Randomized Trial of Ultrashort Psychotherapy vs Sustained-Release Bupropion for Smoking Cessation
Condition: Nicotine Dependence; Substance Abuse; Substance Dependence; Tobacco Dependence
MeSH terms: Substance-Related Disorders; Tobacco Use Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      Background

      Smokers often reject drugs as smoking cessation aids. Nonpharmacological interventions are
      notoriously under-evaluated.

      Methods

      We conducted a randomized clinical trial in which we compared a medication, i.e.,
      sustained-release bupropion (Zyban®; 413 subjects), at the time of the trial the most
      efficacious pharmacological smoking cessation aid, with an ultrashort psychotherapeutic
      intervention, Psychodynamic Model Training® (366 subjects), a manual-based psychodynamically
      oriented 1 ½ day autosuggestion training. Outcome criterion was 12-month self-reported
      continuous abstinence confirmed by urine cotinine levels below the level of detection (13
      ng/ml) or, in an independent analysis, by exhaled carbon monoxide of 10 ppm or less at all
      interviews conducted at 3, 6, and 12 months.
    

Detailed description: 
      Study design

      This randomized clinical trial was designed to compare the efficacy and safety of a
      manual-based 1.5-day psychotherapeutic intervention, i.e., Psychodynamic Model Training®,
      with a medication, i.e., sustained-release bupropion (Zyban®), as smoking cessation aids. In
      order to render the data comparable to previously obtained bupropion data, the bupropion
      treatment regimen and study protocol closely followed that by Jorenby et al. 1999.(3) As an
      improvement over previous protocols(3-5), nonsmoking status was verified not only by
      determination of exhaled carbon monoxide (CO) levels but also by tandem mass spectrometric
      (LC/MS/MS) analysis of urine cotinine(6;7), a marker of higher sensitivity than CO.(8)

      Subjects, screening, inclusion and exclusion criteria, and randomization

      Female and male smokers were recruited between July 2005 and December 2005 by announcements
      in the local media (press, local radio stations) and in the newsletter
      (http://www.stgkk.at/mediaDB/104832.PDF) of the governmental Styrian Regional Health Care
      System (Steiermaerkische Gebietskrankenkasse, STGKK), the sponsor of the present study.
      Interested smokers were first screened by telephone interview and then scheduled for the
      study intake interview. The first subject was enrolled in July 2005, and follow-up was
      completed in January 2007. Of a total of 951 persons screened, 790 met the screening criteria
      and were enrolled and randomized to one of two treatments according to a randomization list
      in the care of the steering committee at the Medical University Innsbruck. Great care was
      taken to preserve treatment allocation concealment: Only after the subject had given his/her
      written consent, a sealed envelope containing the treatment allocation was broken by the
      interviewer and presented to the subject. The study protocol was registered with the European
      Medicines Agency (emea.europa.eu; EudraCT-Nr. 2005-006189-32) and was approved by the local
      governmental review board. The study was conducted in compliance with the ethical principles
      of the Declaration of Helsinki (www.wma.net/e/policy/b3.html ; accessibility verified May 16,
      2007) and the standards on good clinical practice developed by the International Conference
      on Harmonization (www.ich.org/cache/compo/276-254-1.html ; accessibility verified May 16,
      2007.)

      Inclusion criteria were an age of at least 18 years, a cigarette consumption of at least 15
      cigarettes per day in the last 3 months, and the willingness to contribute EUR 70 to the
      treatment costs, regardless of the treatment modality. Exclusion criteria, as assessed by the
      study-site physicians, were any psychiatric diagnosis except nicotine or caffeine dependence,
      any current psychopharmacological treatment, known hypersensitivity to bupropion, epilepsy,
      liver cirrhosis, brain tumor, pregnancy (verified by an immunological test at the intake
      interview and 3 weeks after the first day of the first menses occurring within treatment),
      lactation, any serious or unstable cardiac, renal, hypertensive, pulmonary, endocrine, or
      neurologic disorder, ulcers, dermatologic disorders, current use of other smoking cessation
      treatments, and regular use of any noncigarette tobacco product. After induction of the first
      620 subjects, it became apparent that more subjects randomized to the bupropion group dropped
      out immediately after learning of their treatment allocation. To compensate for this higher
      rejecter rate in the bupropion group, the remaining 170 subjects were randomized to bupropion
      vs psychotherapy at a ratio of 2:1. Seven of the 420 subjects randomly allocated to the
      bupropion group and 4 of the 370 to the psychotherapy group were found to meet exclusion
      criteria by the study's physicians only after the randomization (bupropion: bulimia, 3 cases
      of major depression, 2 cases with antidepressant medication, anticoagulant medication;
      psychotherapy: 4 cases with a previously undisclosed psychiatric diagnosis) and had to be
      excluded before treatment started. Therefore, the final intention-to-treat (ITT) sample
      consisted of 413 subjects in the bupropion and 366 subjects in the psychotherapy group.

      Treatments

      The treatment period in the sustained-release bupropion (Zyban®) group was nine weeks(3),
      following the protocol given in Zyban®'s product information as provided by its manufacturer
      (GlaxoSmithKline, Vienna, Austria): After an initial medical consultation, a dose run-up
      period of 1 week to a final 150 mg sustained-release bupropion twice daily on day 7, a target
      quitting date was set for the second week, usually day 8. Subjects returned for a second
      visit, scheduled between days 26 and 33 of the treatment, to the study's physicians for a
      medical checkup and to receive the second 60-tablet package of Zyban®. Failure to show up for
      this second medical checkup was considered treatment failure.

      Psychodynamic Model Training® is a manual(9)-based psychodynamically oriented ultrashort
      psychotherapeutic intervention, consisting of a very brief psychoeducation and an initial
      training in autosuggestion techniques that are taught during a single 1.5-day program (day 1,
      0900-2000 h; day 2, 0900 - 1300 h). Subjects, approximately 30 per group, were introduced to
      five guided imagery scenarios aimed at strengthening the following psychotherapeutically
      defined aspects of functioning: (1) self-worth, self-determination, self-assurance; (2)
      self-acceptance; (3) health, vitality, relaxation, awareness of bodily functions; (4)
      creativity, self-worth, remuneration and emotional reward for one's work; and (5) ability to
      sustain intimate personal relationship.

      Follow-up period

      Subjects of either group were contacted by telephone to schedule follow-up assessments in the
      study physicians' offices at the Institute for Clinical Psychology, Psychotherapy, and Health
      Promontion, Graz, at the end of months 3, 6, and 12, and had to present for the appointment
      within 36 h of the telephone call in order to facilitate the detection of any smoking. During
      these assessments, subjects were asked about their non/smoking status, their breathalyzer CO
      levels were determined by associates of the study's sponsor, the STGKK, and they had to
      provide a urine sample for cotinine analysis. Family members of randomly selected subjects
      also received telephone calls from a staff member of the STGKK to confirm their non/smoking
      status. No relapse-prevention counseling was administered during the follow-up period.

      Assessments

      At baseline, demographic data, medical and smoking history were obtained, and vital signs and
      exhaled CO levels were determined. The Beck Depression Inventory(10) was used to assess
      depressive symptoms (scores of 0 to 9 are considered to be normal, scores of 10 to 18
      indicated mild-to-moderate depression, scores of 19 to 29 indicated moderate-to-severe
      derpession, and scores of 30 to 63 indicate severe depression). The Fagerström Tolerance
      Questionnaire(11;12) was used to quantify the severity of nicotine dependence (scores of 0 to
      11, with higher scores indicating more severe dependence). A separate questionnaire contained
      the portion of the Structured Clinical Interview for the Diagnostic and Statistical Manual
      version 4 (DSMIV)(13) concerning substance dependence disorders.

      During follow-up interviews, CO levels were determined in the expired air by breathalyzer
      (piCOsmokerlyzer®, www.bedfont.com). Urine samples were obtained and quantified for cotinine,
      a major metabolite of nicotine with a urine elimination half-life around 20 h,(7) by HPLC
      coupled with tandem mass spectrometry (LC/MS/MS) as previously described.(14) The cotinine
      (mass transition 177 > 80 m/z) standard curve (internal standard, 50 ng/ml d3-methadone) was
      essentially linear up to the highest concentration tested, i.e., 2000 ng/ml (quadratic
      equation fit, weighting 1/x, r>0.99). The level of detection (LOD) was 13 ng/ml at a
      signal/noise ratio of 2/1). The level of quantification (LOQ) in the actual urine samples of
      the study was 30 ng/ml.

      Measures of outcome

      The primary outcome criterion was a biochemically/pharmacologically-confirmed 12-month
      continuous abstinence as evidenced by self-reports of nonsmoking status in all interviews
      (i.e., at 3, 6, and 12 months). Self-reports of nonsmoker status were confirmed by urine
      cotinine levels below the level of detection (13 ng/mL at a signal/noise-ratio of 2/1 in the
      LC/MS/MS analysis) at all 3 follow-up interviews. Subjects in the bupropion group had to
      report abstinence from the target quitting date onwards, subjects in the psychotherapy group
      had to report abstinence from the end of the 1.5-day program onwards. Subjects who
      self-reported nonsmoker status but for which urine samples could not be collected or at any
      of the 3 follow-up time points or which refused to provide a urine sample at any of the 3
      follow-up time points were considered smokers. In order to better compare the data of the
      present study with previously published bupropion data,(3;4) nonsmoker status was confirmed,
      independently of the urine cotinine analysis, by exhaled carbon monoxide (CO) levels at or
      below 10 parts per million (ppm) at all 3 follow-up interviews, following the nonsmoker
      criterion of Jorenby and coworkers for low-frequency follow-ups.(3;4) The secondary outcome
      was point prevalence of self-reported abstinence confirmed by urine cotinine levels below the
      level of detection for each follow-up time point. Outcome criteria were assessed both in the
      ITT- and the completer-sample.

      Statistical analysis

      The sample size of approximately 380 subjects per group was determined such that, under
      standard conditions regarding power (80%) and two-sided alpha level (0.05), the following
      differences between the two treatment groups may be detected: continuous abstinence rates of
      17% in one group vs 10% in the other or 23% vs 15 % or 29% vs 20%. Baseline comparisons of
      the two treatment groups were performed by the chi-square test for categorical data,
      Student's t-test for normally distributed and Mann-Whitney U-test for non-normally
      distributed numerical variables. Differences between the two groups regarding primary
      (12-month continuous abstinence rate) and secondary (point prevalence of abstinence) outcome
      criteria, TEAE rates, and rejecter rates were analysed by means of the chi-square test
      (two-sided). In order to quantify the differences between the two groups, the Odds Ratio
      (OR), Relative Benefit (RB; in analogy to the Relative Risk), and the Number Needed to Treat
      (NNT) were determined. Agreement between the two detection methods (cotinine level, CO level)
      was evaluated by the kappa coefficient, significant differences in continuous abstinence
      rates between the two detection methods were determined by means of the McNemar test. All
      analyses were performed by a certified statistician using the SPSS® software (www.spss.com).
      Measures of variance were either the standard deviation (S.D.) for the treatment groups'
      baseline characteristics or the 95 % confidence interval for OR, RB, and NNT.
    

Intervention name(s): sustained-release bupropion (Zyban(R)); Psychodynamic Model Training (R) = PDM(R)
Intervention type(s): Drug; Behavioral
Intervention MeSH terms: Bupropion
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: randomized controlled trial; smoking cessation; nicotine dependence; sustained-release bupropion; psychotherapy; psychodynamic model training