Stress Neuroadaptation in Tobacco Dependence

One hundred and twenty eight smokers will provide complete data for this study. Smokers are
randomly assigned at a screening session to complete the NPU stressor task pre-quit or
post-quit (i.e., nicotine deprived or non-deprived). Participants are also randomized to
receive either placebo or active combination nicotine replacement therapy (NRT; patches and
lozenges) for a two week smoking cessation period. The NPU stressor task measures stressor
reactivity to predictable and unpredictable stressors (i.e., electric shock). Startle
potentiation during predictable and unpredictable stressors (relative to no-shock) provides
the primary measures of stressor reactivity in this task. Predictable and unpredictable
startle potentiation are used to calculate overall stressor reactivity and selective
unpredictable stressor reactivity. Further detail on these reactivity measures is provided in
the Independent Variables section. Detail on the quantification of startle potentiation is
provided at the end of this registration.

Smokers provide three weeks (1 week pre-quit, 2 weeks post-quit) of brief 4x daily, real-time
web-survey reports of recent cigarette use, NRT use, and other measures not relevant to this
study's purpose on the participants' smartphones. At two weeks post-quit, smokers are
scheduled for a laboratory visit where participants provide an additional report via staff
interview of any smoking during the two-week smoking cessation period.

The stressor reactivity measures from the NPU task will be tested as predictors of clinical
outcome (i.e., continuous abstinence during the two-week cessation period) to evaluate the
validity of each as surrogate endpoints for use in research on stress mechanisms in smoking
relapse. Deprivation status at the time of the NPU stressor task will be examined as a
moderator of the effect of stressor reactivity to determine if the surrogate endpoints
predict clinical outcome generally or only as deprivation increases.

Inclusion Criteria:

- cigarette use over 10 cigarettes/day for over two years;

- smoking within the first 30 minutes of waking up

- expired air carbon monoxide (CO) level >6 ppm

- self-reported motivation to quit smoking

- and an agreement to respond to ecological momentary assessment prompts (via SMS)
throughout the day for three weeks.

Exclusion Criteria:

- Health screening are performed by questionnaire and reviewed by study staff (RA or
Research Specialist) to ensure that smokers can safely use the nicotine patch and
lozenge. Specifically, smokers will be excluded for FDA contraindications for nicotine
replacement therapy (i.e., no uncontrolled hypertension, recent myocardial infarction,
diabetes, heart disease, asthma, stomach ulcers).

- All women of child-bearing potential will be required to agree to use an approved
method of birth control to prevent pregnancy during the course of the study.

- All participants will report no medical or psychiatric condition that would
contraindicate exposure to electric shock.

- Participants with uncorrected auditory or visual problems will be excluded.

Additional Data Exclusions

1. As part of the NPU stressor task, smokers are asked to indicate if the participant
"can be shocked in the next 5 seconds" at various points during the task. Responses to
these questions are used to verify that the participant understands the cue-shock
contingencies. Smokers who answer < 10 out of 14 questions correctly the NPU stressor
task during the experimental session will be excluded from all analyses and replaced.

2. Smokers with 20% of cue trials identified as artifact in the NPU task will be excluded
from all analyses and replaced.

3. The analysis will NOT exclude smokers who are startle non-responders given that the
use of these surrogate endpoints in practice would likely need to include these
individuals to avoid unnecessary data loss.

4. Smokers who do not report a complete abstinence between quit date/time and final
laboratory visit (which occurs 12-36 hours later) will be considered to not have quit
and will be excluded from all analyses and replaced.

5. Smokers for whom the investigators cannot definitively quantify an outcome with
respect to continuous abstinence will be excluded from all analyses and replaced. Any
report of smoking during the two-week cessation period (reported either during the 4x
daily web surveys or the laboratory visit at 2 weeks) is sufficient to code the smoker
to have lapsed (i.e., not continuously abstinent), even if the participants do not
complete the full two weeks of web surveys and/or the 2-week laboratory visit.
However, the status of smokers who report no smoking during the cessation attempt but
have both a high level of missing data from the web surveys (> 25% of reports) and no
two-week laboratory visit report will be deemed uncertain. These smokers will be
excluded and replaced.

6. The investigators will conduct case analyses to identify participants who are model
outliers with Bonferroni-corrected studentized residuals p < 0.05. These model
outliers will be excluded but NOT replaced (because the participants are not
identified until after data collection has been completed).