7.16 Pharmacotherapy

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The development and introduction of drug therapies has provided much needed assistance for smokers trying to quit, particularly for more dependent smokers. However, it is important to note that 'no form of pharmacotherapy is a substitute for motivation.'249

Choice of pharmacotherapy should take into account potential adverse effects as well as benefits.263 Few studies have been published directly comparing the effectiveness of available drug therapies.263

When pharmacotherapy combinations or dosages beyond those contained in consumer product information are used, medical supervision is necessary.

7.16.1 Nicotine replacement therapy (NRT)

Nicotine is the drug in tobacco that causes addiction, and is released from tobacco when it is smoked, chewed or sucked.21 It is the decrease in nicotine levels that is mainly responsible for withdrawal symptoms after stopping smoking.21 Nicotine replacement therapy (NRT) replaces some of the nicotine in the blood previously obtained from cigarettes, but without the many thousands of other chemicals produced when tobacco is smoked, which are largely responsible for tobacco-related disease. Hence NRT has been thought of as 'clean nicotine'.264 At least three main mechanisms of action by which NRT may assist smoking cessation have been proposed, although evidence for them is not conclusive. Firstly, NRT decreases the intensity of cravings and withdrawal symptoms, enabling people to better function while dealing with the social and psychological aspects of their dependence. Secondly, it may reduce the reinforcing effects of tobacco-delivered nicotine. Lastly, it may provide some of the effects for which the smoker previously relied on cigarettes such as sustaining desirable mood and coping with stressful situations.265, 266

Research indicates that NRT increases the rate of long-term quitting by 50 to 70%,263 although trials with industry funding tend to show higher success rates than those independently funded.267 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 be quit four years later than those who quit without using NRT.268 NRT works with or without additional counselling, however counselling does further increase the odds of success.6, 57 All forms of NRT appear to be about as effective as each other, but research is limited on the most recently released products.263

Five forms of NRT are available in Australia: chewing gum, transdermal (skin) patch, lozenge, inhaler and sublingual tablet. Nicotine nasal spray is available in other countries, but not permitted for sale in Australia. The gum and lozenge come in 4mg and 2mg doses, while the inhaler and tablet come in the 2mg dose only. Sets of patches come in three sizes; the 24-hour patch has dosages of 21mg, 14mg and 7mg, and the 16 hour patch has dosages of 15mg, 10mg and 5mg. Nicotine chewing gum first became available on prescription in Australia in 1984, followed by the patch in 1993.269 The 2mg gum became available over-the-counter without prescription in pharmacies in 1988, and the 4mg gum and patches in late 1997.96, 246 The nicotine inhaler, lozenges and sublingual tablets were introduced as over-the-counter products in 1999, 2002 and 2003 respectively.270–272 In 2005, NRT products started to appear in supermarkets. Direct advertising to the public of nicotine replacement therapy began in 1998, which markedly increased sales.246

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.265, 273

There are different advantages and disadvantages associated with each form of NRT. Nicotine patches, the most popular choice,246 are simple to use and the compliance rate tends to be higher than other NRT products.265, 274 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.265 However, some users only use acute NRT in response to cravings, and underdosing is a common problem with the use of these products.265

In 2006, the Therapeutic Goods Administration (TGA) approved combination therapy for the concurrent use of the 15mg 16-hour patch with 2mg gum. Evidence suggests combination therapy is better than the use of a single product alone.263 Precisely how smokers benefit from combination therapy is not clear. Factors may include a higher percentage of nicotine substitution, better relief of cravings by having constant levels of nicotine from the patch plus faster acting 'rescue' medication for sudden intense cravings, and the sensory effects of different types of products.263, 265

In 2007, the TGA approved the use of the 'cut down and stop method', where smokers using NRT 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.275 Studies where participants used NRT while smoking in order to cut down the amount smoked found this method also significantly increased the odds of quitting.276 While using the nicotine gum or inhaler can help smokers cut down the number of cigarettes they smoke and their intake of carbon monoxide, there is insufficient evidence of a long-term benefit to recommend this in place of quitting altogether.276 Another approach now available is the use of pre-quit patches followed by patches after the quit date.

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.263, 277 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.276 Smoking while using NRT does not significantly increase the risk of a heart attack or other cardiovascular events.263, 277 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.265, 276 Other potential symptoms of nicotine overdose include pallor, sweating, tachycardia, agitation, and a number of less common symptoms.48

The manufacturer's recommended period of use for NRT products varies between eight to 16 weeks, often with provision for a gradual reduction of dosage levels to avoid withdrawal effects at the end of the period.48 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.263 Highly dependent smokers who still have cravings and withdrawal symptoms eight weeks after quitting may benefit from longer use.265, 278, 279 Short courses of NRT, for example four weeks, may not be effective in the long-term.176

Addictive potential is strongly influenced by speed and method of delivery of nicotine.277, 280 When smoking a cigarette, peak blood nicotine levels are achieved within seconds, taking only 10 to 19 seconds for nicotine absorbed from the lungs to reach the brain, after which time it declines rapidly.277 In contrast, it can take more than 30 minutes to reach the peak blood nicotine level when using oral forms of NRT270, 271, 281, 282, with effects of nicotine evident within 15 to 20 minutes.265 When using the patch, it takes four to nine hours (depending on the patch) to reach peak blood nicotine level, but then it stays constant while wearing the patch.273

All NRT products have a low addictive potential. Prolonged use of NRT is related to the speed of nicotine delivery, with prevalence one year after commencing use ranging from 2% for patches to 13% for nasal spray, with oral products intermediate.279 Although nicotine is not entirely without risk, prolonged use of NRT is far less harmful than continuing to smoke.263, 265, 279

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 than among participants in research trials. A study in NSW 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 about one-third of usage was concurrent with smoking.274 Although smokers making self-initiated quit attempts without formal behavioural support have low long-term success rates, the relative effect of NRT is similar to other settings, offering significant improvement over unaided quitting.263, 284–285

No serious side effects of either short or long-term NRT use have been reported over the 20 years it has been in use.279 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.48, 263, 273, 286

These are relatively minor for most users, and NRT products are generally rated as safe compared to other medications.263, 279

Using NRT to quit is always safer than continuing to smoke.277 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.249, 277

Many smokers believe that nicotine causes cancer, since it is equated with tobacco, but this is not correct.277, 287 There is some evidence that it may accelerate growth of tumours once established, but it is the other carcinogens in tobacco smoke that are responsible for tobacco-related cancers.288, 289 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.277 NRT is safe to use as a cessation aid in people with stable heart conditions, including angina and previous heart attack.263, 277 NRT can also be used by smokers aged 12 to 17 years, and by pregnant or breastfeeding mothers to help them quit, preferably under their doctor's supervision.249, 277

7.16.2 Bupropion

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, Prexaton and Bupropion-RL. Originally developed as an anti-depressant, early users reported that they had less urge to smoke, and further research demonstrated that it was useful as an aid to quitting. Bupropion approximately doubles the odds of quitting success.290 It is comparably effective in different settings and with different levels of behavioural support, and in smokers with or without a history of depression.290 It is believed to act 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.290–292 It is yet to be determined whether bupropion is superior to NRT in the prevention of depressive symptoms or relapse to depression.290 Bupropion appears to reduce weight gain that occurs after quitting, but the effect does not last beyond treatment.292

Bupropion was introduced into Australia in 2000 and was made available on the Pharmaceutical Benefits Scheme in 2001. It is available only on prescription, and one course per year is subsidised under the PBS on condition that users participate in a comprehensive counselling program such as with the Quitline service or their GP. 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.

The most common side effects are sleeping difficulties, and nausea. A small number of allergic reactions to bupropion have been reported, including skin rashes, and less frequently fever, muscle and joint pain. The most serious side effect is a risk of seizure, estimated to occur in one in 1000 patients (0.1%).290, 291 Bupropion is contraindicated for smokers who are allergic to bupropion, who are pregnant or breastfeeding, who are less than 18 years old, 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.48, 293

Several other antidepressants have been investigated for efficacy in smoking cessation. Of these, nortriptyline has been found to double quit rates but has the potential for serious side effects.290 None of these other drugs are currently licensed for smoking cessation in Australia.

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. It is a partial agonist of nicotine receptors, maintaining moderate levels of dopamine to counteract withdrawal symptoms, and reducing the urge to smoke and negative moods. It also acts as an antagonist by blocking nicotine binding to specific receptors that may reduce the rewarding effects of smoking in those who continue to smoke while taking the drug.294 In trials so far, smokers using varenicline are three times more likely to succeed at long-term cessation, compared to those using no medication.294 Early trials have shown it to be superior to bupropion,295 but independent research is needed to substantiate these results.294 The main side effect of varenicline is mild to moderate nausea, which appears to diminish over time.294 Varenicline is not recommended for pregnant women, children or people with a mental illness.249 It was introduced into Australia on 1 January 2008, as a prescription medicine available on the Pharmaceutical Benefits Scheme to smokers enrolled in a counselling program.296

7.16.4 Future developments

The range of interventions for smoking cessation has grown dramatically in the past two decades, giving smokers the choice of different approaches to quitting and increasing their chance of success. New treatments are currently being trialled and some of the most promising at present are:

Rimonabant (trade name Acomplia) is a drug that targets the cannabinoid receptor system. It is used predominantly for treating obesity, but it may also prove useful for smoking cessation, particularly for smokers most concerned about weight gain.265, 297, 299 Clinical trials so far suggest a benefit for long-term smoking cessation and reduction of weight gain, especially in overweight or obese individuals.298 Further trials are needed to gain approval for use in smoking cessation.298

Vaccination is an approach for which several companies are conducting advanced trials. The trial vaccines promote proliferation of nicotine specific antibodies that bind to nicotine in the bloodstream and reduce its uptake in the brain, thus reducing the rewards of smoking.300 The strength of the immune system response varies among individuals. To date, results have shown the effect to be temporary, that is, the vaccinations do not confer long-term immunity as with most other vaccinations.300

Methoxsalen is a medication being trialled. It blocks the enzyme that breaks down nicotine in the body slowing elimination, thus postponing the onset of withdrawal symptoms, and presumably making cessation easier.301