A randomized trial of nicotine replacement therapy in combination with reduced-nicotine cigarettes for smoking cessation

A randomized double-blind, active controlled, parallel group, multi-center phase II clinical trial was conducted to evaluate the efficacy of reduced-nicotine cigarettes as a novel smoking cessation treatment (under Investigational Device Exemption 69,185). The concept for a reduced-nicotine cigarette designed to progressively wean smokers from the smoking habit is based on research demonstrating that successful smoking cessation is not only dependent on withdrawal of nicotine, but also on weaning from the habitual sensory and behavioral reinforcement of smoking. Treatment consisted of Quest brand of cigarettes (Quest 1, 2, and 3), which respectively deliver 0.59+/-0.06, 0.3+/-0.05, and less than 0.05 mg nicotine, either alone or in combination with nicotine replacement therapy (NRT). The primary endpoint was 4 weeks of continuous abstinence (Weeks 7-10), with additional follow-up at 3 and 6 months. Adult men and women smokers (N = 346), motivated to quit, were randomized to one of three treatment groups: Quest plus NRT (NRT pretreatment 2 weeks before, and NRT after the quit date), Quest plus placebo patch, or active control plus NRT (conventional cigarette, followed by NRT after quit date). Results showed that Quest plus NRT was more effective than active control plus NRT in achieving 4 weeks of continuous abstinence (32.8% vs. 21.9%). Quest plus placebo patch yielded an abstinence rate similar to that of the active control plus NRT (16.4% vs. 21.9%). No serious adverse events were attributable to the investigational product. Quest plus NRT offers promise as a new smoking cessation treatment.     

Bupropion and cognitive-behavioral treatment for depression in smoking cessation.

This study is a randomized, double-blind, placebo-controlled clinical trial examining the effects of an intensive cognitive-behavioral mood management treatment (CBTD) and of bupropion, both singularly and in combination, on smoking cessation in adult smokers. As an extension of our previous work, we planned to examine the synergistic effects of CBTD and bupropion on smoking cessation outcomes in general and among smokers with depression vulnerability factors. Participants were 524 smokers (47.5% female, M (age) = 44.27 years) who were randomized to one of four 12-week treatments: (a) standard, cognitive-behavioral smoking cessation treatment (ST) plus bupropion (BUP), (b) ST plus placebo (PLAC), (c) standard cessation treatment combined with cognitive-behavioral treatment for depression (CBTD) plus BUP, and (d) CBTD plus PLAC. Follow-up assessments were conducted 2, 6, and 12 months after treatment, and self-reported abstinence was verified biochemically. Consistent with previous studies, bupropion, in comparison with placebo, resulted in better smoking outcomes in both intensive group treatments. Adding CBTD to standard intensive group treatment did not result in improved smoking cessation outcomes. In addition, neither CBTD nor bupropion, either alone or in combination, was differentially effective for smokers with single-past-episode major depressive disorder (MDD), recurrent MDD, or elevated depressive symptoms. However, findings with regard to recurrent MDD and elevated depressive symptoms should be interpreted with caution given the low rate of recurrent MDD and the low level of depressive symptoms in our sample. An a priori test of treatment effects in smokers with these depression vulnerability factors is warranted in future clinical trials.     

Use of nicotine replacement therapy in socioeconomically deprived young smokers: a community-based pilot randomised controlled trial

Background

Smoking is common in young people, particularly in disadvantaged groups, and continued smoking has a major impact on quality and quantity of life. Although many young smokers want to stop smoking, little is known about the design and effectiveness of cessation services for them.

Objective

To determine whether nicotine replacement therapy (NRT) when combined with counselling is effective in young smokers in a deprived area of Nottingham, UK

Methods and subjects

We surveyed smoking prevalence and attitudes to smoking and quitting in young people accessing an open access youth project in a deprived area of Nottingham, and used the information gained to design a community based smoking cessation service incorporating a randomised controlled trial of nicotine patches against placebo given in association with individual behavioural support. We resurveyed smoking prevalence among project attendees after completing the pilot study.

Results

Of 264 young people surveyed (median age 14 years, range 11–21), 49% were regular smokers. A total of 98 young people were recruited and randomised to receive either active nicotine patches on a six week reducing dose regimen (49 participants), or placebo (49 participants). Adherence to therapy was low, the median duration being one week, and 63 participants did not attend any follow up. At four weeks, five subjects receiving active NRT and two receiving placebo were abstinent, and at 13 weeks none were. Adverse effects were more common in the active group but none were serious. Smoking prevalence among 246 youth project attendees surveyed after the trial was 44%.

Conclusions

This study suggests that NRT in this context is unlikely to be effective in young smokers, not least because of low adherence to therapy. It also suggests that young smokers want help with smoking cessation, but that establishing the efficacy of smoking cessation services for young people who need them most will be very difficult.     

Nortriptyline for smoking cessation: a review.

This article reviews the efficacy of nortriptyline for smoking cessation based on a meta-analysis of the Cochrane Library. Six placebo-controlled trials have shown nortriptyline (75-100 mg) doubles quit rates (OR = 2.1). Between 4% and 12% of smokers dropped out because of adverse events, but no serious adverse events occurred. The efficacy of nortriptyline did not appear to be related to its antidepressant actions. Nortriptyline is an efficacious aid to smoking cessation with a magnitude of effect similar to that for bupropion and nicotine replacement therapies. Whether nortriptyline produces serious side effects at these doses in healthy, nondepressed smokers remains unclear because it has been tested in only 500 smokers. The finding that nortriptyline and bupropion are effective for smoking cessation but that selective serotonin-reuptake inhibitors are not suggests that dopaminergic or adrenergic, but not serotonergic, activity is important for cessation efficacy. Until further studies can verify a low incidence of significant adverse events, nortriptyline should be a second-line treatment for smoking cessation.     

Designing smoking cessation services for school-age smokers: A survey and qualitative study.

To identify the preferred design characteristics of smoking cessation services for school-age smokers, we conducted focus groups with teenage smokers motivated to stop smoking. We surveyed all pupils in years 9-11 (aged 13-16) in a random sample of 10 schools in Nottinghamshire, United Kingdom, to elicit details of smoking behavior, and conducted 25 focus groups in 6 schools with current smokers who wanted to stop smoking. Of 4,065 pupils surveyed, 888 (22%) were current smokers, and 438 (50% of smokers) wanted to quit smoking. We sampled 226 of these individuals for focus group studies, and 135 (60%) participated. These participants were motivated to quit, and almost all had tried to do so but had found it too difficult. Many were aware of smoking cessation methods but had low perceptions of their effectiveness based on their own or others' poor experiences of these interventions, and few were aware of the possibility of professional cessation support. Given clear, nondirective information about interventions, participants reported a preference for confidential, nonjudgmental services delivered during school time by a trained counselor, allowed the option to attend with friends, and offered nicotine replacement therapy (NRT). School-age smokers in Nottinghamshire, United Kingdom, who are motivated to stop smoking have low knowledge and opinions of smoking cessation interventions. Our findings indicate that young smokers would favor school-based services offering confidential professional counseling and NRT.     

The impact of smoking cessation on objective and subjective markers of sleep: review, synthesis, and recommendations.

Sleep disturbance is commonly reported as a prominent subjective symptom by quitting smokers. However, little research on this issue has used objective measures of sleep quality. Previous research has relied mainly on retrospective report of sleep disturbance, with few studies investigating sleep during the initial period after quitting tobacco use. Studies that have used objective measurements suggest that sleep fragmentation is a common occurrence during the withdrawal period. In sleep medicine, sleep disturbance is viewed as a consequence of frequent arousals and is now considered to have particularly deleterious daytime consequences, including sleepiness and dysphoric mood. Recent work also indicates that such awakenings affect the cardiovascular system by providing repetitive bursts of sympathetic nervous system activation, possibly contributing to elevated levels of cardiovascular and cerebrovascular morbidity. Pharmacological treatments designed to facilitate smoking cessation are ineffective for sustained abstinence in many smokers, which may be related to sleep disturbance. Indeed, preliminary evidence suggests that the administration of nicotine replacement therapy (NRT) or bupropion can result in disrupted sleep, particularly in women. However, to better understand the role that nicotine withdrawal and bupropion or NRT treatment, independently and in combination, might play in sleep disturbance, it is necessary to develop a better understanding of the nature of the sleep disturbance than can be provided by self-report. This is particularly important for the development of treatment approaches targeted to ameliorate sleep disruption as part of an overall smoking cessation strategy. The present review seeks to report the current state of knowledge based on extant findings and argues for the need to conduct more detailed polysomnographic investigations of the potentially vicious cycle of smoking cessation leading to sleep disturbances that may prove iatrogenic to sustained cessation.     

A randomized, open-label pilot comparison of gabapentin and bupropion SR for smoking cessation.

This 6-week, randomized, open-label pilot study estimated the treatment effect size of gabapentin (n = 17) compared with bupropion SR (n = 19) for smoking cessation, thereby allowing sample size calculations for a definitive comparison study. The primary outcome measure was smoking cessation. Secondary outcome measures included smoking reduction and withdrawal severity. Gabapentin was less efficacious than bupropion for smoking cessation but was associated with fewer dropouts from adverse effects. Withdrawal severity was less with bupropion. Bupropion remains the first-line non-nicotine pharmacotherapy for smoking cessation. Further study is required to determine if gabapentin has any useful role in smoking cessation. Based on our primary outcome measure, 79 subjects would be required in each treatment group of a two-armed study to achieve 90% power for detecting a difference in efficacy between gabapentin and bupropion.     

Costs and benefits of smoking cessation aids: making a case for public reimbursement of nicotine replacement therapy in Australia

Background

Tobacco smoking is the leading preventable cause of morbidity and mortality in Australia and other developed countries. Of the pharmacological aids that are available for smoking cessation, bupropion (Zyban SR) is eligible for public reimbursement on the Australian Pharmaceutical Benefits Scheme (PBS), whereas nicotine replacement therapy (NRT) is not. Information on the cost‐effectiveness and financial impact of public reimbursement of these strategies can better inform debate about their inclusion or exclusion in public reimbursement schemes.

Objective

To estimate the cost‐effectiveness of bupropion and NRT, and the potential financial impact of public reimbursement of NRT in Australia.

Design

A cost‐effectiveness analysis using a deterministic Markov model, and cost per disability‐adjusted life year (DALY) averted over a lifetime as the outcome measure.

Population

Current smokers, motivated to quit, in Australia in 2000.

Interventions

(1) NRT; (2) bupropion; and (3) a combined strategy using bupropion as the first‐line treatment and NRT in those who fail to quit smoking or have adverse reactions to bupropion.

Results

Quitting smoking can increase life expectancy of current smokers by 1–7.6 years depending on age at cessation and sex. Providing bupropion to current smokers who are motivated to quit would cost A$7900 (95% uncertainty interval A$6000 to A$10 500) for each DALY averted; NRT patches would cost A$17 000 (A$9000 to A$28 000) for each DALY averted, with similar results even if used as a second‐line treatment following initial failure to quit using bupropion. If 6% of current smokers were to use NRT following inclusion on the PBS, this would result in an annual cost of A$40–110 million to the PBS depending on the listed price.

Conclusions

Compared with other drugs included on the PBS, bupropion and NRT are both highly cost‐effective smoking cessation interventions, and including NRT on the PBS would have a moderate financial impact. Given the sizeable health burden of smoking, and the large individual benefits of quitting smoking, increasing the availability of alternative aids and uptake of these strategies through public reimbursement would be a positive and rational step towards further reducing tobacco‐related disease burden in Australia and other countries where NRT is currently not subsidised.Tobacco smoking is the largest preventable cause of morbidity and mortality in Australia and other developed countries. Despite projected declines in tobacco‐related diseases in line with decreasing prevalence, tobacco is still expected to be among the leading causes of disease burden in 2016.¹ Worldwide, it is the second highest cause of death and fourth highest cause of disease burden.Effective policies to control tobacco use are crucial. Although preventing individuals from starting smoking is an important aim of tobacco control, cessation in current smokers is also critical. As nicotine is highly addictive, smokers often require assistance to maintain abstinence. Modestly effective cessation aids are available, including pharmacological agents, such as bupropion (Zyban SR) and nicotine replacement therapy (NRT).^2,3Australia has implemented many strong tobacco control policies. The retail price of tobacco in Australia is among the top three worldwide.⁴ Advertising and promoting tobacco products has been totally banned, pictorial pack warnings have recently been implemented, opportunities to smoke cigarettes in public places are severely limited and there is legislation in place forcing an upcoming ban of smoking in bars and hotels.^5,6,7 Despite these measures, nearly one in five Australian adults still smoke daily, indicating the need for further strategies to encourage cessation.⁸In 1995, the Australian government rejected a recommendation by the Pharmaceutical Benefits Advisory Committee to include NRT on the public reimbursement scheme—the Pharmaceutical Benefits Scheme (PBS).⁹ By contrast, bupropion was made available on the PBS in February 2001.¹⁰ The continued exclusion of NRT and inclusion of bupropion may or may not be a rational decision. Valid and comparable information on the cost‐effectiveness and financial implications of including these interventions on the PBS are important inputs into this debate.The cost‐effectiveness of both NRT and bupropion has been studied previously.² A lack of consistency in the methods of these studies, however, makes comparisons difficult, and the context‐specific nature of inputs into cost‐effectiveness analyses such as disease outcomes means that these results may not be applicable to the Australian setting.^2,11 This study aims to evaluate the cost‐effectiveness of NRT and bupropion in the Australian context, as well as the potential financial impact of including NRT on the PBS.     

Interest in gradual cessation.

Prior surveys have not determined smokers' interest in gradual cessation. In Study 1A, we advertised in six U.S. east coast newspapers for "smokers who plan to quit smoking" to participate in a nontreatment study. Among the 461 respondents, 66% planned to reduce and then stop smoking, 13% planned to stop abruptly, and 21% reported they planned to reduce but not quit. In Study 1B, we ran a similar ad but asked for "smokers who plan to reduce their smoking." Among the 263 respondents, 57% planned to reduce and then stop smoking and 33% planned to reduce but not stop smoking. In Study 2, we asked 125 smokers to rate their interest in quitting smoking (on a 1-10 scale) given two scenarios. When nicotine replacement therapy (NRT) was not mentioned, interest in gradual cessation was high and was higher than interest in abrupt cessation (6.9 and 4.7, respectively, p<.0001). When NRT was assumed to be available for gradual or abrupt cessation, interest in gradual cessation remained high (7.1) and was similar to that for abrupt cessation (7.0). In both scenarios, over three-fourths of smokers were at least as interested in gradual cessation as they were in abrupt cessation.     

Smoking cessation pharmacotherapy preferences in rural primary care.

Pharmacotherapy is a critical adjunct to smoking cessation therapy. Little is known about relative preferences for these agents among smokers in primary care settings. In the context of a population-based clinical trial, we identified 750 smokers in primary care practices and independent of their readiness to quit offered them a free treatment course of either bupropion or transdermal nicotine replacement (TNR). Smokers opting for pharmacotherapy completed standardized contraindication screens that were reviewed by the patient's primary care physician. Most participants (67%) requested pharmacotherapy. Use of pharmacotherapy was positively associated with higher nicotine dependence and readiness to quit. Of the smokers requesting pharmacotherapy, 51% requested bupropion and 49% requested TNR. Choice of bupropion was related to no history of heart disease and no previous use of bupropion. Although potential contraindications to treatments were identified for 21.7% of bupropion and 6.6% of TNR recipients, physicians rarely felt that these potential contraindications precluded the use of these agents. When cost is removed as a barrier, a large proportion of rural smokers are eager to use smoking cessation pharmacotherapy, especially agents that they have not tried before. Although some comorbid conditions and concurrent drug therapies were considered contraindications, particularly to bupropion, physicians rarely considered these clinically significant risks enough to deny pharmacotherapy.     

Variations in treatment benefits influence smoking cessation: results of a randomised controlled trial

OBJECTIVE: To assess the impact and costs of coverage for tobacco dependence treatment benefits with no patient cost sharing for smokers with employer sponsored coverage in two large independent practice association (IPA) model health maintenance organisations (HMOs) in California, USA. METHODS: A randomised experimental design was used. 1204 eligible smokers were randomly assigned either to the control group, which received a self-help kit (video and pamphlet), or to the treatment group, which received the self-help kit and fully covered benefits for over the counter (OTC) nicotine replacement therapy (NRT) gum and patch, and participation in a group behavioural cessation programme with no patient cost sharing. RESULTS: The quit rates after one year of follow up were 18% in the treatment group and 13% in the control group (adjusted odd ratio (OR) 1.6, 95% confidence interval (CI) 1.1 to 2.4), controlling for health plan, sociodemographics, baseline smoking characteristics, and use of bupropion. Rates of quit attempts (adjusted OR 1.4, 95% CI 1.1 to 1.8) and use of nicotine gum or patch (adjusted OR 2.3, 95% CI 1.6 to 3.2) were also higher in the treatment group. The annual cost of the benefit per user who quit ranged from $1495 to $965 or from $0.73 to $0.47 per HMO member per month. CONCLUSIONS: Full coverage of a tobacco dependence treatment benefit implemented in two IPA model HMOs in California has been shown to be an effective and relatively low cost strategy for significantly increasing quit rates, quit attempts, and use of nicotine gum and patch in adult smokers.     

Attitudes and knowledge about nicotine and nicotine replacement therapy.

Nicotine replacement therapies (NRTs) represent an effective means of promoting smoking cessation, but they remain underutilized. Negative attitudes and false beliefs about nicotine and nicotine replacement may cause NRT underutilization. In a randomized, controlled, single-blind study of nicotine gum, 97 smokers were assessed on their attitudes and knowledge about nicotine, nicotine replacement, and smoking cessation therapy. Information from these self-report measures was used in an intervention that provided tailored, brief feedback to promote positive attitudes and accurate knowledge about NRT. Considerable variability in pretreatment attitudes and knowledge was observed across individuals. Moreover, attitudes and knowledge showed a consistent pattern of intercorrelation and were systematically related to smoking characteristics (e.g., prior use of NRT, nicotine dependence, treatment completion). The brief feedback intervention led to a significant global elevation in attitudes about nicotine, NRT, and assisted cessation but not knowledge about nicotine. Changes in attitudes and knowledge were not significantly related to gum use or smoking cessation. Recommendations for the appropriate application of brief feedback are offered.     

The relationship between smoking cessation and mouth ulcers.

Patients who stop smoking often complain of aphthous (mouth) ulcers. This symptom is sometimes attributed to the use of smoking cessation medications, but little is known about it. We investigated the incidence, severity, and time course of mouth ulcers in abstaining smokers and the effect of different smoking cessation medications on the symptom. The sample consisted of 1234 smokers who sought treatment at a large smoking cessation clinic, maintained at least 1 week of continuous biochemically validated abstinence, and provided usable data. Participants assessed their mouth ulcers by rating a mouth ulcer item added to the Mood and Physical Symptoms Scale. Subjects made ratings weekly on three occasions while still smoking and over 4 weeks following smoking cessation. After stopping smoking, some 40% of patients developed mouth ulcers, mostly in the first 2 weeks. The problem was generally mild, but 8% reported severe ulceration. The ulcers resolved within 4 weeks in 60% of patients affected. The ulcer ratings in patients using oral nicotine replacement products were higher than in those using patch, nasal spray or bupropion in the first week of abstinence but not afterward. Mouth ulcers were more prevalent in more dependent smokers, and the occurrence of ulcers correlated with other tobacco withdrawal symptoms. Our results confirm that mouth ulcers are a common result of stopping smoking, affecting two in five quitters. Patients should be reassured that the lesions are a result of stopping smoking and not a side-effect of smoking cessation medication.     

The influence of depressive symptoms on smoking cessation among African Americans in a randomized trial of bupropion.

The influence of depressive symptoms on smoking cessation was examined among 600 African American smokers who participated in a randomized, placebo-controlled trial of sustained-release bupropion hydrochloride. Depressive symptoms were assessed at baseline, at week 6 (end of treatment), and at 6-month follow-up. The study examined three separate questions: (a) Whether depressive symptom levels were related to smoking cessation, (b) whether bupropion was more effective for smokers who had higher depressive symptoms at baseline (i.e., a moderator model), and (c) whether changes in depressive symptoms would account for the efficacy of bupropion for smoking cessation (i.e., a mediator model). Depressive symptoms at baseline were not predictive of cessation; however, increases in depressive symptoms from baseline predicted reduced cessation at the end of treatment, and higher depressive symptoms at week 6 and month 6 were associated with a reduced likelihood of smoking cessation at those time points. The moderator model was not supported, but the mediation analyses indicated that alleviation of depressive symptoms partly accounted for bupropion-assisted smoking cessation at end of treatment. Results extend prior findings to African American smokers and suggest that clinicians consider increases in depressive symptoms after quitting rather than baseline depressive symptoms in predicting risk of treatment failure. Results also suggest that even though bupropion may facilitate cessation in part by reducing depressive symptoms, it appears to be no more effective for more depressed smokers, and that mechanisms other than depressive symptom alleviation account for most of its efficacy.     

Characteristics of selectors of nicotine replacement therapy

Objective: To assess differences in demographic and smoking characteristics between smokers who have and have not used nicotine replacement therapy (NRT). Design: Mail survey of US smokers from a national research panel. Participants: Smokers 18 years and over who returned a survey on smoking (n = 9630). The sample was weighted to match the US smoker population on age and sex. Main outcome measures: Compared smokers who had/had not used NRT in a quit attempt (ever NRT use or over the counter (OTC) NRT use) on: demographic characteristics, nicotine dependence, history of craving and withdrawal, expected difficulty quitting, and self reported history of smoking related medical illness and psychopathology. Results: NRT users (both ever-users and OTC users) were more likely to be older, male, and better educated. They were also heavier smokers, had experienced more craving and withdrawal upon quitting, and scored higher on measures of dependence. These differences were evident among light smokers, and remained even when smoking rate and time to first cigarette were controlled. Conclusion: Smokers who elect to use NRT differ from non-NRT users in ways that predispose them to failure in cessation. Controlling for smoking rate and time to first cigarette does not eliminate these differences, even among light smokers. These differences must be considered when comparing the effectiveness of NRT among samples of smokers who self select their treatment and are likely to bias such outcome comparisons.     

Smokers' interest in using nicotine replacement to aid smoking reduction.

In recent years the public health community has considered the risks and benefits of encouraging smokers to reduce their smoking, perhaps with the aid of nicotine replacement therapy (NRT). Little is known, however, about whether smokers themselves are interested in smoking reduction; whether they see reduction as an endpoint, or primarily as a route to cessation; or whether they are receptive to the notion of using NRT to achieve reduction. We conducted a population-based national telephone survey of 1,000 current daily cigarette smokers (499 male, 501 female). Most smokers (57%) reported previously trying to reduce their smoking, and many (26%) said that they plan to reduce within the next year. Almost half of those planning to quit in the next 12 months (44%) preferred to quit via gradual cessation and most (68%) indicated that they would consider using a reduction product or medication. Respondents reported that they would prefer a product with a cessation endpoint rather than a reduction endpoint (63% vs. 21%). Interest in reduction was highest among smokers who were less interested in quitting and among heavier smokers. We conclude that many smokers are interested in gradually reducing prior to quitting and that promoting reduction is unlikely to undermine motivation to quit smoking.