Medical Hypotheses 83 (2014) 352–354

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Nicotine gum chewing: A novel strategy to shorten duration of

postoperative ileus via vagus nerve activation q
Z. Wu a,⇑, G.S.A. Boersema a, J. Jeekel b, J.F. Lange a
a
Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands
b
Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Postoperative ileus (POI) is a transit cessation of bowel motility after surgery. Substantial evidences
Received 29 April 2014 suggest that gum chewing accelerate the recovery of bowel motility after surgery. Perioperative nicotine
Accepted 9 June 2014 administration reduces postoperative opioid use and prevents postoperative nausea and vomiting.
Nicotine gum chewing combines stimulation of the cephalic-vagal reflex by gum chewing, and activation
of the cholinergic anti-inflammatory pathway by nicotine administration. We therefore hypothesized
that nicotine gum chewing reduces POI and improves patient outcomes such as shortening the length
of hospitalization as well as saving medical costs. As nicotine gum is commercially available, inexpensive,
and has been in use for many years without any severe side effects, it may have a wide clinical application
in POI prevention.
Ó 2014 Elsevier Ltd. All rights reserved.

Introduction it remains unavailable in clinical practice. In experimental studies

Postoperative ileus (POI) is a common complication after
abdominal surgery. It is a transit cessation of bowel mobility after
surgery. Clinical manifestation of POI include nausea, vomiting,
abdominal distension, and lack of flatus and defecation [1].
Delayed recovery of bowel function leads to other serious morbid-
ity such as pulmonary complications, hospital-acquired infections,
and longer hospitalization, and it also lead to higher medical cost
[2]. The economic burden of POI in the USA health care system is
estimated to surpass $1.5 billion per year [3].
Numerous risk factors such as previous surgery, general anes-
thesia and postoperative opioid consumption have been reported,
contributing to prolonged bowel dismotility [4]. Targeting on
them, multimodal fast-track perioperative care programs such as
Enhanced Recovery After Surgery (ERAS) including adequate pain
relief, minimal invasive surgery, and early enteral nutrition, are
now being implemented with promising results. Previous research
revealed that surgical procedures trigger two different phases of
POI: an early neurogenic phase and a late inflammatory phase.
The latter one is considered to be a more clinically relevant cause
of gastrointestinal dismotility [4], but efficient strategies targeting
anti-inflammation therapy with stimulation of the vagus nerve
showed promising results in preventing POI. Activation the vagus
nerve increases bowel motility by controlling inflammatory cell
recruitment via the cholinergic anti-inflammatory pathway
[1,4,5]. With the promising experimental results, different strate-
gies of vagus nerve stimulation (e.g. physiological, pharmacologi-
cal, and electrical stimulation) are now being attempted in
human patients.
The hypothesis
Nicotine chewing gum may have double effect on stimulating
the vagus nerve via physiological pathways by chewing, and via
pharmacological pathways by the nicotine administration.
Although no direct evidence is available to date, accumulative data
from clinical and experimental studies are in favor of the hypoth-
esis: nicotine gum chewing reduces the time of POI and improve
patient’s outcomes via vagus nerve activation. We evaluated the
current evidence supporting this hypothesis in the following parts.
Evaluation of the hypothesis

q
Part I. Influence of gum chewing in preventing POI
This work is supported by Stichting Coolsingel, Rotterdam, The Netherlands.
⇑ Corresponding author. Address: Erasmus MC, Laboratory of Experimental
Surgery, Room Ee-173, Postbus 2040, 3000 CA Rotterdam, The Netherlands. Tel.: Gum chewing is a form of sham feeding, which mimics the
+31 10 70 43 683; fax: +31 10 70 44 746. cephalic phase of digestion, stimulates the gastrointestinal motility
E-mail address: wuzhouqiao@gmail.com (Z. Wu). via the vagal pathways [6]. In addition to the vagal pathway,

http://dx.doi.org/10.1016/j.mehy.2014.06.011
0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.
 Z. Wu et al. / Medical Hypotheses 83 (2014) 352–354
ingesting contents of maxitols in sugar-free chewing gum may also
accelerate the intestinal transit [7]. Since Asao et al. first demon-
strated that gum chewing stimulated bowel motility and aided
early recovery from POI in surgical patients [8], many randomized
clinical trials have reported similar results [2,9–12]. In general,
consensus has been reached that gum chewing reduces the dura-
tion of POI in abdominal surgery in the recent decade [13]. The
postoperative gum chewing is supported by many systemic
reviews and meta-analysis [6,14–17], which reported that chewing
gum could shorten both POI duration and postoperative hospital-
ization for approximately one day [18]. Importantly, gum chewing
is not only beneficial in POI prevention after gastrointestinal
surgery. It has shown satisfactory results in the prevention of POI
in other types of intra-abdominal surgery (e.g. gynecological
operations) as well [19,20].
Part II. Influence of perioperative administration of nicotine
Nicotine, a selective cholinergic agonist, is an essential regula-
tor of the cholinergic anti-inflammatory pathway [21]. In animal
models, nicotine has been shown to improve survival rates of sep-
sis by stimulating a7 nicotinic acetylcholine receptor (nAchR) [22].
Experimental studies have also shown the effect of specific a7
receptor agonist that ameliorates POI in rats [5], while other nAchR
also play important roles mediating the cholinergic anti-
inflammatory pathway [5,23].
Despite the nicotine replacement therapy (NRT), nicotine
administration has also been investigated for other medical indica-
tions, and many of them provide us indirect evidence of its possible
effect on preventing POI. Perioperative administration of nicotine
(e.g. nicotine patch) has been shown to reduce postoperative nau-
sea and vomiting [24–26], which are common clinical manifesta-
tions of POI. Prevention of those symptoms may significantly
accelerate the recovery of bowel function after surgery. Preopera-
tive nicotine administration also reduces postoperative opioid con-
sumption [27–30], while reducing opioid consumption is an
important strategy of shortening POI [1,4,31]. This effect might
be more evident to smoker patients because they may require
more opioid compared to nonsmoker patients after surgery [32–
34]. Given that approximately 25–40% of colorectal patients are
smokers [35,36], respective recommendations of nicotine gum
chewing (i.e. dosage, frequency) should be considered between
smoker and non-smoker patients due to their different require-
ments in postoperative analgesia and varied responses to nicotine
administration.
It is important to notice that postoperative nausea and vomiting
are strongly influenced by opioid administration in a dose-
dependent pattern [37]. Also, the a7 nicotinic receptor seems to
mediate the nicotine-induced analgesia [38], so its activation by
nicotine administration may benefit the control of both postoper-
ative pain and POI.
One main concern of perioperative nicotine use is its potential
systemic influence or intoxication [39], especially in non-smoker
patients. However, no obvious adverse events (e.g. cardiovascular
events) were reported in the studies included in Part II, many of
which only included non-smoker patients. There was no significant
difference between the groups in postoperative heart rate, arterial
blood pressure, respiratory rate, or oxygen saturation after tempo-
ral nicotine administration [28,29]. The effective nicotine dosage in
those studies were lower than that in NRT, let alone the dosage in
cigarette smoking [40]. However, localized side effects such as dis-
like the taste, irritation of the tongue, mouth, and throat, and occa-
sional nausea caused by nicotine gum chewing should be expected
[41]. But the incidence of these side effects is now much lower than
it was with the earlier forms of the gum.
353
Consequences of the hypothesis and conclusion
Substantial evidence suggests gum chewing accelerates the
recovery of bowel motility after surgery. Nicotine gum chewing
combines the stimulation of the cephalic-vagal reflex by gum
chewing, and the activation of the cholinergic anti-inflammatory
pathway by nicotine administration, it might be beneficial to the
prevention of POI. As nicotine gum is commercially available, inex-
pensive, and has been in use for many years without any severe
side effects, it may have a wide clinical application in POI preven-
tion. Nicotine gum chewing may reduce POI via activating the
vagal pathway and result in better patient outcomes such as short-
ening the length of hospitalization as well as saving medical costs.
Funding
This work is supported by Stichting Coolsingel, Rotterdam, The
Netherlands.
Conflict of interest
The authors do not have any conflicts of interest.
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