Nurse-led smoking cessation with cytisinicline in primary care: An intervention study

Abstract

Background

Smoking is a major risk factor for several leading causes of death worldwide and is the primary cause of chronic obstructive pulmonary disease. Smoking cessation remains the only effective intervention to halt disease progression. Evidence on smoking cessation outcomes with cytisinicline in primary care programmes remains limited, particularly in nurse-led intervention models. In addition, respiratory diseases are frequently underdiagnosed in smokers, representing an opportunity for early detection in primary care when integrated into smoking cessation support.

Objective

To describe smoking cessation outcomes of a comprehensive nurse-led intervention using cytisinicline in primary care and to explore factors associated with relapse and the detection of respiratory disease during follow-up.

Desing

Prospective multicentre observational study conducted in primary care. The intervention was based on a structured nursing care model grounded in established behaviour change frameworks, integrating intensive behavioural counselling, pharmacological treatment with cytisinicline, adherence monitoring, structured follow-up, and respiratory assessment using spirometry. Participants were followed for 12 months. An intention-to-treat analysis was performed, with losses to follow-up considered as relapses.

Results

A total of 192 participants were included (46.9% women), with a mean age of 50.7 years (standard deviation 12.9). Abstinence rates were 76.6% at 1 month, 58.9% at 3 months, and 47.4% at 6 months. Biochemically verified abstinence at 12 months was 40.1%. The mean time to relapse was 84 days, and the median was 60 days. In multivariable analysis, higher nicotine dependence and greater withdrawal symptoms at the end of treatment were independently associated with an increased risk of relapse, while a diagnosis of asthma during the study was associated with a lower likelihood of relapse. Adverse events were reported by 23.9% of participants and were mostly mild, predominantly gastrointestinal, and well-tolerated. Previously undiagnosed respiratory disease was identified in 28% of participants during the study.

Conclusions

A comprehensive nurse-led smoking cessation model in primary care was associated with favourable abstinence outcomes and enabled the identification of previously undiagnosed respiratory disease. Higher nicotine dependence and withdrawal symptoms were associated with an increased risk of relapse, whereas a diagnosis of asthma during the study was associated with a lower likelihood of relapse. We suggest that integrating behavioural, pharmacological, and respiratory assessment components within nurse-led primary care pathways may support smoking cessation in routine practice, although causal inferences cannot be established.

What is already known.

• •Cytisinicline is a World Health Organization-recommended pharmacological treatment for smoking cessation with demonstrated efficacy and a favourable safety profile.
• •Respiratory diseases, such as chronic obstructive pulmonary disease, are frequently underdiagnosed, and early detection in smokers is associated with improved clinical outcomes.

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What this paper adds.

• •A structured nurse-led intervention in primary care using cytisinicline showed high smoking cessation rates in real-world practice.
• •The integration of behavioural counselling, pharmacological support, and respiratory testing by nurses supported a comprehensive smoking cessation approach in primary care.
• •Smoking cessation consultations in primary care may offer an opportunity to integrate tobacco dependence treatment with the identification of previously undiagnosed respiratory disease.

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1. Background

Tobacco use is a risk factor for six of the eight leading causes of death worldwide. In addition to cancer and cardiovascular disease, smoking worsens asthma and is the primary cause of chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease is currently one of the three leading causes of death globally (Global Initiative for Chronic Obstructive Lung Disease, 2026). As a largely preventable disease, it represents a major public health challenge, with morbidity and mortality increasing with age (Soriano et al., 2017). Smoking cessation remains the only effective measure to halt disease progression (Global Initiative for Chronic Obstructive Lung Disease, 2026). Given the central role of smoking in respiratory disease and the importance of early intervention in primary care, integrating structured smoking cessation programmes in this setting may be essential.

According to the World Health Organization, most people who smoke require support to stop smoking (World Health Organization, 2025). Success rates increase when cognitive-behavioural therapy is combined with pharmacological treatment for nicotine dependence (Hartmann-Boyce et al., 2019; Stead et al., 2016). Interestingly, during the Second World War, tobacco shortages led some soldiers to use leaves from cytisinicline-containing plants (mainly Cytisus laburnum, family Leguminosae) as a tobacco substitute, as this alleviated nicotine withdrawal symptoms (Tutka et al., 2019).

Shortly thereafter, cytisinicline was used in Central and Eastern Europe for smoking cessation, typically as an over-the-counter medication (Tutka et al., 2019). Currently, its use has expanded as a publicly-funded treatment in several countries, including Spain, the Netherlands, and the United Kingdom. However, it has not yet received approval from major regulatory agencies, such as the United States Food and Drug Administration (Foulds et al., 2023). Cytisinicline is a partial agonist of the α4β2 nicotinic acetylcholine receptors and acts as a functional antagonist by competing with nicotine for receptor binding, thereby reducing the satisfaction and reward associated with tobacco use. It also induces moderate dopamine release, helping to control craving and dysphoria during smoking cessation attempts (Gotti and Clementi, 2021).

Cytisinicline has been shown to be more effective than placebo (World Health Organization, 2024) and less effective than varenicline when administered using the standard 25-day regimen (Courtney et al., 2021), although it is associated with a lower incidence of adverse effects (Livingstone-Banks et al., 2023; Ofori et al., 2023). However, evidence on the use of cytisinicline in primary care remains scarce (Lindson et al., 2021; Oreskovic et al., 2023), despite primary care being the main entry point to publicly-funded health systems (Ministerio de Sanidad. Dirección General de Salud Pública y Equidad en Salud, 2024; Van Schayck et al., 2017) and the setting where most people receive treatment for smoking cessation (World Health Organization, 2024).

In primary care, nurses deliver a structured approach (Junta de Castilla y León. Consejería de Sanidad. Gerencia Regional de Salud. Dirección General de Planificación y Asistencia Sanitaria, 2019) to both tobacco prevention and the care and treatment of people who smoke, based on the 5As model (Krist et al., 2021). More recently, nurses have been authorised to indicate, use and dispense medications to support smoking cessation (Ministerio de Sanidad. Dirección General de Salud Pública y Equidad en Salud, n.d.), although this role has not yet been fully implemented in practice. At the same time, nurses are responsible for performing spirometry, a key technique for the detection, diagnosis, and follow-up of respiratory diseases.

To support the development of this expanded professional role, we conducted a study under real-world clinical practice conditions. The primary aim of this prospective observational study was to describe smoking cessation outcomes over 12 months among individuals seeking to quit smoking who received a comprehensive nurse-led intervention within a multidisciplinary primary care setting, including treatment with cytisinicline. A secondary aim was to identify previously diagnosed and undiagnosed respiratory diseases in this population.

2. Methods

2.1. Research design

This was a prospective, multicentre cohort study with 12-month follow-up, conducted among people who smoke, treated with cytisinicline for smoking cessation. The study was carried out in six primary care health centres (two urban, two semi-urban, and two rural) within the Zamora Health Care Area, Spain, between 2024 and 2025. In this study, the term nurse-led refers to a model in which nurses were responsible for delivering the behavioural intervention, coordinating follow-up visits, and monitoring treatment adherence within a structured care pathway, while pharmacological treatment was prescribed by primary care physicians in accordance with routine clinical practice. This definition is consistent with previously described nurse-led models of care, in which nurses played a central role in delivering and coordinating patient care within multidisciplinary primary care teams (Laurant et al., 2018).

2.2. Participants and setting

A non-probability convenience sampling strategy was used. The target sample size was calculated to estimate the proportion of participants achieving smoking cessation with adequate precision. An expected cessation rate of 15% was assumed based on previously reported long-term abstinence rates in cytisinicline trials using 1.5 mg tablets administered over a standard 25-day treatment course ((Courtney et al., 2021), 11.7%; (Phusahat et al., 2022), 14.9%). Based on this assumption, a minimum sample size of 190 participants was estimated to achieve a precision of ±5% with a 95% confidence level, assuming a potential 5% loss to follow-up. The study protocol, including the sample size calculation, was previously published in the Revista Española de Salud Pública (Majo García, Fernández-Martínez, Espinosa Villoria, et al., 2025b).

All eligible patients attending primary care who were in the preparation or action stage of the smoking cessation process were consecutively invited to participate, meaning that all individuals meeting the inclusion criteria during the study period were approached without selection. The preparation stage was defined as the intention to quit smoking in the near future, typically within the following month, while the action stage referred to individuals who had already initiated the behavioural change process and were actively engaged in a quit attempt (Prochaska and DiClemente, 1983).

A prior clinical training session was conducted at each health centre to standardise the interventions delivered by healthcare professionals. In addition, professionals had continuous access to the integrated care pathway on which the study procedures and interventions were based (Junta de Castilla y León. Consejería de Sanidad. Gerencia Regional de Salud. Dirección General de Planificación y Asistencia Sanitaria, 2019).

Inclusion criteria were age ≥18 years and meeting the requirements established by the public health service for treatment funding. These included having made a previous smoking cessation attempt in the preceding year, being a current user of combustible cigarettes, smoking ≥10 cigarettes per day, having a score of ≥7 points on the Fagerström Test for Nicotine Dependence, and being in the preparation or action stage for smoking cessation. All inclusion criteria were recorded in the patients’ electronic health records (Junta de Castilla y León. Consejería de Sanidad. Gerencia Regional de Salud. Dirección General de Planificación y Asistencia Sanitaria, 2019). Exclusion criteria included attempting to quit smoking without using cytisinicline, being in the precontemplation or contemplation stage, having undertaken a funded smoking cessation treatment within the previous year, or lacking adequately completed electronic health records required for a funded prescription. Use of other smoking cessation pharmacotherapies (e.g., nicotine replacement therapy) was not permitted during the intervention, as the programme was specifically designed to evaluate cytisinicline within the structured care pathway.

2.3. Ethics

The study was approved by the Research Ethics Committee for Medicinal Products of the Zamora Health Care Area (approval number 625) in 2024. All candidates were informed in advance about the purpose of the study and received both verbal and written information. Participants were included after providing written informed consent. The study was conducted in accordance with the principles of the Declaration of Helsinki.

2.4. Data collection

Data collected included demographic variables (date of birth, age, and sex), anthropometric variables (height, weight, and body mass index), history of mental health conditions (anxiety, depression, etc.), and respiratory disease (asthma, chronic obstructive pulmonary disease, and restrictive lung disease). Variables related to tobacco use were also recorded, including age at smoking initiation, number of cigarettes smoked per day, cumulative tobacco exposure expressed as pack-years, number of previous quit attempts, and duration of abstinence during the previous attempt. Nicotine dependence was assessed using the Fagerström Test for Nicotine Dependence, motivation to quit smoking using a visual analogue scale, and withdrawal symptoms using the Minnesota Nicotine Withdrawal Scale. The Minnesota Nicotine Withdrawal Scale was administered at two time points: during pharmacological treatment and a few days after treatment completion.

Regarding cytisinicline treatment, pharmacological adherence was assessed based on patient self-report and by verifying medication dispensing through the electronic prescribing module of the interconnected health record and pharmacy system. The occurrence and type of adverse events were recorded, as well as the treatment initiation date and the first day of complete abstinence.

Participants were followed up with assessments of smoking abstinence at 1, 3, and 6 months (self-reported), and at 12 months (self-reported with biochemical verification using exhaled carbon monoxide measurement, with a cut-off point lower than 6 ppm (Benowitz et al., 2020), or urinary cotinine testing), which constituted the primary outcome. The occurrence of lapses during smoking cessation was recorded, and, in the event of relapse, the number of cigarettes smoked per day was documented.

Pre- and post-bronchodilator spirometry was performed. Respiratory disease, both previously diagnosed and newly detected during the study, was classified as one of the following: normal spirometry pattern; obstructive pattern with positive bronchodilator test (possible asthma); obstructive pattern with negative bronchodilator test (chronic obstructive pulmonary disease); mixed chronic obstructive pulmonary disease–asthma pattern; or possible restrictive pattern. The severity of chronic airflow obstruction was categorised into four grades according to the Global Initiative for Chronic Obstructive Lung Disease criteria (Vogelmeier et al., 2025).

2.5. Intervention

This nurse-led intervention was designed as a comprehensive primary care model based on behavioural change principles and supported by established theoretical frameworks, including the Behaviour Change Wheel (Michie et al., 2011) which involves three essential conditions relating to the individual—ability, opportunity and motivation— around which are positioned the nine intervention functions aimed at addressing deficits in one or more of these conditions, and the Ask–Advise–Assess–Assist–Arrange (5As) approach (Krist et al., 2021). These frameworks were used to structure behavioural counselling, pharmacological support, follow-up, and patient self-management. The intervention also incorporated elements of self-efficacy theory and cognitive–behavioural approaches to smoking cessation.

The intervention was delivered by trained primary care nurses following a structured smoking cessation protocol (Junta de Castilla y León. Consejería de Sanidad. Gerencia Regional de Salud. Dirección General de Planificación y Asistencia Sanitaria, 2019). Nurses conducted the behavioural counselling sessions, monitored treatment adherence, and performed follow-up assessments throughout the programme. Each face-to-face counselling session lasted approximately 10–30 min, as detailed in Table 1. Pharmacological treatment with cytisinicline was prescribed by primary care physicians, while nurses delivered behavioural support and coordinated follow-up within the structured care pathway.

Table 1.

Nursing-led interventions throughout the smoking cessation process.

Phase / Period and objectives	Intensive interventions delivered	Timing – frequency – duration
Preparation: Planning cessation	• Clinical assessment (medical history) • Physical examination (weight, height, BMI, blood pressure) • Assessment and recording of personal history (respiratory and mental health conditions) • Assessment and recording of smoking history • Assessment of motivation and nicotine dependence (FTND) • Setting the quit day • Development of an individualised cessation plan • Provision of educational and support materials • Cognitive–behavioural techniques • Initiation of pharmacological treatment • Spirometry	Three visits prior to the quit day 10–30 min per visit
Action (Quit day – 2 weeks) Initiate and sustain abstinence	• Behavioural support • Monitoring of withdrawal symptoms • Behavioural strategies, social support and stimulus control • Positive reinforcement and validation of effort • Management of craving, irritability and insomnia • Training in avoidance, coping and relaxation techniques • Assessment of craving intensity • Monitoring of pharmacological adherence • Monitoring of adverse effects • Dietary and physical activity counselling	Quit day and 7–15 days 10–30 min
Early follow-up: Maintaining abstinence	• Monitoring of treatment adherence • Relapse prevention • Assessment of craving intensity • Review of goals • Reinforcement of benefits • Monitoring of adverse effects • Cognitive–behavioural techniques • Dietary and physical activity counselling • Identification of high-risk situations • Review of coping skills	1 month (face-to-face or telephone) 10–30 min
Follow-up: Maintaining abstinence	• Relapse prevention • Assessment of craving intensity • Review of goals • Reinforcement of benefits • Cognitive–behavioural techniques • Dietary and physical activity counselling • Identification of high-risk situations • Review of coping skills	3 months (face-to-face or telephone) 10–30 min
Maintenance: Consolidating abstinence	• Long-term reinforcement • Relapse prevention • Review of coping skills	6 months (face-to-face or telephone) 10–30 min
Maintenance: Consolidating abstinence	• Long-term reinforcement • Weight monitoring • Relapse prevention • Review of coping skills • Carbon monoxide testing and/or urinary cotinine testing	12 months (face-to-face) 10–30 min
Relapse	• Analysis of relapse causes • Measurement of time to relapse • Motivational interviewing • Therapeutic re-planning	At any time

Table 1 footnote. BMI, Body Mass Index; FTND, Fagerström Test for Nicotine Dependence.

A minimum of three face-to-face sessions were conducted prior to the quit day. During the first session, nurses performed a clinical assessment, including smoking history, motivation to quit, nicotine dependence (using the Fagerström Test for Nicotine Dependence), and delivered an intensive intervention focused on the health impact of tobacco use and the benefits of smoking cessation. Educational and support materials were provided in either paper or digital format.

During the second session, pharmacological treatment was established collaboratively by physicians and nurses. Prescriptions were issued by physicians because nurse-prescribing guidelines had not yet been fully implemented. The quit day was scheduled in accordance with the product information and the individual’s readiness to quit.

During the third intensive session, nurses delivered training on tobacco avoidance and craving-management strategies, addressed withdrawal symptoms, and provided lifestyle counselling on diet and sleep quality. At this visit, pre- and post-bronchodilator spirometry was performed following administration of a short-acting bronchodilator. During pharmacological treatment, nurses delivered at least two cognitive–behavioural interventions, either face-to-face or by telephone, focusing on avoidance strategies, promotion of physical activity, dietary counselling, and monitoring of treatment adherence and adverse effects. At the 3- and 6-month follow-up visits, additional emphasis was placed on coping skills, delivered either in person or by telephone according to patient preference and availability. A face-to-face visit was conducted at 12 months. The nursing interventions, their timing, and the duration of nursing activities are summarised in Table 1. These interventions were applied uniformly across all participating health centres.

The interventions were delivered through a standardised public health system care pathway, supported by reference materials, electronic health record–based checklists (Junta de Castilla y León. Consejería de Sanidad. Gerencia Regional de Salud. Dirección General de Planificación y Asistencia Sanitaria, 2019), and regular supervision across participating health centres.

2.6. Data analysis

Descriptive and inferential statistical analyses were performed using IBM SPSS Statistics (version 29). An intention-to-treat approach was applied, considering participants lost to follow-up as having relapsed to smoking. Univariate analyses were conducted to identify factors associated with abstinence, using chi-square or Student’s t tests, and Fisher’s exact test or the Mann–Whitney U test for variables that did not follow a normal distribution. Survival analysis was performed using Kaplan–Meier curves stratified by sex.

Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using univariate logistic regression models with smoking relapse at 12 months as the dependent variable. Variables with p < 0.10 in univariate analysis, together with clinically relevant variables identified a priori (age, sex, and history of psychiatric disorder), were entered into a multivariable logistic regression model. A backward stepwise (Wald) procedure was used to identify independent predictors of relapse. A p-value < 0.05 was considered statistically significant in all analyses.

3. Results

3.1. Participant characteristics

Fig. 1 summarises the flow diagram of participant inclusion, follow-up, and main outcomes. A total of 192 participants met the inclusion criteria (53.1% men and 46.9% women), with a mean age of 50.7 years (standard deviation [SD] 13.0). A history of mental health conditions was present in 30.7% of the sample (n = 58), with anxiety being the most prevalent condition (56.9%), followed by depression (20.7%). Additionally, 12.1% of participants reported a history of both conditions. Two participants reported a previous suicide attempt.

Fig. 1.

Flow diagram of participant inclusion, follow-up and main outcomes. The analysis was conducted according to the intention-to-treat principle, considering losses to follow-up (n = 6) and missing data on time to relapse (n = 4) as smoking relapse at 1 month. COPD, chronic obstructive pulmonary disease.

Baseline demographic characteristics and smoking history are presented in Table 2. Overall, participants reported early smoking initiation, a high daily cigarette consumption, and substantial cumulative tobacco exposure. Most had previous quit attempts, although sustained abstinence had been limited. At study enrolment, no participants reported current use of other nicotine or tobacco products (e.g., electronic cigarettes or heated tobacco products).

Table 2.

Baseline demographic characteristics and smoking-related variables by sex.

	Total	Women	Men	p value
	n = 192	n = 90	n = 102
Age, years, mean (SD)	50.71 (12.98)	50.19 (12.55)	51.18 (13.40)	0.706 a
Height, cm, mean (SD)	167.25 (15.41)	159.51 (18.18)	174.00 (7.76)	<0.001 a
Weight, kg, mean (SD)	75.88 (18.72)	66.41 (16.15)	84.23 (16.83)	<0.001 a
Body Mass Index, kg/m2, mean (SD)	26.87 (5.70)	25.79 (6.24)	27.88 (5.00)	<0.001 a
Systolic blood pressure, mmHg, mean (SD)	125.34 (16.48)	120.02 (14.90)	130.12 (16.43)	<0.001 a
Diastolic blood pressure, mmHg, mean (SD)	77.73 (10.15)	75.81 (10.29)	79.46 (9.74)	0.022 a
History of psychiatric disorder, n (%)	58 (30.2)	34 (37.8)	24 (23.5)	0.027 b
Smoking characteristics
Age at smoking initiation, years, mean (SD)	16.91 (3.62)	16.52 (3.17)	17.24 (3.94)	0.091 a
Cigarettes per day, mean (SD)	20.31 (8.18)	18.00 (7.00)	22.00 (9.00)	0.001 a
Pack-years, mean (SD)	31.42 (16.80)	27.43 (14.29)	34.87 (18.08)	0.009 a
Previous quit attempts, mean (SD)	2.06 (1.65)	2.18 (1.84)	1.96 (1.48)	0.654 a
Months abstinent in last attempt, mean (SD)	11.05 (27.90)	14.35 (32.46)	8.29 (23.24)	0.058 a
Fagerström Test for Nicotine Dependence, mean (SD)	7.21 (1.89)	7.23 (1.70)	7.19 (2.00)	0.787 a
Minnesota Withdrawal Scale during treatment, mean (SD)	3.75 (3.81)	4.22 (4.13)	3.35 (3.48)	0.259 a
Minnesota Withdrawal Scale after treatment, mean (SD)	3.59 (4.37)	4.16 (4.69)	3.10 (4.00)	0.157 a
Motivation, (Visual Analogue Scale), mean (SD)	8.61 (1.32)	8.61 (1.50)	8.60 (1.12)	0.458 a

Table 2 footnote. Data are presented as mean (standard deviation) unless otherwise indicated. Group comparisons were performed using the Mann–Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Percentages are calculated within each sex category.

^aMann–Whitney U test;

^bFisher´s exact test; SD: standard deviation.

The mean time from initiation of cytisinicline treatment to the quit day was 3.5 days (SD 1.9).

Body weight at 12-month follow-up was available for a subset of participants. The mean weight gain was 2.9 kg (SD 4.7), with no significant differences between those who relapsed and those who maintained abstinence. No significant differences in weight gain were observed by sex.

3.2. Smoking cessation outcomes

Using an intention-to-treat analysis, abstinence rates declined over time, with the highest rates observed shortly after treatment initiation and progressively lower rates at subsequent follow-up points. Biochemically verified abstinence at 12 months, the primary outcome, is shown in Fig. 1.

Among participants who relapsed, the mean reduction in the number of cigarettes smoked per day was 7.3 cigarettes (SD 8.1; p < 0.001). Before the quit attempt, women smoked fewer cigarettes per day than men (Table 2), and this difference persisted after relapse (5 vs 9 cigarettes per day, respectively).

Adverse events were reported by 46 participants (23.9%). The most frequent were gastrointestinal symptoms (n = 14), followed by anxiety (n = 6), insomnia (n = 4), and vivid or unusual dreams (n = 4). One participant with a previous history of depression reported suicidal ideation.

Fourteen participants discontinued cytisinicline treatment before completion. Two of them reported doing so due to the severity of gastrointestinal symptoms (bloating, dry mouth, nausea). Despite premature treatment discontinuation, three participants achieved smoking cessation.

Among the 115 participants who relapsed during follow-up, the time to relapse was available for 105 cases (91.3%). Six participants were lost to follow-up, and, for four participants, the exact time of relapse was not recorded; these cases were classified as having relapsed at 1 month. Considering only the 105 participants with a recorded time to relapse, 33.3% relapsed during the first month and 32.4% between the first and third months. An additional 21% relapsed around the sixth month, and 13.3% relapsed between 6 and 12 months of follow-up. Fig. 2 shows Kaplan–Meier curves describing the distribution of time to smoking relapse among participants with a recorded relapse time, with relapse as the event of interest, stratified by sex. The mean time from initiation of cytisinicline treatment to relapse was 84 days (SD 88.5; 95% CI 66.9–101.1), and the estimated median time to relapse was 60 days.

Fig. 2.

Kaplan–Meier curve showing the distribution of time to smoking relapse among participants with a recorded relapse time (n = 105), stratified by sex.

By sex, relapse occurred in 63.3% of women (n = 57) and 56.9% of men (n = 58), with no statistically significant difference between groups.

The estimated median time to relapse among participants with recorded relapse times was 60 days after treatment initiation (day 50 for women and day 68 for men; Fig. 2), with no statistically significant difference between sexes (log-rank Mantel–Cox p = 0.473; Breslow p = 0.391). Notably, 20 participants (17.4% of those classified as relapsed) never achieved complete abstinence.

3.3. Factors associated with smoking relapse

Univariate and multivariable logistic regression analyses were performed to identify factors associated with smoking relapse at 12 months (Table 3). Higher nicotine dependence and withdrawal symptom scores were associated with an increased risk of relapse, whereas a diagnosis of asthma during the study was associated with lower odds of relapse. A history of psychiatric disorders showed a non-significant trend towards lower relapse risk.

Table 3.

Univariate and multivariable logistic regression analyses of factors associated with smoking relapse at 12 months.

Variable	Unadjusted OR	95% CI	p value	Adjusted OR	95% CI	p value
Age (years)	0.98	0.96–1.00	0.127	—	—	—
Female sex	1.31	0.73–2.34	0.362	—	—	—
Age at smoking initiation (years)	0.98	0.90–1.06	0.588	—	—	—
Cigarettes per day	1.00	0.96–1.04	0.954	—	—	—
Pack-years	1.00	0.98–1.02	0.942	—	—	—
Previous quit attempts	0.98	0.83–1.17	0.844	—	—	—
Previous pharmacological quit attempts	0.63	0.32–1.25	0.187	—	—	—
History of psychiatric disorder	0.56	0.30–1.05	0.069	—	—	—
Nicotine dependence score (Fagerström Test) (per point increase)	1.18	1.01–1.39	0.041	1.33	1.05–1.68	0.017
Withdrawal symptoms during treatment (Minnesota scale) (per point increase)	1.19	1.07–1.31	0.001	—	—	—
Withdrawal symptoms after treatment (Minnesota scale) (per point increase)	1.19	1.08–1.32	0.001	1.19	1.07–1.34	0.002
Motivation (visual analogue scale) (per point)	0.99	0.78–1.26	0.942	—	—	—
Previous diagnosis of chronic obstructive pulmonary disease	1.61	0.48–5.43	0.442	—	—	—
Previous diagnosis of asthma	0.86	0.22–3.32	0.828	—	—	—
Chronic obstructive pulmonary disease diagnosed during study	1.10	0.47–2.60	0.828	—	—	—
Asthma diagnosed during study	0.27	0.11–0.65	0.004	0.13	0.03–0.53	0.005
Possible restrictive ventilatory	1.01	0.31–3.33	0.981	—	—	—
Any adverse events	1.75	0.86–3.54	0.122	—	—	—

Table 3 footnote. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using univariate and multivariable logistic regression models, with smoking relapse at 12 months as the dependent variable. Variables included in the multivariable model were selected based on univariate analysis (p < 0.10) and clinical relevance (age, sex, and history of psychiatric disorder), using a backward stepwise (Wald) method. Adjusted estimates correspond to the final multivariable model. Continuous variables are expressed as the change in odds per one-unit increase.

Variables included in the initial multivariable model were selected based on univariate results (p < 0.10) and clinical relevance (age, sex, and history of psychiatric disorder). A backward stepwise (Wald) method was used to obtain the final model.

In the final model, higher nicotine dependence was independently associated with an increased risk of relapse (OR 1.33, 95% CI 1.05–1.68; p = 0.017). Similarly, higher withdrawal symptom scores at the end of treatment were associated with a higher likelihood of relapse (OR 1.19 per point increase, 95% CI 1.07–1.34; p = 0.002). In contrast, a diagnosis of asthma during the study was associated with a lower risk of relapse (OR 0.13, 95% CI 0.03–0.53; p = 0.005) (Table 3).

The model showed good calibration (Hosmer–Lemeshow test, p = 0.599) and moderate explanatory power (Nagelkerke R² = 0.262). The final model demonstrated acceptable goodness-of-fit and explanatory capacity.

3.4. Respiratory assessment findings

Spirometry was performed in 168 participants, of whom 155 also completed post-bronchodilator testing. Spirometry values are presented in Supplementary Table S1.

Prior to study enrolment, 19 participants had a diagnosis of respiratory disease (11 chronic obstructive pulmonary disease, 7 asthma and 2 asthma–chronic obstructive pulmonary disease overlap). During the study, previously undiagnosed respiratory disease was identified in 54 participants (26 women and 28 men), including chronic obstructive pulmonary disease in 16 participants (five mild, nine moderate, one severe, and one very severe), asthma in 17 participants, and asthma–chronic obstructive pulmonary disease overlap in nine participants. The 12 participants classified as having possible restrictive patterns were referred to the respiratory medicine department for diagnostic confirmation.

4. Discussion

We have described smoking cessation outcomes observed in a comprehensive nurse-led intervention using cytisinicline in primary care. The abstinence rates observed—47.4% at six months (self-reported) and 40.1% at 12 months of follow-up (biochemically verified)—were almost three times higher than the expected rate of 15% estimated in the initial study design (Majo García, Fernández-Martínez, Espinosa Villoria, et al., 2025b). We have provided evidence on the implementation of a structured nursing care pathway that combines behavioural support, pharmacological treatment, and structured follow-up for people attempting to quit smoking. We have highlighted the importance of comprehensive care for individuals facing the complex process of smoking cessation, combining cognitive-behavioural interventions (Krist et al., 2021), structured follow-up, and monitoring of treatment adherence.

The observed benefits in overall health status and the early detection of respiratory disease as part of the same care pathway underscore the potential value of this integrated model of care. Such an approach may contribute to improving accessibility and equity within public healthcare systems, particularly in primary care (Camarelles Guillem et al., 2025).

In this context, the abstinence rates observed in this primary care setting appear higher than those reported in previous studies. A Cochrane review (Livingstone-Banks et al., 2023), estimated that between 18 and 23 out of every 100 individuals treated with cytisinicline would achieve abstinence, while Oreskovic et al. (2023) in a clinical trial reported a self-reported abstinence rate of 23.1% at 24 weeks in primary care. Lower abstinence rates have also been reported in other clinical settings, such as the 11.7% biochemically-verified abstinence at 7 months described by Courtney et al. (2021). These differences should be interpreted with caution due to substantial variation in study design, patient populations, outcome definitions, and follow-up intensity. In the present study, participants were managed within a structured care pathway that combined behavioural support, pharmacological treatment, and scheduled follow-up, which may have facilitated engagement and continuity of care. In addition, participants were actively seeking support to quit smoking, which may reflect a higher level of motivation compared with other populations. While more intensive behavioural support has been associated with improved cessation outcomes (Hartmann-Boyce et al., 2019; Stead et al., 2016), the magnitude of this effect is generally moderate. Therefore, the observed outcomes likely reflect a combination of intervention structure, patient characteristics, and implementation rather than any single explanatory factor.

More recent evidence has reported abstinence rates of 22.3% at 6 months and 20.8% at 12 months among patients treated with a standard 25-day course of cytisinicline (Majo García, Espinosa Villoria, et al., 2025a). By contrast, researchers conducting contemporary observational studies in hospital-based smoking cessation units have reported higher abstinence rates, with 38% at 6 months and 27% at 12 months of follow-up, in populations with greater tobacco dependence and more severe comorbidities (Majo García, Fernández-Martínez, Crespo Sedano, et al., 2025b). The specialised training of healthcare professionals may be a key factor underlying these differences in outcomes.

Identifying factors associated with relapse contributes to a better understanding of the challenges faced by individuals dealing with smoking as a chronic and relapsing condition. In this regard, it is noteworthy that 20 participants never achieved abstinence during the study period. A similar pattern has been reported in the ORCA-2 (Rigotti et al., 2023) and ORCA-3 (Rigotti et al., 2025) trials, which evaluated extended cytisinicline regimens (6 and 12 weeks) and showed an abrupt decline in abstinence probabilities both at treatment initiation and at the end of follow-up.

This perspective may help explain the findings of a population-based study conducted across an entire health area, which reported adherence below 50% for longer-duration, publicly-funded pharmacotherapies for nicotine dependence (e.g., varenicline and bupropion) (Majo García et al., 2024).

We have highlighted the importance of delivering interventions before the initiation of a quit attempt (Majo García et al., 2024) and intensifying support at critical time points, such as the quit day, while emphasising the need to train patients in relapse-prevention strategies (Krist et al., 2021). In the present study, participants who relapsed had a 50% probability of returning to smoking by 60 days of follow-up (Fig. 2), suggesting that closer follow-up during the first 2 months after the quit day may be particularly important.

Multivariable analysis showed that higher nicotine dependence, and greater withdrawal symptoms at the end of treatment were independently associated with an increased risk of relapse. In contrast, a diagnosis of asthma during the study was associated with a lower likelihood of relapse, suggesting that the identification of respiratory disease may act as a potential motivational trigger for smoking cessation.

These findings are consistent with results from the large-scale EAGLES trial (Anthenelli et al., 2016), which evaluated the efficacy and safety of varenicline, nicotine replacement therapy, and bupropion. In that study, older age and later age of smoking initiation were identified as predictors of abstinence, while higher levels of nicotine dependence were associated with relapse (West et al., 2018). However, three key differences should be considered when comparing EAGLES with the present study: the earlier age of smoking initiation observed in our sample (mean 16.9 years, consistent with national data (Ministerio de Sanidad, 2024)), the older age of participants, and the use of biochemically-verified abstinence at 12-month follow-up as the primary outcome. Consistent with findings from the EAGLES trial, a slightly higher risk of relapse was observed among women, although this difference did not reach statistical significance (West et al., 2018).

Cytisinicline is administered as a pharmacological treatment for nicotine dependence within a broader therapeutic approach to a complex condition characterised by chronicity and psychological, behavioural, and social components. It is important to note that the Fagerström Test for Nicotine Dependence assesses only physical dependence on nicotine and does not capture all dimensions of tobacco addiction (West et al., 2018). As a result, this measure may underestimate the severity of dependence in a substantial proportion of individuals (Ripoll Perelló et al., 2023). The absence of a specific recording field within the electronic health record prevented the assessment of psychological dependence, which represents a limitation of the study.

In the univariate analysis, a history of psychiatric disorder was associated with a higher probability of abstinence; however, this factor did not reach statistical significance in the multivariate analysis.

We also have highlighted that smoking cessation consultations in primary care may represent a valuable opportunity for the detection of previously undiagnosed respiratory disease through spirometry. Integrating respiratory assessment into smoking cessation care may, therefore, contribute to earlier identification of conditions, such as chronic obstructive pulmonary disease or asthma among people who smoke, particularly in settings where underdiagnosis remains common. Individuals with chronic obstructive pulmonary disease attend primary care consultations approximately 2.5 times more frequently than the general population (Ministerio de Sanidad. Informes, 2024), reinforcing the relevance of this setting for early case detection. Within this care pathway, spirometry was performed as part of the clinical assessment, following an approach similar to that used in hospital-based smoking cessation units (López-Campos et al., 2022).

In the absence of a previous diagnosis, respiratory disease was identified in 28% of participants during the study, with a slightly higher prevalence of underdiagnosis among women (Soriano et al., 2021) (28.9%vs 27.4%). We have underscored the role of nurse-led interventions in smoking cessation strategies within health systems and emphasise the importance of comprehensive care for individuals living with tobacco dependence as a chronic and relapsing condition. When combined with cases with a prior diagnosis, the high rate of underdiagnosis and the overall prevalence of respiratory disease observed in this study are of particular concern (Soriano et al., 2017), exceeding those reported in the EPISCAN II national survey conducted in the general population (Soriano et al., 2021). Early detection is a key determinant of prognosis, follow-up, and appropriate management of respiratory disease (Global Initiative for Asthma, 2025). In people with chronic obstructive pulmonary disease, early diagnosis enables timely interventions aimed at slowing long-term deterioration of lung function (Global Initiative for Chronic Obstructive Lung Disease, 2026). As a limitation, the lack of access to body plethysmography or gas dilution techniques prevented confirmation of restrictive lung disease in this healthcare setting.

Interestingly, a lower relapse rate was observed among participants diagnosed with asthma during the study. One possible explanation is that receiving a new diagnosis may have represented a teachable moment that reinforced motivation to quit smoking, as patients may have perceived a more immediate impact of smoking on their respiratory health. Smoking exacerbates symptoms in people with asthma and can reduce the effectiveness of their treatment (Lu et al., 2025). It is essential to raise awareness of the risks associated with smoking and to advise people to give it up, whilst ensuring comprehensive support for those trying to quit (Lu et al., 2025). In contrast, a new diagnosis of chronic obstructive pulmonary disease during the study did not show a clear relationship with relapse risk. Although this finding should be interpreted cautiously given the relatively small number of new diagnoses.

Although the use of spirometry in primary care has gradually increased, it remains insufficient (Calle Rubio et al., 2022). Spirometry may encourage symptomatic individuals who smoke, as well as individuals with chronic obstructive pulmonary disease or at increased risk of developing the disease, to initiate a smoking cessation attempt (Jiménez Ruiz et al., 2017). While this motivational effect has not been shown to be statistically significant among patients with normal spirometry results, the observed differences may still be clinically relevant.

Losses to follow-up during the study were minimal. In this regard, there is little doubt about the relevance of follow-up being provided by the participants’ usual primary care team, which may have contributed to sustained engagement throughout the study. In addition, overall pharmacological adherence was good among most participants, with a low number of premature treatment discontinuations.

Cytisinicline is associated with a lower frequency and intensity of adverse effects compared with other pharmacological treatments for smoking cessation (Ofori et al., 2023); however, two of the 14 participants who did not complete treatment reported discontinuation due to the severity of gastrointestinal symptoms. When prescribing cytisinicline, it is important to inform patients about potential adverse effects, their expected intensity and duration (Pacek et al., 2018), as many occur only during the first days of treatment, and some may actually be attributable to nicotine withdrawal rather than to the medication itself.

Given the recent public funding of cytisinicline in Spain, healthcare professionals initially reported limited experience with the drug and expressed concerns that its dosing regimen—starting with six tablets daily for 3 days, followed by five tablets daily for 9 days and then a gradual reduction to two tablets per day—might represent a barrier to adherence. However, patients demonstrated good treatment adherence. This dosing schedule, is likely related to the short plasma half-life of cytisinicline and its lower penetration of the blood–brain barrier compared with nicotine (Gotti and Clementi, 2021). The frequent dosing schedule required during the first days of treatment may also contribute to behavioural reinforcement during early abstinence. Regular tablet intake may act as a structured routine that partially replaces smoking-related habits, such as the repeated hand-to-mouth gesture associated with cigarette use. Although this mechanism was not specifically evaluated in our study, it should be considered a hypothesis-generating explanation and may represent an additional behavioural component supporting adherence during the early stages of smoking cessation.

From the data analysis, we found a moderate weight gain, with no differences between participants who maintained abstinence and those who relapsed. Although cytisinicline would likely require chronic administration to exert a sustained effect, it may help limit post-cessation weight gain by reducing the intake of sugars and other foods through its effects on dopaminergic activity within the mesolimbic reward pathway (Gotti and Clementi, 2021).

Concerns related to body image and weight gain represent one of several sex-related differences (Ministerio de Sanidad. Dirección General de Salud Pública y Equidad en Salud, 2024) observed at different stages of smoking behaviour, including smoking initiation (Ozbay et al., 2020), maintenance, and difficulties in quitting (Pacek et al., 2018). Aesthetic pressure and fear of weight gain are, therefore, relevant factors to consider when analysing relapse from a sex perspective and may partly explain a greater behavioural component and lower nicotine dependence among women. In addition, sex-related bias contributes to the substantial underdiagnosis of respiratory disease in women (Haeberer et al., 2020; Soriano et al., 2021), as previously highlighted.

Globally, only approximately one-third-of the population has access to comprehensive smoking cessation services. Supporting people to quit smoking is, therefore, a public health priority and has been recognised as a human rights issue (World Health Organization, 2025). In this context, nurse-led interventions incorporating publicly-funded pharmacological treatment within a comprehensive approach to tobacco dependence may enhance overall health benefits while reducing socioeconomic barriers to care.

4.1. Limitations

This study has several limitations. Firsts of all, as an observational study without a comparison group, the findings should be interpreted as descriptive of outcomes observed in this care pathway rather than as evidence of causal effectiveness. Second, the use of convenience sampling and the absence of a control group limit causal inference; however, the consecutive inclusion of participants seeking smoking cessation reflects real-world primary care practice. Third, although a standardised care pathway and preparatory training were provided, some variability in the delivery and intensity of behavioural interventions and follow-up cannot be excluded. Fourth, follow-up bias may have occurred, as participants who successfully quit smoking were generally more engaged with follow-up visits. Fifth, time-to-relapse analysis was limited to participants with a recorded relapse date, which may affect the precision of the survival estimates. Finally, spirometry data were not available for all participants, which may have limited the assessment of respiratory outcomes. In addition, eligibility criteria for publicly funded pharmacological treatments may restrict access for some individuals, potentially affecting generalisability.

5. Conclusions

We have described the implementation of a comprehensive nurse-led model of care for people who smoke within a multidisciplinary primary care setting. Participants receiving the intervention showed relatively high smoking cessation rates at 12 months, alongside the identification of previously undiagnosed respiratory disease within the same care pathway.

Higher nicotine dependence and greater withdrawal symptoms at the end of treatment were associated with an increased risk of relapse. In contrast, a diagnosis of asthma during the study was associated with a lower likelihood of relapse, which may reflect a potential motivational effect related to increased awareness of respiratory health.

Based on the findings, we support the integration of behavioural support, pharmacological treatment, and respiratory assessment within routine primary care as a feasible and clinically-relevant approach to addressing tobacco dependence, while also highlighting the coordinating role of nurses within multidisciplinary teams.

However, given the observational design and absence of a comparison group, these findings should be interpreted as descriptive of outcomes observed within this care pathway rather than as evidence of effectiveness. Further research using controlled designs is needed to evaluate the impact of such models on smoking cessation outcomes and healthcare delivery.

Funding of the research

This work has been selected by the Gerencia Regional de Salud (SACYL), Consejería de Sanidad de la Junta de Castilla y León, with funding granted as part of a bio sanitary research, health management and social and health care project to be developed in 2024. GRS 2748/C/2023. Principal Investigator: Mr. Raúl Majo García

CRediT authorship contribution statement

Raúl Majo García: Writing – review & editing, Writing – original draft, Supervision, Investigation, Funding acquisition, Formal analysis, Conceptualization. María Guadalupe Espinosa Villoria: Writing – review & editing, Supervision, Investigation. María Nélida Fernández-Martínez: Writing – review & editing, Writing – original draft, Validation, Methodology, Formal analysis. Alfonso Díaz Madero: Writing – review & editing, Methodology, Funding acquisition. Daniel Fernández-García: Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Formal analysis, Data curation.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Raúl Majo García reports a relationship with Adamed Pharma S.A. that includes: consulting or advisory and paid expert testimony. Has also received speaker fees from Chiesi and Aflofarm. Maria Guadalupe Espinosa Villoria reports a relationship with Roche Diagnostics SL that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

The majority of the research data is presented in this article. The rest of the data for this study are not publicly available due to privacy concerns. However, for any additional information about the data the corresponding author can be contacted.