The present study evaluated the hypothesis that extending the pre-quit run-in period for varenicline from 1 to 4 weeks would alter smoking behavior and subjective effects in a manner consistent with the theorized reduction-of-reinforcement mechanism (12
). Consistent with our primary hypothesis, the Extended Run-In group exhibited greater pre-quit reductions in smoking rate, as well as greater decreases in the taste and buzz from the first cigarette of the day, compared to the Standard Run-In group. Although the pattern of pre-quit expired-air CO was not as clear, CO-verified continuous abstinence (an exploratory outcome) during the final four weeks of the three-month post-quit period were encouraging. The odds ratio for quitting with extended pre-cessation varenicline was 1.8, relative to the standard run-in of one week. The preliminary outcome data are particularly notable when one considers that the “control” condition in the present study is at least as effective as any other front-line cessation strategy (2
) and produced a 3-month abstinence rate of 40% in the present study.
The results of another recently published clinical trial with a nearly identical research design (20
) also found that pre-quit reductions of CPD, CO, and cigarette enjoyment, and 3-month abstinence rates were enhanced with four weeks of pre-quit varenicline compared to one week. Important limitations of that study, including missing pre-quit data from 15-30% of participants on each key pre-quit measure and the absence of bioverification of 3-month abstinence, are addressed in the present study. For example, the daily PDA-based assessment method employed in the present study minimized retrospective biases (21
) and resulted in complete time series data for every participant, ruling out possible selection biases or differences due to attrition. More generally, the replication of key results across both studies bolsters confidence in suggesting that increasing pre-quit duration of varenicline treatment is a strong candidate for further study in larger trials with longer follow-up periods.
Together with data from other research examining pre-quit strategies to enhance tobacco cessation (14
), the present findings can be integrated within a broader reinforcement and extinction framework (24
). For extinction to occur, people must continue smoking in order to learn that the reinforcing effects are attenuated. Extinction is maximized when numerous “trials” are conducted over a long period of time and across a range of contexts (25
). Though there are promising data with as little as 2 weeks of pre-quit NRT therapy, the pre-quit CPD data () suggests that the effect or pre-quit treatment grows over the three-week drug manipulation phase (see also (20
)). Indeed, the results of one study of smokers who were not trying to quit suggest that the decline in smoking seen with varenicline may continue gradually over a period of weeks or even months (30
). Future work might consider whether pre-quit therapy might optimally be combined with a flexible quit date(31
) in order to begin a quit date only once a critical reduction in smoking behavior - some studies suggest 50%(10
) – has occurred.
The above discussion implicitly assumes that varenicline is reducing the positively reinforcing
aspects of smoking – eliminating the positive consequences that follow smoking. However, the marked increase in nausea prompted by extended pre-quit varenicline raises the possibility that the changes in subjective effects and smoking behavior develop because smoking at one’s normal rate during varenicline treatment is aversive. Nausea is the most common side effect with varenicline and is also a relatively common reason for discontinuation of varenicline treatment (32
). However, in both the present study and in Hajek et al.(20
), extended pre-quit varenicline increased nausea prior to cessation without leading to discontinuation. Perhaps nausea that develops with standard varenicline therapy, typically around and shortly after cessation, is more readily attributed to varenicline, increasing the likelihood of stopping medication; conversely, nausea that occurs in the pre-quit period with an extended run-in may be most proximally associated with smoking, leading to reductions in smoking rate. Tests of competing positive reinforcement (reductions in smoking due to reduced reward from smoking) versus negative reinforcement (e.g., reductions in smoking in an attempt to limit nausea) mechanisms will require adequate sampling of both processes over time in a large sample of smokers. Such data could provide valuable data regarding causal processes that may aid in setting a quit date or suggest a target in the development of new therapies.
No treatment helps everyone, and it is important to consider potential moderators of treatment (33
). In the present work, the effects of extended-pre-quit were consistently, albeit unexpectedly, moderated by gender across behavioral, biochemical, and subjective measures. Among women, extended pre-quit varenicline prompted greater reductions in self-reported smoking rate and biochemical evidence of smoking exposure (expired-air CO) prior to the TQD and greater nausea pre-TQD, and it doubled rates of bio-verified abstinence at 3-month follow-up. Among males, none of these effects were statistically significant. However, consistent with data from larger clinical trials of varenicline which report equivalent abstinence rates for men and women (7
), we observed no gender differences among those receiving standard treatment, and abstinence rates were solidly within the range typically observed with standard varenicline treatment.
These data raise the possibility that gender specifically moderates pre-quit processes that are the focus of extended run-in period. The results of the largest existing trial of extended pre-quit treatment are broadly consistent with this hypothesis. Specifically, the beneficial effects of a pre-quit regimen of transdermal nicotine and denicotinized cigarettes on short-term abstinence were driven primarily by women.(34
It is important to consider whether the ‘sex’ differences observed here are really reflective of a more proximal variable, such as differences in drug concentration. Indeed, steady-state varenicline levels are predictive of cessation outcome (35
). Although the lack of robust sex differences in weight or medication adherence fail to support the hypothesis that varenicline concentrations were markedly different in the present study, future work should include direct measures over time (see also 36
Still, we are not suggesting that extending pre-quit treatment is ineffective among men. The results of one recent study raise the possibility that, on average, the effects of pre-quit varenicline may emerge more slowly among men (37
). More generally, rather than propose that sex is the
critical factor to examine, we suggest that future large-scale studies of extended pre-quit treatment explicitly consider individual differences in a range of parameters, including baseline smoking rate(38
), nicotine metabolism(33
), and varenicline concentration(35
In summary, the present data demonstrate that extended use of varenicline during the weeks leading up to a quit attempt reduces smoking behavior and subjective effects of smoking during the pre-quit period. The data are consistent with an extinction model of the mechanism of varenicline. The outcome data, though exploratory, suggest that extending the duration of pre-quit varenicline improves short-term abstinence rates above the already notable rates obtained with standard varenicline dosing, at least for a subset of smokers. The combination of a strong theoretical foundation, straightforward treatment modification, and encouraging data on both process and outcome suggest that Phase III trials of extended run-in varenicline therapy for smoking cessation are warranted.