Addictive Behaviors 38 (2013) 1865–1875

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Addictive Behaviors

Does combination pharmacological intervention for smoking cessation preventpost-cessation weight gain? A systemic review

Mo Yang, Debajyoti Bhowmik, Xin Wang, Susan Abughosh ⁎Department of Clinical Sciences and Administration, College of Pharmacy, University of Houston, 1441 Moursund St., Houston, TX 77030, USA

H I G H L I G H T S

► Combination therapy had less post-cessation weight gain than monotherapy in short term.► Long term weight gain was not well documented by most of the studies.► Smoking cessation medication plus behavioral intervention is suggested for weight gain.

⁎ Corresponding author at: Tel.: +1 713 795 8395; faE-mail addresses: myang8@uh.edu (M. Yang), debaj

(D. Bhowmik), xwang40@uh.edu (X. Wang), smabugho@

0306-4603/$ – see front matter © 2012 Elsevier Ltd. Allhttp://dx.doi.org/10.1016/j.addbeh.2012.11.007

a b s t r a c t

a r t i c l e i n f o

Keywords:

Systematic reviewCombination pharmacological treatmentSmoking cessation interventionWeight gain

Background: Most smokers who quit smoking gain weight. There are some interventions designed to limitweight gain following smoking cessation.Objective: To conduct a systematic review to evaluate if combination pharmacological therapy interventionsfor smoking cessation are effective in reducing post-cessation weight gain.Methods: The following databases were researched: Medline, PubMed, PsycINFO, CENTRAL and EMBASE.

Detailed inclusion and exclusion criteria were specified a priori before conducting abstract and full textscreening. Included studies were required to: (1) report data on combination pharmacotherapy includingat least one FDA-approved smoking cessation medication; (2) report outcome measure of weight changefrom baseline to the end of follow up; (3) incorporate a minimum of 2-week follow-up; (4) recruit adultsmokers. Studies were excluded if they had (1) behavioral interventions; (2) sample size of b30; (3) switchingmedications; or (4) they were not written in English. Abstracts and the full texts were reviewed independentlyby two investigators. Inclusion of studies was decided by a third independent investigator in case of disagree-ment between the two primary investigators.Results:Out of 1873 studies identified, 1083 studies were included for abstract screening. Finally, 12 studies metthe eligibility criteria after full text screening of 242 studies. Seven studies showed that participants in thecombined therapy group had less post-cessation weight gain than those in the group of individual drugs orplacebo. Four studies did not report differential weight gain measures by treatment groups. Only one studyshowed that post-treatment weight gain in the combined therapy group was more than the monotherapygroup, although the result was not statistically significant.Conclusions: Seven out of twelve studies indicated that combination smoking cessation medications had lesspost-cessation weight gain than monotherapy or placebo in short term. Long term weight gain was not welldocumented by most of the studies and future research is warranted.

© 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Tobacco use remains the primary preventable cause of prema-ture mortality and morbidity in the United States, with an estimat-ed 443,000 deaths from diseases including cardiovascular and

x: +1 713 795 8383.yoti_bhowmik@yahoo.co.incentral.uh.edu (S. Abughosh).

rights reserved.

respiratory diseases and cancer (Centers for Disease Control,Prevention (CDC), 2012). It was estimated that smoking cost theUnited States $193 billion in annual health-related expendituresbetween 2000 and 2004, with $96 billion in direct medical costsand approximately $97 billion in lost productivity (Centers forDisease Control, Prevention (CDC), 2008). An estimated 46.5 mil-lion Americans acknowledged smoking; of these, 70% reportedthat they were willing to quit completely (Corelli & Hudmon,2002). It was reported that around 52% in the United States madea serious attempt to quit; however, without receiving proper assis-tance in smoking cessation, more than 70% and 93% failed to quit

1866 M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

smoking at 1 month and 1 year after their initial quit date, respectively(Berg et al., 2010). Efforts to promote smoking cessation amongsmokers should be a routine preventive health care measure sincetobacco-related disease is preventable (Corelli & Hudmon, 2002).

Cigarette smoking has had the perception of controlling bodyweight for many years (Audrain-McGovern & Benowitz, 2011).Female adolescents report initiating and continuing with cigarettesmoking to control and lose weight (Fulkerson & French, 2003).Weight gain is one of the major reasons that hinder smoking cessa-tion success (Meyers et al., 1997). Borrelli and Mermelstein (1998)noted that weight gain was associated with subsequent relapse ofsmoking behavior; Swan, Ward, Carmelli, and Jack (1993) found that“weight concerned” female smokers were more likely to reinitiatesmoking than any other group; Meyers et al. (1997) concluded a lowerlikelihood of quitting smoking among weight-concerned smokers thanany other group. One exploratory study with a sample of 113 partici-pants reported that 40% of recruited female respondents expressed anunwillingness to gain any weight at all (Pomerleau & Kurth, 1996) postcessation, however, it is estimated that 80% of smokers who quitsmoking gain weight in the United States (USDHHS, 2000). Moreover,smokers gain weight differentially after quitting smoking (Hall, McGee,Tunstall, Duffy, & Benowitz, 1989; Kawachi, Troisi, Rotnitzky, Coakley,& Colditz, 1996; Moffatt & Owens, 1991; Stamford, Matter, Fell, &Papanek, 1986; Williamson et al., 1991). Smokers gain between 7 to 19pounds within 8 years of their successful initial quitting, whereas thosewho continue to smoke gain an average of 4 to 5 pounds (Lycett,Munafò, Johnstone, Murphy, & Aveyard, 2011; O'Hara et al., 1998).Williamson et al. (1991) reported that approximately 10% of smokersgained nearly 30 pounds in weight after quitting smoking. Weight gainoccurs greatest in the first 1–2 months and mostly within the first5 months, although continues to increase for 6 or more months afterquitting smoking (Audrain-McGovern & Benowitz, 2011; Klesges et al.,1997).

It is therefore not surprising that a widespread concern prevailsamong smokers that quitting smoking is in general accompaniedwith weight gain; this weight gain can lessen some of the health ben-efits of quitting smoking (Audrain-McGovern & Benowitz, 2011).Although most health care providers would agree that the benefitsof smoking cessation significantly outweigh the health risks associat-ed with post-cessation weight gain (Audrain-McGovern & Benowitz,2011); nonetheless, post-cessation weight gain may contribute toan increased risk of type 2 diabetes (Yeh, Duncan, Schmidt, Wang, &Brancati, 2010), hypertension (Janzon, Hedblad, Berglund, & Engström,2004), and a reduced improvement of lung function (Chinn et al., 2005).

The US Public Health Service Clinical Practice Guidelines suggestthat smoking cessation interventions should include at least one FDA-approved medication, if feasible and not medically contraindicated, incombination with tobacco dependence counseling, to increase the like-lihood of smoking cessation success (Fiore et al., 2008). In someinstances, combination pharmacological interventions may be appro-priate (Fiore et al., 2008). Several smoking cessation pharmacotherapieshave been evaluated to be effective and are available for preventingpost-cessation weight gain. First-line smoking cessation medications,which are approved by the FDA, include nicotine agonists (also namesas nicotine replacement therapies (NRTs)), nicotine antagonists(sustained-release bupropion hydrochloride bamfebutamone>), andnicotine partial agonists (varenicline bChantix>). NRTs include nicotinegum, nicotine transdermal patches, nicotine nasal spray, and nicotineinhaler. Second-line medications, which are not approved by the FDAfor smoking cessation but have demonstrated some effectiveness,include clonidine hydrochloride and nortriptyline hydrochloride(Table 1). The use of approved smoking cessation medications dou-bles the likelihood of quitting smoking (Fiore et al., 2008; West,McNeill, & Raw, 2000); and new evidence has revealed that combina-tion pharmacological interventions are especially effective. Cliniciansalso should consider the use of certain combination pharmacological

interventions identified as effective in this Clinical Practice Guideline(Fiore et al., 2008).

The effects of these smoking cessation medications on weight gainhave been reviewed (Parsons, Shraim, Inglis, Aveyard, & Hajek, 2009).Several trials have demonstrated a lesser post cessation weight gainwhen using bupropion compared to varenicline or placebo (Gadde &Xiong, 2007; Parsons et al., 2009). At the end of treatment, participantstaking bupropion were found to gain significantly less weight thanthose on varenicline (−0.51 kg (−0.09 to −0.93)) (Gonzales et al.,2006; Jorenby et al., 2006; Nides et al., 2006) and placebo (−1.11 kg(−1.47 to −076)) (Parsons et al., 2009). However, varenicline had nosignificant effect on post-cessation weight gain compared with placeboat the endof treatment (Gonzales et al., 2006; Jorenby et al., 2006; Nideset al., 2006; Oncken et al., 2006). The reduction in weight was less withbupropion compared to placebo at 1-year (3.8 vs. 5.6 kg) and 2-yearfollow-up (4.1 vs. 5.4 kg) (Jorenby et al., 1999). However, no studiesreported varenicline treatment differences versus placebo or bupropionin weight gain in the longer term follow up (Parsons et al., 2009). Thereare evidences from randomized control trials (RCTs) and observationalstudies that NRT, antidepressants (i.e., bupropion) and probablyvarenicline for smoking cessation all reduce weight gain after smokingcessation in the short term (Parsons et al., 2009). Combination therapyhas been introduced as an aid for smoking cessation with the hope oflimiting gain in weight. Combining agents with different mechanismsof action such as bupropion with NRT, varenicline with NRT, NRTwith NRT seems to be promising (Fagerström, 1994; Sweeney, Fant,Fagerstrom, McGovern, & Henningfield, 2001). Unfortunately, there isno gold standard for selection among the first-line medications (Fioreet al., 2008). Nevertheless, efficacy of combination pharmacotherapiesfor smoking cessation in reducing post-cessation weight gain is notwell summarized as the correspondingmonotherapies. A systematic re-viewwas conducted to examinewhether combination pharmacologicaltherapy for smoking cessation offers an effective way to reduce post-cessation weight gain.

2. Materials and methods

2.1. Data sources and systematic searches

The following databases were researched: Medline (Ovid; 1989 toSeptember 2011; & In-Process &OtherNon-Indexed Citations September2011; searched September 21, 2011); PubMed (National Library of Med-icine; searched October 6, 2011); PsycINFO (Ovid; 1987 to January 2ndweek, 2012); Cochrane Central Register of Controlled Trials (CENTRAL)(searched January 13, 2012), EMBASE (Ovid Embase Classic plus Embase;1947 to 2012 January 19; searched January 20, 2012), assisted by anexperienced health sciences librarian (H.V) in developing search strate-gies. The core search criteriawere: pharmacological/medication smokingcessation interventions, andweight gain orweight loss orweight change.An example of comprehensive search strings for Ovid Medline databasecan be found in Appendix A. Appropriate terms regarding FDA-approvedpharmacotherapy for smoking cessation andweight gain specific to eachdatabase and keyword searchingwithin the title and abstract fieldswereemployed to retrieve relevant studies. Searches were limited to studiespublished before October 2011 with both abstract and full text writtenin English. Gray literature sources, unpublished conference abstracts,newspaper or magazine articles, researches in progress, or unpublisheddissertations or theses were not included to retain quality of literatureensured by peer review. References from included studieswere searchedmanually to identify relevant articles. An update search of literaturedatabaseswas repeated using the same search strategy for each databasewith an additional limit to retrieve references published or updatedbetween October 2011 and January 2012. The flowchart (Fig. 1) indi-cates the total number of references that were found through allsearches.

Table 1FDA-approved first-line pharmacologic agents for smoking cessation.

Medication type Cessation agent Genericavailability

Dosage Use Availability Cost/day*

Nicotine Agonists(Nicotine ReplacementTherapies)

Nicotinegum/Nicotinepolacrilex

Yes 2 mgb25 cig/day and4 mg>25 cig/day;one piece every 1–2 hoursfor weeks 1–6,one every 2–4 hours forweeks 7–9,one every 4–8 hours forweeks 10–12

Up to 12 weeks Traditional, mint, andorange flavors OTC:

*Nicorelief®*Nicorette®*Nicorette Plus®*Thrive®

2 mg or 4 mg:$2.16–$4.68

Nicotine patch Yes >10 cig/day:21 mg for 4 weeks, then 14 mgfor 2 weeks, then 7 mg for 2 weeks;b10 cig/day:14 mg for 4 weeks, then 7 mgfor 4 weeks

6–8 weeks Clear and skin colorOTC:

*Nicoderm CQ®*Nicotrol®*Generic

Prescription:*Generic (Legend)

$1.90–3.89(1 patch)

Nicotine nasal spray No 2 squirts (one dose) per hour;minimum 8, maximum40 doses/day;do NOT inhale

3–6 months Prescription Only,*Nicotrol NS®

$3.92 (8 doses)

Nicotine oral inhaler No 6–16 cartridges/day up to 12 weeks,then gradual reduction for another12 weeks

Up to 6 months Prescription only:*Nicotrol inhaler®

$7.32 (6 cartridge)

Nicotine lozenges No If smoking within first 30 minutesafter awake, use 4-mg lozenge;if smoking after 30 minutes,use 2-mg lozenge;one every 1–2 hours for 6 weeks,one every 2–4 hours for 3 weeks,one every 4–8 hours for 3 weeks;minimum 8, maximum20 lozenges/day

Up to 12 weeks Mint and cherry flavorsOTC:

*Commit®*Generic (Nicabate)

2 mg or 4 mg:$3.24–$4.95(9 pieces)

NicotineAntagonists

Bupropion-SR 150 Yes 150 mg each morning for days 1–3,150 mg twice daily for days 4-end

Start 1–2 weeks beforequit date;Recommend use for3 months

Prescription only:*Zyban®*Wellbutrin SR®*Generic SR

$3.63–$7.78(2 tablets)

NicotinePartialagonists

Varenicline No 0.5 mg every morning for days 1–3,0.5 mg twice daily for days 4–7,1 mg twice daily for days 8-end

Start 1 week beforequit date; recommenduse for 3–6 months

Rx only:*Chantix®

$4.90–$5.18(2 tablets)

FDA: the Food and Drug Administration; Cig: cigarette; OCT: over the counter.*Average wholesale price from Medi-Sapn Electronic Drug File. Indianapolis, IN: Wolters Kluwer Health, October 2010. Check patient insurance plan for coverage.

1867M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

2.2. Study selection

The search protocol included randomized controlled trials andobservational studies in which pharmacological interventions weredesigned to quit smoking and limit weight gain during and post-cessation, and the association between combination pharmacologicalsmoking cessation interventions and weight gain was evaluated withpre- and post-treatment measurements of weight. In accordance witha systematic review methodology, explicit inclusion and exclusioncriteria were established prior to the literature search and reviewprocess. Included studies were required to: (1) report data on combi-nation pharmacotherapy for smoking cessation with at least oneFDA-approved smoking cessation medication, for example, nicotinereplacement treatment (NRT) which consists of nicotine polacrilexgum, transdermal nicotine patch, nicotine nasal spray, and nicotineinhaler; varenicline, and sustained-release bupropion (FDA-unapprovedclonidine hydrochloride and nortriptyline hydrochloride were notincluded); (2) report outcome measures of weight change from base-line to the end of follow up; (3) incorporate a minimum of 2-weekfollow-up; (4) recruit adult smokers who were aged 18 years old andabove and were willing to quit smoking. Studies were excluded if they(1) incorporated behavioral interventions (including diet, energyintake, energy expenditure, and physical activities) accompanied withsmoking cessationmedication (counseling or cognitive behavioral ther-apy only were not excluded); (2) lack information or relevance to

outcome of interest; (3) had sample size of less than 30; (4) hadswitching of pharmacological medications; (5) were not written inEnglish.

2.3. Data extraction and quality assessment

Two investigators (M.Y. and X.W.) independently reviewed list oftitles and abstracts for relevance to outcomes of interest for inclusion.For each of the articles that were deemed eligible after abstractscreening for further review of full texts; data were extracted usinga data extraction form. Each of the two reviewers independentlyabstracted data into a structured form from each article, includinginformation on author and publication year, location, study design/type, funding sources, sample population, interventions, follow-uptime, and results of weight change. Quality assessment was conductedindependently by two investigators (M.Y. and D.B.) according toCochrane Handbook using STROBE for observational studies andCochrane Guidelines for RCTs (Appendix B).

3. Results

A total of 1873 studies were identified from Medline, PubMed,PsycINFO, CENTRAL and EMBASE using systematic searches, with790 internal or external duplicates. A number of 1083 titles andabstracts were finally screened (Fig. 1). According to the exclusion

Fig. 1. Flow diagram summarizing systematic study selection.

1868 M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

criteria, total 841 studies were excluded: four hundred and fifty twostudies were excluded due to study design, such as economic studies,or behavioral intervention studies; thirty nine studies were excludeddue to study population, such as study cohort aged less than 18 yearsold, or sample population was less than 30; one hundred and twentysix studies were excluded due to publication type, such as review,editorial; two hundred and seventeen studies were excluded due tomedication studied, such as not FDA-approved drug(s), not combina-tion pharmacological intervention; and seven studies were excludeddue to combination of a behavioral intervention with a pharmacolog-ical smoking cessation intervention. With a total of 242 full textsscreened, two hundred and thirty were excluded. Of the excludedstudies from full text screening, thirty four studies were for study de-sign, two studies for study population, forty-nine studies for publica-tion type, forty four studies for intervention drug; four studies forcombination of behavioral intervention with medications; ninety-fivestudies lacked relevance to the outcome of interest; one study did notreport the weight change from baseline to the end of follow up, andone citation had switching of pharmacological medications in thestudy. Finally 12 studies met all the eligibility criteria and wereaccepted for inclusion.

The selected 12 studies were conducted between 1999 and 2010.Nine out of twelve studies were conducted in the United States; theother three were in France, Canada, and Brazil (Table 2). Nine studieswere randomized control trials, while one was a retrospective cohortstudy, one was an open-label, one-arm, phase II clinic trial, and onewas an open-label matched control study. Five of the selected studieswere financially supported by pharmaceutical companies; two others

did not disclose financial information, while the remaining of thestudies was supported by organizations such as National Institute ofHealth, Veteran Administration, or Mayo Clinic Cancer Center. Thesample size of each study ranged from 32 to 893. Medication inter-ventions included a combination of NRT and any one of the followingdrugs: rimonabant, naltrexone, nicotine inhaler, bupropion, nortripty-line, selegiline, pralidoxime and ipratropium (ProBAN), or bupropionplus varenicline, or naltrexone plus bupropion. Indicated follow-uptime ranged from the end of treatment at 2 weeks to 52 weeks. Weightchange after smoking cessation medication intervention at differenttime points of followupweremeasured and compared among treatmentgroups, and abstinent and non-abstinent (quitters and continuedsmokers).

Seven studies showed that participants in the combined therapygroup had less post-cessation weight gain than those in the groupof individual drugs or placebo during the short-term follow-up. Thestudy which conducted by Bohadana, Nilsson, Rasmussen, and Martinet(2000) found that therewas a significant difference ofweight change be-tween combination treatment group (nicotine inhaler plus nicotinepatch: 0.49±1.39 kg) and monotherapy treatment group (nicotine in-haler plus placebo patch: 0.99±1.02 kg) (p=0.01) at the end of the2-week follow up. Combination treatment group was reported to haveless weight gain compared to monotherapy treatment group at the endof 12 months follow-up (4.22±3.96 kg vs. 5.06±2.70 kg), althoughthe result was not statistically significant (p=0.14) (Bohadana et al.,2000). Jorenby et al. (1999) reported that combination treatmentgroup (nicotine patch plus bupropion: 1.1 kg) had a less mean weightgain compared to monotherapy (bupropion: 1.7 kg) or placebo group

1869M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

(2.1 kg) (pb0.05) at the end of the 7-week follow-up time period.However, the differences between groups in mean weight changeswere not significant after week 7 (Jorenby et al., 1999). Another studyby Krishnan-Sarin, Meandzija, and O'Malley (2003) exhibited that thecombination treatment group (naltrexone plus nicotine patch) had amean weight decrease of 2.76±1.6 pounds, while the monotherapytreatment group (nicotine patch) had a mean weight gain of 2.17±1.6pounds during the treatment week 1 to 4. The differences remain tillthe end of 4-week treatment, that a decrease of 0.9±0.8 pounds in thecombination treatment group versus an increase of 2.6±0.8 pounds inmonotherapy treatment group (Krishnan-Sarin et al., 2003). A studyconducted by Leigh et al. (2001) reported that participants on a newlydeveloped compound (ProBAN) plus nicotine gum experienced anaverage weight loss of 0.28 kg at the end of 12-week treatment, com-pared to a mean weight gain of 0.83 kg by nicotine gum treatmentgroup, although the change of weight over treatment time period wasnot statistically significant (Leigh et al., 2001). O'Malley et al. (2006)measured the weight change outcome at the end of the 6-week treat-ment in two ways: (1) among continuous abstainers, naltrexone plusnicotine patch combination treatment group gained less weight com-pared to placebo treatment group (naltrexone 100 mg, 50 mg, 25 mg,vs. placebo: 1.5±0.27 kg, 1.1±0.33 kg, 0.7±0.31 kg, 1.9±0.34 kg, re-spectively, pb0.05), while (2) among treatment completers, irrespectiveof smoking abstinence, the weight gain among naltrexone 100 mg,50 mg, 25 mg, versus placebo group was: 1.4±0.22 kg, 1.0±0.23 kg,0.8±0.21 kg, and 1.9±0.22 kg respectively (pb0.05) (O'Malley et al.,2006). However, in a study conducted by Rigotti et al. (2009), the differ-ences in weight change were not significant regardless of abstinence(p=0.15) or non-abstinence (p=0.93). Among abstinent, the averageweight gain in combination treatment group (rimonabant plus nicotinepatch: 0.04±0.20) was less than that in monotherapy treatmentgroup (rimonabant plus placebo patch: 0.49±0.24) (p=0.15); where-as among non-abstinent, the weight loss among both groups weresimilar (combination treatment group: 0.44±0.16 vs. monotherapytreatment group: 0.46±0.16) (p=0.93) (Rigotti et al., 2009). Toll etal. (2008) observed that at the end of week 6, among the continuouslyabstinent participants, combination treatment group (naltrexone plusbupropion) had less average weight gain compared to monotherapytreatment group (bupropion) (1.67±3.17 lbs vs. 3.17±2.04 lbs). Asimilar finding was also reported by Toll et al., that among the entiresample population, the combination treatment group gained less aver-age weight than that of monotherapy treatment group (0.28±3.88 lbsvs. 1.25±2.90 lbs) at the end of week 7, although neither of the differ-ences were statistically significant (Toll et al., 2008).

Four studies did not report differential weight gain values amongparticipants by treatment groups. Instead they reported weight gainvalue of the entire sample population or that by categorizing partici-pants as abstainers or non-abstainers. Covey et al. (2007) reportedthe weight change among abstainers after receiving 16 weeks of main-tenance treatment (4.1±6.9 lbs) and that among abstainers after 24weeks of no-treatment (3.9±8.0 lbs), and found no significant differ-ences (Covey et al., 2007); while Ebbert et al. (2009) noted that theweight change at the end of 12 weeks treatment was 1.6±2.4 kg, and4.2±3.5 kg at the end of 6 months follow up (Ebbert et al., 2009).This finding was similar to the study conducted by Prado et al. (2011),which found that the average absolute gain in weight among abstinentwas 4.2±4.3 kg at the end of 6 months follow-up and 5.0±7.0 kg atthe end of 1 ear follow-up (Prado et al., 2011). Another study conductedby Piper et al. (2007) found a similar result for the short term follow-up:that at week 8, the mean change in weight was 1.53±2.41 kg amongthe participants, although the effects of treatment on weight gainfrom baseline to the end of treatment were not significant.

Only one study by Biberman, Neumann, Katzir, and Gerber (2003)showed that average weight gain of participants in the combinedtherapy group (selegiline plus nicotine patch: 5.1±6.3 kg) was morethan that in the monotherapy treatment group (placebo plus nicotine

patch: 3.7±6.4 kg), although the result was not statistically significant(Biberman et al., 2003).

4. Discussion

Six out of twelve studies had a combination pharmacological reg-imen including bupropion for smoking cessation. Jorenby et al.(1999) concluded that treatment with nicotine patch and bupropionalone resulted in less weight gain following smoking cessation ascompared to the use of placebo. This finding was consistent with pre-vious studies in which bupropion monotherapy and NRTmonotherapies were found to reduce post-cessation weight gain(Hurt et al., 1997; Jorenby et al., 1996; Leischow, Sachs, Bostrom, &Hansen, 1992; Nides et al., 1994). Weight gain was lowest in the com-bination treatment group (nicotine patch plus bupropion) as com-pared to monotherapy treatment groups (nicotine patch orbupropion alone) and placebo group. However, there was no statisti-cally significant difference in weight gain between the groups afterweek 7 of treatment (Jorenby et al., 1999). Ebbert et al., concludedthat varenicline as monotherapy although an effective drug forsmoking cessation, did not have any significant effect on the attenua-tion of post-cessation weight gain, but bupropion did (Gonzales et al.,2006; Hays & Ebbert, 2003; Jorenby et al., 2006). The salutary effect ofbupropion in reducing weight associated with smoking cessation mayprovide additional rationale for combining it with varenicline aspolytherapy regimen for smoking cessation. Toll et al. concludedthat the combination use of naltrexone and bupropion may help re-duce weight gain following smoking cessation (Toll et al., 2008).The effects on weight gain were not statistically significant possiblydue to small sample size. Although there were weight change mea-sures as outcome in studies conducted by Covey et al. and Piper etal., there were no discussions or comments after reporting the resultsin their studies.

Naltrexone, an opiate antagonist, along with counseling andsocial support, is used to help people who have already stoppeddrinking or using drugs continuously avoid these two behaviors bydecreasing the craving for alcohol and blocking the effects of opioidmedications and opioid street drugs. Krishnan-Sarin et al. concludedthat subjects on naltrexone did not gain weight and appeared to losesome weight at the end of the treatment period (Krishnan-Sarin etal., 2003). This findingwas similar to an earlier pilot study that inves-tigated the effect of naltrexone on preventing weight gain (O'Malleyet al., 2006). Although the nicotine patch has exhibited minimaleffect on weight gain following smoking cessation, naltrexoneaugmentation of NRT thus may provide advantage of preventingpost cessation weight gain. O'Malley et al. concluded that the dailyaddition of naltrexone to the nicotine patch resulted in less post-cessation weight gain than placebo plus the nicotine patch (O'Malleyet al., 2006); this result replicated previous preliminary studies(Krishnan-Sarin et al., 2003). In addition, the optimal naltrexonedose may depend on the outcome of interest since the fact thatthere was no single dose of naltrexone was efficacious in both limit-ing weight gain and improving smoking abstinence. For example, theexpected reduction in short-term weight with low-dose naltrexonemay motivate weight-concerned smokers to make an attempt toquit. Toll et al. concluded that the combination use of naltrexoneand bupropion may help minimize weight gain following smokingcessation, but compared to bupropion monotherapy, the combina-tion use did not result in higher smoking cessation rates (Toll et al.,2008). The moderate effect size suggests that naltrexone deservesfurther investigation as a way to reduce post-cessation weightgain in combination with effective pharmacotherapy for weight-concerned smokers.

Rimonabant, an inverse agonist of the cannabinoid receptor type 1(CB1), is an anorectic anti-obesity drug which acts by reducingappetite. It has been officially withdrawn from the market by the

Table 2Evidence table of selected studies.

Author, year Location Study type Funding agency Sample population and treatment arms Interventions Results

Bohadanaet al., 2000

France RCT Pharmacia & UpjohnConsumer Healthcare,Helsingborg, Sweden

N=400 Combination (n=200):nicotine inhaler+nicotine patchMonotherapy (n=200): nicotineinhaler+placebo patch

6 weeks Combination: nicotine inhaler+nicotine patchMonotherapy: nicotine inhaler+placebo patch 7–12 weeksCombination and monotherapy placebo patch

Week 2, p=.01* Combination: 0.49 (±1.39) kgMonotherapy: 0.99 (±1.02) kg 12 months, p=.14Combination: 4.22 (±3.96) kg Monotherapy: 5.06(±2.70) kg

Bibermanet al., 2003

US RCT NA N=109 Combination (n=56):selegiline+nicotine patchMonotherapy (n=53):Placebo+nicotine patch

1 week before quit day Combination: selegiline, 2.5 mg Monotherapy:placebo twice/day 26 weeks Combination: selegiline, 5 mgMonotherapy: placebo twice/daynicotine patch to all participants for the first 8 weeks

Week 52, p=NSCombination: 5.1 (±6.3) kgMonotherapy: 3.7 (±6.4) kg

Coveyet al., 2007

US RCT RO1 #13490 (Covey)from theNational Institute onDrug Abuse;GlaxoSmithKline, Pfizer

N=588Combination (n=73)bupropion+nicotine gumMonotherapybupropion+placebo gum (n=73)placebo pill+nicotine gumPlacebo (n=71)Placebo pill+placebo gum

8 weeksBupropion 150 mg once/d for 3 days and twice/d since day 4 untilweek 8Nicotine patch 21 mg, 14 gm, 7 gm for weeks 4-2-1 after 1 weekof bupropion9 weeksPlacebo group: bupropion 150 mg/dayBupropion group: bupropion 300 mg/day10–16 weeksPlacebo group: placebo pillsBupropion group: bupropion 300 mg/dayFirst week non-treatment follow-upBupropion group: bupropion 150 mg/dayPlacebo group: placebo pill

Weeks 16 maintenance treatmentabstainers (n=129)=4.1 (±6.9) lbs(F3,125=0.41, p=0.75)Weeks 24 non-treatment follow-upabstainers (n=76)=3.9 (±8.0) lbs(F3,72=1.64, p=0.19)

Ebbertet al., 2009

US Open-label,one-arm,Phase IIclinical trail

Mayo Clinic CancerCenter; FraternalOrder of Eaglescompetitive pilotproject program

N=38CombinationBupropion+varenicline

12 weeksVarenicline 0.5 mg once daily for 3 days, 0.5 mg twice daily for Days4–7, and 1.0 mg twice daily maintenance dose for 12 weeksBupropion 150 mg once daily for days 1–3, then twice daily for12 weeks.

At the end of 12 weeks treatmentabstainers=1.6 (±2.4) kg (mean)abstainers=1.4 (IQR: – 0.3 - 3.4) kg (median)At 6 monthsabstainers=4.2 (±3.5) kg (mean)abstainers=4.0 (IQR: 2.9 - 6.6) kg (median)

Jorenby et al.,1999

US RCT Industries (i.e.:GlaxoSmithKline,Novartis)

N=893Combination (n=245): nicotinepatch+bupropionMonotherapy (n=244 each):nicotine patchbupropionPlacebo (n=160)

Bupropion group: one tablet (150-mg) in the morning and oneplacebo in the evening on day 1–3, one each on days 4 – 63Nicotine patch group used one patch for 8 weeks since quittingday (day 8).

Week 7Combination group (1.1 kg) vs.Placebo group (2.1 kg): pb0.05*Combination group vs. Bupropion group (1.7 kg):pb0.05*Monotherapy:Nicotine patch group: 1.6 kg (*NS differencesbetween groups in mean weight changes afterweek 7.)

Krishnan-Sarinet al., 2003

US RCT NIH grantsK02-AA00171,M01-RR00125, andP50-DA84733; Novartis

N=32Combination (n=32):naltrexone+nicotine patchMonotherapy (n=16):nicotine patch

Combination:Day 1 & 2naltrexone (25 mg/day)+nicotine patch (21 mg/day)Day 3 to 4 weeksnaltrexone (50 mg/day)+nicotine patch

Weeks 1–4Combination: -2.76 (±1.6) lbsMonotherapy: 2.17 (±1.6) lbsAt end of 4-week treatmentCombination: -0.9 (±0.8) lbsMonotherapy:2.6 (±0.8) lbs

Leighet al., 2001

Canada RCT NA N=80Combination (n=40):pralidoxime and ipratropium(ProBAN)+nicotine gumMonotherapy (n=40):nicotine gum

1 week before quit dateProBAN+nicotine gum (2 mg up to 3 times/day)Placebo+nicotine gum (2 mg up to 3 times/day)ProBAN+nicotine gum 6 weeks: up to 12 doses/day7–8 weeks: up to 6 doses/day9 – 10 weeks: up to 4 doses/day11 – 12 weeks: up to 2 doses/day

At end of 12-week treatmentCombination: −0.28 kg, p=NSMonotherapy: +0.83 kg, p=NS

O'Malley et al.,2006

US RCT P50-DA-13334P50AA15632,K02-AA00171, andR01-AA11197from the National

N=385Combinationnaltrexone 25 mg/d+nicotine patch(n=93)naltrexone 50 mg/d+nicotine patch

21-mg transdermal nicotine patches for 6 weeks, then placebo or 1 ofthe following 3 dosages of naltrexone: 25, 50, 100 mg/dayFirst weekNaltrexone: 12.5 mg for 1 day, 25 mg for 1 day, 50 mg for 2 days, and100 mg thereafter

At end of 6-week treatmentSituation A:Continuous abstinent (n=157): pb .05*Combination:25-mg N: n=38, 0.7 (±0.31) kg pb .01*

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Author, year

Location Studytype

Fundingagency

Sample population andtreatment arms

Interventions Results

Institute of Health;grant 039787 from theRobert WoodJohnson Foundation;Department of VeteransAffairs, Newington,Conn.

(n=96)naltrexone 100 mg/d+nicotine patch(n=103)Monotherapynicotine patch (n=93)

50-mg N: n=33, 1.1 (±0.33) kg p=.06100-mg N: n=52, 1.5 (±0.27) kg p=.33Placebo: n=34, 1.9 (±0.34) kg (reference)Situation B:Treatment completers (irrespective of smokingabstinence) (n=287): pb .01*Combination:25-mg N: n=75, 0.8 (±0.21) kg pb .001*50-mg N: n=67, 1.0 (±0.23) kg p=.006*100-mg N: n=73, 1.4 (±0.22) kg p=.13Placebo: n=72, 1.9 (±0.22) kg (reference)

Pradoet al., 2011

Brazil Retrospectivecohort study

NA N=868NRT (n=642)nortriptyline (n=69)bupropion (n=35)nortriptyline+NRT (n=70)bupropion+NRT (n=52)

2 weeks before the target quit day for bupropion andnortriptyline usersOne the day before quitting for patients receiving NRTAt least 12 weeks treatment

6 monthsAbsolute gainGeneral: 4.3 (±4.6) kgAbstinent: 4.2(±4.3) kgPresent smokers: 5.1 (±2.4) kgPercentage gainGeneral: 5.8 (±7.1) kgAbstinent: 6.8 (±6.7) kgPresent smokers: 3.7 (±7.7) kg1 yearAbsolute gainGeneral: 1.5 (±7.5) kgAbstinent: 5.0 (±7.0) kgPresent smokers: −0.4 (±5.7) kgPercentage gainGeneral: 2.2 (±10) kgAbstinent: 7.1 (±9.8) kgPresent smokers: −0.4 (±6.7) kg

Piper et al.,2007

US RCT NIH Grants#P50-CA84724-05 and# P50-DA0197-06

N=608Combination (n=228):bupropion+nicotine gumMonotherapy (n=224)bupropion+placebo gum Placebo(n=156)placebo bupropion+placebo gum

8 weeks treatment with 1 week before quit daybupropion (150 mg, b.i.d.)+nicotine gum (4-mg, up to12 pieces/day)bupropion (150 mg, b.i.d.)+placebo gum placebobupropion+placebo gum

8 weeksSample participants=1.53 (±2.41) kg, p=NSWomen=1.23 (±2.38) kgMen=1.90 (±2.41) kgt(417)=2.85, pb .05*

Rigottiet al., 2009

US RCT Sanofi-Aventis N=735Combination (n=369):rimonabant+nicotine patchMonotherapy (n=366)rimonabant+placebo patch

Week 1Rimonabant (20 mg daily for 9 weeks)Week 2 – 11Rimonabant+nicotine patch (21 mg daily for 8 weeks, 14 mg ailyfor 1 week, and 7 mg daily for 1 week)Rimonabant+placebo patch

Weeks 6 – 9abstinent (n=222): p=.15R+nicotine patch: +0.04 (±0.20) kgR+placebo patch: +0.49 (±0.24) kgNon-abstinent (n=398): p=0.93R+nicotine patch: - 0.44 (±0.16) kgR+placebo patch: −0.46 (±0.16) kg

Toll, 2008 US Open labelmatchedcontrol study

NIH grantsK12-DA00167,K05-AA014715,P50-DA13334, andP50-AA15632.

N=40Combination (n=20)naltrexone+bupropionMonotherapy (n=20)Bupropion

Combination:1 week before quit dayBupropion (150 mg) once daily for 3 days, then twice daily for eduration of 7-week treatment. Naltrexone (12.5 mg initial dose nd25 mg for the duration of the 7-week treatment) on the sixth d ofbupropion treatment.Monotherapy:bupropion (300 mg) daily for 7 weeks

Situation AAt treatment week 6: Continuously abstinentCombination: 1.67 (±3.17) lbsMonotherapy: 3.17 (±2.04) lbst (10)=0.97; p=.35; Cohen's d=0.56Situation BAt end of treatment week 7: Entire sampleCombination: 0.28 (±3.88) lbsMonotherapy: 1.25 (±2.90) lbst (38)=0.90; p=.37; Cohen's d=0.28

Abbreviation: RCT=Randomized Control Trials; NA=Not Available; IQR=interquartile range; NRT=Nicotine replacement therapy; R=Rimonabant; N=Naltrexone; F=Flu xetine; NS=not significant.*Indicates statistically significant at less than 0.05 level.

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d

th, aay

o

1 Smoking/2 exp Tobacco/3 (tobacco or smoking or cigar*).ti,ab.4 or/1-35 (quit* or cessation).ti,ab.6 4 and 57 exp "Tobacco Use Cessation"/8 6 or 79 body weight changes/or weight gain/or body weight/10 (weight gain or weight change* or body weight or weight concern*).ti,ab.11 (adverse effect* or adverse event*).ti,ab.12 prognosis/or remission reduction/or predictor*.ti,ab.13 9 or 10 or 11 or 1214 8 and 1315 drug therapy/or drug administration schedule/or drug delivery systems/or

drug therapy, combination/16 exp antidepressive agents/or bupropion/or fluoxetine/17 Naltrexone/18 exp Benzazepines/or exp nicotinic agonists/19 exp Piperidines/20 exp Pyrazoles/21 phenylpropanolamine/22 (phenylpropanolamine or naltrexone or varenicline or bupropion or

fluoxetine or nicotine replacement or nrt or pyrazole* or piperdine* orantidepressive* or benzapiens).ti,ab.

23 or/15-2224 14 and 2325 exp Clinical Trial/or double-blind method/or (clinical trial* or randomized

controlled trial or multicenter study).pt. or exp Clinical Trials as Topic/or((randomi?ed adj7 trial*) or (controlled adj3 trial*) or (clinical adj2 trial*) or((single or doubl* or tripl* or treb*) and (blind* or mask*))).ti,ab.

26 24 and 2527 limit 26 to English language

Appendix. A Ovid Medline search strategy

1872 M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

European Medicines Agency (EMEA) at the beginning of 2009 for thereason that the benefits of rimonabant no longer outweigh its risks.Rigotte et al. concluded that the combination use of rimonabantplus nicotine patch maintained rimonabant's suppression of weightgain following smoking cessation (Rigotti et al., 2009). A longercourse of rimonabant or adding dietary and/or physical activity inter-vention might be helpful for the long term weight suppression(Marcus et al., 1999).

Leigh et al. concluded that the mean weight did not change overthe 12-week study period in subjects who received ProBAN and suc-cessfully quitted, compared to a mean gain of 1 kg (non-significant)in subjects who received placebo treatment and quitted (Leigh etal., 2001). Typically average weight gain associated with successfulsmoking cessation was reported to be 3 kg to 4 kg over a six-monthperiod (Williamson et al., 1991). There were weight change measuresand outcomes in studies conducted by Bohadana et al. andBiberman et al.; however, there were no discussions or commentsafter reporting the results in their studies (Biberman et al., 2003;Bohadana et al., 2000).

Due to presence of heterogeneity among these twelve studies interms of widely varying follow-up period from the end of treatmentat 2 weeks to 52 weeks, disparate measures of differential weightchanges by study groups (by treatment groups or smoking cessationsuccess groups), and different combination pharmacological regi-mens, it was not feasible to conduct meta-analysis to obtain a pooledeffect of combination treatment regimens on their effect on post ces-sation weight change in this study. Regarding follow-up time period,there were measures at the end of treatment, which included multi-ple treatment duration from 4 weeks to 16 weeks; there were mea-sures of follow-up after treatment from 2 weeks to 52 weeks. Theweight change after smoking cessation medication interventionswas measured and compared among treatment groups, or abstinentand non-abstinent (quitters and continued smokers). The p-valuesof the statistical tests were either pre–post within group differencesor between group differences, or description of statistically signifi-cance, in different studies. Combination pharmacological regimensincluded NRT plus rimonabant, naltrexone, fluoxetine, nicotine inhal-er, bupropion, nortriptyline, selegiline, pralidoxime and ipratropium(ProBAN), or bupropion plus varenicline, or naltrexone plusbupropion.

There are certain limitations in this study as well. First of all,among the eleven studies that reported funding sources, five of thestudies were supported by pharmaceutical companies, which mighthave biased the results favoring the products of those companies.Publication bias may be an issue in this study, for post-cessationweight change is generally not a major outcome of interest. Fourout of twelve studies did not discuss or comment on the available re-sults of weight gain following smoking cessation. There are also cer-tain strengths of this study. This systematic review was conductedwith the help of an experienced librarian. A frequently updated datasource was set for comprehensive searches to assure qualifiednewly published studies to be included in our searches.

In future, RCTs can be conducted using standardized follow up pe-riod with post cessation weight change as the primary outcome thatwill help in performing meta-analysis to assess efficacy of specificcombination pharmacotherapies in smoking cessation along with at-tenuating post cessation weight gain. Combination pharmacologicalintervention and combination of pharmacological intervention plusbehavioral intervention in the long term to promote smoking cessa-tion and prevent weight gain can also be studied in future. Alsomost of the studies on combination pharmacotherapies for smokingcessation and influencing post cessation weight gain have beenconducted in RCTs, only one observational study (Prado et al., 2011)was reported our systematic search in this regard. In future, cohortstudies on specific pharmacological combinations with bigger samplesizes and long term follow up period can be conducted to evaluate the

long term effects of the combination regimens on post cessationweight gain, and also weight gain related metabolic events such asdiabetes.

5. Conclusions

More than half of the selected studies indicated that combination ofsmoking cessation medications (with at least one FDA-approved drug)had less post-cessation weight gain than individual drugs or placebo inthe short term. Long term weight gain was not well documented bymost of the studies. According to the discussions in the selected articles,smoking cessation medication in the short term plus behavioral inter-vention(s) for the long term is suggested as an effective strategy forsmoking cessation intervention and prevention of post cessationweightgain.

Role of funding sourcesNone.

ContributorsXin Wang and Mo Yang screened the abstracts and the texts.Mo Yang analyzed the data, assessed the selected citation's quality, and drafted the

manuscript.Debajyoti Bhowmik analyzed the data, assessed the selected citation's quality, and

revised the manuscript.Mo Yang and Susan Abughosh designed the study.All authors gave final approval to the manuscript.

Conflict of interest statementNone of any author.

AcknowledgmentsThe authors thank Ms. Helena M. VonVille, MLS, MPH, for her help of systematic

search in this research project.

Prado et al., 2011

Item No Recommendation Check

Title and abstract 1 (a) Indicate the study's design with a commonly used term in the title orthe abstract

No

(b) Provide in the abstract an informative and balanced summary of whatwas done and what was found

Yes

IntroductionBackground/rationale 2 Explain the scientific background and rationale for the investigation being

reportedYes

Objectives 3 State specific objectives, including any prespecified hypotheses Partly (No hypotheses)MethodsStudy design 4 Present key elements of study design early in the paper YesSetting 5 Describe the setting, locations, and relevant dates, including periods of

recruitment, exposure, follow-up, and data collectionYes

Participants 6 Cohort study—Give the eligibility criteria, and the sources and methods ofselection of participants. Describe methods of follow-up

Yes

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders,and effect modifiers. Give diagnostic criteria, if applicable

Partly (no confoundersnor effect modifiers)

Data sources/measurement

8* For each variable of interest, give sources of data and details of methods ofassessment (measurement). Describe comparability of assessment methodsif there is more than one group

Yes

Bias 9 Describe any efforts to address potential sources of bias NoStudy size 10 Explain how the study size was arrived at NoQuantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and whyPartly (continuous andcategorical only)

Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding Yes(b) Describe any methods used to examine subgroups and interactions No(c) Explain how missing data were addressed No(d) Cohort study—If applicable, explain how loss to follow-up was addressed No(e) Describe any sensitivity analyses No

ResultsParticipants 13* (a) Report numbers of individuals at each stage of study—e.g. numbers

potentially eligible, examined for eligibility, confirmed eligible,included in the study, completing follow-up, and analyzed

Yes

(b) Give reasons for non-participation at each stage Yes(c) Consider use of a flow diagram No

Descriptive data 14* (a) Give characteristics of study participants (e.g. demographic, clinical, social)and information on exposures and potential confounders

Partly(no confoundersinformation)

(b) Indicate number of participants with missing data for each variable of interest NA(c) Cohort study—Summaries follow-up time (e.g., average and total amount) Yes

Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time YesMain results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates

and their precision (e.g., 95% confidence interval). Make clear which confounderswere adjusted for and why they were included

Partly (no confoundersinformation)

(b) Report category boundaries when continuous variables were categorized Yes(c) If relevant, consider translating estimates of relative risk into absolute risk for ameaningful time period

Yes

Other analyses 17 Report other analyses done—e.g. analyses of subgroups and interactions,and sensitivity analyses

No

DiscussionKey results 18 Summaries key results with reference to study objectives YesLimitations 19 Discuss limitations of the study, taking into account sources of potential bias

or imprecision. Discuss both direction and magnitude of any potential biasPartly (no directionnor magnitude)

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations,multiplicity of analyses, results from similar studies, and other relevant evidence

Partly

Generalizability 21 Discuss the generalizability (external validity) of the study results NoOther informationFunding 22 Give the source of funding and the role of the funders for the present study and, if applicable,

for the original study on which the present article is basedNo

Toll et al., 2008Title and abstract 1 (a) Indicate the study's design with a commonly used term in the title or the abstract Yes

(b) Provide in the abstract an informative and balanced summary of what was doneand what was found

Yes

IntroductionBackground/rationale 2 Explain the scientific background and rationale for the investigation being reported YesObjectives 3 State specific objectives, including any pre-specified hypotheses YesMethodsStudy design 4 Present key elements of study design early in the paper YesSetting 5 Describe the setting, locations, and relevant dates, including periods of recruitment,

exposure, follow-up, and data collectionPartly

Participants 6 (a)Case–control study—Give the eligibility criteria, and the sources and methods ofselection of participants.

Yes

(b) Case–control study—For matched studies, give matching criteria and the number of controls per case YesVariables 7 Clearly define all outcomes, exposures, predictors, potential confounders,

and effect modifiers. Give diagnostic criteria, if applicablePartly (only outcomes)

Appendix. B Methodological quality summary: review authors' judgments about each methodological quality item for each included study

(continued on next page)

1873M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

(continued)

Prado et al., 2011

Item No Recommendation Check

Data sources/measurement

8* For each variable of interest, give sources of data and details ofmethods of assessment (measurement).Describe comparability ofassessment methods if there is more than one group

Yes

Bias 9 Describe any efforts to address potential sources of bias NoStudy size 10 Explain how the study size was arrived at NoQuantitative variables 11 Explain how quantitative variables were handled in the analyses.

If applicable, describe which groupings were chosen and whyPartly

Statistical methods 12 (a) Describe all statistical methods, including those used tocontrol for confounding

Yes

(b) Describe any methods used to examine subgroups and interactions No(c) Explain how missing data were addressed No(d) Cross-sectional study—If applicable, describe analytical methodstaking account of sampling strategy

No

(e) Describe any sensitivity analyses NoResultsParticipants 13* (a) Report numbers of individuals at each stage of study—e.g. numbers

potentially eligible, examined for eligibility, confirmed eligible, included in the study,completing follow-up, and analyzed

Partly

(b) Give reasons for non-participation at each stage No(c) Consider use of a flow diagram No

Descriptive data 14* (a) Give characteristics of study participants (e.g. demographic, clinical, social)and information on exposures and potential confounders

Partly

(b) Indicate number of participants with missing data for each variable of interest NoOutcome data 15* Case–control study—Report numbers of outcome events or summary measures NoMain results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates

and their precision (e.g., 95% confidence interval). Make clear which confounderswere adjusted for and why they were included

Partly

(b) Report category boundaries when continuous variables were categorized No(c) If relevant, consider translating estimates of relative risk into absolute risk fora meaningful time period

Yes

Other analyses 17 Report other analyses done—e.g. analyses of subgroups and interactions,and sensitivity analyses

No

DiscussionKey results 18 Summarise key results with reference to study objectives YesLimitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision.

Discuss both direction and magnitude of any potential biasPartly

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations,multiplicity of analyses, results from similar studies, and other relevant evidence

Partly

Generalizability 21 Discuss the generalizability (external validity) of the study results NoOther informationFunding 22 Give the source of funding and the role of the funders for the present study and,

if applicable, for the original study on which the present article is basedYes

Appendix. B (continued)

Adequate sequencegeneration?

Allocationconcealment?

Blinding? Incomplete outcome dataaddressed?

Free of selectivereporting?

Free of otherbias?

Bohadana et al., 2000 Yes Yes Yes Yes Yes Not clearBiberman et al., 2003 Yes Yes Not clear Not clear Not clear Not clearCovey et al., 2007 Yes Not clear No Yes Yes YesEbbert et al., 2009a No No No No Yes NoJorenby et al., 1999 Yes Not clear Not clear Yes Yes Not clearKrishnan-Sarin et al.,2003

Yes Not clear Not clear Yes Yes Yes

Leigh et al., 2001 Yes Yes Not clear Yes Yes YesO'Malley et al., 2006 Yes Yes Yes Yes Yes YesPiper et al., 2007 Yes Yes Yes Yes Yes YesRigotti et al., 2009 Yes Yes Yes Yes Yes Yes

a This is an open-label, one-arm, phase II clinical trial.

Cochrane Guideline

1874 M. Yang et al. / Addictive Behaviors 38 (2013) 1865–1875

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