Many researchers also believe that combinations of different types of nicotine replacements might be more effective than single agents alone (Fiore et al., 2000). Combination products would result in higher levels of nicotine replacement, which may lead to less desire to smoke and less reinforcement from a cigarette when smoked due to the development of tolerance. Interestingly, doses greater than 21 mg of nicotine generally show minimal increases in long-term abstinence rates (Hughes et al., 1999a,b), although the Cochrane Group found that high-dose nicotine patches were marginally more effective than a standard dose (1.2, 95% CI=1.0 to 1.4; N=6 trials). However, combinations of nicotine patch with nicotine products that can be used ad libitum have resulted in better treatment success. The use of the nicotine patch would result in a steady-state trough level of nicotine to prevent withdrawal symptoms, whereas the ad libitum product could be used during periods when an urge to smoke is experienced. Treatment studies have been conducted that examine a combination of nicotine gum and patch (Kornitzer et al., 1995); nicotine spray and patch (Blondal et al., 1999); and nicotine inhaler and patch (Westman et al., 2000). Results from the meta-analyses conducted with some of these studies showed that a combination treatment approach was more effective than a single treatment approach (OR=1.9, 28.6% vs. 17.4%, respectively) (Fiore et al., 2000). Furthermore, two studies showed that a combination approach led to greater reductions in withdrawal symptoms compared to a single treatment approach (Fagerström, 1994; Fagerström et al., 1993).

Antidepressants

To date, the antidepressants that have been successful in treating smokers are bupropion SR and nortriptyline. Bupropion SR, or Zyban, which is approved by the FDA, is recommended as a first-line pharmacotherapy similar to other nicotine replacement therapies (Fiore et al., 2000). Nortriptyline, which is not approved for this indication by the FDA, is recommended as a second-line treatment for smokers who were unresponsive to the first-line treatment. The mechanism of action of various antidepressants is unknown. Understanding these mechanisms is important in order to refine and develop drugs that are targeted to specific population of smokers or essential neurotransmitter systems. As one mechanism, it is possible that since a higher incidence of depression is observed among smokers than nonsmokers (Breslau et al., 1991; Glassman et al., 1990; Kendler et al., 1993) and smokers with a history of depression are more likely to relapse (e.g., Anda et al., 1990; Covey et al., 1990; Glassman et al., 1990; Hall et al., 1993) and experience depressive symptoms or mood after cessation (Borrelli et al, 1996; Glassman et al., 1990),



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