Four trials of nortriptyline and 5 trials of bupropion were identified. A number of other studies involving bupropion were excluded for the following reasons: published in abstract form only, included patients with psychiatric diseases, dealt specifically with relapse, had inadequate duration of follow-up, was not placebo- controlled, or evaluated predictors of success or other aspects of smoking cessation. Only one trial specifically included patients with COPD, and that study population had much less severe disease than the population intended as the focus of the current review. One paper compared nortriptyline and bupropion.
Nortriptyline versus Placebo
Prochazka and others conducted a double-blind, randomized, controlled trial of nortriptyline in 214 veteran subjects who were already enrolled in a behavioural smoking cessation program. Subjects in the treatment group received nortriptyline, titrated to a target dose of 75 mg/day over 1 week, with target blood concentrations of 50-150 ng/mL, based on concentrations established for the treatment of depression. The primary endpoint was self-reported sustained smoking abstinence within 1 week, confirmed by an expired carbon monoxide concentration of 9 ppm or less and verified by urine cotinine concentration of less than 50 ng/mL at 6 months. The point prevalence abstinence rate was significantly higher at 6 months in the nortriptyline group (14%) than in the placebo group (3%), an absolute difference of 11%. The number needed to treat to achieve abstinence in one patient was 9 (95% confidence interval [CI] 6-25). The incidence of adverse effects was significantly higher in the nortriptyline group than the placebo group: dry mouth (59% v. 22%), dysgeusia (19% v. 8%), gastrointestinal upset (38% v. 23%), and drowsiness (22% v. 8%).
Nortriptyline was also evaluated as a smoking cessation aid by Hall and others. This randomized, double-blind, placebo-controlled trial enrolled 199 participants and employed a 2 x 2 x 2 factorial design, in which the efficacy of nortriptyline was assessed, along with that of cognitive behavioural therapy and health education. The duration of follow-up was 64 weeks. Patients were further classified with respect to the presence or absence of major depressive disorder. A history of major depressive disorder was present in 65 (33%) of the patients. Nortriptyline was associated with a better smoking cessation rate after 12 weeks of treatment (as assessed by carbon monoxide concentrations less than 10 ppm and urine cotinine concentrations less than 341 nmol/L) than placebo (odds ratio [OR] 2.4, 95% CI 1.8-3.4, p < 0.04). The absolute risk reduction for this endpoint was 17%, and the number needed to treat was 6. In the nortriptyline group, 24% of the subjects achieved continuous abstinence over the 64-week trial, compared with 12% in the placebo group (OR 2.3, 95% CI 1.1-5.0), which translates to a number needed to treat of 8. The incidences of dry mouth (78% v. 33%), lightheadedness (49% v. 22%), shaky hands (23% v. 11%), and blurred vision (16% v. 6%) were significantly higher in the nortriptyline group than in the placebo group. The authors concluded that there is evidence to support use of nortriptyline for smoking cessation in patients with or without a major depressive disorder.
A third study evaluated the efficacy of nortriptyline relative to that of placebo in 144 patients enrolled in a 5-week antismoking program. The primary endpoint of this randomized, double-blind study was smoking cessation for at least 1 week at the end of the 5-week behavioural program. Secondary endpoints included 3- and 6-month abstinence rates, adherence, and side effects. The investigators also performed a univariate analysis of prognostic factors influencing cessation rates.
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The 6-week cessation rate was significantly higher among patients receiving nortriptyline than those receiving placebo (44% v. 19%, p < 0.001). The absolute risk reduction was 25%, resulting in a number needed to treat of 4. Abstinence rates at 6 months were 21% for the nortriptyline group and 5% for the placebo group (number needed to treat 6). The most common side effects cited were dry mouth and constipation; however, the incidence of adverse effects in the 2 groups was not significantly different. In this study, the Fagerstrom questionnaire was used to determine the degree of nicotine dependence. Patients scoring at least 7 points were considered highly nicotine-dependent. In the univariate analysis of prognostic factors influencing smoking cessation, the Fagerstrom test score (p = 0.005) and use of nortriptyline (p < 0.001) were the only significant prognostic factors. In the subset of patients with Fagerstrom scores of at least 7, nortriptyline was highly effective for smoking cessation (p < 0.001), but in patients scoring less than 7 points, there was no difference in cessation rates between nortriptyline and placebo (n = 20 in both groups, p = 0.1). Although the subgroup analysis was underpowered, these findings suggest, but do not prove, that nortriptyline may be effective only for patients with a strong physiological dependence on nicotine. In the study by Prochazka and others, Fagerstrom test score did not significantly influence cessation rates, but the average score in that study was 5.8, which is under the 7-point cut-off used by da Costa and others.
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