Home » Chapter 7: Cessation » 7.16 Pharmacotherapies

7.16 Pharmacotherapies

Last updated: December 2019

Suggested citation: Greenhalgh, EM., Stillman, S., & Ford, C. 7.16 Pharmacotherapies. In Scollo, MM and Winstanley, MH [editors]. Tobacco in Australia: Facts and issues. Melbourne: Cancer Council Victoria; 2019. Available from: http://www.tobaccoinaustralia.org.au/chapter-7-cessation/7-16-pharmacotherapy

The development and introduction of drug therapies has provided much-needed assistance for those 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.^{1, 2} First-line treatments for smoking cessation include nicotine replacement therapy (NRT), bupropion, and varenicline. NRT, bupropion, and varenicline all provide therapeutic effects in assisting with smoking cessation.^{3, 4}

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.^{5, 6}

Choice of pharmacotherapy should take into account potential adverse effects as well as benefits.⁷ When pharmacotherapy combinations or dosages beyond those contained in consumer product information are used, medical supervision is necessary. Cost is also taken into account by the Australian government in deciding which pharmaceuticals to subsidise under the Repatriation Pharmaceutical Benefits Scheme (PBS). Nicotine patches were listed on the PBS in August 1994 and December 1995 and then made available under the Pharmaceutical Benefits Scheme for Indigenous smokers from 2009.^{8, 9} 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 products listed. Bupropion (Zyban SR® and Prexaton ®) and varenicline (Champix®) are scheduled S4 in Australia so that they are available only on prescription,¹⁰ and have been available on Australia’s PBS since 2001 and 2008 respectively. As of January 2019, the dispensed price for subsidised medicines was $6.50 for people with a concession card and $40.30 for other patients.¹¹ Subsidy of medications 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 January 2001 to September 2019.

Figure 7.16.1
Annual total number of prescriptions for anti-smoking medications, Australia, January 2001 to September 2019: 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 (ordinary, those with healthcare cards and those covered by Repatriation Benefits Scheme) and same 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 (Zyban) and other anti-depressants

7.16.3 Varenicline (Champix)

7.16.4 Vaccines

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

7.16.6 Other less commonly used pharmacotherapies, and

7.16.7 Other treatments under investigation

It also examines:

7.16.8 The effects of dispensing arrangements and subsidies, and

7.16.9 Methodological and ethical issues in smoking cessation trials

7.16.1 Nicotine replacement therapy

Nicotine is the drug in tobacco that causes addiction, which is released when tobacco is smoked, chewed, or sucked.¹² It is the decrease in nicotine levels that is mainly responsible for withdrawal symptoms after stopping smoking.¹² 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.⁷ 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’.¹³

NRT products are either sustained dosing formulations or acute dosing formulations.² There are advantages and disadvantages associated with each form of NRT. Nicotine patches, the most popular choice, are simple to use and the compliance rate tends to be higher than other NRT products.^{14, 15} However, patches deliver nicotine more slowly than other products and may not adequately protect against increased cravings from smoking-related stimuli. Users of the oral products (or acute dosing forms) have greater control over the amount and timing of the dose, and these products are better suited to respond to sudden increases in cravings.¹⁵ However, some users only use acute NRT in response to cravings, and under-dosing is a common problem with these products.¹⁵ Nicotine delivered via a mouth spray is absorbed faster than nicotine delivered via gum or lozenge.¹⁶ Personal vapourisers/e-cigarettes 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.¹⁷ 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.¹⁸ 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.^{15, 19, 20} The nicotine inhaler is designed to mimic the hand-to-mouth ritual of smoking.

7.16.1.2 Efficacy and effectiveness of NRT

The benefit of NRT has been supported by both efficacy and effectiveness studies.²¹ A Cochrane review published in 2018 concluded that NRTs increase the rate of quitting by 50 to 60%, and all of the commercially available products can help increase the chances of a quit attempt being successful.²² However, some have suggested that this effect size may be an overestimate.^23-25 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.²⁶ 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.²⁷

NRT works with or without additional counselling, however counselling further increases the odds of success.^28-30 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.³¹ 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.^{7, 32-34}

Some evidence suggests that dosage and speed of delivery has an impact on outcomes.^35-38 A review of high-dose transdermal NRT (patches) for tobacco 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.³⁹ More recently, a 2019 Cochrane review found that people were also more likely to quit successfully if they used higher‐dose compared with lower-dose nicotine patches or nicotine gum.⁴⁰

In terms of specific products and populations, one study found that the nicotine nasal spray may be slightly more effective than the standard dose patch or the short-term gum.²⁹ The 4 mg nicotine lozenge appears to reduce the weight gain that may occur after quitting but does not have a lasting effect beyond its use.^{36, 41} NRT appears to be less effective at reducing relapse among women with higher BMIs.⁴² A randomised controlled trial found that NRT was not effective in promoting long-term abstinence among adolescents.⁴³

An important factor affecting success rates appears to be the duration of NRT use. Pre-quit nicotine patch us appears to increase quit rates⁴⁰ and may engage additional smokers who are unwilling to quit.⁴⁴ The manufacturer’s recommended period of use for NRT products varies between eight and 16 weeks, often with provision for a gradual reduction of dosage levels to avoid withdrawal effects at the end of the period.⁴⁵ 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.⁷ Highly dependent smokers who still have cravings and withdrawal symptoms eight weeks after quitting may benefit from longer use.^{15, 46, 47} Short courses of NRT, for example four weeks, may not be effective in the long term.⁴⁸ 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.⁴⁹ 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.⁵⁰ Continued use of NRT and tobacco during a lapse or relapse does not appear harmful and could enhance quitting outcomes.⁵¹

The widespread availability and promotion of NRT products 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 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.⁵² 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.¹⁴ Research suggests that many smokers are misinformed about the health risks of NRT, which makes them less likely to use the product or use it correctly.^{30, 37, 53} Smokers tend to use less than the recommended dose or not complete the full course of treatment.^{54, 55} Treatment adherence has been found to significantly increase abstinence rates.⁵⁶ 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.⁵⁷ Providing accurate safety information may increase a smoker’s willingness to use NRT as part of their quit attempt. The literacy levels of smoking cessation product packaging instructions have been assessed as being above the reading levels recommended to ensure maximum comprehension.⁵⁸ There is some evidence that enabling smokers to sample the products prior to use may result in more realistic choice of NRT and better compliance.⁵⁹

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 mist 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.⁶⁰ 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.⁶¹

7.16.1.3 Combination NRT therapy

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 shorter-acting form (e.g., lozenge) is more effective than NRT monotherapy and is safe.^{7, 44, 62-66} A 2013 Cochrane review found that, comparable with varenicline, combination NRT (e.g., patch plus inhaler) was the most effective available pharmacological intervention for achieving smoking cessation,⁶⁷ and a 2019 Cochrane review similarly concluded that using combination NRT versus single‐form NRT can increase the chances of successfully stopping smoking.⁴⁰ New Zealand research examining the effectiveness of combination NRT found that the addition of a nicotine mouth spray to a patch in a sample of smokers receiving a low level of behavioural support improved quit rates up to six months, although the effects were not sustained.⁶⁸ More recently, a randomised controlled trail found that inhaled nicotine from a metered dose inhaler combined with a nicotine patch substantially improved rates abstinence for 6 months.⁶⁹ Overall, researchers suggest that combination NRT likely represents the most promising cessation strategy moving forward.⁷⁰ Some have recommended that NRT labelling allow for combined use of faster-acting NRT medications with nicotine patch.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 types of products.^{7, 15}

7.16.1.4 Safety of NRT

In general, NRT is considered to be safe for most users. Discontinuation because of adverse reactions is relatively low.⁷ Using NRT to quit is always safer than continuing to smoke.⁷¹ 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.^{15, 72} 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.^{71, 73, 74} Further, research suggests that using acute delivery NRT products (i.e. the oral products) alongside smoking does not appear to increase average nicotine levels, although smoking while using the nicotine patch does.⁷³ Smoking while using NRT does not significantly increase the risk of a heart attack or other cardiovascular events.^{7, 71} 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.^{15, 73} Other potential symptoms of nicotine overdose include pallor, sweating, tachycardia, agitation, and a number of less common symptoms.⁴⁵

All NRT products have a low addictive potential.⁷⁵ Addictive potential is strongly influenced by speed and method of delivery of nicotine.^{71, 76} 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.⁷¹ In contrast, it can take more than 30 minutes to reach the peak blood nicotine level when using oral forms of NRT,^{41, 77-79} with effects of nicotine evident within 15–20 minutes.¹⁵ 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.⁷²

No serious side effects of either short or long-term NRT use have been reported over the 20 years it has been in use.⁴⁷ The most common side effects of the patch are skin rashes where it is applied and sleep disturbance. Common side effects for the oral products include irritation of the mouth or throat, headaches, hiccups, indigestion, nausea and coughing.^{7, 45, 72, 80, 81} These are relatively minor for most users, and NRT products are generally rated as safe compared to other medications.^{7, 47} Although such use is uncommon, extended duration NRT is safe, and is at least as effective as short courses.^{44, 82} After quitting, extended use of NRT appears to be beneficial for lapse recovery and relapse prevention in some smokers.⁴⁴

NRT can be used by smokers aged 12–17 years, and by pregnant or breastfeeding mothers to help them quit, preferably under their doctor’s supervision.^{71, 83} There is little risk associated with NRT use, except for pregnant women, for whom there may be a risk to the foetus, and people with acute cardiovascular disease.^{71, 83} NRT is safe to use as a cessation aid in people with stable heart conditions, including angina and previous heart attack.^{7, 71} 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.⁷¹

Many smokers believe that nicotine causes cancer, since it is equated with tobacco;^{71, 84} however, the US Surgeon General’s most recent report concluded that there is insufficient data to conclude that nicotine causes or contributes to cancer.⁸⁵ It appears to be the other carcinogens in tobacco smoke that are responsible for smoking-related cancers.^{86, 87}

7.16.1.5 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 (inhaler, 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.²¹ Pre-quit nicotine patch us appears to increase quit rates and may engage additional recalcitrant smokers compared with starting the patch on quit day.^{44, 73, 88, 89}

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.^90-92 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.^{93, 94} Evidence suggests that use of NRT to ‘cut down to quit’ is effective and cost effective compared to no quit attempt.⁹⁵

7.16.1.6 Scheduling and subsidy of NRT

In Australia, NRT is available in the forms of patches, gum, lozenges, mouth sprays, oral strips, and inhalers. The gum and lozenge come in 4 mg and 2 mg doses, while the inhaler and tablet come in the 2 mg dose only. There are also mini lozenges that come in strengths of 1.5mg and 4mg. Mouth sprays provide 150 doses per pump (1 mg per dose), 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 has dosages of 21 mg, 14 mg and 7 mg, and the 16-hour patch has dosages of 25mg, 15 mg, and 10 mg.⁹⁶ Nicotine chewing gum first became available on prescription in Australia in 1984, followed by the patch in 1993.⁹⁷ The 2 mg gum became available over-the-counter without prescription in pharmacies in 1988, and the 4 mg gum and patches in late 1997.⁹⁸ The nicotine inhaler, lozenges and sublingual tablets were introduced as over-the-counter products in 1999, 2002 and 2003 respectively.^78-80 In 2005, NRT products started to appear in supermarkets. Direct advertising to the public of NRT began in 1998, which markedly increased sales.⁹⁹

Subsidised nicotine patches have also been available since 1994 to patients eligible for repatriation benefits and to Indigenous patients since January 2009. Access to nicotine patches under the Pharmaceutical Benefits Scheme (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 discount is that the smoker participates in cessation counselling. If a patient is unsuccessful in quitting using nicotine patches, they are able to access other smoking cessation therapies on the Pharmaceutical Benefits Scheme (bupropion and varenicline) during that 12-month period.

As of December 2019, there were 11 nicotine replacement products available on the PBS and/or RBS, 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. It is sold under various brand names including Zyban SR®, Clorpax® and Bupropion-RL®. 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, which is also present in certain antidepressant medicines. The tablets are ‘sustained release’ bupropion and the drug is slowly released into the body.¹⁰⁰ It acts as an antagonist by blocking nicotine receptors in the brain and affecting the brain’s reward/pleasure system. It also relieves withdrawal symptoms and may reduce depressed mood,^100-103 and symptoms of depression.¹⁰⁴ Use of bupropion is associated with improved ability to resist cravings that result from ‘cues’ to smoke.¹⁰⁵ Bupropion appears to reduce the weight gain that occurs after quitting, but the effect does not last beyond treatment.¹⁰⁰

7.16.2.2 Efficacy of bupropion

A Cochrane review published in 2014 concluded that there is high quality evidence that bupropion increases the likelihood of long-term smoking cessation.¹⁰⁴ Bupropion increases the odds of quitting success by about 1.5 to 1.8 times, which is similar to that for NRT, but lower than when using varenicline.¹⁰⁴ It is comparably effective in different settings and with different levels of behavioural support, and in smokers with or without a history of depression.^{104, 106} There is some evidence that positive beliefs and attitudes about bupropion are associated with being positive about quitting, better compliance, and potentially better outcome.¹⁰⁷ 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.¹⁰⁸ 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.⁵⁰ People with certain genetic variants appear to have lower success rate with bupropion, highlighting the potential for genetic markers to guide individualised pharmacotherapy.¹⁰⁹

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 course per year is subsidised under the Pharmaceutical Benefits Scheme on condition that users participate in a comprehensive counselling program such as with the Quitline service or their GP. 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 are sleeping difficulties, dry mouth, headache, dizziness, anxiety and nausea.^{104, 110} A small number of allergic reactions to bupropion have been reported, including skin rashes or breathlessness, and, less frequently, fever, muscle and joint pain.¹¹⁰ ¹⁰⁰ 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.¹⁰⁰ The most serious side effect is a risk of seizure, estimated to occur in 1 in 1000 patients.¹⁰⁴ A recent 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.¹¹¹ Use of bupropion also does not appear to increase the risk of neuropsychiatric adverse events.¹¹²Bupropion 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 history of seizures or eating disorders, who are 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.^{113, 114}

7.16.2.5 Other antidepressants

A number of other antidepressants have been or are under investigation for smoking cessation, however most require larger studies to verify early results.^{2, 115}¹⁰⁴ A 2014 Cochrane review concluded that there is moderate quality evidence that the antidepressant nortriptyline increases quit rates, regardless of whether or not the user has a history of depression or depressive symptoms when they stop smoking. 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 inhibitor antidepressants (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.¹⁰⁴

None of these drugs are currently licensed for smoking cessation in Australia; however, nortriptyline is sometimes prescribed ‘off-label’ for people trying to quit.¹¹⁶

7.16.3 Varenicline

Varenicline (trade name Chantix® or Champix®) 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.¹¹⁷ 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.¹¹⁸

7.16.3.1 Mechanisms and pharmacokinetics of varenicline

Varenicline is a nicotinic receptor partial agonist (i.e., it binds to nicotine receptors), which maintains moderate levels of dopamine to counteract withdrawal symptoms, and reduces negative moods 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.^{117, 119-122} 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.¹²³ Some evidence suggests that varenicline improves cognitive performance among highly dependent smokers using the medication to quit.¹²⁴

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.¹²² 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.¹²⁵ 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.¹²⁶ Results from a randomised controlled trial found that varenicline appears to be a safe and well-tolerated treatment for hospitalised smokers who have smoking-related chronic disease.¹²⁷ 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.^128-141 It also appears to be equally effective for light and heavy smokers.¹⁴²

Varenicline has generally been shown to be superior to bupropion and NRT.^{101, 112, 136, 143-148} 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,¹⁴⁹ and the 2016 Cochrane review also concluded that varenicline was more effective than bupropion or NRT.¹²² 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.¹⁵⁰ 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.¹⁵¹ One meta-analysis similarly concluded that combination NRT and varenicline are equally effective for quitting.⁶⁷

Extended use of varenicline may also be effective.^152-154 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.¹⁵⁵ A 2019 Cochrane review similarly found that extended treatment with varenicline can help to prevent relapse.⁵⁰ 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.¹⁵⁶ Lower doses are also beneficial while lessening the incidence of adverse events.¹²² One study found that increasing varenicline dose in smokers with low response to the drug had no significant effect on tobacco withdrawal symptoms or smoking cessation.¹⁵⁷ Although some studies have shown compliance to be an issue,¹⁵⁸ varenicline appears to be effective in increasing cessation at 12 months even when compliance with the medication is not 100%.¹⁵⁹ Certain genotypes also appear to be associated with higher odds ratio for success in individuals on varenicline therapy.¹⁶⁰

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.¹⁶¹ 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, people with a mental illness or people allergic to varenicline tartrate.^{83, 117} The manufacturers’ list of illnesses for which medical advice may be needed includes having a mental illness or a history of mental illness, kidney problems, haemodialysis treatment, and repeated fits or convulsions.¹¹⁷ Caution is recommended when operating vehicles or heavy machinery.¹⁶²

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.⁵ 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.¹⁶³ Canadian research concluded that both standard and extended courses of varenicline are cost-effective treatment regimens compared with alternative smoking cessation interventions.¹⁶⁴

7.16.3.4 Adverse events associated with varenicline

Varenicline is well tolerated by most people who use it.^{117, 162, 165} The main side effect of varenicline is mild to moderate nausea, affecting about 3 out of 10 people.^{117, 122} 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.¹¹⁷ These side effects are usually mild to moderate and decrease over time.^{117, 122, 148, 165} Side effects usually occur in the first week of taking the medicine.¹¹⁷ There is some evidence of adverse gastrointestinal effects when varenicline is used at maintenance dose.¹⁶⁶ 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.¹⁶⁷

Varenicline may cause other, less common side effects.¹¹⁷ Serious side effects are rare and estimated to affect up to 1 in 1000 people (0.1%).¹⁴⁸ Very serious side effects that require urgent medical attention or hospitalisation may affect up to 1 in 10,000 people (0.01%).¹¹⁷ Safety warnings and revised labels have been issued in response to serious side effects from overdosing.¹¹⁷ 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.¹⁶⁸ A meta-analysis also found no increase in the risk of all cardiovascular disease events with bupropion or varenicline.¹⁶⁹ 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.¹⁷⁰

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.^{117, 122} 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.¹²² 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.¹⁷¹ Results of a large-scale randomised controlled trial similarly found that there was not a significant increase in neuropsychiatric adverse events attributable to varenicline.¹¹²

Nonetheless, the Therapeutic Goods Administration (TGA) issued an advisory in December 2015 for consumers and health professionals stating that the production information for varenicline (Champix) has been updated with new safety information. The production information now includes a warning that consuming alcohol may increase the risk of psychiatric symptoms, and aims to increase awareness that serious psychiatric symptoms have been reported in patients taking the drug.¹⁷²

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.^{2, 173} ^{174, 175} Despite promising preclinical trials,¹⁷⁶ clinical trials have not supported the efficacy of the products,^177-179 and none are yet approved cessation aids. Nonetheless, researchers have suggested that there is good reason for continued optimism,¹⁷⁹ and that next-generation immunotherapies are likely to be substantially more effective than first-generation vaccines.¹⁸⁰ For example, some studies have found that subjects with high anti-nicotine antibody levels demonstrate higher quit rates after receiving nicotine vaccines.^181-185 Therefore, vaccines that consistently generate higher antibody levels could be effective therapies.¹⁸⁰ Another study has identified which of two types of nicotine is the best to target when developing nicotine vaccines.¹⁸⁶

7.16.5 Combination treatments

7.16.5.1 Drug combinations

Combining approved medications is one approach to potentially improving cessation outcomes. Combination NRT is discussed in Section 7.16.1.2. The purpose of combining different forms of NRT is to increase nicotine levels and delivery to better match a smoker’s needs. NRT combinations appear to be more effective than single type use.⁷

Drugs with different mechanisms and pharmacokinetics may also be combined. Most of these combinations are yet to be approved but early trials have shown some promise.⁵⁶ Some studies have suggested that combination bupropion and NRT is more effective than either medication alone,⁵⁶ while others have not found any additional benefit of combining the products.¹⁸⁷ A systematic review and meta-analysis found that combination therapy of varenicline with NRT is better than varenicline alone.¹⁸⁸ A systematic review published in 2016 concluded that combination bupropion and varenicline appears to have greater efficacy in smoking cessation than varenicline alone.¹⁸⁹

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.¹⁹⁰ 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.¹⁹¹ 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.¹⁹² 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%.¹⁹³ A review of combination therapies found that varenicline combined with behavioural therapy appears to be more effective than other pharmacotherapies combined with behavioural therapy.⁶⁶

7.16.6 Other less commonly used pharmacotherapies

Cystine is a nicotine receptor partial agonist.¹⁹⁴ 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,¹⁹⁵ and another more recent review similarly concluded that cytisine is a low-cost medication that can increase the likelihood of smoking cessation.¹⁹⁶ 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.¹⁹⁷ One evaluation estimated that cytisine is both more clinically effective and cost-effective than varenicline.¹⁹⁸

The second-line medications clonidine and nortriptyline are frequently used for aiding cessation in some countries, but have not been approved for smoking cessation in most places.^{2, 56, 175, 199}

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.²⁰⁰

7.16.7 Other treatments under investigation

Many pharmaceutical companies and research institutions are investigating the potential for developing smoking cessation products that interfere with mechanisms involved in nicotine addiction.^{2, 18, 56, 175, 201} Drugs that target the cannabinoid receptor system have also been investigated. 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.^{15, 202} Early clinical trials suggested a benefit for long-term smoking cessation and reduction of weight gain, especially in overweight or obese individuals.²⁰³ However, increased psychiatric side effects appeared in clinical trials.² In October 2008 the manufacturer discontinued development of the drug.¹⁷⁵

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.²⁰⁴ However, a subsequent systematic review did not support its use for aiding cessation.²⁰⁵ 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.²⁰⁶ Initial research in mice suggests that combining the drug with NRT may have a beneficial role in treating nicotine dependence.^{207, 208} 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.^209-212 A pilot randomised controlled trial found that topiaramate, alone or in combination with NRT, resulted in a higher quit rate than placebo and decreased weight.²¹³ Although naltrexone has been used to successfully treat opioid and alcohol dependence,^{214, 215} 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.^{216, 217} 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.²¹⁸

New research focusing on pharmacogenetics is emerging, based on the discovery of genetic properties influencing the pharmacokinetics and pharmacodynamics of nicotine.⁵⁶ Genetic-based methods may be useful in predicting response to pharmacotherapy for sub-groups of smokers and assist the personalisation of treatments.^{48, 219-223} See Section 7.7.1.4 for a detailed discussion.

7.16.8 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.²²⁴ 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.²²⁵ 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.²²⁶

Since February 2011, Australian smokers have been able to access a 12-week supply of nicotine patches under the Pharmaceutical Benefits Scheme (PBS) as long as they have a medical prescription.²²⁷ 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).²²⁸ Similarly, Australian research has found that reported use of prescription medication to quit smoking rose sharply with the addition of varenicline to the PBS.²²⁹

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.^230-241 One US study also reported that the majority of recipients of their program were from disadvantaged groups.²⁴² 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.²⁴³ Another found that providing free NRT samples engaged both motivated and unmotivated smokers into the quitting process and produced positive changes in smoking outcomes.²⁴⁴

7.16.9 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.²⁴⁵ 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.²⁴⁵ A meta-analysis published in 2007 concluded that NRT trials with pharmaceutical industry funding tend to show higher success rates than those independently funded.²⁴⁶ 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.²⁴⁶ 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.²⁴⁷ 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.²⁴⁵ Such trials may receive more scientific attention than trials with unfavourable findings, resulting in an overestimation of effectiveness.⁵⁶

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.⁵⁶ 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.^{248, 249} 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.²¹ 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.^{190, 250}

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).²⁵¹ 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.²⁵²

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.⁵⁶ There is evidence that the majority of smokers using stop-smoking medications do not complete the recommended course of treatment.⁵⁴ 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.⁵⁴ Smokers may have unreasonable expectations of how effective stop-smoking medications are likely to be for them.⁵⁴ One trial showed that good adherence to varenicline was associated with a twofold increase in six-month quit rates compared with poor adherence.²⁵³ 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.²⁵⁴ 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.²⁵⁵

Smokers’ beliefs about a particular treatment may influence their choice of a particular medication as well as their medication experience.²⁵⁶ A perceived lack of need for cessation aids and beliefs that cessation aids do not help with cessation are consistently associated with medication nonadherence.²⁵⁷ One study found that positive medication expectancies in smokers may contribute to better treatment response, and the authors suggest that assessing treatment expectancies and attempting to maintain or improve them may be important for the delivery, evaluation, and targeting of smoking cessation treatments.²⁵⁸ 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. ²⁵⁹

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.²⁶⁰ 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.²⁶¹

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.²⁶² 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.²⁶³

Relevant news and research

For recent news items and research on this topic, click here.(Last updated May 2019)

References

1. Mills E, Wu P, Spurden D, Ebbert J, and Wilson K. Efficacy of pharmacotherapies for short-term smoking abstinance: A systematic review and meta-analysis. Harm Reduction Journal, 2009; 6:25. Available from: http://www.harmreductionjournal.com/content/6/1/25

2. Fant RV, Buchhalter AR, Buchman AC, and Henningfield JE. Pharmacotherapy for tobacco dependence. Handbook of Experimental Pharmacology, 2009; (192):487–510. Available from: http://www.springerlink.com/content/t3v711x3n7224242/

3. Wu P, Wilson K, Dimoulas P, and Mills EJ. Effectiveness of smoking cessation therapies: A systematic review and meta-analysis. BMC Public Health, 2006; 6:300. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17156479

4. Eisenberg M, Filion K, Yavin D, Belisle P, Mottillo S, et al. Pharmacotherapies for smoking cessation: A meta-analysis of randomized controlled trials. Canadian Medical Association Journal, 2008; 179(2):135–44. Available from: http://www.cmaj.ca/cgi/content/full/179/2/135

5. 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):222–3. Available from: http://www.mdpi.com/1660-4601/8/1/222/pdf

6. Narayanan S, Ebbert J, 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: http://www.ncbi.nlm.nih.gov/pubmed/19682663

7. 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: http://www.ncbi.nlm.nih.gov/pubmed/23152200

8. 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.

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

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

11. Australian Government Department of Health. Pharmaceutical benefits scheme – what are the current patient fees and charges? 2019. Available from: http://www.pbs.gov.au/info/about-the-pbs#What_are_the_current_patient_fees_and_charges.

12. 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: http://profiles.nlm.nih.gov/NN/B/B/Z/D/_/nnbbzd.pdf.

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

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

15. 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: http://www.ncbi.nlm.nih.gov/pubmed/16166074

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

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

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

19. 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.

20. Beaver J, Long C, Cole D, Durcan M, Bannon L, et al. The effects of nicotine replacement on cognitive brain activity during smoking withdrawal studied with simultaneous fmri/eeg. Neuropsychopharmacology, 2011; 36:1792–800. Available from: http://www.nature.com/npp/journal/vaop/ncurrent/full/npp201153a.html

21. 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

22. 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

23. Stanley T and Massey S. Evidence of nicotine replacement's effectiveness dissolves when meta-regression accommodates multiple sources of bias. Journal of Clinical Epidemiology, 2016. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27079846

24. Hughes JR, Fanshawe TR, and Stead LF. Is nicotine replacement really ineffective? A reply to stanley and massey. Journal of Clinical Epidemiology. Available from: http://www.sciencedirect.com/science/article/pii/S0895435616304413

25. Stanley TD. Yes, nicotine replacement therapy's effectiveness is much lower than often reported. Journal of Clinical Epidemiology. Available from: http://www.sciencedirect.com/science/article/pii/S0895435616304425

26. Green G. Nicotine replacement therapy for smoking cessation. American Family Physician, 2015; 92(1):Online. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26132134

27. Etter JF. Nicotine replacement therapy for long-term smoking cessation. Tobacco Control, 2006; 15:280–5. Available from: http://tobaccocontrol.bmj.com/cgi/content/abstract/15/4/280

28. 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

29. 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.

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

31. 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

32. Hughes J, 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: http://tobaccocontrol.bmj.com/cgi/content/abstract/12/1/21

33. 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

34. Schnoll R, Patterson F, Wileyto E, Heitjan D, Shields A, et al. Effectiveness of extended-duration transdermal nicotine therapy: A randomized trial. Annals of Internal Medicine, 2010; 152(3):144–51. Available from: http://www.annals.org/content/152/3/144.long

35. 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: http://www.sciencedirect.com/science/journal/01492918

36. 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. Wisconsin Medical Journal, 2008; 107(5):237–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18777992

37. 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

38. Perkins K, Briski J, Fonte C, Scott J, and Lerman C. Severity of tobacco abstinence symptoms varies by time of day. Nicotine & Tobacco Research, 2009; 11(1):84–91. Available from: http://ntr.oxfordjournals.org/cgi/content/full/11/1/84

39. 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: http://www.ncbi.nlm.nih.gov/pubmed/24688036

40. 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). Available from: https://doi.org//10.1002/14651858.CD013308

41. 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: http://www.ncbi.nlm.nih.gov/pubmed/12038945

42. Strong DR, David SP, Johnstone EC, Aveyard P, Murphy MF, et al. Differential efficacy of nicotine replacement among overweight and obese women smokers. Nicotine & Tobacco Research, 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25481918

43. Scherphof CS, van den Eijnden RJ, Engels RC, and Vollebergh WA. Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug and Alcohol Dependence, 2014; 140:217–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24811201

44. 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 & Tobacco Research, 2014; 16(7):909–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24919399

45. 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.

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

47. 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: http://www.ncbi.nlm.nih.gov/pubmed/17207524

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

49. 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: http://www.ncbi.nlm.nih.gov/pubmed/25740789

50. 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). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003999.pub6/full

51. Zapawa L, Hughes J, Benowitz N, Rigotti N, 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: http://www.ncbi.nlm.nih.gov/pubmed/21220188

52. 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, 2014; 40C:33–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25218069

53. 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: http://www.ncbi.nlm.nih.gov/pubmed/21859499

54. 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 & Tobacco Research, 2011; 13(2):94–102. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21147894

55. 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

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

57. 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 & Tobacco Research, 2008; 10(8):1405–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18686189

58. Weiss S and Smith-Simone S. 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: http://www.ajpm-online.net/article/PIIS0749379709008617/fulltext

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

60. 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

61. 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

62. 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: http://dx.doi.org/10.1002/hup.947

63. Piper M, Smith S, Schlam T, Fiore M, Jorenby D, et al. A randomized placebo-controlled clinical trial of 5 smoking cessation pharmacotherapies. Archives of General Psychiatry, 2009; 66(11):1253–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19884613

64. 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: http://ebm.bmj.com/content/15/3/77.long

65. Prochazka A. 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: http://www.annals.org/content/152/10/JC5-2.long

66. 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. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27617367

67. 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:Cd009329. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23728690

68. Caldwell BO, Adamson SJ, and Crane J. Combination rapid-acting nicotine mouth spray and nicotine patch therapy in smoking cessation. Nicotine & Tobacco Research, 2014; 16(10):1356–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24872027

69. Caldwell BO and Crane J. Combination nicotine metered dose inhaler and nicotine patch for smoking cessation: A randomized controlled trial. Nicotine & Tobacco Research, 2016. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27185903

70. 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: http://www.ncbi.nlm.nih.gov/pubmed/23572407

71. 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

72. Fant RV, Owen L, and Henningfield JE. Nicotine replacement therapy. Primary Care: Clinics in Office Practice, 1999; 26(3):633–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10436291

73. 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

74. 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 & Tobacco Research, 2009; 11(1):99–105. Available from: http://ntr.oxfordjournals.org/cgi/content/full/ntn020v1

75. Etter J. Addiction to the nicotine gum in never smokers. BMC Public Health, 2007; 7(147):159. Available from: http://www.biomedcentral.com/content/pdf/1471-2458-7-159.pdf

76. Perkins KA. Nicotine self-administration. Nicotine & Tobacco Research, 1999; 1(suppl. 2):S133–S7; discussion S9–S40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11768171

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

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

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

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

81. Mills E, Wu P, Lockhart I, Wilson K, and Ebbert J. 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. Tobacco Induced Diseases, 2010; 8(1):8. Available from: http://www.tobaccoinduceddiseases.com/content/pdf/1617-9625-8-8.pdf

82. 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: http://www.ncbi.nlm.nih.gov/pubmed/20653619

83. 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.

84. 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 & Tobacco Research, 2004; 6 (suppl. 3):S303–S10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15799593

85. U.S. 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.

86. 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

87. 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

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

89. 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

90. Dalack GW and Meador-Woodruff JH. Acute feasibility and safety of a smoking reduction strategy for smokers with schizophrenia. Nicotine & Tobacco Research, 1999; 1(1):53–7. Available from: http://ntr.oxfordjournals.org/content/1/1/53.abstract

91. Bolliger C, Zellweger J, 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 (Clinical Research Ed.), 2000; 321(7257):329–33. Available from: http://www.bmj.com/cgi/content/full/321/7257/329

92. Fagerström 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: http://tobaccocontrol.bmj.com/content/6/4/311.abstract

93. 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. British Medical Journal, 2009; 338:b1024. Available from: http://www.bmj.com/cgi/content/full/338/apr02_3/b1024?view=long&pmid=19342408

94. Etter J 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: http://www.ncbi.nlm.nih.gov/pubmed/17414237

95. 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

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

97. 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.

98. 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.

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

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

101. 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: http://www.expertopin.com/doi/abs/10.1517/14656566.9.1.15

102. Kotlyar M, Drone D, Thuras P, Hatsukami D, Brauer L, et al. Effect of stress and bupropion on craving, withdrawal symptoms, and mood in smokers. Nicotine & Tobacco Research, 2011; [Epub ahead of print]. Available from: http://ntr.oxfordjournals.org/content/early/2011/03/03/ntr.ntr011.full

103. Paterson N. Behavioural and pharmacological mechanisms of bupropion's anti-smoking effects: Recent preclinical and clinical insights. European Journal of Pharmacology, 2008; 603(1–3 ): 1–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19101536

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

105. Culbertson C, Bramen J, Cohen M, London E, Olmstead R, 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: http://www.ncbi.nlm.nih.gov/pubmed/21199957

106. Rovina N, Nikoloutsou I, Katsani G, Dima E, Fransis K, et al. Effectiveness of pharmacotherapy and behavioral interventions for smoking cessation in actual clinical practice. Therapeutic Advances in Respiratory Disease, 2009; 3(6):279–87. Available from: http://tar.sagepub.com/cgi/reprint/3/6/279

107. Fucito L, Toll B, Salovey P, and O'Malley S. Beliefs and attitudes about bupropion: Implications for medication adherence and smoking cessation treatment. Psychology of Addictive Behaviors, 2009; 23(2):373–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19586156

108. Hawk Jr LW, Ashare RL, Rhodes JD, Oliver JA, Cummings KM, et al. Does extended pre-quit bupropion aid in extinguishing smoking behavior? Nicotine & Tobacco Research, 2015. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25589680

109. 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: http://www.ncbi.nlm.nih.gov/pubmed/26153084

110. 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

111. 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. Clin Cardiol, 2017. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28605035

112. 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. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27116918

113. 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

114. Roddy E. Bupropion and other non-nicotine pharmacotherapies. British Medical Journal, 2004; 328(7438):509–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14988194

115. Kahn R, Gorgon L, Jones K, McSherry F, Glover E, et al. Selegiline transdermal system (sts) as an aid for smoking cessation. Nicotine & Tobacco Research, 2012; 14(3):377–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21846661

116. McDonough M. Update on medicines for smoking cessation. Australian Prescriber, 2015; 38(4):106–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26648633

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

118. Williams J, Steinberg M, Steinberg M, Gandhi K, Ulpe R, et al. Varenicline for tobacco dependence: Panacea or plight? Expert Opinion on Pharmacotherapy, 2011; 12(11):1799–812. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21644843

119. Brandon T, Drobes D, Unrod M, Heckman B, Oliver J, et al. Varenicline effects on craving, cue reactivity, and smoking reward. Psychopharmacology, 2011; 218(2):391–403. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21559801

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

121. Franklin T, Wang Z, Suh J, 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: http://www.ncbi.nlm.nih.gov/pubmed/21199958

122. 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:CD006103. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27158893

123. 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. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25742873

124. Loughead J, Ray R, Wileyto E, 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: http://www.ncbi.nlm.nih.gov/pubmed/20207347

125. 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: http://www.ncbi.nlm.nih.gov/pubmed/26829065

126. 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. Journal of the American Medical Association, 2015; 313(7):687–94. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25688780

127. Carson KV, Smith BJ, Brinn MP, Peters MJ, Fitridge R, et al. Safety of varenicline tartrate and counseling versus counseling alone for smoking cessation: A randomized controlled trial for inpatients (stop study). Nicotine & Tobacco Research, 2014; 16(11):1495–502. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25031315

128. Gonzales D, Rennard S, 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. Journal of the American Medical Association, 2006; 296(1):47–55. Available from: http://jama.ama-assn.org/cgi/content/full/296/1/47

129. 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

130. 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: http://www.ncbi.nlm.nih.gov/pubmed/19715382

131. Bae J, Kim C, and Lee E. Evaluation of cost-utility of varenicline compared with existing smoking cessation therapies in South Korea. Value Health, 2009; 12 Suppl 3:S70–3. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1524-4733.2009.00631.x/full

132. Bolin K, Mork A, 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: http://www.ncbi.nlm.nih.gov/pubmed/19536915

133. 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: http://www.ncbi.nlm.nih.gov/pubmed/19354344

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

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

136. Fagerström K and Hughes J. Varenicline in the treatment of tobacco dependence. Neuropsychiatric Disease and Treatment, 2008; 4(2):353–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18728741

137. Fagerstrom K, Nakamura M, Cho H, Tsai S, 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: http://informahealthcare.com/doi/abs/10.1185/03007995.2010.505130

138. Ebbert J, Croghan I, North F, and Schroeder D. A pilot study to assess smokeless tobacco use reduction with varenicline. Nicotine & Tobacco Research, 2010; 12(10):1037–40. Available from: http://ntr.oxfordjournals.org/content/12/10/1037.long

139. Ebbert J, Montori V, Erwin P, and Stead L. Interventions for smokeless tobacco use cessation. Cochrane Database of Systematic Reviews, 2011; 2:CD004306. Available from: http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD004306/pdf_fs.html

140. Bolliger C, Issa J, 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: http://www.ncbi.nlm.nih.gov/pubmed/21635992

141. 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: http://www.ncbi.nlm.nih.gov/pubmed/21294601

142. Ebbert JO, Croghan IT, Hurt RT, Schroeder DR, and Hays JT. Varenicline for smoking cessation in light smokers. Nicotine & Tobacco Research, 2016. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27117285

143. Jorenby D, Hays J, Rigotti N, Azoulay S, Watsky E, 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. Journal of the American Medical Association, 2006; 296(1):56–63. Available from: http://jama.ama-assn.org/cgi/content/full/296/1/56

144. Potts L and Garwood C. Varenicline: The newest agent for smoking cessation. American Journal of Health System Pharmacy, 2007; 64(13):1381–4. Available from: http://www.ajhp.org/cgi/content/abstract/64/13/1381

145. 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

146. 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: http://www.atypon-link.com/doi/abs/10.5555/ajhb.2008.32.6.664

147. 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):9–13. Available from: http://www.hta.ac.uk/erg/supplements/supplement1302.pdf#nameddest=article02

148. 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: http://www.ncbi.nlm.nih.gov/pubmed/19236119

149. 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: http://www.ncbi.nlm.nih.gov/pubmed/25392075

150. 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. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25727442

151. Baker TB, Piper ME, Stein JH, and et al. Effects of nicotine patch vs varenicline vs combination nicotine replacement therapy on smoking cessation at 26 weeks: A randomized clinical trial. Journal of the American Medical Association, 2016; 315(4):371-9. Available from: http://dx.doi.org/10.1001/jama.2015.19284

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

153. Keating G and Lyseng-Williamson K. Varenicline: A pharmacoeconomic review of its use as an aid to smoking cessation. PharmacoEconomics, 2010; 28(3):231–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20108995

154. 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: http://www.ncbi.nlm.nih.gov/pubmed/27099479

155. Hajek P, Tønnesen 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: http://www.ncbi.nlm.nih.gov/pubmed/19686530

156. 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: http://www.ncbi.nlm.nih.gov/pubmed/24911368

157. 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 Internal Medicine, 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25545858

158. Jung J, Jeon E, Kim J, Yang S, Choi J, et al. Clinical experience of varenicline for smoking cessation. The Clinical Respiratory Journal, 2010; 4(4):215–21. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1752-699X.2009.00178.x/full

159. Grassi M, Enea D, Ferketich A, 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: http://www.ncbi.nlm.nih.gov/pubmed/21349681

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

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

162. Garrison G and Dugan S. Varenicline: A first-line treatment option for smoking cessation. Clinical Therapeutics, 2009; 31(3):463–91. Available from: http://www.clinicaltherapeutics.com/articles/0463_gar.pdf

163. 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, 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25331778

164. 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: http://www.ncbi.nlm.nih.gov/pubmed/24472120

165. Galanti L. Tobacco smoking cessation management: Integrating varenicline in current practice. Vascular Health and Risk Management, 2008; 4(4):837–45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19066000

166. 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: http://www.ncbi.nlm.nih.gov/pubmed/21955317

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

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

169. 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: http://www.ncbi.nlm.nih.gov/pubmed/24323793

170. 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: http://www.ncbi.nlm.nih.gov/pubmed/25410148

171. 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. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27043328

172. Therapeutic Goods Administration, Varenicline (champix): Safety advisory – risks of psychiatric symptoms and potential interaction with alcohol. Australian Government; 2015. Available from: https://www.tga.gov.au/alert/varenicline-champix.

173. Hatsukami D, Jorenby D, Gonzales D, Rigotti N, Glover E, et al. Immunogenicity and smoking-cessation outcomes for a novel nicotine immunotherapeutic. Clinical Pharmacology and Therapeutics, 2011; 89(3):392–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21270788

174. Cerny E and Cerny T. Vaccines against nicotine. Human Vaccines, 2009; 5(4):6–11. Available from: http://www.landesbioscience.com/journals/vaccines/article/7310

175. Casella G, Caponnetto P, and Polosa R. Therapeutic advances in the treatment of nicotine addiction: Present and future. Therapeutic Advances in Chronic Disease, 2010; 1(3):95–106. Available from: http://taj.sagepub.com/content/1/3/95.full.pdf+html

176. Escobar-Chavez J, Dominguez-Delgado C, and Rodriguez-Cruz I. Targeting nicotine addiction: The possibility of a therapeutic vaccine. Drug Design, Development and Therapy, 2011; 5:211–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21607018

177. 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: http://www.ncbi.nlm.nih.gov/pubmed/24894701

178. Tonstad S, Heggen E, Giljam H, Lagerbäck P-Å, Tønnesen P, et al. Niccine®, a nicotine vaccine, for relapse prevention: A phase ii, randomized, placebo-controlled, multicenter clinical trial. Nicotine & Tobacco Research, 2013; 15(9):1492–501. Available from: http://ntr.oxfordjournals.org/content/15/9/1492.abstract

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

180. Pentel PR and LeSage MG. New directions in nicotine vaccine design and use. Advances in Pharmacology, 2014; 69:553–80. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047682/

181. 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: http://www.ncbi.nlm.nih.gov/pubmed/16321612

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

183. 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: http://www.informapharmascience.com/doi/abs/10.1517/13543784.17.5.691

184. Cornuz J, Zwahlen S, Jungi W, 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: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002547

185. 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.

186. Lockner JW, Lively JM, Collins KC, Vendruscolo JCM, 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: http://dx.doi.org/10.1021/jm501625j

187. Stapleton J, West R, Hajek P, Wheeler J, Vangeli E, et al. Randomized trial of nicotine replacement therapy (NRT), bupropion and NRT plus bupropion for smoking cessation: Effectiveness in clinical practice. Addiction, 2013; 108(12):2193–201. Available from: http://dx.doi.org/10.1111/add.12304

188. Chang P-H, Chiang C-H, Ho W-C, Wu P-Z, Tsai J-S, 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):1–8. Available from: http://dx.doi.org/10.1186/s12889-015-2055-0

189. Vogeler T, McClain C, and K EE. Combination bupropion sr and varenicline for smoking cessation: A systematic review. American Journal of Drug and Alcohol Abuse, 2016:1–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26809272

190. 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: http://www.ncbi.nlm.nih.gov/pubmed/24372901

191. 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 US preventive services task force. Annals of Internal Medicine, 2015. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26389650

192. 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: http://www.ncbi.nlm.nih.gov/pubmed/27009521

193. 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

194. Etter J-F, Lukas RJ, Benowitz NL, West R, and Dresler CM. Cytisine for smoking cessation: A research agenda Drug and Alcohol Dependence, 2007; 92(1–3):3–8. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0376-8716(07)00274-8

195. 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: http://www.ncbi.nlm.nih.gov/pubmed/23404838

196. 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. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31240783

197. 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: http://www.ncbi.nlm.nih.gov/pubmed/25517706

198. 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: http://www.ncbi.nlm.nih.gov/pubmed/24831822

199. 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

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

201. Rose J. Disrupting nicotine reinforcement. Annals of the New York Academy of Sciences, 2008; 1141:233–56. Available from: http://www.nyas.org/annals/detail.asp?annalID=940

202. Siu E and Tyndale R. Non-nicotinic therapies for smoking cessation. Annual Review of Pharmacology and Toxicology, 2007; 47:541–64. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17209799

203. 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

204. Schmaal L, Berk L, Hulstijn K, Cousijn J, Wiers R, 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: http://www.ncbi.nlm.nih.gov/pubmed/21606648

205. Asevedo E, Mendes AC, Berk M, and Brietzke E. Systematic review of n-acetylcysteine in the treatment of addictions. Rev Bras Psiquiatr, 2014; 36(2):168–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24676047

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

207. Bagdas D, Muldoon PP, Zhu AZX, 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: http://www.sciencedirect.com/science/article/pii/S0028390814001737

208. Alsharari SD, Siu ECK, Tyndale RF, and Damaj MI. Pharmacokinetic and pharmacodynamics studies of nicotine after oral administration in mice: Effects of methoxsalen, a cyp2a5/6 inhibitor. Nicotine & Tobacco Research, 2014; 16(1):18–25. Available from: http://ntr.oxfordjournals.org/content/16/1/18.abstract

209. 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: http://www.ncbi.nlm.nih.gov/pubmed/16432681

210. 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

211. Arbaizar B, Gómez-Acebo I, and Llorca J. Decrease in tobacco consumption after treatment with topiramate and aripiprazole: A case report. Journal of Medical Case Reports, 2008; 2:198. Available from: http://www.jmedicalcasereports.com/content/pdf/1752-1947-2-198.pdf

212. Khazaal Y and Zullino D. 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. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19512990

213. Oncken C, Arias AJ, Feinn R, Litt M, Covault J, et al. Topiramate for smoking cessation: A randomized, placebo-controlled pilot study. Nicotine & Tobacco Research, 2014; 16(3):288–96. Available from: http://ntr.oxfordjournals.org/content/16/3/288.abstract

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

215. 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

216. 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: http://www.ncbi.nlm.nih.gov/pubmed/24633528

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

218. 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/

219. Drgon T, Johnson C, Walther D, Albino A, Rose J, 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: http://www.ncbi.nlm.nih.gov/pubmed/19593411

220. 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 & Tobacco Research, 2011; 13(3):157–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21330274

221. Sturgess J, George T, Kennedy J, Heinz A, and Muller D. Pharmacogenetics of alcohol, nicotine and drug addiction treatments. Addiction Biology, 2011; 16(3):357–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21362114

222. 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 & Tobacco Research, 2017. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28472521

223. Salloum NC, Buchalter EL, Chanani S, Espejo G, Ismail MS, et al. From genes to treatments: A systematic review of the pharmacogenetics in smoking cessation. Pharmacogenomics, 2018. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29914292

224. 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, 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24842854

225. 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: http://www.ncbi.nlm.nih.gov/pubmed/24885542

226. Reda A, Kotz D, Evers S, and Van Schayck CP. Healthcare financing systems for increasing the use of tobacco dependence treatment. Cochrane Database of Systematic Reviews, 2012. Available from: http://onlinelibrary.wiley.com/enhanced/doi/10.1002/14651858.CD004305.pub4

227. 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.

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

229. Cooper J, Borland R, and Yong H-H. 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: http://dx.doi.org/10.1111/j.1753-6405.2011.00733.x

230. 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: http://tobaccocontrol.bmj.com/cgi/content/abstract/15/4/286

231. Grigg M and Glasgow H. Subsidised nicotine replacement therapy. Tobacco Control, 2003; 12:238–9. Available from: http://tobaccocontrol.bmj.com/cgi/content/full/12/2/238-a

232. 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):i42–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18048631

233. 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: http://www.ncbi.nlm.nih.gov/pubmed/17897996

234. 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):i53−i9. Available from: http://tobaccocontrol.bmj.com/cgi/content/abstract/16/Suppl_1/i53

235. 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 & Practice, 2006; 12(1):37–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16340514

236. 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: http://www.ncbi.nlm.nih.gov/pubmed/16829336

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

238. 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 Behaviours, 2004; 29(9):1763–78. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15530720

239. 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.

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

241. 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 randomised controlled trial. Addiction, 2011; 106(6):1176–85. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21371155

242. 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: http://www.ncbi.nlm.nih.gov/pubmed/15924980

243. 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: http://www.ncbi.nlm.nih.gov/pubmed/20690396

244. 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 & Tobacco Research, 2014; 16(7):992–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24610399

245. 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: http://www.ncbi.nlm.nih.gov/pubmed/23235689

246. Etter J, 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: http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2007.01822.x/full

247. Greene N, Taylor E, Gage S, and Munafo M. 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. Available from: http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03155.x/full

248. Moberg CA and Humphreys K. Exclusion criteria in treatment research on alcohol, tobacco and illicit drug use disorders: A review and critical analysis. Drug Alcohol Rev, 2016. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27324921

249. 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

250. 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: http://www.ncbi.nlm.nih.gov/pubmed/25282429

251. 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 & Tobacco Research, 2019. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31271211

252. Benowitz NL, Bernert JT, Foulds J, Hecht SS, Jacob P, et al. Biochemical verification of tobacco use and abstinence: 2019 update. Nicotine & Tobacco Research, 2019. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31570931

253. Catz S, Jack L, McClure J, Javitz H, Deprey M, et al. Adherence to varenicline in the compass smoking cessation intervention trial. Nicotine & Tobacco Research, 2011; 13(5):361–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21350041

254. 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:CD009164. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25914910

255. 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

256. Schlagintweit HE, Perry RN, Darredeau C, and Barrett SP. Non-pharmacological considerations in human research of nicotine and tobacco effects: A review. Nicotine & Tobacco Research, 2019. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31058286

257. Pacek LR, McClernon FJ, and Bosworth HB. Adherence to pharmacological smoking cessation interventions: A literature review and synthesis of correlates and barriers. Nicotine & Tobacco Research, 2017. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29059394

258. Fucito LM, Toll BA, Roos CR, and King AC. Smokers’ treatment expectancies predict smoking cessation success. Journal of Smoking Cessation, 2014; FirstView:1–7. Available from: http://dx.doi.org/10.1017/jsc.2014.17

259. 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910821/

260. 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

261. 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483860/

262. Richter KP and Ellerbeck EF. It's time to change the default for tobacco treatment. Addiction, 2014. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25323093

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