Varenicline attenuates nicotine-enhanced brain-stimulation reward by activation of α4β2 nicotinic receptors in rats

Abstract

Varenicline, a partial α4β2 and full α7 nicotinic receptor agonist, has been shown to inhibit nicotine self-administration and nicotine-induced increases in extracellular dopamine in the nucleus accumbens. In the present study, we investigated whether varenicline inhibits nicotine-enhanced electrical brain-stimulation reward (BSR), and if so, which receptor subtypes are involved. Systemic administration of nicotine (0.25–1.0 mg/kg, i.p.) or varenicline (0.03–3 mg/kg, i.p.) produced biphasic effects, with low doses producing enhancement (e.g., decreased BSR threshold), and high doses inhibiting BSR. Pretreatment with low dose (0.03–1.0 mg/kg) varenicline dose-dependently attenuated nicotine (0.25 or 0.5 mg/kg)-enhanced BSR. The BSR-enhancing effect produced by varenicline was blocked by mecamylamine (a high affinity nicotinic receptor antagonist) or dihydro-β-erythroidine (a relatively selective nicotinic α4-containing receptor antagonist), but not methyllycaconitine (a selective α7 receptor antagonist), suggesting an effect mediated by activation of α4β2 receptors. This suggestion is supported by findings that the α4β2 receptor agonist SIB-1765F produced a dose-dependent enhancement of BSR, while pretreatment with SIB-1765F attenuated nicotine (0.5 mg/kg)-enhanced BSR. In contrast, the selective α7 receptor agonist ARR-17779, altered neither BSR itself nor nicotine-enhanced BSR, at any dose tested. These findings suggest that: 1) varenicline inhibits nicotine-enhanced BSR, supporting its use as a smoking cessation aid; and 2) varenicline-enhanced BSR by itself and varenicline's anti-nicotine effects are mediated by activation of α4β2, but not α7, receptors.

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Drug, Healthcare and Patient Safety 2010:2 39–48
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Preclinical pharmacology, efficacy, and safety
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Zheng-Xiong Xi
National Institute on Drug Abuse,
Intramural Research Program,
Baltimore, MD, USA
Correspondence: Zheng-Xiong Xi
National Institute on Drug Abuse,
Intramural Research Program,
Baltimore, MD 21224, USA
Tel +1 443 740 2517
Fax +1 443 740 2781
Email zxi@intra.nida.nih.gov
Abstract: Smoking is still the most prominent cause of preventable premature death in
the United States and an increasing cause of morbidity and mortality throughout the world.
Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are
effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable
effects of smoking are mediated predominantly by nicotine, which activates the brain reward
system by activation of brain α4β2 nicotinic acetylcholine receptors (nAChRs). Varenicline is
a novel α4β2 nAChR partial agonist and has been found to be even more effective than NRT or
bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms
after abstinence. Thus, varenicline has been recently approved to be a first-line medication
for smoking cessation in the United States and European countries. Varenicline is generally
well tolerated in healthy adult smokers, with the most commonly reported adverse effects being
nausea, insomnia, and headache. However, growing postmarketing data has linked varenicline
to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, depression, and
psychosis as well as serious injuries potentially relating to unconsciousness, dizziness, visual
disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high
risk populations, such as patients with mental illness and operators of commercial vehicles and
heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been
banned from taking varenicline.
Keywords: nicotine, varenicline, α4β2 nicotinic acetylcholine receptor, nAChRs, partial
agonist, smoking cessation
Introduction
It is estimated that about 1.3 billion people smoke cigarettes worldwide and about
500 million people die annually from tobacco-related diseases.1–3 In the United States
(US), about 45 million adults (∼20%) smoke cigarettes or are exposed to secondhand
smoking, resulting in about 18% of total mortality and 440,000 annual premature
deaths.1,2 The annual economic cost of smoking in the US is about 200 billion dollars.
Smoking cessation has shown to significantly reduce the risk of many smoking-related
diseases such as lung cancer, chronic lung diseases, myocardial infarction, and stroke
as well as decrease morbidity and mortality related to tobacco use.3
However, tobacco dependence is a chronic relapse disorder that is difficult to treat.3
Despite the availability of effective pharmacologic aids, such as nicotine replacement
therapy (NRT) and bupropion sustained-release, these treatments only help 5%–15%
of people to maintain long-term abstinence from smoking.4–6 Craving and withdrawal
symptoms after tobacco cessation are the most important reasons to prevent smokers
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from achieving long-term tobacco abstinence. For these
reasons, novel pharmacotherapies are being developed in
an attempt to improve long-term abstinence outcomes.
Among the most promising of treatments is varenicline, a
novel partial α4β2 nicotinic acctylcholine receptors (nAChR)
agonist, which has recently been approved by the US Food
and Drug Administration (FDA) as a smoking cessation aid.
Varenicline has been found to be even more effective than
placebo, NRT or bupropion in clinical trials.5,6 In this article,
we review the mechanism-based medication development
strategies, preclinical pharmacology, efficacy, and safety
profiles of varenicline in the treatment of cigarette smoking
in humans.
Mechanism of tobacco dependence
The mechanisms underlying tobacco addiction are not
completely understood. Accumulating evidence indicates that
nicotine is the major addictive component in tobacco.7 Nicotine
binds to central and peripheral nAChRs. Acetylcholine (Ach)
is an endogenous neurotransmitter that binds to and acti-
vates both nAChRs and muscarinic acetylcholine receptors.
Neuronal nAChRs are ligand-gated ion channels with high
permeability to Ca++, and are formed from combinations of
five subunits.8,9 To date, twelve different neuronal nAChR
subunits have been cloned, including nine α-subunits
(α2–α10) and three β-subunits (β2–β4). Non-neuronal
subunits, α1, β1, γ, δ, and ε, form peripheral nicotinic
receptors at the neuromuscular junction.10 The neuronal sub-
units combine with two α- and three β-, or five α7-subunits to
form nAChRs (Figure 1).10,11 Both the α4β2 and α7 subtypes
of nAChRs are the most abundant subtypes in the brain and
are localized on presynaptic terminals, somatodendrites, and
postsynaptic cells.8,9 Activation of presynaptic nAChRs by
ACh or nicotine potentiates neurotransmitter release, while
activation of postsynaptic nAChRs increases excitability of
postsynaptic cells by increasing influx of Na+ and Ca++ via
nAChR channels.10–12
One third of the α4β2 nAChRs are located on the
dopamine (DA) cells in the mesolimbic DA system
(Figure 1).13,14 This system originates from DA neurons
in the ventral tegmental area (VTA) in the midbrain and
projects to the forebrain nucleus accumbens (NAc) and
the prefrontal cortex (PFC).15 The α4β2 nAChR subtype
has been thought to play a vital role in mediating nicotine
reward.8–10 This is supported by the finding that blockade of
α4β2 nAChRs by dihydro-β-erythroidine (DHβE) inhib-
its nicotine self-administration in rats.16 Genetic deletion
of α4 or β2 subunits largely abolishes nicotine binding
to mouse brain and inhibits nicotine self-administration
and nicotine-induced increases in NAc DA.17,18 Similarly,
nicotine-mediated currents from VTA (DA) neurons are also
inhibited by DHβE17,19 or dramatically decreased on midbrain
neurons in β2-kockout mice.17,19,20 These data suggest that
both the behavioral and DA-releasing effects of nicotine are
Cingulate
Dorsal striatum
VTA
α4β2nAChR
NAc
PFC
Out
In
Nicotine
Na+/Ca++
α4
α4
β2
β2
β2
Figure 1 Schematic diagram of the mesolimbic DA projection pathway in human brain, illustrating that nicotine activates α4β2 nAChRs located on DA neurons in the VTA
and increases VTA DA neuron activity as well as DA release in the NAc, dorsal striatum, and PFC. Insert: Simplified structure of α4β2 nAChR (ion channel) located on surface
of VTA DA neurons. Activation of α4β2 nAChR opens the receptor ion channel, causing influx of Na+ and/or Ca++ and depolarization of VTA DA neuron.
Abbreviations: DA, dopamine; NAc, nucleus accumbens; nAChR, nicotinic acetylcholine receptors; PFC, prefrontal cortex; VTA, ventral tegmental area.

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mediated predominantly by activation of α4β2 nAChRs in
the mesolimbic DA system.8,9,17,21 As stated above, the α4β2
nAChR is a receptor ion channel with high affinity to nicotine.
High concentrations of nicotine binds to the α4β2 receptor,
causing the ion channel opening and Na+ influx, which sub-
sequently depolarizes VTA DA neurons and increases DA
release in the NAc (Figure 1).21
Medication strategies for the
treatment of nicotine addiction
Modulating nAChRs can be achieved using nAChR agonists,
antagonists, or partial agonists. Full agonists, such as
NRT, mimic the effects of nicotine by activating the receptor,
therefore reducing withdrawal symptoms during nicotine
abstinence.22 NRT is proven effective in smoking cessation,23
although it does not produce complete abstinence because
the smoker is still physically dependent on the effects of
smoking. Antagonists, such as mecamylamine, compete with
nicotine or ACh for occupancy of the receptors.24 Therefore,
a full antagonist may fully block the pharmacological action
of nicotine, such as nicotine reward. However, antagonists
are prone to induce withdrawal symptoms by themselves.22
Surprisingly, mecamylamine in combination with NRT is
more effective than NRT alone or mecamylamine alone in
smoking cessation.25,26 This could be due to a functional effect
of the agonist NRT (reduction of the withdrawal syndromes)
in combination with the effect of the antagonist mecamyla-
mine (attenuation of the reinforcing effects of nicotine). This
finding suggests that the development of a nicotine partial
agonist such as cytisine and varenicline may be optimal in
the treatment of nicotine dependence because partial agonists
display the properties of both agonists and antagonists. Partial
agonists occupy the receptors, but only partially activate them.
As a consequence, the action of a partial agonist is dependent
on the receptor occupancy.27 In cigarette smokers, a partial
agonist would mostly work as an antagonist during smoking
(ie, high nicotine occupancy), but as an agonist during absti-
nence or withdrawal (ie, low nicotine occupancy). Thus, the
rewarding effects of smoking would decrease substantially
but not disappear completely, whereas withdrawal symptoms
and craving episodes would occur less frequently during drug
abstinence due to the release of a low-to-moderate level of
DA produced by a partial agonist itself.28–30
Cytisine – an unnoticed smoking
cessation drug since the 1960s
Cytisine has a molecular structure somewhat similar to that
of nicotine and varenicline (Figure 2). Cytisine is a natural
insecticide present in plants called Cytisus laburnum (Golfen
Rain).28 Cytisine (Tabex®; Sopharma, Sofia, Bulgaria) has
been used in Bulgaria, Germany, Poland, and Russia as
a smoking cessation aid since the 1960s.29–32 Despite its
widespread use in Eastern and Central Europe, cytisine has
remained largely unnoticed elsewhere, possibly due to limited
access to the non-English literature.32 In addition, the underly-
ing mechanisms have remained unclear until the 1990s when
it was reported that cytisine is a partial agonist of nAChRs
with high affinity for α4β2 receptors.28,33 Behavioral stud-
ies in experimental animals suggest that cytisine produces
low-to-moderate behavioral activation,34,35 conditioned place
preference,36 and drug discriminative effects.37 In addition,
drug-naive mice also self-administer cytisine intravenously,
suggesting that cytisine has certain reinforcing effects.38
Preclinical pharmacology
of varenicline
Varenicline as a smoke-cessation aid was developed by
Pfizer in 1997, largely based on cytisine described above.39,40
N
NN
H
N
N
N
NH
CH3
O
3
5
Nicotine(−)-Cytisine Varenicline
Figure 2 Chemical structures of nicotine, cytisine, and varenicline.

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In vitro binding assays indicate that varenicline has higher
binding affinity (Ki = 0.15 nM) to α4β2 nAChRs than
cytisine (Ki = 0.23 nM) or nicotine (Ki = 1.6 nM). It has
500–20,000-fold selectivity for α4β2 receptors over other
nAChR subtypes (Table 1).39–41 In vitro functional patch
clamp studies in HEK cells expressing nAChRs show
that varenicline is a partial agonist with 45% of nicotine’s
maximal efficacy at α4β2 nAChRs.39 In neurochemical
models varenicline has significantly lowered (40%–60%)
efficacy than nicotine in stimulating [3H]-DA release from
rat brain slices in vitro, and in increasing DA release from
rat NAc in vivo.39 When combined with nicotine, varenicline
effectively attenuates the nicotine-induced DA release,
consistent with partial agonism.39
In animal models of addiction (Table 2), varenicline
significantly inhibits nicotine self-administration,39 nicotine-
enhanced brain stimulation reward,42 and nicotine priming,
but not nicotine-associated cue-induced reinstatement of
drug-seeking behavior.43 Varenicline itself does not induce
reinstatement of nicotine seeking when administered as
a priming injection.43 Varenicline partially substitutes for
nicotine in self-administration testing in animals and partially
generalizes to nicotine in the drug discrimination preclinical
animal paradigm,39,44 suggesting that it may have some
abuse potential, but lower than that of nicotine. In addition,
varenicline also enhanced the basal locomotor activity in
drug-naive rats by itself, while pretreatment with varenicline
attenuated acute nicotine-induced hyperlocomotion and
repeated nicotine-induced behavioral sensitization.45
In addition to being an α4β2 nAChR partial agonist,
varenicline is also a full α7 nAChR agonist.46 To determine
which receptor subtype underlies the action of varenicline,
we have recently investigated the effects of α4β2 or α7
receptor agonists or antagonists on varenicline-enhanced
electrical brain-stimulation reward (BSR). We found
that systemic administration of nicotine or varenicline
produced significant BSR enhancement, while pretreatment
with varenicline dose-dependently attenuated nicotine-
enhanced BSR. The BSR-enhancing effect produced by
varenicline was blocked by mecamylamine (a full nAChR
antagonist) and DHβE (a selective α4-containing nAChR
antagonist), but not by methyllycaconitine (a selective
α7 nAChR antagonist), suggesting an effect mediated
by activation of α4β2 receptors.42 This suggestion is
further supported by findings that SIB-1765F, another
selective α4β2 nAChR agonist, produced a dose-dependent
enhancement of BSR, while pretreatment with SIB-1765F
also attenuated nicotine-enhanced BSR. In contrast, the
selective α7 receptor agonist, ARR-17779, altered neither
BSR itself nor nicotine-enhanced BSR, at any dose tested.42
These findings are consistent with other reports that neither
deletion of α7 receptors nor pharmacological blockade of
α7 receptors alters the nicotine-produced discriminative
stimulus effect.47–49 Together, these data suggest that the
pharmacotherapeutic effects of varenicline on nicotine’s
action are mediated by activation of the α4β2, rather than
the α7 nAChR subtype.
The bioavailability of varenicline is high and is unaffected
by the time of dosing or administration with food.50 After
serial measurements, varenicline followed first-order kinetics,
with an elimination T1/2 of ∼24 h after single and multiple
doses.50,51 Steady-state levels were achieved within four
days with repeated oral dosing.51 Pharmacokinetic assays
in healthy adult smokers indicated that varenicline did not
undergo significant hepatic metabolism. Varenicline is 20%
plasma protein bound. Its clearance is predominantly renal,
with 90% excreted unchanged in the urine. Elimination
of varenicline by the kidney primarily involves glomerular
filtration and active tubular secretion via the renal organic
cation transporter hOCT2.51,52
Therapeutic efficacy in humans
Following promising results in preclinical studies, together
with a strong theoretical foundation for its use, testing
of varenicline began in clinical safety and efficacy trials.
Table 3 summarizes the results of the ten clinical trials
with varenicline since it was approved by the US FDA in
2006. These trials were conducted in Australia, Canada,
Europe, Japan, South Korea, China, Thailand, Singapore,
and the US, and enrolled both male and female subjects
Table 1 In vitro binding affinity and functional activity of nicotine, cytisine, and varenicline at human brain nAChRs28,29,41
α4β2a (Ki, nM)
α3β4b (Ki, nM,)
α7c (Ki, nM)
α1β1γδd (Ki, nM)
Functional activity
at α4β2e
–
56%
45%
Nicotine
Cytisine
Varenicline
1.6
0.23
0.15
530
840
83.2
6,300
4,200
616.6
6,300
250
3,388.4
Notes: a[3H]-Nicotine, b[3H]-Epibatidine, c[125I]-α-Bungarotoxin, d[125I]-α-Bungarotoxin, e% Response of 10 µM cytisine or varenicline relative to 10 µM (-)-nicotine.

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(age range, 18–75 years) with no major comorbidities in the
past year. The primary end point in most of the studies was
efficacy, which was assessed primarily in terms of the con-
tinuous abstinence rate (CAR) or continuous quit rate (CQR)
based on subjective reporting and confirmation by exhaled
carbon monoxide (CO) measurement (10 ppm). The second
end points included the urge to smoke, withdrawal symptoms,
and the reinforcing effects of nicotine. In addition, odds ratio
(OR) meta-analysis was also used to measure the comparative
efficacy and abstinence rates for various smoking cessation
medications in some of those clinical trials.
One of the trials reported follow-up data to 24 weeks,53
and the others reported data to 52 weeks.54–62 During treatment
with oral varenicline titrated to 1 mg twice per day (bid),
CO-confirmed CQRs or CARs at week 12 ranged from
28.8% to 65.4%, at week-24 from 20.8% to 70.5%, and at
week-52 from 14.4% to 43.6%. In all these trials, varenicline
1 mg bid was associated with significantly higher CARs or
CQRs compared with placebo at either week 12, week 24, or
week 52 when compared with placebo. Three trials reported
significantly higher CARs or CQRs with varenicline 1 mg
bid compared to bupropion,55,57,58 and one trial reported
significantly higher CARs with varenicline compared with
NRT (Table 3).62 In a relapse-prevention study, CARs were
significantly improved at 24 weeks with varenicline relative
to placebo (70.5% vs 49.6%).59
Nides et al63 conducted a pooled data analysis from the
Phase III trials by Gonzales et al57 and Jorenby et al58 to
explore the relative efficacy of varenicline, bupropion, and
placebo for smoking cessation. Pooled CARs for weeks 9
through 12 were significantly greater for varenicline com-
pared with bupropion and placebo (44.0%, 29.7%, and
17.7%, respectively; both comparisons P  0.001).
West et al64 conducted a similar analysis of pooled
data from the same two Phase III trials57,58 to evaluate
the effects of varenicline, bupropion, and placebo on
craving and withdrawal symptoms among smokers. They
used the Minnesota Nicotine Withdrawal Scale (MNWS)
to score craving and withdrawal symptoms in abstinent
smokers (n = 612) and the Modified Cigarette Evaluation
Questionnaire (mCEQ) to score the reinforcing effects of
smoking in nonabstinent smokers (n = 1,115). They found
that among all participants, cravings (urge to smoke) were
significantly reduced with varenicline or bupropion com-
pared with placebo (both P  0.001) and with varenicline
compared with bupropion (P = 0.008). Overall, varenicline
or bupropion significantly inhibited negative withdrawal syn-
dromes (depression, irritability, anxiety, difficulty concentrat-
ing, and insomnia) compared with placebo. In addition, they
also found that varenicline-treated patients had significantly
lower pleasurable effects of smoking compared with those
treated with bupropion and placebo, as assessed by mCEQ
scores for smoking satisfaction, psychological reward and
enjoyment of respiratory tract sensations.
Cahill et al65 conducted a systemic review and meta-
analysis of the efficacy and tolerability of varenicline for
Table 2 Behavioral effects of cytisine and varenicline in animal models related nicotine addiction
Animal modelsCytisine Varenicline
Locomotor behavior
↑ Locomotion
by itself 34,35
↑ Locomotion by itself45
↓ Nicotine-induced hyperactivity45
↓ Nicotine-induced sensitization45
Self-administration
(SA)
Naïve mice self-
administer cytisine38
↓ Nicotine SA39
No effect on food taking39
Supports low SA by itself39,43
Brain-stimulation reward (BSR)
↑ BSR by itself42
­ –
↓ Nicotine-enhanced BSR42
Reinstatement
↓ Nicotine-induced reinstatement43
But not on cue-induced reinstatement43
No reinstatement by itself43
–
Condition place preference (CPP)Intra-VTA cytisine
produces CPP36
–
Drug discrimination (DD) Producing DD by itselfFully substitutes nicotine in DD39
Partially substitutes nicotine in DD37
Dopamine (DA) in the
nucleus accumbens
↑ DA by itself39
↓ Nicotine-enhanced DA39
–

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smoking cessation in seven placebo-controlled trials, one
relapse-prevention trial, and one open-label trial comparing
varenicline with NRT. The nine trials covered 7,267
participants, 4,744 of whom used varenicline. The pooled
ORs for CAR for varenicline versus placebo at six months or
longer was 2.33 (95% confidence interval [CI]: 1.95–2.80),
for varenicline versus bupropion at one year was 1.52 (95%
CI: 1.22–1.88), and for varenicline versus NRT at one year
was 1.31 (95% CI: 1.01–1.71). These data suggest that var-
enicline is even more effective than bupropion or NRT.
Mills et al66 conducted large-scale pooled data analysis
from nine trials with varenicline (n = 5,192), 101 clinical
trials with NRT (n = 31,321), and 31 trials with bupropion
(n = 11,118) in order to compare treatment effects across
interventions. They found that the pooled ORs for smoking
cessation at four weeks post-target quit data with varenicline,
NRT, and bupropion were 3.16, 2.25, and 2.05, respectively
(P  0.001, compared to placebo). Two trials evaluated head
to head comparisons of varenicline and bupropion, and found
a pooled OR 1.86 (P  0.001). Indirect comparison between
Table 3 Clinical efficacy (CARs) of varenicline in human clinical trials
Varenicline doseCARs (%)
(Week 12)
CARs (%)
(Week 24)
CARs (%)
(Week 52)
Nides et al55
(n = 638)
Placebo
0.3 mg/d, 6 wks
1 mg/d, 6 wks
1 mg, bid, 6 wks
Bupropion:
150 mg, bid, 6 wks
10.6
16.7
15.1
28.8**
19.8*
7.3
9.5
9.5
20.8**
10.3
4.9
7.9
5.6
14.4**
6.3
Oncken et al56
(n = 1,210)
Placebo
0.5 mg/d, 12 wks
(Titrated)
0.5 mg, bid, 12 wks
(Nontitrated)
1 mg, bid, 12 wks
(Titrated)
1 mg, bid
(Nontitrated)
11.6
40.8***
47.3***
54.6***
44.2***
–
–
–
–
–
3.9
Pooled (Titrated
and Nontitrated):
18.5***
Pooled (Titrated
and Nontitrated):
22.4***
Gonzales et al57
(n = 1,025)
Placebo
1 mg, bid, 12 wks
Bupropion:
150 mg, bid
17.7
44.0***
29.5***
10.5
29.5***
20.7***
8.4
21.9***
16.1***
Jorenby et al58
(n = 1,027)
Placebo
1 mg, bid, 12 wks
Bupropion:
150 mg, bid, 12 wks
17.6
43.9***
29.8***
13.2
29.7***
20.2**
10.3
23***
14.6
Tonstad et al59
(n = 1,210)
Placebo
1 mg, bid, 12 wks
–
–
49.6
70.5***
36.9
43.6*
Tsai et al53
(n = 250)
Placebo
1 mg, bid, 12 wks
32.3
59.5***
21.8
46.8***
Nakamura et al60
(n = 619)
Placebo
0.25 mg, bid, 12 wks
0.5 mg, bid, 12 wks
1 mg, bid, 12 wks
39.5
54.7*
55.5**
65.4***
29.5
33.6
35.2
37.7
23.3
27.3
28.9
34.6
Niaura et al61
(n = 320)
Placebo
0.5–2 mg/d, 12 wks
11.6
40.1***
9
28***
7.7
22.3***
Aubin et al62
(n = 757)
NRT, 21 mg/d, 6 wks
1 mg, bid, 12 wks
42.2
55.6###
26.6
32.2
19.8
25.9#
Wang et al67
(n = 333)
Placebo
1 mg, bid, 12 wks
–
–
31.6
50.3***
25
38.2**
Notes: ***P  0.05, **P  0.01, *P  0.001, compared to placebo; #P  0.05, ###P  0.001, compared to NRT.

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varenicline and NRT was OR 1.56 (P  0.001), and between
varenicline and bupropion OR 1.40 (P = 0.01).
Taken together, all these clinical data suggest that
varenicline is superior to placebo, NRT, and bupropion
for achieving abstinence from smoking in the short-term.
Varenicline not only significantly attenuates the craving and
withdrawal symptoms that occur during abstinence from
smoking, but also significantly reduces the rewarding effects
of nicotine and delay smoking relapse. Thus, varenicline, as
the newest agent approved for smoking cessation, offers a new
therapeutic option for the treatment of nicotine addiction.
Tolerability
Varenicline is generally well tolerated, with the most
commonly reported adverse effects being nausea (28.8%,
9.9%, and 9.1%), insomnia (14.2%, 21.5%, and 12.6), and
headache (14.2%, 11.1%, and 12.4) when compared to
bupropion or placebo.54
Nausea
Mild to moderate nausea was the most frequently reported
adverse effect (overall incidence, 24.4%–52.0%) that
occurred at a higher rate in varenicline group than in placebo
groups. Most episodes of nausea began in the first week of
treatment and lasted for a median duration of 12 days. Dose
titration appeared to reduce the overall incidence of nausea.56
There was a low incidence of nausea (13.4%) in varenicline-
treated patients in the self-regulated flexible dosing study.61 In
clinical trials, rates of treatment discontinuation due to nausea
were generally 5% in varenicline-treated patients.54
Insomnia
Insomnia was another commonly reported adverse effect
(14.0%–37.2%) associated with varenicline in the clinical
trials.5,54 In general, insomnia occurred during the first four
weeks of treatment with varenicline and became less common
as treatment continued. In one extended treatment study,67 the
incidence of insomnia was 19.1% with varenicline and 9.5%
with placebo, suggesting that insomnia may be a common
symptom of nicotine withdrawal during smoking-cessation
attempts.
Headache
Other common adverse effects include headache, abnormal
dreams, sleep disturbance, dizziness, dry mouth, increased
appetite, weight gain, and constipation, which generally
occurred at rates twice those with placebo.55–67 These adverse
events were mild-to-moderate and transient, occurring
predominantly during the first four weeks of therapy. The
rates of discontinuation of varenicline treatment due to these
adverse effects were 2% of participants.
Utility in high risk people
Since the approval of varenicline in May 2006, post-marketing
surveillance suggests an association between varenicline and
increased risk of erratic behavior, agitation, suicidal attempt,
depression, psychosis, and severe injuries.68 While some of
the behavioral and mood changes may be associated with
nicotine withdrawal, some occurred in people who continued
smoking while on the medication. The Institute for Safe
Medication Practices (ISMP), an independent safety group,
analyzed all adverse effects since the approval for marketing
and found that varenicline accounted for more reports of
serious adverse effects than any other drug in the US.69,70
Accordingly, the following people are thought to be high-risk
to the use of varenicline.
Patients with mental illnesses
In the fourth quarter report of 2007,71 the FDA reported that
among the total 988 serious injuries related to varenicline
from 2006 to December 2007, there were 227 reports of
suicidal attempt or behavior, 397 cases of possible psychosis,
and 525 reports of hostility or aggression within days to
weeks of initiating varenicline therapy for smoking cessation.
Based on these reports, in November 2007, the FDA issued
an early alert about the safety of varenicline, emphasizing the
need for screening for pre-existing psychiatric illness before
using varenicline and the importance of monitoring/reporting
of mood or behavior changes.71 In May 2008, the FDA
updated the previous Public Health Advisory and required
that all patients should be observed and report to their
physicians immediately for any mood or behavior changes, or
worsening of preexisting psychiatric illness, during or upon
discontinuation of varenicline therapy.72 This safety concern
in such high-risk patients was further emphasized in more
recent clinical reports.73–76 For example, about 5% patients
(from the total 2,682 patients since December 2006) in the
UK reported psychiatric effects during treatment with vareni-
cline, including sleep disorder (43, 1.6%), anxiety (33, 1.2%),
depression (29, 1.0%), abnormal dreams (26, 1.0%), mood
change (17, 0.6%), and suicidal events (n = 5).77
Commercial vehicle drivers
and heavy machinery operators
In addition to those psychiatric effects described above, in the
fourth quarter report of 2007,71 the FDA also reported 372

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46
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movement disorders, 173 serious accidental injuries (includ-
ing 28 traffic accidents and 77 falls), at least 148 reports of
visual disturbances, 224 reports of potential cardiac rhythm
disturbances, 338 moderate to severe skin reactions, and
numerous reports of drowsiness that may affect patients’ abil-
ity to drive or operate machinery. Based on these reports, the
ISMP issued immediate safety concerns related to varenicline
use among operators of vehicles and heavy machinery as
well as in any setting in which alertness and motor control
are required to avoid serious injury. In May 2008, the Federal
Motor Carrier Safety Administration and Federal Aviation
Administration announced that pilots, air-traffic controllers,
and truck and bus drivers are barred from taking smoking-
cessation drug.78,79
Conclusions
Varenicline (Chantix®; Pfizer, New York, NY), an α4β2
nAChR partial agonist, is the first in a new class of agents
for smoking cessation. In the updated clinical practice
guideline from the US Public Health Service, varenicline is
recommended as a well-tolerated and effective first-line
treatment option for smoking cessation. We should note
that the majority of published clinical trials of the efficacy
and tolerability of varenicline have generally excluded
smokers with comorbid conditions (ie, psychiatric disor-
ders, cardiovascular diseases), obese patients, adolescents,
pregnant women, and light smokers (10 cigarettes/d),
which may reduce the generalization of the results to the
broad population of smokers. To date, almost all clinical
trials have been sponsored by the manufactures of var-
enicline, suggesting that potential clinician bias may also
affect the results even when double-blind procedures are
used. Thus, more clinical-trials and postmarketing data are
needed to confirm its efficacy, safety, and tolerability. Given
the growing evidence suggesting a possible association
between varenicline and increased psychiatric symptoms
and other severe injuries potentially relating to uncon-
sciousness, the FDA has issued special warning for the
use of varenicline in patients with pre-existing psychiatric
illnesses, and the Federal Motor Carrier Safety Administra-
tion and Federal Aviation Administration have banned the
use of varenicline in pilots, air-traffic controllers, and truck
and bus drivers.
Acknowledgments
This work was supported by the Intramural Research Program
of the National Institute on Drug Abuse (NIDA) and National
Institutes of Health (NIH), USA.
Disclosure
The author reports no conflicts of interest in this work.
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