Dissociating nicotine and nonnicotine components of cigarette smoking

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Abstract

To dissociate the sensorimotor aspects of cigarette smoking from the pharmacologic effects of nicotine, smokers rated the subjective effects of nicotine-containing or denicotinized cigarettes, and intravenous (IV) nicotine or saline infusions. Three groups of participants (n=20 per group) received either: (1) continuous nicotine, (2) pulsed nicotine, or (3) saline. Each group was exposed to an IV condition once while smoking a denicotinized cigarette and once while not smoking, in a 3×2 mixed design. A fourth group (n=20) received saline while smoking their usual brand of cigarette. The dose and rate of nicotine administration were individualized based on previous measures of ad lib smoke intake. Denicotinized cigarette smoke significantly reduced craving and was rated significantly more satisfying and rewarding than the no-smoking conditions. IV nicotine reduced craving for cigarettes, and increased ratings of lightheadedness and dizziness. However, no significant satisfaction or reward was reported after IV nicotine. The combination of IV nicotine and denicotinized cigarette smoke produced effects similar to those of smoking the usual brand of cigarette. The results suggest that sensorimotor factors are critical in mediating the immediate subjective response to smoking, and that the immediate subjective effects of nicotine administered in doses obtained from cigarette smoking are subtle. Thus, addressing smokers' needs for both for the sensorimotor aspects of smoking as well as for the direct CNS effects of nicotine may be critical in enhancing smoking cessation treatment outcome.

Introduction

Considerable evidence supports the view that cigarette smoking is maintained by an addiction to nicotine [28]. This view has led to the development of smoking cessation treatment methods that provide nicotine replacement. One of the goals of nicotine replacement therapy is to partially substitute for the rewarding effects of cigarette smoke, reducing the need for tobacco [11]. However, the effects of nicotine, when delivered without cigarette smoke, have generally been found to be much less rewarding than smoking [10], [18], [19]. Moreover, most people trying to quit smoking eventually relapse even when provided with nicotine in the form of gum, patches, nasal spray, or inhaler [7]. While these alternative forms of nicotine delivery can effectively relieve some smoking withdrawal symptoms [12], craving for cigarettes is only partially alleviated during the initial days of smoking abstinence [1], [23].

Why do current methods of nicotine replacement fail to provide adequate substitution for the reinforcing effects of cigarette smoking? Two main explanations have been proposed to account for the relatively low effectiveness of nicotine replacement. The first is that nicotine replacement techniques do not provide an adequate dose or rate of nicotine administration. Not only do many smokers inhale more nicotine per day than is delivered from alternative nicotine delivery systems, but in addition, the inhalation route is more rapid than current nicotine-based treatments. It has been argued that this rapid delivery is critical to the reinforcing potency of cigarette smoking [26]. However, a second explanation is that nicotine replacement methods lack important sensory/behavioral components of cigarette smoking [20]. Indeed, smokers report missing the behavioral aspects as well as the sensory cues of smoking, such as the taste, aroma, and respiratory tract sensations accompanying each puff of smoke [22], [23]. In several studies we have shown that these sensations are especially important in relieving craving for cigarettes, and they have also been shown to facilitate smoking abstinence [2], [29].

To evaluate these contrasting explanations it is important to dissociate nicotine administration from the behavior of cigarette smoking, using a method of nicotine administration that preserves the rapid pharmacokinetic profile of pulmonary delivery. Recently, we reported that the arterial nicotine concentrations measured at 5-s intervals following intravenous (IV) nicotine administration were very similar to those of inhaled nicotine [21]. Thus, IV nicotine delivery offers a feasible approach to duplicating the pharmacologic effects of smoking with minimal sensory/behavioral cues. In a preliminary study [30], we reported that IV nicotine, when administered in conjunction with smoking a denicotinized cigarette, had minimal effects on subjective measures such as satisfaction and craving for cigarettes. In contrast, smoking a denicotinized cigarette had robust effects on these subjective measures, demonstrating the importance of nonnicotine cues in mediating responses to smoking. However, this study had limited statistical power, as it included only six subjects, and a saline control was lacking in the no-smoking conditions, which would have allowed an assessment of the effects of IV nicotine in the absence of smoking.

In the present study, a considerably larger subject sample size was used, and a saline control condition was included in both smoking and no-smoking conditions. Our main goal was to evaluate the hypothesis that presentation of pharmacologic component of smoking using IV nicotine would produce significant rewarding effects. Moreover, individualized tailoring of IV nicotine doses was incorporated into the design to better evaluate the importance of the nicotine component of smoking with realistic dosing parameters. A second goal of this study was to determine with greater precision whether IV bolus nicotine injections are more effective in providing subjective rewarding effects than continuous nicotine infusions. Furthermore, we sought to assess how nicotine dose and sensory/behavioral cues interact in affecting subjective smoking reward. To accomplish this, we measured the immediate subjective responses to the nicotine and nonnicotine components of smoking, individually and in combination. As in the previous study, we assessed the effects of the sensory/behavioral components of smoking using denicotinized tobacco cigarettes, which presented most of the nonnicotine constituents of cigarette smoke with minimal doses of nicotine.

Section snippets

Design

Eighty subjects were randomly assigned to four groups (see Fig. 1) receiving either: (1) rapid IV injections (boli) of puff-sized doses of nicotine, (2) continuous IV infusions of nicotine, or (3) saline infusions. Subjects in these three groups received two identical IV presentations in the same session, separated by 90 min. During one presentation, subjects smoked a denicotinized cigarette, and during the other presentation no smoke was given (order counterbalanced across subjects); (4) a

Subject characteristics

Table 1 shows the subject characteristics, broken down by infusion condition. There were no significant differences between groups in age, years smoked, gender, FTC nicotine, cigarettes/day, baseline expired air CO, Fagerstrom test for Nicotine Dependence score (FTND) [9], or plasma cotinine levels.

Effects of denicotinized smoke and IV nicotine

In this section, all effects of smoking refer to the denicotinized cigarette. Comparisons with the usual brand cigarette condition will be described in the next section.

Discussion

The main goal of the study was to determine how the pharmacologic actions of nicotine and the sensory/behavioral aspects of cigarette smoking contribute to the immediate subjective effects of cigarette smoking. Overall, the sensory/behavioral aspects presented by smoking a denicotinized cigarette were marked, and replicated many of the immediate subjective responses evoked by smoking the usual brand of nicotine-containing cigarette. Smoking the denicotinized cigarette produced satisfaction,

Acknowledgements

This work was supported by Grant DA 02665 from the National Institute on Drug Abuse and National Center for Research Resources General Clinical Research Program Grant MO1-RR30.

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