Precessation treatment with nicotine skin patch
facilitates smoking cessation
Jed E. Rose, Frederique M. Behm, Eric C. Westman, Prity Kukovich
[Received 7 December 2004; accepted 18 April 2005]
Nicotine replacement therapy (NRT) is a well-established treatment to aid smoking cessation, and current products
recommend using NRT only after quitting smoking. However, theoretical arguments and previous data support the
hypothesis that precessation use of NRT might be useful in reducing dependence on inhaled nicotine and serve as a
helpful prelude to smoking cessation. The present study explored the use of NRT for 2 weeks before a target quit-
smoking date, during which subjects continued to smoke ad libitum. Three experimental conditions varied the
nicotine delivery of the cigarettes smoked during these 2 weeks so that we could examine the effects of concurrent
nicotine administration on compensatory smoking of low tar and nicotine cigarettes. Subjects smoked (a) their
usual brands of cigarettes, (b) conventional low tar and nicotine cigarettes, or (c) denicotinized cigarettes. After the
quit date, subjects received pharmacotherapy consisting of various doses of NRT (0, 21, or 42mg/24-hr) in
combination with the nicotinic antagonist mecamylamine (10mg/day). Results showed that precessation nicotine
patch treatment was associated with a significantly higher rate of continuous smoking abstinence at 4 weeks,
regardless of cigarette condition. Ad libitum smoking before the target quit date was modulated by nicotine patch
treatment, and compensatory increases in smoking low tar and nicotine cigarettes were prevented by concurrent use
of nicotine patches. These results suggest that use of NRT before a target quit-smoking date deserves further
evaluation as a possible smoking cessation treatment. Moreover, while nicotine patches were well tolerated when
subjects smoked nicotine-containing cigarettes, the use of nicotine skin patches with reduced-nicotine cigarettes
potentially offers the advantage of increased efficacy without introducing concern about toxic effects of excessive
The mainstay of pharmacological treatment for
smoking cessation continues to be nicotine replace-
ment therapy (NRT), which is currently available in
the form of skin patches, gum, nasal spray, inhaler,
lozenge, and tablet (Fiore et al., 2000). All NRT
products have labeling that admonishes the smoker
from continuing to smoke while using NRT. The
rationale behind this instruction is twofold: Not only
are efforts to maintain abstinence sabotaged by any
smoking after a target quit-smoking date (Kenford
et al., 1994; Westman, Behm, Simel, & Rose, 1997),
but it is also widely believed that continuing to
smoke while using NRT could lead to symptoms
of nicotine overdose, such as nausea and vomiting,
and in extreme cases, death (Bansal, Cummings,
Hyland, & Giovino, 2004). However, studies of the
effects of using NRT concurrently with cigarette
smoking, as well as studies of high-dose NRT using
multiple skin patches or combinations of two or
more forms of NRT, have found no evidence of
dangerous consequences of moderate increases in
daily nicotine intake (Benowitz, 2004; Benowitz,
Zevin, & Jacob, 1998; Working Group for the
Study of Transdermal Nicotine in Patients with
Coronary Artery Disease, 1994). Nonetheless, the
belief remains in the minds of many smokers and
clinicians alike that it is unsafe or, at the very least,
unwise to use NRT in conjunction with cigarette
smoking (Duplay, 2005).
ISSN 1462-2203 print/ISSN 1469-994X online # 2006 Society for Research on Nicotine and Tobacco
Jed E. Rose, Ph.D., VA Medical Center and Department of Psychiatry,
Duke University Medical Center, Durham, NC; Frederique M. Behm,
B.A., Prity Kukovich, B.A., Department of Psychiatry, Duke
University Medical Center, Durham, NC; Eric C. Westman, M.D.,
M.H.S., VA Medical Center and Department of Medicine, Duke
University Medical Center, Durham, NC.
Correspondence: Jed E. Rose, Ph.D., Nicotine Research Program,
Duke University & VA Medical Centers, 2424 Erwin Road, Suite 201,
Durham, NC 27705, USA. Tel: +1 (919) 668-5055; Fax: +1 (919) 668-
5088; E-mail: firstname.lastname@example.org
Nicotine & Tobacco Research Volume 8, Number 1 (February 2006) 89–101
Arguing against this position is the finding that
smoking while using NRT might diminish the
reinforcing effects of cigarette smoking or reduce
the dependence on inhaled nicotine, thereby making
it easier to ultimately relinquish smoking. In several
previous studies we have found evidence that
smokers rate cigarettes as less rewarding when
smoking while wearing nicotine skin patches (Levin
et al., 1993; Rose & Behm, 2004a; Rose et al., 1994a,
b; but see Cardenas, Busto, MacDonald, & Corrigall,
2002, for a negative report), and in one small study a
trend was observed for abstinence rates to be higher
when nicotine patches were worn for 4 weeks before
the target quit-smoking date (Rose, Behm, &
Westman, 1998). The present study addressed the
question of whether rates of smoking cessation could
be enhanced by having smokers receive NRT for a
specified period before a target quit-smoking date. A
previous study in our laboratory, using precessation
treatment with the nicotinic cholinergic receptor
antagonist mecamylamine (Rose et al., 1994b), found
that 2 weeks of precessation treatment had signifi-
cant effects in promoting smoking abstinence.
Therefore, early NRT treatment, beginning 2 weeks
before the target quit-smoking date, was compared
with initiating NRT after the quit date.
In addition to varying the presence of NRT before
the quit date, we also manipulated the type of
cigarettes smoked during the 2 weeks, so that we
could collect data regarding the tolerability of
nicotine patches when used in conjunction with
cigarettes of different nicotine deliveries. Moreover,
we were interested in studying how supplemental
nicotine administration might influence compensa-
tory smoking with reduced-nicotine cigarettes, and in
exploring potential mechanisms underlying any
beneficial effect of early patch treatment. For
example, because supplemental nicotine administra-
tion might attenuate the reinforcing effects of inhaled
nicotine, we tracked changes in the subjective
rewarding effects of smoking. In addition, and not
inconsistent with this hypothesis, supplemental nico-
tine administration might reduce the degree to which
subjects felt dependent on cigarettes; we assessed
changes in dependence using the Fagerstro ¨m Test
for Nicotine Dependence
Kozlowski, Frecker, & Fagerstro ¨m, 1991), which
was administered twice at baseline (at the screening
physical exam and at session 1, approximately 1 week
later) and after 2 weeks of treatment (1 day prior to
the quit-smoking date). According to either view, the
effects of early patch treatment on subsequent
smoking abstinence might be diminished by switch-
ing the type of cigarettes smoked before the quit-
smoking date, because the latter manipulation would
also be expected to greatly diminish nicotine rein-
forcement of smoking behavior.
A secondary aim of the present study was to
evaluate the effects of NRT dose after the quit date
and, more specifically, to evaluate the effects of
nicotine dose in the context of postcessation treat-
ment with the nicotinic acetylcholine antagonist
mecamylamine. Previous studies have suggested that
mecamylamine might facilitate smoking cessation,
and we administered mecamylamine in the present
study to provide a basis of comparison with other
ongoing studies in our laboratory. Moreover, our
previous results have indicated that NRT can
effectively relieve tobacco withdrawal symptoms
even in the presence of low doses of mecamylamine
(e.g., 10mg; Rose, Behm, & Westman, 2001).
Therefore we sought to examine the dose-response
relationship (in terms of withdrawal symptoms or
smoking behavior) in the presence of 10mg/day
mecamylamine administration after the quit-smoking
date. However, the present study was not designed to
evaluate the efficacy of mecamylamine administered
after the quit date (which would require a placebo
addressed in other studies.
The study comprised six treatment groups, present-
ing a 3 (usual brand vs. low tar and nicotine cigarette
vs. denicotinized cigarette)62 (21-mg nicotine patch
vs. placebo patch for 2 weeks before the quit-
smoking date)63 (0-mg vs. 21-mg vs. 42-mg nicotine
patch dose for 4 weeks after the quit date) factorial
Subjects were randomly assigned to the nicotine
patch groups in double-blind fashion; the cigarette
condition was not blinded. After the quit-smoking
date, all subjects received active mecamylamine
treatment (10mg/day, subject to dose reduction to
5mg/day in the event of side-effects).
A total of 96 healthy male and female smokers were
recruited from the community by newspaper and
radio advertisements and by word of mouth.
Table 1. Experimental conditions.
Low tar and nicotine
Low tar and nicotine
NICOTINE SKIN PATCH FACILITATES SMOKING CESSATION
predicted to increase abstinence, did not do so,
although there was an effect of postcessation nicotine
dose on symptoms of underarousal (e.g., difficulty
concentrating). The absence of an effect on absti-
nence is not altogether surprising in view of other
recent clinical trials finding little effect of higher
doses of nicotine replacement (Hughes et al., 1999).
It is further likely that the precessation treatments
averted severe withdrawal symptoms for most of the
participants, reducing the potential benefits of
postcessation NRT. Postcessation mecamylamine
treatment also may have attenuated the effects of
Some limitations of the present study should be
noted. The sample sizes were relatively small; hence,
the study was powered only for detecting large
effects. The large number of treatment groups also
raises the possibility of Type I error. Thus the
conclusions should be viewed as preliminary until
further confirmation is obtained. Finally, the present
results may be limited in terms of generalizability,
because mecamylamine was used as a postcessation
treatment. However, Schuurmans et al. (2004), which
did not use mecamylamine, also found that precessa-
tion nicotine patch treatment enhanced quit rates,
thus supporting the general conclusion of the present
In summary, the results of the present study may
point the way to the development of improved
smoking cessation treatments that focus on the
precessation period as a critical time during which
patch administration, might reduce dependence on
cigarettes and substantially increase the likelihood of
achieving abstinence from smoking. Use of nicotine
patches for a period of time before a target quit-
smoking date would be a readily disseminated
and easily implemented change in current treatment
practices. Moreover, if concerns remain about the
possibility of nicotine overdose from smoking in
conjunction with wearing nicotine patches, these
concerns could be mitigated by having smokers
switch to the use of reduced-nicotine cigarettes
during the period of patch use. In view of the
doubling quit rates, using a method that could
be implemented easily on a wide scale, further
large-scale efficacy trials are clearly indicated to
evaluate definitively the promise of precessation
nicotine patch treatment.
Acknowledgments and disclosure
This research was supported by grant DA 02665 from the National
Institute on Drug Abuse. The authors appreciate the assistance of
Sarabeth Dermer, Joanne Schaffer, Suzanne Schweitzer, and Benjamin
Isbell in conducting this study. Dr. Rose is an inventor named on
several patent applications dealing with nicotine skin patch and
combination nicotine/mecamylamine treatment, and receives royalties
from sales of certain nicotine patches. Dr. Rose currently receives
research funding from Phillip Morris USA, Inc.
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