Skip to main content

An observational study of the effects of smoking cessation earlier on the clinical characteristics and course of acute exacerbations of chronic obstructive pulmonary disease

Abstract

Background

Previous studies have focused on the negative effects of continued smoking on chronic obstructive pulmonary disease (COPD). However, few studies have investigated the positive effects of long-term smoking cessation on patients suffering from acute exacerbations of COPD.

Methods

The study recruited and followed current or former smokers who had been hospitalized and diagnosed with AECOPD. An in-depth analysis of clinical and laboratory indicators was conducted.

Results

125 patients were covered, including 72 short-term quitters and 53 long-term quitters. The results showed that long-term smoking cessation may result in milder dyspnea and cough, a higher oxygenation index, a lower arterial partial pressure of carbon dioxide, and milder pulmonary hypertension, airflow restriction, and gas retention in patients with AECOPD. However, despite the lower treatment intensity for long-term quitters, improvement in dyspnea and an increase in oxygenation index were comparable to those achieved by short-term quitters. Furthermore, patients with mild phlegm, which accounted for 84% of all subjects, showed greater improvement in phlegm in AECOPD patients with long-term cessation of smoking.

Conclusion

It was found that in patients with AECOPD who quit smoking for a long period of time, there was a reduction in symptoms, improvement in lung function, reduction in treatment intensity, and better improvement in phlegm symptoms after therapy. It is beneficial and necessary to quit smoking early, even if you smoke a small amount of cigarettes.

Peer Review reports

Introduction

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic respiratory diseases, characterized by persistent restrictions in airflow and respiratory symptoms. It is the third leading cause of death worldwide, with China accounting for nearly one-third of those deaths [1,2,3].

Smoking has generally been considered to be the most significant risk factor for COPD [1]. Nearly two-thirds of COPD patients are current or former smokers [4], making it crucial to study their clinical characteristics. A number of studies have demonstrated that continuous smoking adversely impacts symptom control, lung function maintenance, exacerbation frequency, and mortality [5,6,7,8], as well as a quantitative relationship between cigarette smoking and ventilatory function [9]. However, only Scanlon explored the effect of different smoking cessation periods on lung function improvement [6] and no study has investigated the impact of different smoking cessation periods on the clinical characteristics and treatment response of COPD patients, particularly those with exacerbated disease.

The purpose of this study is to determine whether there are any differences in clinical characteristics and therapeutic responses between AECOPD patients with different smoking cessation periods. The study recruited current or former smokers with AECOPD. The symptoms, objective indicators, and therapeutic details of short-term and long-term quitters were recorded and compared. COPD patients may benefit from quitting smoking early by not only preventing the harmful effects of cigarettes, but also allowing them to recover from the more severe illness.

Methods

Study population

Similar with our previous study [10], from January 2021 until December 2021, the Haian Hospital affiliated with Nantong University screened and employed adults with previously clinically diagnosed COPD and acute exacerbations of symptoms, and at the affiliated Ruijin Hospital of Shanghai Jiao Tong University School of Medicine. As approved by the Institutional Review Boards of affiliated Haian Hospital of Nantong University and Shanghai Jiao Tong University School of Medicine affiliated Ruijin Hospital, the present study followed the Declaration of Helsinki. The present study was conducted with the written informed consent of all adult participants.

Criteria include: (1) Patients clinically diagnosed with AECOPD upon admission; (2) Lung function ascertained prior to the present exacerbation when the patients were in stable condition, with a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) less than 70%, conforming to diagnosis criteria of the Global Initiative for COPD (GOLD) [1]; (3) current or former smokers.

Exclusion criteria: Patients suffering from pneumonia, acute asthma exacerbations, active tuberculosis, bronchiectasis, bronchiolitis obliterans, generalized bronchiolitis, or unstable cardiac conditions in the last four months. In addition, patients with a previous clinical diagnosis of asthma or a positive bronchodilator reversibility test prior to the present exacerbation were excluded from the study.

In accordance with previous research on the definition of successful smoking cessation, five years is considered sufficient time to qualify [11, 12]. A threshold of five pack-year was used to distinguish between long-term and short-term smoking cessation because most study participants smoked a pack of cigarettes a day.

Data collection

During the recruitment process, all patients underwent a medical interview, a physical examination, and laboratory tests. A day-time cough symptom scoring system [8], grading cough symptoms from 0 to 3, with a score of 0 denoting no cough, was used to assess cough severity. Similar to cough severity, phlegm severity was recorded. A modified Medical Research Council scale (mMRC) was used to assess the severity of dyspnea. The symptoms were reassessed 24 h before discharge from the hospital. Critical information about symptoms and smoking status were double checked by two different researchers and discrepancies were addressed by discussion among all the researchers.

Spirometry was performed in accordance with the recommendations of the American Thoracic Society (ATS) and European Respiratory Society (ERS) when patients were stable [9]. We assessed FEV1, FEV1% of predicted value (FEV1%), FEV1/FVC, the ratio of residual volume to total lung capacity (RV/TLC), the diffusing capacity of the lung for carbon monoxide (DLCO), and the ratio of DLCO to alveolar volume (DLCO/VA).

An arterial blood gas analysis was performed upon admission and 24 h prior to discharge to determine the arterial oxygenation index (calculated as oxygen partial pressure (mmHg) divided by oxygen fraction inspired) and carbon dioxide partial pressure (PaCO2).

The use of medications (e.g., antibiotics, inhaled corticosteroid (ICS), long-acting β2 agonists (LABA) or long-acting anti-muscarinic antagonists (LAMA), short-acting β2 agonists (SABA), and systemic corticosteroid) was recorded. Additionally, the non-invasive ventilation time and the hospital stay were recorded.

Statistical analysis

Numbers (percentages) are used for categorical variables, while the mean ± standard deviations (SD) are used for continuous variables. In order to compare differences between the groups, Fisher’s exact test was used for categorical variables, and one-way analysis of variance (ANOVA) or non-parametric Mann-Whitney tests were used for continuous or ordinal variables, respectively. Analysis of covariance and logistic regression analyses were conducted taking into account possible confounding factors.

Statistical analyses were performed using IBM SPSS, version 20.0 (IBM Corp., Armonk, NY, USA), and a p-value of < 0.05 was considered significant.

Results

  1. 1.

    Demographic characteristics of AECOPD patients who have ceased smoking at different times.

The study screened 222 patients, and ultimately 125 patients were covered (see Fig. 1). Seventy-two of these patients had quit smoking no more than five years ago, three were current smokers who had quit smoking during this period of disease exacerbation, and 53 had quit smoking more than five years ago. The subjects were all male. A balance was observed across the groups in terms of characteristics such as age, BMI, educational level, occupation, occupation exposure, biomass exposure, and prior respiratory disease. The short-term quitters smoked more (smoking pack-year, 11.3 ± 3.8 vs. 9.8 ± 2.4, P < 0.01, short-term and long-term quitters, respectively), but this difference was not observed among smokers who did not exceed 10 pack-years (8.4 ± 2.0 vs. 8.8 ± 1.6, P > 0.05). A more detailed description of demographic characteristics can be found in Table 1.

Fig. 1
figure 1

Flowchart of the study

Table 1 Demographic Characteristic of subjects
  1. 2.

    In AECOPD patients with a longer smoking cessation time, the severity of the disease and the number of acute exacerbations were less severe.

It is important to note that although there was no difference between short-term and long-term quitters in the proportion of group D patients (93.1 vs. 84.9%, P > 0.05, according to the ABCD assessment tool of GOLD guideline), patients who had longer periods without smoking were more likely to experience mild airway obstruction (percentage of patients with GOLD grade severity 1 or 2, 25.0 vs. 62.3%, P < 0.001, short-term and long-term quitters, respectively, Fig. 2 A). Additionally, in spite of the fact that long-term smoking cessation did not influence phlegm severity (percentage of patients with mild phlegm, 79.2 vs. 90.6%, P > 0.05), patients with long-term smoking cessation reported milder dyspnea and cough symptoms (percentage of patients with mild cough, 63.9 vs. 83.0%, P < 0.05, Fig. 2B; percentage of patients with mMRC score < 3, 19.4 vs. 54.7%, P < 0.001, Fig. 2 C).

Fig. 2
figure 2

Proportion of patients with different (A) GOLD grade classification, (B) cough severity, (C) mMRC score, and (D) phlegm severity. **P < 0.01, and ***P < 0.001

In terms of objective indicators, smoking cessation for a longer period of time was associated with a higher oxygenation index (222.5 ± 42.1 vs. 253.1 ± 36.8mmHg, P < 0.001), lower PaCO2 (73.7 ± 11.8 vs. 61.5 ± 10.3mmHg, P < 0.001), and a milder form of pulmonary hypertension, airflow restriction, gas retention, and acute exacerbations (systolic pulmonary arterial pressure (SPAP), 50.0 ± 9.5 vs. 42.3 ± 8.4mmHg, P < 0.001; FEV1, 1.1 ± 0.4 vs. 1.6 ± 0.6 L, P < 0.001; FEV1%, 40.7 ± 16.1 vs. 57.5 ± 16.8%, P < 0.001; RV/TLC, 57.0 ± 10.9 vs. 51.7 ± 7.8%, P < 0.01; number of acute exacerbations per year, 2.7 ± 1.0 vs. 1.9 ± 1.0, P < 0.001). In accordance with this phenomenon, AECOPD patients who had stopped smoking for a longer period of time were treated less intensively. There was a shorter course of antibiotics (9.6 ± 1.7 vs. 8.7 ± 1.1 days, P < 0.01), a reduced use of systemic glucocorticoids (137.8 ± 67.8 vs. 100.0 ± 78.8 mg, P < 0.01), and a shorter duration of non-invasive ventilation (6.8 ± 4.5 vs. 1.9 ± 3.8 days, P < 0.001, Table 2).

Table 2 Clinical and pulmonary functional characteristic of subjects

As noted above, patients who quitted smoking earlier also smoked less, which affected the severity of COPD as well, according to previous studies [9, 13]. Analysis of covariance or logistic regression was conducted in order to eliminate this possible confounding factor. Similar results were obtained (cough severity, short-term vs. long-term quitters, odds ratio (OR) = 2.0, 95% confidence interval (CI) 0.9 ~ 4.2, P > 0.05; mMRC score, OR = 2.5, 95% CI 1.3 ~ 4.8, P < 0.01; phlegm severity, OR = 1.5, 95% CI 0.7 ~ 3.5, P > 0.05; adjustable oxygenation index, 220.6 ± 39.0 vs. 255.7 ± 39.1mmHg, P < 0.001; adjustable PaCO2, 73.5 ± 11.3 vs. 61.7 ± 11.3mmHg, P < 0.001; adjusted SPAP 50.0 ± 9.1 vs. 42.2 ± 9.1mmHg, P < 0.001; adjusted FEV1 1.1 ± 0.5 vs. 1.6 ± 0.5 L, P < 0.001; adjusted FEV1%, 41.6 ± 15.9 vs. 56.4 ± 15.9%, P < 0.001; adjusted RV/TLC 57.2 ± 9.7 vs. 51.5 ± 9.8%, P < 0.01; adjusted number of acute exacerbations per year, 2.7 ± 1.0 vs. 2.0 ± 1.0, P < 0.01). Additionally, since short-term and long-term quitters shared similar smoking amounts for patients with ≤ 10 pack-years, these subjects were subjected to a focused analysis to confirm the results. There were 39 short-term quitters and 42 long-term quitters. Similarly, longer smoking cessation was associated with milder dyspnea, cough, and phlegm symptoms (percentage of patients with mMRC score < 3, 23.1 vs. 57.1%, P < 0.01; percentage of patients with mild cough, 61.5 vs. 88.1%, P < 0.01; percentage of patients with mild phlegm, 76.9 vs. 92.9%, P < 0.05). In addition, there was a higher oxygenation index (211.2 ± 47.7 vs. 254.3 ± 36.1mmHg, P < 0.001), a lower PaCO2 (73.0 ± 13.0 vs. 60.9 ± 9.7mmHg, P < 0.001), and a milder form of pulmonary hypertension, airflow restriction, gas retention, and acute exacerbations in long-term quitters (SPAP, 50.0 ± 10.0 vs. 41.6 ± 8.3mmHg, P < 0.001; FEV1, 1.2 ± 0.5 vs. 1.7 ± 0.6 L, P < 0.001; FEV1%, 42.9 ± 16.8 vs. 59.5 ± 16.6%, P < 0.001; RV/TLC, 58.6 ± 12.0 vs. 51.5 ± 8.1%, P < 0.01; number of acute exacerbations per year, 2.6 ± 1.0 vs. 1.9 ± 0.9, P < 0.01).

  1. 3.

    Patients with long-term smoking cessation with AECOPD showed more obvious improvements in phlegm.

Despite the fact that patients with short-term smoking cessation received more intensive treatment, their therapeutic response was similar to that of patients with long-term smoking cessation, except for coughing symptoms and PaCO2 improvement. In AECOPD patients with short-term smoking cessation (Table 3), there was an better improvement in cough symptoms (37.5 vs. 18.9%, P < 0.05, short-term and long-term quitters, respectively) and PaCO2 (-14.4 ± 8.0 vs. -6.4 ± 6.2mmHg, P < 0.001), which may be due to more severe cough symptoms (correlation coefficient 0.960, P < 0.001) and CO2 retention (correlation coefficient − 0.939, P < 0.001). For patients with mild phlegm, who accounted for 84% of all the subjects, the improvement in phlegm was more pronounced in AECOPD patients with long-term smoking cessation (percentage of patients with phlegm improvement, 71.9 vs. 89.6%, P < 0.05).

Table 3 Therapeutic response of AECOPD patients with different smoking cessation time

Discussion

Cigarette smoking, especially active smoking, has long been considered one of the most significant risk factors for COPD, and smoking cessation is recognized as one of the most effective ways to slow the progression of the disease. Although previous studies have mainly focused on the negative effects of continuous smoking on COPD patients, few studies have elaborated on the positive effects of smoking cessation on COPD patients. In our study, the majority of patients (97.6%) had quitted smoking for more than a year, allowing us to evaluate the impact of smoking cessation duration on the clinical characteristics of AECOPD patients. As expected, The effects of long-term cessation of smoking on AECOPD patients were more positive than those of short-term cessation, including reduced symptoms, improved pulmonary function, less intense therapy, and better improved phlegm after treatment.

There has been a correlation between impaired lung function and cigarette smoking since the 1960s, and Burrows’ study also established a quantitative relationship between smoking and reduced lung function [9]. Moreover, several studies have demonstrated that continuous smoking can result in persistent symptoms, reduced lung function, frequent exacerbations, and high mortality rates among COPD patients [6, 8, 14, 15]. According to our previous study, non-smokers with AECOPD had less severe disease symptoms than those who smoked [10]. However, only Paul’s study examined the effect of smoking cessation time duration and found that those who stopped smoking experienced improvements in FEV1 one year after quitting, and the subsequent decline in FEV1 was comparable with that of non-smokers [6]. This suggests that COPD patients can recover from obstructive airway limitation to some extent after smoking cessation. This conclusion was supported by our findings. In addition, long-term smoking cessation significantly reduced cough, dyspnea, hypoxemia, CO2 retention, and pulmonary arterial hypertension, suggesting that long-term smoking cessation has significant and extensive benefits.

We found that patients who had stopped smoking for a longer time were also treated less intensively, similar to our previous study, which found that non-smokers were also treated less intensively [10]. The treatment response was not significantly different between patients with different cessation times, except for improvement in cough, phlegm, and CO2 retention. There was a greater improvement in cough symptoms and CO2 retention in patients with short-term smoking cessation, potentially due to more severe baseline disease conditions and more intensive treatment strategies, especially non-invasive ventilation, and a decreased chance that mild cough would improve after treatment (percentage of improvement, 2% vs. 100% vs. 100%, mild, intermittent, and severe cough, respectively). Phlegm improvement was more pronounced in AECOPD patients who had stopped smoking for a longer period of time, possibly due to improved mucociliary function and decreased goblet cell hyperplasia as a result of cessation of smoking [16].

The present study was not without limitations. First, as an observational study, even with multiple statistical methods, it is not possible to balance all confounding factors between groups. Besides, selection and patient recall bias could not be completely avoided even we did our best to deal with them by recruiting patients from hospitals located in urban (Shanghai) and suburban (Haian) areas, screening all the possible AECOPD patients admitted to the hospitals, double checking critical medical history information by two different researchers. In addition, the number of subjects was limited, making it difficult to extrapolate the results to a larger population. Finally, the findings of this study may not apply to patients with mild AECOPD, as it included patients with severe AECOPD requiring hospitalization.

Conclusion

A unique perspective was presented in this study regarding the impact of smoking cessation on AECOPD patients. Furthermore, different smoking cessation time durations led to different clinical characteristics and treatment responses in patients with AECOPD. Symptoms, hypoxemia, CO2 retention, and lung function impairment were less severe in patients who had stopped smoking for a long period of time as opposed to those who had stopped smoking for a short period of time. In addition, patients who had stopped smoking for a long period of time had a better improvement in phlegm, even with a lower intensity of treatment. Early smoking cessation not only prevents the harms caused by smoking, but also improves patients’ health. Even for patients with small amounts of smoking, early cessation was beneficial and necessary.

Data availability

Upon reasonable request, the corresponding author will provide the datasets used and/or analyzed during the current study.

Abbreviations

COPD:

chronic obstructive pulmonary disease

AECOPD:

acute exacerbation of COPD

mMRC:

modified Medical Research Council scale

FEV1:

forced expiratory volume in 1 s

FVC:

forced vital capacity

GOLD:

Global Initiative for COPD

ATS:

American Thoracic Society

ERS:

European Respiratory Society

FEV1%:

FEV1% of predicted value

RV:

residual volume

TLC:

total lung capacity

DLCO:

diffusing capacity of the lung for carbon monoxide

VA:

alveolar volume

PaCO2 :

carbon dioxide partial pressure

ICS:

inhaled corticosteroid

LABA:

long-acting β2 agonists

LAMA:

long-acting anti-muscarinic antagonists

SABA:

short-acting β2 agonists

SD:

standard deviation

ANOVA:

analysis of variance

BMI:

body mass index

SPAP:

systolic pulmonary arterial pressure

OR:

odds ratio

CI:

confidence interval

References

  1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2022. Available from: https://goldcopd.org.

  2. Halpin DMG, Celli BR, Criner GJ, et al. The GOLD Summit on chronic obstructive pulmonary disease in low- and middle-income countries. Int J Tuberc Lung Dis. 2019;23(11):1131–41.

    Article  CAS  PubMed  Google Scholar 

  3. Yin P, Wang H, Vos T, et al. A Subnational Analysis of Mortality and Prevalence of COPD in China From 1990 to 2013: Findings From the Global Burden of Disease Study 2013. Chest. 2016;150(6):1269–80.

    Article  PubMed  Google Scholar 

  4. M Montes de Oca. Smoking Cessation/Vaccinations. Clin Chest Med. 2020;41(3):495–512.

    Article  Google Scholar 

  5. Kanner RE, Connett JE, Williams DE, et al. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the lung health study. Am J Med. 1999;106(4):410–6.

    Article  CAS  PubMed  Google Scholar 

  6. Scanlon PD, Connett JE, Waller LA, et al. Smoking Cessation and Lung Function in Mild-to-Moderate Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2000;161(2):381–90.

    Article  CAS  PubMed  Google Scholar 

  7. Godtfredsen NS, Lam TH, Hansel TT, et al. COPD-related morbidity and mortality after smoking cessation: status of the evidence. Eur Respir J. 2008;32(4):844.

    Article  CAS  PubMed  Google Scholar 

  8. Au DH, Bryson CL, Jason WC, et al. The Effects of Smoking Cessation on the Risk of Chronic Obstructive Pulmonary Disease Exacerbations. J Gen Intern Med. 2009;24(4):457–63.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Burrows B, Knudson RJ, Cline MG, et al. Quantitative relationships between cigarette smoking and ventilatory function. Am Rev Respir Dis. 1977;115(2):195–205.

    CAS  PubMed  Google Scholar 

  10. Li X, Wu Z, Xue M, et al. Smoking status affects clinical characteristics and disease course of acute exacerbation of chronic obstructive pulmonary disease: A prospectively observational study. Chron Respir Dis. 2020;17:1479973120916184.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Huber GL, Mahajan VK. Successful Smoking Cessation. Disease Manage Health Outcomes. 2008;16(5):335–43.

    Article  CAS  Google Scholar 

  12. Xiao D, Chu SL, Jing X, et al. Discussion about criteria of successful smoking cessation. Chin J Tuberc Respir Dis. 2011;34(4):316–7.

    Google Scholar 

  13. Rennard SI, Vestbo J. COPD: the dangerous underestimate of 15%. Lancet. 2006;367(9518):1216–9.

    Article  PubMed  Google Scholar 

  14. Fruchter O, Yigla M. Predictors of long-term survival in elderly patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. Respirology. 2008;13(6):851–5.

    Article  PubMed  Google Scholar 

  15. Dusemund F, Baty F, Brutsche MH. Significant reduction of AECOPD hospitalisations after implementation of a public smoking ban in Graubünden. Switz Tob control. 2015;24(4):404–7.

    Article  Google Scholar 

  16. Ramos FL, Krahnke JS, Kim V. Clinical issues of mucus accumulation in COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:139–50.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Nantong Science and Technology Bureau (MSZ20095), Shanghai Sailing Program (20YF1428300), and Shanghai Municipal Health Commission (2019SY006) sponsored this study.

Author information

Authors and Affiliations

Authors

Contributions

The review was conceptualized by WD (Wei Du), ZW (Zhen Wu) and XL (Xiaolong Li). The subjects were screened and selected by WD, ZW, and MX (Mingyue Xue). WD and ZW documented the patients’ data, and WD, ZW, and XL conducted statistical analyses and wrote the manuscript. The paper was guaranteed by XL and WD. The work was equally contributed by XL and ZW. The final manuscript was read and approved by all authors.

Corresponding author

Correspondence to Wei Du.

Ethics declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki. Institutional Review Boards of affiliated Haian Hospital of Nantong University and Institutional Review Boards of Shanghai Jiao Tong University School of Medicine affiliated Ruijin Hospital approved this human study. To participate in this study, all adult participants provided written informed consent.

Publication consent

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary Material 2

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, X., Wu, Z., Xue, M. et al. An observational study of the effects of smoking cessation earlier on the clinical characteristics and course of acute exacerbations of chronic obstructive pulmonary disease. BMC Pulm Med 22, 390 (2022). https://doi.org/10.1186/s12890-022-02187-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12890-022-02187-5

Keywords

  • AECOPD
  • Smoking cessation
  • Therapeutics