioc OA, and Bero L. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews, 2012; 12:MR000033. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23235689

259. Etter JF, Burri M, and Stapleton J. The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: A meta-analysis. Addiction, 2007; 102(5):815-22. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17493109

260. Greene NM, Taylor EM, Gage SH, and Munafo MR. Industry funding and placebo quit rate in clinical trials of nicotine replacement therapy: A commentary on etter et al. (2007). Addiction, 2010; 105(12):2217-8; author reply 9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21054610

261. Moberg CA and Humphreys K. Exclusion criteria in treatment research on alcohol, tobacco and illicit drug use disorders: A review and critical analysis. Drug and Alcohol Review, 2017; 36(3):378-88. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27324921

262. Motschman CA, Gass JC, Wray JM, Germeroth LJ, Schlienz NJ, et al. Selection criteria limit generalizability of smoking pharmacotherapy studies differentially across clinical trials and laboratory studies: A systematic review on varenicline. Drug and Alcohol Dependence, 2016; 169:180-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27863344

263. Kotz D, Brown J, and West R. Prospective cohort study of the effectiveness of smoking cessation treatments used in the "real world". Mayo Clinic Proceedings, 2014; 89(10):1360-7. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25282429

264. Piper ME, Bullen C, Krishnan-Sarin S, Rigotti NA, Steinberg ML, et al. Defining and measuring abstinence in clinical trials of smoking cessation interventions: An updated review. Nicotine and Tobacco Research, 2020; 22(7):1098-106. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31271211

265. Benowitz NL, Bernert JT, Foulds J, Hecht SS, Jacob P, et al. Biochemical verification of tobacco use and abstinence: 2019 update. Nicotine and Tobacco Research, 2020; 22(7):1086-97. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31570931

266. Catz SL, Jack LM, McClure JB, Javitz HS, Deprey M, et al. Adherence to varenicline in the compass smoking cessation intervention trial. Nicotine and Tobacco Research, 2011; 13(5):361-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21350041

267. Hollands GJ, McDermott MS, Lindson-Hawley N, Vogt F, Farley A, et al. Interventions to increase adherence to medications for tobacco dependence. Cochrane Database of Systematic Reviews, 2015; 2(2):CD009164. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25914910

268. Hollands GJ, Naughton F, Farley A, Lindson N, and Aveyard P. Interventions to increase adherence to medications for tobacco dependence. Cochrane Database of Systematic Reviews, 2019; 8:CD009164. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31425618

269. Schlagintweit HE, Perry RN, Darredeau C, and Barrett SP. Non-pharmacological considerations in human research of nicotine and tobacco effects: A review. Nicotine and Tobacco Research, 2020; 22(8):1260-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31058286

270. Pacek LR, McClernon FJ, and Bosworth HB. Adherence to pharmacological smoking cessation interventions: A literature review and synthesis of correlates and barriers. Nicotine and Tobacco Research, 2018; 20(10):1163-72. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29059394

271. Fucito LM, Toll BA, Roos CR, and King AC. Smokers' treatment expectancies predict smoking cessation success. J Smok Cessat, 2016; 11(3):143-9. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27594921

272. Bailey SR, Fong DM, Bryson SW, Fortmann SP, and Killen JD. Perceived drug assignment and treatment outcome in smokers given nicotine patch therapy. Journal of Substance Abuse Treatment, 2010; 39(2):150-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/20598833

273. Hughes J. Ethical concerns about non-active conditions in smoking cessation trials and methods to decrease such concerns. Drug and Alcohol Dependence, 2009; 100(3):187–93. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19058924

274. Rosen L, Manor O, Engelhard D, and Zucker D. In defense of the randomized controlled trial for health promotion research. American Journal of Public Health, 2006; 96(7):1181-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/16735622

275. Black N, Eisma MC, Viechtbauer W, Johnston M, West R, et al. Variability and effectiveness of comparator group interventions in smoking cessation trials: A systematic review and meta-analysis. Addiction, 2020; 115(9):1607-17. Available from: https://www.ncbi.nlm.nih.gov/pubmed/32043675

276. Richter KP and Ellerbeck EF. It's time to change the default for tobacco treatment. Addiction, 2015; 110(3):381-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25323093

277. Ashcroft RE. The ethics of an opt-out default in tobacco treatment. Addiction, 2015; 110(3):389-90. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25678286