Bupropion and other non-nicotine pharmacotherapies
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《英国医生杂志》
University of Nottingham, Nottingham
Introduction
Although nicotine replacement has been the first line drug treatment for smoking cessation for many years, other drugs of proved efficacy are also now available. Foremost among these is bupropion (marketed as Zyban). Bupropion was developed and initially introduced in the United States as an antidepressant but was subsequently noted to reduce the desire to smoke cigarettes and shown in clinical trials to be effective in smoking cessation.
Mechanism of action
Bupropion is an atypical antidepressant structurally similar to diethylpropion, an appetite suppressant. The mechanism of the antidepressant effect of bupropion is not fully understood, but bupropion inhibits reuptake of dopamine, noradrenaline, and serotonin in the central nervous system, is a non-competitive nicotine receptor antagonist, and at high concentrations inhibits the firing of noradrenergic neurons in the locus caeruleus.
It is not clear which of these effects accounts for the antismoking activity of the drug, but inhibition of the reductions in levels of dopamine and noradrenaline levels in the central nervous system that occur in nicotine withdrawal is likely to be important. The antismoking effect of bupropion does not seem to be related to the antidepressant effect as bupropion is equally effective as a smoking cessation therapy in smokers with and without depression.
Effects of bupropion on the central nervous system
Evidence for effectiveness
When given in association with intensive behavioural support, bupropion is as effective as nicotine replacement therapy (NRT), and like NRT, leads to a near doubling of the smoking cessation rate, achieving long term abstinence in 19% of smokers who use it to quit.
The effectiveness of bupropion in conjunction with less intensive levels of behavioural support has not been tested in clinical trials. Like NRT, however, bupropion therapy probably increases the chance of success with any quit attempt but is most effective when combined with intensive behavioural support. No evidence suggests that bupropion is any more or less effective in any specific subgroups of smokers, such as those in hospital or those with a smoking related disease.
Abstinence from smoking in relation to sustained release bupropion or nicotine patch, or both. Adapted from Jorenby et al. N Engl J Med 1999;340: 685-91
Bupropion also seems to attenuate the weight gain that often occurs after quitting. More prolonged use of bupropion (beyond the recommended eight weeks) seems to confer further protection against relapse.
Using bupropion
Dose
Bupropion is marketed in the United Kingdom as an oral prolonged release 150 mg tablet. An eight week course of treatment is recommended and costs about ￡86 ($143; 123). Smokers should start taking bupropion one week before their intended quit date. A reduced dose—that is, one tablet daily—is recommended in elderly people and those with liver or renal impairment.
Dose regimen for bupropion
Bupropion is the only non-nicotine drug licensed for use in smoking cessation in the United Kingdom and the European Union; it became available for use in 2000
Unwanted effects
The most serious adverse effect of bupropion is seizure, which affects an estimated 1 in 1000 users. More common side effects include dry mouth, insomnia, skin rash, pruritus, and hypersensitivity. Rarely the drug may cause a reaction resembling serum sickness.
Power of the press
Contraindications and precautions
Bupropion is contraindicated in patients with current or past epilepsy. It should also be used with extreme caution in patients with conditions predisposing to a low threshold for seizure—history of head trauma, alcohol misuse, diabetes treated with hypoglycaemic agents or insulin—and in patients taking drugs that lower the seizure threshold (for example, theophylline, antipsychotics, antidepressants, and systemic corticosteroids).
Bupropion is also contraindicated in patients with a history of anorexia nervosa and bulimia, severe hepatic necrosis, or bipolar disorder.
Pharmacokinetics and interactions
Bupropion reaches a peak plasma concentration three hours after oral administration, with steady state concentration reached within eight days. It has a half life of 20 hours and is metabolised in the liver by cytochrome p450.
Interactions of bupropion
Use with NRT
One study has suggested that combined nicotine patch therapy and bupropion may produce higher quit rates than nicotine patches alone. Combination therapy may therefore be recommended to patients attending specialist cessation clinics who find it difficult to quit using a single pharmacotherapy. Monitoring for hypertension is recommended when combined therapy is used.
Special groups
Chronic obstructive pulmonary disease—Smoking cessation is the most important intervention in this disease. Bupropion has been shown to be effective and well tolerated in this group of patients.
Long term abstinence from smoking in patients with chronic obstructive pulmonary disease, after treatment with bupropion. Adapted from Tashkin et al. Lancet 2001;357: 1571-5
Ischaemic heart disease—Smoking cessation is one of the most important interventions in this disease. Bupropion is not contraindicated or subject to caution except in diabetic patients treated with hypoglycaemic agents or insulin (caution) or in patients taking propafenone or flecainide (dose reduction of antiarrhythmics advised).
Bupropion should not be used with a monoamine oxidase inhibitor, and at least 14 days should elapse between stopping such treatment and starting bupropion
Bupropion interacts with a number of commonly used drugs, including some antidepressants, type 1c antiarrhythmics, and antipsychotics
Pregnant women—No trials of bupropion have been done in pregnant women. Bupropion is therefore not recommended for use in pregnancy.
Other antidepressants
Nortriptyline, a tricyclic antidepressant with mostly noradrenergic properties and a small amount of dopaminergic activity, is also effective in cessation therapy, and although few clinical trials have been done, these suggest an effect of similar magnitude to that of bupropion. Again, this effect seems to be independent of the presence of depressive symptoms.
Non-nicotine therapies for smoking cessation
Several other antidepressants have been used in smoking cessation including imipramine, doxepin, venlafaxine, fluoxetine, and the reversible monoamine oxidase inhibitor moclobemide. The latter may be effective in some patients, but the effectiveness of other therapies is unproved.
Other pharmacotherapies
Clonidine is an noradrenergic agonist that suppresses sympathetic activity and has been used for hypertension and to reduce withdrawal symptoms associated with misuse of alcohol and opiates. Both in its oral and low dose patch formulation, clonidine increased smoking cessation in eight out of nine trials, but the drug is associated with serious side effects, including sedation and postural hypotension. Clonidine is therefore probably best reserved for smokers who cannot or do not wish to use NRT, bupropion, or nortriptyline.
Key points
Mecamylamine is a nicotinic antagonist originally used to decrease cholinergic activity and thus reduce blood pressure. It blocks the effects of nicotine but does not precipitate withdrawal symptoms. Two trials have suggested that a low dose mecamylamine patch combined with a nicotine patch was superior to placebo, but a recent multicentre trial has failed to show efficacy.
Sensory replacement therapy could be useful for the many smokers who report missing the sensory aspects of smoking. Sensory effects of smoking are important in reinforcing smoking behaviour, and loss of these effects may contribute to relapse. Two inhalers containing ascorbic acid or citric acid have been tested, and both increased rates of short term cessation. Further testing of these adjuncts to NRT or other non-nicotine therapies is warranted, but neither of these treatments is currently used routinely in specialist cessation clinics.
No trials of bupropion have been done in smokers aged under 18, and the drug is not licensed or recommended for smoking cessation in this age group
Further reading
? Antidepressants for smoking cessation. Cochrane Database Syst Rev 2003;(3): CD000031
? Royal College of Physicians of London. Nicotine addiction in Britain. London: RCP, 2000.
? Hurt RD, Sachs DPL, Glover ED, Offord KP, Johnston JA, Dale LC, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337: 1195-202.
Competing interests: ER has been reimbursed by GlaxoSmithKline, the manufacturer of bupropion, for attending one international meeting and has attended educational events sponsored by Pharmacia, the manufacturer of Nicorette. See first article in this series (24 January 2004) for the series editor's competing interests.
Elin Roddy is clinical research fellow at the University of Nottingham in the division of respiratory medicine at City Hospital, Nottingham.
The ABC of smoking cessation is edited by John Britton, professor of epidemiology at the University of Nottingham in the division of epidemiology and public health at City Hospital, Nottingham. The series will be published as a book in the late spring.(Elin Roddy)
Introduction
Although nicotine replacement has been the first line drug treatment for smoking cessation for many years, other drugs of proved efficacy are also now available. Foremost among these is bupropion (marketed as Zyban). Bupropion was developed and initially introduced in the United States as an antidepressant but was subsequently noted to reduce the desire to smoke cigarettes and shown in clinical trials to be effective in smoking cessation.
Mechanism of action
Bupropion is an atypical antidepressant structurally similar to diethylpropion, an appetite suppressant. The mechanism of the antidepressant effect of bupropion is not fully understood, but bupropion inhibits reuptake of dopamine, noradrenaline, and serotonin in the central nervous system, is a non-competitive nicotine receptor antagonist, and at high concentrations inhibits the firing of noradrenergic neurons in the locus caeruleus.
It is not clear which of these effects accounts for the antismoking activity of the drug, but inhibition of the reductions in levels of dopamine and noradrenaline levels in the central nervous system that occur in nicotine withdrawal is likely to be important. The antismoking effect of bupropion does not seem to be related to the antidepressant effect as bupropion is equally effective as a smoking cessation therapy in smokers with and without depression.
Effects of bupropion on the central nervous system
Evidence for effectiveness
When given in association with intensive behavioural support, bupropion is as effective as nicotine replacement therapy (NRT), and like NRT, leads to a near doubling of the smoking cessation rate, achieving long term abstinence in 19% of smokers who use it to quit.
The effectiveness of bupropion in conjunction with less intensive levels of behavioural support has not been tested in clinical trials. Like NRT, however, bupropion therapy probably increases the chance of success with any quit attempt but is most effective when combined with intensive behavioural support. No evidence suggests that bupropion is any more or less effective in any specific subgroups of smokers, such as those in hospital or those with a smoking related disease.
Abstinence from smoking in relation to sustained release bupropion or nicotine patch, or both. Adapted from Jorenby et al. N Engl J Med 1999;340: 685-91
Bupropion also seems to attenuate the weight gain that often occurs after quitting. More prolonged use of bupropion (beyond the recommended eight weeks) seems to confer further protection against relapse.
Using bupropion
Dose
Bupropion is marketed in the United Kingdom as an oral prolonged release 150 mg tablet. An eight week course of treatment is recommended and costs about ￡86 ($143; 123). Smokers should start taking bupropion one week before their intended quit date. A reduced dose—that is, one tablet daily—is recommended in elderly people and those with liver or renal impairment.
Dose regimen for bupropion
Bupropion is the only non-nicotine drug licensed for use in smoking cessation in the United Kingdom and the European Union; it became available for use in 2000
Unwanted effects
The most serious adverse effect of bupropion is seizure, which affects an estimated 1 in 1000 users. More common side effects include dry mouth, insomnia, skin rash, pruritus, and hypersensitivity. Rarely the drug may cause a reaction resembling serum sickness.
Power of the press
Contraindications and precautions
Bupropion is contraindicated in patients with current or past epilepsy. It should also be used with extreme caution in patients with conditions predisposing to a low threshold for seizure—history of head trauma, alcohol misuse, diabetes treated with hypoglycaemic agents or insulin—and in patients taking drugs that lower the seizure threshold (for example, theophylline, antipsychotics, antidepressants, and systemic corticosteroids).
Bupropion is also contraindicated in patients with a history of anorexia nervosa and bulimia, severe hepatic necrosis, or bipolar disorder.
Pharmacokinetics and interactions
Bupropion reaches a peak plasma concentration three hours after oral administration, with steady state concentration reached within eight days. It has a half life of 20 hours and is metabolised in the liver by cytochrome p450.
Interactions of bupropion
Use with NRT
One study has suggested that combined nicotine patch therapy and bupropion may produce higher quit rates than nicotine patches alone. Combination therapy may therefore be recommended to patients attending specialist cessation clinics who find it difficult to quit using a single pharmacotherapy. Monitoring for hypertension is recommended when combined therapy is used.
Special groups
Chronic obstructive pulmonary disease—Smoking cessation is the most important intervention in this disease. Bupropion has been shown to be effective and well tolerated in this group of patients.
Long term abstinence from smoking in patients with chronic obstructive pulmonary disease, after treatment with bupropion. Adapted from Tashkin et al. Lancet 2001;357: 1571-5
Ischaemic heart disease—Smoking cessation is one of the most important interventions in this disease. Bupropion is not contraindicated or subject to caution except in diabetic patients treated with hypoglycaemic agents or insulin (caution) or in patients taking propafenone or flecainide (dose reduction of antiarrhythmics advised).
Bupropion should not be used with a monoamine oxidase inhibitor, and at least 14 days should elapse between stopping such treatment and starting bupropion
Bupropion interacts with a number of commonly used drugs, including some antidepressants, type 1c antiarrhythmics, and antipsychotics
Pregnant women—No trials of bupropion have been done in pregnant women. Bupropion is therefore not recommended for use in pregnancy.
Other antidepressants
Nortriptyline, a tricyclic antidepressant with mostly noradrenergic properties and a small amount of dopaminergic activity, is also effective in cessation therapy, and although few clinical trials have been done, these suggest an effect of similar magnitude to that of bupropion. Again, this effect seems to be independent of the presence of depressive symptoms.
Non-nicotine therapies for smoking cessation
Several other antidepressants have been used in smoking cessation including imipramine, doxepin, venlafaxine, fluoxetine, and the reversible monoamine oxidase inhibitor moclobemide. The latter may be effective in some patients, but the effectiveness of other therapies is unproved.
Other pharmacotherapies
Clonidine is an noradrenergic agonist that suppresses sympathetic activity and has been used for hypertension and to reduce withdrawal symptoms associated with misuse of alcohol and opiates. Both in its oral and low dose patch formulation, clonidine increased smoking cessation in eight out of nine trials, but the drug is associated with serious side effects, including sedation and postural hypotension. Clonidine is therefore probably best reserved for smokers who cannot or do not wish to use NRT, bupropion, or nortriptyline.
Key points
Mecamylamine is a nicotinic antagonist originally used to decrease cholinergic activity and thus reduce blood pressure. It blocks the effects of nicotine but does not precipitate withdrawal symptoms. Two trials have suggested that a low dose mecamylamine patch combined with a nicotine patch was superior to placebo, but a recent multicentre trial has failed to show efficacy.
Sensory replacement therapy could be useful for the many smokers who report missing the sensory aspects of smoking. Sensory effects of smoking are important in reinforcing smoking behaviour, and loss of these effects may contribute to relapse. Two inhalers containing ascorbic acid or citric acid have been tested, and both increased rates of short term cessation. Further testing of these adjuncts to NRT or other non-nicotine therapies is warranted, but neither of these treatments is currently used routinely in specialist cessation clinics.
No trials of bupropion have been done in smokers aged under 18, and the drug is not licensed or recommended for smoking cessation in this age group
Further reading
? Antidepressants for smoking cessation. Cochrane Database Syst Rev 2003;(3): CD000031
? Royal College of Physicians of London. Nicotine addiction in Britain. London: RCP, 2000.
? Hurt RD, Sachs DPL, Glover ED, Offord KP, Johnston JA, Dale LC, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337: 1195-202.
Competing interests: ER has been reimbursed by GlaxoSmithKline, the manufacturer of bupropion, for attending one international meeting and has attended educational events sponsored by Pharmacia, the manufacturer of Nicorette. See first article in this series (24 January 2004) for the series editor's competing interests.
Elin Roddy is clinical research fellow at the University of Nottingham in the division of respiratory medicine at City Hospital, Nottingham.
The ABC of smoking cessation is edited by John Britton, professor of epidemiology at the University of Nottingham in the division of epidemiology and public health at City Hospital, Nottingham. The series will be published as a book in the late spring.(Elin Roddy)