INTRODUCTION

Tobacco use remains one of the leading preventable causes of morbidity and mortality worldwide, accounting for more than 8 million deaths annually¹. Despite global reductions in smoking prevalence, nicotine dependence continues to represent a significant public health challenge, particularly in low- and middle-income countries where cessation support and pharmacotherapies are less accessible¹. In recent decades, the use of pharmacological treatments such as nicotine replacement therapy (NRT), bupropion, and cytisine has become a cornerstone of evidence-based strategies for smoking cessation, often combined with behavioral counseling to maximize abstinence outcomes².

Cytisine, a naturally occurring plant alkaloid extracted from Laburnum anagyroides, functions as a partial agonist of the α4β2 nicotinic acetylcholine receptor³. By mimicking nicotine’s action on these receptors, cytisine reduces withdrawal symptoms and craving while attenuating nicotine’s reinforcing effects^3,4. Randomized controlled trials and observational studies have shown that cytisine significantly increases quit rates compared with placebo and demonstrates efficacy comparable to other first-line pharmacotherapies^3,4. Its affordability and short 25-day treatment regimen make it a promising option, especially in resource-limited health systems. Furthermore, recent real-world studies in Central and Eastern Europe have demonstrated cytisine’s high tolerability and adherence, reinforcing its role as a practical cessation aid⁵. In Turkey, cytisine has recently gained attention following regulatory approval, yet evidence regarding its real-world effectiveness in outpatient cessation settings remains scarce. Understanding its comparative performance against other established pharmacotherapies, such as NRT and bupropion, is therefore crucial.

Bupropion, a monocyclic antidepressant and norepinephrine–dopamine reuptake inhibitor, exerts its smoking cessation effect by modulating dopaminergic activity within the mesolimbic pathway and antagonizing nicotinic acetylcholine receptors^6,7. These mechanisms alleviate craving and withdrawal symptoms while simultaneously counteracting the post-cessation depressive mood commonly observed in smokers⁶. Evidence from randomized trials indicates that bupropion approximately doubles the odds of long-term abstinence compared with placebo^6,7. Additionally, studies have shown that bupropion can be safely and effectively combined with long-acting NRT, offering synergistic effects in highly dependent smokers^7,8. Despite these advantages, its clinical use may be limited by contraindications such as seizure risk, insomnia, or concurrent psychiatric conditions⁶. Therefore, patient selection, adherence monitoring, and behavioral support remain key determinants of treatment success in real-world practice.

NRT remains the most widely utilized pharmacological intervention for smoking cessation globally. By supplying controlled doses of nicotine through transdermal patches, gums, lozenges, inhalers, or nasal sprays, NRT mitigates withdrawal symptoms and facilitates gradual dissociation from smoking behavior⁹. A meta-analysis indicates that NRT approximately doubles the likelihood of quitting compared with placebo⁹. Combination NRT, in which a steady nicotine patch is complemented by a rapid-acting form such as gum or lozenge, has shown superior outcomes over monotherapy and is endorsed as first-line treatment in most clinical guidelines^10,11. Nonetheless, adherence remains a critical determinant of real-world effectiveness. A systematic review and meta-analysis demonstrated a strong association between adherence to NRT and higher abstinence rates¹². Yet adherence rates in community-based populations are notably lower than in controlled trials, especially among younger adults and women, suggesting a gap between clinical efficacy and practical effectiveness^12,13. Furthermore, data from Turkey highlight variable use of NRT in primary care and smoking cessation clinics, with inconsistent follow-up protocols potentially affecting long-term outcomes¹⁴.

While pharmacotherapies have substantially improved cessation success, their real-world effectiveness depends heavily on accessibility, patient adherence, and structured clinical support¹⁴. Smoking cessation clinics, by integrating pharmacological and behavioral interventions, represent a key setting for optimizing these outcomes. However, limited national data exist on the comparative performance of cytisine, bupropion, and NRT in such real-world conditions. Therefore, this study aimed to evaluate patients attending a smoking cessation clinic, focusing on demographic characteristics, pharmacotherapy modalities, and cessation outcomes, with a particular emphasis on the relative effectiveness of cytisine, bupropion, and NRT in routine clinical practice.

METHODS

RESULTS

A total of 113 patients who applied to the Smoking Cessation Outpatient Clinic were included in the study. Of these, 67 patients (59.3%) successfully quit smoking, while 46 patients (40.7%) did not achieve smoking cessation. The mean age was 44.3 ± 17 years in the smoking cessation group and 47.5 ± 14.3 years in the non-cessation group, with no statistically significant difference between groups (p=0.296). Sex distribution was also similar between the two groups; 40.3% of patients in the cessation group were female, and 59.7% were male, compared with 39.1% female and 60.9% male in the non-cessation group (p=0.901).

There were no significant differences between the groups in education level, area of residence, marital status, income level, or the presence of comorbid diseases. Daily cigarette consumption and nicotine dependence levels assessed by the Fagerström test for nicotine dependence were comparable between patients who quit smoking and those who did not. Among patients who quit smoking, 14.9% had low, 43.3% had moderate, and 41.8% had high nicotine dependence, while corresponding proportions among those who did not quit were 13.0%, 39.1%, and 47.8%, respectively (p=0.816) (Table 1).

When reasons for applying to the Smoking Cessation Outpatient Clinic were evaluated, patients who reported financial burden as a reason for application were more likely to quit smoking compared with those who did not (31.3% vs 13.0%, p=0.025). Similarly, health concern was reported more frequently among patients who quit smoking than among those who did not (71.6% vs 50.0%, p=0.019). Concern about deterioration in self-care was reported by 38.8% of patients who quit smoking and 21.7% of those who did not, although this difference did not reach statistical significance (p=0.056). No significant differences were observed between groups in the reasons for application, including respiratory symptoms or social pressure (Table 1).

In terms of treatment adherence, completion of smoking cessation therapy was significantly higher among patients who successfully quit smoking compared with those who did not (77.6% vs 30.4%, p<0.001). The frequency of reported adverse effects, including headache, dizziness, nausea/vomiting, insomnia, dry mouth, and other symptoms, did not differ significantly between the two groups. Approximately half of the patients in both groups reported no treatment-related adverse effects (Table 2).

Evaluation of pharmacological treatment modalities revealed that treatment with bupropion use was more common among patients who did not quit smoking compared with those who quit (41.3% vs 20.9%, p=0.019). In contrast, treatment with cytisine use was significantly higher among patients who successfully quit smoking (58.2% vs 39.1%, p=0.046). No significant difference was observed between the groups regarding the use of nicotine replacement therapy (19.4% vs 19.6%, p=0.983) (Table 2).

No statistically significant differences were found between users and non-users of bupropion, cytisine, or NRT, with respect to nicotine dependence levels, treatment completion rates, reasons for treatment discontinuation, or the frequency of treatment-related adverse effects. Across all pharmacological modalities, the most commonly reported reasons for failure to complete treatment were insufficient reduction in smoking urge (42.9–60.0%) and adverse effects related to therapy (42.9–50.0%). This marked difference highlights treatment completion as a clinically important factor associated with smoking cessation success in routine outpatient practice (Table 3).

Regarding clinical and psychosocial changes after smoking cessation, improvement or reduction in dyspnea was reported more frequently among patients receiving cytisine compared with those not receiving cytisine (p=0.015). Other perceived benefits, including reduced cough and/or sputum production, increased comfort in social settings, improved self-confidence, and financial gain, were reported at similar rates across treatment modalities (Table 3).

Among patients who experienced relapse, no significant differences were observed between pharmacological treatment groups in terms of completion of smoking cessation treatment, timing of relapse, or reasons for resuming smoking. Across all treatment modalities, the most frequently reported reasons for relapses were inability to resist smoking urges, influence of social environment, and exposure to stressful life events. Relapse information was obtained during routine follow-up visits or telephone interviews (Table 4).

DISCUSSION

The primary finding of this research was that cytisine treatment was associated with the highest smoking cessation success rate, followed by bupropion, while NRT did not show a statistically significant effect on cessation outcomes. These findings are consistent with the growing body of evidence indicating that cytisine is an effective, safe, and affordable pharmacotherapy for nicotine dependence, particularly in low- and middle-income countries where cost and accessibility limit the use of other agents³. Importantly, our findings extend this evidence by demonstrating cytisine’s effectiveness under routine clinical conditions rather than controlled trial environments.

The superior cessation rates achieved with cytisine in this study align with findings from randomized controlled trials and network meta-analyses demonstrating higher abstinence rates with cytisine compared with placebo^2,4. Cytisine’s pharmacological action as a partial agonist at α4β2 nicotinic acetylcholine receptors effectively mitigates withdrawal symptoms while reducing nicotine reward, thereby promoting abstinence⁵. In the present study, a considerable proportion of cytisine users reported discontinuing treatment early due to achieving abstinence by the fifth day of therapy. This rapid onset of effect has also been reported in previous real-world evaluations, suggesting that cytisine’s partial agonist mechanism suppresses early craving, which may contribute to its high adherence and satisfaction rates. Furthermore, improvement in shortness of breath, reported significantly more often among cytisine users in this study, supports the hypothesis that early abstinence yields measurable respiratory benefits within weeks of cessation¹⁶.

Bupropion also demonstrated a statistically significant relationship with cessation success in our cohort, though its efficacy was lower than that of cytisine. Bupropion’s dual mechanism – dopaminergic and noradrenergic reuptake inhibition combined with non-competitive antagonism of nicotinic receptors – modulates the reward circuitry associated with nicotine withdrawal⁶. The cessation rates observed in this study are consistent with a previous study reporting significantly higher abstinence rates with bupropion compared with placebo⁸. However, comorbid conditions such as diabetes mellitus and chronic pulmonary disease were more prevalent in the bupropion group, possibly reflecting physician selection bias favoring bupropion in patients with contraindications to NRT or cytisine. Additionally, while bupropion is well tolerated, adverse effects such as insomnia and dry mouth may limit adherence⁷. Nonetheless, its positive impact on mood and anhedonia remains clinically relevant, particularly among smokers with depressive symptoms.

In contrast, NRT did not show a significant association with smoking cessation in this sample. Although meta-analyses consistently demonstrate that NRT significantly increases quit rates compared with placebo⁹, real-world adherence remains suboptimal. Studies have shown that full adherence to NRT regimens is associated with substantially higher cessation success rates^9,12, while inconsistent use markedly reduces effectiveness. The relatively lower success rate of NRT in our cohort likely reflects limited adherence and underdosing, as many patients reported early discontinuation or sporadic use. Moreover, behavioral support accompanying NRT is crucial for optimizing outcomes¹⁰; in resource-limited clinical settings, such structured follow-up may be inconsistent, contributing to lower observed efficacy.

Treatment adherence emerged as one of the most critical determinants of cessation success in this study, with patients completing their pharmacotherapy achieving more than twice the quit rate of those who discontinued prematurely. This finding aligns with previous work emphasizing adherence as a central factor in treatment success across all pharmacotherapies^12,17. The strong association between adherence and cessation underscores the importance of structured behavioral counseling and follow-up in smoking cessation clinics. In Turkey, recent analyses of national cessation programs have highlighted that patient follow-up intensity and clinician continuity are key predictors of success¹⁸.

Beyond pharmacological efficacy, motivational and socioeconomic factors strongly influenced cessation outcomes. In our study, patients who reported health concerns or the financial burden of smoking as reasons for attending the clinic were significantly more likely to achieve abstinence¹⁹. These findings are consistent with recent population-based evidence. A large study from England found that health concerns remain the leading reason for quit attempts, cited in approximately half of cases between 2018 and 2023. In contrast, financial reasons have become increasingly salient, motivating over one-quarter of recent quit attempts¹⁹. Likewise, a multi-country analysis across low- and middle-income nations found that socio-economic status and affordability strongly determine cessation behaviors, with higher quit rates among those experiencing economic constraints or unemployment¹³. At the macroeconomic level, tobacco use imposes a substantial financial burden worldwide due to healthcare costs and productivity losses²⁰. Together, these data indicate that both perceived health risks and financial pressures act as powerful, complementary motivators for cessation in diverse populations.

The low overall incidence of side effects across treatment groups in this study supports the established safety profiles of cytisine, bupropion, and NRT². The most common adverse events – dry mouth, nausea, and insomnia – were mild and self-limited, consistent with prior reports^6,16. Importantly, no serious neuropsychiatric events were observed, which supports the broader safety of these agents in real-world clinical practice. Functional improvements were reported across all groups, suggesting that early perceived health benefits may reinforce motivation to maintain abstinence.

CONCLUSIONS

In this real-world study of patients attending a tertiary smoking cessation clinic, cytisine demonstrated the highest rate of smoking cessation success, followed by bupropion. At the same time, NRT showed no significant association with abstinence outcomes. These results reinforce the evidence supporting cytisine as an effective, safe, and affordable pharmacological option for tobacco dependence treatment. Bupropion remains a valuable alternative, particularly for smokers with comorbid depressive symptoms, whereas the limited impact of NRT highlights the importance of adherence and structured behavioral support.

Treatment completion emerged as the strongest determinant of success, underscoring the necessity of close clinical follow-up and patient-centered counseling in smoking cessation programs. Future multicenter, prospective studies using biochemical verification of abstinence and standardized behavioral interventions are warranted to validate and extend these real-world findings.