Non-nicotine pharmacotherapy for smoking cessation - Mechanisms and prospects

Nicotine replacement therapy (NRT) has been the mainstay of smoking cessati on therapy for >15 years, However, 70 to 90% of smokers fail to quit despit e NRT. Non-nicotine medications have been investigated as alternative thera pies to achieve smoking cessation, NRT is believed to work by relieving withdrawal symptoms, and perhaps by de sensitising nicotinic cholinergic receptors. Non-nicotine medications may w ork in a variety of ways, including nicotinic cholinergic receptor agonism (lobeline), nicotine-like effects on neurotransmitter systems (antidepressa nts, clonidine), nicotinic cholinergic receptor antagonism (mecamylamine) a nd 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 dem onstrated the benefit of the drug, with cessation ratios more than twice th at of placebo. Amfebutamone is effective in increasing smoking cessation re gardless of a history of or current depression and is generally well tolera ted, although it occasionally produces agitation and in excessive doses can cause seizures. Clinical trials suggest the benefit of a number of other non-nicotine medic ations: the tricyclic antidepressant nortriptyline, the antihypertensive cl onidine, and silver acetate. A mecamylamine-nicotine combination may be eff ective, 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 smokin g cessation therapy. A stepped care approach for the selection of pharmacot herapies is presented in this review. With this approach, initial therapy w ould involve an attempt to quit using over-the-counter nicotine products. I f 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 t he second step should lend to combinations of nicotine and non-nicotine the rapies, as well as clonidine and other newer treatments. Future prospects for the pharmacotherapy of smoking cessation include the u se of nicotine receptor subtype-specific agonists and antagonists, targeted to deal with specific reinforcement and/or specific withdrawal symptoms. A lso of future interest is the development of nicotine antibodies that might neutralise the effects of nicotine. It is hoped that ultimately medication s can be matched with the individual characteristics of a smoker. and that smoking cessation could be facilitated in most smokers.