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Research paper
How generalisable to community samples are clinical trial results for treatment of nicotine dependence: a comparison of common eligibility criteria with respondents of a large representative general population survey
  1. Yann Le Strat1,2,3,4,5,
  2. Jürgen Rehm6,7,8,
  3. Bernard Le Foll1,2
  1. 1Translational Addiction Research Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  2. 2Addiction Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
  3. 3INSERM U894, Team 1, Centre for Psychiatry and Neurosciences, Paris, France
  4. 4Department of Psychiatry, Louis-Mourier Hospital, AP-HP, Colombes, France
  5. 5Faculty of Medicine, University Paris 7 Denis-Diderot, Paris, France
  6. 6Centre for Addiction and Mental Health (CAMH), Toronto, Canada
  7. 7Dalla Lana School of Public Health (DLSPH), University of Toronto, Canada
  8. 8Institute for Clinical Psychology and Psychotherapy, TU Dresden, Germany
  1. Correspondence to Dr Yann Le Strat, INSERM and Centre for Addiction and Mental Health, 2 ter rue d'Alèsia, Paris, 75014, France; yann.lestrat{at}inserm.fr

Abstract

Objective To examine the generalisability of findings from clinical trials of individuals with nicotine dependence to a large general population sample.

Methods Eligibility criteria were drawn from typical criteria of clinical trials for nicotine dependence. The National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large national sample of the US population, was used to assess how many potentially eligible people would fulfil the eligibility criteria. NESARC interviewed more than 43 000 adults aged 18 years and older. We applied a standard set of eligibility criteria representative of smoking cessation clinical trials to all the 4962 adults with nicotine dependence in the past 12 months, and then to a subgroup of participants motivated to quit (n=4121).

Results We found that approximately six out of 10 participants (65.89%) with nicotine dependence were excluded by at least one criterion. In the subgroup of nicotine-dependent participants motivated to quit, more than half (58.60%) were excluded by at least one criterion. For the overall sample, smoking 10 cigarettes per day or less and lack of motivation to quit were the two criteria leading to exclusion for the greatest percentage of individuals (32.02% and 17.60%, respectively). For the sample motivated to quit, smoking 10 cigarettes or fewer per day and current depression led most frequently to exclusion (33.79% and 15.71%, respectively).

Conclusions Further studies and interventions should explore the efficacy of tobacco treatment interventions in a larger segment of the population, notably in the subpopulations of people with nicotine dependence who smoke fewer than 10 cigarettes per day or who have comorbid depression.

  • Addiction

https://doi.org/10.1136/tc.2010.038703

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    Clinical guidelines are developed based on the evidence obtained using clinical trials.1–4 In smoking cessation trials, exclusion and eligibility criteria are often used in order to maximise treatment efficacy and safety.5 However, they may impair the external validity of the study, since they often exclude a substantial proportion of participants, resulting in a selection bias,5 and extending the gap between research and clinical practice.6 Common exclusion criteria include age, current or past psychiatric/drug disorder, minimal levels of tobacco use and medical conditions.7 There is a risk that this selection of participants affects the results of the treatment trial for nicotine dependence.8 9 The impact of eligibility/exclusion criteria on the generalisability of clinical trials has been described for antidepressant efficacy trials,5 10–14 antipsychotic efficacy trials15–17 and clinical trials for alcohol dependence18–21 and cannabis dependence.22 The percentage of subjects excluded by these criteria ranged between 50.5% and 75.8% in these studies.10 18

    The impact of eligibility criteria in smoking cessation trials has been discussed in the literature.7 23–29 As called for by CONSORT guidelines, several studies reported the reasons for ineligibility.7 28 For example, Robinson et al screened 1347 adolescents for a nicotine replacement treatment trial, and found that only 24.4% were eligible for inclusion in the trial.28 The main reason for ineligibility was a failure to meet minimum requirements regarding the number of cigarettes smoked per day and/or a low level of nicotine dependence (criterion present in 39.1% of ineligible individuals).28 More recently, Kamholtz et al assessed 97 non-eligible and 201 eligible participants in a laboratory research on smoking.7 They reported that the main reasons for ineligibility were current alcohol and substance use disorders (present in 23.7% and 11.3% of ineligible individuals, respectively) and failure to meet minimum requirement regarding cigarettes smoked per day (24.7%). However, when comparing eligible and non-eligible participants, they found no difference in levels of nicotine dependence as assessed by the Fagerström Test for Nicotine Dependence Questionnaire.30

    A limitation of the clinical trials reported in the literature is that they rely on a sample of participants, and therefore cannot be extrapolated to individuals with nicotine dependence in the community. As suggested by Robinson et al,28 and in order to understand the impact of eligibility criteria in the population, an analysis of the application of eligibility criteria to a representative sample of the general population of individuals with nicotine dependence is required.

    With that in mind, we assessed the effect of exclusion criteria commonly applied in clinical trials in a large, nationally representative sample, the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). NESARC is a survey conducted in the United States, including a broad range of psychiatric disorders as well as measures of various medical conditions. We used a method previously described by Blanco et al in clinical trials for major depression 10 and alcohol dependence.18 We wanted to estimate the population generalisability of clinical trials for nicotine-dependent individuals. We applied common clinical trial eligibility criteria to all individuals with a current diagnosis of nicotine dependence, and then to a subsample of individuals who were motivated to quit, to examine the proportion who would have been excluded in treatment trials for nicotine dependence.

    Methods

    Participants

    Subjects were participants in NESARC, a nationally representative face-to-face survey of 43 093 respondents aged 18 years and older (response rate 81%), conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) in 2001–2002.31 32 NESARC assessed the civilian non-institutionalised population residing in the United States. African-Americans and Hispanics were oversampled, as were young adults. The research protocol, including informed consent procedures, received full ethical review and approval from the US Census Bureau and the Office of Management and Budget. Data were adjusted for oversampling and household-level and person-level non-response. The weighted data were then further adjusted to represent the civilian population in the United States based on the 2000 census.

    Measure of nicotine dependence

    NESARC used the National Institute on Alcohol Abuse and Alcoholism's Alcohol Use Disorder and Associated Disabilities Interview Schedule DSM-IV version (AUDADIS-IV), a structured diagnostic interview made for non-clinician interviewers.33 Algorithms were designed to produce diagnoses of nicotine dependence consistent with the final DSM-IV criteria. For example, the ‘using nicotine to relieve or avoid withdrawal symptoms’ criterion was defined by the following four items: (1) the use of nicotine on waking up, (2) the use of nicotine after being in a situation in which use was forbidden, (3) the use of nicotine to decrease nicotine withdrawal symptoms, and (4) waking up in the middle of the night to use tobacco.34 Several studies have documented good to excellent retest reliability.35

    Data analysis

    Exclusion criteria commonly applied in clinical trials of treatments for nicotine dependence (see below in Clinical Trial Exclusion Criteria) were applied to individuals from the general population to determine the proportion of these individuals with current nicotine dependence according to DSM-IV criteria who would be eligible for the clinical trials. The same criteria were applied to the subset of individuals with current nicotine dependence motivated to quit, and examining potential differences in eligibility between motivated and less motivated individuals, using a pattern of analysis described elsewhere.10 18 In these studies, Blanco et al used attempts to quit a substance in the last 12 months as a proxy variable for motivation to quit in the future.10 18

    The appropriate statistical weight was employed when mentioned to ensure the data were representative of the population.

    Clinical trial exclusion criteria

    We examined eligibility criteria from clinical trials included in a recent meta-analysis comparing the effectiveness of pharmacotherapies for smoking cessation.36 We collected all eligibility criteria from 54 randomised clinical trials,37–92 and ranked them according to their frequency. Criteria included in more than 10% of the studies are listed in table 1. The median of the number of eligibility criteria used in a study was 12 (considering not only criteria included in table 1 but also criteria present in less than 10% of the studies). We thus applied the 12 most frequently used criteria to the NESARC sample.

    View this table:
    Table 1

    Eligibility criteria in 54 randomised clinical trials assessing pharmacotherapies for smoking cessation

    The percentages of individuals excluded by criteria 1, 3, 5, 6, 7, 8, 11 and 12 were estimated from data collected by the AUDADIS-IV. Information to approximate criterion 4 (use of psychotropic medications), criterion 9 (use of bupropion or nicotine replacement therapy) and criterion 10 (history of eating disorder) was not available in the NESARC.

    Criterion 1 (pregnancy status) was assessed with a single question (“Were you pregnant at any time during the past year?”).

    The presence of a recent cardiac event (criterion 2) was assessed by series of questions on chest pain, angina pectoris, heart attack, myocardial infarction or any other form of heart disease in the last 12 months, and whether the diagnosis was confirmed by a physician.

    Criterion 3 (‘Smoking 10 cigarettes or fewer per day on average’) was applied using a 12-month time frame (as it is assessed in the NESARC).

    Criterion 5 (‘Alcohol dependence’) was defined having a diagnosis of alcohol dependence within the last 12 months.

    Criterion 6 (‘Being not motivated to quit smoking’) was assessed by two questions: “In your entire life, did you ever, more than once, want to stop or cut down your tobacco use?”), and “Did this happen in the last 12 months?” Participants who respond positively to both questions were classified as being motivated to quit smoking. Other participants were classified as being not motivated to quit smoking. This assessment is therefore at variance with standard questions about motivation in research trials, that usually asked whether participants want to cut down/attempt to stop in the future rather than if they have done so in the past.

    Criterion 7 (‘Dependence on other drugs’) was defined having a diagnosis of dependence on an illicit substance (sedatives, tranquillisers, opiates, stimulants, hallucinogens, cannabis, cocaine (including crack cocaine), inhalants/solvents, heroin or other drugs) within the last 12 months.

    Criterion 8 (‘Having current depression’) was assessed using the criteria for major depressive disorder within the last 12 months.

    Criterion 11 (‘Having a current psychosis’) was assessed by two questions: “Did a doctor or other health professional ever diagnose you with schizophrenia or psychotic illness or episode?” Participants who respond positively to this were classified as having a ‘psychosis’.

    Participants with a lifetime history of mania were classified as having a bipolar disorder (criterion 12). We chose to consider only bipolar type I disorder because hypomania, the hallmark of bipolar type II disorder, is a more subtle form of the disorder and therefore not likely to be screened routinely in eligibility assessments of clinical trials for nicotine-dependent individuals. For the same reason, we considered participants as having bipolar disorder if they had a history of mania even if manic episodes were induced by a substance or an illness, and did not restrict our analysis to independent bipolar disorders. As a control, we did a sensitivity analysis to examine how the results would change if (i) substance-induced and illness-induced mania were ruled out, and (ii) if bipolar type II disorder was also included in the eligibility criteria (with substance-induced and illness-induced disorders being ruled out).

    Analysis

    We first determined the number and percentage of nicotine-dependent participants in the NESARC who would be excluded by individually applying each of the 12 most frequent eligibility criteria reported previously. Because individuals might have been excluded by more than one criterion, we also calculated the overall percentage of subjects who would have been excluded by the simultaneous application of all the measurable criteria. We conducted these analyses for all individuals with a current DSM-IV diagnosis of nicotine dependence (n=4962), and for the subsample of individuals who want to stop or cut down on tobacco use in the last 12 months (n=4121). Weighted prevalence estimates and 95% CIs were computed using SUDAAN, version 10.01 (Research Triangle Park, NC, USA). This software implements a Taylor linearisation to adjust for complex survey sampling design effects including clustering data.

    Results

    The percentage of subjects excluded by at least one criterion was 65.89% among respondents who met DSM-IV criteria for nicotine dependence and 58.60% for those motivated to quit smoking in the past year (table 2).

    View this table:
    Table 2

    Estimated percentage of adults with nicotine dependence in NESARC excluded from typical clinical trials of treatments for nicotine dependence by traditional efficacy eligibility criteria

    The percentage of respondents excluded owing to the application of a single criterion ranged from 2.14% (lifetime diagnosis of psychosis) to 32.02% (smoking fewer than 10 cigarettes per day) in the overall sample of respondents with nicotine dependence, and 1.95% (lifetime diagnosis of psychosis) to 33.79% (smoking fewer than 10 cigarettes per day) among those motivated to quit smoking.

    For the overall sample, smoking 10 or fewer cigarettes per day and lacking motivation to quit were the two criteria including the highest percentage of individuals. For the treatment-seeking sample, having current depression and smoking 10 or fewer cigarettes per day were the criteria comprising the greatest percentage of individuals who would not be eligible. Current alcohol dependence and a history of bipolar disorder also excluded a notable proportion of individuals in both samples (table 2).

    A history of bipolar disorder (type I) was present in 10.33% of the participants with nicotine dependence (95% CI 8.16 to 10.50). As a control, ruling out illness-induced and substance-induced mania only slightly decreased to 9.26% the percentage of participants excluded because of these criteria (95% CI 8.16 to 10.50). When bipolar type II disorder was also included in this eligibility criteria (substance-induced and illness-induced disorder still ruled out), the percentage of participants excluded because of this criterion increased to 14.70% (95% CI 13.55 to 15.93). The overall exclusion rate was 65.58% when considering bipolar I disorder after ruling out illness-induced and substance-induced mania, and 66.8% when considering bipolar I and II after ruling out illness-induced and substance-induced mania, compared to an overall exclusion rate of 64.13% when considering only bipolar I disorder even if manic episodes were induced by a substance or an illness. This suggests that the criteria used to define bipolar disorder have little or no impact on the overall inclusion rate.

    More than six out of 10 respondents from the full nicotine-dependent sample and more than half of the subsample of individuals motivated to quit smoking would have been excluded by one or more of the study criteria.

    Discussion

    This study ascertains the proportion of community-dwelling adults with nicotine dependence who would have been eligible for a typical nicotine-dependence treatment study. The results of this study suggest that traditional criteria used in nicotine-dependence trials tend to exclude from participation half of individuals with nicotine dependence who are likely to seek out treatment. These results are in line with previous findings, suggesting that a majority of individuals who were screened for a nicotine-cessation trial were not eligible to participate in the trial. For example, among the 54 randomised clinical trials assessed in the present paper,37–92 the ineligibility rates varied widely, ranging from 12.9%37 to 85.31.5 6

    Consistent with the existing literature, we found that a lack of motivation to quit and a low level of cigarette consumption explain a large proportion of ineligibility.7 28

    Our study has several limitations

    First of all, our exclusion criteria are somehow arbitrary. We considered eligibility criteria from 54 randomised clinical trials included in a recent meta-analysis,36 but the use of another methodology could have led to other results. An important point is that the exclusion criterion based on alcohol consumption varies widely across studies. It has been emphasised that an alcohol-related exclusion criterion appears frequently in smoking cessation pharmacotherapy trials.29 95 A recent review showed that 41.6% of trials (45 of 125 nicotine-replacement trials, 15 of 22 bupropion trials and three of three varenicline trials) involved exclusion of participants with either current or recent alcohol problems, leading to a lack of information on the effects of alcohol use disorders on smoking cessation.29 95

    A second restriction is that three of the 12 exclusion criteria initially included could not be used in our study, because the relevant information was not assessed in the NESARC sample, including (1) participants currently taking psychotropic medication, (2) participants “currently taking bupropion or nicotine replacement therapy”, and (3) participants having an eating disorder. This may theoretically lead to an underestimation of the proportion of patients excluded in clinical trials. However, these criteria are rarely met in the general population. For example, the estimated percentage of smokers in Australia who used bupropion in a year was only 3.6% in 2005.96 Eating disorders have a low prevalence, affecting less than 4.5% 97 of the general population. While an investigation of the impact of these exclusion criteria on the generalisability of clinical trials is required in a future study, they are not likely to exclude a significant proportion of smokers.

    A third limitation is that the NESARC sample included only individuals aged 18 years or older. Information was unavailable for adolescents, who maybe have a lower level of comorbidities, and may therefore be more likely to be eligible for clinical trials.

    Some of the criteria have been implemented for safety reasons (eg, pregnancy, potential interaction with psychotropic drugs or with alcohol) while some others may contribute to stigmatise a significant proportion of the population (eg, having a history of substance abuse but with no use within the last 12 months should not be considered as a valid exclusion criterion in a clinical trial).

    The exclusion of participants with alcohol dependence is particularly relevant, since nicotine dependence is a major issue in alcohol-dependent patients. For example, smokers with a lifetime history of alcohol dependence are more likely to die from smoking-related diseases rather than from alcohol-related diseases.98 Moreover, alcohol-dependent subjects with nicotine dependence have a higher prevalence of nearly all psychiatric and addictive disorders,99 making treatment for smoking cessation in this specific population an unmet need.

    In summary, we found that the current criteria of eligibility applied in clinical trials involving nicotine-dependent individuals are highly restrictive and exclude a majority of participants, thus limiting the generalisability of their findings. Particularly, our findings suggested that (1) individuals smoking few cigarettes in a day or (2) having a current or past history of mood disorders (major depressive disorder or bipolar disorder) are under-represented in clinical trials. These two related groups should be the focus of further investigations.

    What this paper adds

    Clinical trials for treatment of nicotine dependence often exclude sizeable segments of the general population with nicotine dependence. This article quantifies the lack of generalisability by using a large representative US general population survey. It was found that the majority of nicotine-dependent subjects would have been excluded from participating in clinical trials.

    References

    1. ↵
      1. Fiore MC,
      2. Jaén CR,
      3. Baker TB
      . Treating Tobacco Use and Dependence: 2008 Update. US Dept of Health and Human Services, 2008.
    2. ↵
      1. Le Foll B,
      2. George TP
      . Treatment of tobacco dependence: integrating recent progress into practice. CMAJ 2007;177:1373–80.
      OpenUrlAbstract/FREE Full Text
    3. ↵
      1. Le Foll B,
      2. Melihan-Cheinin P,
      3. Rostoker G,
      4. et al.
      ; Working Group of AFSSAPS. Smoking cessation guidelines: evidence-based recommendations of the French Health Products Safety Agency. Eur Psychiatry 2005;20:431–41.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      National Institute for Clinical Excellence. Brief Interventions and Referral for Smoking Cessation in Primary Care and Other Settings. Public Health Intervention Guidance No. 1. London: NICE, 2006.
    5. ↵
      1. Weisberg HI,
      2. Hayden VC,
      3. Pontes VP
      . Selection criteria and generalizability within the counterfactual framework: explaining the paradox of antidepressant-induced suicidality? Clin Trials 2009;6:109–18.
      OpenUrlAbstract/FREE Full Text
    6. ↵
      1. Dzewaltowski DA,
      2. Estabrooks PA,
      3. Klesges LM,
      4. et al
      . Behavior change intervention research in community settings: how generalizable are the results? Health Promot Int 2004;19:235–45.
      OpenUrlAbstract/FREE Full Text
    7. ↵
      1. Kamholz BW,
      2. Gulliver SB,
      3. Helstrom A,
      4. et al
      . Implications of participant self-selection for generalizability: who participates in smoking laboratory research? Subst Use Misuse 2009;44:343–56.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      1. Weiss NS,
      2. Koepsell TD,
      3. Psaty BM
      . Generalizability of the results of randomized trials. Arch Intern Med 2008;168:133–5.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      1. Dhruva SS,
      2. Redberg RF
      . Variations between clinical trial participants and Medicare beneficiaries in evidence used for Medicare national coverage decisions. Arch Intern Med 2008;168:136–40.
      OpenUrlCrossRefPubMed
    10. ↵
      1. Blanco C,
      2. Olfson M,
      3. Goodwin RD,
      4. et al
      . Generalizability of clinical trial results for major depression to community samples: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 2008;69:1276–80.
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      1. Zimmerman M,
      2. Chelminski I,
      3. Posternak MA
      . Generalizability of antidepressant efficacy trials: differences between depressed psychiatric outpatients who would or would not qualify for an efficacy trial. Am J Psychiatry 2005;162:1370–2.
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Zimmerman M,
      2. Mattia JI,
      3. Posternak MA
      . Are subjects in pharmacological treatment trials of depression representative of patients in routine clinical practice? Am J Psychiatry 2002;159:469–73.
      OpenUrlCrossRefPubMedWeb of Science
    13. ↵
      1. Posternak MA,
      2. Zimmerman M,
      3. Keitner GI,
      4. et al
      . A reevaluation of the exclusion criteria used in antidepressant efficacy trials. Am J Psychiatry 2002;159:191–200.
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      1. Zetin M,
      2. Hoepner CT
      . Relevance of exclusion criteria in antidepressant clinical trials: a replication study. J Clin Psychopharmacol 2007;27:295–301.
      OpenUrlCrossRefPubMedWeb of Science
    15. ↵
      1. Boter H,
      2. Derks EM,
      3. Fleischhacker WW,
      4. et al
      . Generalizability of the results of efficacy trials in first-episode schizophrenia: comparisons between subgroups of participants of the European First Episode Schizophrenia Trial (EUFEST). J Clin Psychiatry 2010;71:58–65.
      OpenUrlCrossRefPubMedWeb of Science
    16. ↵
      1. Leucht S,
      2. Heres S,
      3. Hamann J,
      4. et al
      . Methodological issues in current antipsychotic drug trials. Schizophr Bull 2008;34:275–85.
      OpenUrlAbstract/FREE Full Text
    17. ↵
      1. Khan AY,
      2. Preskorn SH,
      3. Baker B
      . Effect of study criteria on recruitment and generalizability of the results. J Clin Psychopharmacol 2005;25:271–5.
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Blanco C,
      2. Olfson M,
      3. Okuda M,
      4. et al
      . Generalizability of clinical trials for alcohol dependence to community samples. Drug Alcohol Depend 2008;98:123–8.
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      1. Humphreys K,
      2. Weingardt KR,
      3. Harris AH
      . Influence of subject eligibility criteria on compliance with National Institutes of Health guidelines for inclusion of women, minorities, and children in treatment research. Alcohol Clin Exp Res 2007;31:988–95.
      OpenUrlCrossRefPubMedWeb of Science
    20. ↵
      1. Humphreys K,
      2. Weingardt KR,
      3. Horst D,
      4. et al
      . Prevalence and predictors of research participant eligibility criteria in alcohol treatment outcome studies, 1970–98. Addiction 2005;100:1249–57.
      OpenUrlCrossRefPubMedWeb of Science
    21. ↵
      1. Humphreys K,
      2. Weisner C
      . Use of exclusion criteria in selecting research subjects and its effect on the generalizability of alcohol treatment outcome studies. Am J Psychiatry 2000;157:588–94.
      OpenUrlCrossRefPubMedWeb of Science
    22. ↵
      1. Okuda M,
      2. Hasin DS,
      3. Olfson M,
      4. et al
      . Generalizability of clinical trials for cannabis dependence to community samples. Drug Alcohol Depend 2010;111:177–81.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      1. Andrews JA,
      2. Severson HH,
      3. Akers L,
      4. et al
      . Who enrolls in a self-help cessation program for smokeless tobacco? Addict Behav 2001;26:757–64.
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Graham AL,
      2. Bock BC,
      3. Cobb NK,
      4. et al
      . Characteristics of smokers reached and recruited to an internet smoking cessation trial: a case of denominators. Nicotine Tob Res 2006;(8 Suppl 1):S43–8.
    25. ↵
      1. Howard-Pitney B,
      2. Fortmann SP,
      3. Killen JD
      . Generalizability of findings from a chewing tobacco cessation clinical trial. Nicotine Tob Res 2001;3:347–52.
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Hughes JR
      . Data to estimate the similarity of tobacco research samples to intended populations. Nicotine Tob Res 2004;6:177–9.
      OpenUrlAbstract/FREE Full Text
    27. ↵
      1. Hughes JR,
      2. Callas PW
      . Data to assess the generalizability of samples from studies of adult smokers. Nicotine Tob Res 2010;12:73–6.
      OpenUrlAbstract/FREE Full Text
    28. ↵
      1. Robinson ML,
      2. Schroeder JR,
      3. Moolchan ET
      . Adolescent smokers screened for a nicotine replacement treatment trial: correlates of eligibility and enrollment. Nicotine Tob Res 2006;8:447–54.
      OpenUrlAbstract/FREE Full Text
    29. ↵
      1. Schmelzle J,
      2. Rosser WW,
      3. Birtwhistle R
      . Update on pharmacologic and nonpharmacologic therapies for smoking cessation. Can Fam Physician 2008;54:994–9.
      OpenUrlAbstract/FREE Full Text
    30. ↵
      1. Fagerstrom KO
      . Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978;3:235–41.
      OpenUrlCrossRefPubMedWeb of Science
    31. ↵
      1. Grant BF,
      2. Dawson DA,
      3. Stinson FS,
      4. et al
      . The Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV (AUDADIS-IV): reliability of alcohol consumption, tobacco use, family history of depression and psychiatric diagnostic modules in a general population sample. Drug Alcohol Depend 2003;71:7–16.
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Grant BF,
      2. Dawson DA,
      3. Stinson FS,
      4. et al
      . The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991–1992 and 2001–2002. Drug Alcohol Depend 2004;74:223–34.
      OpenUrlCrossRefPubMedWeb of Science
    33. ↵
      1. Leboyer M,
      2. Bellivier F
      1. Gorwood P
      . Clinical assessment in psychiatric genetics. In: Leboyer M, Bellivier F, eds. Psychiatric Genetics: Methods and Protocols: John M Walker. Totowa, NJ: Humana Press Inc, 2003:99–126.
    34. ↵
      1. Grant B,
      2. Hasin D,
      3. Chou S,
      4. et al
      . Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry 2004;61:1107–15.
      OpenUrlCrossRefPubMedWeb of Science
    35. ↵
      1. Grant BF,
      2. Harford TC,
      3. Dawson DA,
      4. et al
      . The Alcohol Use Disorder and Associated Disabilities Interview schedule (AUDADIS): reliability of alcohol and drug modules in a general population sample. Drug Alcohol Depend 1995;39:37–44.
      OpenUrlCrossRefPubMedWeb of Science
    36. ↵
      1. Eisenberg MJ,
      2. Filion KB,
      3. Yavin D,
      4. et al
      . Pharmacotherapies for smoking cessation: a meta-analysis of randomized controlled trials. CMAJ 2008;179:135–44.
      OpenUrlAbstract/FREE Full Text
    37. ↵
      1. Tsai ST,
      2. Cho HJ,
      3. Cheng HS,
      4. et al
      . A randomized, placebo-controlled trial of varenicline, a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist, as a new therapy for smoking cessation in Asian smokers. Clin Ther 2007;29:1027–39.
      OpenUrlCrossRefPubMedWeb of Science
    38. ↵
      1. Nakamura M,
      2. Oshima A,
      3. Fujimoto Y,
      4. et al
      . Efficacy and tolerability of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, in a 12-week, randomized, placebo-controlled, dose-response study with 40-week follow-up for smoking cessation in Japanese smokers. Clin Ther 2007;29:1040–56.
      OpenUrlCrossRefPubMedWeb of Science
    39. ↵
      1. Fossati R,
      2. Apolone G,
      3. Negri E,
      4. et al
      . A double-blind, placebo-controlled, randomized trial of bupropion for smoking cessation in primary care. Arch Intern Med 2007;167:1791–7.
      OpenUrlCrossRefPubMed
    40. ↵
      1. Oncken C,
      2. Gonzales D,
      3. Nides M,
      4. et al
      . Efficacy and safety of the novel selective nicotinic acetylcholine receptor partial agonist, varenicline, for smoking cessation. Arch Intern Med 2006;166:1571–7.
      OpenUrlCrossRefPubMedWeb of Science
    41. ↵
      1. Nides M,
      2. Oncken C,
      3. Gonzales D,
      4. et al
      . Smoking cessation with varenicline, a selective alpha4beta2 nicotinic receptor partial agonist: results from a 7-week, randomized, placebo- and bupropion-controlled trial with 1-year follow-up. Arch Intern Med 2006;166:1561–8.
      OpenUrlCrossRefPubMed
    42. ↵
      1. Jorenby DE,
      2. Hays JT,
      3. Rigotti NA,
      4. et al
      . Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 2006;296:56–63.
      OpenUrlCrossRefPubMedWeb of Science
    43. ↵
      1. Gonzales D,
      2. Rennard SI,
      3. Nides M,
      4. et al.
      ; Varenicline Phase 3 Study Group. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006;296:47–55.
      OpenUrlCrossRefPubMedWeb of Science
    44. ↵
      1. Holt S,
      2. Timu-Parata C,
      3. Ryder-Lewis S,
      4. et al
      . Efficacy of bupropion in the indigenous Maori population in New Zealand. Thorax 2005;60:120–3.
      OpenUrlAbstract/FREE Full Text
    45. ↵
      1. Cooper TV,
      2. Klesges RC,
      3. Debon MW,
      4. et al
      . A placebo controlled randomized trial of the effects of phenylpropanolamine and nicotine gum on cessation rates and postcessation weight gain in women. Addict Behav 2005;30:61–75.
      OpenUrlCrossRefPubMedWeb of Science
    46. ↵
      1. Dalsgareth OJ,
      2. Hansen NC,
      3. Soes-Petersen U,
      4. et al
      . A multicenter, randomized, double-blind, placebo-controlled, 6-month trial of bupropion hydrochloride sustained-release tablets as an aid to smoking cessation in hospital employees. Nicotine Tob Res 2004;6:55–61.
      OpenUrlCrossRefPubMedWeb of Science
    47. ↵
      1. Collins BN,
      2. Wileyto EP,
      3. Patterson F,
      4. et al
      . Gender differences in smoking cessation in a placebo-controlled trial of bupropion with behavioral counseling. Nicotine Tob Res 2004;6:27–37.
      OpenUrlAbstract
    48. ↵
      1. Aubin HJ,
      2. Lebargy F,
      3. Berlin I,
      4. et al
      . Efficacy of bupropion and predictors of successful outcome in a sample of French smokers: a randomized placebo-controlled trial. Addiction 2004;99:1206–18.
      OpenUrlCrossRefPubMedWeb of Science
    49. ↵
      1. Tonnesen P,
      2. Tonstad S,
      3. Hjalmarson A,
      4. et al
      . A multicentre, randomized, double-blind, placebo-controlled, 1-year study of bupropion SR for smoking cessation. J Intern Med 2003;254:184–92.
      OpenUrlCrossRefPubMedWeb of Science
    50. ↵
      1. Glavas D,
      2. Rumboldt M,
      3. Rumboldt Z
      . Smoking cessation with nicotine replacement therapy among health care workers: randomized double-blind study. Croat Med J 2003;44:219–24.
      OpenUrlPubMedWeb of Science
    51. ↵
      1. Shiffman S,
      2. Dresler CM,
      3. Hajek P,
      4. et al
      . Efficacy of a nicotine lozenge for smoking cessation. Arch Intern Med 2002;162:1267–76.
      OpenUrlCrossRefPubMedWeb of Science
    52. ↵
      1. Hall SM,
      2. Humfleet GL,
      3. Reus VI,
      4. et al
      . Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry 2002;59:930–6.
      OpenUrlCrossRefPubMedWeb of Science
    53. ↵
      1. Glover ED,
      2. Glover PN,
      3. Franzon M,
      4. et al
      . A comparison of a nicotine sublingual tablet and placebo for smoking cessation. Nicotine Tob Res 2002;4:441–50.
      OpenUrlAbstract/FREE Full Text
    54. ↵
      1. Ahluwalia JS,
      2. Harris KJ,
      3. Catley D,
      4. et al
      . Sustained-release bupropion for smoking cessation in African Americans: a randomized controlled trial. JAMA 2002;288:468–74.
      OpenUrlCrossRefPubMedWeb of Science
    55. ↵
      1. Gonzales DH,
      2. Nides MA,
      3. Ferry LH,
      4. et al
      . Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study. Clin Pharmacol Ther 2001;69:438–44.
      OpenUrlCrossRefPubMedWeb of Science
    56. ↵
      1. Wallstrom M,
      2. Nilsson F,
      3. Hirsch JM
      . A randomized, double-blind, placebo-controlled clinical evaluation of a nicotine sublingual tablet in smoking cessation. Addiction 2000;95:1161–71.
      OpenUrlCrossRefPubMedWeb of Science
    57. ↵
      1. Garvey AJ,
      2. Kinnunen T,
      3. Nordstrom BL,
      4. et al
      . Effects of nicotine gum dose by level of nicotine dependence. Nicotine Tob Res 2000;2:53–63.
      OpenUrlAbstract
    58. ↵
      1. Tonnesen P,
      2. Paoletti P,
      3. Gustavsson G,
      4. et al
      . Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society. Eur Respir J 1999;13:238–46.
      OpenUrlAbstract
    59. ↵
      1. Jorenby DE,
      2. Leischow SJ,
      3. Nides MA,
      4. et al
      . A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340:685–91.
      OpenUrlCrossRefPubMedWeb of Science
    60. ↵
      1. Hughes JR,
      2. Lesmes GR,
      3. Hatsukami DK,
      4. et al
      . Are higher doses of nicotine replacement more effective for smoking cessation? Nicotine Tob Res 1999;1:169–74.
      OpenUrlAbstract
    61. ↵
      1. Hays JT,
      2. Croghan IT,
      3. Schroeder DR,
      4. et al
      . Over-the-counter nicotine patch therapy for smoking cessation: results from randomized, double-blind, placebo-controlled, and open label trials. Am J Public Health 1999;89:1701–7.
      OpenUrlCrossRefPubMedWeb of Science
    62. ↵
      1. Daughton D,
      2. Susman J,
      3. Sitorius M,
      4. et al
      . Transdermal nicotine therapy and primary care. Importance of counseling, demographic, and participant selection factors on 1-year quit rates. The Nebraska Primary Practice Smoking Cessation Trial Group. Arch Fam Med 1998;7:425–30.
      OpenUrlCrossRefPubMedWeb of Science
    63. ↵
      1. Hurt RD,
      2. Sachs DP,
      3. Glover ED,
      4. et al
      . A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;337:1195–202.
      OpenUrlCrossRefPubMedWeb of Science
    64. ↵
      1. Hjalmarson A,
      2. Nilsson F,
      3. Sjostrom L,
      4. et al
      . The nicotine inhaler in smoking cessation. Arch Intern Med 1997;157:1721–8.
      OpenUrlCrossRefPubMedWeb of Science
    65. ↵
      1. Blondal T,
      2. Franzon M,
      3. Westin A
      . A double-blind randomized trial of nicotine nasal spray as an aid in smoking cessation. Eur Respir J 1997;10:1585–90.
      OpenUrlAbstract
    66. ↵
      1. Schneider NG,
      2. Olmstead R,
      3. Nilsson F,
      4. et al
      . Efficacy of a nicotine inhaler in smoking cessation: a double-blind, placebo-controlled trial. Addiction 1996;91:1293–306.
      OpenUrlCrossRefPubMedWeb of Science
    67. ↵
      1. Paoletti P,
      2. Fornai E,
      3. Maggiorelli F,
      4. et al
      . Importance of baseline cotinine plasma values in smoking cessation: results from a double-blind study with nicotine patch. Eur Respir J 1996;9:643–51.
      OpenUrlAbstract
    68. ↵
      1. Hall SM,
      2. Munoz RF,
      3. Reus VI,
      4. et al
      . Mood management and nicotine gum in smoking treatment: a therapeutic contact and placebo-controlled study. J Consult Clin Psychol 1996;64:1003–9.
      OpenUrlCrossRefPubMedWeb of Science
    69. ↵
      1. Stapleton JA,
      2. Russell MA,
      3. Feyerabend C,
      4. et al
      . Dose effects and predictors of outcome in a randomized trial of transdermal nicotine patches in general practice. Addiction 1995;90:31–42.
      OpenUrlCrossRefPubMedWeb of Science
    70. ↵
      1. Schneider NG,
      2. Olmstead R,
      3. Mody FV,
      4. et al
      . Efficacy of a nicotine nasal spray in smoking cessation: a placebo-controlled, double-blind trial. Addiction 1995;90:1671–82.
      OpenUrlCrossRefPubMedWeb of Science
    71. ↵
      1. Kornitzer M,
      2. Boutsen M,
      3. Dramaix M,
      4. et al
      . Combined use of nicotine patch and gum in smoking cessation: a placebo-controlled clinical trial. Prev Med 1995;24:41–7.
      OpenUrlCrossRefPubMedWeb of Science
    72. ↵
      1. Herrera N,
      2. Franco R,
      3. Herrera L,
      4. et al
      . Nicotine gum, 2 and 4 mg, for nicotine dependence. A double-blind placebo-controlled trial within a behavior modification support program. Chest 1995;108:447–51.
      OpenUrlCrossRefPubMedWeb of Science
    73. ↵
      1. Gourlay SG,
      2. Forbes A,
      3. Marriner T,
      4. et al
      . Double blind trial of repeated treatment with transdermal nicotine for relapsed smokers. BMJ 1995;311:363–6.
      OpenUrlAbstract/FREE Full Text
    74. ↵
      1. Hurt RD,
      2. Dale LC,
      3. Fredrickson PA,
      4. et al
      . Nicotine patch therapy for smoking cessation combined with physician advice and nurse follow-up. One-year outcome and percentage of nicotine replacement. JAMA 1994;271:595–600.
      OpenUrlCrossRefPubMedWeb of Science
    75. ↵
      1. Hjalmarson A,
      2. Franzon M,
      3. Westin A,
      4. et al
      . Effect of nicotine nasal spray on smoking cessation. A randomized, placebo-controlled, double-blind study. Arch Intern Med 1994;154:2567–72.
      OpenUrlCrossRefPubMedWeb of Science
    76. ↵
      1. Fiore MC,
      2. Kenford SL,
      3. Jorenby DE,
      4. et al
      . Two studies of the clinical effectiveness of the nicotine patch with different counseling treatments. Chest 1994;105:524–33.
      OpenUrlCrossRefPubMedWeb of Science
    77. ↵
      1. Westman EC,
      2. Levin ED,
      3. Rose JE
      . The nicotine patch in smoking cessation. A randomized trial with telephone counseling. Arch Intern Med 1993;153:1917–23.
      OpenUrlCrossRefPubMedWeb of Science
    78. ↵
      1. Tonnesen P,
      2. Norregaard J,
      3. Mikkelsen K,
      4. et al
      . A double-blind trial of a nicotine inhaler for smoking cessation. JAMA 1993;269:1268–71.
      OpenUrlCrossRefPubMedWeb of Science
    79. ↵
      1. Sachs DP,
      2. Sawe U,
      3. Leischow SJ
      . Effectiveness of a 16-hour transdermal nicotine patch in a medical practice setting, without intensive group counseling. Arch Intern Med 1993;153:1881–90.
      OpenUrlCrossRefPubMedWeb of Science
    80. ↵
      1. Anonymous
      . Effectiveness of a nicotine patch in helping people stop smoking: results of a randomised trial in general practice. Imperial Cancer Research Fund General Practice Research Group. BMJ 1993;306:1304–8.
      OpenUrlAbstract/FREE Full Text
    81. ↵
      1. Sutherland G,
      2. Stapleton JA,
      3. Russell MA,
      4. et al
      . Randomised controlled trial of nasal nicotine spray in smoking cessation. Lancet 1992;340:324–9.
      OpenUrlCrossRefPubMedWeb of Science
    82. ↵
      1. Tonnesen P,
      2. Norregaard J,
      3. Simonsen K,
      4. et al
      . A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation. N Engl J Med 1991;325:311–15.
      OpenUrlCrossRefPubMedWeb of Science
    83. ↵
      1. Daughton DM,
      2. Heatley SA,
      3. Prendergast JJ,
      4. et al
      . Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. A randomized, placebo-controlled, double-blind study. Arch Intern Med 1991;151:749–52.
      OpenUrlCrossRefPubMedWeb of Science
    84. ↵
      1. Killen JD,
      2. Fortmann SP,
      3. Newman B,
      4. et al
      . Evaluation of a treatment approach combining nicotine gum with self-guided behavioral treatments for smoking relapse prevention. J Consult Clin Psychol 1990;58:85–92.
      OpenUrlCrossRefPubMedWeb of Science
    85. ↵
      1. Hall SM,
      2. Tunstall CD,
      3. Ginsberg D,
      4. et al
      . Nicotine gum and behavioral treatment: a placebo controlled trial. J Consult Clin Psychol 1987;55:603–5.
      OpenUrlCrossRefPubMedWeb of Science
    86. ↵
      1. Hjalmarson AI
      . Effect of nicotine chewing gum in smoking cessation. A randomized, placebo-controlled, double-blind study. JAMA 1984;252:2835–8.
      OpenUrlCrossRefPubMedWeb of Science
    87. ↵
      1. Hughes JR,
      2. Gust SW,
      3. Keenan RM,
      4. et al
      . Nicotine vs placebo gum in general medical practice. JAMA 1989;261:1300–5.
      OpenUrlCrossRefPubMedWeb of Science
    88. ↵
      1. Jamrozik K,
      2. Fowler G,
      3. Vessey M,
      4. et al
      . Placebo controlled trial of nicotine chewing gum in general practice. Br Med J (Clin Res Ed) 1984;289:794–7.
      OpenUrlAbstract/FREE Full Text
    89. ↵
      1. Jarvik ME,
      2. Schneider NG
      . Degree of addiction and effectiveness of nicotine gum therapy for smoking. Am J Psychiatry 1984;141:790–1.
      OpenUrlPubMedWeb of Science
    90. ↵
      1. Jarvis MJ,
      2. Raw M,
      3. Russell MA,
      4. et al
      . Randomised controlled trial of nicotine chewing-gum. Br Med J (Clin Res Ed) 1982;285:537–40.
      OpenUrlAbstract/FREE Full Text
    91. ↵
      1. Malcolm RE,
      2. Sillett RW,
      3. Turner JA,
      4. et al
      . The use of nicotine chewing gum as an aid to stopping smoking. Psychopharmacology (Berl) 1980;70:295–6.
      OpenUrlCrossRefPubMed
    92. ↵
      1. Schneider NG,
      2. Jarvik ME,
      3. Forsythe AB,
      4. et al
      . Nicotine gum in smoking cessation: a placebo-controlled, double-blind trial. Addict Behav 1983;8:253–61.
      OpenUrlCrossRefPubMedWeb of Science
    93. ↵
      1. Abelin T,
      2. Buehler A,
      3. Muller P,
      4. et al
      . Controlled trial of transdermal nicotine patch in tobacco withdrawal. Lancet 1989;1:7–10.
      OpenUrlPubMedWeb of Science
    94. ↵
      1. Fortmann SP,
      2. Killen JD,
      3. Telch MJ,
      4. et al
      . Minimal contact treatment for smoking cessation. A placebo controlled trial of nicotine polacrilex and self-directed relapse prevention: initial results of the Stanford Stop Smoking Project. JAMA 1988;260:1575–80.
      OpenUrlCrossRefPubMedWeb of Science
    95. ↵
      1. Leeman RF,
      2. Huffman CJ,
      3. O'Malley SS
      . Alcohol history and smoking cessation in nicotine replacement therapy, bupropion sustained release and varenicline trials: a review. Alcohol Alcohol 2007;42:196–206.
      OpenUrlAbstract/FREE Full Text
    96. ↵
      1. Lutsenko H,
      2. Doran CM,
      3. Hall WD
      . Australian smokers' use of bupropion and nicotine replacement therapies and their relation to reimbursement, Australia 2001–05. Drug Alcohol Rev 2008;27:160–4.
      OpenUrlCrossRefPubMedWeb of Science
    97. ↵
      1. Hudson JI,
      2. Hiripi E,
      3. Pope HG Jr.,
      4. et al
      . The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol Psychiatry 2007;61:348–58.
      OpenUrlCrossRefPubMedWeb of Science
    98. ↵
      1. Hurt RD,
      2. Offord KP,
      3. Croghan IT,
      4. et al
      . Mortality following inpatient addictions treatment. Role of tobacco use in a community-based cohort. JAMA 1996;275:1097–103.
      OpenUrlCrossRefPubMedWeb of Science
    99. ↵
      1. Le Strat Y,
      2. Ramoz N,
      3. Gorwood P
      . In alcohol-dependent drinkers, what does the presence of nicotine dependence tell us about psychiatric and addictive disorders comorbidity? Alcohol Alcohol 2010;45:167–72.
      OpenUrlAbstract/FREE Full Text

    Footnotes

    • Funding The National Epidemiologic Survey on Alcohol and Related Conditions was sponsored by the National Institute on Alcohol Abuse and Alcoholism and funded, in part, by the Intramural Program of DHHS-NIH-NIAAA. YLS is funded by a grant from the Société Française de Tabacologie and the Addiction Program of CAMH.

    • Competing interests None.

    • Ethics approval This study was conducted with the approval of the US Census Bureau and the Office of Management and Budget.

    • Provenance and peer review Not commissioned; externally peer reviewed.