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Tuesday, June 25, 2019

Treatment of nicotine dependence


By: Andrea H. Weinberger, Pamela Walters, Taryn M. Allen, Melissa M. Dudas, Kristi A. Sacco and Tony P. George

Nicotine dependence is found in at least a billion people worldwide and in millions in the United States and Great Britain. It is a major cause of morbidity and mortality in all countries, and both active smoking and exposure to passive smoke has significant health care consequences.

There currently are public health campaigns in both the UK and USA to combat smoking, and laws against smoking in public places are just one, if not one of the most visible, of the various public and community campaigns against smoking. While these campaigns are effective, most smokers wishing to quit will utilize pharmacological treatments which involve primarily nicotine replacement therapy (NRT) or the use of bupropion. Both have substantial evidence as to effectiveness, though there are other secondary pharmacological treatments that also are beginning to find some support such as vareniciline, clonidine and nortriptyline. The NRTs come in various forms from patches to nasal sprays to gum, inhalers, and lozenges. All have substantial support for their effectiveness. Cognitive-behavioural therapies, especially multimodal interventions that are tailored to the specific patient, have a good deal of success and support for that success as well. Despite these effective interventions, smoking remains a major public health problem.

Introduction

Cigarette smoking is the single largest preventable cause of substantial morbidity and mortality in developed countries. In the United States, approximately 23% of the general population reports cigarette smoking, which is the most common (> 98%) method of tobacco use (Center for Disease Control (CDC), 2002; Giovino, 2002). Approximately 430 000 people in the USA die each year as a result of smoking-attributable medical illnesses such as lung cancer, chronic obstructive pulmonary disease, cardiovascular disease and stroke (Giovino, 2002). It is estimated that 29% of adults in the United Kingdom smoke (Lader & Meltzer, 2000). This equates to approximately 16 million British smokers. Worldwide, it is estimated that approximately 1.1 billion people use tobacco on a regular basis (CDC, 2002).


In the UK, the proportions of men and women who currently smoke are similar. Over the past 5 years the overall proportion of smokers in the UK population has stabilized, although in some groups, such as adolescents, there has been an increase. It is thought around 25% of 15-year-olds are regular smokers (NICE, 2002; Lader & Meltzer, 2000). As a result of the implementation of tobacco control policies in the USA (e.g. tobacco excise taxes, advertising health dangers), the prevalence of cigarette smoking was reduced from 45% in the 1960s to about 22.9% in 2002 (CDC, 2002). However, it appears that many of these remaining smokers have more difficulty quitting smoking, and today’s smoker has often failed multiple quit attempts despite using behavioural therapies combined with pharmacological interventions such as nicotine replacement therapies (NRTs) and sustained-release bupropion. In fact, quit rates with NRTs over the past 15 years in controlled clinical trials appear to be declining (Irvin et al., 2003). The remaining population of smokers has characteristics associated with smoking persistence and quit attempt failures such as lower education attainment, less interest in behavioural treatments to assist with cessation, and medical, substance abuse and psychiatric co-morbidities (Hughes, 1996b). In addition, women are smoking at higher rates than in the past, may have more intense nicotine withdrawal and depressed mood during quit attempts than men (Gritz et al., 1996), and may be less responsive to quitting with NRTs (Perkins et al., 1999).

Smokers who have failed initial quit attempts generally embrace pharmacotherapies, and given that a large proportion of remaining smokers do not respond to conventional pharmacotherapies, the development of novel and more effective medication treatment for smoking cessation is critical in our efforts to treat nicotine dependence.

Recent advances in our understanding of nicotine’s effects on central neurotransmitter systems are guiding basic and clinical pharmacologists to develop medications for new pharmacological targets to treat nicotine dependence.

The hazards of smoking are important and well established. Smokers have a larger number of chronic respiratory diseases and have a substantially higher risk of cancers and cardiovascular disease. They are twice as likely as nonsmokers to suffer from fatal ischemic heart disease and four times as likely to suffer a fatal aortic aneurysm (Parrott et al., 1998). The National Institute for Clinical Excellence (NICE) has estimated that treatment for smoking related disease cost the National Health Service (UK) around £1.5 billion (Edwards, 2004).

Nicotine addiction is closely linked to socio-economic disadvantage. Smoking prevalence is higher and nicotine use heavier amongst poorer smokers. The socio-economic gradient in smoking behaviour accounts for about two-thirds of the excess premature mortality associated with deprivation.

Smoking is now increasing rapidly throughout the developing world, and it is estimated that current cigarette smoking will cause about 450 million deaths worldwide in the next 50 years. Reducing current smoking by 50% would prevent 20–30 million premature deaths in the first quarter of this century and 150 million in the second quarter (Doll et al., 1994). For most smokers, quitting is the single most important thing they can do to improve their health.

Clinical features of nicotine dependence

Most tobacco users (> 98%) are smokers of cigarettes, and while there are a subset of cigarette smokers who do not smoke every day, most cigarette smokers are daily users and have some degree of physiological dependence on nicotine (Rigotti, 2002). Determination of nicotine dependence is typically accomplished clinically by historical documentation of daily smoking (typically 10–40 cigarettes per day) for several weeks, evidence of tolerance (e.g. lack of aversive effects of nicotine such as nausea and excessive stimulation) and the presence of symptoms of nicotine withdrawal upon smoking cessation. These withdrawal symptoms include dysphoria, anxiety, irritability, decreased heart rate, insomnia (waking in the middle of the night), increased appetite and craving for cigarettes (American Psychiatric Association, 2006). In addition, most dependent smokers state that they smoke their first cigarette of the day within thirty minutes of awakening. Scales such as the Fagerstrom Test for Nicotine Dependence (FTND) allow assessment of the evel of nicotine dependence with scores of 4 on a scale of 0–10 consistent with physiological dependence to nicotine. These scales have been empirically validated (Heatherton et al., 1991).


Interestingly, the positive effects of cigarette smoking (e.g. taste, satisfaction) appear to be mediated by non-nicotine components of tobacco such as tar (Dallery et al., 2003). Besides positive reinforcement, withdrawal and craving, there are several secondary effects of nicotine and tobacco use that may contribute to both maintenance of smoking and to smoking relapse including mood modulation (e.g. reduction of negative affect), stress reduction, and weight control. In addition, conditioned cues can elicit the urge to smoke even after prolonged periods of abstinence. Specific effects might be most relevant to individuals high on dietary restraint (weight reduction), and psychiatric disorders (mood modulation, stress reduction). These secondary effects may present additional targets for pharmacological intervention in certain subgroups of smokers (e.g. schizophrenic, depressed, or overweight smokers).

National guidelines

There are clinical practice guidelines available in both the USA and UK. The US Public Health Service published the monograph Treating Tobacco Use and Dependence in 2000 (Fiore et al., 2000), and the American Psychiatric Association recently updated its Practice Guidelines for the treatment of nicotine dependence (APA, 2006). In the UK, a series of guidelines and key documents were published in the late nineties. The paper ‘Smoking kills’ (DOH 98) outlined the government’s plan of action to stop people from smoking. This plan included proposals for abolishing tobacco advertising and promotion. It also looked at ways of altering public attitudes, preventing tobacco smuggling and supporting further research into this important area of public health. Partnerships with other agencies such as businesses were pivotal in order to start the restriction of smoking in public places.


The Royal College of Physicians published smoking cessation guidelines in 1998 which were updated in 2000 (West et al., 2000). Expert committees such as the Cochrane Tobacco Addiction review group were set up to operate in much the same manner as its American equivalent, The Agency for Health Care Policy Research.

As a direct result of the change in priority given to the management of smoking, smoking cessation services were launched in a variety of health action zones throughout England and Wales in 1999–2000. In the 3 years up to and including 2001–2002, £53 million was made available for these services with further substantial amounts earmarked for the years 2003–2006, £41 million, £46 million and £51 million, respectively. Quarterly reports are fed back to the government by these services so that progress towards specified targets can be audited. The government’s guidance on management of smoking cessation is implemented through The National Institute for Health and Clinical Excellence (NICE). This organization is part of The National Health Service (NHS) and its role is to provide guidance for both the NHS and patients on medicines, medical equipment, and diagnostic tests. It was specifically asked to review the available evidence on nicotine replacement therapy (NRT) and bupropion and provide guidance that would inform the NHS about effective evidence-based treatments for smoking cessation.

Before we proceed to examine the treatments for smoking, a quick glance at these official guidelines suggests the manner and context in which, in the UK, smoking cessation treatment should take place. Nicotine replacement therapy or bupropion should normally only be prescribed as part of an abstinent contingent treatment (ACT) programme in which the smoker makes a commitment to stop smoking. Smokers should be offered advice and encouragement to aid their attempt to quit. Ideally, initial prescription of NRT or bupropion should be sufficient to last only until 2 weeks after the target stop date. Normally, this will be after 2 weeks of NRT and 3–4 weeks for bupropion to allow for the different methods of administration and mode of action. Second prescriptions should be given only to people who have demonstrated that their quit attempt is continuing on reassessment. If a smoker’s attempt to quit is unsuccessful with treatment using either NRT or bupropion, the NHS should normally fund no further attempts within 6 months. It is thought that there is insufficient evidence to recommend a combination of bupropion and NRT.

It is recommended that smokers who are under the age of 18 years, who are pregnant or breastfeeding, or who have unstable cardiovascular disorders should consult a health care professional before either treatment is prescribed. Bupropion is not recommended for smokers under the age of 18 years as its safety and efficacy have not been evaluated for this group. Women who are pregnant or breastfeeding should not use bupropion.

Conclusions

It is important to identify smoking in health care settings, particularly populations that are high risk for smoking (e.g. individuals with psychiatric and addictive disorders). Identifying and urging people to stop smoking and making sure they are aware of the medical consequences of smoking is important. Many smokers are able to quit with minimal therapeutic interventions. Simple advice to give up smoking is one of the most cost effective interventions we can make in medicine, and yet this is not part of routine health care delivery in many settings both in the US and the UK. Initial attempts to assist individuals with smoking cessation should utilize stepped-care approaches, reserving more intensive behavioural therapies and pharmacological interventions for treatment-resistant smokers. More intensive therapies may be needed for smokers who have had multiple failed quit attempts and smokers with co-morbid psychiatric, alcohol or drug, or medical disorders.


There are a number of empirically validated pharmacotherapies for the treatment of nicotine dependence in the USA, including five NRT formulations, varenicline and sustained-release bupropion, as well as a number of non-approved pharmacotherapies which appear promising. Nicotine replacement therapy may be the most cost effective, and it is the treatment that has the largest data base supporting its effectiveness. Bupropion is currently the best non-nicotine treatment, although in a single head-to-head trial, varenicline was superior to bupropion and to placebo. Intensive behavioral support from a trained counsellor is the most effective non-drug treatment for smokers, and it appears equally effective in both an individual and a group setting. Given that 80% of adult smokers start as teenagers, we should target this age group in order to have a significant impact on smoking cessation. Little real research has taken place with this group.

The issue of passive smoking has received less attention in the UK than in the US in the past, though the recent ban on smoking in pubs and other public places reveals that this issue is taking hold in the UK. Efforts need to continue to be made to make government and business leaders aware of the impact of active as well as passive smoking on morbidity and mortality.

In ever increasing pharmacologic dependent societies, additional research on medications that target neurotransmitter systems involved in nicotine dependence (e.g. selective GABA and DA receptor agonists) may be important for treatment-resistant smokers. If people thought that a simple pill with minimal side effects could help them avoid the discomfort of withdrawal that accompanies smoking cessation, then perhaps greater progress could be made on this important public health issue.

References

Peter Tyrer and Kenneth R. Silk, Cambridge Textbook of Effective Treatments in Psychiatry, Cambridge University Press 2008.

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