Relevant BNF section: 4.10
Cigarette smoking remains the commonest cause of preventable mortality in the UK, accounting for about 120, 000 deaths each year among people aged 35 years or more.1 In all, smoking-related disease costs a typical health authority around £15 million a year.2 It is notoriously difficult to stop smoking but success rates are increased if cigarettes are replaced by nicotine given as a medicine. When reviewing nicotine replacement in 1993, we recommended a "combined approach, using nicotine patches plus advice and support".3 Since then, other forms of nicotine replacement have become available. Here we discuss current evidence on the efficacy and safety of different forms of nicotine replacement and consider the place of such therapy.
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Relevant BNF section: 4.10
In the UK, 29% of adults smoke cigarettes,4 of whom more than two-thirds want to stop and about one-third intend to give up within the year.5 The chance that an unaided effort to give up smoking (a quit attempt) will succeed has been estimated at less than 3%,6 with failure being primarily due to dependence on nicotine.7 Family and wider socio-economic factors can also influence who gives up smoking.8
Approaches in nicotine replacement
To use nicotine replacement, smokers are advised to set a date and time for stopping smoking and, from that point onwards, to use the replacement product instead of cigarettes, generally for up to 3 months.
Five types of nicotine replacement are available in the UK: chewing gum, transdermal patches, an inhalator, a sublingual tablet and a nasal spray.
Three brands of gum are marketed: Boots (2mg and 4mg strengths); Nicorette (2mg and 4mg); and Nicotinell (2mg and 4mg). Nicotine is released from such gum over about 30 minutes of intermittent chewing and is mainly absorbed into the blood through the buccal mucosa. Smokers are recommended to start with 8-12 pieces of 2mg gum daily. The maximum dose is 15 pieces of 4mg gum daily. All of these products are available 'over the counter' from pharmacies. The 2mg gum is now on the General Sale List and the manufacturers say that it will soon be available through general stores.
There are four brands of nicotine patch: Boots (5mg, 10mg and 15mg strengths); Nicorette (5mg, 10mg and 15mg); Nicotinell (7mg, 14mg and 21mg); and NiQuitin CQ (7mg, 14mg and 21mg). The Boots and Nicorette patches are designed to be applied for 16 hours, while the Nicotinell and NiQuitin CQ patches are designed to be applied for 24 hours but can be removed after 16 hours, if desired. All of these patches are available over the counter from pharmacies.
Nicorette nasal spray is the only such formulation available. It consists of 10mg/mL nicotine solution in a small bottle with a mechanical spray device. A single spray into one nostril delivers 0.5mg of nicotine, which is rapidly absorbed mostly through the lining of the nose. Peak plasma concentrations of nicotine are reached after about 10-15 minutes. The manufacturer recommends one spray in each nostril, as required, up to a maximum of twice hourly for 16 hours in every 24. The nasal spray is a 'prescription-only medicine'.
There are two brands of inhalator, Nicorette and Boots. Each consists of a mouthpiece and a replaceable nicotine cartridge. Through sucking on the inhalator, nicotine vapour is drawn into the mouth, where it is absorbed through the buccal mucosa. Little or no nicotine reaches the lungs. The maximal dose of nicotine is achieved after about 20 minutes of intense use. Each cartridge provides up to three 20-minute sessions of use. The manufacturer advises using 6-12 cartridges daily for the first 8 weeks and then reducing use to zero over the next 4 weeks. These inhalators can be bought over the counter from pharmacies.
Nicorette sublingual tablet ('Microtab') is the most recent formulation of nicotine replacement. When held under the tongue and allowed to dissolve over about 30 minutes, the tablet releases 2mg of nicotine, 1mg of which is then absorbed through the buccal mucosa. The manufacturer advises using 1-2 tablets hourly, depending on usual cigarette consumption, up to a maximum of 40 tablets daily. These tablets can be bought over the counter from pharmacies.
Most nicotine replacement products are on the Selected List and cannot be prescribed on an FP10 NHS prescription. The Nicorette Inhalator, Microtab and the NiQuitin CQ patches are not currently on this list.
Extra manufacturer-derived support
Manufacturers of nicotine replacement products offer various forms of adjunctive non-pharmacological support to encourage smoking cessation. With the Nicotinell products comes an offer of information and advice via the Internet, and also a freephone counselling service via the charity QUIT. The Nicorette products come with access to two free telephone helplines (one offering pre-recorded information, the other staffed by trained counsellors) and a free 'stop-smoking' programme and audiotape. Interestingly, the practical value of free telephone support is questionable, given evidence that less than 1% of people offered such support actually use it.9 Buyers of NiQuitin CQ products are offered a support programme. These smokers make a free telephone call, during which they answer questions about their smoking habit. This information is then used to prepare a personalised behavioural support programme, which is posted to them at various stages during the quit attempt.
In clinical trials, the effectiveness of nicotine replacement as an aid to smoking cessation has conventionally been gauged by the proportion of smokers who maintain total abstinence from cigarettes for 1 year starting from 2 weeks after the target quit date. Abstinence has usually been assessed by self-reporting and confirmed at all follow-up points using an objective biochemical marker, such as salivary cotinine levels or the amount of carbon monoxide in expired air.
Overall efficacy of nicotine replacement
Numerous randomised controlled trials of nicotine replacement have been conducted in a variety of settings such as smoking-cessation clinics, community self-help and primary care. A systematic review of 81 such trials suggests that, whatever the setting, nicotine replacement products (gum, patches, sprays and inhalers) all increase smokers' cessation rates to 18% when compared with the control groups (11% with placebo or nothing).10 All the trials included some form of additional support. Where such support was of 'high intensity' (i.e. more than 30 minutes spent at initial consultation or more than two reinforcement visits), the absolute probability of not smoking at 6-12 months was greater than with 'low-intensity' support (as in routine care). There was no evidence of any difference in the effectiveness of the four forms of nicotine replacement therapy tested. In addition, 8 weeks of patch therapy was as effective in facilitating cessation as were longer courses and there was no evidence that tapering patch therapy was better than abrupt withdrawal. Applying a patch only in the daytime (for 16 hours) was as effective as using it for 24 hours.
Nicotine replacement reduces, but does not usually eliminate, the withdrawal symptoms experienced when stopping smoking (e.g. urge to smoke, anxiety, irritability, increased appetite, weight gain and difficulty in concentrating).11
There are very few data on direct comparisons of the different forms of nicotine replacement with each other or in different types of smoker. However, there is evidence suggesting that nicotine nasal spray is more effective in high-dependence smokers (i.e. those typically smoking 20 or more cigarettes daily) than low-dependence smokers,12 and that 4mg gum is more effective than 2mg gum in high-dependence smokers.10 In addition, high-dose (25mg) nicotine patches appear more effective than standard-dose (15mg) patches in facilitating long-term smoking cessation.13 However, 25mg patches are not currently available in the UK. No published trial has directly compared different brands of a given form of nicotine replacement.
Efficacy of combinations of nicotine replacement
The summaries of product characteristics (SPCs) for nicotine replacement products advise smokers not to combine different forms of replacement. However, some randomised studies suggest that certain combinations may almost double a smoker's chance of remaining abstinent for at least a year.14 Adding nicotine gum to patch treatment improves 3-month abstinence rates by around 11% but this improvement may not be sustained at 1-year follow-up.15,16 Combining patches with nasal spray improves short- and long-term abstinence rates compared to patches plus placebo spray, doubling the rate seen at 6 years.17 There is some evidence to suggest that using a combination of gum and patch leads to fewer withdrawal symptoms in the first 3 weeks after quitting than patch or gum therapy alone.18 Presumably combination usage may offer a particularly effective plasma concentration profile. Both the wanted and unwanted effects of this need investigation.
Safety and unwanted effects
Most smoking-related diseases, including cancers and heart disease, are caused not by nicotine but by other harmful components of the smoke.19 Nicotine replacement products do not appear to increase the risk of heart disease nor exacerbate known cardiac problems such as angina or arrhythmias.19–21 Nicotine can, however, cause dizziness, nausea, headaches and palpitations in people who have not become tolerant to it, and there have been reports that the 24-hour patches can lead to vivid dreams and sleep disturbance. The various nicotine replacement formulations differ primarily in terms of the irritation they produce at the site of application. Patches can cause skin reddening and irritation. In the short term, gum can irritate the throat. The nasal spray may irritate the nose and throat and make the eyes water. The most common local unwanted effects with the inhalator are cough and irritation of the throat, and the sublingual tablet can cause mild irritation in the mouth and throat that declines with use.
Nicotine replacement is not generally recommended for use in pregnant or breast-feeding women. The manufacturers recommend that nicotine replacement products should be used with caution in people with a history of peptic ulcer, recent myocardial infarction or stroke, serious cardiac arrhythmias, systemic hypertension, peripheral vascular disease, renal or hepatic impairment, diabetes mellitus, hyperthyroidism or phaeochromocytoma.
Potential for dependence
Many smokers worry that they will transfer their dependence from cigarettes to nicotine replacement therapy, and there is some evidence suggesting that this might occur. Around 13-38% of those who succeed in stopping with the aid of nicotine gum continue to use it for 1 year.22 However, results from a 1-year follow-up study of 538 clients who were treated with 2mg nicotine gum suggest that, for many, the continued use of gum is essential for the success of their attempt to stop smoking.23 Abrupt cessation of nicotine gum can produce withdrawal symptoms, the incidence and prevalence of which are not known.19 There are also reports of long-term use of nicotine nasal spray, but existing studies do not suggest long-term use of patches is a problem; long-term use of the inhalator or Microtab has not been studied.19 Whether any other forms of nicotine replacement apart from the gum induce withdrawal is not known.19
Most smokers will repeatedly make quit attempts without professional help.24 Brief advice from a GP can encourage more smokers to try to stop, thereby increasing overall cessation rates.25 However, there is no evidence that the limited advice and support routinely available from GPs improves the chances of success of any given quit attempt. Smokers who attend specialist smokers' clinics improve their chance of successfully quitting; about 20% of smokers who attempt to stop will remain abstinent at 1 year if helped by a clinic plus nicotine replacement bought from a pharmacy (vs. 6% with replacement from a pharmacy alone).2
The Department of Health recognises that nicotine replacement is an important component in any overall strategy to reduce smoking26 and, since April 1999, have offered smokers exempt from prescription charges and living in Health Action Zones a week's supply of nicotine replacement free if they attend a smokers' clinic. From the year 2000, this arrangement will be available throughout the UK.
The approximate cost of 3 months' nicotine replacement for products bought over the counter and following the manufacturers' recommended course (using the average dose and largest pack size) varies from around £120 for Boots 2mg gum to £300 for the Nicorette inhalator. The Nicorette nasal spray typically costs £110 for 3 months' treatment, but this sum excludes a private prescription dispensing fee.
In clinical trials, nicotine replacement therapy nearly doubles smokers' chances of successfully stopping smoking (18% vs. 11%). There is little evidence to suggest that any of the different forms of replacement holds a particular advantage. Attending a specialist smokers' clinic helps increase a smoker's chance of stopping but few such clinics are available. Combining different forms of nicotine replacement may also increase success rates, but this needs confirming. We welcome moves to make nicotine gum available outside pharmacies, and see some advantage of offering patients exempt from prescription charges a week's free supply of nicotine replacement therapy if they attend a specialist clinic. However, we believe success in helping smokers quit will be limited unless arrangements for providing nicotine replacement within the NHS are extended further.
[M=meta-analysis; R=randomised controlled trial]