Failure to improve cigarette smoking abstinence with transdermal selegiline + cognitive behavior therapy

Cigarette smoking cessation is typically accompanied by urges and cravings that can weaken a smoker’s resolve to maintain abstinence [1–3]. The development of cravings and other withdrawal symptoms is common to a variety of drugs of abuse, including nicotine, and may result from neuroadaptations that occur in response to chronic drug use [4,5]. Koob and co-workers have elaborated a model of the development of withdrawal symptoms built upon a conceptual framework provided by opponent process theory [6,7]. In Koob’s model, withdrawal phenomena are triggered by the depletion of dopamine, serotonin and other neurotransmitter systems that occur under conditions of drug deprivation. The emergence of withdrawal phenomena reflects the operation of a homeostatic opponent process in which initial drug effects (“A processes”) are countered by homeostatic mechanisms (“B processes”) that attempt to restore system parameters [5,8]. Under conditions of drug deprivation, “B processes”, which are long lasting in comparison to “A processes”, are unopposed leading to neurotransmitter depletion and the emergence of craving, negative affect and various other subjective abstinence effects. In accord with this model, there is evidence that nicotine increases central DA [9–11] and that central DA depletion is associated with nicotine deprivation [12]. Selegiline is a selective inhibitor of MAO B and is used clinically in combination with levodopa to treat late-stage Parkinsonism and, in transdermal form (EMSAM), to treat depression. Selegiline permits the stabilization of DA levels in the brain by preventing the rapid degradation of DA via MAO B. It is used as an adjunct to levodopa therapy causing a dose-sparing effect and enhancing DA transmission [13]. Because tobacco smoke inhibits CNS MAO B [14], we reasoned that treatment with selegiline might produce better smoking cessation outcomes by more effectively preventing or alleviating craving and depression symptoms through its inhibiting effects on MAO B and resulting potentiation of central DA. Although no previous smoking cessation trials have been conducted with the selegiline transdermal system (“STS”), the oral form of the medication has been examined in two short-term studies and one randomized clinical trial. Houtsmiller and colleagues [15] reported that selegiline reduced craving and cigarette consumption relative to placebo in a two-week study of 15 smokers given selegiline and placebo in counter-balanced order. George and colleagues [16] randomized 40 smokers to an 8-week course of selegiline or placebo. At the end of treatment, 7-day point prevalence abstinence rates were 45% for selegiline and 15% for placebo (p≤.05). Finally, Biberman and colleagues [17] randomized 109 smokers to 26 weeks of selegiline or placebo. In addition, all received nicotine patch for 8 weeks. At 52 week follow-up, continuous abstinence rates were 25% for selegiline and 11% for placebo (p≤.08). An analysis of moderators of treatment response was also included in this trial. A “moderator” of treatment is a pre-randomization factor (hence uncorrelated with treatment in a randomized clinical trial (RCT) that has an interactive effect with treatment on outcome [18]. Subgroups of the population sampled in an RCT, identified by strata of a moderator variable, may have different treatment effect sizes. Moderators may help clinicians to develop better treatment targeting algorithms, can be used by researchers to identify appropriate study inclusion/exclusion criteria and serve as factors on which a study may be stratified to amplify power.