tobacco dependence treatment

Pharmacotherapy for tobacco dependence is an important component of a comprehensive treatment plan that includes behavioral interventions and psychosocial support. The primary effects of nicotine are mediated by nicotinic acetylcholine receptors, many subtypes of which are widely distributed throughout the central nervous system. A high concentration of α4 subunits is found in the ventral tegmental area of the brain, where a dense supply of dopamine neurons is linked to the brain’s main “reward center,” the nucleus accumbens. An increase in extra-synaptic dopamine in the extracellular space appears to be associated with the reinforcing and addictive properties not only of nicotine but also of other psychostimulant drugs of abuse (eg, amphetamine, cocaine).

The goal of using cessation medications is to reduce cravings for tobacco and symptoms of nicotine withdrawal that are especially severe during the first few weeks after discontinuing tobacco use. Over the past 20 years, many forms of cessation medications have been developed to assist smokers in quitting. The most commonly utilized cessation medications are nicotine replacement medications. These agents deliver nicotine to the brain via various routes in order to replace the nicotine previously supplied by tobacco. “Medicinal nicotine” is delivered in its safest form, as opposed to its most dangerous form accompanied by over 4000 toxins in tobacco smoke, and binds to nicotinic receptors in the brain, reducing cravings and withdrawal. All of these medications have been shown to be effective at increasing abstinence rates in clinical trials and roughly double long-term quit rates.

Other non-nicotine medications, such as antidepressants, have been approved for use in smoking cessation and have slightly different mechanisms of action. Bupropion Sustained-Release (Zyban®, GlaxoSmithKline) was approved for smoking cessation in 1997. This medication inhibits reuptake of dopamine and norepinephrine in the central nervous system, resulting in similar effects on these neurotransmitters as caused by nicotine. In addition, bupropion antagonizes nicotinic receptors which may reduce the reinforcing properties of nicotine. Varenicline (Chantix®, Pfizer) was approved in 2006 for smoking cessation, and is a selective alpha-4-beta-2 nicotinic acetylcholine receptor partial agonist. By this mechanism, varenicline binds to the nicotinic receptors in the ventral tegmental area, generating a dopamine response in the nucleus accumbens that is lower in magnitude than that caused by nicotine. This low-level dopamine response is less likely to result in dependence, yet is effective in reducing withdrawal symptoms in the absence of nicotine. In addition, this compound acts as an antagonist at the alpha-4-beta-2 nicotinic receptor, thus reducing nicotine’s ability to bind to the receptor and cause high-level dopamine release. Thus, varenicline should help in reducing cravings and withdrawal as well as reduce relapse by reducing the rewarding effects of tobacco. In two recent clinical trials, varenicline has been shown to improve abstinence rates over both bupropion and placebo and in another trial, longer term use (24 weeks) was shown to reduce relapse.

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