Non-nicotine pharmacotherapy for smoking cessation - Mechanisms and prospects

Nicotine replacement therapy (NRT) has been the mainstay of smoking cessation therapy for >15 years, However, 70 to 90% of smokers fail to quit despite NRT. Non-nicotine medications have been investigated as alternative therapies to achieve smoking cessation, NRT is believed to work by relieving withdrawal symptoms, and perhaps by desensitising nicotinic cholinergic receptors. Non-nicotine medications may work in a variety of ways, including nicotinic cholinergic receptor agonism (lobeline), nicotine-like effects on neurotransmitter systems (antidepressants, clonidine), nicotinic cholinergic receptor antagonism (mecamylamine) and sensory stimulation/aversion (citric or ascorbic acid inhalants or spray, silver acetate). The only non-nicotine drug approved for smoking cessation in the US is the antidepressant amfebutamone (bupropion). Two large clinical trials have demonstrated the benefit of the drug, with cessation ratios more than twice that of placebo. Amfebutamone is effective in increasing smoking cessation regardless of a history of or current depression and is generally well tolerated, although it occasionally produces agitation and in excessive doses can cause seizures. Clinical trials suggest the benefit of a number of other non-nicotine medications: the tricyclic antidepressant nortriptyline, the antihypertensive clonidine, and silver acetate. A mecamylamine-nicotine combination may be effective, and sensory stimulants, such as citric or ascorbic acid inhalers or sprays, might enhance the effects of nicotine or other pharmacotherapies. The availability of non-nicotine medications expands the options for smoking cessation therapy. A stepped care approach for the selection of pharmacotherapies is presented in this review. With this approach, initial therapy would involve an attempt to quit using over-the-counter nicotine products. If this fails, therapy with other forms of NRT, such as nicotine nasal spray or non-nicotine medication such as amfebutamone or other antidepressants, and/or intensive behavioural therapy, should be tried. Failure to quit at the second step should lend to combinations of nicotine and non-nicotine therapies, as well as clonidine and other newer treatments. Future prospects for the pharmacotherapy of smoking cessation include the use of nicotine receptor subtype-specific agonists and antagonists, targeted to deal with specific reinforcement and/or specific withdrawal symptoms. Also of future interest is the development of nicotine antibodies that might neutralise the effects of nicotine. It is hoped that ultimately medications can be matched with the individual characteristics of a smoker. and that smoking cessation could be facilitated in most smokers.