Sleep-related adverse events of smoking cessation drugs: A network meta-analysis of randomized controlled trials.

Smoking cessation medications have the potential to affect the functioning of the nervous system, leading to sleep disturbances. Our study aimed to compare the sleep-related side effects (such as insomnia, abnormal dreams, nightmares, and somnolence) induced by different smoking cessation medications in non-psychiatric smokers. We conducted a thorough search of five electronic databases (Cochrane, EMBASE, PubMed, PsycInfo, and Web of Science) for randomized controlled trials. This study was registered with the PROSPERO (registration number CRD42022347976). A total of 79 full-text articles, encompassing 36,731 participants, were included in our analysis. Individuals using bupropion, bupropion in combination with a nicotinic acetylcholine receptor agonist (NRA), and bupropion in conjunction with nicotine replacement therapy (NRT) exhibited a higher likelihood of experiencing insomnia compared to those using NRT alone. Bupropion plus NRA had the highest ranking on the surface under the cumulative ranking curve (SUCRA) for insomnia risk, while placebo had the lowest ranking. Additionally, NRA plus NRT ranked first for abnormal dream outcomes, NRA alone for nightmares, and nortriptyline for somnolence, based on the SUCRA results. Healthcare providers should exercise caution when prescribing smoking cessation drugs, particularly in consideration of their potential sleep-related side effects.

Comparison of Acute Effects of E-cigarettes With and Without Nicotine and Tobacco Cigarettes on Hemodynamic and Endothelial Parameters: A Systematic Review and Meta-analysis.

INTRODUCTION: Smoke from traditional cigarettes and e-cigarette aerosols have distinct chemical compositions that may impact blood pressure (BP) and heart rate (HR) differently. AIMS: This study compared the impact of nicotine-containing e-cigarettes (EC+) versus nicotine-free (EC-) on BP, HR and endothelial markers, and assessed if EC+ posed fewer risks than tobacco cigarettes (TC). METHODS: Electronic databases were searched from inception until November 2023 for studies reporting changes in systolic and diastolic BP (SBP, DBP) and HR and endothelial parameters before and after the use of EC+, EC- and TC. Data were analyzed using weighted mean differences (WMDs) and 95% confidence intervals (CIs). RESULTS: Fifteen studies (n = 752) were included in our meta-analysis. We demonstrate that EC+ significantly increased systolic BP (WMD = 3.41, 95% CI [0.1,6.73], p = 0.04], diastolic BP (WMD = 3.42, 95% CI [1.75, 5.09]; p < 0.01], and HR (WMD = 5.36 BPM, 95% CI [1.87, 8.85]; p < 0.01) compared to EC-. However, EC+ was observed to cause less detrimental effect on SBP (WMD = - 4.72 mmHg, 95% CI [- 6.58, - 2.86], p < 0.01), and HR (WMD = - 3.11 BPM, 95% CI [- 4.54, - 1.68]; p < 0.01) as compared to TC with no difference on DBP (WMD = - 1.14 mmHg, 95% CI [- 2.38, 0.1]; p = 0.07). EC+ also led to greater deterioration of endothelial parameters as compared to EC- but to a lesser degree as compared to TC. CONCLUSION: EC+ shows greater impairment in hemodynamic and endothelial parameters than EC- but less than TC. Additional studies are needed to evaluate prolonged effects of EC use.

Addressing Cardiovascular Toxicity Risk of Electronic Nicotine Delivery Systems in the Twenty-First Century: "What Are the Tools Needed for the Job?" and "Do We Have Them?"

Cigarette smoking is positively and robustly associated with cardiovascular disease (CVD), including hypertension, atherosclerosis, cardiac arrhythmias, stroke, thromboembolism, myocardial infarctions, and heart failure. However, after more than a decade of ENDS presence in the U.S. marketplace, uncertainty persists regarding the long-term health consequences of ENDS use for CVD. New approach methods (NAMs) in the field of toxicology are being developed to enhance rapid prediction of human health hazards. Recent technical advances can now consider impact of biological factors such as sex and race/ethnicity, permitting application of NAMs findings to health equity and environmental justice issues. This has been the case for hazard assessments of drugs and environmental chemicals in areas such as cardiovascular, respiratory, and developmental toxicity. Despite these advances, a shortage of widely accepted methodologies to predict the impact of ENDS use on human health slows the application of regulatory oversight and the protection of public health. Minimizing the time between the emergence of risk (e.g., ENDS use) and the administration of well-founded regulatory policy requires thoughtful consideration of the currently available sources of data, their applicability to the prediction of health outcomes, and whether these available data streams are enough to support an actionable decision. This challenge forms the basis of this white paper on how best to reveal potential toxicities of ENDS use in the human cardiovascular system-a primary target of conventional tobacco smoking. We identify current approaches used to evaluate the impacts of tobacco on cardiovascular health, in particular emerging techniques that replace, reduce, and refine slower and more costly animal models with NAMs platforms that can be applied to tobacco regulatory science. The limitations of these emerging platforms are addressed, and systems biology approaches to close the knowledge gap between traditional models and NAMs are proposed. It is hoped that these suggestions and their adoption within the greater scientific community will result in fresh data streams that will support and enhance the scientific evaluation and subsequent decision-making of tobacco regulatory agencies worldwide.

Efficacy of Electronic Cigarettes vs Varenicline and Nicotine Chewing Gum as an Aid to Stop Smoking: A Randomized Clinical Trial.

Importance: Electronic cigarettes (ECs) are often used by smokers as an aid to stopping smoking, but evidence is limited regarding their efficacy compared with nicotine replacement therapy (NRT), and no evidence is available on how their efficacy compares with that of varenicline. Objective: To evaluate whether ECs are superior to NRT and noninferior to varenicline in helping smokers quit. Design, Setting, and Participants: This was a randomized clinical trial conducted at 7 sites in China and including participants who were smoking at least 10 cigarettes per day and motivated to quit, not using stop-smoking medications or EC, and willing to use any of the study products. Participants were first recruited in May 2021, and data analysis was conducted in December 2022. Interventions: A cartridge-based EC (30 mg/mL nicotine salt for 2 weeks and 50 mg/mL after that), varenicline (0.5 mg, once a day for 3 days; 0.5 mg, twice a day for 4 days; and 1 mg, twice a day, after that), and 2 mg (for smokers of ≤20 cigarettes per day) or 4 mg (>20 cigarettes per day) nicotine chewing gum, all provided for 12 weeks and accompanied by minimal behavioral support (an invitation to join a self-help internet forum). Main Outcomes and Measures: The primary outcome was sustained abstinence from smoking at 6 months as validated by an expired-air carbon monoxide reading (<8 parts per million). Participants lost to follow-up were included as nonabstainers. Results: Of 1068 participants, 357 (33.5%) were female, and the mean (SD) age was 33.9 (3.1) years. A total of 409 (38.3%), 409 (38.3%), and 250 (23.4%) participants were randomized to the EC, varenicline, and NRT arms, respectively. The 6-month biochemically validated abstinence rates were 15.7% (n = 64), 14.2% (n = 58), and 8.8% (n = 22) in the EC, varenicline, and NRT study arms, respectively. The quit rate in the EC arm was noninferior to the varenicline arm (absolute risk reduction, 1.47%; 95% CI, -1.41% to 4.34%) and higher than in the NRT arm (odds ratio, 1.92; 95% CI, 1.15-3.21). Treatment adherence was similar in all study arms during the initial 3 months, but 257 participants (62.8%) in the EC arm were still using ECs at 6 months, with no further use in the 2 other study arms. The most common adverse reactions were throat irritation (32 [7.8%]) and mouth irritation (28 [6.9%]) in the EC arm, nausea (36 [8.8%]) in the varenicline arm, and throat irritation (20 [8.0%]) and mouth irritation (22 [8.8%]) in the NRT arm. No serious adverse events were recorded. Conclusions and Relevance: The results of this randomized clinical trial found that when all treatments were provided with minimal behavior support, the efficacy of EC was noninferior to varenicline and superior to nicotine chewing gum. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100048156.

Adolescent Tobacco/Nicotine Use and the Potential Role of Contingency Management-based Interventions.

ABSTRACT: The high prevalence of tobacco/nicotine use among youth, including e-cigarettes, is a public health problem in the United States. Early exposure leads to an increased risk of dependence and health consequences in adulthood. We reviewed the literature on current treatment approaches for nicotine/tobacco use in adolescents/young adults and highlighted underexplored areas of treatment research. There are no current Food and Drug Administration-approved medications for treatment of nicotine/tobacco use disorders in adolescents. However, in research settings and on a case-to-case basis, clinical practice medications (including nicotine replacement therapy, bupropion, and varenicline) have been prescribed to this population with consideration of risk-benefit analysis when behavioral treatments are not sufficient to address dependence. Among the nonpharmacological interventions, there is evidence to support the potential for expanded use of contingency management in youth. Neural differences predisposing adolescents to substance use, along with higher attentiveness to value of options in decision making (flexible reward system) may enhance the effectiveness of reward-based approaches for treatment of substance use disorders in this population. The overall high rates of nonresponders across psychosocial and pharmacological treatments highlight the importance of considering novel strategies to improve existing interventions. We suggest that future research be done that considers unique characteristics of today's adolescents, such as high social activism and engagement with digital rewards to tailor contingency management for this age group and assess its effectiveness. Adolescents could potentially benefit from rewards administered through digital media (eg, video games, computer-based apps, and social media influencers).

Patient interest in acupuncture for smoking cessation: a survey.

BACKGROUND/OBJECTIVE: Tobacco use remains the leading cause of preventable death in the United States. The most widely available treatment options to assist patients in smoking cessation are limited by side effects and moderate efficacy at best. Acupuncture may be an effective option for smoking cessation. The goal of this study was to establish the need for and interest in acupuncture therapy to potentially assist with smoking cessation from a patient perspective. METHODS: We conducted a cross-sectional survey study among patients aged 18 years or older whose medical record reported current tobacco use with English as their preferred language. REDCap surveys were administered to patients during office visits and included questions regarding opinions and use of all treatments available for smoking cessation (including acupuncture) as well as perceived barriers to acupuncture treatment. RESULTS: A total of 57 surveys were distributed, and 42 (74%) were completed. Most patients reported previous attempts at quitting (76%) and had tried a variety of treatments including nicotine replacement (45%), Chantix (varenicline; 23%), Wellbutrin (bupriopion; 19%), "cold turkey" (65%) and hypnosis (3%). No respondents reported having tried acupuncture for smoking cessation. CONCLUSION: When comparing treatment options, patients reported more interest in acupuncture than other treatment options with a statistically significant difference in the level of interest between acupuncture and bupropion. All barriers (cost, time and effectiveness) were equally rated on a Likert-type scale with a median of 50 on a 101-point scale.

Cytisine as a smoking cessation aid: Preliminary observations with a modified therapeutic scheme in real life.

INTRODUCTION: Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral model of intervention. Cytisine is a partial agonist of nicotinic receptors. Trials conducted to date have demonstrated its good efficacy in promoting smoking cessation. The cytisine scheme of treatment consists of 25 days of treatment. A 40-day regimen, with an escalating dose and an extended duration of the treatment, has been in use in many anti-smoking centers in Italy for several years, but to date there are no reports on the use of cytisine with this scheme. METHODS: A retrospective, real-life, observational study was conducted between January 2016 and September 2022. The 300 patients who had received at least one dose of study medication were selected. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. Univariate and multivariate logistic regression models were implemented for self-reported seven-day point prevalence for abstinence at three, six and 12 months. RESULTS: The median age of the patients was 59 years, 57% were women. The median smoking exposure was 33.8 pack-years. Self-reported smoking abstinence at three, six and 12 months was 68.7%, 56.3% and 47.3% respectively. 84% completed the cytisine treatment, 31.3% reported adverse events and in 8.3% these led to dropping out of the treatment. CONCLUSION: Cytisine, administered with a novel therapeutic scheme in the real-life setting of a specialized anti-smoking center, significantly promotes smoking abstinence. However, more studies are needed to assess the tolerability and efficacy of this new regimen.

Competitive inhibition of nicotine acetylcholine receptors using microneedles of nicotine and varenicline for smoking withdrawal therapy.

Current strategies for smoking withdrawal conditions involve monotherapy of nicotine and combinational therapy of nicotine with varenicline or bupropion as per the CDC and FDA. The available dosage forms for nicotine are patches, gums, inhalers and nasal sprays, bupropion and varenicline are available in tablet form. This research work focused on developing a microneedle delivery system to deliver combination drug for overcoming the obstacles encountered by oral route of administration of varenicline such as severe side effects (mood swings, agitation, depressed behaviour, seizures, etc), and nicotine therapy challenges such as short half-life, repeated dosing, nausea, and vomiting. The nanoparticles of nicotine prepared by nanoprecipitation method showed particle size PTZ (356.6 ± 65.98), percentage entrapment efficiency (35.55 % ± 0.007), in-vitro drug release (47.89 % ± 0.7) for 72 h. Microneedles showed height (600 µm), width (350 µm), and tip diameter (10 µm). The nanoparticles encapsulated in microneedles showed in-vitro sustained delivery of nicotine (67.00 % ± 4.92) and varenicline (79.78 % ± 1.09) in 48 h. Nicotine released in a sustained manner attaches to the nicotine acetylcholine receptors (nAchR) to release dopamine for controlling the withdrawal challenges such as anxiety, irritability, cravings, disturbed sleep pattern, etc. The varenicline released from microneedles binds to the nAchR and inhibits dopamine release responsible for the euphoric effect induced by nicotine, and thus assists in curbing the nicotine withdrawal symptoms. This combination microneedle system offers prolonged treatment in a single application for smoking withdrawal conditions wherein patients are not in stage of oral dosing because of repeated dosing resulting in adverse effects like seizures, hypertension, sleep disturbances, insomnia, and nausea.

Varenicline and counseling for vaping cessation: a double-blind, randomized, parallel-group, placebo-controlled trial.

BACKGROUND: Vaping cessation is virtually unexplored. The efficacy and safety of varenicline for vaping cessation has not been studied and rigorous research is required to advance best practice and outcomes for people who use electronic cigarettes (EC) and want to quit. The objective is to evaluate the efficacy and safety of varenicline (1 mg BID, administered for 12 weeks, with follow-up to week 24) combined with vaping cessation counseling in exclusive daily EC users intending to quit vaping. METHODS: Design: Double-blind, randomized, parallel-group, placebo-controlled trial. SETTING: The study took place at a University-run smoking cessation center. PARTICIPANTS: People who exclusively use ECs daily and intend to quit vaping. INTERVENTION: A total of 140 subjects were randomized to either varenicline (1 mg, administered twice daily for 12 weeks) plus counseling or placebo treatment (administered twice daily, for 12 weeks) plus counseling. The trial consisted of a 12-week treatment phase followed by a 12-week follow-up, nontreatment phase. MAIN OUTCOMES AND MEASURES: The primary efficacy endpoint of the study was biochemically validated continuous abstinence rate (CAR) at weeks 4 to 12. Secondary efficacy end points were CAR at weeks 4 to 24 and 7-day point prevalence of vaping abstinence at weeks 12 and 24. RESULTS: CAR was significantly higher for varenicline vs placebo at each interval: weeks 4-12, 40.0% and 20.0%, respectively (OR = 2.67, 95% CI = [1.25-5.68], P = 0.011); weeks 4-24, 34.3% for varenicline with counseling and 17.2% for placebo with counseling (OR = 2.52, 95% CI = [1.14-5.58], P = 0.0224). The 7-day point prevalence of vaping abstinence was also higher for the varenicline than placebo at each time point. Serious adverse events were infrequent in both groups and not treatment-related. CONCLUSIONS: The findings of the present RCT indicate that inclusion of varenicline in a vaping cessation program for people who use electronic cigarettes and intending to quit may result in prolonged abstinence. These positive findings establish a benchmark of intervention effectiveness, may support the use of varenicline combined with counseling in vaping cessation programs, and may also help guiding future recommendations by health authorities and healthcare providers. TRIAL REGISTRATION: The study has been registered in EUDRACT with Trial registration ID: 2016-000339-42.

Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation.

BACKGROUND: Nicotine replacement therapy (NRT) aims to replace nicotine from cigarettes. This helps to reduce cravings and withdrawal symptoms, and ease the transition from cigarette smoking to complete abstinence. Although there is high-certainty evidence that NRT is effective for achieving long-term smoking abstinence, it is unclear whether different forms, doses, durations of treatment or timing of use impacts its effects. OBJECTIVES: To determine the effectiveness and safety of different forms, deliveries, doses, durations and schedules of NRT, for achieving long-term smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning NRT in the title, abstract or keywords, most recently in April 2022. SELECTION CRITERIA: We included randomised trials in people motivated to quit, comparing one type of NRT use with another. We excluded studies that did not assess cessation as an outcome, with follow-up of fewer than six months, and with additional intervention components not matched between arms. Separate reviews cover studies comparing NRT to control, or to other pharmacotherapies. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. We measured smoking abstinence after at least six months, using the most rigorous definition available. We extracted data on cardiac adverse events (AEs), serious adverse events (SAEs) and study withdrawals due to treatment.  MAIN RESULTS: We identified 68 completed studies with 43,327 participants, five of which are new to this update. Most completed studies recruited adults either from the community or from healthcare clinics. We judged 28 of the 68 studies to be at high risk of bias. Restricting the analysis only to those studies at low or unclear risk of bias did not significantly alter results for any comparisons apart from the preloading comparison, which tested the effect of using NRT prior to quit day whilst still smoking.  There is high-certainty evidence that combination NRT (fast-acting form plus patch) results in higher long-term quit rates than single form (risk ratio (RR) 1.27, 95% confidence interval (CI) 1.17 to 1.37; I2 = 12%; 16 studies, 12,169 participants). Moderate-certainty evidence, limited by imprecision, indicates that 42/44 mg patches are as effective as 21/22 mg (24-hour) patches (RR 1.09, 95% CI 0.93 to 1.29; I2 = 38%; 5 studies, 1655 participants), and that 21 mg patches are more effective than 14 mg (24-hour) patches (RR 1.48, 95% CI 1.06 to 2.08; 1 study, 537 participants). Moderate-certainty evidence, again limited by imprecision, also suggests a benefit of 25 mg over 15 mg (16-hour) patches, but the lower limit of the CI encompassed no difference (RR 1.19, 95% CI 1.00 to 1.41; I2 = 0%; 3 studies, 3446 participants). Nine studies tested the effect of using NRT prior to quit day (preloading) in comparison to using it from quit day onward. There was moderate-certainty evidence, limited by risk of bias, of a favourable effect of preloading on abstinence (RR 1.25, 95% CI 1.08 to 1.44; I2 = 0%; 9 studies, 4395 participants). High-certainty evidence from eight studies suggests that using either a form of fast-acting NRT or a nicotine patch results in similar long-term quit rates (RR 0.90, 95% CI 0.77 to 1.05; I2 = 0%; 8 studies, 3319 participants). We found no clear evidence of an effect of duration of nicotine patch use (low-certainty evidence); duration of combination NRT use (low- and very low-certainty evidence); or fast-acting NRT type (very low-certainty evidence). Cardiac AEs, SAEs and withdrawals due to treatment were all measured variably and infrequently across studies, resulting in low- or very low-certainty evidence for all comparisons. Most comparisons found no clear evidence of an effect on these outcomes, and rates were low overall. More withdrawals due to treatment were reported in people using nasal spray compared to patches in one study (RR 3.47, 95% CI 1.15 to 10.46; 1 study, 922 participants; very low-certainty evidence) and in people using 42/44 mg patches in comparison to 21/22 mg patches across two studies (RR 4.99, 95% CI 1.60 to 15.50; I2 = 0%; 2 studies, 544 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is high-certainty evidence that using combination NRT versus single-form NRT and 4 mg versus 2 mg nicotine gum can result in an increase in the chances of successfully stopping smoking. Due to imprecision, evidence was of moderate certainty for patch dose comparisons. There is some indication that the lower-dose nicotine patches and gum may be less effective than higher-dose products. Using a fast-acting form of NRT, such as gum or lozenge, resulted in similar quit rates to nicotine patches. There is moderate-certainty evidence that using NRT before quitting may improve quit rates versus using it from quit date only; however, further research is needed to ensure the robustness of this finding. Evidence for the comparative safety and tolerability of different types of NRT use is limited. New studies should ensure that AEs, SAEs and withdrawals due to treatment are reported.

Cytisine Versus Varenicline for Smoking Cessation in a Primary Care Setting: A Randomized Non-inferiority Trial.

INTRODUCTION: A smoking-cessation program was implemented as a randomized non-inferiority trial in primary care practices in Croatia and Slovenia to investigate whether a standard 4-week treatment with cytisine was at least as effective and feasible as a standard 12-week treatment with varenicline in helping smokers quit. AIMS AND METHODS: Out of 982 surveyed smokers, 377 were recruited to the non-inferiority trial: 186 were randomly assigned to cytisine and 191 to varenicline treatment. The primary cessation outcome was 7-day abstinence after 24 weeks, while the primary feasibility outcome was defined by adherence to the treatment plan. We also compared the rates of adverse events between the two treatment groups. RESULTS: The cessation rate after 24 weeks was 32.46% (62/191) in the varenicline group and 23.12% (43/186) in the cytisine group (odds ratio [OR]: 95%, credible interval [CI]: 0.39 to 0.98). Of 191 participants assigned to varenicline treatment 59.16% (113) were adherent, while 70.43% (131 of 186) were adherent in the cytisine group (OR: 1.65, 95% CI: 1.07 to 2.56). Participants assigned to cytisine experienced fewer total (incidence rate ratio [IRR]: 0.59, 95% CI: 0.43 to 0.81) and fewer severe or more extreme adverse events (IRR: 0.72, 95% CI: 0.35 to 1.47). CONCLUSIONS: This randomized non-inferiority trial (n = 377) found the standard 4-week cytisine treatment to be less effective than the standard 12-week varenicline treatment for smoking cessation. However, adherence to the treatment plan, ie, feasibility, was higher, and the rate of adverse events was lower among participants assigned to cytisine treatment. IMPLICATIONS: The present study found the standard 12 weeks of varenicline treatment to be more effective than the standard 4 weeks of cytisine treatment for smoking cessation in a primary care setting in Croatia and Slovenia. Participants assigned to cytisine, however, had a higher adherence to the treatment plan and a lower rate of adverse events. Estimates from the present study may be especially suitable for generalizations to high-smoking prevalence populations in Europe. Given the much lower cost of cytisine treatment, its lower rate of adverse events, and higher feasibility (but its likely lower effectiveness with the standard dosage regimen), future analyses should assess the cost-effectiveness of the two treatments for health policy considerations.

Antidepressants for smoking cessation.

BACKGROUND: The pharmacological profiles and mechanisms of antidepressants are varied. However, there are common reasons why they might help people to stop smoking tobacco: nicotine withdrawal can produce short-term low mood that antidepressants may relieve; and some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction. OBJECTIVES: To assess the evidence for the efficacy, harms, and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register, most recently on 29 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people who smoked, comparing antidepressant medications with placebo or no pharmacological treatment, an alternative pharmacotherapy, or the same medication used differently. We excluded trials with fewer than six months of follow-up from efficacy analyses. We included trials with any follow-up length for our analyses of harms. DATA COLLECTION AND ANALYSIS: We extracted data and assessed risk of bias using standard Cochrane methods. Our primary outcome measure was smoking cessation after at least six months' follow-up. We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Our secondary outcomes were harms and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropouts due to treatment. We carried out meta-analyses where appropriate. MAIN RESULTS: We included a total of 124 studies (48,832 participants) in this review, with 10 new studies added to this update version. Most studies recruited adults from the community or from smoking cessation clinics; four studies focused on adolescents (with participants between 12 and 21 years old). We judged 34 studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk of bias did not change clinical interpretation of the results.  There was high-certainty evidence that bupropion increased smoking cessation rates when compared to placebo or no pharmacological treatment (RR 1.60, 95% CI 1.49 to 1.72; I2 = 16%; 50 studies, 18,577 participants). There was moderate-certainty evidence that a combination of bupropion and varenicline may have resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I2 = 15%; 3 studies, 1057 participants). However, there was insufficient evidence to establish whether a combination of bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.17, 95% CI 0.95 to 1.44; I2 = 43%; 15 studies, 4117 participants; low-certainty evidence). There was moderate-certainty evidence that participants taking bupropion were more likely to report SAEs than those taking placebo or no pharmacological treatment. However, results were imprecise and the CI also encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I2 = 0%; 23 studies, 10,958 participants). Results were also imprecise when comparing SAEs between people randomised to a combination of bupropion and NRT versus NRT alone (RR 1.52, 95% CI 0.26 to 8.89; I2 = 0%; 4 studies, 657 participants) and randomised to bupropion plus varenicline versus varenicline alone (RR 1.23, 95% CI 0.63 to 2.42; I2 = 0%; 5 studies, 1268 participants). In both cases, we judged evidence to be of low certainty. There was high-certainty evidence that bupropion resulted in more trial dropouts due to AEs than placebo or no pharmacological treatment (RR 1.44, 95% CI 1.27 to 1.65; I2 = 2%; 25 studies, 12,346 participants). However, there was insufficient evidence that bupropion combined with NRT versus NRT alone (RR 1.67, 95% CI 0.95 to 2.92; I2 = 0%; 3 studies, 737 participants) or bupropion combined with varenicline versus varenicline alone (RR 0.80, 95% CI 0.45 to 1.45; I2 = 0%; 4 studies, 1230 participants) had an impact on the number of dropouts due to treatment. In both cases, imprecision was substantial (we judged the evidence to be of low certainty for both comparisons). Bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.73, 95% CI 0.67 to 0.80; I2 = 0%; 9 studies, 7564 participants), and to combination NRT (RR 0.74, 95% CI 0.55 to 0.98; I2 = 0%; 2 studies; 720 participants). However, there was no clear evidence of a difference in efficacy between bupropion and single-form NRT (RR 1.03, 95% CI 0.93 to 1.13; I2 = 0%; 10 studies, 7613 participants). We also found evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants), and some evidence that bupropion resulted in superior quit rates to nortriptyline (RR 1.30, 95% CI 0.93 to 1.82; I2 = 0%; 3 studies, 417 participants), although this result was subject to imprecision. Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression. AUTHORS' CONCLUSIONS: There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion may increase SAEs (moderate-certainty evidence when compared to placebo/no pharmacological treatment). There is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with people receiving placebo or no pharmacological treatment. Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo, although bupropion may be more effective. Evidence also suggests that bupropion may be as successful as single-form NRT in helping people to quit smoking, but less effective than combination NRT and varenicline. In most cases, a paucity of data made it difficult to draw conclusions regarding harms and tolerability. Further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over other licensed smoking cessation treatments; namely, NRT and varenicline. However, it is important that future studies of antidepressants for smoking cessation measure and report on harms and tolerability.

Nicotine receptor partial agonists for smoking cessation.

BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). This is an update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the effectiveness of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialised Register in April 2022 for trials, using relevant terms in the title or abstract, or as keywords. The register is compiled from searches of CENTRAL, MEDLINE, Embase, and PsycINFO.  SELECTION CRITERIA: We included randomised controlled trials that compared the treatment drug with placebo, another smoking cessation drug, e-cigarettes, or no medication. We excluded trials that did not report a minimum follow-up period of six months from baseline. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. Our main outcome was abstinence from smoking at longest follow-up using the most rigorous definition of abstinence, preferring biochemically validated rates where reported. We pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. We also reported the number of people reporting serious adverse events (SAEs). MAIN RESULTS: We included 75 trials of 45,049 people; 45 were new for this update. We rated 22 at low risk of bias, 18 at high risk, and 35 at unclear risk. We found moderate-certainty evidence (limited by heterogeneity) that cytisine helps more people to quit smoking than placebo (RR 1.30, 95% confidence interval (CI) 1.15 to 1.47; I2 = 83%; 4 studies, 4623 participants), and no evidence of a difference in the number reporting SAEs (RR 1.04, 95% CI 0.78 to 1.37; I2 = 0%; 3 studies, 3781 participants; low-certainty evidence). SAE evidence was limited by imprecision. We found no data on neuropsychiatric or cardiac SAEs. We found high-certainty evidence that varenicline helps more people to quit than placebo (RR 2.32, 95% CI 2.15 to 2.51; I2 = 60%, 41 studies, 17,395 participants), and moderate-certainty evidence that people taking varenicline are more likely to report SAEs than those not taking it (RR 1.23, 95% CI 1.01 to 1.48; I2 = 0%; 26 studies, 14,356 participants). While point estimates suggested increased risk of cardiac SAEs (RR 1.20, 95% CI 0.79 to 1.84; I2 = 0%; 18 studies, 7151 participants; low-certainty evidence), and decreased risk of neuropsychiatric SAEs (RR 0.89, 95% CI 0.61 to 1.29; I2 = 0%; 22 studies, 7846 participants; low-certainty evidence), in both cases evidence was limited by imprecision, and confidence intervals were compatible with both benefit and harm. Pooled results from studies that randomised people to receive cytisine or varenicline showed that more people in the varenicline arm quit smoking (RR 0.83, 95% CI 0.66 to 1.05; I2 = 0%; 2 studies, 2131 participants; moderate-certainty evidence) and reported SAEs (RR 0.67, 95% CI 0.44 to 1.03; I2 = 45%; 2 studies, 2017 participants; low-certainty evidence). However, the evidence was limited by imprecision, and confidence intervals incorporated the potential for benefit from either cytisine or varenicline. We found no data on neuropsychiatric or cardiac SAEs. We found high-certainty evidence that varenicline helps more people to quit than bupropion (RR 1.36, 95% CI 1.25 to 1.49; I2 = 0%; 9 studies, 7560 participants), and no clear evidence of difference in rates of SAEs (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; 5 studies, 5317 participants), neuropsychiatric SAEs (RR 1.05, 95% CI 0.16 to 7.04; I2 = 10%; 2 studies, 866 participants), or cardiac SAEs (RR 3.17, 95% CI 0.33 to 30.18; I2 = 0%; 2 studies, 866 participants). Evidence of harms was of low certainty, limited by imprecision. We found high-certainty evidence that varenicline helps more people to quit than a single form of nicotine replacement therapy (NRT) (RR 1.25, 95% CI 1.14 to 1.37; I2 = 28%; 11 studies, 7572 participants), and low-certainty evidence, limited by imprecision, of fewer reported SAEs (RR 0.70, 95% CI 0.50 to 0.99; I2 = 24%; 6 studies, 6535 participants). We found no data on neuropsychiatric or cardiac SAEs. We found no clear evidence of a difference in quit rates between varenicline and dual-form NRT (RR 1.02, 95% CI 0.87 to 1.20; I2 = 0%; 5 studies, 2344 participants; low-certainty evidence, downgraded because of imprecision). While pooled point estimates suggested increased risk of SAEs (RR 2.15, 95% CI 0.49 to 9.46; I2 = 0%; 4 studies, 1852 participants) and neuropsychiatric SAEs (RR 4.69, 95% CI 0.23 to 96.50; I2 not estimable as events only in 1 study; 2 studies, 764 participants), and reduced risk of cardiac SAEs (RR 0.32, 95% CI 0.01 to 7.88; I2 not estimable as events only in 1 study; 2 studies, 819 participants), in all three cases evidence was of low certainty and confidence intervals were very wide, encompassing both substantial harm and benefit. AUTHORS' CONCLUSIONS: Cytisine and varenicline both help more people to quit smoking than placebo or no medication. Varenicline is more effective at helping people to quit smoking than bupropion, or a single form of NRT, and may be as or more effective than dual-form NRT. People taking varenicline are probably more likely to experience SAEs than those not taking it, and while there may be increased risk of cardiac SAEs and decreased risk of neuropsychiatric SAEs, evidence was compatible with both benefit and harm. Cytisine may lead to fewer people reporting SAEs than varenicline. Based on studies that directly compared cytisine and varenicline, there may be a benefit from varenicline for quitting smoking, however further evidence could strengthen this finding or demonstrate a benefit from cytisine. Future trials should test the effectiveness and safety of cytisine compared with varenicline and other pharmacotherapies, and should also test variations in dose and duration. There is limited benefit to be gained from more trials testing the effect of standard-dose varenicline compared with placebo for smoking cessation. Further trials on varenicline should test variations in dose and duration, and compare varenicline with e-cigarettes for smoking cessation.

Efficacy and Safety of E-Cigarette Use for Smoking Cessation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: People who smoke conventional cigarettes are increasingly turning to electronic cigarettes (e-cigarettes) as a pathway to quitting. However, the efficacy and safety of e-cigarettes for smoking cessation remains controversial. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), identified through a systematic search of the MEDLINE, EMBASE, and Cochrane CENTRAL databases. Inclusion was restricted to RCTs with a follow-up duration ≥6 months. The primary endpoint was the most rigorous criterion of biochemically validated abstinence at maximum follow-up, and the primary comparison was nicotine e-cigarettes versus any conventional (ie, non-e-cigarette) smoking cessation therapy. The Cochrane Risk of Bias Tool was used to assess bias. Count data were pooled across trials using random-effects models with inverse variance weighting to estimate relative risks (RRs) and corresponding 95% confidence intervals (CIs). We registered the study protocol with the Open Science Framework Registries (osf.io/26fkq). RESULTS: A total of 5 RCTs (n = 3253) were included. Compared with conventional smoking cessation therapies, the use of nicotine e-cigarettes was associated with an increase in abstinence, defined by the most rigorous criterion of abstinence reported (RR 1.77; 95% CI, 1.29-2.44). Nicotine e-cigarettes also increased abstinence (defined by the most rigorous criterion) compared with non-nicotine e-cigarettes (RR 1.56; 95% CI, 1.13-2.15). The incidence of death or serious adverse events was low across all trials at maximum follow-up. CONCLUSIONS: Among individuals attempting to quit smoking, nicotine e-cigarettes are more efficacious than conventional nicotine replacement or behavioral smoking cessation therapies, and may prove beneficial in reducing smoking-related health risks.

Varenicline-induced drug eruption: case and review of the literature.

Cutaneous side-effects of varenicline, a selective partial agonist of the a4B2 nicotinic acetylcholine receptor used to treat smoking addiction, are relatively rare and mainly consist of acute generalized exanthematous pustulosis. We describe an atypical clinical presentation of a varenicline-induced drug eruption, which occurred one day after drug initiation. We report this case since we believe no drug reaction to varenicline has had this clinical presentation or rapidity of onset. Clinicians should be aware of this potential adverse cutaneous reaction in patients taking varenicline for smoking cessation.

How do patients and staff in an opioid agonist treatment service view smoking cessation medications and e-cigarettes?

INTRODUCTION: Tobacco use and related mortality is common in people receiving opioid agonist treatment (OAT). Smoking cessation medications are available and e-cigarettes are increasingly recommended for high risk populations. This study explores experience, knowledge and attitudes around smoking cessation medications (nicotine replacement therapy [NRT], bupropion and varenicline) and e-cigarettes in patients and clinicians in two public Australian OAT clinics. METHODS: Cross-sectional surveys of patients and clinicians and a randomly sampled retrospective medical record review. Patients were recruited through an advertisement in the clinic, and clinicians through advertisement at an educational session. RESULTS: Ninety-one patients and 10 clinicians completed the surveys. Most patients had at least one quit attempt and 43% were currently trying to quit. There were high levels of exposure to NRT, lower levels with varenicline and very limited exposure to bupropion. Patients considered e-cigarettes most helpful, but were more likely to consider using NRT. Few patients reported smoking cessation interventions from their clinicians. Most clinicians identified high tobacco use prevalence, considered this problematic, but reported low rates of smoking cessation intervention. NRT was the preferred medication. E-cigarettes were not considered helpful. Sixty-six percent of the 140 records reviewed documented patients as smokers. Tobacco cessation medication was rarely discussed or provided. DISCUSSION AND CONCLUSIONS: Patients report high rates of tobacco cessation planning, but low rates of intervention. Experience of varenicline and bupropion is limited. E-cigarettes were preferred over varenicline and bupropion. Improving patient's and clinician's knowledge of tobacco cessation medications could improve smoking cessation interventions and uptake of approved medications.

Comparative effect of varenicline and nicotine patches on preventing repeat cardiovascular events.

OBJECTIVE: To determine the comparative effectiveness of postdischarge use of varenicline versus prescription nicotine replacement therapy (NRT) patches for the prevention of recurrent cardiovascular events and mortality and whether this association differs by sex. METHODS: Our cohort study used routinely collected hospital, pharmaceutical dispensing and mortality data for residents of New South Wales, Australia. We included patients hospitalised for a major cardiovascular event or procedure 2011-2017, who were dispensed varenicline or prescription NRT patches within 90day postdischarge. Exposure was defined using an approach analogous to intention to treat. Using inverse probability of treatment weighting with propensity scores to account for confounding, we estimated adjusted HRs for major cardiovascular events (MACEs), overall and by sex. We fitted an additional model with a sex-treatment interaction term to determine if treatment effects differed between males and females. RESULTS: Our cohort of 844 varenicline users (72% male, 75% <65 years) and 2446 prescription NRT patch users (67% male, 65% <65 years) were followed for a median of 2.93 years and 2.34 years, respectively. After weighting, there was no difference in risk of MACE for varenicline relative to prescription NRT patches (aHR 0.99, 95% CI 0.82 to 1.19). We found no difference (interaction p=0.098) between males (aHR 0.92, 95% CI 0.73 to 1.16) and females (aHR 1.30, 95% CI 0.92 to 1.84), although the effect among females deviated from the null. CONCLUSION: We found no difference between varenicline and prescription NRT patches in the risk of recurrent MACE. These results should be considered when determining the most appropriate choice of smoking cessation pharmacotherapy.

Smoking cessation and vaccination.

A significant proportion of COPD patients (∼40%) continue smoking despite knowing that they have the disease. Smokers with COPD exhibit higher levels of nicotine dependence, and have lower self-efficacy and self-esteem, which affects their ability to quit smoking. Treatment should be adapted to the needs of individual patients with different levels of tobacco dependence. The combination of counselling plus pharmacotherapy is the most effective cessation treatment for COPD. In patients with severe COPD, varenicline and bupropion have been shown to have the highest abstinence rates compared with nicotine replacement therapy. There is a lack of evidence to support that smoking cessation reduction or harm reduction strategies have benefits in COPD patients. The long-term efficacy and safety of electronic cigarettes for smoking cessation need to be evaluated in high-risk populations; therefore, it is not possible to recommend their use for smoking cessation in COPD. Future studies with the new generation of nicotine vaccines are necessary to determine their effectiveness in smokers in general and in COPD patients.

A pragmatic review of varenicline prescribing practices.

BACKGROUND: Smoking is the leading preventable cause of illness and premature death worldwide. Most tobacco users desire to quit, but few are successful. Guidelines recommend varenicline as an initial treatment recommendation to support smoking cessation. OBJECTIVES: Determine whether historic warnings preclude the use of varenicline as an initial treatment recommendation in patients with and without certain comorbidities. Appendix 1 shows the questions asked in the survey. METHODS: This study was conducted in 2 parts. Part 1 of this study was a provider survey. Part 2 was a multicenter, retrospective chart review. Survey respondents were primary care providers (PCPs) or internal medicine residents within a large health system. Patients included in the chart review had a PCP appointment between January 1, 2017, and December 31, 2020, and a diagnosis of tobacco dependence or tobacco cessation therapy prescription. RESULTS: In total, 352 providers were included in survey distribution and 56 responses were received, resulting in a response rate of 16%. Most providers (77%) indicated that they would be likely to use varenicline as an initial treatment recommendation in a patient with no comorbidities. Providers indicated they would be unlikely to use varenicline in a patient with certain mental health comorbidities (43%, 43%, and 55% for patients with bipolar disorder, schizophrenia, or history of suicide attempts, respectively, with 25%, 30%, and 27% having no opinion for each group). In addition, chart review yielded data for 25,128 patients. Notably, patients with schizophrenia were found to have an odds ratio of 0.55 (95% confidence interval [CI] 0.39-0.77) to receive varenicline at any point in therapy, and patients with diabetes had an odds ratio of 2.66 (95% CI 2.22-3.19) to receive no treatment. CONCLUSIONS: Historic warnings for neuropsychiatric events with varenicline may still preclude usage in patients with serious psychiatric comorbidities such as schizophrenia. In addition, patients with diabetes were less likely to receive any form of tobacco cessation therapy.