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Original Investigation |

A Randomized Trial of Nortriptyline Combined With Transdermal Nicotine for Smoking Cessation FREE

Allan V. Prochazka, MD, MSc; Steven Kick, MD, MSPH; Connie Steinbrunn; Thomas Miyoshi, MSW; George E. Fryer, PhD
[+] Author Affiliations

Author Affiliations: Division of General Internal Medicine (Drs Prochazka and Kick) and Department of Family Medicine (Mr Miyoshi), University of Colorado Health Sciences Center, Denver; Ambulatory Care, Denver Veterans Affairs Medical Center, Denver, (Dr Prochazka and Ms Steinbrunn); and American Academy of Family Physicians, Robert Graham Center for Policy Studies in Family Practice and Primary Care, Washington, DC (Dr Fryer).


Arch Intern Med. 2004;164(20):2229-2233. doi:10.1001/archinte.164.20.2229.
Text Size: A A A
Published online

Background  Smoking cessation rates with current therapy are suboptimal. Tricyclic antidepressants improve cessation rates. We hypothesized that addition of nortriptyline hydrochloride to transdermal nicotine would enhance cessation rates.

Methods  We conducted a randomized, double-blind, placebo-controlled trial at a Department of Veterans Affairs medical center. Subjects were aged 18 to 65 years, smoked 10 or more cigarettes per day, and did not have current major depression. Nortriptyline hydrochloride or matched placebo was started at 25 mg 14 days before quit day, titrated to 75 mg/d as tolerated, and continued for 12 weeks after quit day. Transdermal nicotine (21 mg/d) was started on quit day and continued for 8 weeks. The behavioral intervention consisted of 12 brief, individual visits. Withdrawal symptoms were measured by means of a daily diary, and smoking cessation was defined as self-reported abstinence, expired carbon monoxide level of 9 ppm or less, and a 6-month urine cotinine level less than 50 ng/mL (284 nmol/L).

Results  A total of 158 patients were randomized (79 to nortriptyline and 79 to placebo). There was no significant reduction in withdrawal symptoms. The cessation rates at 6 months were 23% (18/79) and 10% (8/79), respectively (absolute difference, 13%; 95% confidence interval, 1.3%-24.5%; P = .052). Nortriptyline caused frequent side effects, including dry mouth (38%) and sedation (20%).

Conclusions  Nortriptyline combined with transdermal nicotine resulted in an increased cessation rate with little effect on withdrawal symptoms. This combination may represent an option for smokers in whom standard therapy has failed.

Figures in this Article

Smoking is an important preventable cause of mortality; however, current approaches to cessation are only partially successful.1 The relationship between depressed mood and smoking behavior2,3 was explored extensively in the 1980s and early 1990s and suggested that antidepressant drugs might have a role in smoking cessation. Drugs in several antidepressant classes, including bupropion hydrochloride,4,5 doxepin hydrochloride,6 nortriptyline hydrochloride,7,8 and moclobemide,9 have shown effectiveness in smoking cessation. However, fluoxetine hydrochloride appears to have relatively little benefit for cessation.10 Sustained-release bupropion (Zyban; GlaxoSmithKline, Research Triangle Park, NC) has been tested most extensively and is approved by the US Food and Drug Administration for smoking cessation both as a single agent and in combination with transdermal nicotine. Nortriptyline has been included as a second-line agent in the 2000 Agency for Healthcare Quality and Research guidelines for smoking cessation.1

This study was designed to test our hypothesis that the addition of transdermal nicotine to nortriptyline would increase cessation rates and reduce tobacco withdrawal symptoms.

This was a double-blind, randomized, controlled trial of nortriptyline vs placebo, in subjects who all received transdermal nicotine and were enrolled in a behavioral smoking cessation program. The study was conducted at Denver Veterans Affairs Medical Center, Denver, Colo. This project was approved by the institutional review board of the University of Colorado Health Sciences Center, Denver.

Subjects were recruited from the outpatient clinics and from campus advertisements and provided written informed consent before participation. Inclusion criteria were readiness to set a quit date in the next 3 weeks, aged 18 to 65 years, and current smoking of at least 10 cigarettes per day. Potential subjects were excluded for current major depression or other significant psychiatric disorder, alcohol or drug dependence, significant cardiopulmonary or liver disease, active malignancy, pregnancy, contraindication or allergy to nortriptyline, use of thyroid or anticonvulsant medications, other therapy for smoking cessation, or inability to give informed consent. Subjects were enrolled from January 1, 1999, through June 30, 2000.

We used a questionnaire to assess smoking history and estimated the degree of nicotine dependence with the Fagerstrom Nicotine Dependence Questionnaire.11 The Computerized Diagnostic Interview Schedule was used to identify subjects with current major depression or previous depression.12 This is a self-administered, computer-based instrument that has been validated against psychiatric interviewers. All subjects had a medical history and physical examination performed by a physician, along with a 12-lead electrocardiogram to identify other potential exclusions. Women of childbearing potential had a serum pregnancy test done at the qualification visit and were asked to use accepted means of contraception during the study period.

Subjects set a quit date within 21 days of study entry and underwent individual smoking cessation counseling by the study coordinators to prepare for quitting before the start of drug therapy.

Subjects were stratified by history of previous major depression and randomized by means of a computer-generated random number list that was held by the Research Pharmacy Service of the Denver Veterans Affairs Medical Center. Once a patient was enrolled, the Research Pharmacy Service randomized the subject according to the randomization list.

Drug therapy began after randomization. Subjects took 1 capsule of the study drug before bed, either nortriptyline hydrochloride (25 mg) or matching placebo, beginning 14 days before quit day; increased to 2 capsules per day (50 mg of nortriptyline hydrochloride) after 4 days; and then after 4 more days increased to 3 capsules per day (75 mg of nortriptyline hydrochloride), if tolerated. They continued taking the maximum tolerated dosage for 10 weeks after their quit date and then had the dosage tapered during a 2-week period. Transdermal nicotine (21 mg/24 h) was started on the subject’s quit day and continued for 4 weeks. It was then tapered to 14 mg/24 h for 2 weeks and then 7 mg/24 h for 2 weeks. In total, subjects received transdermal nicotine for 8 weeks. If subjects had been smoking between 10 and 15 cigarettes per day, they were treated with a lower starting dosage of transdermal nicotine (14 mg/24 h) for 6 weeks, followed by 7 mg/24 h for 2 weeks.

All visits while subjects were taking study drugs consisted of individual sessions with the study nurse, who reviewed problems quitting and helped develop strategies for abstinence from smoking. The study drug was dispensed in weekly increments, and the returned pills were collected at each visit to reduce the possibility of overdose and to monitor compliance. If adverse effects developed, the dosage was reduced as necessary.

Blood samples were drawn 1 week after quit day, when subjects had been taking the maximum dosage of the study drug for at least 14 days. An unblinded research pharmacist recommended dosage reductions for those with nortriptyline levels above the therapeutic range (≥150 ng/mL) and dosage increases for those whose levels were subtherapeutic (<50 ng/mL). To maintain blinding, dosage reductions and increases on an equal number of randomly selected placebo-treated subjects were also recommended. The dosage of study drug was tapered to 50 mg/d beginning 10 weeks after quit day (day 70). All subjects had discontinued therapy with the study drug by week 12 (day 84).

Expired carbon monoxide concentration was determined with an expired carbon monoxide analyzer (Bedfont Technical Instruments Ltd, Sittingbourne, England). Urine cotinine levels were measured by means of a radioimmunoassay with gas chromatographic–mass spectroscopic confirmation by the Laboratory Services Department, Denver Veterans Affairs Medical Center.

Subjects completed a daily diary of the number of cigarettes smoked for the 14 days after quit day and selected nicotine withdrawal symptoms rated on a scale from 0 to 5, with 5 representing severe symptoms.13 We used the Beck Depression Inventory to identify depressive symptoms at baseline, 1 week after cessation, and at the end of nortriptyline therapy.14

The primary outcome was sustained smoking abstinence, defined as self-reported cessation within 1 week of the quit day and expired carbon dioxide concentration of 9 ppm or less at each visit, and verified by urine cotinine level less than 50 ng/mL (284 nmol/L) at the final visit (6 months). The sample size for the study (150 per group) was estimated on the basis of assumptions of 80% power, α = .05, a 15% absolute difference in the 6-month validated quit rates between the groups, and a cessation rate of 15% in the transdermal nicotine group. Although interim analyses were initially planned, they were not performed because recruitment was less than anticipated as a result of administrative matters affecting all clinical research at the University of Colorado Health Sciences Center from 1999 to 2000. The data were analyzed by means of SPSS PC software (SPSS Inc, Chicago, Ill) and with Stat-Exact 3 (Cytel Software Corp, Cambridge, Mass). We compared the groups on continuous variables by unpaired, 2-tailed t tests and Mann-Whitney tests as appropriate, and on categorical variables by χ2 tests and Fisher exact tests as appropriate. We compared the 6-month cessation rates in the 2 groups by Fisher exact tests based on an intention-to-treat analysis. P = .05 was used to indicate statistical significance. We used backward stepwise logistic regression and the likelihood ratio test to compare models with cessation as the dependent variable and study group as the primary independent variable while adjusting for covariates.

We screened 402 patients and found that 244 did not meet screening criteria, leaving 158 who were randomized (79 to nortriptyline and 79 to placebo) (Figure 1). Table 1 shows there were few significant differences between the baseline characteristics of the study groups. The nortriptyline group smoked slightly less on average than the placebo group (21.0 vs 23.7 cigarettes per day; P = .02). Only 6% (9/158; 5 placebo, 4 nortriptyline) had a history of depression as assessed by the Computerized Diagnostic Interview Schedule. Of the patients who continued in the study until 1 week after quit day, the mean number of capsules of study drug taken per day was 2.5 for the nortriptyline group (corresponding to a dosage of 62.5 mg/d) and 3.0 for the placebo group (P = .02). The mean nortriptyline level at the final drug dosage was 55 ng/mL (range, 25-156 ng/mL). There was little difference between the study groups in tobacco withdrawal symptoms (Table 2).

Place holder to copy figure label and caption
Figure 1.

Trial profile. Some patients had more than 1 reason for discontinuing the study; therefore, the total numbers of patients who discontinued because of adverse events (AEs), who never quit, and who relapsed exceed the difference between the number treated and the number of validated quitters.

Graphic Jump Location
Table Graphic Jump LocationTable 1. Demographic Characteristics and Smoking History of Study Subjects
Table Graphic Jump LocationTable 2. Mean Withdrawal Symptom Scores 7 Days After Quit Day by Study Group

The validated cessation rate during the follow-up period was higher in the nortriptyline group at every time point. The nortriptyline group had a 6-month sustained abstinence rate of 23% (18/79) compared with 10% (8/79) in the placebo group, with an absolute difference of 13% (95% confidence interval, 1.3%-24.5%; P = .052) (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Validated continuous smoking cessation rates from 1 week after quit day until the completion of follow-up at 6 months. Continuous cessation was defined as no self-report of smoking at any visit, all expired carbon dioxide readings less than 9 ppm, and the final urine cotinine level less than 50 ng/mL (284 nmol/L). Subjects who dropped out were counted as smokers. P value represents the comparison of the nortriptyline hydrochloride group and the placebo group 6-month validated cessation rate determined by Fisher exact test. CI indicates confidence interval.

Graphic Jump Location

In a backward stepwise logistic regression procedure, the only significant predictor of cessation was receipt of nortriptyline (odds ratio, 2.62; 95% confidence interval, 1.06-6.44). The covariates, including history of previous depression (P = .25), sex (P = .25), number of cigarettes per day (P = .12), expired carbon monoxide level (P = .77), Fagerstrom score (P = .89), and Beck Depression Inventory scores (P = .90), did not enter into the final model. We also forced cigarettes per day at baseline into a model along with study group to assess the impact of the baseline imbalance in that variable between the nortriptyline and placebo groups. The odds ratio for nortriptyline dropped to 2.31 (95% confidence interval, 0.92-5.76; P = .07), with an odds ratio for cigarettes per day of 1.06 (95% confidence interval, 0.99-1.13; P = .07).

Rates of adverse effects were significantly higher in the nortriptyline group than the placebo group (Table 3), especially dry mouth and sedation. Nortriptyline therapy was discontinued because of adverse events in 13% of subjects (10/79) (dry mouth in 4, sedation in 2, constipation in 2, and subjective fast heart beat and asymptomatic prolonged QT interval in 1 each), while placebo was discontinued in 1% of subjects (1 patient with irritability) in the placebo group (P = .03). Transdermal nicotine was discontinued in 4% of subjects (3/79) in the nortriptyline group compared with 1% of subjects (1/79) in the placebo group (P = .62).

Table Graphic Jump LocationTable 3. Cumulative Number of Subjects Experiencing Adverse Events During Study Drug Treatment by Study Group*

At the end of drug therapy, the study nurse identified the treatment assignment correctly in 69% of subjects (33/48) who continued in follow-up to that point.

This study is the first demonstration, to our knowledge, that the addition of nortriptyline to transdermal nicotine is associated with improved 6-month smoking cessation rates, although a baseline imbalance in cigarettes smoked per day attenuated that effect. We did not observe an improvement in withdrawal symptoms with nortriptyline combined with transdermal nicotine. We also found a higher rate of anticholinergic adverse effects, which were typical of nortriptyline, in the combined therapy group, and there was a greater rate of drug discontinuation than was seen with nicotine replacement alone.

Nortriptyline as a single agent has been tested in several randomized trials and found to be effective and reasonably safe.7,8 A recent article by Hall et al15 found that the cessation rate with nortriptyline was similar to that seen with sustained-release bupropion and both were superior to placebo at 24 weeks, although at 1 year of follow-up the advantage over placebo had diminished. da Costa et al16 found that nortriptyline doubled the cessation rate compared with placebo at 3 months of follow-up. The current study is, to our knowledge, the first examination of the use of nortriptyline in combination with transdermal nicotine.

Smoking behavior is determined by a complex interaction of biological, psychological, and behavioral factors.17 The mechanisms of nicotine dependence and withdrawal are incompletely understood. Nevertheless, there are several possible mechanisms of action for nortriptyline’s effect in enhancing smoking cessation. Nortriptyline may reduce depressive symptoms18 and the need for “negative affect reduction smoking.”19,20 Other antidepressant agents are also effective in smoking cessation, suggesting that the antidepressant effect may be the common mechanism. We had very few patients with previous depression and we saw no significant relationship between baseline Beck Depression Inventory scores and quitting, indicating that treatment of depressive symptoms or of an underlying depressive tendency is probably not the only mechanism.

It is also possible that antidepressants suppress the symptoms of nicotine withdrawal with central noradrenergic receptor systems. Nortriptyline affects a number of neurotransmitter systems, predominantly acting to block reuptake of norepinephrine, with a lesser effect on serotonin.21 Other drugs that are effective in smoking cessation, including bupropion and clonidine, also have effects on the central noradrenergic systems and also suppress withdrawal symptoms.22 The fact that withdrawal symptoms were comparable in the 2 groups studied would suggest that control of withdrawal was achieved with transdermal nicotine and that the addition of nortriptyline did not have an impact on withdrawal. The cessation effect of nortriptyline may be due to anticholinergic actions,23 especially the dry mouth and taste changes. Rose24 and Westman et al25 demonstrated the importance of upper-airway sensory stimulation in smoking and cessation. Most likely, the beneficial effects of nortriptyline are due to a combination of these, and perhaps other mechanisms, with different mechanisms being more or less important in different individuals.

There are several limitations that must be kept in mind when the results of this study are interpreted. First, we required subjects to be smoking at least 10 cigarettes per day at the time of study entry, and many were trying to quit and had already reduced the number of cigarettes smoked before their formal “quit date.” If they were already past the peak of their withdrawal symptoms, the apparent benefits of nortriptyline would have been minimized. Second, our blinding was only partially effective. Because of the high frequency of dry mouth, the study nurse was often able to identify the active drug. Third, our small sample size means that conclusions regarding the efficacy of nortriptyline combined with transdermal nicotine must be tentative and subject to further research. In addition, our ability to analyze the effect of potential predictors of cessation such as sex, previous depression, level of nicotine dependence, and number of previous quit attempts is limited. Since we enrolled fewer subjects with symptoms of depression than anticipated, we cannot determine whether nortriptyline would be more effective in depressed smokers. There was an imbalance between the study groups, with the placebo group smoking more than the nortriptyline group. Inclusion of this factor in the analysis reduced the effect of nortriptyline, since the placebo group might have been more resistant to quitting. Finally, the success rate with transdermal nicotine at 6 months was relatively low at 10%. This is not as high as has been found in the early studies of transdermal nicotine but is comparable with that seen in other studies in Veterans Affairs settings.26 These quit rates are also consistent with recent concerns that have been raised about the efficacy of transdermal nicotine as an over-the-counter smoking cessation aid.27 We have demonstrated potential efficacy of nortriptyline combined with transdermal nicotine in smoking cessation; however, there was a high rate of discontinuation of nortriptyline and frequent adverse effects. It is also clear from our data that subjects treated with nortriptyline require close monitoring for adverse events. The fact that one subject with a normal baseline electrocardiogram developed asymptomatic prolongation of the QT interval argues for obtaining an electrocardiogram while patients are receiving nortriptyline therapy. However, nortriptyline combined with transdermal nicotine may prove to be a useful alternative for smokers in whom first-line smoking cessation therapies have failed.

Accepted for Publication: May 11, 2004.

Correspondence: Allan V. Prochazka, MD, MSc, Ambulatory Care 11B, 1055 Clermont, Denver, CO 80220 (Allan.Prochazka@med.va.gov).

Financial Disclosure: None.

Funding/Support: This study was supported by a grant from the Department of Veterans Affairs, Washington, DC.

Disclaimer: The opinions expressed are the private views of the authors and do not represent official statements of the Department of Veterans Affairs.

Previous Presentation: This study was presented in part before the Society of Research on Nicotine and Tobacco; March 23, 2001; Seattle, Wash.

Fiore  MCBailey  WCCohen  SJ  et al.  Treating Tobacco Use and Dependence: Clinical Practice Guideline.  Rockville, Md US Dept of Health and Human Services Public Health Service June2000;
Glassman  AHStetner  FWalsh  BT  et al.  Heavy smokers, smoking cessation and clonidine: results of a double-blind, randomized trial. JAMA 1988;2592863- 2866
PubMed Link to Article
Breslau  NKilbey  MMAndreski  P Nicotine withdrawal symptoms and psychiatric disorders: findings from an epidemiologic study of young adults. Am J Psychiatry 1992;149464- 469
PubMed
Hurt  RDSachs  DPLGlover  ED  et al.  A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;3371195- 1202
PubMed Link to Article
Jorenby  DELeishow  SJNides  MA  et al.  A controlled trial of sustained release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340685- 691
PubMed Link to Article
Edwards  NBSimmons  RCRosenthal  TLHoon  PWDowns  JM Doxepin in the treatment of nicotine withdrawal. Psychosomatics 1988;29203- 206
PubMed Link to Article
Prochazka  AVWeaver  MJKeller  RT  et al.  A randomized trial of nortriptyline for smoking cessation. Arch Intern Med 1998;1582035- 2039
PubMed Link to Article
Hall  SMHumfleet  GLReus  VI  et al.  Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry 2002;59930- 936
PubMed Link to Article
Berlin  ISaid  SSpreux-Varoquaux  O  et al.  A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin Pharmacol Ther 1995;58444- 452
PubMed Link to Article
Niaura  RSpring  BBorrelli  B  et al.  Multicenter trial of fluoxetine as adjunct to behavioral smoking cessation treatment. J Consult Clin Psychol 2002;70887- 896
PubMed Link to Article
Fagerstrom  KO Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978;3235- 241
PubMed Link to Article
Bucholz  KKRobins  LNShayka  JJ  et al.  Performance of two forms of a computer psychiatric screening interview: version I of the DISSI. J Psychiatr Res 1991;25117- 129
PubMed Link to Article
Gritz  ERCarr  CRMarcus  AC The tobacco withdrawal syndrome in unaided quitters. Br J Addict 1991;8657- 69
PubMed Link to Article
Beck  ATRial  WYRickels  K Short form of the Depression Inventory: crossvalidation. Psychol Rep 1974;341184- 1186
PubMed
Hall  SMHumfleet  GLReus  VI  et al.  Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry 2002;59930- 936
PubMed Link to Article
da Costa  CLYounes  RNLourenço  MTC Stopping smoking: a prospective, randomized, double-blind study comparing nortriptyline to placebo. Chest 2002;122403- 408
PubMed Link to Article
Seidman  DFRosecan  JRole  L Biological and clinical perspectives on nicotine addition. DF  SeidmanLS  CoveyHelping the Hardcore Smoker: A Clinician’s Guide Mahwah, NJ Lawrence A Erlbaum Associates1999;
Covey  LSGlassman  AHStetner  F Major depression following smoking cessation. Am J Psychiatry 1997;154263- 266
PubMed
Ikard  FFTomkins  S The experience of affect as a determinant of smoking behavior. J Abnorm Psychol 1973;81172- 181
PubMed Link to Article
Shiffman  S Relapse following smoking cessation: a situational analysis. J Consult Clin Psychol 1982;5071- 86
PubMed Link to Article
Potter  WZManji  HKRudorfer  MV Tricyclics and tetracyclics. AF  SchatzbergCB  Nemeroffeds.Textbook of Psychopharmacology Washington, DC American Psychiatric Press Inc1995;141- 160
Gourlay  SGBenowitz  NL Is clonidine an effective smoking cessation therapy? Drugs 1995;50197- 207
PubMed Link to Article
Bachynsky  N The use of anticholinergic drugs for smoking cessation: a pilot study. Int J Addict 1986;21789- 805
PubMed
Rose  JE The role of upper airway stimulation in smoking. OF  PomerleauCS  Pomereaueds.Nicotine Replacement: a Critical Evaluation New York, NY Alan R Liss Inc1988;95- 106
Westman  ECBehm  FMRose  JE Airway sensory replacement combined with nicotine replacement for smoking cessation: a randomized, placebo-controlled trial using a citric acid inhaler. Chest 1995;1071358- 1364
PubMed Link to Article
Joseph  AMNorman  SMFerry  LH  et al.  The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996;3351792- 1798
PubMed Link to Article
Pierce  JPGilpin  EA Impact of over-the-counter sales on effectiveness of pharmaceutical aids for smoking cessation. JAMA 2002;2881260- 1264
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Trial profile. Some patients had more than 1 reason for discontinuing the study; therefore, the total numbers of patients who discontinued because of adverse events (AEs), who never quit, and who relapsed exceed the difference between the number treated and the number of validated quitters.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Validated continuous smoking cessation rates from 1 week after quit day until the completion of follow-up at 6 months. Continuous cessation was defined as no self-report of smoking at any visit, all expired carbon dioxide readings less than 9 ppm, and the final urine cotinine level less than 50 ng/mL (284 nmol/L). Subjects who dropped out were counted as smokers. P value represents the comparison of the nortriptyline hydrochloride group and the placebo group 6-month validated cessation rate determined by Fisher exact test. CI indicates confidence interval.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Characteristics and Smoking History of Study Subjects
Table Graphic Jump LocationTable 2. Mean Withdrawal Symptom Scores 7 Days After Quit Day by Study Group
Table Graphic Jump LocationTable 3. Cumulative Number of Subjects Experiencing Adverse Events During Study Drug Treatment by Study Group*

References

Fiore  MCBailey  WCCohen  SJ  et al.  Treating Tobacco Use and Dependence: Clinical Practice Guideline.  Rockville, Md US Dept of Health and Human Services Public Health Service June2000;
Glassman  AHStetner  FWalsh  BT  et al.  Heavy smokers, smoking cessation and clonidine: results of a double-blind, randomized trial. JAMA 1988;2592863- 2866
PubMed Link to Article
Breslau  NKilbey  MMAndreski  P Nicotine withdrawal symptoms and psychiatric disorders: findings from an epidemiologic study of young adults. Am J Psychiatry 1992;149464- 469
PubMed
Hurt  RDSachs  DPLGlover  ED  et al.  A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 1997;3371195- 1202
PubMed Link to Article
Jorenby  DELeishow  SJNides  MA  et al.  A controlled trial of sustained release bupropion, a nicotine patch, or both for smoking cessation. N Engl J Med 1999;340685- 691
PubMed Link to Article
Edwards  NBSimmons  RCRosenthal  TLHoon  PWDowns  JM Doxepin in the treatment of nicotine withdrawal. Psychosomatics 1988;29203- 206
PubMed Link to Article
Prochazka  AVWeaver  MJKeller  RT  et al.  A randomized trial of nortriptyline for smoking cessation. Arch Intern Med 1998;1582035- 2039
PubMed Link to Article
Hall  SMHumfleet  GLReus  VI  et al.  Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry 2002;59930- 936
PubMed Link to Article
Berlin  ISaid  SSpreux-Varoquaux  O  et al.  A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. Clin Pharmacol Ther 1995;58444- 452
PubMed Link to Article
Niaura  RSpring  BBorrelli  B  et al.  Multicenter trial of fluoxetine as adjunct to behavioral smoking cessation treatment. J Consult Clin Psychol 2002;70887- 896
PubMed Link to Article
Fagerstrom  KO Measuring degree of physical dependence to tobacco smoking with reference to individualization of treatment. Addict Behav 1978;3235- 241
PubMed Link to Article
Bucholz  KKRobins  LNShayka  JJ  et al.  Performance of two forms of a computer psychiatric screening interview: version I of the DISSI. J Psychiatr Res 1991;25117- 129
PubMed Link to Article
Gritz  ERCarr  CRMarcus  AC The tobacco withdrawal syndrome in unaided quitters. Br J Addict 1991;8657- 69
PubMed Link to Article
Beck  ATRial  WYRickels  K Short form of the Depression Inventory: crossvalidation. Psychol Rep 1974;341184- 1186
PubMed
Hall  SMHumfleet  GLReus  VI  et al.  Psychological intervention and antidepressant treatment in smoking cessation. Arch Gen Psychiatry 2002;59930- 936
PubMed Link to Article
da Costa  CLYounes  RNLourenço  MTC Stopping smoking: a prospective, randomized, double-blind study comparing nortriptyline to placebo. Chest 2002;122403- 408
PubMed Link to Article
Seidman  DFRosecan  JRole  L Biological and clinical perspectives on nicotine addition. DF  SeidmanLS  CoveyHelping the Hardcore Smoker: A Clinician’s Guide Mahwah, NJ Lawrence A Erlbaum Associates1999;
Covey  LSGlassman  AHStetner  F Major depression following smoking cessation. Am J Psychiatry 1997;154263- 266
PubMed
Ikard  FFTomkins  S The experience of affect as a determinant of smoking behavior. J Abnorm Psychol 1973;81172- 181
PubMed Link to Article
Shiffman  S Relapse following smoking cessation: a situational analysis. J Consult Clin Psychol 1982;5071- 86
PubMed Link to Article
Potter  WZManji  HKRudorfer  MV Tricyclics and tetracyclics. AF  SchatzbergCB  Nemeroffeds.Textbook of Psychopharmacology Washington, DC American Psychiatric Press Inc1995;141- 160
Gourlay  SGBenowitz  NL Is clonidine an effective smoking cessation therapy? Drugs 1995;50197- 207
PubMed Link to Article
Bachynsky  N The use of anticholinergic drugs for smoking cessation: a pilot study. Int J Addict 1986;21789- 805
PubMed
Rose  JE The role of upper airway stimulation in smoking. OF  PomerleauCS  Pomereaueds.Nicotine Replacement: a Critical Evaluation New York, NY Alan R Liss Inc1988;95- 106
Westman  ECBehm  FMRose  JE Airway sensory replacement combined with nicotine replacement for smoking cessation: a randomized, placebo-controlled trial using a citric acid inhaler. Chest 1995;1071358- 1364
PubMed Link to Article
Joseph  AMNorman  SMFerry  LH  et al.  The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996;3351792- 1798
PubMed Link to Article
Pierce  JPGilpin  EA Impact of over-the-counter sales on effectiveness of pharmaceutical aids for smoking cessation. JAMA 2002;2881260- 1264
PubMed Link to Article

Correspondence

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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