Monaldi Arch Chest Dis
2013; 79: 1, 20-26
Varenicline and evaluated outcomes
in smoking cessation programmes
P. Santus, L. Bassi, A. Airoldi, F. Giovannelli, D. Radovanovic
Epidemiology of cigarettes smoking
Tobacco use is widely considered the most pre-
ventable cause of illness and death and its world-
wide use causes more than 5 million deaths per
year and if the current trends in the use of tobacco
will continue, it will cause 8 million deaths per year
by 2030 [1, 2]. It must also be underlined that also
exposure to environmental tobacco smoke results
in an estimated 49,000 deaths every year [2, 3]. A
recent experience reported that prevalence of
smokers in general population is 26% with the
same distribution in all age classes .
The numerous harmful health consequences of
smoking are represented by cancer, with particular
attention to: the lung, oral cavity, oesophagus,
stomach and larynges; the cardiovascular system.
Tobacco use is also implicated in pathophysiolog-
ical process that interesting gastrointestinal system
(decreased appetite, increase insulin resistance,
peptic ulcer, etc.); respiratory system (bronchitis,
chronic obstructive pulmonary disease, chronic
cough, dyspnea, idiopathic pulmonary fibrosis,
etc.); reproductive effects (fertility, low birth
weight, pregnancy complications, etc.); muscu-
loskeletal (decreased bone mineral density, in-
creased risk for fractures, increased spinal disk dis-
ease); mental health and psychosocial status [5-11,
3]. For these reasons it is necessary to convince the
population of smokers to stop smoking, because
are also known a number of beneficial effects on
various body systems. First of all, numerous stud-
ies have focused on the strict correlation between
smoking cessation and a reduction of central blood
pression and arterial stiffness . Smoking cessa-
tion produces effects inflammatory processes and
mucosal on lung function. In fact a reduction in the
number of alveolar macrophages and polymor-
phonuclear in BAL fluid after 6 months of smok-
ing cessation, which is also dependent from smok-
ing history was also observed [12-15].
For all these reasons stopping smoking is the
first therapeutical and principal aim in treating
subjects with respiratory diseases and, with this in
mind, a lot of strategies can be adopted, going
from pharmacological approaches to psychologi-
cal support. So the purpose of this review is to per-
form a brief summary of the possible approaches
for smoking cessation with more attention on
varenicline, analysing the outcomes evaluated in
various studies published in the last years in the
Keywords: Smoking cessation, Varenicline, Tobacco, Smoking, Outcomes.
Università degli Studi di Milano, Dipartimento di Scienze della Salute, Pneumologia Riabilitativa, Fondazione Salvatore
Maugeri, Istituto Scientifico di Milano, IRCCS, Milano, Italy.
Correspondence: Pierachille Santus, Università degli Studi di Milano, Dipartimento di Scienze della Salute, Pneumologia
Riabilitativa, Fondazione Salvatore Maugeri, Istituto Scientifico di Milano, IRCCS, Via Camaldoli 64, 20138 Milano, Italy;
ABSTRACT: Varenicline and evaluated outcomes in smoking
cessation programmes. P. Santus, L. Bassi, A. Airoldi,
F. Giovannelli, D. Radovanovic.
The morbidity and mortality rates attributed to
smoking are substantial and cigarette smoke remains the
first preventable cause of premature death worldwide. De-
spite the knowledge of the adverse consequences of smok-
ing, many smokers struggle to quit. Cigarette smoking is
the primary cause of chronic obstructive pulmonary dis-
ease, and smoking cessation represents the most effective
way of stopping its progression. Varenicline is one of the
first-line smoking cessation aids recommended in many
Clinical Practice Guidelines and its efficacy and safety
have been demonstrated in several clinical trials. Vareni-
cline has a unique mechanism of action and clinical trials
support its use as an effective and generally well-tolerated
This article reviews the clinical pharmacological trials on
smoking cessation published in recent years on varenicline,
with particular attention to the outcomes used in the studies.
MedLine, the Cochrane database and Embase were evaluated.
Almost all the trials have, as a primary endpoint, the
abstinence from cigarettes at 9-12 weeks of treatment. On-
ly one study considers lung function spirometric changes
as a secondary endpoint. No study has evaluated lung
function. This marker could be very important as a way of
evaluating, objectively, an improvement in lung function,
which correlates also with subjective parameters, as dysp-
nea and fatigue.
Monaldi Arch Chest Dis 2013; 79: 1, 20-26.
VARENICLINE AND EVALUATED OUTCOMES IN SMOKING CESSATION PROGRAMMES
Current therapies for smoking cessation
Pharmacological treatments for tobacco addiction
Seven medications for smoking cessation are
currently approved by US Food and Drug Admin-
istration (FDA): five nicotine replacement thera-
pies (NRTs) as nicotine patch, gum, lozenge, nasal
spray and inhaler, and two other medications with
a different mechanism of action: bupropion and
Bupropion, an atypical antidepressant, is ap-
proved for treatment of smoking cessation. In
preclinical studies bupropion, reduced nicotine’s
rewarding effects and attenuated nicotine with-
drawal symptoms. Its mechanism of action is
thought to be mediated by its ability to block the
reuptake of norepinephrine (NE) and dopamine
(DA) in the mesolimbic system and nucleus ac-
cumbens, a key area for nicotine reinforcement.
Additionally, bupropion antagonizes brain nico-
tinic receptors and blocks the reinforcing effects
of nicotine. Following oral administration, bupro-
pion is metabolised extensively in the liver and
excreted through the kidneys with a half-life of
about 20 hours .
A new drug, which was approved by FDA in
2006 is varenicline. It is a partial agonist for the
α4β2 subtype of nicotinic acetylcholine receptors
(nAChRs), which are associated with the addictive
effects of nicotine. Varenicline is also a full agonist
at the α7 nAChR. In smokers, varenicline attenu-
ates the subjective rewarding responses and heart
rate increases induced by intravenous nicotine;
verenicline also improves tobacco withdrawal
symptoms, mood, and cognitive performance in
abstinent smokers . All these effects may con-
tribute to varenicline’s efficacy for smoking cessa-
In clinical settings, health care professionals
typically spend limited time on solving tobacco
addiction, because of the huge amount of clinical
duties they are involved in. However, even a 3-
minute counselling session performed by a physi-
cian can increase the likelihood of prolonged ab-
stinence (OR, 1.3) compared with no counseling.
A recent meta-analysis of 50 randomised behav-
ioural treatments for smoking cessation concluded
that telephone counseling, group treatment, and in-
dividual treatments all seem to increase the
chances of quitting the smoking habit .
New perspectives: vaccines
Since approved treatment options, combined
with intensive counselling, guarantee only a long-
term continuous abstinence rates that rarely exceed
30%, and patient adherence to treatment is modest,
new treatment options are needed. Vaccination
against nicotine is an intriguing novel therapeutic
approach to treat nicotine addiction. In fact, by pre-
venting the passage of nicotine into the brain, anti-
bodies might abolish the rewarding properties of
smoking. Animal studies indicate that antibodies
profoundly change the pharmacokinetics of the
drug and can interfere with nicotine self-adminis-
tration. However, in recent phase I/II trials and one
unpublished phase III trial, these findings were not
fully replicated. So treatment of dependent smokers
cannot be reduced to a course of vaccine injections
but needs to acknowledge the complex pharmaco-
logical and behavioural aspects of smoking .
Brief focus on varenicline
Mechanism of action
The pharmacologic actions of nicotine in the
brain, including nicotine’s dependence-producing
properties, are mediated by the nAChRs, predomi-
nantly the a4b2 nicotinic receptor .
The pleasurable effects of nicotine are mediat-
ed by the mesolimbic dopaminergic system that
consists of ventral tegmental area neurons which
project into the nucleus accumbens and prefrontal
cortex [22, 23]. The release of dopamine in the nu-
cleus accumbens is a key component of the plea-
surable and rewarding effects of nicotine [24, 25].
The partial agonist activity of varenicline at
the α4β2 nAChR promotes a sustained, low level
of dopamine release, which reduces withdrawal
symptoms. Through its higher affinity, lower effi-
cacy, and relatively long half-life compared with
nicotine, varenicline is able to prevent nicotine
from occupying and activating the α4β2 nAChRs
during a smoking cessation relapse. In this way
varenicline acts functionally as an antagonist at the
α4β2 neuronal nAChR, and has the potential to in-
hibit the immediate rewarding effects of nicotine
and reduce smoking satisfaction [26, 27].
The most commonly reported adverse events
in varenicline treated subjects are nausea, abnor-
mal dreams, insomnia, taste perversion, flatulence,
dyspepsia, constipation and headache . Whilst
risks of neuropsychiatric adverse events due to
varenicline have already been reported in a polled
analysis , the likelihood of major gastrointesti-
nal adverse effects (such as nausea, constipation
and flatulence) during maintenance phase lacks
precise documentation .
Singh et al meta-analysis showed a signifi-
cantly increased risk of serious, although not pre-
specified, adverse cardiovascular events associat-
ed with varenicline compared with placebo and the
authors concluded that clinicians should carefully
balance this risk against the known benefits of the
drug on smoking cessation . On the other
hand, a more recent meta-analysis by Prochaska
better defined what the authors mean with “cardio-
vascular adverse event”, including any ischaemic
or arrhythmic adverse cardiovascular event like
myocardial infarction, unstable angina, coronary
revascularisation, coronary artery disease, arrhyth-
mias, transient ischaemic attacks, stroke, sudden
P. SANTUS ET AL.
death or cardiovascular related death, or conges-
tive heart failure .
We conducted a MEDLINE using the key-
words “varenicline” and “smoking cessation”. We
concentrated the attention only on varenicline,
compared with placebo or other pharmachological
approaches, because it is the last and the most ef-
ficient drug on the market.
Of the resulting 622 articles, 533 had been
published in the last five years. These papers could
be classified as follows: 85 clinical trials, 68 ran-
domised controlled trials, 23 meta-analyses, 114
reviews. Guidelines and reviwes were discarded.
Among clinical trials, we took into consideration
those that were performed following a randomisa-
tion design and those which included a representa-
tive number of patients (> 200). With these restric-
tions, only 16 papers could be taken into consider-
ation (table 1).
Varenicline and considered studies outcomes
Tsukahara et al conducted the first randomised
controlled open comparative trial of varenicline vs
nicotine patch in adult smokers in Japan, evaluat-
ing efficacy, safety and withdrawal symptoms in
the 2 groups. The primary endpoint of this trial
was the incidence of smoking cessation in the 2
groups at weeks 9-12 and weeks 9-24, and the
safety and withdrawal symptoms, including stress,
at weeks 12.
Reports of no smoking at week 12 were con-
firmed by measuring the end-expiratory CO con-
centration, using a cut off value of 8 ppm. With-
drawal symptoms were assessed using the Min-
nesota Nicotine Withdrawal Scale (MNWS),
which contains 9 items, while stress was evaluated
using self-monitoring questionnaires, the Stress
Check List (SCL: 30 items), and the State-Trait
Anxiety Inventory (STAI: A-Trait and A-State).
This trial concluded that the continuous abstinence
rates at weeks 9-12 and 9-24 were almost equal in
both groups, heavy smokers quit smoking at only
a low frequency and with tolerable adverse effects,
which means that the choice of drugs should de-
pend on the patient’s request .
The multi-center, randomised, double-blind,
placebo-controlled trial by Rigotti et al was con-
ducted to test the efficacy of varenicline for smok-
ing cessation in patients with stable car-diovascu-
lar disease. Also in this case the primary outcome
was the 4-week continuous abstinence rate (CAR)
during the last 4 weeks of study drug treatment
(weeks 9 to 12), confirmed by the measurement of
exhaled CO (upper limit 10 ppm). The secondary
endpoints, besides drug safety, were particularly
focused on cardiovascular adverse effects and
mortality, CAR from week 9 through 52, for weeks
9 to 24 and 7-day point prevalence of tobacco ab-
stinence at weeks 12, 24, and 52.
The trial has also provided an opportunity to
observe any occurrence of psychiatric adverse
events (AEs) that have been reported in the post
marketing of varenicline, in particular cases of ab-
normal behaviour, depression, suicidal ideation,
and suicide. As expected, varenicline demonstrat-
ed its superiority versus placebo in smoking cessa-
tion, was well tolerated and was not associated
with increases in cardiovascular events, deaths,
blood pressure, or heart rate in patients with histo-
ry of cardiovascular diseases. Also rates of psychi-
atric AEs, were low and similar in the varenicline
and placebo groups .
A very interesting paper by Tashkin, Rennard
et al  studies the effects of varenicline versus
placebo in smokers with mild to moderate COPD
defined as the proportion of participants who re-
ported no smoking or use of any nicotine contain-
ing products, with smoking abstinence confirmed
by exhaled CO < 10 ppm. The secondary efficacy
end point was CO-confirmed CAR for weeks 9 to
52, CAR for weeks 9 to 24 and 7-day point preva-
lence of abstinence (self-reported abstinence from
smoking during the preceding 7 days at each visit
confirmed by CO measures) at weeks 12, 24, and
52. In a separate analysis the authors also consid-
ered the pulmonary function testing, in terms of
Forced Expiratory Volume in the 1st second
(FEV1), Forced Vital Capacity (FVC), FEV1/FVC
ratio, Forced Expiratory Flow rate at 25% to 75%
of the FVC and Peak Expiratory Flow rate (PEF),
but tis data has not been published yet. This trial
has shown that varenicline demonstrated superior
efficacy compared with placebo among smokers
with mild to moderate COPD, with prolonged time
of smoking abstinence both at the end of treatment
and over the subsequent year-long follow-up. In
the Norwegian double blind, placebo controlled,
randomised, multicentre, parallel group clinical
trial by Fagerstrom et al  the primary efficacy
end point was the CAR over the last four weeks of
study treatment (weeks 9-12), defined as cotinine
measurements during clinic visits. Secondary end
points included long term continuous abstinence
rate (weeks 9-26), seven day point prevalence of
abstinence (defined as the proportion of partici-
pants who abstained from smokeless tobacco for
the seven days before the end of treatment (week
12) and the end of the study (week 26)), and the
safety and tolerability of varenicline versus place-
bo for 12 weeks of treatment. The limitation of this
study can be the fact that salivary cotinine mea-
surement in smokeless tobacco users might not re-
flect the same relation to nicotine metabolism in
smokers, because some nicotine is swallowed, un-
dergoes presystemic metabolism in the liver, and is
immediately converted to cotinine. Furthermore,
cotinine concentrations and Fagerstrom test scores
did not predict outcomes, which is contrary to
findings in the smoking cessation literature.
Mitchell Nides et al conducted a randomised,
multicenter, double-blind, parallel-group, placebo-
and active-controlled phase 2 clinical trial of the
efficacy and safety of varenicline in smoking ces-
sation in a population of healthy smokers. The pri-
mary efficacy measure was the continuous quit
rate (CQR) for any 4 weeks, defined as abstinence
VARENICLINE AND EVALUATED OUTCOMES IN SMOKING CESSATION PROGRAMMES
Table 1. - Primary and secondary outcomes evaluated in varenicline studies
AuthorsPrimary outcome Secondary outcomes
Tsukahara H et al  12- and 24-week CO-confirmed CAR• Safety
• Stress and anxiety at weeks 12 evaluated with SCL,
STAI and MNWS
Rigotti NA et al  CO-confirmed CAR for weeks 9 to 12
(last 4 weeks of treatment)
• CAR from week 9 through 52
• CAR for weeks 9 to 24
• 7-d point prevalence of tobacco abstinence at weeks
12, 24, and 52
Tashkin DP et al  CO-confirmed CAR for weeks 9 to 12 • CO-confirmed CAR for weeks 9 to 52
• CAR for weeks 9 to 24
• 7-day point prevalence of abstinence (self-reported
abstinence from smoking during the preceding 7 days at
each visit confirmed by CO measures) at weeks 12, 24,
• Pulmonary function tests
Lough LO et al  Smoking abstinence confirmed
with exhaled carbon monoxide (CO)
Fagerstrom K et al  4- weeks CAR at weeks 9-12 confirmed
with cotinine concentration
• CAR for weeks 9-26
• Seven day point prevalence of abstinence at week 12
• Safety and tolerability of varenicline versus placebo
for 12 weeks of treatment
Nides M et al  4-week CO-confirmed CAR at week 7• CO-confirmed 4-week CAR for weeks 4 to 7, and at 12,
24, and 52 weeks
• Adverse event
• Modification in the MNWS and QSU-Brief questionnaires
Oncken C et al  4 weeks CO-confirmed CAR for weeks
4-7, 9-12 and 9-52
• CO-confirmed 7-day point prevalence abstinence
• Changes in the MNWS and the mCEQ
• CO-confirmed 7-d point prevalence abstinence at weeks
24 and 52
Douglas E et al  4 weeks CAR for weeks 9-12• 4 weeks CAR during the follow-up period (weeks 9-24
Gary E et al  7- and 30-day point prevalent abstinence
Rennard S et al  CO-confirmed CAR during weeks 9-12• CAR during weeks 9-24
• 7-day point prevalence of abstinence at Weeks 12 and 24
• Time to first quit attempt
Moore JT et al  Suicidal/self-injurious behavior or
depression defined as a case with SMQ
Dhelaria K et al Smoking status at 52 weeks • Follow up visits
• Behavioural counselling
• Side effects
Boudrez H et al  CAR in the 7 days between week
11 and 12 based on verbal reporting
• Safety profile
Fagerstrom et al  CAR for 9-24 weeks • Fagerstrom test for nicotine dependence
• Modifications in HIS
• 4 weeks CAR through weeks 24 and 52
• 7-day point prevalence of abstinence at the end of treatment
and at the week 24 and week 52 visits
• Measures of craving (MNWS, mCEQ)
Aubin HJ et al  4 weeks exhaled CO and self-reported
CAR from weeks 9 to 12
P. Wu et al  Smoking cessation at 1 year • Short-term smoking cessation (~3 months)
• Adverse events
CO = carbon monoxide; CAR = continuous abstinence rate; MNSW = Minnesota Nicotine Withdrawal Scale; SCL = Stress
Check List of 30 items; STAI = State-Trait Anxiety Inventory; SMQ = Standardized MedDRA Query; QSU-Brief = Brief
Questionnaire of Smoking Urges; mCEQ = Cigarette Evaluation Questionnaire.
P. SANTUS ET AL.
for any consecutive 28-day period during the treat-
ment phase (determined by diary data). Secondary
efficacy measures included the CO-confirmed
(< 10 ppm) 4-week CQR for weeks 4 to 7, as well
as CQRs from week 4 to weeks 12, 24, and 52. The
Authors concluded that varenicline has better
short-term and long-term efficacy vs placebo and a
good profile of safety .
Oncken et al  conducted a multicenter,
double-blind, placebo controlled study randomis-
ing healthy smokers to assess the efficacy of
varenicline in smoking cessation. The primary ef-
ficacy measures were the CO-confirmed (10 ppm
or lower) 4-week continuous quit rates by pooled
dosage group for weeks 4 through 7 and 9 through
12 and the CAR for weeks 9 through 52. Sec-
ondary efficacy end points during the treatment
period included the CO-confirmed 7-day point
prevalence abstinence (abstaining from smoking
during the preceding 7 days) and changes in the
MNWS and the modified Cigarette Evaluation
Questionnaire (mCEQ) by treatment group. Sec-
ondary long-term outcomes also included the CO-
confirmed 7-day point prevalence abstinence at
weeks 24 and 52. In this case too varenicline
showed its superiority versus placebo, even if the
percentages of nausea experienced among the
treated group varied from 16 to 42%.
More or less the same primary outcome were
took in consideration by Rennard et al , Joren-
by et al  and Aubin et al  in their trials
which investigated varenicline’s efficacy and safe-
ty and compared it respectively with placebo, sus-
tained release bupropion and nicotine transdermal
The study by Swan et al  compared the ef-
fectiveness of three modalities of a behavioural
smoking cessation program in smokers using
varenicline: web-based counseling, proactive tele-
phone-based counseling, or combined telephone
and web counselling. Self-report determined the
primary outcomes (7-day point prevalent absti-
nence at 3- and 6-month follow-up). This study re-
veals two important issues in nicotine addiction
treatment. First, that there were no differences in
abstinence outcomes at 6 months suggests that any
of the three programmes offered here hold promise
as alternative interventions in combination with
varenicline. Second, this study provides important
data regarding the use of varenicline in real-world
settings and is responsive to the need for commu-
nity-based trials involving varenicline. Use of
varenicline in a real-world setting, with less strin-
gent eligibility criteria and less clinical follow up
than in the Phase III trials, still results in substan-
tial abstinence outcomes when paired with behav-
Moore’s study aim  was to assess the rate
of suicidal behaviour and depression in smoking
cessation treatments. In particular bupropion and
varenicline were analysed and the study shows a
substantial, statistically significant increased risk
for varenicline of reported depression and suici-
dal/self-injurious behavior. Bupropion for smok-
ing cessation had instead smaller increased risks.
The study by Dhelaria et al  is a retrospective
cohort study, comparing the effectiveness of
varenicline with nicotine replacement therapy at
one year. The primary endpoint was the smoking
status at 52 weeks, than secondary endpoints in-
cluded follow up visits, behavioural counselling
and side effects. The message of the study is in
contradiction with others clinical trials, because
the authors affirm that varenicline and nicotine re-
placement were equally effective for smoking ces-
sation and varenicline effectiveness is lower than
reported in other clinical trials. Moreover behav-
ioural therapy was rarely proscribed, but is very ef-
Almost all articles we considered have absti-
nence from cigarettes at 9-12 weeks of treatment
with varenicline as primary endpoint. Only one
study considers changes in lung function measured
with spirometry as a secondary endpoint (table 1).
It should be noted from the data reported in table 1
that often the time lag considered to assess the per-
manent smoking cessation varies from study to
study. A certain inhomogeneity between long and
short observation periods can be found throughout
the trials taken in account.
Another important aspect is the assessment
method of smoking cessation; two are the possible
approaches: the measure of urinary or salivary co-
tinite, which allows to discriminate between active
and secondhand smoking, and the non-invasive
measurement of exhaled CO. Some authors claim
that an exhaled CO cut off of 8 ppm  identifies
only the 80% of actual smokers , thus appear-
ing to have insufficient sensibility. Chatkin et al,
on the other hand, have shown that the cut off val-
ue for exhaled CO of 10 ppm could not be appro-
priate for smoking confirmation in patients with
chronic obstructive pulmonary disease (COPD)
with a FEV1< 50%; this because it is possible that
the degree of bronchial obstruction has interfered
in the measure of the exhaled CO .
Only Fagerstrom used urinary cotinine to eval-
uate the smoking state of the subjects studied and
he found no correlation between the cotinine con-
centrations and Fagerstrom test scores. These re-
sults appeared to contrast with the findings in
smoking cessation literature [53, 54, 36]. A possi-
ble explanation of this fact could be that salivary
cotinine measurement in smokeless tobacco users
might not reflect the same relation with nicotine
metabolism present in cigarette smokers, as some
nicotine is swallowed, undergoes first pass metab-
olism in the liver, and is immediately converted to
Surely, having an objective parameter to fol-
low as a confirmation technique for cigarette with-
drawal is mandatory. The patient report alone is
not enough to elaborate a secure and reliable report
on smoking cessation. The monitoring methods
should be standardized and the measures at differ-
ent timings should become the primary outcome in
an efficacy-centered varenicline trial.
VARENICLINE AND EVALUATED OUTCOMES IN SMOKING CESSATION PROGRAMMES
Only one study considered changes in lung
function measured with spirometry as a secondary
endpoint . The study population in this case
was composed by mild and moderate COPD pa-
tients. It is known from numerous studies [50, 51]
that the cessation of smoking habit correlates with
a reduction in the rate of decline in lung function
connected both to cigarettes smoking as to the age.
Thus, the evaluation of lung function changes, not
only considering spirometric-related volumes as
FEV1, Inspiratory Capacity (IC) or Vital Capacity
(VC), but also a more complete functional frame
comprehending for example Specific AirWay Re-
sistance (sRAW), should be assessed, in order to
have a global physiopathological picture of the pa-
tient. However, these part of the results of the pa-
per by Tashkin and Rennard have not been pub-
lished yet .
If we consider the secondary endpoints, the
profile of varenicline tolerability is an aspect which
was often evaluated. In particular, the medication
has shown a good profile of safety and efficacy,
though in some categories of patients, such as those
with active psychiatric diseases, there were cases of
psychosis . Maybe this particular aspect should
be more investigated creating safety-based trials
with primary outcomes designed especially to fo-
cus on the psychiatric side effects.
The modifications in the score of some fre-
quently used questionnaires were used in many pa-
pers to demonstrate presence of withdrawal symp-
toms: Fagerstrom test for nicotine dependence,
Heaviness of Smoking Index (HSI) , the Min-
nesota Nicotine Withdrawal Scale (MNWS) [32,
38, 46, 37], the modified Cigarette Evaluation
Questionnaire (mCEQ) [38, 46]. In all these stud-
ies varenicline has proved its capability in reduc-
ing the scores in parallel with smoking cessation.
A parameter which is missing in all studies and
in our opinion of fundamental importance in the
evaluation of the cessation of smoking is lung
function. It is in fact known that the cessation of
smoking causes a lag of the speed of reduction in
lung function and this is of fundamental impor-
tance especially for pneumologists and for patients
affected of COPD.
This marker could be very important also as a
way to evaluate, objectively, an improvement in
lung function, which correlates also with subjec-
tive parameters, as dyspnea and fatigue. Other
studies are required to investigate these important
aspects in this complex field of smoking cessation
for the care and welfare of the patient with respi-
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